WO2023160582A1 - Inhibiteur de thiazolamine mbl, son procédé de préparation et son utilisation - Google Patents

Inhibiteur de thiazolamine mbl, son procédé de préparation et son utilisation Download PDF

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WO2023160582A1
WO2023160582A1 PCT/CN2023/077670 CN2023077670W WO2023160582A1 WO 2023160582 A1 WO2023160582 A1 WO 2023160582A1 CN 2023077670 W CN2023077670 W CN 2023077670W WO 2023160582 A1 WO2023160582 A1 WO 2023160582A1
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substituted
alkyl
compound
amino
phenyl
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李国菠
颜宇航
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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • C07D417/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D417/10—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 carbon chain containing aromatic rings

Definitions

  • the invention belongs to the field of medicinal chemistry, and in particular relates to a thiazolamine MBL inhibitor and its preparation method and application.
  • ⁇ -lactam antibiotics have the characteristics of broad antibacterial spectrum, high safety and good clinical efficacy, and are currently the most commonly used antibiotics.
  • bacteria due to the abuse and irrational use of antibiotics, bacteria are severely resistant to antibiotics, and human health is seriously threatened.
  • the World Health Organization listed antimicrobial resistance as one of the top ten global health threats.
  • the problem of antibiotic resistance of Gram-negative bacteria is particularly severe.
  • Gram-negative bacteria such as Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter, which are resistant to carbapenem antibiotics, have been listed as extremely dangerous pathogenic bacteria by the World Health Organization.
  • ⁇ -lactamase can be divided into serine ⁇ -lactamase (serine- ⁇ -lactamase, SBL) and metallo- ⁇ -lactamase (metallo- ⁇ -lactamase, MBL). category.
  • MBL can be further divided into three subtypes: B1, B2, and B3.
  • B1 MBL includes the most clinically relevant subtypes of VIM, NDM, and IMP. All major Gram-negative bacterial pathogens, including Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii, were found in clinically common pathogens.
  • MBL has a wide range of substrate specificity, and can hydrolyze all ⁇ -lactam antibiotics and ⁇ -lactam SBL inhibitors except monocyclics, and some MBL can even hydrolyze non- ⁇ -lactam SBL inhibitors. Vibatam.
  • NDM-1 can slowly hydrolyze the monocyclic ⁇ -lactam antibiotic aztreonam, which may mean that MBL has acquired the ability to hydrolyze the monocyclic ⁇ -lactam antibiotic during continuous evolution.
  • MBL genes exist on bacterial mobile genetic elements, which can spread rapidly and widely among bacteria through horizontal gene transfer. Therefore, the production of MBL enzymes in bacteria is one of the most worrying drug resistance factors, and the development of effective MBL inhibitors is imminent and has important clinical significance.
  • MBL inhibitors include sulfhydryls, carboxylic acids, phosphoric acid
  • sulfhydryls due to the large number of MBL subtypes with large differences in structure, and the flexible loop in the active site, most inhibitors lack the ability to target multiple MBL subtypes, especially clinically relevant VIM, NDM, IMP, etc.
  • Broad-spectrum inhibitory activity of isoforms In addition, the low permeability of the bacterial outer membrane is also a common shortcoming of the reported MBL inhibitors. Therefore, there is an urgent need to develop MBL inhibitors with broad-spectrum inhibitory activity and good antibacterial activity, so as to provide new lead compounds for the development of clinically effective MBL inhibitors.
  • the object of the present invention is to provide a thiazolamine MBL inhibitor and its preparation method and application.
  • the present invention provides a compound represented by formula I, or a salt thereof, or an isomer thereof, or a hydrate thereof, or a solvate thereof, or a prodrug thereof:
  • R 1 is selected from hydrogen, C 1 -C 8 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, -NHR 1 ';
  • R 1 ' is selected from C 1 to C 8 alkyl substituted by 0 to 5 R 3 , -C(O)R 3 ';
  • R3 are independently selected from 5-10 membered aryl groups and 5-10 membered heteroaryl groups
  • R 3 ' is selected from C 1 -C 8 alkyl, 5-10 membered aryl;
  • L is selected from none, C 1 to C 8 alkylene substituted by 0 to 5 R 4 , -S-, -O-,
  • R 4 are independently selected from C 1 -C 8 alkyl groups
  • R 2 is selected from C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, 5-10 membered aryl substituted by 0-5 R 5 , 0-5 R 5- substituted 3-10-membered heteroaryl, 3-10-membered heterocyclic group substituted by 0-5 R 5 , 3-10-membered cycloalkyl substituted by 0-5 R 5 ;
  • R 5 are independently selected from C 1 -C 8 alkyl substituted by 0-5 R 6 , C 1 -C 8 alkoxy substituted by 0-5 R 6 , halogen, carboxyl, nitro, amino, Hydroxyl, -C(O)R 7 , -C(O)OR 7 , 5-10-membered aryl substituted by 0-5 R 6 , 5-10-membered heteroaryl substituted by 0-5 R 6 ;
  • R 6 are independently selected from C 1 -C 8 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, C 2 -C 8 alkynyl, C 2 -C 8 alkenyl, 5-10 membered aryl ;
  • R 7 is selected from C 1 -C 8 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, 5-10-membered aryl, 5-10-membered heteroaryl;
  • R 1 is selected from amino
  • R 2 is selected from phenyl
  • L 2 is not selected from C 1 alkylene
  • L 2 is not selected from C 1 alkylene, 1 C 1 alkyl substituted C 1 alkylene, C 2 alkylene;
  • R 1 is selected from amino
  • L is selected from none
  • R 2 is not selected from thienyl, C 1 ⁇ C 5 alkyl
  • R 1 is selected from amino
  • R 2 is selected from C 1 alkyl
  • L is not selected from C 2 ⁇ C 4 alkylene, none, 1 C 1 alkyl substituted C 2 alkylene, 1 C 1 Alkyl substituted C alkylene ;
  • R 1 is selected from hydrogen and R 2 is selected from C 1 alkyl
  • L is not selected from 1 C 1 alkyl substituted C 2 alkylene, 1 C 1 alkyl substituted C 1 alkylene;
  • R 1 is selected from amino
  • L is selected from C 1 alkylene
  • R is not selected from
  • R 1 is selected from hydrogen, C 1 -C 8 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, -NHR 1 ';
  • R 1 ' is selected from C 1 to C 8 alkyl substituted by 0 to 3 R 3 , -C(O)R 3 ';
  • R3 are independently selected from phenyl, pyridyl, thienyl, pyrazolyl, furyl;
  • R 3 ' is selected from C 1 ⁇ C 8 alkyl, phenyl
  • L is selected from none, C 1 to C 8 alkylene substituted by 0 to 3 R 4 , -S-, -O-,
  • R 4 are independently selected from C 1 -C 8 alkyl groups
  • R 2 is selected from C 1 to C 8 alkyl, C 2 to C 8 alkenyl, C 2 to C 8 alkynyl, phenyl substituted by 0 to 3 R 5 , thiophene substituted by 0 to 3 R 5 radical, furanyl substituted by 0 to 3 R 5 , pyrazolyl substituted by 0 to 3 R 5 , piperidinyl substituted by 0 to 3 R 5 , nitrogen substituted by 0 to 3 R 5 Heterocyclobutane, naphthyl substituted by 0 to 3 R 5 , substituted by 0 to 3 R 5 Replaced by 0 to 3 R 5
  • R 5 are independently selected from C 1 -C 8 alkyl substituted by 0-3 R 6 , C 1 -C 8 alkoxy substituted by 0-3 R 6 , halogen, carboxyl, nitro, amino, Hydroxy, -C(O)R 7 , -C(O)OR 7 , phenyl substituted by 0 to 3 R 6 , pyridyl substituted by 0 to 3 R 6 ;
  • R 6 are independently selected from C 1 -C 8 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, C 2 -C 8 alkynyl, C 2 -C 8 alkenyl, phenyl;
  • R 7 is selected from C 1 ⁇ C 8 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, phenyl, furfuryl Anyl.
  • R 1 is selected from hydrogen, halogen, hydroxyl, amino, -NHR 1 ';
  • R 1 ' is selected from C 1 to C 3 alkyl substituted by 0 to 1 R 3 , -C(O)R 3 ';
  • R3 are independently selected from phenyl, pyridyl, thienyl, pyrazolyl, furyl;
  • R 3 ' is selected from C 1 -C 3 alkyl, phenyl
  • L is selected from none, C 1 to C 6 alkylene substituted by 0 to 1 R 4 , -S-, -O-,
  • R 4 are independently selected from C 1 -C 3 alkyl groups
  • R 2 is selected from C 1 -C 7 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl substituted by 0-2 R 5 , thiophene substituted by 0-1 R 5 radical, furyl substituted by 0-1 R5 , pyrazolyl substituted by 0-1 R5 , piperidinyl substituted by 0-1 R5 , nitrogen substituted by 0-1 R5 Heterocyclobutane, naphthyl substituted by 0 to 1 R 5 , substituted by 0 to 1 R 5 Replaced by 0 to 1 R 5
  • R 5 are independently selected from C 1 -C 4 alkyl substituted by 0-3 R 6 , C 1 -C 3 alkoxy substituted by 0-3 R 6 , halogen, carboxyl, nitro, amino, Hydroxy, -C(O)R 7 , -C(O)OR 7 , phenyl substituted by 0 to 1 R 6 , pyridyl substituted by 0 to 1 R 6 ;
  • R 6 are independently selected from C 1 -C 3 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, C 2 -C 4 alkynyl, C 2 -C 4 alkenyl, phenyl;
  • R 7 is selected from C 1 -C 4 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, phenyl, furyl.
  • L is selected from none, C 1 to C 6 alkylene substituted by 0 to 1 R 4 , -S-, -O-,
  • R 4 are independently selected from C 1 -C 3 alkyl groups
  • R 2 is selected from C 1 -C 7 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl substituted by 0-2 R 5 , thiophene substituted by 0-1 R 5 radical, furyl substituted by 0-1 R5 , pyrazolyl substituted by 0-1 R5 , piperidinyl substituted by 0-1 R5 , nitrogen substituted by 0-1 R5 Heterocyclobutane, naphthyl substituted by 0 to 1 R 5 , substituted by 0 to 1 R 5 Replaced by 0 to 1 R 5
  • R 5 are independently selected from C 1 -C 4 alkyl substituted by 0-3 R 6 , C 1 -C 3 alkoxy substituted by 0-3 R 6 , halogen, carboxyl, nitro, amino, Hydroxy, -C(O)R 7 , -C(O)OR 7 , phenyl substituted by 0 to 1 R 6 , pyridyl substituted by 0 to 1 R 6 ;
  • R 6 are independently selected from C 1 -C 3 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, C 2 -C 4 alkynyl, C 2 -C 4 alkenyl, phenyl;
  • R 7 is selected from C 1 -C 4 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, phenyl, furyl.
  • R 1 is selected from hydrogen, halogen, hydroxyl, amino, -NHR 1 ';
  • R 1 ' is selected from C 1 to C 3 alkyl substituted by 0 to 1 R 3 , -C(O)R 3 ';
  • R3 are independently selected from phenyl, pyridyl, thienyl, pyrazolyl, furyl;
  • R 3 ' is selected from C 1 -C 3 alkyl, phenyl
  • L is selected from none, C 1 to C 6 alkylene substituted by 0 to 1 R 4 , -S-, -O-,
  • R 4 are independently selected from C 1 -C 3 alkyl groups
  • R 5a , R 5b , and R 5c are independently selected from hydrogen, C 1 -C 4 alkyl substituted by 0-3 R 6 , C 1 -C 3 alkoxy substituted by 0-3 R 6 , halogen , carboxyl, nitro, amino, hydroxyl, -C(O)R 7 , -C(O)OR 7 , phenyl substituted by 0 to 1 R 6 , pyridyl substituted by 0 to 1 R 6 ;
  • R 6 are independently selected from C 1 -C 3 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, C 2 -C 4 alkynyl, C 2 -C 4 alkenyl, phenyl;
  • R 7 is selected from C 1 -C 4 alkyl, halogen, hydroxyl, carboxyl, amino, nitro, cyano, phenyl, furyl.
  • R 1 is selected from hydrogen, halogen, amino, -NHR 1 ';
  • R 1 ' is selected from C 1 to C 3 alkyl substituted by 0 to 1 R 3 , -C(O)R 3 ';
  • R3 are independently selected from phenyl, pyridyl, thienyl, pyrazolyl, furyl;
  • R 3 ' is selected from C 1 -C 3 alkyl
  • L is selected from none, C 1 to C 6 alkylene substituted by 0 to 1 R 4 , -S-, -O-,
  • R 4 are each independently selected from C 1 -C 3 alkyl groups.
  • the compound is one of the following compounds:
  • the present invention also provides the use of the aforementioned compound, or its salt, or its isomer, or its hydrate, or its solvate, or its prodrug in the preparation of MBL inhibitor and/or the preparation of antibacterial drug.
  • the present invention also provides a drug, which is composed of the aforementioned compound, or its salt, or its isomer, or its hydrate, or its solvate, or its prodrug as the active ingredient, plus pharmaceutically Preparations prepared with acceptable excipients or auxiliary ingredients.
  • the present invention also provides a thiazole amine compound, or its salt, or its isomer, or its hydrate, or its solvate, or its prodrug in the preparation of MBL inhibitors and/or the preparation of antibacterial drugs purposes, the thiazole amine compound is one of the following compounds:
  • the compounds and derivatives provided in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.
  • substitution means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
  • C a to C b alkyl indicates any alkyl group containing "a" to "b” carbon atoms.
  • C 1 -C 8 alkyl refers to an alkyl group containing 1 to 8 carbon atoms
  • C 1 to C 8 alkoxy refers to an alkoxy group containing 1 to 8 carbon atoms.
  • Alkyl means a saturated hydrocarbon chain having the indicated number of carbon atoms.
  • C 1 -C 8 alkyl refers to an alkyl group having 1 to 8 carbon atoms, ie, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms.
  • Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two or three branches. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl base) and hexyl, etc.
  • Halogen is fluoro, chloro, bromo or iodo.
  • the compound of the present invention has good inhibitory activity to metallo- ⁇ -lactamases (MBL), especially to multiple clinically relevant MBL subtypes, such as subtypes such as VIM, NDM, IMP have good inhibitory activity, and has strong revolutionary
  • MBL metallo- ⁇ -lactamases
  • the permeability of Lambert-negative bacteria can be used to prepare a broad-spectrum MBL inhibitor, and has a good development prospect as a drug molecule for overcoming antibacterial drug resistance.
  • the raw materials and equipment used in the specific embodiments of the present invention are all known products, obtained by purchasing commercially available products.
  • compound 1 was prepared by replacing the raw material n-hexanal with phenylacetaldehyde
  • compound 2 was prepared by replacing the raw material n-hexanal with 2-phenylpropanal
  • compound 11 was prepared by replacing the raw material n-hexanal with n-valeraldehyde
  • Compound 11 was prepared by replacing the raw material n-hexanal with n-heptanal to obtain compound 12, and the raw material n-hexanal was replaced with n-octylaldehyde to obtain compound 13, and the raw material n-hexanal was replaced with n-butyraldehyde to prepare compound 14, and the raw material n-hexanal was replaced
  • Compound 18 was prepared for p-nitrophenylacetaldehyde
  • compound 20 was prepared by replacing the raw material n-hexanal with acetaldehyde
  • compound 21 was prepared by replacing the raw material n-hexanal with thiophene
  • the raw material 1-(tert-butoxycarbonyl)azetidine-3-acetic acid was replaced with phenylpropionic acid to prepare compound 5, and the raw material 1-(tert-butoxycarbonyl)nitrogen Compound 17 was prepared by replacing heterotidine-3-acetic acid with p-nitrophenylacetic acid, and the raw material 1-(tert-butoxycarbonyl)azetidine-3-acetic acid was replaced by 3-nitrophenylacetic acid to obtain Compound 46, the raw material 1-(tert-butoxycarbonyl)azetidine-3-acetic acid was replaced by 3-aminophenylacetic acid to prepare compound 47, the raw material 1-(tert-butoxycarbonyl)azetidine Compound 50 was prepared by replacing alkane-3-acetic acid with 4-biphenylacetic acid, and replacing the raw material 1-(tert-butoxycarbonyl)azetidine-3-acetic acid with 4-(trifluoromethoxy)phenylacetic acid
  • the raw material 1-(tert-butyl Oxycarbonyl) azetidine-3-acetic acid was replaced by 3-(4-fluorophenyl) propionic acid to prepare compound 83
  • the raw material 1-(tert-butoxycarbonyl) azetidine-3- Acetic acid was replaced by 3-(3-methoxyphenyl)propionic acid to prepare compound 84
  • the starting material 1-(tert-butoxycarbonyl)azetidine-3-acetic acid was replaced by 3-(2,4- Dichlorophenyl)propionic acid was prepared to obtain compound 85
  • the raw material 1-(tert-butoxycarbonyl)azetidine-3-acetic acid was replaced with 3-(4-methoxyphenyl)propionic acid to obtain compound 86
  • the raw material 1-(tert-butoxycarbonyl)azetidine-3-acetic acid was replaced by 3-(1-naphthyl)propionic acid to prepare compound 87
  • Embodiment 3 the synthesis of compound 51,54,57,62
  • compound 54 was prepared by replacing the raw material 3-methoxyphenethyl alcohol with thiophene-3-ethanol
  • compound 57 was prepared by replacing the raw material 3-methoxyphenethyl alcohol with 3-bromophenethyl alcohol
  • Compound 62 was prepared by replacing the raw material 3-methoxyphenethyl alcohol with p-fluorophenethyl alcohol.
  • the structure of each compound is shown below:
  • Compound 44 and Compound 41 are obtained by de-Boc of Compound 43 and Compound 40, respectively.
  • compound 41 was prepared by replacing the starting material compound 43 with compound 40.
  • the structure of compound 41 is shown below:
  • X is a bromine atom, and R is a different substituent.
  • compound 56 was prepared by replacing the raw material 3-bromopropene with 4-bromo-1-butene
  • compound 61 was prepared by replacing the raw material 3-bromopropene with Bian bromide
  • the intermediate b was directly hydrolyzed
  • Compound 63 was prepared.
  • the structure of each compound is shown below:
  • Embodiment 6 the synthesis of compound 59,70
  • R CH 3 , Br, CH 3 O, C(CH 3 ) 3
  • compound 96 was prepared by replacing the raw material 3-thiopheneboronic acid with phenylboronic acid
  • compound 97 was prepared by replacing the raw material 3-thiopheneboronic acid with 1-methyl-1H-pyrazole-5-boronic acid
  • compound 98 was prepared by replacing the starting material 3-thiopheneboronic acid with 2-furanboronic acid. The structure of each compound is shown below:
  • Test example 1 the inhibitory activity of compound of the present invention to MBL
  • the activity test reaction was carried out in a black 96-well microtiter plate, the total volume was 60 ⁇ L, and the specific operation steps were as follows:
  • the MBL enzyme is formulated into a certain concentration of enzyme solution (VIM-2, VIM-1 and VIM-5: 1.2nM; NDM-1: 0.5nM; IMP-1: 4.8nM) with the test buffer, and the substrate FC-5 uses the test buffer to prepare a 30 ⁇ M substrate solution for future use.
  • VIP-2, VIM-1 and VIM-5 1.2nM; NDM-1: 0.5nM; IMP-1: 4.8nM
  • step (3) In a 96-well ELISA plate, 10 ⁇ L of compound working solution obtained in step (1), 30 ⁇ L of test buffer and 10 ⁇ L of enzyme solution were sequentially added to each well, and incubated at room temperature for 10 min.
  • test results show that the compounds of the present invention have good inhibitory activity on MBL, especially on multiple MBL subtypes, especially clinically relevant subtypes such as VIM, NDM, and IMP, among which compound 64 is the best.
  • Test Example 2 Antibacterial activity of the compound of the present invention combined with meropenem
  • Bacterial solution dilution Use an inoculation loop to pick a single clone from the plate and place it in normal saline, adjust the OD 630 to 0.08-0.13 (equivalent to 1 ⁇ 10 8 CFU/mL), and dilute the bacterial solution 100 times with CAMHB. Add 100 ⁇ L to each well. At this time, the concentration of meropenem was 128 ⁇ g/mL to 0.25 ⁇ g/mL, and the concentration of the enzyme inhibitor was 10 ⁇ g/mL.
  • the compounds of the present invention have good inhibitory activity on metallo- ⁇ -lactamases (MBL), especially on multiple clinically relevant MBL subtypes, such as subtypes such as VIM, NDM, and IMP. It has strong gram-negative bacteria permeability, can be used to prepare broad-spectrum MBL inhibitors, and has good development prospects as a drug molecule for overcoming antibacterial drug resistance.
  • MBL metallo- ⁇ -lactamases

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Abstract

La présente invention concerne un inhibiteur de thiazolamine MBL, son procédé de préparation et son utilisation, se rapportant au domaine de la chimie médicale. L'inhibiteur de la thiazolamine MBL est un composé représenté par la formule I, ou un sel, un isomère, un hydrate, un solvate ou un promédicament de celui-ci. Le composé selon la présente invention a une bonne activité inhibitrice sur la métallo-β-lactamase (MBL), et en particulier une bonne activité inhibitrice sur de multiples sous-types de MBL cliniquement pertinents, tels que les sous-types de VIM, NDM, IMP, etc, a une perméabilité bactérienne à Gram négatif élevée, peut être utilisé pour préparer un inhibiteur de MBL à large spectre, peut être utilisé en tant que molécule médicamenteuse pour surmonter la résistance aux bactéries et la résistance aux médicaments, et présente une bonne perspective de développement.
PCT/CN2023/077670 2022-02-28 2023-02-22 Inhibiteur de thiazolamine mbl, son procédé de préparation et son utilisation WO2023160582A1 (fr)

Applications Claiming Priority (2)

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CN202210190185.1A CN116693467A (zh) 2022-02-28 2022-02-28 一种噻唑胺类mbl抑制剂及其制备方法和用途
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