WO2023065182A1 - 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 PDF

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WO2023065182A1
WO2023065182A1 PCT/CN2021/125101 CN2021125101W WO2023065182A1 WO 2023065182 A1 WO2023065182 A1 WO 2023065182A1 CN 2021125101 W CN2021125101 W CN 2021125101W WO 2023065182 A1 WO2023065182 A1 WO 2023065182A1
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alkynyl
linking arm
benzothiazinone
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group
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乔春华
吴小美
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苏州大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • 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
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
    • C07D279/08—1,3-Thiazines; Hydrogenated 1,3-thiazines condensed with carbocyclic rings or ring systems
    • 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

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  • the invention belongs to the small-molecule drug technology, and specifically relates to a benzothiazinone derivative with an alkynyl group as a connecting arm, a preparation method and application thereof.
  • pBTZ169 phase II is an anti-tuberculosis drug targeting DprE1 with benzothiazinone (BTZ) as the backbone, which has a good application effect in the research and development stage. It is compatible with the existing clinical first-line drug isoniazid (MIC 0.5 ⁇ M), it has obvious antibacterial advantages in vitro, but its water solubility and in vivo pharmacokinetic properties are poor, resulting in poor druggability. In the prior art, the positions of the side chains of benzothiazinone, especially the piperazine ring are changed, and a series of compounds are obtained. Compared with isoniazid, the first-line clinical drug, the MIC value is significantly lower. For pharmaceutical applications, in addition to in vitro effects, in vivo effects are more important.
  • the invention discloses a benzothiazinone derivative whose side chain uses an alkynyl group as a connecting arm, a preparation method and an application thereof, and creatively improves the position of the side chain connected to the benzothiazinone skeleton to obtain a new benzothiazinone derivative.
  • Buprofezin derivatives in addition to their excellent antibacterial properties, especially have very good in vivo pharmacokinetic properties.
  • a benzothiazinone derivative based on an alkynyl linking arm has the following chemical structural formula: .
  • the invention discloses a method for preparing the above-mentioned benzothiazinone derivatives based on an alkynyl linking arm.
  • Compound A4 is subjected to a ring closure reaction with an amine compound containing an alkynyl group to obtain a derivative of benzothiazinone based on an alkynyl linking arm. things.
  • the structural formula of the amine compound containing alkynyl is as follows: .
  • R 1 is hydrogen or methyl, ethyl
  • R 2 is a benzene ring or a substituted benzene ring; under this structure, the compound has a better technical effect, most preferably, in the substituted benzene ring of R 2 ,
  • the substituent is halogen, preferably fluorine, and there are 1 to 5 substituents; it has good pharmacokinetic effect in vivo while having the best antibacterial performance.
  • compound A4 reacts with an alkynyl-containing amine compound at room temperature to obtain a benzothiazinone derivative based on an alkynyl linking arm.
  • the benzothiazinone derivatives based on the alkynyl linking arm of the present invention are used for antibacterial drugs, and can treat tuberculosis or other bacillus infection of humans or other mammals;
  • the application of the benzothiazinone derivatives of the linked arms in the preparation of antibacterial drugs, the bacterial strain is preferably Bacillus, which includes but not limited to Mycobacterium tuberculosis, multidrug-resistant or broad-spectrum drug-resistant Mycobacterium tuberculosis; also includes Bacillus leprae , Corynebacterium or Nocardia.
  • the benzothiazinone derivatives with side chains containing alkynyl groups as linking arms disclosed in the present invention are the result of creative work based on previous work. Compared with the previously disclosed compounds, the in vitro antibacterial activity of the benzothiazinone derivatives containing alkyne groups in the side chain of the present invention is further improved, and the minimum inhibitory concentration even reaches 1.0 ng/mL, and more importantly, the benzothiazinone derivatives whose side chains use alkyne groups as linking arms of the present invention have significantly better drug metabolism properties in vivo than the existing PBTZ169.
  • Fig. 1 is a metabolic map of compound WXM-1-33 in vivo.
  • the raw materials of the present invention are existing compounds, and the specific preparation operation methods and performance testing methods are existing methods and also conventional methods.
  • the inventiveness of the present invention lies in maintaining the skeleton structure of benzothiazinone, creatively changing the structure of linking arms and side chain groups, and the obtained novel benzothiazin derivatives with alkynyl groups as linking arms have excellent antibacterial properties performance, and has obviously excellent in vivo drug metabolism performance.
  • R 3 is trifluoromethyl;
  • the structural formula of the amine compound containing alkynyl is as follows: .
  • the preparation method of benzothiazinone with an alkynyl group as a linking arm in the side chain is as follows: the compound 2-chloro-5-trifluoromethylbenzoic acid A1 (1.0 g, 4.45 mmol) was dissolved in 50 mL of concentrated sulfuric acid, Potassium nitrate (900 mg, 8.91 mmol) was then added at 0 °C. Stirring was then continued at 90 °C, monitored by a TLC plate, and the reaction was completed in 3 h.
  • the antibacterial experiment adopts the microplate Alamar Blue (Alamar Blue) chromogenic method, which is an existing routine test method.
  • Alamar Blue Alamar Blue
  • the experimental procedure is briefly described as follows: Scrape the colony of tuberculosis strain H37Rv (standard strain purchased from ATCC25618) grown on Roche’s medium for 4 weeks into a grinding bottle containing 5% Tween 80, and vortex for 20 s to separate the bacteria . Grind the bacteria grinding bottle evenly, let it stand for 20 minutes, add physiological saline, and compare the turbidity with No.
  • Pharmacokinetics experiment in mice The test compound was orally administered to BALB/C mice at 10 mg/kg, and parallel experiments were performed on 3 mice in each group. All experiments were in accordance with the regulations on animal experiments of Soochow University. Before administration and 15 minutes, 30 minutes, 1h, 2h, 4h, 6h, 8h and 24h after administration, 0.25mL of blood was collected by vein. Heparin sodium was added for anticoagulation, and the blood samples were centrifuged at 8000 rpm at 4°C for 6 minutes to separate the plasma. Take 1.0 ⁇ L supernatant from the collected plasma for LC-MS/MS analysis, take the average of the test results of the three groups, draw the average drug concentration-time curve, and calculate the relevant pharmacokinetic parameters.
  • the results are shown in Table 2.
  • TB anti-tuberculosis
  • MDR-TB multidrug-resistant TB
  • PBTZ169 is considered to have a good technical effect, and the research and development of many new benzothiazinone derivatives are also used as a comparison.
  • the present invention discloses new benzothiazinone derivatives with an MIC value as low as 1ng/mL, in particular, compared with PBTZ169, the concentration of the drug in the body is higher at the same dose (larger C max and AUC, which means a potentially lower dosage), which is conducive to practical application.

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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

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 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。
 技术问题
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。
 技术解决方案
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：
Figure 876343dest_path_image001
。
   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。
合物A4的结构式如下：  
Figure 502497dest_path_image002
。
含有炔基的胺化合物的结构式如下：
Figure 92878dest_path_image003
。
本发明中，R 1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；R 2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；R 3为三氟甲基、卤素、砜基、亚砜基、硝基、氰基、磺酰胺基等。
优选的，R 1为氢或者甲基、乙基，R 2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，R 2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。
 有益效果
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。
 本发明的实施方式
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。
Figure 462680dest_path_image004
。
化合物A4中，R 3为三氟甲基；含有炔基的胺化合物的结构式如下：
Figure 618854dest_path_image003
。
R 1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；R 2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%），R f =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（50 mL×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。
Figure 619172dest_path_image005
。
SR-2-168。 1H NMR indicates 3:1 atropisomeric ratio through the integral value of – CH 2 protons; 1H NMR (400 MHz, CDCl 3) 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 for C 20H 12F 3N 4O 3S + [M+H] += 445.0577, found 445.0571. MIC为0.012μg/mL。
Figure 493587dest_path_image006
。
SR-2-170。 1H NMR indicates 3:1 atropisomeric ratio through the integral value of – CH 2 protons; 1H NMR (400 MHz, CDCl 3) 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 C 19H 12F 3N 3O 3ClS + [M+H] += 454.0235, found 454.0227. MIC为0.006μg/mL。
Figure 667079dest_path_image007
。
SR-2-171。 1H NMR indicates 3:1 atropisomeric ratio through the integral value of – CH 2 protons 1H NMR (400 MHz, CDCl 3) 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 C 20H 15F 3N 3O 4S + [M+H] += 450.0730, found 450.0721. MIC为0.042μg/mL。
Figure 881023dest_path_image008
。
SR-2-177。 1H NMR indicates 3:1 atropisomeric ratio through the integral value of – CH2 protons;1H NMR (400 MHz, CDCl 3) 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 C 19H 11F 4N 3O 3ClS + [M+H] += 472.0140, found 472.0132。MIC为0.006μg/mL。
Figure 114558dest_path_image009
。
SR-2-178。 1H NMR indicates 3:1 atropisomeric ratio through the integral value of – CH2 protons 1H NMR (400 MHz, CDCl 3) 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 for C 19H 19F 3N 3O 3S + [M+H] += 426.1094, found 426.1089。MIC为0.001μg/mL。
Figure 413952dest_path_image010
。
SR-2-181。 1H NMR indicates 3:1 atropisomeric ratio through the integral value of – CH2 protons 1H NMR (400 MHz, CDCl 3) 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 C 17H 17F 3N 3O 3S + [M+H] += 400.0937, found 400.0932. MIC为0.010μg/mL。
Figure 125556dest_path_image011
。
WXM-1-33. 1H NMR indicates 3:1 atropisomeric ratio through the integral value of – CH2 protons; 1H NMR (400 MHz, CDCl 3) 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 C 19H 13F 3N 3O 3S + [M+H] += 420.0624, found 420.0620。MIC为0.003μg/mL。
Figure 256323dest_path_image012
。
WXM-1-81。 1H NMR indicates 3:1 atropisomeric ratio through the integral value of – CH2 protons; 1H NMR (400 MHz, CDCl 3) 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/z calcd for C 19H 12F 4N 3O 3S + [M+H] += 438.0530, found 438.0520. MIC为0.005μg/mL。
Figure 598443dest_path_image013
。
WXM-1-84。 1H NMR indicates 3:1 atropisomeric ratio through the integral value of – CH2 protons; 1H NMR (400 MHz, CDCl 3) 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 for C 19H 12F 3N 3O 3ClS + [M+H] += 454.0235, found 454.0226。MIC为0.008μg/mL。
Figure 447450dest_path_image014
。
WXM-1-86。 1H NMR (400 MHz, CDCl 3) 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 C 13H 8F 3N 3O 3S + [M+H] +=344.0311, found 344.0307. MIC为0.479 μg/mL。
Figure 697166dest_path_image015
。
WXM-1-95。 1H NMR indicates 3:1 atropisomeric ratio through the integral value of – CH2 protons; 1H NMR (400 MHz, CDCl 3) 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 C 20H 15F 3N 3O 3S + [M+H] += 434.0781, found 434.0774。MIC为0.012μg/mL。
Figure 885702dest_path_image016
。
WXM-1-96。 1H NMR indicates 3:1 atropisomeric ratio through the integral value of – CH2 protons; 1H NMR (400 MHz, CDCl 3) 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 C 20H 15F 3N 3O 3S + [M+H] += 434.0781, found 434.0776。MIC为0.023μg/mL。
Figure 461040dest_path_image017
。
WXM-1-97。 1H NMR (400 MHz, CDCl 3) 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 C 20H 12F 3N 4O 3S + [M+H] += 445.0577, found 445.0571。MIC为0.046μg/mL。
Figure 732096dest_path_image018
。
WXM-1-100。 1H NMR indicates 3:1 atropisomeric ratio through the integral value of – CH2 protons; 1H NMR (400 MHz, CDCl 3) 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 for C 19H 12F 4N 3O 3S + [M+H] += 438.0530, found 438.0524。MIC为0.006μg/mL。
Figure 51082dest_path_image019
。
WXM-1-103。 1H NMR indicates 3:1 atropisomeric ratio through the integral value of – CH2 protons; 1H NMR (400 MHz, CDCl 3) 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 C 19H 11F 5N 3O 3S + [M+H] += 456.0436, found 456.0428。MIC为0.006μg/mL。
Figure 890862dest_path_image020
。
WXM-1-104。 1H NMR indicates 3:1 atropisomeric ratio through the integral value of – CH2 protons; 1H NMR (400 MHz, CDCl 3) 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 C 19H 11F 5N 3O 3S + [M+H] += 456.0436, found 456.0430. MIC为0.003μg/mL。
Figure 574785dest_path_image021
。
WXM-1-116。 1H NMR indicates 3:1 atropisomeric ratio through the integral value of – CH2 protons; 1H NMR (400 MHz, CDCl 3) 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 C 19H 12F 4N 3O 3S + [M+H] += 438.0530, found 438.0522。MIC为0.006μg/mL。
Figure 132805dest_path_image022
。
WXM-1-118。 1H NMR (400 MHz, CDCl 3) 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 C 17H 11F 3N 3O 3S 2 + [M+H] += 426.0188, found 426.0184。MIC为0.007μg/mL。
Figure 193165dest_path_image023
。
WXM-1-122。 1H NMR indicates 3:1 atropisomeric ratio through the integral value of – CH2 protons; 1H NMR (400 MHz, CDCl 3) 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 C 19H 17F 3N 3O 3S + [M+H] +=412.0937, found 412.0926。MIC为0.002μg/mL。
Figure 887451dest_path_image024
。
FDG-4-4。 1H NMR (400 MHz, CDCl 3) 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 C 19H 15F 3N 3O 4S + [M+H] += 450.0730, found 450.0723。MIC为0.014μg/mL。
Figure 804592dest_path_image025
。
WXM-1-181。 1H NMR indicates 3:1 atropisomeric ratio through the integral value of – CH2 protons 1H NMR (300 MHz, CDCl 3) 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: C 16H 13F 3N 3O 3S+[M+H] += 384.0624, found 384.0630. MIC为0.008μg/mL。
Figure 53171dest_path_image026
。
SR-3-39。 1H NMR(300 MHz,CDCl 3) δ 9.13(s, 1H),8.79(s, 1H), 4.75(s, 2H), 3.45(s, 3H), 2,38(s, 1H); HRMS calcd for: C 15H 9F 3N 3O 3S + = 368.0311, found 368.0317; MIC为：0.121μg/mL。
Figure 713959dest_path_image027
。
SR-3-40。 1H NMR(300 MHz,CDCl 3) 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: C 18H 13F 3N 3O 3S + = 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0.2-0.001 μg/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37 oC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100 mM, 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。
Figure 466014dest_path_image028
Figure 554056dest_path_image029
Figure 86669dest_path_image030
。
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15 min, 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C max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 AUC 0- ∞，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。
Figure 488831dest_path_image031
。
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（C max和AUC更大，意味着潜在更低的给药剂量），利于实际应用。

Claims (10)

  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：
    Figure 794340dest_path_image001
       其中，R 1为氢或者烷基；m =1～3，n=0～3；R 2为烷基、芳基或者杂环基；R 3为三氟甲基、卤素、砜基、亚砜基、硝基、氰基或者磺酰胺基。
  2. 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，R 1为甲基、乙基或氘代甲基、三氟甲基；R 2为开链或环状饱和烷基、苯环或取代的苯环、吡啶环、噻吩环、炔基中的一种。
  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：
      
    Figure 241502dest_path_image002
       含有炔基的胺化合物的结构式如下：
    Figure 431175dest_path_image003
    其中，R 1为氢或者烷基；m =1～3，n=0～3；R 2为烷基、芳基或者杂环基；R 3为三氟甲基、卤素、砜基、亚砜基、硝基、氰基或者磺酰胺基。
  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，R 1为甲基、乙基或氘代甲基、三氟甲基；R 2为开链或环状饱和烷基、苯环或取代的苯环、吡啶环、噻吩环、炔基中的一种。
  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. 含有炔基的胺化合物在制备基于炔基连接臂的苯并噻嗪酮衍生物中的应用，其特征在于，含有炔基的胺化合物的结构式如下：
    Figure 534260dest_path_image003
    其中，R 1为氢或者烷基；m =1～3，n=0～3；R 2为烷基、芳基或者杂环基。
  7. 含有炔基的胺化合物在制备抗菌药物中的应用，其特征在于，含有炔基的胺化合物的结构式如下：
    Figure 365950dest_path_image003
    其中，R 1为氢或者烷基；m =1～3，n=0～3；R 2为烷基、芳基或者杂环基。
  8. 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菌药物中的应用。
  9. 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菌药物中的应用。
  10. 根据权利要求8或者9所述的应用，其特征在于，菌为杆菌。
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