CN116589448A - 一种3,4-二氢喹啉酮衍生物及其应用 - Google Patents
一种3,4-二氢喹啉酮衍生物及其应用 Download PDFInfo
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- CN116589448A CN116589448A CN202310447391.0A CN202310447391A CN116589448A CN 116589448 A CN116589448 A CN 116589448A CN 202310447391 A CN202310447391 A CN 202310447391A CN 116589448 A CN116589448 A CN 116589448A
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- Prior art keywords
- mmol
- added
- derivative
- quinolinone
- dihydroquinolinone
- Prior art date
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- TZOYXRMEFDYWDQ-UHFFFAOYSA-N 3,4-dihydro-1h-quinolin-2-one Chemical class C1=CC=C2NC(=O)CCC2=C1 TZOYXRMEFDYWDQ-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 239000003814 drug Substances 0.000 claims abstract description 20
- BUWPZNOVIHAWHW-UHFFFAOYSA-N 2,3-dihydro-1h-quinolin-4-one Chemical class C1=CC=C2C(=O)CCNC2=C1 BUWPZNOVIHAWHW-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000002360 preparation method Methods 0.000 claims description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 201000008827 tuberculosis Diseases 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000000539 amino acid group Chemical group 0.000 claims description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 claims description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 125000005956 isoquinolyl group Chemical group 0.000 claims 1
- 125000004076 pyridyl group Chemical group 0.000 claims 1
- 125000005493 quinolyl group Chemical group 0.000 claims 1
- -1 peniprenimmunolone Chemical compound 0.000 abstract description 43
- 229940079593 drug Drugs 0.000 abstract description 15
- 150000001875 compounds Chemical class 0.000 abstract description 13
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- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical group C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 abstract description 9
- LAXFAGHIJVQGNK-UHFFFAOYSA-N Buchapine Chemical compound C1=CC=C2C(=O)C(CC=C(C)C)(C(C)(C)C=C)C(=O)NC2=C1 LAXFAGHIJVQGNK-UHFFFAOYSA-N 0.000 abstract description 6
- 230000002365 anti-tubercular Effects 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 5
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
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- 102000004190 Enzymes Human genes 0.000 abstract description 4
- CVWJKBJRSZXDIW-UHFFFAOYSA-N Penigequinolones A and B Natural products OC1=C2C(C=3C=CC(OC)=CC=3)(O)C(OC)C(=O)NC2=CC=C1C=CC1(C)CCC(C)(C)CO1 CVWJKBJRSZXDIW-UHFFFAOYSA-N 0.000 abstract description 3
- CVWJKBJRSZXDIW-NURUMYOOSA-N penigequinolone B Chemical compound O=C([C@@H]([C@@](C1=C2O)(O)C=3C=CC(OC)=CC=3)OC)NC1=CC=C2\C=C\[C@@]1(C)CCC(C)(C)CO1 CVWJKBJRSZXDIW-NURUMYOOSA-N 0.000 abstract description 3
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 2
- 229940121657 clinical drug Drugs 0.000 abstract description 2
- 238000011960 computer-aided design Methods 0.000 abstract description 2
- WBHOECNXRGZKAH-UHFFFAOYSA-N 4,7-dimethoxy-3-(methoxymethyl)-1h-quinolin-2-one Chemical compound C1=C(OC)C=C2NC(=O)C(COC)=C(OC)C2=C1 WBHOECNXRGZKAH-UHFFFAOYSA-N 0.000 abstract 2
- 230000002194 synthesizing effect Effects 0.000 abstract 1
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
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- 238000003756 stirring Methods 0.000 description 5
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- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
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- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 4
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- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
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- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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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
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- A61P31/06—Antibacterial agents for tuberculosis
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- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
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- 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
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- 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
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Abstract
本发明公开了一种3,4‑二氢喹啉酮衍生物及其应用,属于生物医药技术领域。本发明基于具有抗菌作用的天然产物Buchapine,Semecarpifoline,Peniprequinolone,Penigequinolone B等喹啉酮结构,结合DprE1酶的计算机辅助设计,简化了含喹啉酮母核的天然产物的结构,合成和发现了具有3,4‑二氢喹啉酮类结构的抗结核活性的化合物,所得喹啉酮衍生物对结核分枝杆菌具有良好的抑制活性,对临床耐药结核杆菌也具有较好的抑制活性。
Description
技术领域
本发明属于生物医药技术领域,具体涉及一种3,4-二氢喹啉酮衍生物及其应用。
背景技术
结核病是困扰人类数千年的传染病,被列为全球十大死因之一,同时也是单一传染病中的头号杀手。结核病(tuberculosis)是一种主要由结核分枝杆菌(Mycobacteriumtuberculosis)引起的严重传染病。当前用于治疗结核病的药物大部分是20世纪40-70年代发现的,已经使用了半个多世纪。常见的抗结核治疗药物有一线抗结核药物:异烟肼(INH)、利福平(RFP)、吡嗪酰胺(PZA)、乙胺丁醇(EMB)、链霉素(SM),二线药物:对氨基水杨酸(PAS)、丙硫异烟胺(PTH)、阿米卡星(AMK)、卷曲霉素(CPM)、氧氟沙星(OXF)、乙硫异烟胺(ETO)、莫西沙星(MFX)、利福布汀(RFB)、利福喷汀(RPT)、环丝氨酸(CS)等,以及近50年来首个新机制抗结核药贝达喹啉。但是结核病的治疗通常需要四种以上的一线药物联用,疗程在半年以上才能治愈。当一线药物疗效不明显时辅以二、三线药物。近年来,由于传统药物的长期使用和不规范治疗,临床上产生的耐药问题越来越严重。多药耐药(multi-drugresistance,MDR)、广泛耐药(extensively drug-resistance,XDR)和全耐药(total drug-resistance,TDR)结核菌株的出现,使得现有药物和治疗方案难以奏效,甚至面临无药可医的危险境地。一旦这些耐药菌株广泛传播,后果不堪设想。因此,研发新型抗结核药物成为全人类迫在眉睫的任务。
结核病的防治和新药研发首先需要发现和阐明其致病菌关键生理活动的分子机制。其中,结核分枝杆菌的细胞壁合成过程和能量代谢过程被认为是理想突破口,许多抗结核药物和在研药物均作用于这些重要生理途径。比如,一线药物异烟肼(isoniazid)和乙胺丁醇(ethambutol)、临床在研药物SQ109均是通过抑制细胞壁合成发挥抗结核作用的,上市新药呗达喹啉(bedaquilin)和临床在研药物Q203则通过抑制能量代谢途径的呼吸链达到杀死结核菌的效果。故细胞壁合成通路中的关键蛋白被公认为是很好的药物靶标,而DprE1酶作为细胞壁重要组成部分的阿拉伯聚糖关键合成酶,是一个重要的抗结核药物的靶点,它能阻断结核分支杆菌细胞壁必要组成部分阿拉伯糖的合成,从而杀死结核杆菌,该靶点具有特异性,高效性。
发明内容
针对上述现有技术,本发明提供一种3,4-二氢喹啉酮衍生物及其应用,以制备新的结核病的诊断和防治药物。
为了达到上述目的,本发明所采用的技术方案是,提供一种3,4-二氢喹啉酮衍生物,结构式如式I或II所示,
其中,X为C或N;X1为H或F;
R1为H或-OH或醚键或碳原子数为5~18的长链酯基;
R2为H或-OR4,R4为碳原子数为5~18的长链烷基,或碳原子数为5~18的长链酯基,或氨基酸残基,或Y1~Y9中的任意一种,
R5为碳原子数为1~16的烷基,或-PH(=O)OH;R6为碳原子数为1~16烷基,或碳原子数为1~5的酰基;n为0~10的整数;
R3为
A为取代芳基,或取代杂环基,或吡啶基、噻吩基、喹啉基、异喹啉基、苯并噻吩基、喹噁啉基、苯并呋喃基、苯并二氧杂环戊稀基、苯并噁唑基、苯并咪唑基中的任意一种;X2为O、S或N。
在上述技术方案的基础上,本发明还可以做如下改进。
进一步,3,4-二氢喹啉酮衍生物为A1~A13中的任意一种:
本发明还公开了上述3,4-二氢喹啉酮衍生物在制备诊断、预防和/或治疗结核病的药物中的应用。
本发明的有益效果是:
本发明在结核杆菌抑制剂筛选中,基于具有抗菌作用的天然产物Buchapine,Semecarpifoline,Peniprequinolone,Penigequinolone B等喹啉酮结构,结合DprE1酶的计算机辅助设计,简化了含喹啉酮母核的天然产物的结构,合成和发现了具有3,4-二氢喹啉酮类结构的抗结核活性的化合物。
本发明所合成的3,4-二氢喹啉酮与已知的喹啉酮(如CN201580045974,WO2016/031255A中公开的喹啉酮)具有在化合物中间的Linker哌啶环的明显不同,且A环部分采用了具有与DprE1酶结合力更强的苯并噻嗪类芳杂环结构。本发明中Linker环采用螺环、并环以及卤代哌啶结构,母核3,4喹啉酮中的苯环部分保留天然产物Buchapine,Semecarpifoline,Peniprequinolone,Penigequinolone B中的取代部分特征,最终所得喹啉酮衍生物对结核分枝杆菌具有良好的抑制活性,对临床耐药结核杆菌也具有较好的抑制活性。
具体实施方式
下面结合实施例对本发明的具体实施方式做详细的说明。
实施例1
一种3,4-二氢喹啉酮衍生物,该衍生物为5-{[1-(4-氯-2,6-二氟苯基)-4-羟基哌啶-4-基]甲氧基}-8-氟-3,4-二氢喹啉-2(1H)-酮(A1),其结构式如下:
本实施例中的3,4-二氢喹啉酮衍生物经过以下步骤制得:
(1)制备8-氟-5-羟基-2(1H)-喹啉酮(a1),其结构式如下:
氮气保护下,将3,3-二甲氧基丙酸(9.5g,63mmol)加入到装有试剂级甲苯(95mL)的三颈圆底烧瓶中,然后加入N,N-二异丙基乙胺(14mL,1.25eq,79mmol)。然后将反应混合物冷却至0℃,并在5分钟内逐滴加入三甲基乙酰氯(9.7mL,1.25eq,79mmol)。滴加完成后反应混合物变浑浊并形成沉淀,然后将反应混合物升温至室温并搅拌4小时。在室温下将3-氨基-4-氟苯酚(8.9g,63mmol,1eq)固体快速加到反应混合物中,然后将非均相反应混合物搅拌过夜。HPLC分析显示N-(2-氟-5-羟基苯基)-3,3-二甲氧基丙酰胺已形成。将反应混合物再次冷却至0℃,在45分钟内将浓硫酸(50mL,15eq,950mmol)通过加料漏斗逐滴加入。滴加完成后,反应再次升至室温并搅拌45分钟,期间,清楚观察到两层的形成。然后将反应混合物小心地转移到装有冷水(~30V,300mL)的500mL锥形瓶中并置于冰浴,有沉淀析出。对圆底烧瓶中残留的粘性和油性的底部硫酸层,在冷却条件下依次滴加的额外水(10V,100mL),得到的沉淀物与上述锥形瓶中的物质混合。混合物在室温下搅拌30分钟,过滤沉淀物,并依次用水和甲苯(各5V)洗涤,然后用MTBE(5V)洗涤并在室温真空干燥30分钟。将漏斗放置在烧杯中并在60℃的真空烘箱中干燥15小时以得到12.8g浅黄色固体,纯度为66%,收率75%。将该粗产物加入到)9%碳酸氢钠水溶液(130mL、10V)中并在室温下搅拌1小时。当气体逸出完全后(约40分钟),过滤收集固体并用水(2×20mL)洗涤,并在60℃的真空烘箱中和温和的氮气流下干燥15小时,得到7.5g米色固体,总收率62%;熔点:192~195℃;1H NMR(400MHz,DMSO-d6)δ8.01(dd,J=9.8Hz,0.9Hz,1H),7.19(dd,J=10.9,8.8Hz,1H),6.52(dd,J=8.8,3.3Hz,1H),6.45(d,J=9.8Hz,1H);ESI-MS:m/z=180.0432[M+H]+。
(2)制备8-氟-5-乙酰氧基-2(1H)-喹啉酮(a2),其结构式如下:
向20mL反应瓶中加入12mL乙酸酐和8-氟-5-羟基-2(1H)-喹啉酮(2g,10.4mmol,纯度93%)并加热至120℃保持2h。将反应混合物冷却至室温(冷却后发生沉淀)并倒入10V的冰水中。将混合物在此温度下搅拌1小时。过滤收集沉淀并用水(3V)洗涤,得到米色固体2.1g,收率90%;熔点:241~244℃;ESI-MS:m/z=224.0389[M+H]+。
(3)制备8-氟-5-乙酰氧基-3,4-二氢-2(1H)-喹啉酮(a3),其结构式如下:
在小型高压反应釜中,将10% Pd/C(20mg,纯度10%)添加到8-氟-5-乙酰氧基-2(1H)-喹啉酮(0.2g,0.832mmol)的2mL乙酸(10V)中。容器通过氮气排气并回填,然后在60psi(4atm)的氢气氛围下,将混合物在75℃加热8小时。将容器冷却至40℃,高压釜排气并更换氮气。残余物通过重量为2%的硅藻土过滤。减压浓缩滤液得白色固体214mg,收率97%;熔点:176~179℃;ESI-MS:m/z=224.0389[M+H]+。
(4)制备8-氟-5-羟基-3,4-二氢-2(1H)-喹啉酮(a4),其结构式如下:
将8-氟-5-乙酰氧基-3,4-二氢-2(1H)-喹啉酮(214mg,0.95mmol)加到1mL的MeOH(5V)中并添加1mL浓盐酸(5V)。将反应混合物在100℃加热1小时。然后将其冷却至40℃,并加入水(2mL)(发生沉淀),然后在30℃下搅拌1小时。然后将反应混合物冷却至0℃并再搅拌1小时。过滤收集沉淀并干燥得白色固体113mg,收率79%;熔点:192~194℃;1H NMR(400MHz,DMSO-d6)δ9.89(s,1H),9.45(s,1H),6.85(t,J=10.4Hz,1H),6.41(dd,J=8.9,4.0Hz,1H),2.80(t,J=7.8Hz,2H),2.44(dd,J=7.8,6.3Hz,2H);ESI-MS:m/z=182.0330[M+H]+。
(5)制备8-(4-氯-2,6-二氟苯基)-1,4-二氧杂-8-氮杂螺[4.5]癸烷(a5),其结构式如下:
于微波反应试管中加入1-溴-2,6-二氟-4-氯苯(940mg,4.13mmol)、叔丁醇钠(473mg,4.9mmol)、三(二苯亚甲基丙酮)二钯(38mg,0.041mmol)、2,2'-双(二苯基膦基)-1,1'-联萘(77mg,0.12mol)、1,4-二氧杂-8-氮杂螺[4.5]癸烷(590uL,4.6mmol)及甲苯(3mL)。密封试管,然后于130℃用微波照射1小时。反应完成后,向混合物中加入水和乙酸乙酯并分离各层,有机层用盐水洗涤,经无水硫酸钠干燥,过滤并减压浓缩。残余物经柱层析(乙酸乙酯/石油醚=1/10)纯化得浅黄色晶体800mg,收率67%;熔点72~75℃;1H NMR(400MHz,CDCl3)δ6.91-6.84(m,2H),4.01(s,4H),3.24(t,J=5.6Hz,4H),1.84(t,J=5.6Hz,4H);ESI-MS:m/z=290.0317[M+H]+。
(6)制备1-(4-氯-2,6-二氟苯基)哌啶-4-酮(a6),其结构式如下:
于8-(4-氯-2,6-二氟苯基)-1,4-二氧杂-8-氮杂螺[4.5]癸烷(800mg,2.76mol)的丙酮(20mL)溶液中添加5N盐酸(10mL),并将反应混合物加热回流3小时。减压浓缩除去丙酮,然后将残余物用5N氢氧化钠中和,用乙酸乙酯萃取,有机层用盐水洗涤,经无水硫酸钠干燥,过滤并减压浓缩。残余物经柱层析(乙酸乙酯/石油醚=1/10)纯化得黄色固体521mg,收率76%;熔点53~55℃;1H NMR(400MHz,CDCl3)δ6.97–6.89(m,2H),3.47(t,J=6.0Hz,4H),2.59(t,J=6.0Hz,4H);ESI-MS:m/z=246.0310[M+H]+。
(7)制备6-(4-氯-2,6-二氟苯基)-1-氧杂-6-氮杂螺[2.5]辛烷(a7),其结构式如下:
氮气保护下,于装有三甲基碘化亚砜(550mg,2.49mmol)和叔丁醇钠(240mg,2.49mmol)的反应瓶中加入二甲基亚砜(6.8mL),并将反应混合物于室温搅拌30分钟。于反应混合物中添加1-(4-氯-2,6-二氟苯基)哌啶-4-酮(516mg,2.1mmol)的二甲基亚砜(3mL)溶液,将反应混合物于室温搅拌2.5小时。在冰冷却下,于反应溶液中添加水,然后用乙酸乙酯萃取。有机层用盐水洗涤,经无水硫酸钠干燥,过滤并减压浓缩。残余物经柱层析(乙酸乙酯/石油醚=1/10)纯化得黄色固体415mg,收率76%;熔点55~58℃;1H NMR(400MHz,CDCl3)δ6.93–6.85(m,2H),3.42–3.34(m,2H),3.25–3.19(m,2H),2.72(s,2H),1.99–1.91(m,2H),1.66–1.60(m,2H);ESI-MS:m/z=260.0263[M+H]+。
(8)制备5-{[1-(4-氯-2,6-二氟苯基)-4-羟基哌啶-4-基]甲氧基}-8-氟-3,4-二氢喹啉-2(1H)-酮(A1)
氮气保护下,将8-氟-5-羟基-3,4-二氢-2(1H)-喹啉酮(453mg,2.5mmol)、6-(4-氯-2,6-二氟苯基)-1-氧杂-6-氮杂螺[2.5]辛烷(650mg,2.5mmol)与七水磷酸钾(846mg,2.5mmol)加入N,N-二甲基甲酰胺/异丙醇(1:1)(5mL)溶液中,完全溶解后于70℃过夜搅拌反应。反应完成后,冷却至室温,于反应溶液中添加水(发生沉淀),然后将混合物继续搅拌10分钟。过滤收集沉淀并干燥得白色固体710mg,收率64%;熔点(乙酸乙酯/甲醇):205~208℃;1H NMR(400MHz,DMSO-d6)δ10.00(brs,1H),7.29–7.21(m,2H),7.01(t,J=9.7Hz,1H),6.58(dd,J=9.1,3.7Hz,1H),4.70(brs,1H),3.77(s,2H),3.40–3.35(m,2H),2.99–2.96(m,2H),2.93(t,J=7.6Hz,2H),2.47(t,J=7.6Hz,2H),1.81–1.78(m,2H),1.65–1.62(m,2H);ESI-MS:m/z=441.1204[M+H]+。
实施例2
一种3,4-二氢喹啉酮衍生物,该衍生物为5-{[1-(4-氯-2,6-二氟苯基)-1,2,3,6-四氢吡啶-4-基]甲氧基}-8-氟-3,4-二氢喹啉-2(1H)-酮(A2),其结构式如下:
氮气保护下,于5-{[1-(4-氯-2,6-二氟苯基)-4-羟基哌啶-4-基]甲氧基}-8-氟-3,4-二氢喹啉-2(1H)-酮(A1)(441mg,1mmol)的四氢呋喃(8mL)溶液中,添加伯吉斯试剂(Burgess reagent)(597mg,2.5mmol),此反应混合物于室温搅拌16.5小时,接着于60℃搅拌2小时。反应完成后,冷却至室温,于反应溶液中添加水(发生沉淀),过滤收集沉淀并干燥得白色固体350mg,收率82%;熔点:218~220℃;1H NMR(400MHz,DMSO-d6)δ10.02(s,1H),7.34–7.26(m,3H),7.07–7.00(m,1H),5.88(brs,1H),4.48(s,2H),3.64(brs,2H),3.29–3.24(m,2H),3.22–3.03(m,2H),2.89(t,J=7.6Hz,2H),2.27–2.23(m,2H);ESI-MS:m/z=423.0367[M+H]+。
实施例3
一种3,4-二氢喹啉酮衍生物,该衍生物为(3R,4R)-1-(4-氯-2,6-二氟苯基)-4-{[(8-氟-2-氧代-1,2,3,4-四氢喹啉-5-基)氧基]甲基}-4-羟基哌啶-3-基-L-缬氨酸(A3),其结构式如下:
本实施例中的3,4-二氢喹啉酮衍生物经过以下步骤制得:
(1)制备5-{[(3R,4R)-1-(4-氯-2,6-二氟苯基)-3,4-二羟基哌啶-4-基]甲氧基}-8-氟-3,4-二氢喹啉-2(1H)-酮b1),其结构式如下:
本实施例中的3,4-二氢喹啉酮衍生物经过以下步骤制得:
于室温,搅拌双(二氢喹啉啶基)酞嗪((DHQD)2PHAL)(34.05mg,0.043mmol)与锇(VI)酸钾二水合物(4.03mg,0.011mmol)的丙酮-水(2:1)(20mL)溶液15分钟,在冰浴条件下,于其内添加4.8M N-甲基吗啉-N-氧化物(228uL,1.09mmol)与5-{[1-(4-氯-2,6-二氟苯基)-1,2,3,6-四氢吡啶-4-基]甲氧基}-8-氟-3,4-二氢喹啉-2(1H)-酮(A2)(308mg,0.728mmol)的丙酮-水(2:1)溶液,此混合物于室温搅拌1.5天。反应完成后,于反应液中添加饱和亚硫酸钠水溶液,于室温搅拌反应混合物30分钟。此反应混合物以乙酸乙酯萃取,经无水硫酸钠干燥,过滤并减压浓缩。残余物经柱层析(乙酸乙酯)纯化,残留物以乙酸/水重结晶。过滤收集沉淀物,减压干燥(60℃)得白色固体140mg,(>99%ee),收率42%;熔点:193~195℃;1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),7.30–7.22(m,2H),7.02(t,J=9.2Hz,1H),6.59(dd,J=9.2,3.7Hz,1H),4.87(d,J=6.4Hz,1H),4.52(s,1H),4.03(d,J=8.8Hz,1H),3.76–3.70(m,1H),3.69(d,J=8.8Hz,1H),3.34–3.30(m,1H),3.22(t,J=10.7Hz,1H),2.98(dd,J=10.7,4.5Hz,1H),2.93–2.86(m,3H),2.50–2.45(m,2H),1.91(dt,J=13.4,4.7Hz,1H),1.70(d,J=13.4Hz,1H);ESI-MS:m/z=457.0349[M+H]+。
(2)制备(3R,4R)-1-(4-氯-2,6-二氟苯基)-4-{[(8-氟-2-氧代-1,2,3,4-四氢喹啉-5-基)氧基]甲基}-4-羟基哌啶-3-基{[(9H-芴-9-基)甲氧基]羰基}-L-缬氨酸(b2),其结构式如下:
将Fmoc-L-缬氨酸(30mg,0.088mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(21mg,0.11mmol)和4-二甲氨基吡啶(2.5mg,0.0088mmol)加到DMF/DCM(1:2,1mL)溶液中并于室温搅拌10分钟。然后将5-{[(3R,4R)-1-(4-氯-2,6-二氟苯基)-3,4-二羟基哌啶-4-基]甲氧基}-8-氟-3,4-二氢喹啉-2(1H)-酮(b1)(40mg,0.088mmol)加入到反应液中并于室温过夜反应。反应完成后,向反应液中加入水和二氯甲烷并分离各层,有机层依次经5%盐酸、饱和碳酸氢钠和盐水洗涤,无水硫酸钠干燥,过滤并减压浓缩,残余物经柱层析(石油醚/乙酸乙酯=2:1)纯化得白色固体60mg,收率87%;熔点:87~91℃。
(3)制备(3R,4R)-1-(4-氯-2,6-二氟苯基)-4-{[(8-氟-2-氧代-1,2,3,4-四氢喹啉-5-基)氧基]甲基}-4-羟基哌啶-3-基-L-缬氨酸(A3)
将(3R,4R)-1-(4-氯-2,6-二氟苯基)-4-{[(8-氟-2-氧代-1,2,3,4-四氢喹啉-5-基)氧基]甲基}-4-羟基哌啶-3-基{[(9H-芴-9-基)甲氧基]羰基}-L-缬氨酸(b2)(60mg,0.077mmol)添加到20%的4-甲基哌啶/二氯甲烷溶液中,混合物于室温搅拌40分钟,减压浓缩反应液,残余物经柱层析(二氯甲烷/甲醇/三乙胺=30:1:0.1%)纯化,残留物以异丙醚洗涤,过滤收集沉淀物得白色固体35mg,收率81%;熔点:185~188℃;1H NMR(400MHz,CDCl3)δ7.91(s,1H),6.94–6.86(m,3H),6.44(dd,J=9.1,3.8Hz,1H),5.26(dd,J=9.9,5.0Hz,1H),3.93–3.84(m,2H),3.48(t,J=10.8Hz,2H),3.35(d,J=4.9Hz,1H),3.26(dd,J=11.1,4.8Hz,1H),3.09–2.99(m,3H),2.65(t,J=7.6Hz,2H),2.13(td,J=12.1,4.8Hz,1H),2.01(dd,J=12.1,6.7Hz,1H),1.97–1.91(m,1H),1.71(brs,2H),0.95(d,J=6.8Hz,3H),0.87(d,J=6.8Hz,3H);ESI-MS:m/z=578.2639[M+Na]+。
实施例4
一种3,4-二氢喹啉酮衍生物,该衍生物为(3R,4R)-1-(4-氯-2,6-二氟苯基)-4-{[(8-氟-2-氧代-1,2,3,4-四氢喹啉-5-基)氧基]甲基}-4-羟基哌啶-3-基硬脂酸酯(A4),其结构式如下:
本实施例中的3,4-二氢喹啉酮衍生物经过以下步骤制得:
将硬脂酸(0.088mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(21mg,0.11mmol)和4-二甲氨基吡啶(2.5mg,0.0088mmol)加到DMF/DCM(1:2,1mL)溶液中并于室温搅拌10分钟。然后将5-{[(3R,4R)-1-(4-氯-2,6-二氟苯基)-3,4-二羟基哌啶-4-基]甲氧基}-8-氟-3,4-二氢喹啉-2(1H)-酮(b1)(40mg,0.088mmol)加入到反应液中并于室温过夜反应。反应完成后,向反应液中加入水和二氯甲烷并分离各层,有机层依次经5%盐酸、饱和碳酸氢钠和盐水洗涤,无水硫酸钠干燥,过滤并减压浓缩,残余物经柱层析(石油醚/乙酸乙酯=2:1)纯化得白色固体69mg,收率86%;熔点:65~67℃;1H NMR(400MHz,CDCl3)δ8.15(s,1H),6.92(d,J=9.1Hz,1H),6.90–6.85(m,2H),6.45(dd,J=9.1,3.9Hz,1H),5.22(dd,J=10.0,5.1Hz,1H),3.91–3.82(m,2H),3.52–3.40(m,2H),3.26(dd,J=11.1,4.9Hz,1H),3.09–2.99(m,3H),2.66(t,J=7.7Hz,2H),2.32(t,J=7.2Hz,2H),2.13(td,J=12.2,4.9Hz,1H),1.92(dt,J=13.8,2.4Hz,1H),1.58(t,J=7.0Hz,2H),1.39–1.13(m,28H),0.89(t,J=6.8Hz,3H);ESI-MS:m/z=707.2571[M-17]+。
实施例5
一种3,4-二氢喹啉酮衍生物,该衍生物为1-(4-氯-2,6-二氟苯基)-4-{[(8-氟-2-氧代-1,2,3,4-四氢喹啉-5-基)氧基]甲基}哌啶-4-基硬脂酸酯(A5),其结构式如下:
本实施例中的3,4-二氢喹啉酮衍生物经过以下步骤制得:
将硬脂酸(85.2mg,0.3mmol)添加到氯化亚砜(0.3mL)中,混合物回流反应2小时。反应完成后,减压浓缩反应液除去氯化亚砜得酰氯中间体,待用。冰浴条件下,将60%氢化钠(12mg,0.3mmol)加入到5-{[1-(4-氯-2,6-二氟苯基)-4-羟基哌啶-4-基]甲氧基}-8-氟-3,4-二氢喹啉-2(1H)-酮(A1)(110mg,0.25mmol)的N,N-二甲基甲酰胺(0.5mL)溶液中,然后升至室温反应半小时。然后在冰浴条件下,将上述酰氯中间体的二氯甲烷(0.5mL)溶液缓慢滴加到上述N,N-二甲基甲酰胺反应液中,滴加完成后,将混合物升至室温反应4小时。反应完成后,向反应液中加入水和二氯甲烷并分离各层,有机层经盐水洗涤,无水硫酸钠干燥,过滤并减压浓缩,残余物经柱层析(石油醚/乙酸乙酯=3:1)纯化得白色固体120mg,收率67%;熔点:75~78℃;1H NMR(400MHz,CDCl3)δ6.98(t,J=9.1,1H),6.94–6.87(m,2H),6.73(dd,J=9.1,3.7Hz,1H),3.88(s,2H),3.49(t,J=11.1Hz,2H),3.12–3.05(m,4H),3.01–2.96(m,2H),2.69(dd,J=7.5,6.1Hz,2H),1.91–1.76(m,6H),1.31–1,24(m,28H),0.90(t,J=6.8Hz,3H)。
实施例6
一种3,4-二氢喹啉酮衍生物,该衍生物为5-((1-(1-甲基-1H-吡唑-4-羰基)-1,2,3,6-四氢吡啶-4-基)甲氧基)-3,4-二氢喹啉-2(1H)-酮(A6),其结构式如下:
本实施例中的3,4-二氢喹啉酮衍生物经过以下步骤制得:
(1)制备4-羟基-4-{[(2-氧代-1,2,3,4-四氢喹啉-5-基)氧基]甲基}哌啶-1-甲酸叔丁酯(c1),其结构式如下:
制备方法参考A1,最终得到白色固体1.45g,收率83%;熔点:166~168℃;1H NMR(400MHz,CDCl3)δ8.46(brs,1H),7.13(t,J=8.1Hz,1H),6.57(d,J=8.3Hz,1H),6.48(d,J=7.9Hz,1H),3.87–4.04(m,2H),3.85(s,2H),3.18–3.31(m,2H),2.98(t,J=7.7Hz,2H),2.64(t,J=7.7Hz,2H),2.20–2.23(m,1H),1.66–1.78(m,4H),1.49(s,9H);ESI-MS:m/z=277.1137[M-99]+。
(2)制备4-{[(2-氧代-1,2,3,4-四氢喹啉-5-基)氧基]甲基}-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(c2),其结构式如下:
合成方法参考化合物A2,最终得到米色固体2.2g,收率82%;熔点:186~189℃;ESI-MS:m/z=360.1589[M+H]+。
(3)制备5-[(1,2,3,6-四氢吡啶-4-基)甲氧基]-3,4-二氢喹啉-2(1H)-酮(c3),其结构式如下:
将化合物4-{[(2-氧代-1,2,3,4-四氢喹啉-5-基)氧基]甲基}-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(c2)(675mg,1.88mmol)添加到14mL盐酸/甲醇(1:2)溶液中,混合物于室温搅拌2小时,溶液变得澄清。反应完全后,减压浓缩混合物得黄色固体,该粗产物无需纯化直接用于下一步反应。ESI-MS:m/z=259.1475[M+H]+。
(3)制备5-((1-(1-甲基-1H-吡唑-4-羰基)-1,2,3,6-四氢吡啶-4-基)甲氧基)-3,4-二氢喹啉-2(1H)-酮(A7)
将1-甲基-4-吡唑甲酸(126mg,1mmol)添加氯化亚砜(1mL)中,混合物回流搅拌反应2小时。反应完成后,减压浓缩反应液除去氯化亚砜得酰氯中间体,待用。将酰氯中间体溶解在二氯甲烷(4mL)中,并在冰浴条件下滴加到化合物5-[(1,2,3,6-四氢吡啶-4-基)甲氧基]-3,4-二氢喹啉-2(1H)-酮(c3)(258mg,1mmol)和三乙胺(278uL,2mmol)的二氯甲烷(4.0mL)溶液中,反应液于室温过夜反应。反应完成后,向反应液中加入二氯甲烷和水并分离各层,有机层用饱和食盐水洗涤,用无水硫酸钠干燥,过滤并减压浓缩,残余物通过柱层析(二氯甲烷:甲醇=25:1)纯化得到白色固体194mg,收率53%;熔点:213~215℃;1H NMR(400MHz,DMSO-d6)δ:10.03(s,1H),8.09(s,1H),7.70(s,1H),7.07(t,J=8.1Hz,1H),6.62(d,J=8.3Hz,1H),6.50(d,J=7.9Hz,1H),5.84(brs,1H),4.48(s,2H),4.24–4.03(m,2H),3.86(s,3H),3.71(t,J=5.7Hz,2H),2.83(t,J=7.7Hz,2H),2.42(t,J=7.7Hz,2H),2.29–2.18(m,2H);ESI-MS:m/z=367.1496[M+H]+。
实施例7
一种3,4-二氢喹啉酮衍生物,该衍生物为5-(((3R,4R)-3,4-二羟基-1-(1-甲基-1H-吡唑-4-羰基)哌啶-4-基)甲氧基)-3,4-二氢喹啉-2(1H)-酮(A7),其结构式如下:
本实施例中的3,4-二氢喹啉酮衍生物的合成方法参考化合物b1;最终得到白色固体50mg,收率48%;熔点:230~233℃;1H NMR(400MHz,DMSO-d6)δ:10.02(s,1H),8.06(s,1H),7.67(s,1H),7.08(t,J=8.1Hz,1H),6.58(d,J=8.3Hz,1H),6.49(d,J=7.9Hz,1H),5.07(d,J=5.1Hz,1H),4.70(s,1H),4.03(d,J=8.9Hz,1H),3.86(s,3H),3.72(d,J=8.9Hz,1H),3.62–3.56(m,1H),3.36–3.37(m,4H),2.84–2.76(m,2H),2.41(t,J=7.7Hz,2H),1.76–1.67(m,2H);ESI-MS:m/z=401.1302[M+H]+。
实施例8
一种3,4-二氢喹啉酮衍生物,该衍生物为5-((1-(1H-吡唑-4-羰基)-1,2,3,6-四氢吡啶-4-基)甲氧基)-3,4-二氢喹啉-2(1H)-酮(A8),其结构式如下:
本实施例中的3,4-二氢喹啉酮衍生物的合成方法参考化合物A6;最终得到白色固体103mg,收率40%;熔点:236~240℃;1H NMR(400MHz,DMSO-d6)δ:13.20(s,1H),10.02(s,1H),8.11(s,1H),7.76(s,1H),7.07(t,J=8.1Hz,1H),6.62(d,J=8.4Hz,1H),6.49(d,J=7.9Hz,1H),5.84(brs,1H),4.48(s,2H),4.20–4.06(m,2H),3.72(t,J=5.7Hz,2H),2.83(t,J=7.7Hz,2H),2.42(t,J=7.7Hz,2H),2.26–2.20(m,2H);ESI-MS:m/z=367.1496[M+H]+。
实施例9
一种3,4-二氢喹啉酮衍生物,该衍生物为5-((4-羟基-1-(1-甲基-1H-吡唑-4-羰基)哌啶-4-基)甲氧基)-3,4-二氢喹啉-2(1H)-酮(A9),其结构式如下:
本实施例中的3,4-二氢喹啉酮衍生物经过以下步骤制得:
(1)制备1-(1-甲基-1H-吡唑-4-羰基)哌啶-4-酮(d1),其结构式如下:
制备方法参考A6,最终得到白色固体680mg,收率54%;熔点:122~124℃;1H NMR(400MHz,CDCl3)δ7.75(s,1H),7.65(s,1H),3.97(t,J=6.3Hz,4H),3.92(s,3H),2.51(t,J=6.3Hz,4H);ESI-MS:m/z=208.0993[M+H]+。
(2)制备1-甲基-1H-吡唑-4-基)(1-氧杂-6-氮杂螺[2.5]辛烷-6-基)甲酮(d2),其结构式如下:
制备方法参考a7,该粗产物无需纯化直接用于下一步反应。ESI-MS:m/z=222.0870[M+H]+。
(3)制备5-((4-羟基-1-(1-甲基-1H-吡唑-4-羰基)哌啶-4-基)甲氧基)-3,4-二氢喹啉-2(1H)-酮(A10)
制备方法参考A1,最终得到白色固体250mg,收率65%;熔点:206~208℃;1H NMR(400MHz,DMSO-d6)δ10.02(s,1H),8.04(s,1H),7.66(s,1H),7.07(t,J=8.1Hz,1H),6.58(d,J=8.2Hz,1H),6.49(d,J=7.9Hz,1H),4.86(s,1H),3.86(s,3H),3.78(s,2H),3.39–3.36(m,4H),2.86(t,J=7.7Hz,2H),2.42(t,J=7.7Hz,2H);ESI-MS:m/z=385.1887[M+H]+。
实施例10
一种3,4-二氢喹啉酮衍生物,该衍生物为5-((4-(苄氧基)-1-(1H-吡唑-4-羰基)哌啶-4-基)甲氧基)-3,4-二氢喹啉-2(1H)-酮(A10),其结构式如下:
本实施例中的3,4-二氢喹啉酮衍生物经过以下步骤制得:
(1)制备4-(苄氧基)-4-(((2-氧代-1,2,3,4-四氢喹啉-5-基)氧基)甲基)哌啶-1-甲酸叔丁酯(e1),其结构式如下:
在冰浴条件下,将50%氢化钠(195mg,4.07mmol)添加到4-羟基-4-{[(2-氧代-1,2,3,4-四氢喹啉-5-基)氧基]甲基}哌啶-1-甲酸叔丁酯(c1)(1.4g,3.71mmol)的N,N-二甲基甲酰胺(8mL)溶液中搅拌15分钟。向混合物中加入苄基溴(500uL,4.2mmol),然后将反应混合物升至室温并搅拌1小时。在冰冷却下向反应混合物中加入饱和氯化铵水溶液,用乙酸乙酯萃取,有机层用盐水洗涤,用无水硫酸镁干燥,过滤并减压浓缩。残余物经柱层析(乙酸乙酯/石油醚=1/10~1/1)纯化得黄色油状物1.36g,收率78%;ESI-MS:m/z=411.1974[M-55]+。
(2)制备5-((4-(苄氧基)哌啶-4-基)甲氧基)-3,4-二氢喹啉-2(1H)-酮(e2),其结构式如下:
将三氟乙酸(1.5mL,19.7mmol)添加到4-(苄氧基)-4-(((2-氧代-1,2,3,4-四氢喹啉-5-基)氧基)甲基)哌啶-1-甲酸叔丁酯(e1)(920mg,1.97mmol)的二氯甲烷(4mL)溶液中,将反应混合物于室温搅拌3小时。反应完成后,将反应液中缓慢加入到饱和碳酸钠溶液中和并分离各层,水层用二氯甲烷萃取,合并有机层用饱和食盐水洗涤,用无水硫酸钠干燥,过滤并减压浓缩得到白色固体630mg,收率87%;熔点:176~180℃;1H NMR(400MHz,DMSO-d6)δ7.32–7.28(m,2H),7.23–7.18(m,3H),7.07(t,J=8.3Hz,1H),6.67(d,J=8.3Hz,1H),6.57(d,J=8.3Hz,1H),5.21(s,1H),5.14(s,2H),3.80(s,2H),3.24–3.20(m,2H),3.16–3.10(m,2H),2.96(t,J=7.5Hz,2H),2.67(t,J=7.5Hz,2H),1.95(td,J=13.9,4.7Hz,2H),1.72(d,J=13.6Hz,2H);ESI-MS:m/z=367.1336[M+H]+。
(3)制备5-((4-(苄氧基)-1-(1H-吡唑-4-羰基)哌啶-4-基)甲氧基)-3,4-二氢喹啉-2(1H)-酮(A10)
制备方法参考A6,最终得到白色固体40mg,收率50%;熔点:210~212℃;1H NMR(400MHz,DMSO-d6)δ13.16(s,1H),8.04(s,1H),7.76(s,1H),7.30(t,J=7.4Hz,2H),7.21(t,J=7.5Hz,3H),7.06(t,J=8.3Hz,1H),6.66(d,J=8.3Hz,1H),6.56(d,J=8.3Hz,1H),5.13(s,2H),4.89(s,1H),3.79(s,2H),3.41–3.39(m,4H),2.94(t,J=7.5Hz,2H),2.66(t,J=7.5Hz,2H),1.69–1.63(m,4H);ESI-MS:m/z=461.2200[M+H]+。
实施例11
一种3,4-二氢喹啉酮衍生物,该衍生物为8-硝基-2-(4-(((2-氧代-1,2,3,4-四氢喹啉-5-基)氧基)甲基)-3,6-二氢吡啶-1(2H)-基)-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮(A11),其结构式如下:
本实施例中的3,4-二氢喹啉酮衍生物经过以下步骤制得:
(1)制备2-氯-3-硝基-5-三氟甲基苯甲酸(f1),其结构式如下:
将2-氯-5-三氟甲基苯甲酸(1g,4.45mmol)添加到50mL浓硫酸中,然后在0℃下加入硝酸钾(900mg,8.9mmol),混合物在90℃下搅拌反应3小时。反应完成后,将混合物冷却至室温,倒入冰水中,析出大量固体,过滤固体并用冰水洗涤,得白色固体1.1g,收率91%;熔点:168~170℃;1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.39(s,1H)。
(2)制备3,4-二氢喹啉酮衍生物,该衍生物为8-硝基-2-(4-(((2-氧代-1,2,3,4-四氢喹啉-5-基)氧基)甲基)-3,6-二氢吡啶-1(2H)-基)-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮(A11)
将草酰氯(212uL,2.5mmol)和催化量的N,N-二甲基甲酰胺依次添加到2-氯-3-硝基-5-三氟甲基苯甲酸(f1)(269mg,1mmol)的二氯甲烷(3mL)悬浮液中。将反应混合物在室温下搅拌2小时并真空蒸发溶剂。将残余物溶解在二氯甲烷(4mL)中,并在搅拌下滴加到硫氰酸铵(153mg,2mmol)中。然后向悬浮液中加入催化量的聚乙二醇400,并在室温下搅拌1.5小时。原料消耗完后,加入5-[(1,2,3,6-四氢吡啶-4-基)甲氧基]-3,4-二氢喹啉-2(1H)-酮(c3)(258mg,1mmol),然后在室温下再搅拌2小时。然后向反应混合物加入水稀释并用二氯甲烷萃取。有机层用盐水洗涤,用无水硫酸钠干燥,过滤并减压浓缩。残余物通过柱层析(乙酸乙酯/石油醚=1/1)纯化,得到得黄色固体175mg,收率33%;熔点:249~252℃;1H NMR(600MHz,DMSO-d6)δ10.03(s,1H),8.85(s,1H),8.80(s,1H),7.06(t,J=8.2Hz,1H),6.63(d,J=8.2Hz,1H),6.49(d,J=7.9Hz,1H),5.94(s,1H),4.53(s,2H),4.49–4.32(m,2H),4.17–3.97(m,2H),2.84(t,J=7.8Hz,2H),2.42(t,J=7.8Hz,2H),2.40–2.29(m,2H);ESI-MS:m/z=533.1147[M+H]+。
实施例12
一种3,4-二氢喹啉酮衍生物,该衍生物为2-((3R,4R)-3,4-二羟基-4-(((2-氧代-1,2,3,4-四氢喹啉-5-基)氧基)甲基)哌啶-1-基)-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮(A12),其结构式如下:
合成方法参考化合物b2;最终得到黄色固体8mg,收率45%;熔点:172~175℃;ESI-MS:m/z=567.1199[M+H]+。
实施例13
一种3,4-二氢喹啉酮衍生物,该衍生物为2-(4-(苄氧基)-4-(((2-氧代-1,2,3,4-四氢喹啉-5-基)氧基)甲基)哌啶-1-基)-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮(A13),其结构式如下:
合成方法参考化合物A11;最终得到黄色固体50mg,收率40%;1H NMR(400MHz,DMSO-d6)δ8.85(d,J=1.9Hz,1H),8.80(d,J=1.9Hz,1H),7.29(t,J=7.4Hz,2H),7.20(t,J=7.7Hz,3H),7.06(t,J=8.3Hz,1H),6.67(d,J=8.3Hz,1H),6.56(d,J=8.3Hz,1H),5.13(s,2H)5.12(s,1H),3.84(s,2H),3.35–3.33(m,4H),2.94(t,J=7.5Hz,2H),2.64(t,J=7.5Hz,2H),1.91–1.74(m,4H)。ESI-MS:m/z=641.1674[M+H]+。
实验例
抗结核活性测试例:实验方法采用微孔板药敏试验方法,测试菌株为结核分枝杆菌H37Rv。
实验步骤
1、配药:
待测化合物以DMSO完全溶解,配制成贮存母液(1mg/mL),过滤除菌,-80℃储存分装备用,然后以结核菌Middlebrook 7H9培养液进行系列稀释,临用前以100μl/孔加入96孔培养板。终浓度分别为:16、8、4、2、1、0.5、0.25、0.125、0.0625、0.03125、0.0156μg/mL。
阳性对照药:阳性对照药物利福平(R)和异烟肼(H)为本室提供。终浓度分别为:8、4、2、1、0.5、0.25、0.125、0.0625、0.03125、0.0156、0.0078μg/mL。如表1所示。
表1配药浓度表
结核菌:
取对数生长期的H37Rv,磨菌比浊到OD600=1.0(约5×106CFU/mL),取200μl稀释到10ml培养液中后,以连续加样枪100μl/孔(约104CFU/孔)加入培养板;对照组加入与测试化合物等同菌量(D100),1/10菌量(D10)和1/100菌量(D1)。
2、实验设计
以96孔板排列为例:
化合物 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | |
a3 | A | 4 | 2 | 1 | 0.5 | 0.25 | 0.125 | 0.0625 | 0.03125 | 0.0156 | 0.0078 | 0.0039 | D100 |
a3 | B | 4 | 2 | 1 | 0.5 | 0.25 | 0.125 | 0.0625 | 0.03125 | 0.0156 | 0.0078 | 0.0039 | D100 |
b3 | C | 4 | 2 | 1 | 0.5 | 0.25 | 0.125 | 0.0625 | 0.03125 | 0.0156 | 0.0078 | 0.0039 | D10 |
b3 | D | 4 | 2 | 1 | 0.5 | 0.25 | 0.125 | 0.0625 | 0.03125 | 0.0156 | 0.0078 | 0.0039 | D10 |
c3 | E | 4 | 2 | 1 | 0.5 | 0.25 | 0.125 | 0.0625 | 0.03125 | 0.0156 | 0.0078 | 0.0039 | D10 |
c3 | F | 4 | 2 | 1 | 0.5 | 0.25 | 0.125 | 0.0625 | 0.03125 | 0.0156 | 0.0078 | 0.0039 | D1 |
a1 | G | 4 | 2 | 1 | 0.5 | 0.25 | 0.125 | 0.0625 | 0.03125 | 0.0156 | 0.0078 | 0.0039 | D1 |
a1 | H | 4 | 2 | 1 | 0.5 | 0.25 | 0.125 | 0.0625 | 0.03125 | 0.0156 | 0.0078 | 0.0039 | D1 |
其余孔板排列与上例类似,培养天数为21天。
3、结果观察
在37℃下培养,以1%接种菌量对照孔有明显菌斑生长时,进行结果判读。观察各组菌落生长情况,以无菌落生长的药物组最低浓度作为测试化合物对该菌株的MIC值。
实验结果为肉眼观察药物作用下结核分枝杆菌在96孔培养板液体培养基中生长21天时的情况,与同样接种菌量100%及10%、1%接种菌量的对照组比较。
本次实验菌株培养到21天时100%、10%、1%菌量对照菌株生长明显,1%生长菌量较多,菌斑大小有一定梯度。
结果如下表2所示。
表2化合物体外抗结核分枝杆菌活性
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注:1.90%抑制定义为与接种量为10%的对照组菌斑比较更小;99%抑制定义为与接种量为1%的对照组菌斑比较更小,100%抑制浓度定义为肉眼观察无明显菌斑的最小浓度。
虽然结合实施例对本发明的具体实施方式进行了详细地描述,但不应理解为对本专利的保护范围的限定。在权利要求书所描述的范围内,本领域技术人员不经创造性劳动即可作出的各种修改和变形仍属本专利的保护范围。
Claims (3)
1.一种3,4-二氢喹啉酮衍生物,其特征在于,结构式如式I或II所示,
其中,X为C或N;X1为H或F;
R1为H或-OH或醚键或碳原子数为5~18的长链酯基;
R2为H或-OR4,R4为碳原子数为5~18的长链烷基,或碳原子数为5~18的长链酯基,或氨基酸残基,或Y1~Y9中的任意一种,
R5为碳原子数为1~16的烷基,或-PH(=O)OH;R6为碳原子数为1~16烷基,或碳原子数为1~5的酰基;n为0~10的整数;
R3为
A为取代芳基,或取代杂环基,或吡啶基、噻吩基、喹啉基、异喹啉基、苯并噻吩基、喹噁啉基、苯并呋喃基、苯并二氧杂环戊稀基、苯并噁唑基、苯并咪唑基中的任意一种;X2为O、S或N。
2.根据权利要求1所述的3,4-二氢喹啉酮衍生物,其特征在于,所述3,4-二氢喹啉酮衍生物为A1~A13中的任意一种:
3.权利要求1或2所述的3,4-二氢喹啉酮衍生物在制备诊断、预防和/或治疗结核病的药物中的应用。
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