WO2021203812A1 - 苯并噻嗪酮衍生物及其制备方法与作为抗结核药物的应用 - Google Patents

苯并噻嗪酮衍生物及其制备方法与作为抗结核药物的应用 Download PDF

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WO2021203812A1
WO2021203812A1 PCT/CN2021/074579 CN2021074579W WO2021203812A1 WO 2021203812 A1 WO2021203812 A1 WO 2021203812A1 CN 2021074579 W CN2021074579 W CN 2021074579W WO 2021203812 A1 WO2021203812 A1 WO 2021203812A1
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compound
tuberculosis
benzothiazinone
cycloalkyl
mhz
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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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    • 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
    • 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
    • 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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
    • C07D417/14—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Definitions

  • the technical field of the present invention is related to the application of antibacterial drugs, mainly for the research and development of bacilli, such as tuberculosis or leprosy, after infecting the human body; specifically, it relates to a new class of compounds with a benzothiazinone skeleton, such compounds It is shown to have an inhibitory effect on Mycobacterium tuberculosis, in particular, it also has an inhibitory effect on Mycobacterium tuberculosis that is clinically resistant.
  • tuberculosis bacteria The growth and reproduction of tuberculosis bacteria is slow, and it usually takes 18-24 hours to divide one generation, which makes the screening and diagnosis of tuberculosis difficult.
  • Clinically resistant to at least two first-line drugs are called multi-drug resistant strains (MDR-TB), multi-drug resistant (MDR) and broad-spectrum drug resistant (XDR-TB) branches.
  • MDR-TB multi-drug resistant strains
  • MDR multi-drug resistant
  • XDR-TB broad-spectrum drug resistant
  • the anti-tuberculosis drugs targeting DprE1 with benzothiazinone (BTZ) as the backbone are currently being developed at BTZ043 (phase I) and pBTZ169 (phase II).
  • the MICs of the two compounds against the standard strain of tuberculosis are 0.02 respectively.
  • ⁇ M and 0.004 ⁇ M, compared with the existing first-line clinical drug isoniazid (MIC 0.5 ⁇ M) have obvious in vitro antibacterial advantages.
  • the existing benzothiazinone anti-tuberculosis drugs have a high cLogP value and poor druggability.
  • the development of more drug candidates is worth looking forward to.
  • the present invention creatively changes the benzene ring of the benzothiazinone skeleton, especially the creative changes to the substituents, and obtains a series of compounds with unexpected technical effects; the compounds of the present invention have excellent inhibitory effects on tuberculosis bacteria ,
  • the reported activity of the compound is comparable to the current first-line clinical drug isoniazid (MIC 0.5 ⁇ M), it has a very big advantage. It is important to compare with the existing research-stage benzothiazinone anti-tuberculosis drug pBTZ Compared with 169, the compound of the present invention has a lower cLogP value and a better druggability.
  • the present invention adopts the following technical scheme: a benzothiazinone derivative, the structure of which is as follows: .
  • R 1 includes nitro, halogen, cyano, aldehyde or ester group; for example: nitro (NO 2 ), halogen (F, Cl, Br, I), cyano (CN), aldehyde (CHO) ), ester group (COOCH 3 , COOC 2 H 5 ), etc.
  • R 2 includes one of hydrogen, alkyl, cycloalkyl, alkene, alkyne, alkoxy, hydroxyl, carboxyl, amino, and substituted amino groups , Preferably H, C1-C6 alkyl, C1-C6 cycloalkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, hydroxyl, carboxy, amino, substituted amino, etc.; R 3 Including one of alkyl, cycloalkyl, alkene, alkynyl, alkoxy, hydroxy, carboxy, amino, substituted amino group, preferably C1-
  • R 6 includes hydrogen, alkyl, cycloalkyl, alkene, alkyne, alkoxy, hydroxyl, carboxyl, amino, substituted amino, benzyl, sulfonate
  • One of the acyl groups preferably H, C1-C6 alkyl, C1-C6 cycloalkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, benzyl, sulfonyl Etc.
  • R 9 includes hydrogen, alkyl, cycloalkyl or carbonyl, preferably C1-C6 alkyl, C1-C6 cycloalkyl, ketone, etc.
  • R 10 includes alkyl, cycloalkyl, heterocyclyl, substituted hetero Cyclic or aryl, preferably C1-C6 alkyl, C1-C6 cycloalky
  • the preparation method of the benzothiazinone derivative of the present invention includes the following steps.
  • Compound A5 reacts with an amine compound to obtain a benzothiazinone derivative.
  • step (2) Reducing the benzothiazinone derivative prepared in step (1) to obtain compound A7; compound A7 undergoes a substitution reaction to obtain a benzothiazinone derivative.
  • compound A3 or 2-chloro-5-(methylsulfonyl)benzoic acid undergoes chlorination reaction to obtain compound A4; compound A4 is reacted with isothiocyanate to obtain compound A5.
  • the product of step (1) can be called compound A6, and the product of step (2) can be called compound A8.
  • Compound A6 and compound A8 are both benzothiazinone derivatives of the present invention; compound A3, compound A4
  • the chemical structural formulas of compound A5, compound A6, compound A7, and compound A8 are as follows.
  • the chemical structural formula of the amine compound is as follows.
  • the present invention discloses the application of the above-mentioned benzothiazinone derivatives as the inhibition of tuberculosis bacteria or the application in the preparation of anti-tuberculosis drugs.
  • the present invention discloses the application of a pharmaceutical composition containing the above-mentioned benzothiazinone derivative as a tuberculosis inhibitor or an application in the preparation of anti-tuberculosis drugs;
  • the tuberculosis includes active tuberculosis, single-drug-resistant tuberculosis, and multi-drug-resistant tuberculosis.
  • Tuberculosis extensively multi-drug-resistant tuberculosis; said tuberculosis includes tuberculosis and extrapulmonary tuberculosis.
  • the present invention discloses a pharmaceutical composition using the above-mentioned benzothiazinone derivative as an active ingredient; the pharmaceutical composition is a tablet, capsule, granule, syrup, powder or injection; the benzothiazinone of the present invention can be derivatized
  • the active ingredient is combined with a conventional pharmaceutical carrier to obtain a pharmaceutical composition.
  • the present invention discloses a series of structurally innovative compounds.
  • the results of the examples show that the benzothiazinone derivatives of the present invention show obvious antibacterial effects, far exceeding the positive control isoniazid (existing clinical drugs), especially this
  • the invention solves the defect that the existing pBTZ169 has a high cLogP value.
  • the preparation method of the benzothiazinone derivative of the present invention is as follows: (1) Compound A5 reacts with an amine compound to obtain a benzothiazinone derivative; (2) The benzothiazinone derivative prepared in step (1) Reduction to obtain compound A7; compound A7 undergoes substitution reaction to obtain benzothiazinone derivative.
  • compound A3 is chlorinated to obtain acid chloride A4; compound A4 is reacted with isothiocyanate to obtain compound A5; A4 to A6 are a one-pot reaction.
  • each compound of the present invention can refer to the following schematic route: .
  • the chemical structure of the amine compound is as follows: .
  • the step of A1 ⁇ A3 is: the oxidation of compound A1 in potassium peroxymonosulfonate, followed by nitration with potassium nitrate and concentrated sulfuric acid to obtain compound A3;
  • the step of B1 ⁇ A3 is : Substituting thiol for the F atom on the benzene ring of the raw material compound B1 to obtain compound sulfide B2.
  • compound B3 is prepared, and then the nitro group in B3 is reduced to an amino group to obtain compound B4.
  • the amino group is protected with trifluoroacetic anhydride.
  • Compound B5 is then nitrated with potassium nitrate and concentrated sulfuric acid to obtain compound B6.
  • the trifluoroacetyl group is removed in ammonia methanol solution to obtain compound B7.
  • the amino group is converted into chlorine by diazotization with tert-butyl nitrite and cuprous chloride.
  • Compound B8 is obtained.
  • compound A3 is catalyzed by N , N-dimethylformamide It reacts with oxalyl chloride to generate acid chloride compound A4, and then reacts with ammonium thiocyanate using polyethylene glycol as a catalyst to prepare compound A5.
  • an amine compound is added to generate different benzothiazin-4-ones, also known as compound A6.
  • the steps of A6 ⁇ A8 are: the nitro group of compound A6 is reduced to an amino group under the action of iron powder and ammonium chloride to obtain compound A7, and then through substitution reaction to obtain compound A8, such as through tert-butyl nitrite and The substitution reaction of cuprous chloride generates chlorinated benzothiazin-4-one, which is the product of the present invention.
  • the solvent used in A1 ⁇ A2 is methanol, the reaction temperature is room temperature, and the reaction time is 3 hours; the solvent used in A2 ⁇ A3 is concentrated sulfuric acid, the reaction temperature is 60°C, and the reaction time is 2 hours; the solvent used in B1 ⁇ B2 It is N , N -dimethylformamide, the base used is potassium carbonate, the reaction temperature is room temperature, and the reaction time is 6-12 hours; the solvent used for B2 ⁇ B3 is methanol, the reaction temperature is room temperature, and the reaction time is 2 ⁇ 5 hours; the solvent used for B3 ⁇ B4 is ethanol (75%), the reaction temperature is room temperature, and the reaction time is about 1 hour; the solvent used for B4 ⁇ B5 is methylene chloride, the base used is triethylamine, and the reaction temperature is Ice bath, the reaction time is 0.5 hours; the solvent used for B5 ⁇ B6 is concentrated sulfuric acid, the reaction temperature is ice bath, and the reaction time is 2-10 hours; the solvent used for B6 ⁇ B
  • the time is overnight; the solvent used for B7 ⁇ B8 is acetonitrile, the reaction temperature is reflux, and the reaction time is 0.5 hours; the solvent used for A3 ⁇ A4 is dichloromethane (anhydrous), the reaction temperature is room temperature, and the reaction time is 1 hour; The solvent used in A4 ⁇ A5 is dichloromethane and acetone, the reaction temperature is room temperature, and the reaction time is 0.2 hours; the solvent used in A5 ⁇ A6 is dichloromethane and acetone, the reaction temperature is room temperature, and the reaction time is 2 hours; A6 ⁇ The solvent used in A7 is ethanol (75%), the reaction temperature is room temperature, and the reaction time is 1 hour; the solvent used in A7 ⁇ A8 is acetonitrile, the reaction temperature is reflux, and the reaction time is 0.5 hours.
  • the solvent used for A3 ⁇ A4 is dichloromethane (anhydrous), the reaction temperature is room temperature, and the reaction time is 1 hour;
  • the solvent used in A4 ⁇ A5 is
  • Example 1 Compound 1: 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(methylsulfonyl)-8-nitro-4 H -benzo[ e ] [1,3 ] Thiazin-4-one: .
  • Ammonium thiocyanate (46 mg, 1.2 eq.) was dissolved in 5 mL of anhydrous acetone, polyethylene glycol (0.05 eq., based on compound A3) was added dropwise, and stirred at room temperature to dissolve to obtain isothiocyanate Ammonium acid solution; dissolve compound A3 (50 mg, 1eq., R 3 is methyl) in dichloromethane (anhydrous) (5 mL), and add N , N -dimethylformamide (0.05eq., Based on compound A3), add oxalyl chloride (0.25 mL, 2.5eq.) dropwise, and stir at room temperature for 0.5 hours after the addition is complete.
  • Example 2 Compound 3: 2-(3-(Methoxyimino)azetidin-1-yl)-6-(methylsulfonyl)-8-nitro-4 H -benzo[ e ][ 1,3] Thiazin-4-one: The operation is the same as in Example 1, the amine used is azetidine-3-monooxy-methyloxime, and the rest remain unchanged to obtain compound 3 as a white solid (yield 46%).
  • 1 H NMR 400 MHz, DMSO-d 6 ) ⁇ 9.34 (s, 1H), 9.08 (s, 1H), 5.05 – 5.04 (m, 4H), 3.93 (s, 3H), 3.19 (s, 3H).
  • Example 3 Compound 4: 2-(3-(ethoxyimino)azetidin-1-yl)-6-(methylsulfonyl)-8-nitro-4 H -benzo[ e ][ 1,3] Thiazin-4-one: The operation is the same as in Example 1, the amine used is azetidine-3-monooxo-ethyloxime, and the rest remain unchanged to obtain compound 4 as a white solid (yield 36%).
  • Example 4 Compound 5: 2-(3-((benzyloxy)imino)azetidin-1-yl)-6-(methylsulfonyl)-8-nitro-4 H -benzo[ e ] [1,3] Thiazin-4-one: The operation is the same as in Example 1, and the amine used is azetidine-3-monooxo-benzyl oxime. Compound 5 was obtained as a white solid (yield 41%).
  • Example 5 Compound 6: 2-(7-(cyclohexylmethyl)-2,7-diazaspiro[3.5]nonyl-2-yl)-6-(methylsulfonyl)-8-nitro -4 H -benzo[ e ][1,3]thiazin-4-one: The same operation as in Example 1, the amine used is 7-(cyclohexylmethyl)-2,7-diazaspiro[ 3.5] Nonane. Compound 6 was obtained as a yellow solid (yield 31%).
  • Example 6 Compound 7: ( E )-2-(3-(ethoxyimino)pyrrolidin-1-yl)-6-(methylsulfonyl)-8-nitro-4 H -benzo[ e ] [1,3] Thiazin-4-one: The operation is the same as in Example 1, and the amine used is ( E )-pyrrolidone-3-monooxy-ethyloxime. Compound 7 was obtained as a yellow solid (yield 30%).
  • Example 7 Compound 8: ( E )-2-(3-(ethoxyimino)pyrrolidin-1-yl)-6-(methylsulfonyl)-8-nitro-4 H -benzo[ e ] [1,3] Thiazin-4-one: The operation is the same as in Example 1, and the amine used is ( E )-pyrrolidone-3-monooxo-benzyl oxime. Compound 8 was obtained as a yellow solid (yield 35%).
  • Example 8 Compound 9: 6-(methylsulfonyl)-8-nitro-2-(4-((4-(trifluoromethyl)piperidin-1-yl)methyl)piperidin-1-yl ) -4 H - benzo [e] [1,3] thiazin --4--one: the same procedure as in Example 1, with the amine 1- (piperidin-4-ylmethyl) -4- (C Fluoromethyl)piperidine. Compound 9 was obtained as a yellow solid (yield 31%).
  • Example 9 Compound 10: 2-(4-(Methoxyimino)piperidin-1-yl)-6-(methylsulfonyl)-8-nitro-4 H -benzo[ e ] [1, 3] Thiazin-4-one: The operation is the same as in Example 1, and the amine used is piperidine-4-monooxy-methyloxime. The compound 10 was obtained as a yellow solid (yield 47%).
  • 1 H NMR (400 MHz, CDCl 3 ) ⁇ 9.29 (s, 1H), 9.04 (s, 1H), 4.18 (br, 2H), 4.09 (br, 2H), 3.87 (s, 3H), 3.19 (s, 3H), 2.78 (s, 2H), 2.64 (s, 2H).
  • Example 10 Compound 11: 2-(4-(ethoxyimino)piperidin-1-yl)-6-(methylsulfonyl)-8-nitro-4 H -benzo[ e ] [1, 3] Thiazin-4-one: The operation is the same as in Example 1, and the amine used is piperidine-4-monooxy-ethyloxime. The compound 11 was obtained as a yellow solid (yield 49%).
  • 1 H NMR (400 MHz, CDCl 3 ) ⁇ 9.29 (s, 1H), 9.04 (s, 1H), 4.18 – 4.01 (m, 6H), 3.19 (s, 3H), 2.79 (s, 2H), 2.64 ( s, 2H), 1.24 – 1.28 (m, 3H).
  • Example 11 Compound 12: 2-(4-((benzyloxy)imino)piperidin-1-yl)-6-(methylsulfonyl)-8-nitro-4 H -benzo[ e ][ 1,3] Thiazin-4-one: The operation is the same as in Example 1, and the amine used is piperidine-4-monooxo-benzyl oxime. Compound 12 was obtained as a yellow solid (yield 44%).
  • Example 12 Compound 13: 2-(4-(cyclohexylmethyl)-3-oxapiperazin-1-yl)-6-(methylsulfonyl)-8-nitro-4 H -benzo[ e ] [1,3] Thiazin-4-one: The operation is the same as in Example 1, and the amine used is 1-(cyclohexylmethyl)piperazin-2-one. The compound 13 was obtained as a yellow solid (yield 68%).
  • Example 13 Compound 14: ( R )-2-(2-methyl-1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-(methylsulfonyl)-8 -Nitro-4 H -benzo[ e ] [1,3] thiazin-4-one: The operation is the same as in Example 1, and the amine used is (R-)-2 methyl-1,4-dioxide -8-Azaspirodecane. Compound 14 was obtained as a yellow solid (yield 27%).
  • Example 14 Compound 27: 2-(4-(2-(2-methyl-5-nitro-1 H -imidazol-1-yl)ethyl)piperazin-1-yl)-6-(methanesulfon Acyl)-8-nitro-4 H -benzo[ e ][1,3]thiazin-4-one: The operation is the same as in Example 1. The amine used is 1-(2-(2-methyl- 5-Nitro- 1H -imidazol-1-yl)ethyl)piperazine. The compound 27 was obtained as a yellow solid (yield 51%).
  • Example 15 Compound 28: 2-(4-(cyclohexylmethyl)-4,7-diazaspiro[2.5]octyl-7-yl)-6-(methylsulfonyl)-8-nitro -4 H -Benzo[ e ] [1,3]thiazin-4-one: The operation is the same as in Example 1, and the amine used is 4-(cyclohexylmethyl)-4,7-diazaspiro[ 2.5] Octane. The compound 28 was obtained as a yellow solid (yield 52%). .
  • Example 16 Compound 29: 2-(7-isobutyl-4,7-diazaspiro[2.5]octyl-4-yl)-6-(methylsulfonyl)-8-nitro-4 H -Benzo[ e ][1,3]thiazin-4-one: The operation is the same as in Example 1, and the amine used is 7-isobutyl-4,7-diazaspiro[2.5]octane. Compound 29 was obtained as a yellow solid (yield 60%).
  • Example 17 Compound 38: 6- (methylsulfonyl) -8-nitro-2- (4-phenyl-piperidin-1-yl) -4 H - benzo [e] [1,3] Thiazin-4-one: The operation is the same as in Example 1, and the amine used is 4-phenylpiperidine. Compound 38 was obtained as a yellow solid (yield 44%).
  • Example 18 Compound 20: 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(methylsulfonyl)-4 H -benzo[ e ] [1,3]thiazine-4 -Ketone: The same as in Example 1, the compound A3 was replaced with 2-chloro-5-(methylsulfonyl)benzoic acid, the amine was 1-cyclohexylmethylpiperazine, and the rest remained unchanged to obtain compound 20 as white Solid (50% yield).
  • Example 20 to Example 22 are the same as that of Example 20, and the starting compounds used are replaced with the rest unchanged to obtain different benzothiazinone derivatives.
  • Example 20 Compound 22: 8-chloro-2-(3-(ethoxyimino)azetidin-1-yl)-6-(methylsulfonyl)-4 H -benzo[ e ][ 1,3] Thiazin-4-one: The operation is the same as in Example 19, and the starting material used is compound 4. The compound 22 was obtained as a yellow solid (yield 60%).
  • 1 H NMR (400 MHz, CDCl 3 ) ⁇ 8.96 (s, 1H), 8.18 (s, 1H), 5.02 (s, 2H), 5.00 (s, 2H), 4.18 (d, J 6.8 Hz, 2H) , 3.13 (s, 3H), 1.63 – 1.25 (m, 3H).
  • Example 21 Compound 23: 8-chloro-2-(4-(methoxyimino)piperidin-1-yl)-6-(methylsulfonyl)-4 H -benzo[ e ] [1, 3] Thiazin-4-one: The operation is the same as in Example 20, and the starting material used is compound 10. The compound 23 was obtained as a yellow solid (90% yield).
  • Example 22 8-Chloro-2-(4-(ethoxyimino)piperidin-1-yl)-6-(methylsulfonyl)-4 H -benzo[ e ] [1, 3] Thiazin-4-one: The operation is the same as in Example 20, and the starting material used is compound 11. The compound 24 was obtained as a yellow solid (yield 60%).
  • Example 23 Compound 16: 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(isopropylsulfonyl)-8-nitro-4 H -benzo[ e ] [1 ,3] Thiazin-4-one: Dissolve 4-fluoro-2-methyl-1-nitrobenzene (500 mg, 3.22 mmol) in 20 mL of anhydrous DMF, add potassium carbonate (757 mg, 5.48 mmol) ), and then isopropyl mercaptan (378 mg, 3.55 mmol) was added dropwise, and the system was stirred at room temperature for 12 h.
  • reaction system was slowly poured into an ice-water bath, a white solid precipitated, filtered, washed with ice water three times, and dried to obtain white crystals B6 (385 mg, yield 90%); compound B6 (385 mg, 0.96 mmol) was dissolved In 10mL of 2M methanol solution of ammonia, the system was heated to 80°C for 12h.
  • the mixture is concentrated to obtain a white solid;
  • the white solid was dissolved in dry DCM (20 mL) and added to the ammonium isothiocyanate solution, reacted for 0.5 h under nitrogen protection, and then 1-(cyclohexylmethyl)piperazine (60 mg, 0.3 mmol) was added. After reacting at room temperature for 5 hours, the solvent was spin-dried, slurried with cyclohexane/ethyl acetate (10:1), filtered, and washed with water (30 mL ⁇ 3) to obtain yellow solid compound 16 (40 mg, yield 55%).
  • Example 24 to Example 26 are the same as that of Example 25, the thiol used is replaced, and the rest remain unchanged to obtain different benzothiazinone derivatives.
  • Example 24 Compound 17: 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(ethanesulfonyl)-8-nitro-4 H -benzo[ e ] [1,3 ] Thiazin-4-one: The operation is the same as in Example 24, and the mercaptan used is ethyl mercaptan. Compound 17 was obtained as a yellow solid (61% yield).
  • Example 25 Compound 18: 6-(tert-butylsulfonyl)-2-(4-(cyclohexylmethyl)piperazin-1-yl)-8-nitro-4 H -benzo[ e ] [1 ,3] Thiazin-4-one: The operation is the same as in Example 24, and the mercaptan used is tert-butyl mercaptan. The compound 18 was obtained as a yellow solid (40% yield).
  • Example 26 Compound 19: 2-(4-(cyclohexylmethyl)piperazin-1-yl)-8-nitro-6-(benzenesulfonyl)-4 H -benzo[ e ] [1,3 ] Thiazin-4-one: The operation is the same as in Example 24, and the mercaptan used is thiophenol. Compound 19 was obtained as a yellow solid (yield 55%).
  • Example 27 Compound 25: 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(isopropylsulfonyl)-4 H -benzo[ e ][1,3]thiazine -4-one: The operation is the same as in Example 23, the 4-fluoro-2-methyl-1-nitrobenzene is replaced with 3-fluorotoluene, and the rest remains unchanged, to obtain compound 25 as a yellow solid (yield 50%) .
  • the minimum inhibitory concentration MIC ( ⁇ M) and cLogP value of the above compounds against Mycobacterium tuberculosis (H37Rv, standard tuberculosis strain) are as follows.
  • the compound of the present invention has a significant antibacterial effect, and the antibacterial effect far exceeds the positive control isoniazid, especially compared with the positive control pBTZ169, the compound of the present invention has a significantly better cLogP value.

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  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

Abstract

公开了苯并噻嗪酮衍生物及其制备方法与作为抗结核药物的应用，具体涉及一类新的具有苯并噻嗪酮骨架的化合物，该类化合物显示对结核杆菌具有抑制效果，尤其是其对具有临床抗药性的结核杆菌同样具有抑制效果。该类化合物活性与现有临床一线用药异烟肼(MIC 0.5μM)相比，具有非常大的优势，与现有研究阶段的苯并噻嗪酮抗结核药物pBTZ 169相比，具有更低的cLogP值，具有更好的成药性。

Description

苯并噻嗪酮衍生物及其制备方法与作为抗结核药物的应用 技术领域
本发明的技术领域是有关抗菌药物的应用，主要针对杆菌， 如结核菌或者麻风杆菌，感染人体后的药物的研发；具体涉及一类新的具有苯并噻嗪酮骨架的化合物，该类化合物显示对结核杆菌具有抑制效果，尤其是其对具有临床抗药性的结核杆菌同样具有抑制效果。
 背景技术
结核菌生长繁殖缓慢，***一代通常需要18-24小时，这使得对结核病的筛查和诊断也变得困难。临床上对至少两种一线药物（异烟肼和利福平）耐药的称作耐多药菌株（MDR-TB），耐多药（MDR）以及广谱耐药（XDR-TB)分枝杆菌的持续发展是极其危险的；研发结构新颖，作用机制与现有临床用药不同的新型抗结核药物的应用，是有效控制结核病的途径。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)，两个化合物对结核菌标准株的MIC分别为0.02μM和0.004μM，与现有临床一线用药异烟肼（MIC 0.5μM）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cLogP值高，成药性差。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骨架苯环进行创造性改变，尤其对取代基进行创造性变化，得到的一系列的化合物，取得预料不到的技术效果；本发明化合物具有优异的对结核菌的抑制效果，所报道的化合物活性与现有临床一线用药异烟肼（MIC 0.5 μM）相比，具有非常大的优势，重要的是，与现有研究阶段的苯并噻嗪酮抗结核药物pBTZ 169相比，本发明的化合物具有更低的cLogP值，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：一种苯并噻嗪酮衍生物，其结构如下：
Figure 368414dest_path_image001
。
其中，R 1包括硝基、卤素、氰基、醛基或者酯基；比如为：硝基(NO 2)、卤素(F、Cl、Br、I)、氰基(CN)、醛基(CHO)、酯基(COOCH 3、COOC 2H 5)等；R 2包括氢、烷基、环烷基、烯烃基、炔烃基、烷氧基、羟基、羧基、氨基、取代胺基中的一种，优选为H、C1-C6烷基、C1-C6环烷基、C1-C6的烯烃基、C1-C6炔烃基、C1-C6烷氧基、羟基、羧基、氨基、取代胺基等；R 3包括烷基、环烷基、烯烃基、炔烃基、烷氧基、羟基、羧基、氨基、取代胺基中的一种，优选为C1-C6烷基、C1-C6环烷基、C1-C6烯烃基、C1-C6炔烃基、C1-C6烷氧基、羟基、羧基、氨基或者取代的胺基等；R 4包括氢、烷基、环烷基、烯烃基、炔烃基、烷氧基、羟基、羧基、氨基、取代胺基中的一种，优选为H、C1-C6烷基、C1-C6环烷基、C1-C6的烯烃基、C1-C6炔烃基、C1-C6烷氧基、羟基、羧基、氨基、取代胺基等；R 5为以下取代基
Figure 918344dest_path_image002
。
其中，n1=1～3；n2=1～3；R 6包括氢、烷基、环烷基、烯烃基、炔烃基、烷氧基、羟基、羧基、氨基、取代胺基、苄基、磺酰基中的一种，优选为H、C1-C6的烷基、C1-C6的环烷基、C1-C6的烯烃基、C1-C6炔烃基、C1-C6烷氧基、苄基、磺酰基等；R 9包括氢、烷基、环烷基或者羰基，优选为C1-C6烷基、C1-C6环烷基、酮等；R 10包括烷基、环烷基、杂环基、取代杂环基或者芳基，优选为C1-C6烷基、C1-C6环烷基、苯基、取代苯基等；R 11包括烷基、环烷基或者芳基，优选为C1-C6烷基、C1-C6环烷基、苯基、取代苯基等；R 12包括烷基、环烷基、杂环基、取代杂环基或者芳基，优选为C1-C6烷基、C1-C6环烷基、苯基、取代苯基等，比如R 5为以下取代基：
Figure 534133dest_path_image003
。
本发明苯并噻嗪酮衍生物的制备方法包括以下步骤。
（1）化合物A5与胺化合物反应，得到苯并噻嗪酮衍生物。
（2）将步骤（1）制备的苯并噻嗪酮衍生物还原，得到化合物A7；化合物A7发生取代反应，得到苯并噻嗪酮衍生物。
进一步的，化合物A3或者2-氯-5-(甲基磺酰基)苯甲酸进行氯代反应，得到化合物A4；化合物A4与异硫氰酸盐反应，得到化合物A5。
本发明中，步骤（1）的产物可称为化合物A6，步骤（2）的产物可称为化合物A8，化合物A6、化合物A8都是本发明苯并噻嗪酮衍生物；化合物A3、化合物A4、化合物A5、化合物A6、化合物A7、化合物A8的化学结构式如下。
Figure 827711dest_path_image004
。
胺化合物的化学结构式如下。
Figure 458894dest_path_image005
。
其中，取代基的定义同上文。
本发明公开了上述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。
本发明公开了以上述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。
本发明公开了系列结构创新的化合物，实施例结果显示，本发明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pBTZ169具有高的cLogP值的缺陷。
 具体实施方式
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；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。
本发明苯并噻嗪酮衍生物的制备方法如下：（1）化合物A5与胺化合物反应，得到苯并噻嗪酮衍生物；（2）将步骤（1）制备的苯并噻嗪酮衍生物还原，得到化合物A7；化合物A7发生取代反应，得到苯并噻嗪酮衍生物。
进一步的，化合物A3氯代反应，得到酰氯A4；化合物A4与异硫氰酸盐反应，得到化合物A5；A4到A6为一锅反应。
具体的，本发明各化合物的制备可以参照以下示意路径：
Figure 914146dest_path_image006
。
胺化合物的化学结构式如下：
Figure 17232dest_path_image007
。
其中，取代基的定义同上文。
更具体的，上述反应路径可举例如下：A1→A3的步骤为：化合物A1在过氧单磺酸钾的氧化作用，再经过硝酸钾和浓硫酸进行硝化得到化合物A3；B1→A3的步骤为：用硫醇取代原料化合物B1苯环上的F原子得化合物硫醚B2，经氧化制备化合物B3，再将B3中的硝基还原成氨基得化合物B4，用三氟乙酸酐对氨基进行保护得化合物B5，然后用硝酸钾和浓硫酸硝化得化合物B6，在氨甲醇溶液中脱去三氟乙酰基得化合物B7，用亚硝酸叔丁酯与氯化亚铜通过重氮化将氨基转化成氯得到化合物B8，最后在重铬酸钾和浓硫酸的作用下，将甲基氧化成羧基得到化合物A3；A3→A6的步骤为：化合物A3在 N ， N-二甲基甲酰胺的催化作用下与草酰氯反应生成酰氯化合物A4，再以聚乙二醇为催化剂与硫氰酸铵反应制备化合物A5，最后加入胺化合物，生成不同的苯并噻嗪-4-酮，也称为化合物A6，为本发明产物；A6→A8的步骤为：化合物A6的硝基在铁粉、氯化铵的作用下还原成氨基得化合物A7，再经过取代反应得到化合物A8，比如通过亚硝酸叔丁酯和氯化亚铜发生取代反应生成氯代的苯并噻嗪-4-酮，为本发明产物。
比如，A1→A2使用的溶剂为甲醇，反应温度为室温，反应时间为3小时；A2→A3使用的溶剂为浓硫酸，反应温度为60℃，反应时间为2小时；B1→B2使用的溶剂为 N ， N-二甲基甲酰胺，使用的碱为碳酸钾，反应温度为室温，反应时间为6～12小时；B2→B3使用的溶剂为甲醇，反应温度为室温，反应时间为2～5小时；B3→B4使用的溶剂为乙醇（75%），反应温度为室温，反应时间约为1小时；B4→B5使用的溶剂为二氯甲烷，使用的碱为三乙胺，反应温度为冰浴，反应时间为0.5小时；B5→B6使用的溶剂为浓硫酸，反应温度为冰浴，反应时间为2～10小时；B6→B7使用的溶剂为氨甲醇溶液，反应温度为回流，反应时间为过夜；B7→B8使用的溶剂为乙腈，反应温度为回流，反应时间为0.5小时；A3→A4使用的溶剂为二氯甲烷（无水），反应温度为室温，反应时间为1小时；A4→A5使用的溶剂为二氯甲烷和丙酮，反应温度为室温，反应时间为0.2小时；A5→A6使用的溶剂为二氯甲烷和丙酮，反应温度为室温，反应时间为2小时；A6→A7使用的溶剂为乙醇（75%），反应温度为室温，反应时间为1小时；A7→A8使用的溶剂为乙腈，反应温度为回流，反应时间为0.5小时。
实施例1  化合物1：2-（4-（环己基甲基）哌嗪-1-基）-6-（甲磺酰基）-8-硝基-4 H-苯并[ e] [1,3]噻嗪-4-酮：
Figure 848921dest_path_image008
。
将硫氰酸铵（46 mg, 1.2 eq.）溶于 5 mL无水丙酮中，滴加聚乙二醇（0.05eq.，以化合物A3为基准），室温下搅拌至溶解，得到异硫氰酸铵溶液；将化合物A3（50 mg，1eq. ，R 3为甲基）溶于二氯甲烷（无水）（5 mL），滴加 N ， N-二甲基甲酰胺（0.05eq.，以化合物A3为基准），滴加草酰氯（0.25 mL, 2.5eq.），滴加完成后室温下搅拌0.5小时，反应结束后，旋干溶剂和过量的草酰氯，得到相应的中间体酰氯化合物（化合物A4中，R 3为甲基）；再滴加上述异硫氰酸铵溶液，滴加完成后室温下搅拌20分钟，反应结束，得到中间体A5（化合物A5中，R 3为甲基）；然后滴加1-（环己基甲基）-哌嗪（50 mg, 1.1eq.）的二氯甲烷溶液，滴加完成后室温下搅拌2小时，反应结束，旋干溶剂，直接柱层析纯化，得到化合物1为黄色固体（20 mg，产率48%）。 1H NMR (400 MHz, DMSO-d 6) δ 8.98 (s, 1H), 8.95 (s, 1H), 3.89 (s, 4H), 3.43 (s, 3H), 2.46 (s, 4H), 2.13 (d, J = 10.8 Hz, 2H), 1.75 (d, J = 10.8 Hz, 2H), 1.65 (s, 4H), 1.50 (s, 1H), 1.19 (d, J = 9.2 Hz, 2H), 0.85 (d, J = 10.8 Hz, 2H). 13C NMR (101 MHz, DMSO-d 6) δ 165.6, 161.8, 144.6, 139.7, 135.6, 133.7, 128.2, 126.4, 64.7, 52.8, 46.1, 43.5, 34.7, 31.6, 26.8, 25.9。MS-ESI (m/z): 466.7 [M+H] +。
以下实施例2至实施例18的制备方法与实施例1相同，将所用的胺化合物更换，其余不变，得到不同的苯并噻嗪酮衍生物。
Figure 353852dest_path_image009
。
实施例2 化合物3：2-（3-（甲氧基亚氨基）氮杂环丁-1-基）-6-（甲磺酰基）-8-硝基-4 H-苯并[ e] [1,3]噻嗪-4-酮：与实施例1操作相同，所用的胺为氮杂环丁烷-3-一氧-甲基肟，其余不变，得到化合物3为白色固体（产率46%）。 1H NMR (400 MHz, DMSO-d 6) δ 9.34 (s, 1H), 9.08 (s, 1H), 5.05 – 5.04 (m, 4H), 3.93 (s, 3H), 3.19 (s, 3H)。 13C NMR (101 MHz, DMSO-d 6) δ 165.3, 162.0, 146.0, 144.1, 139.8, 135.6, 134.3, 128.3, 126.1, 62.5, 60.2, 43.52。MS-ESI (m/z): 384.6 [M+H] +。
实施例3 化合物4：2-（3-（乙氧基亚氨基）氮杂环丁-1-基）-6-（甲磺酰基）-8-硝基-4 H-苯并[ e] [1,3]噻嗪-4-酮：与实施例1操作相同，所用的胺为氮杂环丁烷-3-一氧-乙基肟，其余不变，得到化合物4为白色固体（产率36%）。 1H NMR (400 MHz, CDCl 3) δ 9.31 (s, 1H), 9.06 (s, 1H), 5.07 (s, 2H), 5.03 (s, 2H), 4.16 (d, J = 7.0 Hz, 2H), 3.18 (s, 3H), 1.30 – 1.22 (m, 3H). 13C NMR (101 MHz, CDCl 3) δ 165.6, 162.0, 143.6, 142.2, 140.2, 135.6, 135.4, 127.8, 126.7, 70.8, 49.6, 44.1, 14.4. MS-ESI (m/z): 398.7 [M+H] +。
实施例4 化合物5：2-（3-（（苄氧基）亚氨基）氮杂环丁-1-基）-6-（甲磺酰基）-8-硝基-4 H-苯并[ e] [1,3]噻嗪-4-酮：与实施例1操作相同，所用的胺为氮杂环丁烷-3-一氧-苄基肟。得到化合物5为白色固体（产率41%）。 1H NMR (400 MHz, DMSO-d 6) δ 9.04 (s, 1H), 8.98 (s, 1H), 7.39-7.34 (m, 5H), 5.18 (s, 2H), 5.12 (s, 2H), 5.05 (s, 2H), 3.44 (s, 3H). 13C NMR (151 MHz, DMSO-d 6) δ 165.3, 144.1, 139.8, 134.3, 128.8, 128.6, 128.4,128.3, 126.1, 76.2, 43.5. MS-ESI (m/z): 460.6 [M+H] + 。
实施例5 化合物6：2-（7-（环己基甲基）-2,7-二氮杂螺并[3.5]壬基-2-基）-6-（甲磺酰基）-8-硝基-4 H-苯并[ e] [1,3]噻嗪-4-酮：与实施例1操作相同，所用的胺为7-（环己基甲基）-2,7-二氮杂螺[3.5]壬烷。得到化合物6为黄色固体（产率31%）。 1H NMR (400 MHz, CD 3OD) δ 9.08 (s, 1H), 8.99 (s, 1H), 3.89 – 3.67 (m, 4H), 3.29 (s, 3H), 2.97 – 2.87 (m, 4H), 2.57 – 2.52 (m, 2H), 2.23 – 2.21 (m, 2H), 2.13 – 2.01 (m, 2H), 1.85 (d, J = 11.6 Hz, 2H), 1.77 – 1.68 (m, 3H), 1.60 (s, 2H), 1.29 – 1.20 (m, 2H), 1.02 – 0.88 (m, 2H). MS(+ESI) m/z calcd for C 23H 31N 4O 5S 2 [M+H] + = 507.17, found 506.8。
Figure 980005dest_path_image010
。
实施例6 化合物7：（ E）-2-（3-（乙氧基亚氨基）吡咯烷-1-基）-6-（甲磺酰基）-8-硝基-4 H-苯并[ e] [1,3]噻嗪-4-酮：与实施例1操作相同，所用的胺为（ E）-吡咯烷酮-3-一氧-乙基肟。得到化合物7为黄色固体（产率30%）。 1H NMR (400 MHz, CDCl 3) δ 9.29 (s, 2H), 9.03 (s, 2H), 4.60 (s, 2H), 4.43 (s, 2H), 4.19-4.22 (m, 2H), 4.15 (s, 2H), 4.14 (s, 2H), 3.99 (s, 2H), 3.19 (s, 3H), 3.00-3.04 (m, 2H), 2.91 (s, 2H), 1.24-1.27 (m, 3H), (s, 3H)。HRMS (ESI+) m/z [M+Na] + calcd for C 15H 16N 4O 6S 2Na: 435.0403; found: 435.0401。
实施例7 化合物8：（ E）-2-（3-（乙氧基亚氨基）吡咯烷-1-基）-6-（甲磺酰基）-8-硝基-4 H-苯并[ e] [1,3]噻嗪-4-酮：与实施例1操作相同，所用的胺为（ E）-吡咯烷酮-3-一氧-苄基肟。得到化合物8为黄色固体（产率35%）。 1H NMR (400 MHz, CDCl 3) δ 9.29 (s, 2H), 9.03 (s, 2H), 4.60 (s, 2H), 4.43 (s, 2H), 4.20 (s, 2H), 4.15 (s, 2H), 4.14 – 4.06 (m, 2H), 3.99 (s, 2H), 3.19 (s, 3H), 3.19 – 3.13 (m, 3H), 3.03 (s, 2H), 2.91 (d, J = 7.2 Hz, 2H), 1.27 (s, 3H), 1.24 (s, 3H)。 13C NMR (101 MHz, CDCl 3) δ 165.5, 160.3, 143.6, 139.8, 136.3, 135.1, 127.5, 127.2, 63.9, 63.1, 58.7, 53.8, 49.9, 48.6, 47.0, 46.7, 44.1, 37.1, 36.7, 35.7, 35.1, 35.0, 29.6, 29.3, 26.6 , 26.0, 22.7。MS-ESI (m/z): 474.6 [M+H] +。
实施例8 化合物9：6-（甲磺酰基）-8-硝基-2-（4-（（4-（三氟甲基）哌啶-1-基）甲基）哌啶-1-基）-4 H-苯并[ e] [1,3]噻嗪- 4-酮：与实施例1操作相同，所用的胺为1-（哌啶-4-基甲基）-4-（三氟甲基）哌啶。得到化合物9为黄色固体（产率31%）。
1H NMR (400 MHz, CDCl 3) δ9.28 (s, 1H), 9.02 (s, 1H), 3.18 (s, 3H), 2.94 (d, J = 10.0 Hz, 2H), 2.22 (d, J = 6.4 Hz, 2H), 1.99 – 1.93 (m, 8H), 1.83 (d, J = 12.4 Hz, 2H), 1.64 – 1.61 (m, 2H), 1.36 – 1.24 (m, 4H). 13C NMR (151 MHz, CDCl 3) δ 166.1, 161.3, 144.0, 139.8, 136.1, 134.7, 127.6, 127.4 (q, J = 278.6 Hz), 127.1, 63.6, 44.1, 40.3 (q, J = 27.3 Hz), 33.8, 31.5, 30.1, 29.7, 24.6. HRMS (ESI+) m/z [M+H] + calcd for C 21H 26F 3N 4O 5S 2: 535.1291; found: 535.1269。
实施例9 化合物10：2-（4-（甲氧基亚氨基）哌啶-1-基）-6-（甲磺酰基）-8-硝基-4 H-苯并[ e] [1,3]噻嗪-4-酮：与实施例1操作相同，所用的胺为哌啶-4-一氧-甲基肟。得到化合物10为黄色固体（产率47%）。 1H NMR (400 MHz, CDCl 3) δ 9.29 (s, 1H), 9.04 (s, 1H), 4.18 (br, 2H), 4.09 (br, 2H), 3.87 (s, 3H), 3.19 (s, 3H), 2.78 (s, 2H), 2.64 (s, 2H)。 13C NMR (151 MHz, CDCl 3) δ 165.9, 162.5, 144.1, 140.5, 135.4, 135.1, 127.9, 127.0, 44.5, 44.2, 39.9. MS(+ESI) m/z calcd for C 15H 17N 4O 6S 2 [M+H] + = 413.06, found 412.7。
实施例10 化合物11：2-（4-（乙氧基亚氨基）哌啶-1-基）-6-（甲磺酰基）-8-硝基-4 H-苯并[ e] [1,3]噻嗪-4-酮：与实施例1操作相同，所用的胺为哌啶-4-一氧-乙基肟。得到化合物11为黄色固体（产率49%）。 1H NMR (400 MHz, CDCl 3) δ 9.29 (s, 1H), 9.04 (s, 1H), 4.18 – 4.01 (m, 6H), 3.19 (s, 3H), 2.79 (s, 2H), 2.64 (s, 2H), 1.24 – 1.28 (m, 3H)。 13C NMR (151 MHz, CDCl 3) δ 165.9, 144.0, 140.1, 135.7, 134.9, 127.7, 128.0, 69.5, 44.2, 25.2, 14.5. MS(+ESI) m/z calcd for C 16H 19N 4O 6S 2[M+H] + = 427.07, found 426.7。
Figure 367124dest_path_image011
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实施例11 化合物12：2-（4-（（苄氧基）亚氨基）哌啶-1-基）-6-（甲磺酰基）-8-硝基-4 H-苯并[ e] [1,3]噻嗪-4-酮：与实施例1操作相同，所用的胺为哌啶-4-一氧-苄基肟。得到化合物12为黄色固体（产率44%）。 1H NMR (400 MHz, CDCl 3) δ 9.30 (s, 1H), 9.05 (s, 1H), 7.35 (s, 5H), 5.10 (s, 2H), 4.19 (br, 2H), 3.99 (br, 2H), 3.19 (s, 3H), 2.83 (br, 2H), 2.65 (br, 2H). 13C NMR (151 MHz, CDCl 3) δ 165.9, 153.2 144.1 140.2, 137.5, 135.7, 135.0, 128.5, 128.2, 128.0, 127.7, 127.1, 44.2, 29.9, 25.4. MS(+ESI) m/z calcd for C 21H 21N 4O 6S 2[M+H] + = 489.09, found488.6。
实施例12 化合物13：2-（4-（环己基甲基）-3-氧杂哌嗪-1-基）-6-（甲磺酰基）-8-硝基-4 H-苯并[ e] [1,3]噻嗪-4-酮：与实施例1操作相同，所用的胺为1-（环己基甲基）哌嗪-2-酮。得到化合物13为黄色固体（产率68%）。 1H NMR (400 MHz, CDCl 3) δ 9.29 (s, 1H), 9.06 (s, 1H), 4.51 (s, 1H), 4.29 (s, 1H), 4.11 (dd, J = 14.2, 7.2 Hz, 1H), 3.53 (s, 2H), 3.32 (d, J = 7.0 Hz, 2H), 3.19 (s, 3H), 2.04 (s, 1H), 1.72 (s, 2H), 1.67 – 1.64 (m, 5H), 1.27 (s, 2H), 1.00 (s, 2H)。 13C NMR (151 MHz, CDCl 3) δ 144.0, 140.4, 135.1, 127.8, 127.0, 53.6, 45.8, 44.2, 35.9, 30.7, 26.2, 25.7。MS-ESI (m/z): 480.6 [M+H] +。
实施例13 化合物14：（ R）-2-（2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸-8-基）-6-（甲磺酰基）-8-硝基-4 H-苯并[ e] [1,3 ] 噻嗪-4-酮：与实施例1操作相同，所用的胺为（R-)-2甲基-1,4-二氧-8-氮杂螺癸烷。得到化合物14为黄色固体（产率27%）。 1H NMR (400 MHz, CDCl 3) δ 9.31 (s, 1H), 9.04 (s, 1H), 4.29 (s, 2H), 4.13 (d, J = 7.6 Hz, 2H), 3.97 (s, 2H), 3.51 (t, J = 7.9 Hz, 3.18 (s, 3H), 1.87 (s, 4H), 1.32 (d, J = 5.9 Hz, 3H)。 13C NMR (151 MHz, CDCl 3) δ 165.2, 160.5, 143.0, 139.0, 135.0, 134.9, 126.6, 126.1, 105.3, 71.6, 69.9, 43.2, 43.2, 28.7, 17.3。MS-ESI (m/z): 441.6 [M+H] +。
实施例14 化合物27: 2-（4-（2-（2-甲基-5-硝基-1 H-咪唑-1-基）乙基）哌嗪-1-基）-6-（甲磺酰基）-8-硝基-4 H-苯并[ e] [1,3]噻嗪-4-酮：与实施例1操作相同，所用的胺为1-（2-（2-甲基-5-硝基-1 H-咪唑-1-基）乙基）哌嗪。得到化合物27为黄色固体（产率51%）。 1H NMR (400 MHz, CDCl 3) δ 9.30 (s, 1H), 9.05 (s, 1H), 7.94 (s, 1H), 4.48 (s, 2H), 4.11 (s, 2H), 3.90 (s, 2H), 3.18 (s, 3H), 2.75 – 2.62 (m, 6H), 2.53 (s, 3H). MS(+ESI) m/z calcd for C 19H 22N 7O 7S 2 [M+H] += 524.10, found 523.6。
实施例15 化合物28: 2-（4-（环己基甲基）-4,7-二氮杂螺并[2.5]辛基-7-基）-6-（甲磺酰基）-8-硝基-4 H-苯并[ e] [1,3]噻嗪-4-酮：与实施例1操作相同，所用的胺为4-（环己基甲基）-4,7-二氮杂螺[2.5]辛烷。得到化合物28为黄色固体（产率52%）。。 1H NMR (400 MHz, CDCl 3) δ 9.27 (s, 1H), 9.02 (s, 1H), 4.10 – 3.68 (m, 4H), 3.18 (s, 3H), 3.14 (s, 2H), 2.67 (d, J = 4.8 Hz, 2H), 1.77 – 1.70 (m, 4H), 1.43 (s, 1H), 1.25 – 1.19 (m, 4H), 0.91 – 0.88 (m, 4H), 0.73 (s, 2H). MS(+ESI) m/z calcd for C 22H 29N 4O 5S 2 [M+H] += 493.16, found 492.7。
Figure 940188dest_path_image012
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实施例16 化合物29: 2-（7-异丁基-4,7-二氮杂螺并[2.5]辛基-4-基）-6-（甲磺酰基）-8-硝基-4 H-苯并[ e] [1,3]噻嗪-4-酮：与实施例1操作相同，所用的胺为7-异丁基-4,7-二氮杂螺[2.5]辛烷。得到化合物29为黄色固体（产率60%）。 1H NMR (400 MHz, CDCl 3) δ9.28 (s, 1H), 9.02 (s, 1H), 3.18 (s, 3H), 2.87 - 2.68 (m, 2H), 2.21 (s, 2H), 2.07 (s, 2H), 2.03 (s, 2H), 1.74 - 1.70 (m, 2H), 1.67 (s, 1H), 1.04 (m, 2H), 0.88 – 0.87 (m, 6H). MS-ESI (m/z): 452.6 [M+H] +。
[0030] 实施例17 化合物38:  6-（甲磺酰基）-8-硝基-2-（4-苯基哌啶-1-基）-4 H-苯并[ e] [1,3]噻嗪-4-酮：与实施例1操作相同，所用的胺为4-苯基哌啶。得到化合物38为黄色固体（产率44%）。 1H NMR (400 MHz, CDCl 3) δ 9.31 (s, 1H), 9.04 (s, 1H), 7.33 (t, J = 7.2 Hz, 2H), 7.22 (t, J = 10.2 Hz, 3H), 5.47 (s, 1H), 4.54 (s, 1H), 3.44 (s 1H), 3.20 (s, 4H), 2.98 – 2.92 (m, 1H), 2.11 (s, 2H), 1.83 (dd, J = 22.8, 11.8 Hz, 2H), 1.62 (s, 1H). MS(+ESI) m/z calcd for C 20H 21N 3O 5S 2 [M+H] + = 446.08, found445.6。
实施例18 化合物20：2-（4-（环己基甲基）哌嗪-1-基）-6-（甲磺酰基）-4 H-苯并[ e] [1,3]噻嗪-4-酮：与实施例1操作相同，将化合物A3更换为2-氯-5-(甲基磺酰基)苯甲酸，胺为1-环己基甲基哌嗪，其余不变，得到化合物20为白色固体（产率50%）。 1H NMR (400 MHz, CDCl 3) δ 8.97 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 4.11 (s, 2H), 3.71 (s, 2H), 3.11 (s, 3H), 2.52 (s, 4H), 2.19 (s, 2H), 1.78 – 1.62 (m, 6H), 1.50 (s, 1H), 1.25 – 1.20 (m, 2H), 0.89 – 0.87 (m, 2H). 13C NMR (100 MHz, CDCl 3) δ 167.4, 160.9, 140.5, 138.7, 129.7, 129.6, 126.8, 123.8, 65.1, 53.0, 46.2, 44.3, 35.0, 31.7, 26.7, 26.0. MS(+ESI) m/z calcd for C 20H 28N 3O 3S 2 [M+H] += 422.16, found 421.7。
实施例19 化合物21：8-氯-2-（4-（环己基甲基）哌嗪-1-基）-6-（甲磺酰基）-4氢-苯并[ e] [1,3]噻嗪-4-酮：该化合物的制备从8-硝基的化合物1制备得到。
将化合物1 （46.6 mg，1eq.）的EtOH /水（v/v3：1，4 mL）溶液中加入NH 4Cl（21.2 mg，4eq.）和铁粉（22.4 mg，4eq.），将所得混合物在搅拌下加热回流1小时，冷却至室温后，将混合物通过硅藻土过滤，用MeOH洗涤，将滤液在减压下浓缩后的混合物用DCM和水分配，有机相DCM用盐水洗涤、干燥、过滤并浓缩，得到中间产物；再加入60°C预热的亚硝酸叔丁酯（10.3 mg，1eq.）、氯化铜二水合物（17 mg，1eq.）和乙腈的混合物，在60℃下搅拌2小时，冷却至室温，并用乙酸乙酯稀释，有机层用10％盐酸洗涤并过滤、浓缩，残留物通过柱色谱纯化，得到化合物21为黄色固体（24 mg，产率53%）。 1HNMR (400 MHz, CDCl 3) δ 8.86 (s, 1H), 8.11 (s, 1H), 4.12 (s, 2H), 3.79 (s, 2H),3.11 (s, 3H), 2.53 (s, 4H), 2.18 (d, J = 6.4 Hz, 2H), 1.78 – 1.68 (m, 6H), 1.48 (s, 1H), 1.27 – 1.21 (m, 2H), 0.91 – 0.82 (m, 2H). 13C NMR (151 MHz, CDCl 3) δ 167.3 , 160.4, 140.3, 138.2, 131.4, 129.9, 127.7, 125.9, 65.0, 52.9, 44.3, 34.9, 31.7, 29.6, 26.7, 26.0. MS(+ESI) m/z calcd for C 20H 27ClN 3O 3S 2 [M+H] + = 456.12, found 455.7。
以下实施例20至实施例22的制备方法与实施例20相同，将所用的起始化合物更换，其余不变，得到不同的苯并噻嗪酮衍生物。
Figure 96363dest_path_image013
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实施例20 化合物22：8-氯-2-（3-（乙氧基亚氨基）氮杂环丁烷-1-基）-6-（甲磺酰基）-4 H-苯并[ e] [1,3]噻嗪-4-酮：与实施例19操作相同，所用的起始原料为化合物4。得到化合物22为黄色固体（产率60%）。 1H NMR (400 MHz, CDCl 3) δ 8.96 (s, 1H), 8.18 (s, 1H), 5.02 (s, 2H), 5.00 (s, 2H), 4.18 (d, J = 6.8 Hz, 2H), 3.13 (s, 3H), 1.63 – 1.25 (m, 3H). 13C NMR (151 MHz, CDCl 3) δ 166.8, 160.5, 142.6, 140.7, 137.9, 131.4, 130.0, 128.1, 125.6, 70.7, 44.3, 29.6, 14.5. HRMS (ESI+) m/z [M+Na] + calcd for C 14H 14ClN 3O 4S 2Na: 410.0006; found: 409.9986。
实施例21 化合物23：8-氯-2-（4-（甲氧基亚氨基）哌啶-1-基）-6-（甲基磺酰基）-4 H-苯并[ e] [1,3]噻嗪-4-酮：与实施例20操作相同，所用的起始原料为化合物10。得到化合物23为黄色固体（产率90%）。 1H NMR (400 MHz, CDCl 3) δ 8.91 (s, 1H), 8.15 (s, 1H), 4.17 (s, 2H), 3.87 (s, 5H), 3.13 (s, 3H), 2.77 (s, 2H), 2.62 (s, 2H)。 13C NMR (151 MHz, CDCl 3) δ 167.2, 140.6, 138.0, 131.5, 130.0, 127.8, 125.9, 61.6, 46.0, 44.3, 29.9, 25.1. MS(+ESI) m/z calcd for C 15H 17ClN 3O 4S 2 [M+H] + = 402.03, found401.6。
 实施例22 化合物24：8-氯-2-（4-（乙氧基亚氨基）哌啶-1-基）-6-（甲基磺酰基）-4 H-苯并[ e] [1,3]噻嗪-4-酮： 与实施例20操作相同，所用的起始原料为化合物11。得到化合物24为黄色固体（产率60%）。 1H NMR (400 MHz, CDCl 3) δ 8.89 (s, 1H), 8.14 (s, 1H), 4.33 – 4.05 (m, 4H), 3.93 (s, 2H), 3.13 (s, 3H), 2.77 (s, 2H), 2.62 (s, 2H), 1.28 – 1.22 (m, 3H)。 13C NMR (151 MHz, CDCl 3) δ 167.0, 149.9, 140.5, 138.1, 131.5, 130.0, 127.8, 124.5, 120.7, 69.4, 46.0, 44.3, 29.9, 25.2, 14.5. MS(+ESI) m/z calcd for C 15H 19ClN 3O 4S 2 [M+H] + =416.05, found 415.6。
实施例23 化合物16：2-（4-（环己基甲基）哌嗪-1-基）-6-（异丙基磺酰基）-8-硝基-4 H-苯并[ e] [1,3]噻嗪-4-酮：将4-氟-2-甲基-1-硝基苯（500 mg, 3.22 mmol）溶于20 mL无水DMF中，加入碳酸钾（757 mg, 5.48 mmol），而后滴加异丙基硫醇（378 mg, 3.55 mmol），将体系在室温下搅拌12h。将体系置于冰浴下，分批加入过氧单磺酸钾（757mg,5.48mmol），将体系再次在室温下搅拌反应6h;向体系中加入50 mL水，乙酸乙酯（50 mL×3）萃取，有机相依次用碳酸氢钠水溶液、水、盐水洗涤，无水硫酸钠干燥，过滤，浓缩得白色固体B3（726 mg, 产率90%，取代基R 3为异丙基）；将化合物B3（622 mg, 2.42 mmol）溶于12 mL乙醇和4 mL水中，搅拌下加入铁粉（1350 mg, 24.17 mmol）和氯化铵（1290 mg, 24.17 mmol），将体系升温至80℃，搅拌3 h；将体系用硅藻土过滤，DCM（50 mL×3）萃取，无水硫酸钠干燥，过滤，浓缩得黄色固体B4（500 mg, 产率90%）；将化合物B4（500 mg, 2.2 mmol）溶于50 mL DCM中，搅拌下加入三乙胺（445 mg,4.4 mmol）和三氟乙酸酐（540 mg,4.4 mmol），将体系在室温下搅拌3h；将体系用50 mL水，DCM（100 mL×3）萃取，无水硫酸钠干燥，过滤，浓缩得黄色固体B5 (70 0mg, 产率99%）；将化合物B5（368 mg, 1.14 mmol）溶于5mL浓硫酸中，冰浴下缓慢加入硝酸钾（357 mg, 3.53 mmol），搅拌2h后。将反应体系缓慢倒入冰水浴中，有白色固体析出，过滤，冰水洗涤三次，干燥，得白色晶体B6(385 mg, 产率90%)；将化合物B6（385 mg, 0.96 mmol）溶于10mL2M氨的甲醇溶液中，将体系加热至80℃反应12h。将混合物冷却至室温，浓缩，柱层析（PE:EA=2:1）得黄色固体B7 (208 mg, 产率80%)；将化合物B7（200 mg, 0.74 mmol）溶于10 mL乙腈中，搅拌下加入二水合氯化铜（140 mg, 0.92 mmol）和亚硝酸叔丁酯（95 mg, 0.92 mol），将体系升温至65℃，搅拌2 h；将体系用硅藻土过滤，DCM（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B8（130 mg, 产率60%）；将化合物B8（100 mg, 0.34 mmol）加到重铬酸钾（201 mg, 0.69 mmol）在冰醋酸（10 mL）中的溶液中。搅拌15分钟后，加入浓硫酸（336 mg, 1.836 mmol），并将溶液加热回流4小时。然后将混合物冷却，加入水（50 mL），并用乙酸乙酯（3 × 50mL）萃取。 收集有机相，用无水硫酸钠干燥并浓缩。残余物用20 mL乙酸乙酯溶解，有机相用2M氢氧化钠（20 mL）洗涤，将水相用12N HCl调pH2，乙酸乙酯 （3 × 50mL）萃取，收集有机相，用无水硫酸钠干燥并浓缩得白色固体化合物A3（65 mg, 产率60%），MS-ESI (m/z): 329.7 [M+Na] +；将硫氰酸铵（46 mg, 1.2 eq.）溶于 5 mL无水丙酮中，滴加聚乙二醇（0.05eq.，以化合物A3为基准），室温下搅拌至溶解，得到异硫氰酸铵溶液；将化合物A3（65 mg,0.2 mmol）溶于DCM（20 mL），加入催化量的DMF，在氮气保护下缓慢滴加草酰氯(134 mg，1.06 mmol)，在室温下反应2 h,将混合物浓缩得白色固体；将上一步制得白色固体溶于干燥的DCM （20 mL）后加入异硫氰酸铵溶液中，在氮气保护下反应0.5 h，再加入1-（环己基甲基）哌嗪（60 mg,0.3mmol），在室温下反应5h，旋干溶剂，用环己烷/乙酸乙酯（10：1）打浆过滤，用水（30 mL×3）洗涤，得黄色固体化合物16（40 mg, 产率55%）。 1H NMR (400 MHz, CDCl 3) δ 9.23 (s, 1H), 8.95 (s, 1H), 4.14 (s, 2H), 3.87 (s, 2H), 3.38 – 3.30 (m, 1H), 2.54 (s, 4H), 2.18 (d, J = 8.0 Hz, 2H), 1.83 – 1.66 (m, 6H), 1.49 (s, 1H), 1.37 (s, 3H), 1.35 (s, 3H), 1.24 ( s, 2H), 0.93 – 0.85 ( m, 2H)。 13C NMR (151 MHz, CDCl 3) δ 166.1, 161.7, 144.1, 136.1, 129.0, 127.0, 77.2, 76.9, 76.8, 64.9, 55.8, 34.7, 31.6, 31.3, 26.5, 25.9, 25.5, 15.6。 .MS-ESI (m/z): 494.7 [M+H] +。
以下实施例24至实施例26的制备方法与实施例25相同，将所用的硫醇更换，其余不变，得到不同的苯并噻嗪酮衍生物。
Figure 345948dest_path_image014
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实施例24 化合物17：2-（4-（环己基甲基）哌嗪-1-基）-6-（乙磺酰基）-8-硝基-4 H-苯并[ e] [1,3]噻嗪-4-酮：与实施例24操作相同，所用的硫醇为乙硫醇。得到化合物17为黄色固体（产率61%）。 1H NMR (400 MHz, CDCl 3) δ 9.23 (s, 1H), 8.95 (s, 1H), 4.14 (s, 2H), 3.87 (s, 2H), 3.38 – 3.30 (m, 1H), 2.54 (br, 4H), 2.18 (d, J = 8.0 Hz, 2H), 1.83 – 1.66 (m, 6H), 1.49 (s, 1H), 1.37 (s, 3H), 1.35 (s, 3H), 1.24 (d, J = 10.4 Hz, 2H), 0.93 – 0.85 (m, 2H)。 13C NMR (151 MHz, CDCl 3) δ 166.1, 161.6, 144.0, 138.2 , 135.9, 135.4, 128.3, 127.1, 65.0, 50.4, 35.0, 31.7, 26.7, 26.0, 7.3。MS-ESI (m/z): 480.6 [M+H] +。
实施例25 化合物18：6-（叔丁基磺酰基）-2-（4-（环己基甲基）哌嗪-1-基）-8-硝基-4 H-苯并[ e] [1,3]噻嗪-4-酮：与实施例24操作相同，所用的硫醇为叔丁基硫醇。得到化合物18为黄色固体（产率40%）。 1H NMR(400 MHz, CDCl 3) δ 9.22 (s, 1H), 8.93 (s, 1H), 4.14 (s, 2H), 3.88 (s, 2H), 2.54 (br, 4H), 2.18 (d, J = 7.0 Hz, 2H), 1.77 (d, J = 15.2 Hz, 4H), 1.70 (s, 2H), 1.49 (s, 1H), 1.40 (s, 9H), 1.24 (s, 2H), 0.88 (s, 2H)。 13C NMR (151 MHz,CDCl 3) δ 166.0, 161.5, 143.7, 137.4, 135.7, 135.3, 130.0, 126.6, 65.0, 60.7, 53.0, 46.5, 34.9, 31.6, 26.6, 25.9。MS-ESI (m/z): 508.7 [M+H] +。
实施例26 化合物19：2-（4-（环己基甲基）哌嗪-1-基）-8-硝基-6-（苯磺酰基）-4 H-苯并[ e] [1,3]噻嗪-4-酮：与实施例24操作相同，所用的硫醇为苯硫酚。得到化合物19为黄色固体（产率55%）。 1H NMR (400 MHz, CDCl 3) δ 9.25 (s, 1H), 9.03 (s, 1H), 8.02 (d, J = 7.2 Hz, 2H), 7.63 (d, J = 6.7 Hz, 1H), 7.57 (d, J = 7.0 Hz, 2H), 3.98 (br, 4H), 2.52 (br, 4H), 2.17 (s, 2H), 1.84 – 1.64 (m, 6H), 1.48 (s, 1H), 1.21 (s, 2H), 0.87 (s, 2H)。 13C NMR (151 MHz, CDCl 3) δ 166.1 , 161.6 , 160.6 , 144.0 , 141.4 , 139.7 , 135.0 , 134.3 , 129.8 , 128.2 , 127.6 , 65.4 , 65.0 , 54.0 , 45.6 , 39.9 , 35.0 , 26.7。MS-ESI (m/z): 528.6 [M+H] +。
实施例27 化合物25：2-（4-（环己基甲基）哌嗪-1-基）-6-（异丙基磺酰基）-4 H-苯并[ e] [1,3]噻嗪-4-酮：与实施例23操作相同，将4-氟-2-甲基-1-硝基苯更换为3-氟甲苯，其余不变，得到化合物25为黄色固体（产率50%）。 1H NMR (400 MHz, CDCl 3) δ8.84 (s, 1H), 8.07 (s, 1H), 4.13 (s, 2H), 3.79 (s, 2H), 3.28 (dt, J = 13.4, 6.8 Hz, 1H), 2.52 (s, 4H), 2.18 (d, J = 7.0 Hz, 2H), 1.77 (d, J = 16.0 Hz, 3H), 1.65 (d, J = 20.0 Hz, 3H), 1.49 (s, 1H), 1.33 (s, 3H), 1.32 (s, 3H), 1.24 (s, 2H), 0.87 (s, 2H). 13C NMR (151 MHz, DMSO-d 6) δ 165.4, 163.4, 144.5, 133.9 , 128.2 , 121.4 , 117.6 , 117.2, 64.5, 60.2, 53.5, 43.6, 36.4, 21.0, 14.5。MS-ESI (m/z): 449.7 [M+H] +。
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；采用软件ChemDraw Professional 16.0 计算得到cLogP值，为常规测试方法。
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（μM）以及cLogP值如下。
Figure 220363dest_path_image015
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更换原料，根据上述制备方法，得到如下化合物以及对结核分枝杆菌（H37Rv，标准结核菌株）的最小抑菌浓度MIC（μM）。
Figure 597117dest_path_image016
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2-(4-((4,4-二氟环己基)甲基)哌嗪-1-基)-6-(甲磺酰基)-8-硝基-4 H-苯并-[ e][1,3]噻嗪-4-酮: 1H NMR (400 MHz, CDCl 3) δ 9.30 (s, 1H), 9.04 (s, 1H), 4.15 – 3.89 (m, 4H), 3.18 (s, 3H), 2.57 (br, 4H), 2.26 (d, J = 6.6 Hz, 2H), 2.10 (br, 2H), 1.88 (d, J = 11.2 Hz, 2H), 1.76 – 1.67 (m, 1H), 1.27 – 1.25 (m, 4H). MS (+ESI) m/z calcd for C 20H 25F 2N 4O 5S 2 + [M+H] += 503.1229, found 503.1223. MIC: 0.030μM。
6-(甲磺酰基)-8-硝基-2-(4-((四氢-2H-吡喃-4基)甲基)哌嗪-1-基)-4 H-苯并[ e] [1,3]噻嗪-4-酮: 1H NMR (400 MHz, CDCl 3) δ 9.30 (s, 1H), 9.04 (s, 1H), 4.16 – 4.11 (m, 2H), 4.00 – 3.96 (m, 4H), 3.40 (t, J = 11.6 Hz, 2H), 3.18 (s, 3H), 2.60 (br, 4H), 2.29 (d, J = 6.4 Hz, 2H), 1.78 (br, 1H), 1.71 – 1.68 (m, 2H), 1.30 – 1.25 (m, 2H). MS (+ESI) m/z calcd for C 19H 25N 4O 6S 2 + [M+H] += 469.1210, found 469.1208. MIC: 0.512μM。
6-(甲磺酰基)-8-硝基-2-(4-((四氢-2H-噻喃-4基)甲基)哌嗪-1-基)-4 H-苯并[ e] [1,3]噻嗪-4-酮:MS (+ESI) m/z calcd for C 19H 25N 4O 5S 3 + [M+H] += 485.0982, found 485.0983. MIC: 0.100μM。
2-(4-苄基哌嗪-1-基）-6-甲磺酰基)-8-硝基-4H-苯并[ e] [1,3]噻嗪-4-酮: 1H NMR (400 MHz, CDCl 3) δ9.29 (s, 1H), 9.03 (s, 1H), 7.35 (br, 5H), 4.27 – 3.83 (m, 4H), 3.64 (s, 2H), 3.18 (s, 3H), 2.66 (br, 4H). MS (+ESI) m/z calcd for C 20H 21N 4O 5S 2 + [M+H] += 461.0948, found 461.0947. MIC: 0.213μM。
6-(甲磺酰基)-8-硝基-2-(4-(噻吩-2-基甲基)哌嗪-1-基)-4H-苯并[ e] [1,3]噻嗪-4-酮: 1H NMR (400 MHz, CDCl 3) δ 9.27 (s, 1H), 9.02 (s, 1H), 7.26 (br, 1H), 6.95 (d, J = 14.0 Hz, 2H), 4.12 – 4.17 (m, 4H), 3.81 (s, 2H), 3.18 (s, 3H), 2.65 (br, 4H). MS (+ESI) m/z calcd for C 18H 19N 4O 5S 3 + [M+H] += 467.0512, found 467.0508. MIC: 0.251μM。
6-(甲磺酰基)-8-硝基-2-(4-(噻吩-2-基磺酰基)哌嗪-1-基)-4H-苯并[ e][1,3]噻嗪-4-酮: 1H NMR (400 MHz, DMSO- d 6) δ 8.96 (s, 1H), 8.95 (s, 1H), 8.07 (d, J = 4.6 Hz, 1H), 7.67 (br, 1H), 7.29 (t, J = 3.6 Hz, 1H), 4.05 (br, 4H), 3.42 (s, 3H), 3.14 (br, 4H). MS (+ESI) m/z calcd for C 17H 17N 4O 7S 4 + [M+H] += 516.9975, found 516.9976. MIC: 0.108μM。
2-(4-(环丙基磺酰基)哌嗪-1-基)-6-(甲磺酰基)-8-硝基-4H-苯并[ e][1,3]噻嗪-4-酮: 1H NMR (400 MHz, CDCl 3) δ 9.31 (s, 1H), 9.07 (s, 1H), 4.14 (br, 4H), 3.50 (br, 4H), 3.19 (s, 3H), 3.02 (q, J = 7.2 Hz, 1H), 1.40 (t, J = 7.6 Hz, 4H). MS (+ESI) m/z calcd for C 16H 19N 4O 7S 3 + [M+H] += 475.0410, found 475.0414. MIC: 0.328μM。
2-(4-(丁基磺酰基)哌嗪-1-基)-6-(甲磺酰基)-8-硝基-4 H-苯并[ e][1,3]噻嗪-4-酮:MS (+ESI) m/z calcd for C 17H 23N 4O 7S 3 + [M+H] += 491.0723, found 491.0721. MIC: 0.091μM。
2-(4-(乙基磺酰基)哌嗪-1-基)-6-(甲磺酰基)-8-硝基-4 H-苯并[ e][1,3]噻嗪-4-酮: 1H NMR (400 MHz, CDCl 3) δ 9.31 (s, 1H), 9.07 (s, 1H), 4.14 (br, 4H), 3.50 (br, 4H), 3.19 (s, 3H), 3.02 (q, J =7.2 Hz, 2H), 1.40 (t, J = 7.4 Hz, 3H). MS (+ESI) m/z calcd for C 15H 19N 4O 7S 3 + [M+H] += 463.0410, found 463.0411. MIC: 0.259μM。
6-(甲磺酰基)-8-硝基-2-(4-(苯磺酰基)哌嗪-1-基)-4H-苯并[ e][1,3]噻嗪-4-酮: 1H NMR (400 MHz, DMSO- d 6 ) δ 8.94 (br, 2H), 7.76 (d, J = 7.2 Hz, 2H), 7.72 (d, J = 7.2 Hz, 1H), 7.65 (t, J = 7.0 Hz, 2H), 4.02 (br, 4H), 3.41 (s, 3H), 3.10 (br, 4H). MS (+ESI) m/z calcd for C 19H 19N 4O 7S 3 + [M+H] += 511.0410, found 511.0409. MIC: 0.329μM。
6-(甲磺酰基)-8-硝基-2-(4-(甲苯基哌嗪-1-基)-4H-苯并[ e][1,3]噻嗪-4-酮:[M+H] += 525.0567, found 525.0567. MIC: 0.911μM。
6-(甲磺酰基)-8-硝基-2-(4-(苯磺酰基)-1,4-高哌嗪-1-基)- 4 H-苯并[ e][1,3]噻嗪-4-酮: 1H NMR (400 MHz, CDCl 3) δ 9.30 (s, 1H), 9.05 (s, 1H), 7.78 (d, J = 6.4Hz, 2H), 7.55 – 7.49 (m, 3H), 4.24 – 4.13 (m, 2H), 4.03 (br, 2H), 3.50 (br, 2H), 3.34 (s, 2H), 3.18 (s, 3H), 2.24 – 2.16 (m, 2H). HRMS (+ESI) m/z calcd for C 20H 21N 4O 7S 3 + [M+H] += 525.0567, found 525.0566. MIC: >4μM。
6-(甲磺酰基)-8-硝基-2-(4-(对甲苯磺酰基)-1,4-高哌嗪-1-基)- 4 H-苯并[ e][1,3]噻嗪-4-酮:[M+Na] += 561.0543, found 561.0538. MIC: >4μM。
6-(甲磺酰基)-8-硝基-2-(4-(噻吩-2-基磺酰基)-1,4-高哌嗪-1-基)- 4 H-苯并[ e][1,3]噻嗪-4-酮: 1H NMR (400 MHz, DMSO- d 6) δ 9.00 (s, 1H), 8.96 (s, 1H), 7.88 – 7.83 (m, 1H), 7.65 (d, J = 11.6 Hz, 1H), 7.10 (d, J = 3.6 Hz, 1H), 4.10 – 3.92 (m, 4H), 3.61 – 3.49 (m, 4H), 3.43 (s, 3H), 1.98 (br, 2H). HRMS (+ESI) m/z calcd for C 18H 18N 4O 7S 4Na + [M+Na] += 552.9951, found 552.9951. MIC: >4μM。
2-(4-(环丙基磺酰基)-1,4-高哌嗪-1-基)-6-(甲磺酰基)-8-硝基-4 H-苯并[ e][1,3]噻嗪-4-酮: 1H NMR (400 MHz, CDCl 3) δ 9.31 (s, 1H), 9.05 (s, 1H), 4.23 – 4.04 (m, 4H), 3.71 – 3.61 (m, 2H), 3.46 (br, 2H), 3.19 (s, 3H), 2.33 (br, 1H), 2.23 – 2.15 (m, 2H), 1.18 (br, 2H), 1.00 (br, 2H). HRMS (+ESI) m/z calcd for C 17H 21N 4O 7S 3 + [M+H] += 489.0567, found 489.0567. MIC: 0.942μM。
2-(4-(乙基磺酰基)-1,4-高哌嗪-1-基)-6-(甲磺酰基)-8-硝基-4 H-苯并[ e][1,3]噻嗪-4-酮:HRMS (+ESI) m/z calcd for C 16H 21N 4O 7S 3 + [M+H] += 477.0567, found 477.0565. MIC: 2.08μM。
2-(4-(丁基磺酰基)-1,4-高哌嗪-1-基)-6-(甲磺酰基)-8-硝基-4 H-苯并[ e][1,3]噻嗪-4-酮: 1H NMR (400 MHz, DMSO- d 6) δ 9.00 (s, 1H), 8.96 (s, 1H), 4.15 – 3.92 (m, 4H), 3.66 – 3.54 (m, 4H), 3.43 (s, 3H), 3.08 (br, 2H), 1.97 – 1.86 (m, 4H), 1.57 (q, J = 6.4 Hz, 2H), 1.32 – 1.30 (m, 2H), 0.83 (br, 3H). HRMS (+ESI) m/z calcd for C 18H 25N 4O 7S 3 + [M+H] += 505.0880, found 505.0881. MIC: 1.53μM。
6-(甲磺酰基)-8-硝基-2-(4-苯基-1,4-高哌嗪-1-基)-4 H-苯并[ e][1,3]噻嗪-4-酮: 1H NMR (400 MHz, CDCl 3) δ9.30 (s, 1H), 9.03 (s, 1H), 4.27 – 4.12 (m, 2H), 3.93 (s, 2H), 3.19 (br, 3H), 2.96 (br, 2H), 2.71–2.55 (m, 2H), 2.03 (s, 2H), 1.56 –1.51 (m, 2H), 1.32 –1.25 (m, 6H), 0.88 (t, J = 6.6 Hz, 3H). HRMS (ESI+)  calcd for  C 19H 27N 4O 5S 2 +[M + H] +455.1417; found 455.1415. MIC: 0.486μM。
2-(4-异戊基-1,4-高哌嗪-1-基)-6-(甲磺酰基)-8-硝基-4 H-苯并[ e][1,3]噻嗪-4-酮:HRMS (ESI+)  calcd for C 19H 27N 4O 5S 2 +[M + H] +455.1417; found 455.1410. MIC: 0.486μM。
2-(4-异丁基-1,4-高哌嗪-1-基)-6-(甲磺酰基)-8-硝基-4 H-苯并[ e][1,3]噻嗪-4-酮: 1H NMR (400 MHz, CDCl 3) δ 9.31 (s, 1H), 9.03 (s, 1H), 4.17 –4.11 (m, 2H), 3.91 (br, 2H), 3.18 (s, 3H), 2.91 –2.81 (m, 2H), 2.65 (br, 2H), 2.37 –2.31(m, 2H), 2.11 – 1.97 (m, 2H), 1.42 (br, 1H), 0.86 (d, J = 5.4 Hz, 6H). HRMS (ESI+)  calcd for  C 18H 25N 4O 5S 2 +[M + H] +441.1261; found 441.1250. MIC: 0.063μM。
2-(4-环戊基)甲基)-1,4-高哌嗪-1-基)-6-(甲磺酰基)-8-硝基-4 H-苯并[ e][1,3]噻嗪-4-酮:HRMS (ESI+)  calcd for  C 20H 27N 4O 5S 2 +[M + H] + 467.1417; found 467.1417. MIC: 0.214μM。
2-(4-环己基)甲基)-1,4-高哌嗪-1-基)-6-(甲磺酰基)-8-硝基-4 H-苯并[ e][1,3]噻嗪-4-酮: 1H NMR (400 MHz, CDCl 3) δ 9.31 (s, 1H), 9.03 (s, 1H), 4.19 – 4.11 (m, 2H), 3.91 (br, 2H), 3.18 (s, 3H), 2.91 (br, 2H), 2.74 – 2.66 (m, 2H), 2.32 (d, J = 6.4 Hz, 2H), 1.98 (br, 2H), 1.74 (d, J = 12.8Hz, 2H), 1.42 (br, 1H), 1.36 – 1.33 (m, 2H), 1.19 – 1.64 (m, 2H), 0.87 – 0.84 (m, 2H). HRMS (ESI+)  calcd for  C 21H 29N 4O 5S 2 [M + H] +481.1574; found 481.1571. MIC: 0.054μM。
2-(4-苯基-1,4-高哌嗪-1-基)-6-(甲磺酰基)-8-硝基-4 H-苯并[ e][1,3]噻嗪-4-酮: 1H NMR (400 MHz, CDCl 3) δ 9.28 (s, 1H), 8.99 (s, 1H), 7.26 – 7.24 (m, 5H), 4.16 – 4.03 (m, 2H), 3.91 – 3.77 (m, 2H), 3.63 (d, J = 7.6 Hz, 2H), 3.14 (s, 3H), 2.82 (d, J = 24.4 Hz, 2H), 2.66 (s, 2H), 2.06 – 1.96 (m, 2H). HRMS (ESI+) calcd for C 21H 23N 4O 5S 2 + [M + H] + 475.1104; found 475.1100. MIC: 0.487μM。
6-(甲磺酰基)-8-硝基-2-(4-苯基乙基-1,4-高哌嗪-1-基)-4 H-苯并[ e][1,3]噻嗪-4-酮:HRMS (ESI+) calcd for  C 22H 25N 4O 5S 2 + [M+H]+489.1261; found 489.1262. MIC: 1.020μM。
2-(4-(环己基羰基)哌嗪-1-基)-6-(甲磺酰基)-8-硝基-4H-苯并[ e][1,3]噻嗪-4-酮:MS(+ESI) m/z calcd for C 20H 25N 4O 6S 2 + [M+H] += 481.1210, found 481.1206. MIC: 0.961μM。
2-(4-(苯甲酰基)哌嗪-1-基)-6-(甲磺酰基)-8-硝基-4H-苯并[ e][1,3]噻嗪-4-酮:MS(+ESI) m/z calcd for C 20H 19N 4O 6S 2 + [M+H] += 475.0741, found 475.0741. MIC: 0.961μM。
2-(六氢吡咯[1,2-a]哌嗪-2(1H)-基-6-(甲磺酰基)-8-硝基-4 H-苯并[ e][1,3]噻嗪-4-酮:MS(+ESI) m/z calcd for C 16H 19N 4O 5S 2 + [M+H] += 411.0791, found 411.0793. MIC: >4μM。
2-(4-(环己基甲基)哌嗪-1-基)-6-(乙基磺酰基)-8-硝基-4 H-苯并[ e][1,3]噻嗪-4-酮: 1H NMR (400 MHz, CDCl 3) δ 9.26 (s, 1H), 8.99 (s, 1H), 4.14 – 3.88 (m, 4H), 3.25 (dd, J = 13.8, 6.6 Hz, 2H), 2.54 (s, 4H), 2.19 (d, J =4.0 Hz, 2H), 1.79 – 1.64 (m, 6H), 1.49 (s, 1H), 1.35 (t, J = 2.0 Hz, 3H), 1.25 – 1.20 (m, 2H), 0.92 – 0.87 (m, 2H). MS(+ESI) m/z calcd for C 21H 28N 4O 5S 2Na + [M+Na] += 503.1393, found 503.1389. MIC: 0.52μM。
2-(4-(环己基甲基)哌嗪-1-基)-6-(环丙基基磺酰基)-8-硝基-4 H-苯并[ e][1,3]噻嗪-4-酮:MS (+ESI) m/z calcd for C 22H 29N 4O 5S 2 + [M+H] +=493.16，found 492.6. MIC: 0.386μM。
2-(4-(环己基甲基)哌嗪-1-基)-6-(异丙基磺酰基) -8-硝基-4 H-苯并[ e][1,3]噻嗪-4-酮: 1H NMR (400 MHz, CDCl 3) δ 9.23 (s, 1H), 8.95 (s, 1H), 4.14 (s, 2H), 3.87 (s, 2H), 3.38 – 3.30 (m, 1H), 2.54 (s, 4H), 2.18 (d, J = 8.0 Hz, 2H), 1.79 – 1.71 (m, 6H), 1.49 (br, 1H), 1.37 – 1.35 (d, J = 8.0 Hz, 6H), 1.26 – 1.20 ( m, 2H), 0.92 – 0.87 ( m, 2H). MS(+ESI) m/z calcd for C 22H 30N 4O 5S 2Na + [M+Na] += 517.1550, found 517.1545. MIC: >2μM。
6-(叔丁基磺酰基)2-(4-(环己基甲基)哌嗪-1-基)-8-硝基-4 H-苯并[ e][1,3]噻嗪-4-酮:MS(+ESI) m/z calcd for C 23H 32N 4O 5S 2Na + [M+Na] +=531.1706, found 531.1701. MIC: >5μM。
2-(4-(环己基甲基)哌嗪-1-基) -8-硝基-6-(苯基磺酰基)-4 H-苯并[ e][1,3]噻嗪-4-酮: 1H NMR (400 MHz, CDCl 3) δ 9.25 (s, 1H), 9.03 (s, 1H), 8.02 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 4.0 Hz, 1H), 7.57 ( t, J = 4.0 Hz, 2H), 4.11 – 3.85 (m, 4H), 2.52 (s, 4H), 2.17 (s, 2H), 1.78 – 1.70 (m, 6H), 1.48 (br, 1H), 1.22 – 1.15 ( m, 2H), 0.86 – 0.89 ( m, 2H). MS (+ESI) m/z calcd for C 25H 28N 4O 5S 2Na + [M+Na] +=551.1393, found 551.1389. MIC: >5μM。
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，尤其是与阳性对照pBTZ169相比，本发明化合物具有明显好的cLogP值。

Claims (10)

  1. 一种苯并噻嗪酮衍生物，其特征在于，所述苯并噻嗪酮衍生物，的化学结构式如下：
    Figure 404278dest_path_image001
    其中，R 5为以下取代基：
    Figure 550088dest_path_image002
    、
    Figure 253602dest_path_image003
    、
    Figure 877481dest_path_image004
    、
    Figure 615630dest_path_image005
    、
    Figure 729080dest_path_image006
    、
    Figure 106840dest_path_image007
    、
    Figure 596727dest_path_image008
    。
  2. 根据权利要求1所述苯并噻嗪酮衍生物，其特征在于，R 1包括硝基、卤素、氰基、醛基或者酯基；R 2包括氢、烷基、环烷基、烯烃基、炔烃基、烷氧基、羟基、羧基、氨基、取代胺基中的一种；R 3包括烷基、环烷基、烯烃基、炔烃基、烷氧基、羟基、羧基、氨基、取代胺基中的一种；R 4包括氢、烷基、环烷基、烯烃基、炔烃基、烷氧基、羟基、羧基、氨基、取代胺基中的一种；n1=1～3；n2=1～3；R 6包括氢、烷基、环烷基、烯烃基、炔烃基、烷氧基、羟基、羧基、氨基、取代胺基、苄基、磺酰基中的一种；R 9包括氢、烷基、环烷基或者羰基；R 10包括烷基、环烷基、杂环基、取代杂环基或者芳基；R 11包括烷基、环烷基或者芳基；R 12包括烷基、环烷基、杂环基、取代杂环基或者芳基。
  3. 权利要求1所述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。
  4. 含有权利要求1所述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。
  5. 根据权利要求3或者4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；所述结核包括肺结核、肺外结核。
  6. 以权利要求1所述苯并噻嗪酮衍生物为活性成分的药物组合物。
  7. 根据权利要求6所述药物组合物，其特征在于，所述药物组合物为片剂、胶囊、颗粒、糖浆、粉剂或者注射剂。
  8. 权利要求1所述苯并噻嗪酮衍生物的制备方法，其特征在于，包括以下步骤：
    （1）化合物A5与胺化合物反应，得到苯并噻嗪酮衍生物；
    （2）将步骤（1）制备的苯并噻嗪酮衍生物的硝基还原，得到化合物A7；化合物A7发生取代反应，得到苯并噻嗪酮衍生物。
  9. 根据权利要求8所述苯并噻嗪酮衍生物的制备方法，其特征在于，化合物A3或2-氯-5-(甲基磺酰基)苯甲酸进行氯代反应，得到化合物A4；化合物A4与异硫氰酸盐反应，得到化合物A5。
  10. 根据权利要求8所述苯并噻嗪酮衍生物的制备方法，其特征在于，还原在铁粉、氯化铵的作用下进行。
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