CN105622596A - 含有烷氧亚胺基氮杂环片段的苯并噻嗪-4-酮类化合物及其制备方法 - Google Patents
含有烷氧亚胺基氮杂环片段的苯并噻嗪-4-酮类化合物及其制备方法 Download PDFInfo
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- CN105622596A CN105622596A CN201610093216.6A CN201610093216A CN105622596A CN 105622596 A CN105622596 A CN 105622596A CN 201610093216 A CN201610093216 A CN 201610093216A CN 105622596 A CN105622596 A CN 105622596A
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- Prior art keywords
- benzo
- trifluoromethyl
- nitro
- compound
- thiazine
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Abstract
本发明涉及式(I)所示含有烷氧亚胺基氮杂环片段的苯并噻嗪-4-酮类化合物,其制备方法和医药用途以及以其为有效成分的抗结核药物组合物。更具体地讲,本发明涉及一类6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮类化合物,其2-位取代基是含有烷氧亚胺基的1-氮杂环烷基,其中,式(I)中R代表1-4个C原子的链烷基、4-7个C原子的环烷基、苄基、取代苯甲基;n1代表0-1,n2代表1-3。
Description
技术领域
本发明属于医药化学领域,涉及具有抗结核活性的含有烷氧亚胺基氮杂环片段的苯并噻嗪-4-酮类化合物及其制备方法,以及含有它们的抗结核药物组合物;更具体地说,本发明涉及6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮类化合物,其2-位取代基是含有烷氧亚胺基的1-氮杂环烷基。
背景技术
结核病(TB)是由结核分枝杆菌(MTB)引起的严重危害人类健康的重大传染病之一。从20世纪80年代开始,耐药TB,尤其是耐多药TB(MDR-TB)的发病率不断上升以及TB与HIV/AIDS相结合使TB疫情再度上升,成为全球关注的重大公共卫生问题和社会问题。据统计,全球每年有800万新增TB患者,近300万人死于结核,近1/3人口携带潜伏态结核杆菌,具有潜在的发病危险。传统的抗TB药物,如链霉素、异烟肼、利福平、乙胺丁醇和吡嗪酰胺等联合用药可使85%以上的初治肺结核患者痊愈,但存在治疗周期长(大于6个月)且对MDR-TB无效的缺点,同时对潜伏态MTB的作用不强,因此研发抗TB新药,实现对TB的有效治疗与控制迫在眉睫(国外医药-抗生素分册2009,30(1):19-24)。
值得庆幸的是,作为近40年来第1个具有全新作用机制的抗TB新药贝达喹啉(ATP合成酶抑制剂)于2012年被美国FDA批准用于治疗MDR-TB。受此鼓舞,近年来全球多个大制药公司及研究单位加大了对抗结核新药的研发力度,并已公开报道若干具有不同作用机制的抗结核候选化合物。这些候选化合物目前或处于临床试验阶段或处于临床前研究阶段。
2007年,瑞士科学家马卡洛瓦等公开了一类2-位取代基为4,4-二烷氧基哌啶-1-基的4H-苯并[e][1,3]噻嗪-4-酮类化合物的合成与抗结核活性(WO2007/134625A1)。其代表物BTZ043具有体外广谱抗结核活性(AntimicrobAgentChemother,2010,54(4):1616-1618;2012,56(7):3984-3985),但因水溶性较差,BTZ043的体内活性远不如预期(EMBOMolMed,2014,6:372–383)。
2011年,瑞士科学家马卡洛瓦等进一步公开了一类2-位取代基为哌嗪-1-基的4H-苯并[e][1,3]噻嗪-4-酮类化合物的合成与抗结核活性(CN201180055813.5)。其代表物PBTZ169同样具有体外广谱抗结核活性,其体内活性显著强于BTZ043(EMBOMolMed,2014,6:372–383)。作为第二代苯并噻嗪-4-酮类抗结核候选物,PBTZ169目前已接近完成临床前研究。
本发明人进行了广泛的研究,设计合成了2-位含有各种烷氧亚胺基氮杂环片段的苯并噻嗪-4-酮类化合物,并测定了它们的抗结核活性。最终发现,不同于以往文献报道的2-位取代基为含有烷氧亚胺基的1-氮杂环烷基的6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮类化合物具有意想不到的强抗结核活性,与同类苯并噻嗪-4-酮类候选化合物PBTZ169以及一线抗结核药异烟肼和利福平相比,具有更加优越的抗结核活性。
发明内容
本发明的目的是提供一类由通式(I)表示的含有烷氧亚胺基取代的6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮类化合物,
其中:
R代表1-4个C原子的链烷基、4-7个C原子的环烷基、苯甲基、单取代苯甲基;
n1代表0-1,n2代表1-3。
本发明具体包括以下化合物:
2-[(3-甲氧亚胺基)吖丁啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
2-[(3-乙氧亚胺基)吖丁啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
2-[(3-苄氧亚胺基)吖丁啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
2-[(3-对甲氧基苯甲氧亚胺基)吖丁啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
2-[(3-环己基氧亚胺基)吖丁啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
2-[(3-甲氧亚胺基)吡咯烷-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
2-[(3-正丙氧亚胺基)吡咯烷-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
2-[(3-对三氟甲基苯甲氧亚胺基)吡咯烷-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
2-[(4-甲氧亚胺基)哌啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
2-[(4-乙氧亚胺基)哌啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
2-[(4-叔丁基氧亚胺基)哌啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
2-[(4-苄氧亚胺基)哌啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
2-[(4-对三氟甲基苯甲氧亚胺基)哌啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
2-[(4-对三氟甲氧基苯甲氧亚胺基)哌啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
2-[(4-对氟苯甲氧亚胺基)哌啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
2-[(3-对甲氧基苯甲氧亚胺基)哌啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
2-[(3-对三氟甲氧基苯甲氧亚胺基)哌啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
2-[(4-甲氧亚胺基)氮杂卓-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
本发明还涉及式(I)化合物的制备方法,如反应路线1所示。
反应路线1:
在反应路线1中,R、n1和n2如前述的定义。
在质子性溶剂中加入缚酸剂,使式(II)化合物与式(III)化合物通过缩合反应来制备式(I)化合物。用于本反应的质子性溶剂选自水、醇或醇-水混合溶剂;所述的缚酸剂选自三乙胺、碳酸钠、碳酸氢钠、碳酸钾、氢氧化钠或氢氧化钾。
在本发明中用作起始物的式(II)化合物为已知化合物,并参考现有出版物中已知的方法可容易地制得,例如CN201180055813.5。
按照下述反应路线2所示的方法,可制备本发明的另一起始物的式(III)化合物。
反应路线2:
在反应路线2中,R、n1和n2如前述的定义。
在质子性溶剂中加入缚酸剂,使式(IV)化合物与式(V)化合物通过缩合反应来制备式(III)化合物。用于本反应的质子性溶剂选自水、醇或醇-水混合溶剂;所述的缚酸剂选自碳酸钠、碳酸钾、碳酸氢钠、氢氧化钠、氢氧化钾或三乙胺。
用作起始物的式(IV)化合物和式(V)化合物均为已知化合物,国内均有商品供应。
本发明还提供含有如上所定义的式(I)化合物作为活性成分的抗结核组合物。药物组合物含有的本发明化合物在组合物中的重量比为0.1~99.9%,药物可接受的载体在组合物中的重量比为0.1~99.9%。药物组合物以适合药用的制剂形式存在。本发明的药物组合物可以制备成任何可药用的剂型。优选的,药用的制剂为片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、缓释片剂、胶囊剂、硬胶囊剂、软胶囊剂、缓释胶囊剂、散剂。
本发明的药物组合物,作为制剂形式,每剂中含有的本发明化合物的有效量为0.1~1000mg,所述每剂指的是,每一制剂单位,如片剂的每片,胶囊的每粒,也可指每次服用剂量,如每次服用100mg。
本发明的药物组合物在制备成粉剂、片剂、可分散粉剂、胶囊、扁囊剂形式的固体药物制剂时,可使用固体载体。可使用的固体载体优选为选自稀释剂、调味剂、增溶剂、润滑剂、悬浮剂、粘合剂、膨胀剂等中的一种或多种物质,或可为包封物质。适宜的固体载体包括碳酸镁、硬脂酸镁、滑石粉、蔗糖、乳糖、果胶、糊精、淀粉、明胶、甲基纤维素、羧甲基纤维素钠、可可脂等。由于它们易于给药,片剂,粉剂、扁囊剂和胶囊等代表最有利的口服固体制剂。
为了易于给药及剂量均一,将上述药物制剂配制成剂量单位形式是特别有利的。制剂的剂量单位形式指适于作为单一剂量的物理分离单位,每个单位含有产生所期望的治疗效果的计算好的预定量的活性成分。这种剂量单位形式可为包装形式,如片剂、胶囊或装在小管或小瓶中的粉剂。
虽然剂量单位形式中所含活性成分的量可以变化,但一般根据所选择活性成分的效力,调节在1~800mg范围内。
当本发明的式(I)活性化合物用作治疗结核分枝杆菌感染的药物时,优选在第一阶段给以6~14mg/kg体重的量。但给药剂量可随着病人的需要、欲治疗的感染的严重性、所选化合物等而变化。
本领域技术人员可按常规方法确定适于某种情况的优选剂量。一般,开始治疗的量低于活性成分的最佳剂量,然后逐渐增加给药剂量,直到达到最佳治疗效果。为方便起见,总的日剂量可分为几部分,分数次给药。
本发明还提供式(I)所示化合物或含有该化合物的药物组合物在制备治疗结核病的药物中的应用。
本发明所述结核病包括活动性结核病、单耐药结核病、多耐药结核病以及广泛耐多药结核病。
本发明所述结核病包括肺结核、肺外结核。
如上所述,本发明化合物对结核分枝杆菌的活性远高于同类苯并噻嗪-4-酮类候选化合物PBTZ169以及一线抗结核药异烟肼和利福平。例如,实施例1,3,12和13化合物对结核分枝杆菌标准株H37RvATCC27294的体外活性是化合物PBTZ169、异烟肼和利福平的>2->10倍,对临床分离株MDR-MTB20161(对利福平和异烟肼耐药)的体外活性是化合物PBTZ169的10倍以上。
本发明的化合物相对于现有产品而言,在抗结核方面疗效更好,活性更高,副作用更低,合成过程操作也更加简单,有效降低成本,适合大规模生产。
具体实施方式
在以下实施例中,将更加具体地解释本发明。但应理解,下列实施例旨在说明本发明而不对本发明的范围构成任何限制。
实施例12-[(3-甲氧亚胺基)吖丁啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
3-吖丁啶酮盐酸盐(0.27g,2.5mmol)、甲氧胺盐酸盐(0.25g,3mmol)、碳酸钾(0.42g,3mmol)和无水乙醇(10ml)的混合物于室温下搅拌反应3h。过滤,滤液减压浓缩得白色固体(收率81%)。
将2-甲硫基-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮(0.16g,0.5mmol)溶于无水乙醇(8mL),加入三乙胺(0.10g,1.0mmol),滴加上述固体(0.14g,1.0mmol)的无水乙醇(10mL)溶液,于60℃搅拌反应1h过滤,滤液减压浓缩,残余物经柱层析分离得黄色固体(收率59%),mp:146-147℃。
1HNMR(500MHz,CDCl3)δ9.16(s,1H),8.82(s,1H),5.12-5.01(m,4H),3.95(s,3H).
MS-ESI(m/z):375(M+H)+。
实施例22-[(3-乙氧亚胺基)吖丁啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
同实施例1化合物的制备方法,3-吖丁啶酮盐酸盐先与乙氧胺盐酸盐发生缩合反应,然后再与2-甲硫基-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮缩合,得黄色固体(收率:55%),mp:151-152℃。
1HNMR(500MHz,CDCl3)δ9.16(s,1H),8.80(s,1H),5.13-5.01(m,4H),4.14-4.08(q,4H),1.29-1.25(t,3H).
MS-ESI(m/z):389(M+H)+。
实施例32-[(3-苄氧亚胺基)吖丁啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
同实施例1化合物的制备方法,3-吖丁啶酮盐酸盐先与苄氧胺盐酸盐发生缩合反应,然后再与2-甲硫基-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮缩合,得黄色固体(收率:53%),mp:182-184℃。
1HNMR(500MHz,CDCl3)δ9.16(s,1H),8.80(s,1H),7.02-6.92(m,5H),5.20(s,2H),5.15-5.03(m,4H).
MS-ESI(m/z):451(M+H)+。
实施例42-[(3-对甲氧基苯甲氧亚胺基)吖丁啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
同实施例1化合物的制备方法,3-吖丁啶酮盐酸盐先与3-对甲氧基苯甲氧胺盐酸盐发生缩合反应,然后再与2-甲硫基-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮缩合,得黄色固体(收率:54%)。
1HNMR(500MHz,CDCl3)δ9.16(s,1H),8.79(s,1H),7.38-7.31(m,4H),5.20(s,2H),5.15-5.03(m,4H),3.83(s,3H).
MS-ESI(m/z):481(M+H)+。
实施例52-[(3-环己基氧亚胺基)吖丁啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
同实施例1化合物的制备方法,3-吖丁啶酮盐酸盐先与3-环己基氧胺盐酸盐发生缩合反应,然后再与2-甲硫基-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮缩合,得黄色固体(收率:55%)。
1HNMR(500MHz,CDCl3)δ9.16(s,1H),8.79(s,1H),5.15-5.03(m,4H),3.17-3.12(m,1H),1.72-1.43(m,10H).
MS-ESI(m/z):443(M+H)+。
实施例62-[(3-甲氧亚胺基)吡咯烷-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
同实施例1化合物的制备方法,3-吡咯烷酮盐酸盐先与甲氧胺盐酸盐发生缩合反应,然后再与2-甲硫基-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮缩合,得黄色固体(收率:56%),mp:174-177℃。
1HNMR(500MHz,CDCl3)δ9.16(s,1H),8.80(s,1H),4.66(s,1H),4.46(s,1H),4.24-4.20(m,1H),4.04-3.92(m,4H),3.10-3.04(m,1H),2.96-2.90(m,1H).
MS-ESI(m/z):389(M+H)+。
实施例72-[(3-正丙氧亚胺基)吡咯烷-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
同实施例1化合物的制备方法,3-吡咯烷酮盐酸盐先与正丙氧胺盐酸盐发生缩合反应,然后再与2-甲硫基-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮缩合,得黄色固体(收率:58%)。
1HNMR(500MHz,CDCl3)δ9.16(s,1H),8.80(s,1H),4.66(s,1H),4.46(s,1H),4.25-4.18(m,2H),3.55-3.50(t,2H),3.12-3.04(m,1H),2.98-2.92(m,1H),1.53-1.48(m,2H),0.92-0.88(t,3H).
MS-ESI(m/z):417(M+H)+。
实施例82-[(3-对三氟甲基苯甲氧亚胺基)吡咯烷-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
同实施例1化合物的制备方法,3-吡咯烷酮盐酸盐先与对三氟甲基苯甲氧胺盐酸盐发生缩合反应,然后再与2-甲硫基-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮缩合,得黄色固体(收率:59%)。
1HNMR(500MHz,CDCl3)δ9.16(s,1H),8.80(s,1H),7.55-7.16(m,4H),4.90(s,2H),4.66(s,1H),4.46(s,1H),4.24-4.16(m,2H),3.10-3.04(m,1H),2.96-2.90(m,1H).
MS-ESI(m/z):533(M+H)+。
实施例92-[(4-甲氧亚胺基)哌啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
同实施例1化合物的制备方法,4-哌啶酮盐酸盐先与甲氧胺盐酸盐发生缩合反应,然后再与2-甲硫基-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮缩合,得黄色固体(收率:55%),mp:127-129℃。
1HNMR(500MHz,CDCl3)δ9.12(s,1H),8.78(s,1H),4.22(s,2H),4.01(s,3H),3.98(s,2H),2.79(s,2H),2.64(s,2H).
MS-ESI(m/z):403(M+H)+。
实施例102-[(4-乙氧亚胺基)哌啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
同实施例1化合物的制备方法,4-哌啶酮盐酸盐先与乙氧胺盐酸盐发生缩合反应,然后再与2-甲硫基-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮缩合,得黄色固体(收率:54%),mp:130-131℃。
1HNMR(500MHz,CDCl3)δ9.12(s,1H),8.78(s,1H),4.22(s,2H),4.14-4.08(q,4H),3.99(s,2H),2.79(s,2H),2.64(s,2H),1.29-1.25(t,3H).
MS-ESI(m/z):417(M+H)+。
实施例112-[(4-叔丁基氧亚胺基)哌啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
同实施例1化合物的制备方法,4-哌啶酮盐酸盐先与叔丁氧胺盐酸盐发生缩合反应,然后再与2-甲硫基-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮缩合,得黄色固体(收率:53%)。
1HNMR(500MHz,CDCl3)δ9.12(s,1H),8.78(s,1H),4.22(s,2H),4.01(s,2H),2.66(s,2H),2.52(s,2H).
MS-ESI(m/z):445(M+H)+。
实施例122-[(4-苄氧亚胺基)哌啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
同实施例1化合物的制备方法,4-哌啶酮盐酸盐先与苄氧胺盐酸盐发生缩合反应,然后再与2-甲硫基-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮缩合,得黄色固体(收率:59%),mp:160-162℃。
1HNMR(500MHz,CDCl3)δ9.12(s,1H),8.78(s,1H),7.38-7.31(m,5H),5.10(s,2H),4.20(s,2H),3.98(s,2H),2.83(s,2H),2.64(s,2H).
MS-ESI(m/z):479(M+H)+。
实施例132-[(4-对三氟甲基苯甲氧亚胺基)哌啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
同实施例1化合物的制备方法,4-哌啶酮盐酸盐先与对三氟甲基苯甲氧胺盐酸盐发生缩合反应,然后再与2-甲硫基-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮缩合,得黄色固体(收率:52%)。
1HNMR(500MHz,CDCl3)δ9.12(s,1H),8.78(s,1H),7.55-7.16(m,4H),4.90(s,2H),4.20(s,2H),3.63(s,2H),2.55(s,2H),2.04(s,2H).
MS-ESI(m/z):547(M+H)+。
实施例142-[(4-对三氟甲氧基苯甲氧亚胺基)哌啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
同实施例1化合物的制备方法,4-哌啶酮盐酸盐先与对三氟甲氧基苯甲氧胺盐酸盐发生缩合反应,然后再与2-甲硫基-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮缩合,得黄色固体(收率:54%)。
1HNMR(500MHz,CDCl3)δ9.12(s,1H),8.78(s,1H),7.01-6.92(m,4H),4.90(s,2H),4.18(s,2H),3.60(s,2H),2.55(s,2H),2.04(s,2H).
MS-ESI(m/z):563(M+H)+。
实施例152-[(4-对氟苯甲氧亚胺基)哌啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
同实施例1化合物的制备方法,4-哌啶酮盐酸盐先与对氟苯甲氧胺盐酸盐发生缩合反应,然后再与2-甲硫基-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮缩合,得黄色固体(收率:56%)。
1HNMR(500MHz,CDCl3)δ9.12(s,1H),8.78(s,1H),7.17-7.34(m,4H),4.90(s,2H),4.15(s,2H),3.57(s,2H),2.53(s,2H),2.04(s,2H).
MS-ESI(m/z):497(M+H)+。
实施例162-[(3-对甲氧基苯甲氧亚胺基)哌啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
同实施例1化合物的制备方法,3-哌啶酮盐酸盐先与对甲氧基苯甲氧胺盐酸盐发生缩合反应,然后再与2-甲硫基-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮缩合,得黄色固体(收率:48%)。
1HNMR(500MHz,CDCl3)δ9.12(s,1H),8.78(s,1H),7.11-7.01(m,4H),4.85(s,2H),3.95(s,3H),2.62-2.54(m,4H),2.34-2.25(m,2H),1.65-1.54(m,2H).
MS-ESI(m/z):509(M+H)+。
实施例172-[(3-对三氟甲氧基苯甲氧亚胺基)哌啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
同实施例1化合物的制备方法,3-哌啶酮盐酸盐先与对三氟甲氧基苯甲氧胺盐酸盐发生缩合反应,然后再与2-甲硫基-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮缩合,得黄色固体(收率:49%)。
1HNMR(500MHz,CDCl3)δ9.12(s,1H),8.78(s,1H),7.15-7.02(m,4H),4.86(s,2H),2.63-2.56(m,4H),2.35-2.25(m,2H),1.68-1.54(m,2H).
MS-ESI(m/z):564(M+H)+。
实施例182-[(4-甲氧亚胺基)氮杂卓-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮
同实施例1化合物的制备方法,4-氮杂卓酮盐酸盐先与甲氧胺盐酸盐发生缩合反应,然后再与2-甲硫基-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮缩合,得黄色固体(收率:56%),mp:126-129℃。
1HNMR(500MHz,CDCl3)δ9.12(s,1H),8.78(s,1H),4.02(s,2H),2.95(s,2H),2.35-2.12(m,3H),1.95-1.64(m,9H),1.34-1.02(m,7H).
MS-ESI(m/z):417(M+H)+。
生物实施例1
体外抗分枝杆菌活性试验
本发明化合物的抗结核活性是通过测定其对结核分枝杆菌标准株MTBH37RvATCC27294和临床分离株MDR-MTB20161(对利福平和异烟肼耐药)的最小抑菌浓度(MIC,μg/mL)来表示的。在该试验中,以同类苯并噻嗪-4-酮类候选化合物PBTZ169以及一线抗结核药异烟肼和利福平作对照药。最小抑菌浓度按如下方法测定:无菌48孔板(结核菌快速药敏专用微量培养板),按药敏试验设计要求,各孔分别加入用2倍浓度培养基(改良米氏7H9液体培养基)稀释的药物。各化合物制成适当浓度的的初溶液,用培养基(2×)稀释成各所用化合物的二倍浓度,每种化合物各10个梯度,加入48孔板每孔100μL,试验药的终浓度分别为8、4、2……0.015μg/mL。标准株H37RvATCC27294和临床分离株MDR-MTB20161,每孔接种100μl,每孔菌量为4×10-3mg。每板均设2个不含抗菌药的生长阳性对照孔和两个以蒸馏水替代培养基的生长阴性对照孔,将48孔板加盖后周围用透明胶带密封,置于湿盒37℃孵育。第3天后观察阳性生长对照孔和阴性生长对照孔,观察到两者有明确差别时,对各个试验孔细菌生长的数量和形态进行观察,判定抑制或耐药并记录结果,第7天后再观察记录一次进行确认。无菌生长的对照孔中所含药物最小的浓度即为最小抑菌浓度(MIC)。测定结果列于表1。
表1部分实施例化合物对2株结核分枝杆菌的体外活性
MTBa:MTBH37RvATCC27294
MDR-MTBb:MDR-MTB20161(对利福平和异烟肼耐药)
上述表中仅列举本发明部分化合物的体外活性,本发明其他化合物结构相似,也具有和上述化合物相同或者相近的体外活性效果,在此不一一列举。
生物实施例2
口服急性毒性试验
为测定本发明化合物的口服急性毒性,对实施例1化合物和实施例12化合物进行了急性毒性实验,将含不同浓度的这两个化合物的溶液口服给于雄性小鼠,剂量为0.1ml/10g体重,7日后分别记数死鼠量,用Bliss程序计算各化合物的半数致死量(LD50)。结果列于表2中。
表2实施例1和12化合物的小鼠口服急性毒性
实验化合物 | LD50(mg/kg) |
实施例1 | >2000 |
实施例12 | >2000 |
实验结果表明,这些化合物毒性很低,非常适合药用。
组合物实施例
实施例1包衣片
片芯处方:
取上述成分混合均匀,制粒后过筛整粒,干燥、压片制成100片片芯。包衣液处方:欧巴代(Opadry)5g,80%乙醇适量包衣。
实施例2胶囊
处方:
制备方法:
取处方量原辅料,分别过筛,加入5%聚乙烯吡咯烷酮醇液和吐温80制软材,用20目筛制粒,在室温15℃下晾干,加入十二烷基硫酸钠,混合均匀,按0.27g/S装入0号胃溶胶囊,取样化验,溶出限度为Q=80%,含量应为标示量的90~110%。
实施例3颗粒剂
取实施例9的化合物100g,加入适量糊精、甜菊素,干式制粒,整粒,分装,即得。
实施例4注射剂
取实施例4的化合物150g加水溶解,另氯化钠、对羟基苯甲酸乙酯加热水溶解,混匀,调pH值5-7。注射用水稀释至1000ml,用中空纤维膜滤过,灌装,灭菌,即得。
实施例5冻干粉针
取实施例16的化合物150g加水溶解,另加甘露醇500g加热水溶解,混匀,注射用水稀释至5000ml,用中空纤维膜滤过,灌装,灭菌,冻干即得冻干粉针。
实施例6滴丸
取实施例14的化合物20g作为原料药备用;称取滴丸基质200g,加热至80℃融化,搅拌均匀;边搅拌边将原料加入辅料基质中,搅拌30min使之均匀,保持药液温度不低于60℃;将配制好的药液注入滴丸机中,滴成滴丸,即可。
虽然,上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述,但在本发明基础上,可以对之作一些修改或改进,这对本领域技术人员而言是显而易见的。因此,在不偏离本发明精神的基础上所做的这些修改或改进,均属于本发明要求保护的范围。
Claims (10)
1.式(I)所示化合物,
其中:
R代表1-4个C原子的链烷基、4-7个C原子的环烷基、苄基、取代苯甲基;
n1代表0-1,n2代表1-3。
2.根据权利要求1所述的式(I)所示化合物,其特征在于,其化合物为:
2-[(3-甲氧亚胺基)吖丁啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮;
2-[(3-乙氧亚胺基)吖丁啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮;
2-[(3-苄氧亚胺基)吖丁啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮;
2-[(3-对甲氧基苯甲氧亚胺基)吖丁啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮;
2-[(3-环己基氧亚胺基)吖丁啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮;
2-[(3-甲氧亚胺基)吡咯烷-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮;
2-[(3-正丙氧亚胺基)吡咯烷-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮;
2-[(3-对三氟甲基苯甲氧亚胺基)吡咯烷-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮;
2-[(4-甲氧亚胺基)哌啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮;
2-[(4-乙氧亚胺基)哌啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮;
2-[(4-叔丁基氧亚胺基)哌啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮;
2-[(4-苄氧亚胺基)哌啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮;
2-[(4-对三氟甲基苯甲氧亚胺基)哌啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮;
2-[(4-对三氟甲氧基苯甲氧亚胺基)哌啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮;
2-[(4-对氟苯甲氧亚胺基)哌啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮;
2-[(3-对甲氧基苯甲氧亚胺基)哌啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮;
2-[(3-对三氟甲氧基苯甲氧亚胺基)哌啶-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮;
2-[(4-甲氧亚胺基)氮杂卓-1-基]-6-三氟甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮。
3.一种制备权利要求1或2所述式(I)化合物的方法,其特征在于,其包括如下步骤:
将式(Ⅱ)化合物与式(III)化合物,在质子性溶剂存在下并加入缚酸剂,用过量的式(III)化合物来满足需要,在-5℃~60℃,有或无压力条件下搅拌反应0.5~10小时,得式(I)化合物,
其中:
R、n1和n2的定义同权利要求1。
4.根据权利要求3所述式(I)化合物的制备方法,其特征在于,所述的质子性溶剂选自水、醇或醇-水混合溶剂;所述的缚酸剂选自三乙胺、碳酸钠、碳酸氢钠、碳酸钾、氢氧化钠或氢氧化钾。
5.权利要求1或2所述式(I)所示化合物在制备治疗结核病的药物中的应用。
6.含有权利要求1或2所述化合物的药物组合物在制备治疗结核病的药物中的应用。
7.权利要求5或6的应用,其特征在于,所述结核病包括活动性结核病、单耐药结核病、多耐药结核病以及广泛耐多药结核病。
8.权利要求5或6的应用,其特征在于,所述结核病包括肺结核、肺外结核。
9.以权利要求1或2所述化合物为活性成分的药物组合物。
10.根据权利要求9所述的药物组合物,其特征在于,该药物组合物制备成任何可药用的剂型,优选的剂型选自:片剂、胶囊剂、颗粒剂、糖浆剂、粉针剂、注射剂。
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108440446A (zh) * | 2018-04-02 | 2018-08-24 | 中国医学科学院医药生物技术研究所 | 含有肟基片段的苯并噻嗪-4-酮类化合物及其制备方法 |
CN108484601A (zh) * | 2017-03-02 | 2018-09-04 | 浙江司太立制药股份有限公司 | 含有2,8-二氮杂螺[4.5]癸烷片段的苯并噻嗪-4-酮类化合物及其制备方法 |
CN108530447A (zh) * | 2017-03-02 | 2018-09-14 | 浙江司太立制药股份有限公司 | 含有2,7-二氮杂螺[3.5]壬烷片段的苯并噻嗪-4-酮类化合物及其制备方法 |
CN108976227A (zh) * | 2017-06-02 | 2018-12-11 | 浙江司太立制药股份有限公司 | 含有碱性桥环片段的苯并噻嗪-4-酮类化合物及其制备方法 |
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007134625A1 (en) * | 2006-05-24 | 2007-11-29 | Leibniz Institute For Natural Product Research And Infection Biology E.V. Hans-Knöll-Institut (Hki) | New benzothiazinone derivatives and their use as antibacterial agents |
EP2468746A1 (en) * | 2010-12-23 | 2012-06-27 | The University of Queensland | Benzothiazinone compounds and their use as anti-tuberculosis agents |
EP2570413A1 (en) * | 2011-09-15 | 2013-03-20 | The University Of Queensland | Benzothiazinone derivatives as anti-tuberculosis agents |
CN103508980A (zh) * | 2012-06-14 | 2014-01-15 | 四川大学 | 苯并噻嗪-4-酮衍生物及其制备方法和用途 |
-
2016
- 2016-02-19 CN CN201610093216.6A patent/CN105622596B/zh active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007134625A1 (en) * | 2006-05-24 | 2007-11-29 | Leibniz Institute For Natural Product Research And Infection Biology E.V. Hans-Knöll-Institut (Hki) | New benzothiazinone derivatives and their use as antibacterial agents |
EP2468746A1 (en) * | 2010-12-23 | 2012-06-27 | The University of Queensland | Benzothiazinone compounds and their use as anti-tuberculosis agents |
EP2570413A1 (en) * | 2011-09-15 | 2013-03-20 | The University Of Queensland | Benzothiazinone derivatives as anti-tuberculosis agents |
CN103508980A (zh) * | 2012-06-14 | 2014-01-15 | 四川大学 | 苯并噻嗪-4-酮衍生物及其制备方法和用途 |
Non-Patent Citations (2)
Title |
---|
CHANG YONG HONG,等: "Novel Fluoroquinolone Antibacterial Agents Containing Oxime-Substituted (Aminomethyl)pyrrolidines: Synthesis and Antibacterial Activity of 7-(4-(Aminomethyl)-3-(methoxyimino)pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carb", 《J. MED. CHEM.》 * |
TOMISLAV KAROLI,等: "Identification of Antitubercular Benzothiazinone Compounds by Ligand-Based Design", 《J. MED. CHEM.》 * |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
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CN108530447A (zh) * | 2017-03-02 | 2018-09-14 | 浙江司太立制药股份有限公司 | 含有2,7-二氮杂螺[3.5]壬烷片段的苯并噻嗪-4-酮类化合物及其制备方法 |
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