WO2021203812A1 - Dérivé de benzothiazinone, son procédé de préparation et son utilisation en tant que médicament antituberculeux - Google Patents

Dérivé de benzothiazinone, son procédé de préparation et son utilisation en tant que médicament antituberculeux 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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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

L'invention concerne un dérivé de benzothiazinone, son procédé de préparation et son utilisation en tant que médicament antituberculeux. La présente invention concerne en particulier une nouvelle classe de composés ayant un squelette de benzothiazinone. De tels composés présentent un effet inhibiteur sur mycobacterium tuberculosis, et en particulier, un effet inhibiteur également sur mycobacterium tuberculosis ayant une résistance aux médicaments cliniques. Par comparaison avec le médicament de première ligne clinique existant, l'isoniazide (MIC 0,5 μΜ), l'activité de tels composés a un grand avantage; par comparaison avec le médicament antituberculeux de benzothiazinone existant pBTZ 169 à l'étape de recherche, de tels composés ont une valeur cLogP inférieure, et a une meilleure pharmacopotentialité.
PCT/CN2021/074579 2020-04-08 2021-01-31 Dérivé de benzothiazinone, son procédé de préparation et son utilisation en tant que médicament antituberculeux WO2021203812A1 (fr)

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CN113121521B (zh) * 2021-03-26 2022-11-04 苏州大学 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
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