WO2022204902A1 - 6- 位三氟甲基取代的苯并噻嗪酮衍生物及其制备方法与应用 - Google Patents

6- 位三氟甲基取代的苯并噻嗪酮衍生物及其制备方法与应用 Download PDF

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WO2022204902A1
WO2022204902A1 PCT/CN2021/083695 CN2021083695W WO2022204902A1 WO 2022204902 A1 WO2022204902 A1 WO 2022204902A1 CN 2021083695 W CN2021083695 W CN 2021083695W WO 2022204902 A1 WO2022204902 A1 WO 2022204902A1
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compound
trifluoromethyl
substituted
tuberculosis
benzothiazinone
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PCT/CN2021/083695
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French (fr)
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乔春华
范东光
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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

Definitions

  • the technical field of the present invention is related to the application of antibacterial drugs, in particular to benzothiazinone derivatives substituted with 6-position trifluoromethyl, and a preparation method and application thereof.
  • Tuberculosis is one of the infectious diseases. It uses benzothiazinone (BTZ) as the backbone and targets DprE1.
  • BTZ benzothiazinone
  • the anti-tuberculosis drugs are currently in the development stage of BTZ043 (phase I) and pBTZ169 (phase II).
  • MIC 0.5 ⁇ M clinical first-line drug isoniazid
  • it has obvious in vitro antibacterial advantages.
  • the existing benzothiazinone anti-tuberculosis drugs have poor water solubility, poor druggability, and short metabolic half-life in human liver microsomes.
  • due to the high failure rate of drugs in the clinical evaluation period the development of more candidate drugs is worth looking forward to.
  • the position of the benzothiazinone side chain is creatively changed, especially the piperazine ring is creatively changed, and a series of compounds obtained can achieve unexpected technical effects;
  • the compound of the present invention has better water solubility, longer metabolic half-life of human liver microsomes, and better druggability.
  • the present invention adopts the following technical scheme: a benzothiazinone derivative substituted by a 6-position trifluoromethyl, and its chemical structural formula is as follows: .
  • R 1 is hydrogen, methyl or ethyl
  • R 2 is hydrogen, methyl or ethyl
  • R 3 is halogen
  • the chemical structural formula of the benzothiazinone derivative substituted with trifluoromethyl at the 6-position is as follows: .
  • the invention discloses the application of the above-mentioned 6-position trifluoromethyl substituted benzothiazinone derivatives as tuberculosis inhibition, or in the preparation of anti-tuberculosis drugs.
  • the invention discloses the application of the pharmaceutical composition containing the above-mentioned 6-position trifluoromethyl substituted benzothiazinone derivatives as tuberculosis inhibition, or in the preparation of anti-tuberculosis drugs;
  • the tuberculosis includes active tuberculosis , monodrug-resistant tuberculosis, multi-drug-resistant tuberculosis, and extensively multi-drug-resistant tuberculosis;
  • the tuberculosis includes pulmonary tuberculosis, extrapulmonary tuberculosis;
  • bacilli include Mycobacterium tuberculosis, Bacillus leprae, Corynebacterium or Nocardia.
  • the invention discloses a pharmaceutical composition using the above-mentioned 6-position trifluoromethyl substituted benzothiazinone derivative as an active ingredient; the pharmaceutical composition is tablet, capsule, granule, syrup, powder or injection; The benzothiazinone derivative of the present invention is combined as an active ingredient with a conventional pharmaceutical carrier to obtain a pharmaceutical composition.
  • the invention discloses a preparation method of the above-mentioned 6-position trifluoromethyl substituted benzothiazinone derivatives, as follows: compound A5 reacts with an azide compound to obtain a 6-position trifluoromethyl substituted benzothiazine Ketone derivatives; or compound A4 reacts with compound BC to obtain 6-trifluoromethyl substituted benzothiazinone derivatives; or compound A4 reacts with compound D2 to obtain 6-trifluoromethyl substituted benzos Thiazinone derivatives.
  • the chemical structural formula of the compound A5 is as follows: .
  • the chemical structural formula of the azide compound is as follows: .
  • R 1 is hydrogen, methyl or ethyl
  • R 2 is hydrogen, methyl or ethyl
  • R 3 is hydrogen or halogen
  • X is O or S.
  • reaction of compound A5 and azide compound is carried out at room temperature in the presence of copper salt, reducing agent and inorganic base; the reaction of compound A4 and compound BC is carried out at room temperature; the reaction of compound A4 and compound D2 is carried out at room temperature .
  • compound A1 Take compound A1 as starting material, react with oxalyl chloride after nitration, and then react with ammonium thiocyanate to generate compound A4 ;
  • the chemical structural formula of compound A1 is as follows: .
  • the preparation method is as follows: The steps of B0 ⁇ B3 are as follows: the sarcosine ethyl ester hydrochloride B0 is protected by Boc anhydride and converted into N -Boc intermediate B1 . Secondly, intermediate B1 undergoes hydrazine hydrolysis to obtain hydrazide intermediate B2 , which undergoes condensation reaction with various aryl carboxylic acids under the condition of carbonyldiimidazole as a condensation reagent to obtain various dihydrazide intermediates B3 and its derivatives.
  • the steps of D2 are: benzamide D0 and its derivatives react with 1,3-dichloroacetone to generate oxazole ring intermediate D1 and its derivatives, and D1 undergoes nucleophilic substitution with methylamine to generate amine D2 and its derivatives derivative.
  • ⁇ A5 The steps of ⁇ A5 are: compound A1 is the starting material, and the 3-position nitration product A2 is obtained through nitration.
  • the intermediate A2 reacts with oxalyl chloride to convert the carboxyl group into acid chloride A3 , and continues to react with ammonium thiocyanate to generate thiocyanate ester intermediate A4 .
  • A4 undergoes cyclization reaction with N -methylpropargylamine to obtain the cyclization product A5 .
  • Compound A5 reacts with azidobenzene or p-fluoroazidobenzene to obtain the products 2 and 3 of the present invention.
  • A4 undergoes intramolecular cyclization reaction with various amines B5, D2, C2 and their derivatives to obtain the products 1 , 4 , 5 and their derivatives of the present invention.
  • the present invention discloses a series of compounds with innovative structures.
  • the results of the examples show that the benzothiazinone derivatives substituted at the 6-position trifluoromethyl of the present invention have obvious bacteriostatic effect, far exceeding that of the positive control isoniazid ( Existing clinical medicine), especially the present invention solves the defects of low water solubility of the existing bacteriostatic agent and short metabolic half-life value of human liver microsomes.
  • the method of the present invention will be described below through specific examples, but the present invention is not limited thereto.
  • the experimental methods described in the examples, unless otherwise specified, are conventional methods, involving the minimum inhibitory concentration MIC (ng/mL) of the compounds involved against Mycobacterium tuberculosis (H37Rv, standard tuberculosis strain) and the metabolism of human liver microsomes
  • MIC minimum inhibitory concentration
  • H37Rv standard tuberculosis strain
  • the test methods for half-life (T 1/2 ,min) and solubility ( ⁇ g/mL) are existing methods; the reagents and materials can be prepared from commercial channels or conventional methods unless otherwise specified.
  • Example 1 compound 1 : 2- (methyl(( 5- phenyl -1,3,4- oxadiazole -2- group) methyl) amino) -8- Nitro -6- (trifluoromethyl) -4H - Benzo [ e ] [1,3] Thiazine - 4- ketone.
  • Benzoic acid 100 mg, 0.82 mmol was dissolved in acetonitrile, N,N'-carbonyldiimidazole (CDI) (146 mg, 0.90 mmol) was added, the temperature was raised to 45 °C, the system was stirred at this temperature for 45 min, and added Compound B2 (166 mg, 0.82 mmol), then the system was cooled to room temperature and continued to stir, monitored by TLC plate, and the reaction was completed in 13 h.
  • CDI N,N'-carbonyldiimidazole
  • the compound 2-chloro-5-trifluoromethylbenzoic acid A1 (1.0 g, 4.45 mmol) was dissolved in 50 mL of concentrated sulfuric acid, followed by the addition of potassium nitrate (900 mg, 8.91 mmol) at 0 °C. Then continued stirring at 90 °C, monitored by TLC plate, and the reaction was completed for 3 h. The reaction system was cooled to room temperature, poured into ice water, a large amount of white solid was precipitated, filtered, and washed with ice water three times to obtain a white solid compound A2 (1.1 g, yield: 91%).
  • the preceding compound ( acid chloride intermediate ) was dissolved in dry DCM (10 mL) under nitrogen, followed by the addition of 2 drops of polyethylene glycol, followed by dropwise addition of ammonium thiocyanate (21 mg, 0.27 mmol) to the above solution.
  • the anhydrous acetone solution was reacted at room temperature, and the TLC plate was monitored for 20 minutes to complete the reaction to obtain the intermediate compound A4 .
  • the next step was carried out directly without purification.
  • the side chain amine compound B5 (41 mg, 0.21 mmol) was added to the reaction system of the aforementioned compounds, and the cyclization reaction was carried out at room temperature, and the TLC plate was monitored until the reaction was complete.
  • Example 2 compound twenty two- ((( 1- phenyl -1H-1,2,3- triazole -4- base) methyl) (methyl) amino) -8- Nitro -6- (trifluoromethyl) -4H - Benzo [ e ] [1,3] Thiazine -4- ketone.
  • Example 3 Compound: 2- ((((( 1- ( 4- Fluorophenyl) -1H-1,2,3- triazole -4- base) methyl) (methyl) amino) -8- Nitro -6- (trifluoromethyl) -4H- Benzo [e] [1,3] Thiazine -4- ketone.
  • Example 4 compound 4 2- (((( 5- ( 4- Fluorophenyl) -1,3,4- Thiadiazole -2- base) methyl) (methyl) amino) -8- Nitro -6- (trifluoromethyl) -4H- Benzo [e][1,3] Thiazine -4- ketone.
  • the antibacterial test adopts the microporous Alamar Blue color development method, which is the existing conventional test method. , scrape the cultured strain H37Rv (standard strain purchased from ATCC) and put it into it; tighten the grinding bottle, shake it for 5 minutes to separate the bacteria; let it stand for 20 minutes, add normal saline, and compare it with No. 1 turbidity tube.
  • Solubility experiment To a total volume of 1000 ⁇ L of phosphate buffered saline (45 mM KH 2 PO 4 , 45 mM KOAc, 75 mM KCl, 45 mM ethanolamine, pH 7.4), add a DMSO stock solution of the compound to be tested (DMSO final concentration below 1%). Solubility of test compounds. Mix 10 ⁇ L of different concentrations of compound DMSO stock solution and 990 ⁇ L of buffer in a 1.5 mL centrifuge tube and shake at room temperature for 4 h. Filter with a 0.3 ⁇ m pore size membrane filter. The filtrate was quantitatively analyzed by HPLC.
  • the minimum inhibitory concentration MIC (ng/mL) of above-mentioned compound to Mycobacterium tuberculosis (H37Rv, standard tuberculosis strain) and the metabolic half-life (T 1/2 , min), solubility ( ⁇ g/mL) of human liver microsomes as follows: .
  • the compounds of the present invention showed obvious bacteriostatic effect, and the bacteriostatic effect far exceeded that of the positive control isoniazid.
  • the compound of the present invention has significantly better metabolic half-life (T 1/2 ,min) and water solubility of human liver microsomes, indicating that it has good in vivo stability and better water solubility parameters.

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Abstract

一种6-位三氟甲基取代的苯并噻嗪酮衍生物及其制备方法与应用，对苯并噻嗪酮骨架苯环进行改变，尤其对取代基进行变化，得到的一系列的化合物，与其他苯并噻嗪酮衍生物相比，6-位三氟甲基取代的苯并噻嗪酮衍生物对肝微粒体酶更稳定，代谢半衰期T 1/2更长、水溶性更好。

Description

6-位三氟甲基取代的苯并噻嗪酮衍生物及其制备方法与应用 技术领域
本发明的技术领域是有关抗菌药物的应用，具体为6-位三氟甲基取代的苯并噻嗪酮衍生物及其制备方法与应用。
 背景技术
结核病是传染性疾病中的一种，以苯并噻嗪酮（BTZ)为骨架，靶向DprE1的抗结核药物，现在研发阶段的是BTZ043 (phase I)和pBTZ169（phase II)，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，现有苯并噻嗪酮抗结核药物，水溶性差，成药性不够好，在人肝微粒体代谢半衰期短；而且，临床评价期药物的高失败率，更多候选药物的研发值得期待。
 技术问题
本发明对苯并噻嗪酮侧链位置进行创造性改变，尤其对哌嗪环进行创造性变化，得到的一系列的化合物，取得预料不到的技术效果；重要的是，与现有研究阶段的苯并噻嗪酮抗结核药物相比，本发明的化合物具有水溶性更好、更长的人肝微粒体代谢半衰期，具有更好的成药性。
 技术解决方案
本发明采用如下技术方案：一种6-位三氟甲基取代的苯并噻嗪酮衍生物，其化学结构式如下：
Figure 464204dest_path_image001
。
其中，R 1为氢、甲基或者乙基；R 2为氢、甲基或者乙基；R 3为卤素。
优选的，6-位三氟甲基取代的苯并噻嗪酮衍生物的化学结构式如下：
Figure 60402dest_path_image002
。
本发明公开了上述6-位三氟甲基取代的苯并噻嗪酮衍生物作为结核菌抑制的应用，或者在制备抗结核药物中的应用。
本发明公开了含有上述6-位三氟甲基取代的苯并噻嗪酮衍生物的药物组合物作为结核菌抑制的应用，或者在制备抗结核药物中的应用；所述结核包括活动性结核、单耐药结核、多耐药结核、广泛多耐药结核；所述结核包括肺结核、肺外结核；杆菌包括结核分枝杆菌、麻风杆菌，棒状杆菌或者诺卡式菌。
本发明公开了以上述6-位三氟甲基取代的苯并噻嗪酮衍生物为活性成分的药物组合物；所述药物组合物为片剂、胶囊、颗粒、糖浆、粉剂或者注射剂；可以将本发明苯并噻嗪酮衍生物为活性成分与常规药物载体组合，得到药物组合物。
本发明公开了上述6-位三氟甲基取代的苯并噻嗪酮衍生物的的制备方法，如下：化合物A5与叠氮化合物反应，得到6-位三氟甲基取代的苯并噻嗪酮衍生物；或者化合物A4与化合物BC反应，得到6-位三氟甲基取代的苯并噻嗪酮衍生物；或者化合物A4与化合物D2反应，得到6-位三氟甲基取代的苯并噻嗪酮衍生物。
  所述化合物A5的化学结构式如下：
Figure 225804dest_path_image003
。
  叠氮化合物的化学结构式如下：
Figure 57494dest_path_image004
。
  化合物A4的化学结构式如下：
Figure 624741dest_path_image005
。
  化合物BC的化学结构式如下：
Figure 126261dest_path_image006
。
化合物D2的化学结构式如下：
Figure 513380dest_path_image007
。
其中，R 1为氢、甲基或者乙基；R 2为氢、甲基或者乙基；R 3为氢或者卤素；X为O或者S。
进一步的，化合物A5与叠氮化合物的反应在铜盐、还原剂、无机碱存在下，室温下进行；化合物A4与化合物BC的反应在室温下进行；化合物A4与化合物D2的反应在室温下进行。以化合物 A1为起始原料，经过硝化后与草酰氯反应，再与硫氰酸铵反应生成化合物 A4 ；化合物A1的化学结构式如下：
Figure 414340dest_path_image008
。
  具体的，上述6-位三氟甲基取代的苯并噻嗪酮衍生物的的制备方法的路径示意如下：
Figure 304935dest_path_image009
。
制备方法如下： B0→ B3的步骤为：将肌氨酸乙脂盐酸盐 B0通过Boc 酸酐保护，转化成 N-Boc中间体 B1。其次，中间体 B1经过肼解得到酰肼中间体 B2，在羰基二咪唑为缩合试剂的条件下与各类芳基羧酸发生缩合反应得到各类二酰肼中间体 B3及其衍生物。
→ B5的步骤为：中间体 B3经过脱水反应来制备噁二唑环中间体 B4。随后，中间体 B4在三氟乙酸的作用下脱Boc 得到化合物 B5及其衍生物。
→ C2的步骤为：化合物 B3在劳森试剂的作用下，发生分子内的环合反应，生成中间体 C1及其衍生物，三氟乙酸作用脱去保护基Boc生成侧链胺 C2及其衍生物。
→ D2的步骤为：苯甲酰胺 D0及其衍生物与1，3-二氯丙酮发生反应生成噁唑环中间体 D1及其衍生物， D1再与甲胺发生亲核取代生成胺 D2及其衍生物。
→ A5的步骤为：化合物 A1为起始原料，经过硝化得到3-位硝化产物 A2。中间体 A2与草酰氯反应，将羧基转化成酰氯 A3，继续与硫氰酸铵反应生成硫氰酸脂中间体 A4 。最后， A4与 N-甲基丙炔胺发生环合反应，得到环合产物 A5。
化合物A5与叠氮苯，或者对氟叠氮苯发生click反应，得到本发明产物 2、 3。A4与各类胺B5、D2、C2及其衍生物发生分子内环合反应得到本发明产物 1、 4、 5及其衍生物。
有益效果
本发明公开了系列结构创新的化合物，实施例结果显示，本发明6-位三氟甲基取代的苯并噻嗪酮衍生物显示出了明显的抑菌效果，远超过阳性对照异烟肼（现有临床药物），尤其是本发明解决了现有抑菌剂水溶性低，人肝微粒体代谢半衰期值短的缺陷。
 本发明的实施方式
以下通过具体实施例对本发明的方法进行说明，但本发明并不局限于此。实施例中所述实验方法，如无特殊说明，均为常规方法，涉及的化合物对结核分枝杆菌（H37Rv，标准结核菌株）的最小抑菌浓度MIC（ng/mL）以及人肝微粒体代谢半衰期（T 1/2,min）、溶解度（μg/mL）的测试方法为现有方法；所述试剂和材料，如无特殊说明，均可从商业途径或常规方法制备获得。
实施例 1 ：化合物 1 ： 2- （甲基（（ 5- 苯基 -1,3,4- 恶二唑 -2- 基）甲基）氨基） -8- 硝基 -6- （三氟甲基） -4 H- 苯并 [ e] [1,3] 噻嗪 - 4- 酮。
Figure 508515dest_path_image010
。
将肌氨酸盐酸盐（500 mg，3.26 mmol）溶于（20 mL）DMF中，搅拌下加入三乙胺（362 mg，3.58 mmol），冰浴下加入Boc 2O（853 mg，3.90 mmol）。然后在室温下继续搅拌，TLC板监测，12 h反应结束。将反应体系倒入水中，乙酸乙脂（100 mL×3）萃取，有机相用盐水洗涤，无水硫酸钠干燥，过滤除去干燥剂，浓缩，柱层析（PE：EA=5：1）得无色油状化合物 B1（500 mg, 产率：71%）。
将化合物 B1（500 mg，2.30 mmol），溶于乙醇（10 mL）中，搅拌下加入水合肼（2 mL）。然后在室温下继续搅拌，TLC板监测，4 h反应结束。将反应体系浓缩，柱层析（DCM：MeOH=20：1）纯化得化合物 B2 (400 mg, 产率：86%)。MS (+ESI): calcd for C 3H 10N 3O [M-Boc+H] += 104.07, found 104.0。
将苯甲酸（100 mg，0.82 mmol）溶于乙腈中，加入N,N’ -羰基二咪唑（CDI）（146 mg，0.90 mmol），升温至45 ℃，将体系再此温度搅拌45 min，加入化合物 B2（166 mg，0.82 mmol)，然后将体系冷却至室温下继续搅拌，TLC板监测，13 h反应结束。将反应体系倒入2M柠檬酸水溶液（10 mL）中，乙酸乙脂（100 mL×3）萃取，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩，柱层析（PE：EA=1：1）纯化得白色固体化合物 B3（200 mg, 产率：80%）。 1H NMR (400 MHz, DMSO- d 6 ) δ 10.38 (d, J = 11.5 Hz, 1H), 9.99 (d, J = 15.6 Hz, 1H), 7.88 (d, J = 7.2 Hz, 2H), 7.57 (t, J = 6.9 Hz, 1H), 7.49 (t, J = 7.0 Hz, 2H), 3.93 – 3.91 (m, 2H), 2.86 – 2.83 (m, 3H), 1.41 – 1.39 (m, 9H)。
将化合物 B3（200 mg，0.65 mmol）溶于二氯甲烷（DCM）中，依次加入咪唑（89 mg，1.30 mmol）、三苯基磷（341 mg，1.30 mmol）、四溴化碳（432mg，1.30 mmol）。然后在室温下继续搅拌，TLC板监测，8 h反应结束。将体系浓缩，柱层析（PE：EA=2：1）得无色油状物 B4 (150 mg，产率：75%)。 1H NMR (400 MHz, DMSO- d 6 ) δ 7.97 (d, J = 6.5 Hz, 2H), 7.65 – 7.60 (m, 3H), 4.71 (s, 2H), 2.94 (s, 3H), 1.42 – 1.34 (m, 9H)。
将化合物 B4（150 mg，0.52 mmol）溶于DCM（10 mL）中，在冰浴下加入三氟乙酸（4 mL）。然后在室温下继续搅拌，TLC板监测，3 h反应结束。将混合物用饱和碳酸钾溶液调pH = 9，乙酸乙脂（50 mL×3）萃取，无水硫酸钠干燥，过滤除去干燥剂，浓缩，得无色油状物 B5（80 mg，产率：89%）。 1H NMR (400 MHz, DMSO- d 6 ) δ 7.99 (d, J = 6.7 Hz, 2H), 7.61 – 7.59 (m, 3H), 3.94 (s, 2H), 2.33 (s, 3H)。
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（50 mg，0.18 mmol）溶于10 mL重蒸二氯甲烷中，随后加入草酰氯（92 mg，0.72 mmol）以及催化当量的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，直接进行下一步反应。将前述化合物 （酰氯中间体 ）溶在干燥的DCM（10 mL）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（21 mg，0.27 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 A4。不经纯化，直接进行下一步反应。向前述化合物的反应体系中加入侧链胺化合物 B5（41 mg，0.21 mmol），室温下环合反应，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）得黄色固体化合物 1（50 mg，产率 ：59%）。 1H NMR (400 MHz, CDCl 3) δ 9.14 (s, 1H), 8.81 (s, 1H), 8.02 (d, J = 7.6 Hz, 2H), 7.56 – 7.47 (m, 3H), 5.42 (s, 2H), 3.55 (s, 3H). 13C NMR (151 MHz, CDCl 3) δ 166.1, 166.1, 164.9, 160.9, 144.1, 133.9 (d, J = 2.8 Hz), 132.3, 130.3 (q, J = 35.5 Hz), 129.3, 127.2, 126.6, 126.3 (d, J = 3.2 Hz), 122.4 (q, J = 274.0 Hz), 45.2, 36.7. HRMS (+ESI) m/z calcd for C 19H 13F 3N 5O 4S + [M+H] += 464.0635 found 464.0632。
对比例1。
Figure 382930dest_path_image011
。
实施例 2 化合物 2: 2- （（（ 1- 苯基 -1H-1,2,3- 三唑 -4- 基）甲基）（甲基）氨基） -8- 硝基 -6- （三氟甲基） -4 H- 苯并 [ e ] [1,3] 噻嗪 -4- 酮。
Figure 556422dest_path_image012
。
化合物 A5的合成采用化合物 A4（400 mg，1.48 mmol）和 N-甲基炔丙胺（113 mg，1.63 mmol）通过实施例 1中环合反应步骤，柱层析（二氯甲烷：甲醇=200：1）得到黄色固体化合物 A5（40 mg，产率 ：44%）；R f =0.2，石油醚/乙酸乙酯=1:1。 1H NMR (400 MHz, CDCl 3) δ 9.13 (s, 1H), 8.79 (s, 1H), 4.76 (s, 2H), 3.64 (s, 1H), 3.45 (s, 3H)；将化合物 A5（0.014 mmol）与苯基叠氮(0.021 mmol，1.5 eq)溶于乙醇（8 mL）中，搅拌下加入硫酸铜（0.0021 mmol， 0.15 eq）、抗坏血酸钠（0.028 mmol， 0.2 eq）、碳酸钾（0.014 mmol， 1.0 eq）水溶液（4 mL）；将反应体系在室温下搅拌24 h；然后将体系用硅藻土过滤，DCM（3×50 mL）萃取，无水硫酸钠干燥，过滤除去干燥剂，浓缩柱层析得到目标产物 化合物 2。 1H NMR (400 MHz, CDCl 3) δ 9.13 (s, 1H), 8.77 (s, 1H), 8.25 (s, 1H), 7.71 (d, J = 7.6 z, 2H), 7.51 (t, J = 7.2 Hz, 2H), 7.44 (d, J = 7.2 Hz, 1H), 5.20 (s, 2H), 3.58 (s, 3H); 13C NMR (151 MHz, CDCl 3) δ 166.2, 163.5, 144.0, 142.6, 136.9, 134.3, 133.7 (d, J = 3.0 Hz), 130.0 (q, J = 36.2 Hz), 129.9, 129.1, 126.7, 126.2 (d, J = 3.0 Hz), 122.5 (q, J = 273.3 Hz), 122.3, 120.7, 46.7, 37.1; HRMS (+ESI) m/z calcd for C 19H 14F 3N 6O 3S + [M+H] += 463.0795, found 463.0797。
对比例2：
Figure 832683dest_path_image013
。
实施例 3 化合物： 2- （（（（ 1- （ 4- 氟苯基） -1H-1,2,3- 三唑 -4- 基）甲基）（甲基）氨基） -8- 硝基 -6- （三氟甲基） -4H- 苯并 [e ] [1,3] 噻嗪 -4- 酮。
Figure 66218dest_path_image014
。
与实施例2操作相同，叠氮为4-氟苯基叠氮，其余不变，得到化合物 3黄色固体（45 mg，产率：65%）。 1H NMR (400 MHz, CDCl 3) δ 9.12 (s, 1H), 8.77 (s, 1H), 8.27 (s, 1H), 7.70 (dd, J = 7.6, 4.4 Hz, 2H), 7.20 (t, J = 8.0 Hz, 2H), 5.18 (s, 2H), 3.57 (s, 3H). 13C NMR (151 MHz, CDCl 3) δ 166.2, 163.6, 162.7 (d, J = 250.0 Hz), 144.0, 142.7,134.3, 133.7 (d, J = 2.4 Hz), 133.2, 130.0 (q, J = 35.1 Hz), 126.6, 126.2 (d, J = 3.0 Hz), 122.7 (d, J = 8.4 Hz), 122.6, 122.5 (q, J = 273.1 Hz), 116.9 (d, J = 23.3 Hz), 46.7, 37.2.HRMS (+ESI) m/z calcd for C 19H 13F 4N 6O 3S + [M+H] += 481.0700, found 481.0692。
对比例3：
Figure 303295dest_path_image015
。
实施例 4 化合物 4 ： 2- （（（（ 5- （ 4- 氟苯基） -1,3,4- 噻二唑 -2- 基）甲基）（甲基）氨基） -8- 硝基 -6- （三氟甲基） -4H- 苯并 [e] [ 1,3] 噻嗪 -4- 酮。
Figure 280479dest_path_image016
。
与实施例1操作相同，所用侧链胺为1-（5-（4-氟苯基）-1,3,4-噻二唑-2-基）- N-甲基甲胺，得黄色固体化合物 6（45 mg，产率：50%）。 1H NMR (400 MHz, CDCl 3) δ 9.17 (s, 1H), 8.81 (s, 1H), 8.02 – 7.87 (m, 2H), 7.15 (t, J = 8.0 Hz, 2H), 5.43 (s, 2H), 3.54 (s, 3H)； 13C NMR (151 MHz, CDCl 3) δ 170.0, 165.8, 164.7 (d, J = 253.0 Hz), 164.0, 162.1, 144.1, 133.9 (d, J = 3.0 Hz), 130.4, 130.2 (d, J = 8.8 Hz), 129.9 (q, J = 35.4 Hz), 126.6, 126.4 (d, J = 3.2 Hz), 126.1, 122.4 (q, J = 273.2 Hz), 116.6 (d, J = 22.2 Hz), 49.8, 36.9；HRMS (+ESI) m/z calcd for C 19H 12F 4N 5O 3S 2 + [M+H] += 498.0312 found 498.0317。
对比例4：
Figure 411246dest_path_image017
。
实施例 5 化合物 5 ： 2- （甲基（（ 2- 苯基恶唑 -4- 基）甲基）氨基） -8- 硝基 -6- （三氟甲基） -4 H- 苯并 [ e] [1,3] 噻嗪 -4- 酮。
Figure 815682dest_path_image018
。
将化合物苯甲酰胺（2.00 mmol）溶于乙醇：四氢呋喃（14 mL+7 mL=21 mL）（2：1）中，搅拌下加入1，3-二氯丙酮（2.20 mmol，1.1当量），80℃下反应7小时；然后将体系浓缩，乙酸乙酯（20 mL×3）萃取，无水硫酸钠干燥，过滤，浓缩，柱层析（石油醚：乙酸乙酯=15:1），得油状物 D1，R f= 0.3（石油醚：乙酸乙酯=15:1），产率： 90%。
将化合物 D1（1.70 mmol）溶于甲醇（15 mL）中，冰浴下加入甲氨的甲醇溶液（5 mL），升至室温下反应5小时；然后用饱和氯化钠（20 mL）溶液与乙酸乙酯（30 mL×5）萃取，无水硫酸钠干燥，过滤，浓缩，柱层析（二氯甲烷：甲醇=15:1），得油状物 N-甲基-1-（2-苯基恶唑-4-基）甲胺( D2)，R f= 0.3（二氯甲烷：甲醇=15:1），产率：93%；与实施例1操作相同，所用侧链胺为 N-甲基-1-（2-苯基恶唑-4-基）甲胺( D2)，得黄色固体化合物 5（45 mg，产率：48%）。 1H NMR (400 MHz, CDCl 3) δ 9.14 (s, 1H), 8.77 (s, 1H), 8.01 (br, 2H), 7.84 (s, 0.75H, major), 7.78 (s, 0.25H, minor), 7.46 (br, 3H), 5.05 (s, 1.5H, major), 4.87 (s, 0.5H, minor), 3.56 (s, 3H). HRMS (+ESI) m/z calcd for C 20H 12F 3N 4O 4S + [M+H] += 463.0682 found 463.0683。
对比例5：
Figure 548845dest_path_image019
。
抗结核分枝杆菌活性的测定：抗菌实验采用微孔阿尔玛蓝（Alamar Blue）显色法，为现有常规测试方法，实验步骤简述如下：滴2滴5% 吐温80于磨菌瓶中，刮取培养好的菌株H37Rv （购自ATCC的标准株）置入其中；将磨菌瓶拧紧，震荡5分钟使菌分离；静置20 min，加生理盐水，与1号比浊管比浊至相同浓度，测菌液OD（OD=1为3.8*10^8，OD=0.2为1*10^8），确定比浊管浓度；比浊，换算后稀释，混匀备用；加100 μL的7H9分枝杆菌培养基和OADC增菌液于96孔板第1-11孔中，第12列孔加190 μL 的7H9+OADC；取10 μL 配制好的化合物加入已加培养基的96孔板第12列孔中，混匀；将排枪调至100 μL 刻度，从第12列孔中吸取100 μL 混合液加入第11列孔中，混匀后从第11列孔中吸取100 μL 混合液加入第10列孔中...以此类推，直至加到第2列孔，混匀后废弃100 μL ，不加入第1列孔（对照孔）；吸取100 μL备用菌液加入96孔板中，注意枪头尽量不要接触孔里溶液；加好后将96孔板仔细放好，置于37℃孵育箱中培养8天；将5%吐温80：alamar blue=5:2的溶液配制好，取出96孔板，每孔加入70 μL配制液，再次于37℃孵育箱中孵育2天，观察结果，判读MIC值；现有PBTZ169以及异烟肼用作阳性对照。
人肝微粒体代谢半衰期测试方法：化合物浓度为1.0 μM（DMSO），人肝微粒体浓度0.5 mg/mL，37℃下在pH7.4, 1.0mM 浓度的PBS缓冲液中孵育，在0、5、15、30、45 分钟时取样，LC/MS 的分析定量药物的浓度。
溶解度实验：在总体积1000 µL的磷酸盐缓冲盐水溶液(45 mM KH 2PO 4，45 mM KOAc，75 mM KCl，45 mM乙醇胺，pH 7.4)中，加入要测试的化合物的DMSO母液（DMSO终浓度低于1%）。测试化合物的溶解度。将10 µL不同浓度的化合物DMSO母液与990 µL的缓冲液，在1.5 mL 离心管中混合，室温摇动4 h。用0.3 µm孔径的膜过滤器过滤。用HPLC对滤液进行定量分析。
  [0039] 上述化合物对结核分枝杆菌（H37Rv，标准结核菌株）的最小抑菌浓度MIC（ng/mL）以及人肝微粒体代谢半衰期（T 1/2,min）、溶解度（μg/mL）如下：
Figure 64140dest_path_image020
。
结果显示：本发明化合物显示出了明显的抑菌效果，抑菌效果远超过阳性对照异烟肼。与阳性对照PBTZ169相比，本发明化合物具有明显好的人肝微粒体代谢半衰期（T 1/2,min）和水溶性，说明具有好的体内稳定性，水溶性成药性参数更好。

Claims (10)

  1. 一种6-位三氟甲基取代的苯并噻嗪酮衍生物，其特征在于，所述6-位三氟甲基取代的苯并噻嗪酮衍生物的化学结构式如下：
    Figure 724669dest_path_image001
    其中，R 1为氢、甲基或者乙基；R 2为氢、甲基或者乙基；R 3为氢或者卤素。
  2. 根据权利要求1所述6-位三氟甲基取代的苯并噻嗪酮衍生物，其特征在于，所述6-位三氟甲基取代的苯并噻嗪酮衍生物的化学结构式如下：
    Figure 976135dest_path_image002
    。
  3. 权利要求1所述6-位三氟甲基取代的苯并噻嗪酮衍生物作为结核菌抑制的应用。
  4. 权利要求1所述6-位三氟甲基取代的苯并噻嗪酮衍生物在制备抗结核药物中的应用。
  5. 含有权利要求1所述6-位三氟甲基取代的苯并噻嗪酮衍生物的药物组合物作为结核菌抑制的应用，或者在制备抗结核药物中的应用。
  6. 根据权利要求3～5任意一项所述的应用，其特征在于，所述结核包括活动性结核、单耐药结核、多耐药结核、广泛多耐药结核。
  7. 以权利要求1所述6-位三氟甲基取代的苯并噻嗪酮衍生物为活性成分的药物组合物。
  8. 权利要求1所述6-位三氟甲基取代的苯并噻嗪酮衍生物的制备方法，其特征在于，化合物A5与叠氮化合物反应，得到6-位三氟甲基取代的苯并噻嗪酮衍生物；或者化合物A4与化合物BC反应，得到6-位三氟甲基取代的苯并噻嗪酮衍生物；或者化合物A4与化合物D2反应，得到6-位三氟甲基取代的苯并噻嗪酮衍生物；
    所述化合物A5的化学结构式如下：
    Figure 432524dest_path_image003
      叠氮化合物的化学结构式如下：
    Figure 922411dest_path_image004
      化合物A4的化学结构式如下：
    Figure 124853dest_path_image005
      化合物BC的化学结构式如下：
    Figure 674783dest_path_image006
    化合物D2的化学结构式如下：
    Figure 352889dest_path_image007
    其中，R 1为氢、甲基或者乙基；R 2为氢、甲基或者乙基；R 3为氢或者卤素；X为O或者S。
  9. 根据权利要求8所述6-位三氟甲基取代的苯并噻嗪酮衍生物的制备方法，其特征在于，化合物A5与叠氮化合物的反应在铜盐、还原剂、无机碱存在下，室温下进行；化合物A4与化合物BC的反应在室温下进行；化合物A4与化合物D2的反应在室温下进行。
  10. 根据权利要求8所述6-位三氟甲基取代的苯并噻嗪酮衍生物的制备方法，其特征在于，以化合物 A1为起始原料，经过硝化后与草酰氯反应，再与硫氰酸铵反应生成化合物 A4 ；化合物A1的化学结构式如下：
    Figure 646467dest_path_image008
    。
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