WO2013185507A1 - Dérivés de benzothiazine-4-one et procédés de préparation et d'utilisation associés - Google Patents

Dérivés de benzothiazine-4-one et procédés de préparation et d'utilisation associés Download PDF

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WO2013185507A1
WO2013185507A1 PCT/CN2013/074497 CN2013074497W WO2013185507A1 WO 2013185507 A1 WO2013185507 A1 WO 2013185507A1 CN 2013074497 W CN2013074497 W CN 2013074497W WO 2013185507 A1 WO2013185507 A1 WO 2013185507A1
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alkyl
substituted
halogen
group
independently
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余洛汀
魏于全
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四川大学
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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
    • 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
    • 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
    • A61P31/08—Antibacterial agents for leprosy
    • 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
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D497/10—Spiro-condensed systems

Definitions

  • the invention belongs to the field of medicine, and particularly relates to a benzothiazin-4-one derivative, a preparation method thereof and use thereof.
  • Tuberculosis is one of the diseases with the highest prevalence and mortality. In the 21st century, tuberculosis continues to be a major cause of death in developing countries and a renewed disease in developed countries. Due to the prevalence of poverty and HIV/AIDS, the emergence of multidrug-resistant (MDR-TB)/broad-spectrum-resistant tuberculosis (XDR-TB), the number of people dying from tuberculosis worldwide continues to increase, and existing anti-tuberculosis drugs are no longer able to meet the cure Demand is currently one-third of the world's population of 2 billion people carrying tubercle bacilli, tuberculosis kills 3 million people each year, and as one of the developing countries, there are about 4.5 million active tuberculosis patients in China.
  • MDR-TB multidrug-resistant
  • XDR-TB broad-spectrum-resistant tuberculosis
  • Tuberculosis has become a serious public health problem
  • the resurgence of tuberculosis has drawn deep concern from all walks of life. It is extremely urgent to develop new, highly effective and low-toxic anti-tuberculosis drugs. And content
  • the first technical problem to be solved by the present invention is to provide a novel class of benzothiazin-4-one derivatives having the structure of formula I:
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • Ri independently is -H, halogen, ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkoxy, halogen substituted ⁇ 3 ⁇ 4 alkyl, halogen substituted ⁇ 3 ⁇ 4 alkoxy, ⁇ 3 ⁇ 4 alkyl substituted amino, ⁇ 3 ⁇ 4 alkane Substituted carbonyl, ⁇ 3 ⁇ 4 alkyl substituted aminoacyl, ⁇ 3 ⁇ 4 alkyl substituted amide group, ⁇ 3 ⁇ 4 alkyl substituted sulfamoyl group, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO Or -CF 3 ;
  • R 6 and R 7 are independently -H, a substituted -C 8 alkyl group having a substituent, a C 3 -C 8 cycloalkyl group having a substituent, a halogenated to C 8 alkyl group having a substituent, and a band a substituted phenyl group, a substituted benzoyl group, a substituted pyridyl group, and the substituent is - ⁇ , ⁇ 3 ⁇ 4 alkyl, ⁇ alkoxy, ⁇ alkyl substituted a sulfamoyl group, a substituted ⁇ prime ⁇ C 8 alkyl group, ⁇ ⁇ alkyl substituted carbonyl group, substituted amino ⁇ C 8 alkyl group, ⁇ C 8 alkyl-substituted amide group, a halogen, -N0 2, -OH, -OCF 3 , -CF 3 or phenyl; R 8 to R 16 are independently -H, -C 8
  • R 17 When M is oxygen or sulfur, R 17 is -H; when M is nitrogen, R 17 is -H, ⁇ 3 ⁇ 4 alkyl, ⁇ C 8 alkoxy, C 3 ⁇ C 8 cycloalkyl, ⁇ C 8 Alkyl substituted sulfamoyl group, aryl substituted sulfamoyl group, R 27 substituted sulfonyl group, R 27 substituted acyl group, ⁇ substituted ⁇ 3 ⁇ 4 alkyl group, ⁇ 3 ⁇ 4 alkyl substituted carbonyl group, ⁇ 3 ⁇ 4 alkyl substituted aminoacyl group a ⁇ 3 ⁇ 4 alkyl-substituted amide group, a halogen, a tert-butyloxycarbonyl group, -OCF 3 , -OH, -CF 3 or a substituted phenyl group, said substituent being a hetero atom containing N, 0 or S a saturated or unsaturated heterocyclic ring;
  • R 27 is ⁇ 3 ⁇ 4 alkyl, C 3 ⁇ C 8 cycloalkyl, substituted phenyl, C 3 ⁇ C 8 cycloalkyl substituted ⁇ 3 ⁇ 4 alkyl or adamantyl; the substituent of the substituted phenyl is Halogen, -1 ⁇ 0 2 or ⁇ 3 ⁇ 4 alkyl;
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • Ri independently is -H, halogen, ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkoxy, halogen substituted ⁇ 3 ⁇ 4 alkyl, halogen substituted ⁇ 3 ⁇ 4 alkoxy, ⁇ 3 ⁇ 4 alkyl substituted amino, ⁇ 3 ⁇ 4 alkane Substituted carbonyl, ⁇ 3 ⁇ 4 alkyl substituted aminoacyl, ⁇ C 8 alkyl substituted amide, ⁇ alkyl substituted sulfamoyl, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • R 5 is ⁇ R 9 R" R or 3 ⁇ 4 R,usually ;
  • R 6 and R 7 are independently -H, a substituted -C 8 alkyl group having a substituent, a C 3 -C 8 cycloalkyl group having a substituent, a halogenated to C 8 alkyl group having a substituent, and a band A substituted phenyl group, a substituted benzoyl group, a substituted pyridyl group, and the substituent is -H, ⁇ .
  • alkyl ⁇ ⁇ alkoxy, substituted sulfamoyl ⁇ C 8 alkyl group, a substituted ⁇ prime ⁇ C 8 alkyl group, ⁇ ⁇ alkyl substituted carbonyl group, substituted amino ⁇ C 8 alkyl group, C ⁇ 8
  • R 8 to R 16 are independently -H, ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkoxy, ⁇ 3 ⁇ 4 alkyl substituted sulfamoyl, halogen substituted ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkyl substituted carbonyl, ⁇ 3 ⁇ 4 An alkyl substituted aminoacyl group, a ⁇ 3 ⁇ 4 alkyl substituted amide group, a halogen, -OCF 3 , -OH, -CF 3 , -COOH or a phenyl group;
  • R 17 When M is oxygen or sulfur, R 17 is -H; when M is nitrogen, R 17 is - ⁇ , ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkoxy. 3 ⁇ 3 ⁇ 4 cycloalkyl, ⁇ alkyl substituted sulfamoyl group, sulfamoyl group substituted with an aryl group, halogen-substituted Ci ⁇ C 8 alkyl, ⁇ 3 ⁇ 4 alkyl substituted carbonyl group, ⁇ 3 ⁇ 4 alkyl substituted amino group, ⁇ 3 ⁇ 4 alkoxy a substituted amide group, a halogen, a tert-butyloxycarbonyl group, -OCF 3 , -OH, -CF 3 or a substituted phenyl group, said substituent being a saturated or unsaturated group containing a hetero atom of N, 0 or S Heterocycle
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • Ri R 3 is independently -H, -F, -Cl, -Br, ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkoxy, halogen substituted ⁇ (-8 3 ⁇ 43 ⁇ 43 ⁇ 4, fierce 4 ⁇ tf J Li L alkoxy, -N0 2 -NH 2 -CN or -CF 3 ;
  • R 6 R 7 is independently -H, ⁇ alkyl, substituted C 3 C 8 cycloalkyl, halogen substituted Ci C alkyl, substituted phenyl, substituted benzene a formyl group, a pyridyl group having a substituent, said substituent is - ⁇ , ⁇ ⁇ 3 ⁇ 4 alkyl, halo-substituted ⁇ 3 ⁇ 4 alkyl, -F -Cl -Br -CF 3 -OCF 3 -N0 2 - NH 2 or -CN;
  • R 8 R 16 is independently -H -F -Cl -Br -COOH, ⁇ 3 ⁇ 4 alkyl or halogen substituted ⁇ 3 ⁇ 4 fluorenyl;
  • L is nitrogen, oxygen or sulfur;
  • R 17 When M is oxygen or sulfur, R 17 is -H; when M is nitrogen, R 17 is -H, ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkoxy, C 3 C 8 cycloalkyl, C 8 alkyl Substituted sulfamoyl, halogen substituted ⁇ . 8 alkyl, ⁇ . 8- alkyl substituted carbonyl, C 8 alkyl substituted aminoacyl, C Cs alkyl substituted amide, halogen, tert-butyloxycarbonyl, -OCF 3 -OH -CF 3 or substituted phenyl, said substitution
  • the base is a saturated or unsaturated heterocyclic ring containing a N 0 or S hetero atom.
  • R 2 R4 is independently halogen, -N0 2 -NH 2 -OCF 3 -CN, or -CF 3 ;
  • Ri R 3 is independently -H -F -Cl -Br, ⁇ 3 ⁇ 4 alkyl, C 8 -alkoxy, halogen-substituted C 8 alkyl, halogen-substituted C 8 alkoxy, -N M' R 6 W, U ,, ' X "
  • R 5 is R 7 R" R
  • R 6 R 7 is independently -H, ⁇ 3 ⁇ 4 alkyl, halogen-substituted ⁇ 3 ⁇ 4 alkyl, substituted C 3 3 ⁇ 4 cycloalkyl, substituted phenyl, substituted benzoyl
  • An acyl group, a substituted pyridyl group, the substituent is a 3 ⁇ 4 alkyl group, a halogen-substituted ⁇ 3 ⁇ 4 alkyl group, -F-Cl-Br-CF 3 -OCF 3 -N0 2 -NH 2 or -CN ;
  • R 8 R 16 is independently -H-COOH C 8 alkyl or halogen substituted C 8 alkyl
  • M is oxygen, R 17 is -H ; M is nitrogen, R 17 is -HC 8 alkyl, C 8 alkoxy, C 3 C 8 cycloalkyl, C 8 alkyl substituted sulfamoyl, aryl substituted ammonia Sulfonyl, a substituted C 8 alkyl group, an alkyl substituted carbonyl group, a C 8 alkyl substituted amino group, a C 8 alkyl substituted amide group, a compound, a tert-butyloxycarbonyl group, -OCF 3 -OH -CF 3 Or a substituted phenyl group, said substituent being a saturated or unsaturated heterocyclic ring containing a N 0 or S hetero atom;
  • R 2 R 4 is independently halogen, -N0 2 -NH 2 -OCF 3 -CN -OH -CHO or -CF 3;
  • Ri R 3 is independently -H -F -Cl -Br, ⁇ 3 ⁇ 4 alkyl, -CF 3 or -N0 2 ; , 6
  • R 5 is 7
  • R 6 and R 7 are independently -H, -3 ⁇ 4 alkyl, substituted phenyl, substituted C 3 -C 8 cycloalkyl, substituted benzoyl, or a pyridyl group of a substituent, which is - ⁇ , ⁇ 3 ⁇ 4 alkyl, -N0 2 , -F, -Cl, -Br or -CF 3 ;
  • R 8 to R 16 are -H, -COOH or methyl; M is oxygen, R 17 is -H; M is nitrogen, and R 17 is t-butyloxycarbonyl;
  • R 2 and R 4 are independently halogen, -N0 2 , -2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • Ri R 3 is independently -H, -F, -Cl, -Br, -C 4 alkyl, -CF 3 or -N0 2 ;
  • R 5 is H 7 , ;
  • R 6 and R 7 are independently -H, -C 4 alkyl, substituted phenyl, substituted C 3 -C 8 cycloalkyl, substituted benzoyl, or a pyridyl group having a substituent which is -H, -C 4 alkyl, -N0 2 , -F, -Cl, -Br or -CF 3 ;
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 ,
  • Ri R 3 is independently -H, -F, -Cl, -Br, ⁇ ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkoxy, halo-substituted ⁇ ⁇ C 8 alkyl group, a halogen-substituted alkoxy ⁇ ⁇ ⁇ , -N0 2 , -NH 2 , -CN or -CF 3 ;
  • R 5 is R " H 3 , , or r ;
  • R 6 and R 7 are independently -H, a substituted ⁇ 3 ⁇ 4 alkyl group, a substituted C 3 ⁇ C 8 cycloalkyl group, a substituted halogenated ⁇ 3 ⁇ 4 alkyl group, with a substitution a phenyl group, a substituted benzoyl group, a substituted pyridyl group, the substituent is - ⁇ , ⁇ 3 ⁇ 4 alkyl, ⁇ alkoxy, ⁇ alkyl-substituted ammoxime Acyl, n-substituted -3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkyl substituted carbonyl, ⁇ 3 ⁇ 4 alkyl substituted aminoacyl, ⁇ C 8 alkyl substituted amide, halogen, -N0 2 , -OH, -OCF 3 , CF 3 or phenyl;
  • R 8 to R 16 are independently -H, ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkoxy, ⁇ 3 ⁇ 4 alkyl substituted sulfamoyl, halogen substituted ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkyl substituted carbonyl, ⁇ 3 ⁇ 4 An alkyl substituted aminoacyl group, a ⁇ 3 ⁇ 4 alkyl substituted amide group, a halogen, -OCF 3 , -OH, -CF 3 , -COOH or a phenyl group;
  • R 17 When M is oxygen or sulfur, R 17 is -H; when M is nitrogen, R 17 is -H, ⁇ 3 ⁇ 4 alkyl, ⁇ C 8 alkoxy, 3 ⁇ 4 ⁇ 3 ⁇ 4 cycloalkyl, ⁇ 3 ⁇ 4 substituted alkyl Sulfonyl, aryl substituted sulfamoyl, R 27 substituted sulfonyl, R 27 substituted acyl, cyclin substituted ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkyl substituted carbonyl, ⁇ 3 ⁇ 4 alkyl substituted aminoacyl, ⁇ 3 ⁇ 4 Alkyl substituted amide, halogen, tert-butyloxycarbonyl, -OCF 3 , -OH, -CF 3 or substituted a phenyl group, the substituent being a saturated or unsaturated heterocyclic ring containing a N, 0 or S hetero atom;
  • R 27 is -C 8 alkyl, C 3 -C 8 cycloalkyl, substituted phenyl, C 3 -C 8 cycloalkyl substituted ⁇ C 4 alkyl or adamantyl; substituted phenyl substituted The group is halogen, -N0 2 or ⁇ alkyl;
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, or -CF 3 ;
  • Ri R 3 is independently -H, -F, -Cl, -Br, ⁇ . 4 alkyl, ⁇ . 4 alkoxy, halogen substituted ⁇
  • R 6 and R 7 are independently -H, a substituted -C 4 alkyl group having a substituent, a C 3 -C 8 cycloalkyl group having a substituent, a halogenated to C 4 alkyl group having a substituent, and a band a substituted phenyl group, a substituted benzoyl group, a substituted pyridyl group, and the substituent is -H, -C 4 alkyl group, ⁇ C 4 alkoxy group, ⁇ C 4 alkane substituted sulfamoyl group, a halogen-substituted ⁇ C 4 alkyl group, a substituted carbonyl group ⁇ C 4 alkyl group, a substituted amino ⁇ C 4 alkyl group, ⁇ C 4 alkyl substituted amide group, a halogen, -N0 2, -OH, -OCF 3 , -CF 3 or phenyl;
  • R 8 ⁇ R 16 are independent - ⁇ , ⁇ . 4 alkyl, ⁇ . 4 alkoxy, ⁇ . a 4- alkyl substituted sulfamoyl group, a halogen-substituted ⁇ alkyl group, a ⁇ alkyl-substituted carbonyl group, a ⁇ -alkyl-substituted aminoacyl group, a ⁇ alkyl-substituted amide group, a halogen, -OCF 3 , -OH, -CF 3 , -COOH or phenyl;
  • R 17 When M is oxygen or sulfur, R 17 is -H; when M is nitrogen, R 17 is - ⁇ , ⁇ . 4 alkyl, ⁇ . 4 alkoxy, 3 ⁇ 4 ⁇ 3 ⁇ 4 cycloalkyl, ⁇ alkyl substituted sulfamoyl, aryl substituted sulfamoyl, R 27 substituted sulfonyl, R 27 substituted acyl, halogen substituted ⁇ alkyl, ⁇ alkyl Substituted carbonyl, ⁇ alkyl substituted aminoacyl, ⁇ .
  • R 27 is -C 4 alkyl, C 3 -C 8 cycloalkyl, substituted phenyl, C 3 -C 8 cycloalkyl substituted ⁇ C 4 alkyl or adamantyl; substituted phenyl substituted
  • the base is halogen, -N0 2 or ⁇ C 4 alkyl;
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • Ri R 3 is independently -H, -F, -Cl, -Br, -C 4 alkyl, -CF 3 or -N0 2 ;
  • R 6 and R 7 are independently -H, and have a substituent of ⁇ . 4- alkyl, substituted C 3 -C 8 cycloalkyl, substituted halo-C 4 alkyl, substituted phenyl, substituted benzoyl, with The pyridyl group of the substituent, which is - ⁇ , ⁇ . 4 alkyl, ⁇ . 4 alkoxy, ⁇ . 4- alkyl substituted sulfamoyl, halogen substituted ⁇ . 4 alkyl, ⁇ . 4 alkyl substituted carbonyl, ⁇ . 4 alkyl substituted aminoacyl, ⁇ a C 4 alkyl substituted amide group, a halogen, -N0 2 , -OH, -OCF 3 , -CF 3 or a phenyl group;
  • R 8 to R 16 are independently -H, -C 4 alkyl, ⁇ C 4 alkoxy, -C 4 alkyl substituted sulfamoyl, halogen substituted ⁇ C 4 alkyl, ⁇ C 4 alkyl substituted carbonyl ⁇ C 4 alkyl substituted aminoacyl, ⁇ C 4 alkyl substituted amide group, halogen, —OCF 3 , —OH, —CF 3 , —COOH or phenyl;
  • R 17 When M is oxygen or sulfur, R 17 is -H; when M is nitrogen, R 17 is -H, -C 4 alkyl, ⁇ C 4 alkoxy, 3 ⁇ 4 ⁇ 3 ⁇ 4 cycloalkyl, ⁇ alkyl substituted Sulfamoyl, aryl substituted sulfamoyl, R 27 substituted sulfonyl, R 27 substituted acyl, halogen substituted ⁇ alkyl, ⁇ alkyl substituted carbonyl, ⁇ alkyl substituted aminoacyl, ⁇ .
  • R 27 is ⁇ . a 4- alkyl group, a C 3 -C 8 cycloalkyl group, a substituted phenyl group, a C 3 -C 8 cycloalkyl group-substituted alkyl group or an adamantyl group; the substituent of the substituted phenyl group is a halogen, - 1 ⁇ 0 2 or ⁇ alkyl;
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • Ri R 3 is independently -H, -F, -Cl, -Br, -C 4 alkyl, -CF 3 or -N0 2 ;
  • R 6 and R 7 are independently -H, ⁇ . a 4- alkyl group, a substituted phenyl group, a substituted C 3 -C 8 cycloalkyl group, a substituted benzoyl group, or a substituted pyridyl group, wherein the substituent is - ⁇ , ⁇ alkyl, -N0 2 , -F, -Cl, -Br or -CF 3 ;
  • R 8 to R 16 are -H, -COOH or methyl
  • M is oxygen, R 17 is -H; M is nitrogen, R 17 is - H, ⁇ ⁇ . 4 alkyl, ⁇ . 4 alkoxy, C 3 ⁇ C 8 cycloalkyl group, t-butyloxycarbonyl group, a substituted sulfonyl group R 27 R 27 or a substituted acyl group;
  • R 27 is -C 4 alkyl, C 3 -C 8 cycloalkyl, substituted phenyl, C 3 -C 8 cycloalkyl substituted ⁇ C 4 alkyl or adamantyl; substituted phenyl substituted
  • the base is halogen, -N0 2 or ⁇ C 4 alkyl;
  • R 2 and R 4 are independently halogen, -N0 2 , -Gu 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • Ri R 3 is independently -H, -F, -Cl, -Br, -C 4 alkyl, -CF 3 or -N0 2 ;
  • R 6 and R 7 are independent of 11, ⁇ .
  • R 8 to Ri 6 are -H, -COOH or methyl; M is oxygen, R 17 is -H ; M is nitrogen, and R 17 is C 3 -C 8 cycloalkyl, tert-butyloxycarbonyl, R 27 -substituted sulfonyl or R 27 -substituted acyl;
  • R 27 is -C 4 alkyl, C 3 -C 8 cycloalkyl, substituted phenyl, C 3 -C 8 cycloalkyl substituted ⁇ C 4 alkyl or adamantyl; substituted phenyl substituted
  • the base is halogen, -N0 2 or ⁇ C 4 alkyl;
  • L is sulfur or oxygen
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • Ri R 3 is independently -H, halogen, ⁇ C 8 alkane a group, a C 8 alkoxy group, a halogen substituted ⁇ .
  • alkyl halogen substituted ⁇ alkoxy, ⁇ ⁇ alkyl substituted amino, ⁇ ⁇ alkyl substituted carbonyl, ⁇ C 8 alkyl substituted amino, ⁇ C 8 alkyl substituted amide, ⁇ alkyl substituted ammonia Sulfonyl, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • R 7 is -H, a substituted -C 8 alkyl group having a substituent, a halogenated to C 8 alkyl group having a substituent, a phenyl group having a substituent, a pyridyl group having a substituent, and the substitution
  • the base is -H, ⁇ .
  • alkyl group an alkoxy group ⁇ ⁇ , ⁇ C 8 alkyl-substituted sulfamoyl group, a substituted ⁇ prime ⁇ C 8 alkyl group, ⁇ ⁇ alkyl substituted carbonyl group, substituted amino ⁇ C 8 alkyl group, an alkoxy ⁇ C 8 Substituted amide group, halogen, -N0 2 , -OH, -OCF 3 , -CF 3 or phenyl;
  • R 18 to R 22 are independently -H, -C 8 alkyl, ⁇ C 8 alkoxy, -C 8 alkyl substituted sulfamoyl, halogen substituted ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkyl substituted carbonyl, ⁇ 3 ⁇ 4 alkyl substituted aminoacyl, ⁇ 3 ⁇ 4 alkyl substituted amide group, halogen, -N0 2 , -OH, -OCH 3 , -OCF 3 , -CF 3 or phenyl.
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, or -CF 3 ;
  • Ri R 3 is independently -H, -F, -Cl, -Br, ⁇ ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkoxy, halo-substituted ⁇ ⁇ C 8 alkyl group, a halogen-substituted alkoxy ⁇ ⁇ ⁇ , -N0 2 , -NH 2 , -CN or -CF 3 ;
  • R 7 is -H, ⁇ 3 ⁇ 4 alkyl, halogen-substituted ⁇ 3 ⁇ 4 alkyl, substituted phenyl, substituted pyridyl, and the substituent is -H, -F, -Cl, -Br, -CF 3 , -N0 2 , ⁇ 3 ⁇ 4 alkyl or halogen substituted ⁇ 3 ⁇ 4 alkyl;
  • R 18 to R 22 are independently -H, -F, -Cl, -Br, -CF 3 , -OCH 3 , -N0 2 , ⁇ 3 ⁇ 4 alkyl or halogen-substituted ⁇ 3 ⁇ 4 alkyl.
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • Ri R 3 is independently -H, -F, -Cl, -Br, ⁇ 3 ⁇ 4 alkyl, -CF 3 or -N0 2 ;
  • R 7 is -H, -C 8 alkyl, halogen-substituted ⁇ C 8 alkyl, substituted phenyl, substituted pyridyl, said substituent is -H, -F, - Cl, -Br, -CF 3 , -N0 2 , ⁇ C 8 alkyl or halogen substituted ⁇ C 8 alkyl;
  • R 18 to R 22 are independently -H, -F, -Cl, -Br, -CF 3 , -N0 2 , -OCH 3 , -C 8 alkyl or halogen-substituted ⁇ 3 ⁇ 4 alkyl.
  • R 2 and R 4 are independently -F, -N0 2 , -NH 2 , -OCF 3 or -CF 3 ;
  • Ri R 3 is independently -H, -F, ⁇ 3 ⁇ 4 alkyl, -CF 3 or -N0 2; R 7 is -H or ⁇ 3 ⁇ 4 alkyl;
  • Ri 8 to R 22 are -H, -N0 2 , -OCH 3 , -CF 3 , ⁇ 3 ⁇ 4 alkyl or halogen-substituted ⁇ alkyl.
  • R 2 and R 4 are independently -F, -N0 2 , -Gu 2 , -OCF 3 or -CF 3 ;
  • Ri R 3 is independently -H, -F, ⁇ . 4 alkyl, -CF 3 or -N0 2 ;
  • R 7 is -H or ⁇ alkyl;
  • Ri 8 to R 22 are -H, -N0 2 , -OCH 3 , -CF 3 ⁇ . 4 alkyl.
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • Ri R 3 is independently -H, halogen, ⁇ C 8 alkyl, ⁇ . 8 alkoxy, halogen substituted ⁇ . 8 alkyl, halogen substituted ⁇ alkoxy, ⁇ ⁇ alkyl substituted amino, ⁇ ⁇ alkyl substituted carbonyl, ⁇ C 8 alkyl substituted amino, ⁇ C 8 alkyl substituted amide, ⁇ alkyl substituted ammonia Sulfonyl, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • R 7 is -H, a substituted -C 8 alkyl group having a substituent, a halogenated to C 8 alkyl group having a substituent, a phenyl group having a substituent, a pyridyl group having a substituent, and the substitution
  • the base is -H, ⁇ .
  • R 23 to R 26 are independently -H, ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkoxy, ⁇ 3 ⁇ 4 alkyl substituted sulfamoyl, halogen substituted ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkyl substituted carbonyl, ⁇ 3 ⁇ 4 Alkyl substituted aminoacyl, ⁇ 3 ⁇ 4 alkyl substituted amide, halogen, -N0 2 , -OH, -OCF 3 , -CF 3 or phenyl.
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, or -CF 3 ;
  • Ri R 3 is independently -H, -F, -Cl, -Br, ⁇ ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkoxy, halo-substituted ⁇ ⁇ C 8 alkyl, halogen-substituted alkoxy ⁇ C 8, -N0 2 , -NH 2 , -CN or -CF 3 ;
  • R 7 is -H, -C 8 alkyl or halogen substituted ⁇ C 8 alkyl
  • R 23 to R 26 are independently -H, -F, -Cl, -Br, -CF 3 , -N0 2 , ⁇ 3 ⁇ 4 alkyl or halogen substituted d ⁇ Further preferably, R 2 and R 4 are independently -F, -N0 2 , -NH 2 , -0CF 3 or -CF 3 ;
  • Ri R 3 is independently -H, -F, -3 ⁇ 4 alkyl, -CF 3 or -N0 2; R 7 is H or ⁇ C 8 alkyl; R 2 3 to R 2 6 are -H, -F, -Cl, -Br, or ⁇ C 8 alkyl group.
  • R 2 and R 4 are independently -F, -N0 2 , -NH 2 , -OCF 3 or -CF 3 ;
  • Ri R 3 is independently -H, -F, ⁇ . 4 alkyl, -CF 3 or -N0 2 ;
  • R 7 is -H or ⁇ alkyl;
  • L is nitrogen, oxygen or sulfur;
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • Ri independently is -H, halogen, ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkoxy, halogen substituted ⁇ 3 ⁇ 4 alkyl, halogen substituted ⁇ 3 ⁇ 4 alkoxy, ⁇ 3 ⁇ 4 alkyl substituted amino, ⁇ 3 ⁇ 4 alkane Substituted carbonyl, ⁇ 3 ⁇ 4 alkyl substituted aminoacyl, ⁇ 3 ⁇ 4 alkyl substituted amide group, ⁇ 3 ⁇ 4 alkyl substituted sulfamoyl group, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO Or -CF 3 ;
  • R 16 is -H, -F, -Cl, -Br, -COOH, ⁇ 3 ⁇ 4 alkyl or halogen substituted ⁇ 3 ⁇ 4 alkyl.
  • L is oxygen or sulfur
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, or -CF 3 ;
  • Ri R 3 is independently -H, -F, -Cl, -Br, ⁇ ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkoxy, halo-substituted ⁇ ⁇ C 8 alkyl group, a halogen-substituted alkoxy ⁇ ⁇ ⁇ , -N0 2 , -NH 2 , -CN or -CF 3 ;
  • R 16 is -H, -COOH, -C 8 alkyl or halogen-substituted ⁇ C 8 alkyl.
  • L is oxygen or sulfur
  • R 2 and R 4 are independently -F, -N0 2 , -NH 2 , -OCF 3 or -CF 3
  • Ri R 3 is independently -H, -F, ⁇ 3 ⁇ 4 Alkyl, -CF 3 or -N0 2
  • R 16 is -H or methyl.
  • L is oxygen or sulfur
  • R 2 and R 4 are independently -F, -N0 2 , -NH 2 , -OCF 3 or -CF 3 ;
  • Ri R 3 is independently -H, -F, -C 4 alkyl, -CF 3 or -N0 2 ;
  • R 16 is -H or methyl.
  • R 3 is independently -H, halogen, CC 8 alkyl, ⁇ 3 ⁇ 4 alkoxy, halogen substituted ⁇ 3 ⁇ 4 alkyl, Halogen-substituted alkoxy group ⁇ ⁇ ⁇ ⁇ alkyl substituted amino, ⁇ ⁇ alkyl substituted carbonyl group, ⁇ C 8 alkyl substituted amino group, ⁇ C 8 alkyl group substituted with an amide group, an alkyl-substituted sulfamoyl group ⁇ , - N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • R 17 When M is oxygen or sulfur, R 17 is -H; when M is nitrogen, R 17 is -H, -C 8 alkyl, ⁇ C 8 alkoxy, C 3 -C 8 cycloalkyl, ⁇ C 8- alkyl substituted sulfamoyl group, R 27 substituted sulfonyl group, R 27 substituted acyl group, halogen substituted ⁇ 3 ⁇ 4 alkyl group, ⁇ 3 ⁇ 4 alkyl substituted carbonyl group, ⁇ 3 ⁇ 4 alkyl substituted aminoacyl group, ⁇ 3 ⁇ 4 alkyl group Substituting an amide group, a halogen, a tert-butyloxycarbonyl group, -OCF 3 , -OH, -CF 3 or a substituted phenyl group, said substituent being a saturated or unsaturated group containing a N, 0 or S hetero atom Heterocycle
  • R 27 is a ⁇ 3 ⁇ 4 alkyl group, a C 3 ⁇ C 8 cycloalkyl group, a substituted phenyl group, a C 3 ⁇ C 8 cycloalkyl group-substituted ⁇ 3 ⁇ 4 alkyl group or an adamantyl group; the substituent of the substituted phenyl group is Halogen, -1 ⁇ 0 2 or ⁇ 3 ⁇ 4 alkyl.
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • Ri is independently -H, halogen, ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkoxy, halogen substituted ⁇ 3 ⁇ 4 alkyl, halogen substituted ⁇ 3 ⁇ 4 alkoxy, ⁇ 3 ⁇ 4 alkyl substituted amino, ⁇ 3 ⁇ 4 alkyl substituted carbonyl, ⁇ 3 ⁇ 4 alkyl substituted aminoacyl, ⁇ 3 ⁇ 4 alkyl substituted amide group, ⁇ 3 ⁇ 4 alkyl substituted sulfamoyl group, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • R 17 When M is oxygen or sulfur, R 17 is -H; when M is nitrogen, R 17 is -H, -C 8 alkyl, ⁇ C 8 alkoxy, C 3 -C 8 cycloalkyl, ⁇ . 8- alkyl substituted sulfamoyl group, substituted with -C 8 alkyl group, ⁇ alkyl substituted carbonyl group, ⁇ alkyl substituted aminoacyl group, ⁇ alkyl substituted amide group, halogen, tert-butyloxycarbonyl group, -OCF 3 , -OH, -CF 3 or a substituted phenyl group, said substituent being a saturated or unsaturated heterocyclic ring containing a N, 0 or S hetero atom.
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, or -CF 3 ;
  • Ri R 3 is independently -H, -F, -Cl, -Br, ⁇ 3 ⁇ 4 alkyl, ⁇ C 8 alkoxy, halo-substituted ⁇ C 8 alkyl, halogen-substituted alkoxy ⁇ C 8, - N0 2 , -NH 2 , -CN or -CF 3 ;
  • M is oxygen, R 17 is H; M is nitrogen, and R 17 is -H or tert-butyloxycarbonyl.
  • R 2 and R 4 are independently -F, -N0 2 , -NH 2 , -OCF 3 or -CF 3 ;
  • Ri R 3 is independently -H, -F, ⁇ 3 ⁇ 4 alkyl, -CF 3 or -N0 2 ;
  • M is oxygen, R 17 is -H; M is nitrogen and R 17 is tert-butyloxycarbonyl.
  • R 2 and R 4 are independently -F, -N0 2 , -NH 2 , -OCF 3 or -CF 3 ;
  • Ri R 3 is independently -H, -F, ⁇ . 4 alkyl, -CF 3 or -N0 2 ;
  • M is oxygen, R 17 is -H ; M is nitrogen and R 17 is tert-butyloxycarbonyl.
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, or -CF 3 ;
  • Ri R 3 is independently -H, -F, -Cl, -Br, ⁇ ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkoxy, halo-substituted ⁇ ⁇ C 8 alkyl, halogen-substituted alkoxy ⁇ C 8, -N0 2 , -NH 2 , -CN or -CF 3 ;
  • M is oxygen, R 17 is H; M is nitrogen, R 17 R 27 is a substituted sulfonyl group or a substituted acyl group R 27;
  • R 27 is a ⁇ 3 ⁇ 4 alkyl group, a C 3 -C 8 cycloalkyl group, a substituted phenyl group, a C 3 -C 8 cycloalkyl group-substituted alkyl group or an adamantyl group; a substituent of the substituted phenyl group It is a halogen, -1 ⁇ 0 2 or ⁇ 3 ⁇ 4 alkyl. Further preferably, R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -0CF 3 , -CN, or -CF 3 ;
  • Ri R 3 is independently -H, -F, -Cl, -Br, ⁇ C 4 alkyl group, ⁇ C 4 alkoxy, halo-substituted ⁇ C 4 alkyl, substituted by halogen ⁇ C 4 alkoxy group, -N0 2 , -NH 2 , -CN or -CF 3 ;
  • M is oxygen, R 17 is -H; M is nitrogen, R 17 R 27 is a substituted sulfonyl group or a substituted acyl group R 27;
  • R 27 is -C 4 alkyl, C 3 -C 8 cycloalkyl, substituted phenyl, C 3 -C 8 cycloalkyl substituted ⁇ C 4 alkyl or adamantyl; substituted phenyl substituted
  • the group is halogen, -1 ⁇ 0 2 or ⁇ alkyl.
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, or -CF 3 ;
  • Ri R 3 is independently -H, -F, -Cl, -Br, ⁇ . 4 alkyl, ⁇ . 4 alkoxy, halo-substituted ⁇ ⁇ C 4 alkyl, -N0 2, -CN or -CF 3;
  • M is oxygen, R 17 is -H; M is nitrogen, R 17 R 27 is a substituted sulfonyl group or a substituted acyl group R 27;
  • R 27 is ⁇ . a 4- alkyl group, a C 3 -C 8 cycloalkyl group, a substituted phenyl group, a C 3 -C 8 cycloalkyl group-substituted alkyl group or an adamantyl group; the substituent of the substituted phenyl group is a halogen, - 1 ⁇ 0 2 or ⁇ alkyl.
  • R 2 and R 4 are independently -F, -N0 2 , -Gu 2 , -OCF 3 or -CF 3 ;
  • Ri R 3 is independently -H, -F, ⁇ . 4 alkyl, -CF 3 or -N0 2 ;
  • M is oxygen, R 17 is -H; M is nitrogen, R 17 R 27 is a substituted sulfonyl group or a substituted acyl group R 27;
  • R 27 is -C 4 alkyl, C 3 -C 8 cycloalkyl, substituted phenyl, C 3 -C 8 cycloalkyl substituted ⁇ C 4 alkyl or adamantyl; substituted phenyl substituted
  • the group is halogen, -N0 2 or ⁇ C 4 alkyl.
  • the synthetic route is:
  • Route A The procedure of Route A is as follows: 1 ⁇ 1 4 Substituted benzoyl chloride is reacted with ammonium thiocyanate under the action of a catalyst, and then reacted with R 5 H to finally obtain a ⁇ substituted benzothiazin-4-one.
  • the catalyst described in the A route step is crown ether 18-crown-6 or PEG (polyethylene glycol); the PEG is preferably PEG-400 or PEG-300.
  • the reaction solvent in the reaction with ammonium thiocyanate described in the A route step is dichloromethane or toluene.
  • the solvent used is DMF ( ⁇ , ⁇ -dimethylformamide) or DMSO (dimethyl sulfoxide); preferably DMF.
  • the step of the B route is as follows: the benzoic acid substituted by 1 ⁇ 1 4 is reacted to obtain 1 ⁇ 1 4 substituted benzoyl chloride, and then reacted with ammonium thiocyanate under the action of a catalyst, and then reacted with R 5 H to obtain a Ri.
  • ⁇ R4 replaces benzothiazin-4-one.
  • the catalyst described in the B route step is 18-crown-6 or PEG; and the PEG is preferably PEG-400 or PEG-300.
  • the reaction solvent in the reaction with the ammonium thiocyanate described in the step B is dichloromethane or toluene.
  • the solvent used is DMF or DMSO; preferably DMF.
  • the reaction temperature of each of the above reaction steps is normal temperature.
  • the present invention also provides a pharmaceutically acceptable salt, hydrate or prodrug of the above benzothiazin-4-one derivative.
  • the prodrugs are derivatives of the above compounds which may themselves have weak or even no activity, but after administration, are converted under physiological conditions (for example by metabolism, solvolysis or otherwise) into Corresponding biologically active forms.
  • the present invention also provides the use of the above benzothiazin-4-one derivative for the preparation of a medicament for treating tuberculosis or leprosy.
  • the present invention also provides a pharmaceutical composition prepared by adding the pharmaceutically acceptable auxiliary component to the above benzothiazin-4-one derivative.
  • the pharmaceutical composition can be used to prepare a medicament for treating tuberculosis or leprosy.
  • the benzothiazin-4-one derivative of the present invention is a novel compound obtained on the basis of a large number of screenings, has excellent activity against Mycobacterium tuberculosis, is an anti-tuberculosis drug and is resistant to leprosy.
  • the development and application of drugs offers new options. Specific form
  • 2,3,4,5-tetrafluorobenzoyl chloride (3 g, 14.12 mmol) was dissolved in 20 mL of dichloromethane, ammonium thiocyanate (2.14 g, 28.24 mmol), and PEG-400 (0.2 g) was added dropwise. After reacting at room temperature for two hours, the precipitate was filtered off, and the filtrate was slowly added dropwise to a solution of ethylamine in dichloromethane, and the mixture was reacted at room temperature for three hours.
  • Example 5 The procedure was the same as in Example 5, the starting material was 2-chloro -3 nitro -5 -trifluoromethylbenzoic acid, and the amine used was morpholine. A yellow needle solid was obtained in a yield of 59%.
  • Example 5 In the same manner as in Example 5, the starting material was 2-chloro -3 nitro -5 trifluoromethylbenzoic acid, and the amine used was ethylamine. A yellow solid was obtained in 44% yield.
  • Example 10 The same procedure as in Example 10 was carried out, and the acid chloride used was m-nitrobenzoyl chloride. A yellow solid was obtained with a yield of 72%.
  • Example 5 The procedure was the same as in Example 5, the starting material was 2-chloro -3 nitro -5 trifluoromethylbenzoic acid, and the amine used was propylamine. A yellow solid was obtained in a yield of 57%.
  • the starting material was the same as in Example 5, and the starting material was 2-chloro-3nitro-5.
  • Example 20 Compound 20: Preparation of 2-(pyrrolidinyl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one
  • the starting material was 2-chloro-3nitro-5-trifluoromethylbenzoic acid, and the amine used was pyrrolidine.
  • a yellow solid was obtained in a yield of 49%.
  • Example 5 The procedure was the same as in Example 5, the starting material was 2-chloro -3 nitro -5 -trifluoromethyl benzoic acid, and the amine used was 1, 4-homopiperazine. A yellow solid was obtained in a yield of 45%.
  • Example 5 The procedure was the same as in Example 5, the starting material was 2-chloro -3 nitro -5 trifluoromethylbenzoic acid, and the amine used was cyclopentylamine. A yellow solid was obtained in a yield of 56%.
  • Example 5 The procedure was the same as in Example 5, the starting material was 2-chloro -3 nitro -5 trifluoromethylbenzoic acid, and the amine used was N-BOC piperazine. A yellow solid was obtained in a yield of 54%.
  • the starting material was 2-chloro-3-nitro-5-trifluoromethylbenzoic acid, and the amine used was 4-piperidinone ethanedithiol. A yellow solid was obtained in a yield of 56%.
  • Example 5 The procedure was the same as in Example 5, the starting material was 2-chloro-3nitro-5-trifluoromethylbenzoic acid, and the amine used was 2-methyl-1,4-dithia-8 aza snail. [4.5] decane. A yellow solid was obtained in a yield of 58%.
  • the starting material was 2-chloro-3nitro-5-trifluoromethylbenzoic acid, and the amine used was piperazine to give the compound 2-(piperazin-1yl)-8-nitrate.
  • Base-6-trifluoromethyl-1,3-benzothiazin-4-one (0.5 g, 1.4 mmol, yield 52%).
  • 2-(piperazin-1yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one was dissolved in dichloromethane, and methylsulfonate was added dropwise with stirring at room temperature.
  • the acid chloride (0.2 g, 2.1 mmol) and a catalytic amount of triethylamine were reacted for 2 hours.
  • Example 33 Preparation of 2-(4-cyclopropylsulfonylpiperazinyl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one
  • Example 44 Compound 44: 2-(4-(2-cyclohexylethene)piperazinyl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one preparation
  • Example 47 Compound 47: 2-(l,5-Dithia-9-azaspiro[5.5]undec-9-yl)-8-nitro-6-trifluoromethyl-1,3- Preparation of benzothiazin-4-one
  • Example 5 According to the operation of Example 5, the starting material was 2-chloro-3nitro-5-trifluoromethylbenzoic acid, and the amine used was 1,5-dithia-9-azaspiro[5.5 ] -i ⁇ alkane. A yellow solid was obtained in a yield of 54%.
  • Example 48 Compound 48: 2-(4-Cyclopentyl-3-piperazinone)--8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one
  • the starting material was 2-chloro-3nitro-5-trifluoromethylbenzoic acid, and the amine used was
  • Experimental method Inoculum preparation 5 to 10 H37Ra colonies (from the National Type Culture Collection, ATCC 25177) and 1 mL of sterile saline prepared in advance were inoculated into the kit using a BBL pump. Due to the slow growth of Mycobacterium tuberculosis, it is grown for 2-3 weeks; ultrasonic and vortex mixing to obtain a suspension of Mycobacterium tuberculosis of about 10 8 CFU/mL. The specific experimental concentration can be diluted.
  • the suspension was diluted 200-fold by the following method: 0.2 mL of H37Ra-containing suspension was added to 40 mL of sterile 7H9 broth containing 2% glycerol and OADC nutritional supplement (about 10 6 CFU/mL from BD, USA) The ⁇ suspension (approximately 5 ⁇ 10 4 cells) was inoculated into the wells of the test wells and 1 ⁇ M of DMSO dissolved in a specific concentration of the compound to be tested was added.
  • Isoniazid and rifampicin were selected as positive controls, and the test compound and positive control were formulated into 10 mM solution in DMSO, and successively diluted to 100 ⁇ , 50 ⁇ , 25 ⁇ , 12.5 ⁇ , 6.3 ⁇ , 3.1 ⁇ , 1.6 ⁇ , 0.8 ⁇ , 0.4. ⁇ , 0.2 ⁇ , 0.1 ⁇ , 0 ⁇ 05 ⁇ , 0 ⁇ 025 ⁇ , 0 ⁇ 0125 ⁇ , 0 ⁇ 008 ⁇ , 0 ⁇ 004 ⁇ , 0.002 ⁇ for use.
  • the inoculated 96-well plates were incubated for 9 days at 37 ° C in a 5% CO 2 incubator.
  • Liquid medium Middlebrook 7H9 medium dry powder and nutritional supplements (OADC) are purchased from the United States BD the company.
  • Test drugs Compounds 9, 15, 17, 19, 21, 24, 26, 27, 28, 29 and 47.
  • test strain was transferred to a liquid medium, and after activation, cultured at 37 ° C for 2 weeks, a small amount of the culture liquid was aspirated, placed in 4 mL of liquid medium, and 10-20 pieces of sterile glass beads having a diameter of 2 - 3 mm were added. Oscillate for 20-30s, static precipitation for 10-20min, absorb the supernatant of the bacterial suspension, adjust the turbidity to 1 Meth's unit with liquid medium, which is equivalent to lxl0 7 CFU/mL.
  • the drug and the positive control isoniazid were dissolved in an appropriate amount of DMSO to a lmg/mL, 0.22 ⁇ filter.
  • the final concentration of the test drug was set as follows: 0.000125 g/mL, 0.00025 g/mL, 0.00049 g/mL, 0.00098 g/mL, 0.00195 g/mL, 0.0039 g/mL, 0.0078 g/mL, 0.0156 g/mL, 0.03125 g /mL, 0.0625 g/mL, 0.125 g/mL, 0.25 g/mL, 0.5 g/mL, lg/mL, 2 g/mL, 4 g/mL, 8 g/mL, 16 g/mL, 32 g/ There are 20 concentration gradients in mL and 64 g/mL.
  • each of the above drug solution 10 (VL was added to a 96-well microplate, and 10 4 CFU/mL (diluted by 10 7 CFU/mL) was added to the bacterial solution 10 (VL) to achieve a drug concentration. 2) The final concentration was set. At 37 ° C, the blank control group was given no drugs, and the same drug dilution was set up with three sets of parallel controls. The minimum inhibitory concentration of each drug against Mycobacterium tuberculosis was observed.
  • Leprosy is a chronic contagious disease caused by M. leprae.
  • Mycobacterium leprae and Mycobacterium tuberculosis belong to the genus Mycobacterium, and they have many commonalities in biological characteristics.
  • Common anti-tuberculosis drugs such as rifampic can also be used for the treatment of leprosy.
  • rifampic can also be used for the treatment of leprosy.
  • Vera cells are African green monkey kidney cells (from the National Key Laboratory of Biotherapy), so Vera cells can be used for cytotoxicity testing. Adjust the cell concentration to 3 ⁇ 10 4 /mL with complete medium, inoculate 96-well plates, 200 uL per well, and culture overnight. The next day, different doses of compound 14-19, compound 21, compound 23-25, compound 27-29 And compound 47 (final concentrations of 500, 400, 300, 200, 100, 50, 25, 12.5, 6.25, 3.125, 1.5625, 0.78125 ⁇ ) were treated with cells, and an equal volume of blank medium control group, solvent control group The concentration of DMSO was 0.5% (0.5% DMSO had no effect on cell proliferation).

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Abstract

La présente invention concerne des dérivés de benzothiazine-4-one leurs procédés de préparation et d'utilisation. Les dérivés de benzothiazine-4-one représentés par la formule I ont une activité antituberculeuse.
PCT/CN2013/074497 2012-06-14 2013-04-22 Dérivés de benzothiazine-4-one et procédés de préparation et d'utilisation associés WO2013185507A1 (fr)

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CN108947952A (zh) * 2017-05-24 2018-12-07 中国医学科学院药物研究所 2-取代氨基-5-三氟甲基-8-硝基苯并（硫代）吡喃-4-酮类化合物及其制备方法和用途
US10358442B2 (en) * 2015-03-23 2019-07-23 Ecole Polytechnique Federale De Lausanne (Epfl) 2-homopiperazine-1-yl-4H-1,3-benzothiazine-4-one derivatives and process for the preparation of 2-(homo)piperazine 1,3-benzothiazine-4-one hydrochlorides
US11155542B2 (en) 2016-09-22 2021-10-26 University Of Notre Dame Du Lac Antimicrobial compounds, their use for the treatment of mammalian infections and a new metabolic mechanism

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CN108623534B (zh) * 2018-08-07 2020-10-30 惠州拓康生物科技有限公司 一种具有抗菌活性的1,3-苯并噻嗪-2-酮类衍生物及其合成方法和应用
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