CN113816924B - 一种基于炔基连接臂的苯并噻嗪酮衍生物及其制备方法与应用 - Google Patents
一种基于炔基连接臂的苯并噻嗪酮衍生物及其制备方法与应用 Download PDFInfo
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Abstract
本发明公开了一种基于炔基连接臂的苯并噻嗪酮衍生物及其制备方法与应用，为一种苯并噻嗪酮骨架上相连的侧链位置进行的创造性改进，得到新的苯并噻嗪酮衍生物，除了具有优异的抗菌性外，与现有苯并噻嗪酮衍生物相比，本发明基于炔基连接臂的苯并噻嗪酮衍生物具有明显优异的体内药代效果。
Description
技术领域
本发明属于小分子药物技术，具体涉及一种炔基作为连接臂的苯并噻嗪酮衍生物及其制备方法与应用。
背景技术
pBTZ169（phase II)是现在研发阶段具有较好应用效果的、以苯并噻嗪酮（BTZ)为骨架，靶向DprE1的抗结核药物，与现有临床一线用药异烟肼（MIC 0.5 μM）相比，具有明显体外抗菌优势，但是其水溶性、体内药代动力学性质差，导致成药性不好。现有技术对苯并噻嗪酮侧链位置进行改变，尤其对哌嗪环进行变化，得到的一系列的化合物，与临床一线用药异烟肼相比，MIC值明显降低。对于药物应用，除了体外效果外，体内效果更为重要。
发明内容
本发明公开了侧链用炔基做连接臂的苯并噻嗪酮衍生物及其制备方法与应用，对与苯并噻嗪酮骨架上相连的侧链位置进行创造性改进，得到新的苯并噻嗪酮衍生物，除了具有优异的抗菌性外，尤其具有非常好的体内药代动力学方面的性质。
本发明采用如下技术方案：
一种基于炔基连接臂的苯并噻嗪酮衍生物，具有以下化学结构式：
本发明公开了上述基于炔基连接臂的苯并噻嗪酮衍生物的制备方法，将化合物A4与含有炔基的胺化合物进行环合反应，得到基于炔基连接臂的苯并噻嗪酮衍生物。
化合物A4的结构式如下：
含有炔基的胺化合物的结构式如下：
本发明中，R1为氢或者烷基，如甲基、乙基或氘代甲基，三氟甲基等；m =1～3，比如1、2或者3；n=0～3，比如0、1、2或者3；R2为烷基、芳基或者杂环基，比如开链或环状饱和烷基、苯环或取代的苯环、吡啶环、噻吩环，炔基等；R3为三氟甲基、卤素、砜基、亚砜基、硝基、氰基、磺酰胺基等。
优选的，R1为氢或者甲基、乙基，R2为苯环或取代的苯环；此结构下，化合物具有更佳的技术效果，最优选的，R2的取代的苯环中，取代基为卤素，优选为氟，取代基为1～5个；在具有最佳抗菌性能的同时具有好的体内药代效果。
本发明中，化合物A4与含有炔基的胺化合物在室温下反应，得到基于炔基连接臂的苯并噻嗪酮衍生物。
本发明基于炔基连接臂的苯并噻嗪酮衍生物用于抗菌药物，可以治疗结核菌或其他杆菌对人或其他哺乳动物感染后的治疗；因此本发明公开了上述侧链含有炔基做链接臂的苯并噻嗪酮衍生物在制备抗菌药物中的应用，菌株优选为杆菌，所述杆菌包括但不局限于结核菌、多药耐药或广谱耐药结核菌；还包括麻风杆菌、棒状杆菌或者诺卡式菌。
本发明所公开的侧链含有炔基做链接臂的苯并噻嗪酮衍生物，是在前期工作基础上付出创造性劳动的结果。相比之前公开的化合物，本发明的侧链含有炔基做链接臂的苯并噻嗪酮衍生物体外抗菌活性进一步提高，最小抑制浓度甚至达到1.0 ng/mL，更主要的是，本发明侧链用炔基做连接臂的苯并噻嗪酮衍生物较现有PBTZ169具有明显优异的体内药物代谢性能。
附图说明
图1为化合物WXM-1-33体内代谢图。
具体实施方式
本发明的原料为现有化合物，具体制备操作方法以及性能测试方法为现有方法，也为常规方法。本发明的创造性在于保持苯并噻嗪酮骨架结构，创造性的改变链接臂以及侧链基团的结构，得到的新型侧链含有炔基做链接臂的苯并噻嗪酮衍生物具有优异的抗菌性能，并具有明显优异的体内药物代谢性能。
实施例一
化合物A4中，R3为三氟甲基；含有炔基的胺化合物的结构式如下：
R1为氢或者烷基，如甲基、乙基或氘代甲基，三氟甲基等；m =1～3，n=0～3；R2为烷基、芳基或者杂环基，比如开链或环状饱和烷基、苯环或取代的苯环、吡啶环、噻吩环等。
侧链含有炔基做链接臂的苯并噻嗪酮的制备方法具体如下：
将化合物2-氯-5-三氟甲基苯甲酸A1（1.0 g，4.45 mmol）溶在50 mL浓硫酸中，随后在0℃下加入硝酸钾（900 mg，8.91 mmol）。然后在90 ℃下继续搅拌，TLC板监测，3 h反应结束。将反应体系冷却至室温，倒入冰水中，析出大量白色固体，过滤，冰水洗涤三次得白色固体化合物A2（1.1 g，产率: 91%），Rf =0.2，二氯甲烷/甲醇=50:1；
搅拌下将化合物A2（400 mg，1.63 mmol）溶于25 mL重蒸二氯甲烷中，随后加入草酰氯（216 mg，5.79 mmol）以及0.163当量的DMF，室温下反应，TLC板监测1小时反应完全。旋干溶剂，得相应的酰氯中间体A3，直接进行下一步反应。将A3溶在干燥的DCM（20mL）中，氮气保护，随后加入2滴聚乙二醇，再向上述溶液中滴加硫氰酸铵（225 mg，2.97 mmol）的无水丙酮溶液，室温下反应，TLC板监测20分钟反应完全，得到中间体化合物异硫氰酸脂A4。不经纯化，直接用于下一步反应。向前述A4体系中加入含有炔基的胺化合物（1.63 mmol），室温下反应，TLC板监测至反应完全。将反应液减压浓缩，残余物用水（30 mL）稀释，二氯甲烷（50mL×3）萃取，无水硫酸钠干燥，过滤，浓缩，柱层析（PE:EA=1:1）得终产物，具体化合物结构式、核磁氢谱、高分辨质谱的表征、MIC值如下。
SR-2-168。1H NMR indicates 3:1 atropisomeric ratio through theintegral value of – CH2 protons; 1H NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 8.80(s, 1H), 7.71 (s, 1H), 7.64 (t, J=8.0,2H), 7.45 (br, 1H), 4.99 (s, 1.5H,major), 4.77 (s, 0.5H, minor), 3.51 (s, 3H). HRMS(+ESI)m/z calcd forC20H12F3N4O3S+ [M+H]+= 445.0577, found 445.0571. MIC为0.012μg/mL。
SR-2-170。1H NMR indicates 3:1 atropisomeric ratio through theintegral value of – CH2 protons; 1H NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 8.79(s, 1H), 7.42 (s, 1H), 7.31 (br, 2H), 7.25 – 7.20 (m, 1H), 4.98 (s, 1.5H,major), 4.73 (s, 0.5H), 3.50 (s, 3H). HRMS(+ESI)m/z calcd for C19H12F3N3O3ClS+[M+H]+= 454.0235, found 454.0227. MIC为0.006μg/mL。
SR-2-171。1H NMR indicates 3:1 atropisomeric ratio through theintegral value of – CH2 protons1H NMR (400 MHz, CDCl3)δ 9.14 (s, 1H), 8.78 (s,1H), 7.22 (br, 1H), 7.03 (br, 1H), 6.95 (s, 1H), 6.90 (br, 1H), 4.99 (s,1.5H, major), 4.72 (s, 0.5H, minor), 3.79 (s, 3H), 3.51 (s, 3H). HRMS(+ESI)m/ z calcd for C20H15F3N3O4S+ [M+H]+= 450.0730, found 450.0721. MIC为0.042μg/mL。
SR-2-177。1H NMR indicates 3:1 atropisomeric ratio through theintegral value of – CH2 protons;1H NMR (400 MHz, CDCl3) δ9.14 (s, 1H), 8.79(s, 1H), 7.49 (d, J = 6.0 Hz, 1H), 7.35 – 7.28 (m, 1H), 7.09 (t, J = 8.4 Hz,1H), 4.97 (s, 1.5H, major), 4.71 (s, 0.5H, minor), 3.50 (s, 3H). HRMS(+ESI)m/ z calcd for C19H11F4N3O3ClS+ [M+H]+= 472.0140, found 472.0132。MIC为0.006μg/mL。
SR-2-178。1H NMR indicates 3:1 atropisomeric ratio through theintegral value of – CH2 protons 1H NMR (400 MHz, CDCl3) δ9.12 (s, 1H), 8.77(s, 1H), 4.76 (s, 1.5H, major), 4.46 (s, 0.5H, minor), 3.43 (s, 3H), 2.39 (s,1H), 1.79 – 1.75 (m, 2H), 1.72 – 1.63 (m, 2H), 1.60 (s, 1H), 1.53 – 1.48 (m,1H), 1.46 – 1.38 (m, 2H), 1.31 – 1.27 (m, 2H). HRMS(+ESI)m/z calcd forC19H19F3N3O3S+ [M+H]+= 426.1094, found 426.1089。MIC为0.001μg/mL。
SR-2-181。1H NMR indicates 3:1 atropisomeric ratio through theintegral value of – CH2 protons 1H NMR (400 MHz, CDCl3) δ 9.13 (s, 1H), 8.77(d, J = 1.5 Hz, 1H), 4.74 (s, 1.5H, major), 4.44 (s, 0.5H, minor), 3.42 (s,3H), 1.22 (s, 9H). HRMS(+ESI)m/z calcd for C17H17F3N3O3S+ [M+H]+= 400.0937,found 400.0932. MIC为0.010μg/mL。
WXM-1-33.1H NMR indicates 3:1 atropisomeric ratio through theintegral value of – CH2 protons;1H NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 8.79(s, 1H), 7.44 (d, J = 6.4 Hz, 2H), 7.33 – 7.31(m, 3H), 5.00 (s, 1.5H, major),4.72 (s, 0.5H, minor), 3.52 (s, 3H). HRMS(+ESI)m/z calcd for C19H13F3N3O3S+ [M+H]+= 420.0624, found 420.0620。MIC为0.003μg/mL。
WXM-1-81。1H NMR indicates 3:1 atropisomeric ratio through theintegral value of – CH2 protons;1H NMR (400 MHz, CDCl3)δ 9.14 (s, 1H), 8.78(s, 1H), 7.42 (t, J = 7.2 Hz, 1H), 7.35 – 7.30 (m, 1H), 7.11 – 7.05 (m, 2H),5.03 (s, 1.5H, major), 4.81 (s, 0.5H, minor), 3.52 (s, 3H). HRMS(+ESI)m/zcalcd for C19H12F4N3O3S+ [M+H]+= 438.0530, found 438.0520. MIC为0.005μg/mL。
WXM-1-84。1H NMR indicates 3:1 atropisomeric ratio through theintegral value of – CH2 protons; 1H NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 8.79(s, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 4.98 (s, 1.5H,major), 4.74 (s, 0.5H, minor), 3.50 (s, 3H). HRMS(+ESI)m/z calcd forC19H12F3N3O3ClS+ [M+H]+= 454.0235, found 454.0226。MIC为0.008μg/mL。
WXM-1-86。1H NMR (400 MHz, CDCl3) δ9.12 (s, 1H), 8.78 (s, 1H), 4.75 (s,2H), 3.45 (s, 3H), 2.38 (s, 1H). HRMS(+ESI)m/z calcd for C13H8F3N3O3S+ [M+H]+=344.0311, found 344.0307. MIC为0.479 μg/mL。
WXM-1-95。1H NMR indicates 3:1 atropisomeric ratio through theintegral value of – CH2 protons; 1H NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 8.78(s, 1H), 7.25 (s, 1H), 7.22 (d, J = 4.8 Hz, 1H), 7.19 (d, J = 7.4 Hz, 1H),7.15 (d, J = 7.2 Hz, 1H), 4.99 (s, 1.5H, major), 4.73 (s, 0.5H, minor), 3.51(s, 3H), 2.32 (s, 3H). HRMS(+ESI)m/z calcd for C20H15F3N3O3S+ [M+H]+= 434.0781,found 434.0774。MIC为0.012μg/mL。
WXM-1-96。1H NMR indicates 3:1 atropisomeric ratio through theintegral value of – CH2 protons; 1H NMR (400 MHz, CDCl3) δ 9.13 (s, 1H), 8.77(s, 1H), 7.34 – 7.32 (s, 2H), 7.30 (br, 2H), 7.25 – 7.21 (m, 1H), 4.80 (s,1.5H, major), 4.55 (s, 0.5H, minor), 3.63 (s, 2H), 3.45 (s, 3H). HRMS(+ESI)m/ z calcd for C20H15F3N3O3S+ [M+H]+= 434.0781, found 434.0776。MIC为0.023μg/mL。
WXM-1-97。1H NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 8.79 (s, 1H), 7.61(d, J = 8.2 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H), 5.00 (s, 2H), 3.51 (s, 3H).HRMS(+ESI)m/z calcd for C20H12F3N4O3S+ [M+H]+= 445.0577, found 445.0571。MIC为0.046μg/mL。
WXM-1-100。1H NMR indicates 3:1 atropisomeric ratio through theintegral value of – CH2 protons; 1H NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 8.78(s, 1H), 7.42 (dd, J = 8.2, 5.6 Hz, 2H), 7.01 (t, J = 8.6 Hz, 2H), 4.97 (s,1.5H, major), 4.78 (m, 0.5H, minor), 3.50 (s, 3H). HRMS(+ESI)m/z calcd forC19H12F4N3O3S+ [M+H]+= 438.0530, found 438.0524。MIC为0.006μg/mL。
WXM-1-103。1H NMR indicates 3:1 atropisomeric ratio through theintegral value of – CH2 protons; 1H NMR (400 MHz, CDCl3)δ 9.14 (s, 1H), 8.79(s, 1H), 7.22 – 7.20 (m, 1H), 7.14 – 7.10 (m, 2H), 4.97 (s, 1.5H, major),4.72 (s, 0.5H, minor), 3.50 (s, 3H). HRMS(+ESI)m/z calcd for C19H11F5N3O3S+ [M+H]+= 456.0436, found 456.0428。MIC为0.006μg/mL。
WXM-1-104。1H NMR indicates 3:1 atropisomeric ratio through theintegral value of – CH2 protons; 1H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 8.65(s, 1H), 7.12 (br, 1H), 6.70 (br, 2H), 4.87 (s, 1.5H,major), 4.61 (s, 0.5H,minor), 3.37 (s, 3H). HRMS(+ESI)m/z calcd for C19H11F5N3O3S+ [M+H]+= 456.0436,found 456.0430. MIC为0.003μg/mL。
WXM-1-116。1H NMR indicates 3:1 atropisomeric ratio through theintegral value of – CH2 protons; 1H NMR (400 MHz, CDCl3) δ 9.15 (s, 1H), 8.79(s, 1H), 7.33 – 7.27 (m, 1H), 7.22 (d, J = 7.0 Hz, 1H), 7.13 (d, J = 8.8 Hz,1H), 7.06 (t, J = 7.4 Hz, 1H), 4.99 (s, 1.5H, major), 4.71 (s, 0.5H, minor),3.51 (s, 3H). HRMS(+ESI)m/z calcd for C19H12F4N3O3S+ [M+H]+= 438.0530, found438.0522。MIC为0.006μg/mL。
WXM-1-118。1H NMR (400 MHz, CDCl3) δ9.14 (s, 1H), 8.79 (s, 1H), 7.28(d, J = 5.0 Hz, 1H), 7.24 (d, J = 3.2 Hz, 1H), 6.99 – 6.96 (m, 1H), 5.10 –4.60 (m, 2H), 3.50 (s, 3H). HRMS(+ESI)m/z calcd for C17H11F3N3O3S2 + [M+H]+=426.0188, found 426.0184。MIC为0.007μg/mL。
WXM-1-122。1H NMR indicates 3:1 atropisomeric ratio through theintegral value of – CH2 protons;1H NMR (400 MHz, CDCl3) δ9.13 (s, 1H), 8.77(s, 1H), 4.75 (s,1.5H, major), 4.45 (s, 0.5H, minor), 3.42 (s, 3H), 2.65 –2.55 (m, 1H), 1.96 – 1.86 (m, 2H), 1.75 – 1.67 (m, 2H), 1.62 – 1.59 (m, 3H),1.54 – 1.47 (s, 1H). HRMS(+ESI)m/z calcd for C19H17F3N3O3S+ [M+H]+=412.0937,found 412.0926。MIC为0.002μg/mL。
FDG-4-4。1H NMR (400 MHz, CDCl3) δ9.13 (s, 1H), 8.78 (s, 1H), 7.32 –7.25 (m, 2H), 6.94 – 6.92 (m, 3H), 4.79 (s, 2H), 4.72 (s, 2H), 3.37 (s, 3H).HRMS(+ESI)m/z calcd for C19H15F3N3O4S+ [M+H]+= 450.0730, found 450.0723。MIC为0.014μg/mL。
WXM-1-181。1H NMR indicates 3:1 atropisomeric ratio through theintegral value of – CH2 protons 1H NMR (300 MHz, CDCl3) δ 9.13 (s, 1H), 8.77(s, 1H), 4.70(s,1.5H,major), 4.42 (s, 0.5H, minor), 3.41 (s, 3H), 1.25 – 1.23(m, 1H), 0.80 – 0.77 (m, 2H), 0.70 – 0.69 (m 2H). HRMS(+ESI)m/z calcd for:C16H13F3N3O3S+[M+H]+= 384.0624, found 384.0630. MIC为0.008μg/mL。
SR-3-39。1H NMR(300 MHz,CDCl3) δ 9.13(s, 1H),8.79(s, 1H), 4.75(s, 2H),3.45(s, 3H), 2,38(s, 1H); HRMS calcd for: C15H9F3N3O3S+ = 368.0311, found368.0317; MIC为：0.121μg/mL。
SR-3-40。 1H NMR(300 MHz,CDCl3) δ 9.13（s, 1H）,8.79(s, 1H), 4.80(s, 2H),3.43(s, 3H), 1.30-1.33(m, 1H), 0.83-0.86(m, 4H); HRMS calcd for: C18H13F3N3O3S+= 408.0624, found 408.0620; MIC为：0.065μg/mL。
抗结核分枝杆菌活性的测定。抗菌实验采用微孔板阿尔玛蓝（Alamar Blue）显色法，为现有常规测试方法。实验步骤简述如下：刮取罗氏培养基上生长4周的结核菌株H37Rv（购自ATCC25618的标准株）的菌落至含5% 吐温80的磨菌瓶中，涡旋震荡20 s使菌分离。磨菌瓶研磨均匀，静置20 min，加生理盐水，与1号比浊管比浊至相同浓度，然后1:20的比例与含有7H9 培养液（10% vol/vol) OADC和0.2%（vol/vol) 甘油）混合。上述所制备的苯并噻嗪酮衍生物配置1mg/mL的 DMSO母液，然后用培养基倍比稀释，最终测试浓度为0.2-0.001μg/mL，没有抑制剂的孔为阴性对照，异烟肼为阳性对照。含有化合物与菌的96孔板在37oC孵育箱中培养8天后，用阿尔玛蓝试剂盒检测，确定化合物的MIC值。
肝微粒体代谢实验：将测试化合物（1.0 μM）与人源肝微粒体（0.2mg/mL）在100mM, pH7.4的磷酸缓冲液中一起孵育10min。 然后加入NADPH（1.0 MM）引发反应，随后在0、5、15、30、45 min 进行取样。将样品放入含有内标的100 μL冷乙腈中终止反应，然后将样品在13,000 rpm 下离心10min。对上清液进行LC-MS/MS分析，绘制药物浓度-时间曲线，计算化合物体外肝微粒体代谢的半衰期。
表1 不同苯并噻嗪酮衍生物的MIC值（ng/mL）和人源肝微粒代谢半衰期
小鼠体内药代动力学实验：将测试化合物按照10 mg/kg 给BALB/C小鼠口服，每组3只小鼠进行平行实验，所有实验都符合苏州大学动物实验规定。在给药前和给药后15min, 30 min, 1h, 2h, 4h, 6h, 8h 和24h, 静脉采血0.25mL。加入肝素钠抗凝，血样在4℃下8000转/分钟转速离心分离血浆6分钟。对收集的血浆取1.0 μL上清液用于LC-MS/MS分析，三组检测结果取平均值，绘制平均药物浓度-时间曲线，计算相关药代动力学参数，结果见表2。表中的Cmax说明在同样的给药剂量下, 本发明化合物是PBTZ169的15倍(12893/863=14.9), 意味着给药剂量在降低15倍的情况下，体内可以达到同样的药物浓度。另外一个优势参数是药时曲线下面积 AUC0-∞，本发明化合物是PBTZ169的50倍（60218/1188=50.7），同样意味着给低于50倍的剂量在体内也能达到相同的药物浓度。
图1是WXM-1-33体内代谢图，剂量10mg/kg, 给药方式：口服；小鼠：BALB/C，纵坐标为血药浓度、横坐标为时间。可以看出，本发明化合物药物达到最高峰值的时间合适，药物起效快，血药浓度24小时后极低，药物在体内清除较彻底。
抗结核病(TB)新药的研发一直在进行，具有全新结构骨架和作用机制的贝达哇琳和德拉曼尼先后被批准用于临床治疗耐多药TB (MDR-TB )，但由于存在诱发心律失常的风险，二者的临床应用受到很大限制。因此，开发安全有效的抗TB新药是本领域研究人员的目标。现有技术中，PBTZ169被认为具有好的技术效果，诸多新的苯并噻嗪酮衍生物的研发也以此作为对比，本发明公开了新的苯并噻嗪酮衍生物，MIC值低至1ng/mL，特别的，相比PBTZ169，相同剂量下药物在体内的浓度更高（Cmax和AUC更大，意味着潜在更低的给药剂量），利于实际应用。
Claims (7)
1.一种基于炔基连接臂的苯并噻嗪酮衍生物，其特征在于，具有以下化学结构式：
其中，R1为氢或者烷基；m =1～3，n=0～3；R2为开链或环状饱和烷基、苯环或取代的苯环、噻吩环、炔基中的一种；R3为三氟甲基。
2.在根据权利要求1所述基于炔基连接臂的苯并噻嗪酮衍生物，其特征在于，R1为甲基或乙基。
3.权利要求1所述基于炔基连接臂的苯并噻嗪酮衍生物的制备方法，其特征在于，将化合物A4与含有炔基的胺化合物进行环合反应，得到基于炔基连接臂的苯并噻嗪酮衍生物；化合物A4的结构式如下：
含有炔基的胺化合物的结构式如下：
其中，R1为氢或者烷基；m =1～3，n=0～3；R2为开链或环状饱和烷基、苯环或取代的苯环、噻吩环、炔基中的一种；R3为三氟甲基。
4.根据权利要求3所述基于炔基连接臂的苯并噻嗪酮衍生物的制备方法，其特征在于，R1为甲基或乙基。
5.根据权利要求3所述基于炔基连接臂的苯并噻嗪酮衍生物的制备方法，其特征在于，化合物A4与含有炔基的胺化合物在室温下反应，得到基于炔基连接臂的苯并噻嗪酮衍生物。
6.权利要求1所述基于炔基连接臂的苯并噻嗪酮衍生物在制备抗杆菌药物中的应用，其特征在于，所述杆菌为结核菌、多药耐药或广谱耐药结核菌。
7.含有权利要求1所述基于炔基连接臂的苯并噻嗪酮衍生物的组合物在制备抗杆菌药物中的应用，其特征在于，所述杆菌为结核菌、多药耐药或广谱耐药结核菌。
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