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WO2023060369A1 - Nouveaux composés bicycliques à substitution carbimidate et leur utilisation en tant qu'inhibiteurs de bêta-lactamase - Google Patents

Nouveaux composés bicycliques à substitution carbimidate et leur utilisation en tant qu'inhibiteurs de bêta-lactamase Download PDF

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Publication number
WO2023060369A1
WO2023060369A1 PCT/CN2021/122965 CN2021122965W WO2023060369A1 WO 2023060369 A1 WO2023060369 A1 WO 2023060369A1 CN 2021122965 W CN2021122965 W CN 2021122965W WO 2023060369 A1 WO2023060369 A1 WO 2023060369A1
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Prior art keywords
oxo
diazabicyclo
sulfooxy
octane
carbimidate
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PCT/CN2021/122965
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English (en)
Inventor
Zhixiang Yang
Lijuan ZHAI
Jian Sun
Haikang YANG
Jinbo JI
Jingwen JI
Lili He
Yuanyu GAO
Dong TANG
Zafar Iqbal
Yuanbai LIU
Yangxiu MU
Xueqin Ma
Jianqiang Yu
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Ningxia Academy Of Agriculture And Forestry Sciences
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Priority to PCT/CN2021/122965 priority Critical patent/WO2023060369A1/fr
Publication of WO2023060369A1 publication Critical patent/WO2023060369A1/fr

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    • 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
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/54—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
    • A61K31/542—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 heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • 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
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • 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
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • 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
    • C07D495/04—Ortho-condensed systems

Definitions

  • This invention relates to novel beta-lactamase inhibitors and their preparation and their use as antibacterial agents either alone or in combination with an antibiotic (or plural antibiotics) for the treatment of infections caused by ⁇ -lactamase-producing pathogenic bacteria. More particularly, the invention relates to compositions and methods for overcoming bacterial antibiotic resistance.
  • ⁇ -Lactam antibiotics commonly called ⁇ -lactams
  • ⁇ -lactams have been playing an important role for treatment of bacterial infections, but pathogens resistant to them have been increasing in many countries around world.
  • ⁇ -lactamases are enzymes that catalyze the hydrolysis of the ⁇ -lactam ring, which inactivate the antibacterial activity of the ⁇ -lactam antibiotic and allow the bacteria to become resistant.
  • the present invention relates to new diazabicyclic compounds (some of which have potent broad-spectrum ⁇ -lactamase inhibitory activity and others do not have such activity) that when used in combination with a ⁇ -lactam antibiotic or with other non ⁇ -lactam antibiotic enhance the activity of the antibiotic against class A, class B, class C, and class D enzyme producing organisms and thereby enhance the antibacterial properties.
  • the inventive compounds are therefore useful in the treatment of bacterial infections in humans or animals either alone or in combination with ⁇ -lactam antibiotics.
  • X is oxygen or sulfur
  • M is hydrogen or a pharmaceutically acceptable salt forming cation
  • a “pharmaceutically acceptable salt” refers to a salt of a compound, which salt possesses the desired pharmacological activity of the parent compound
  • specified compounds “modified in that they have been deuterated” refer to compounds prepared by modifying the specified compounds so that one or more hydrogen atoms in the compounds have been replaced with or converted to deuterium,
  • R is optionally substituted with one or two substituents independently selected from the following:
  • the compounds of the present invention are new and the structural features are significantly distinct from the compounds described in the prior art.
  • R is a radical selected from any of the following groups:
  • Heterocyclyl (C 1-6 ) alkyl wherein the said heterocycle containing at least one heteroatom selected from O, N and S wherein the said heterocycle is optionally substituted.
  • the ring S is optionally oxidized to S (O) or S (O) 2 and the free ring N atom may optionally take a substituent.
  • Non-limiting examples of such compounds are:
  • Examples of the groups for forming a pharmaceutically acceptable salt represented by M in the formula (I) include: inorganic base salts, ammonium salts, organic base salts, basic amino acid salts, inorganic acid addition salts, and organic acid addition salts.
  • Inorganic bases that can form the inorganic base salts include alkali metals such as sodium, potassium, and lithium and alkaline earth metals such as calcium and magnesium.
  • Organic bases that can form the organic base salts include n-propylamine, n-butylamine, cyclohexylamine, benzylamine, octylamine, ethanolamine, diethanolamine, diethylamine, triethylamine, dicyclohexylamine, procaine, choline, N-methylglucamine, morpholine, pyrrolidine, piperidine, N-ethylpiperidine and N-methylmorpholine.
  • Basic amino acids that can form the basic amino acid salts include lysine, arginine, ornithine and histidine.
  • the compounds of formula (I) containing a basic nitrogen atom are capable of forming acid addition salts.
  • Such salts with pharmaceutically acceptable acids are included in the invention.
  • acids hydrochloric, hydrobromic, phosphoric, sulphuric, citric, oxalic, maleic, fumaric, glycolic, mandelic, tartaric, aspartic, succinic, malic, formic, acetic, p-toluenesulfonic, trifluoroacetic, methanesulfonic, ethanesulfonic, trifluoromethanesulfonic, benzenesulfonic and the like.
  • Another aspect of the present invention is to include all possible isomers of formula (I) .
  • the term ‘isomers’ refers to different compounds that have the same molecular formula but differ in arrangement and configuration of the atoms, such as geometrical isomers and optical isomers.
  • a substituent may be attached at a chiral center of a carbon atom. Therefore the invention includes enantiomers, diastereomers or racemates of the compound.
  • ‘enantiomers’ are a pair of stereoisomers that are non-superimposable mirror images of each other, and 1: 1 mixture of a pair of enantiomers is a racemic mixture.
  • stereoisomers are stereoisomers that have at least two asymmetric carbon atoms but which are not mirror-images of each other.
  • stereochemistry at each chiral carbon may be specified by either R or S.
  • protecting group refers to a group of atoms that when attached to a reactive functional group in a molecule masks, reduces or prevents reactivity of the functional group. Examples of protecting groups can be found in “Protective Groups in Organic Synthesis” , (Theodora W. Greene and Peter G. M. Wuts, John Wiley &Sons. Inc., 3 rd , 1999) .
  • Representative amino protecting groups include, but are not limited to formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ) , tert-butoxycarbonyl (Boc) , trimethylsilyl (TMS) , 9-fluorenylmethyloxycarbonyl (FMOC) , nitro-veratryoxycarbonyl (NVOC) , and the like.
  • hydroxy protecting groups include, but are not limited to, those where the hydroxyl group is either acylated or alkylated such as benzyl, and trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers, and allyl ethers.
  • Lower alkyl including from one to six carbon atoms in any arrangement, e.g., methyl, ethyl, i-propyl or t-butyl,
  • Substituted amino such as -NHCH 3 , -N (CH 3 ) 2 , -NHCH 2 CH 3 , -NHPr i , -NHBu t ,
  • Alkoxy such as -OCH 3 , -OC 2 H 5 , -OPr i (i.e., isopropyloxy) , -OBu t (i.e., isobtutyloxy) ,
  • Hydroxyalkyl such as -CH 2 OH, -CH 2 CH 2 OH,
  • Halogen such as F, Cl, Br,
  • Alkoxycarbonyl such as -COOCH 3 , -COOC 2 H 5 , -COOPr i , and -COOBu t ,
  • Haloalkyl such as -CH 2 Cl, -CH 2 F,
  • Alkylamine such as -CH 2 NH 2 , -CH 2 CH 2 NH 2 ,
  • Substituted alkylamine such as -CH 2 CH 2 NHCH 3 , -CH 2 CH 2 N (CH 3 ) 2 , -CH 2 NHCH 3 , -CH 2 N (CH 3 ) 2 ,
  • Substituted sulfonamide such as -SO 2 NHCH 3 , -SO 2 NHPr i , -SO 2 NHBu t , -SO 2 NHCH 2 CH 3 ,
  • Oxo ( O) when oxygen is bonded through double bond to a carbon atom
  • a particular subject of the invention is those in which M is hydrogen or a pharmaceutically acceptable salt forming cation.
  • compositions comprising a compound of formula (I) of this invention as an active ingredient in combination with an antibiotic (e.g., a ⁇ -lactam antibiotic or some other non ⁇ -lactam antibiotic) and a suitable amount of pharmaceutically acceptable carrier or diluent, so as to provide a form for proper administration to a patient.
  • antibiotic e.g., a ⁇ -lactam antibiotic or some other non ⁇ -lactam antibiotic
  • suitable amount of pharmaceutically acceptable carrier or diluent so as to provide a form for proper administration to a patient.
  • Suitable pharmaceutical vehicles include excipients such as starch, glucose, lactose, sucrose, gelatin, gum arabic, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like.
  • excipients such as starch, glucose, lactose, sucrose, gelatin, gum arabic, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like.
  • Other examples of suitable pharmaceutical vehicles have been described in the art (Remington’s Science and Practice of Pharmacy, 21 st Edition, 2006) .
  • Compositions of the present disclosure can also contain minor amounts of wetting, dispersing or emulsifying agents,
  • compositions can be formulated in a conventional manner. Proper formulation is dependent upon the route of administration chosen.
  • the present pharmaceutical compositions can take the form of injectable preparations, suspensions, emulsions, sugar-coated tablets, pellets, gelatin-capsules, capsules containing liquids, powders, granules, sustained-release formulations, suppositories, aerosols, sprays, ointments, creams or any other form suitable for use.
  • the present invention also provides for the use, in the manufacture of a medicament, of a compound within formula (I) above as an active ingredient in an antibacterial composition in admixture with a carrier.
  • the present invention also provides for the use, in the manufacture of a medicament, of a compound within formula (I) above as an active ingredient.
  • the present invention also provides for the use, in the manufacture of a medicament, of a compound within formula (I) above as an active ingredient, along with one or more ⁇ -lactam antibiotics (e.g., a ⁇ -lactam antibiotic or some other non ⁇ -lactam antibiotic) , in an antibacterial composition in admixture with a carrier.
  • ⁇ -lactam antibiotics e.g., a ⁇ -lactam antibiotic or some other non ⁇ -lactam antibiotic
  • the present invention also provides for the use, in the manufacture of a medicament, of a compound within formula (I) above as an active ingredient, along with one or more ⁇ -lactam antibiotics (e.g., a ⁇ -lactam antibiotic or some other non ⁇ -lactam antibiotic) .
  • ⁇ -lactam antibiotics e.g., a ⁇ -lactam antibiotic or some other non ⁇ -lactam antibiotic
  • compositions for oral delivery can be, for example, in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs.
  • Orally administered compositions can contain one or more optional agents, for example, sweetening agents such as fructose, aspartame, or saccharin, flavoring agents such as peppermint, oil of wintergreen, cherry, coloring agents, and preserving agents to provide a pharmaceutically palatable preparation.
  • sweetening agents such as fructose, aspartame, or saccharin
  • flavoring agents such as peppermint, oil of wintergreen, cherry, coloring agents
  • preserving agents to provide a pharmaceutically palatable preparation.
  • the compositions when in tablet form, can be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over an extended period of time.
  • Oral compositions can include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like.
  • suitable carriers, excipients, or diluents include water, saline, alkyleneglycols (e.g. propylene glycol) , polyalkylene glycols (e.g., polyethylene glycol) , oils, alcohols, slightly acidic buffers ranging from about pH 4 to about pH 6 (e.g., acetate, citrate, ascorbate ranging from about 5 mM to about 50 mM) , and the like.
  • slightly acidic buffers ranging from about pH 4 to about pH 6 (e.g., acetate, citrate, ascorbate ranging from about 5 mM to about 50 mM) , and the like.
  • flavoring agents, preservatives, coloring agents, bile salts, acylcarnitines, and the like can be added.
  • Topical delivery systems also include transdermal patches containing at least one compound of formula (I) to be administered.
  • Formulations of a compound of the present invention, for topical use, such as in creams, ointments, and gels, can include an oleaginous or water soluble ointment base, for example, topical compositions can include vegetable oils, animal fats, and in certain embodiments, semisolid hydrocarbons obtained from petroleum.
  • Topical compositions can further include white ointment, yellow ointment, cetyl esters wax, oleic acid, olive oil, paraffin, petrolatum, white petrolatum, spermaceti, starch glycerite, white wax, yellow wax, lanolin, and glyceryl monostearate.
  • Various water-soluble ointment bases can also be used, including glycol ethers and derivatives, polyethylene glycols, polyoxyl 40 stearate, and polysorbates.
  • the weight ratio of active ingredient to carrier will normally be in the range of 1: 30 to 30: 1, for example, 1: 25 to 25: 1, 1: 20 to 20: 1, 1: 15 to 15: 1, 1: 10 to 10: 1, 1: 5 to 5: 1, 1: 4 to 4: 1, 1: 3 to 3: 1, 1: 2 to 2: 1, or 1: 1.
  • the administered daily dose varies according to the illness treated, and the administration route.
  • an effective dose e.g., in some instances, ⁇ -lactamase inhibiting dose
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof will be a daily dose in the range from about 1 to about 500 mg per kilogram of body weight orally, and from about 1 to about 500 mg per kilogram of body weight parenterally.
  • the weight ratio of the compound of present invention to the antibiotic will normally be in the range from 1: 30 to 30: 1, for example, 1: 25 to 25: 1, 1: 20 to 20: 1, 1: 15 to 15: 1, 1: 10 to 10: 1, 1: 9 to 9: 1, 1: 8 to 8: 1, 1: 7 to 7: 1, 1: 6 to 6: 1, 1: 5 to 5: 1, 1: 4 to 4: 1, 1: 3 to 3: 1, 1: 2 to 2: 1, or 1: 1.
  • an additional object is to provide an improved method for the treatment of bacterial infections caused by ⁇ -lactamase producing bacteria in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of at least one compound chosen from formula (I) or a pharmaceutically acceptable salt thereof in combination with a known ⁇ -lactam antibiotic.
  • the compounds increase the antibacterial effectiveness of ⁇ -lactamase susceptible ⁇ -lactam antibiotics, that is, they increase the effectiveness of the antibiotic against infections caused by ⁇ -lactamase producing microorganisms in mammalian subjects, particularly in human.
  • said compounds of formula (I) or a pharmaceutically salt thereof can be mixed with the ⁇ -lactam antibiotic, and the two agents thereby administered simultaneously.
  • the combination of the compound of the invention and the antibiotic can provide a synergistic effect.
  • the term ‘synergystic effect’ refers to the effect produced when two or more agents are co-administered is greater than the effect produced when the agents are administered individually.
  • the compound of formula (I) or a salt thereof can be administered as a separate agent during a course of treatment with the antibiotic.
  • Therapeutically effective amount refers to the amount of a compound that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease, is sufficient to affect such treatment of the disease, disorder, or symptom.
  • the therapeutically effective amount can vary depending, for example, on the compound, the disease, disorder, and/or symptoms of the disease, severity of the disease, disorder, and/or symptoms of the disease, the age, weight, and/or health of the patient to be treated, and the judgement of the prescribing physician.
  • ⁇ -lactam antibiotic refers to a compound with antibiotic property that contains a ⁇ -lactam functionality.
  • Examples of ⁇ -lactam antibiotics which can be used in combination with the compounds of the present invention represented by formula (I) are commonly marketed penicillins, cephalosporins, penems, carbapenems and monobactams.
  • Examples of ⁇ -lactam antibiotics which can be used in combination with the compounds of the present invention represented by formula (I) are commonly used penicillins, such as amoxicillin, ampicillin, azlocillin, mezlocillin, apalcillin, hetacillin, bacampicillin, carbenicillin, sulbenicillin, ticarcillin, piperacillin, methicillin, ciclacillin, talampicillin, oxacillin, cloxacillin, dicloxacillin and commonly used cephalosporins such as cephalothin, cephaloridine, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cephradine, cephapirin, cefuroxime, cefoxitin, cephacetrile, cefotiam, cefotaxime, cefatriazine, cefsulodin, cefoperazone, ceftizoxime, cefmenoxime
  • ⁇ -lactam antibiotics such as imipenem, meropenem, panipenem, biapenem, doripenem, ertapenem and the like could be used.
  • monobactam class of ⁇ -lactam antibiotics such as aztreonam, carumonam, tigemonam, and the like could be used as the combination partner of antibiotic.
  • antibiotics which are not ⁇ -lactam antibiotics
  • examples of antibiotics which can be used in combination with the compounds of the present invention (i.e., compounds of formula (I) above, salts thereof, solvates of such compounds and salts, and deuterated compounds of any such compounds) include aminoglycosides, quinolones, tetracyclines, glycylcyclines, glycopeptides, lipopeptides, macrolides, ketoliddes, lincosamides, streptogramin, oxazolidinones, polymyxins, and other compounds known to have antibacterial properties.
  • ‘Pharmaceutically acceptable solvate’ refers to a molecular complex of a compound with one or more solvent molecules in a stoichiometric or non-stoichiometric amount.
  • solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to recipient, e.g., water, ethanol, and the like.
  • a molecular complex of a compound or moiety of a compound and a solvent can be stabilized by non-covalent intra-molecular forces such as, for example, electrostatic forces, Van der Waals forces or hydrogen bonds.
  • the term hydrate refers to a complex where the one or more solvent molecules are water.
  • the present invention also relates to methods for the preparation of compounds of formula (I) .
  • the compounds of the present invention of formula (I) can be readily prepared by the following reaction Scheme 1 and examples using readily available starting materials, reagents and conventional synthesis procedures known to those of ordinary skill in this art.
  • the bicyclic intermediate amide (II) may be prepared following the literature (Org. Process Res. Dev. 2016, 20, 1799-1805) .
  • Compounds of the general of formula (I) can be prepared by converting amide (II) to the nitrile (III) in presence of a suitable reagents.
  • the suitable reagents used for carrying out this step include, but are not limited to trifluoroacetic anhydride (TFAA) and triethylamine (TEA) or diisopropylethylamine (DIPEA) , phosphoryl chloride (POCl 3 ) and TEA, and the like.
  • the organic solvents useful in the reaction are not particularly limited and include any of those which do not adversely affect the reaction. Typical solvents include dichlomethane, chloroform, tetrahydrofuran and the like.
  • the reaction is normally carried out at a temperature of from about 0 °C to 40 °C, and preferably at room temperature under nitrogen. After completion of the reaction the desired product can be easily separated by conventional methods such as column chromatography, crystallization or similar methods.
  • the intermediate amide (III) could be converted to the hydroxy compound (IV) under an atmosphere of hydrogen or hydrogen mixed with an inert diluent such as nitrogen or argon in the presence of a hydrogenation catalyst.
  • the catalysts used in this hydrogenation reaction are the type of agents known in the art for this kind of deprotection and typical examples are the noble metals, such as nickel, palladium, platinum and rhodium. Examples of the catalysts are platinum, platinum oxide, palladium, palladium oxide and the like.
  • the catalyst is usually present in the amount from about 1 to about 50 weight percent and preferably from about 5 to about 15 weight percent based on the compound of amide (III) . It is often convenient to suspend the catalyst on an inert support.
  • a particularly convenient catalyst is palladium suspended on an inert support such as carbon, e.g., 5%or 10 %by weight palladium on carbon.
  • This reaction may be conveniently effected at ambient temperature from 15 psi to 60 psi until reaction is complete (2 to 72 hours) .
  • Suitable solvents for this reaction are those which substantially dissolve the starting material of the formula (III) , after reaction, the suitable solvents are sufficiently volatile to be removed by evaporation and do not themselves suffer hydrogenation. Examples of such solvents include methanol, ethanol, dioxane, ethyl acetate, tetrahydrofuran or a mixture of these solvents.
  • the hydroxy intermediate (IV) can be purified by silica gel column chromatography or in many cases can be directly carried out to the next step without further purification.
  • the compound of formula (IV) can be converted to the key intermediate (V) by sulfation of the hydroxy intermediate (IV) using a sulfating reagent (e.g., pyridine-SO 3 complex, SO 3 -NMe 3 complex, SO 3 -triethylamine complex, DMF-SO 3 complex and ClSO 3 H) in an appropriate base (e.g., pyridine, triethylamine or 2-picoline) as described in the literature (WO2017155765A1, Org. Process Res. Dev. 2016, 20, 1799-1805) .
  • a sulfating reagent e.g., pyridine-SO 3 complex, SO 3 -NMe 3 complex, SO 3 -triethylamine complex, DMF-SO 3 complex and ClSO 3 H
  • an appropriate base e.g., pyridine, triethylamine or 2-picoline
  • pyridine-SO 3 complex or SO 3 -NMe 3 complex can be added to a solution of the hydroxy intermediate (IV) in a solvent in an excess amount, if desired, to force the reaction to completion.
  • the organic solvents useful for this transformation are not particularly limited and include those which do not adversely affect the reaction. Typical solvents include, but are not limited to pyridine, tertrahydrofuran, isopropyl alcohol, dimethyl formamide, dimethylacetamide, acetonitrile, or those solvents mixed with water.
  • the transformation can be carried out at from 0 °C to 40 °C, and preferably at room temperature.
  • the compound of formula (Ia or Ib) can be achieved by treatment of the key intermediate (V) with alcohol or thiol and an appropriate base in an suitable organic solvent.
  • suitable base used for carrying out this step include, but are not limited to sodium hydride (NaH) , potassium hydride (KH) , sodium tert-butoxide or potassium tert-butoxide, and the like.
  • suitable organic solvents useful in the reaction are not particularly limited and include any of those which do not adversely affect the reaction. Typical solvents include methanol, ethanol, dichlomethane, N, N-dimethylformamide, tetrahydrofuran and the like.
  • the reaction is normally carried out at a temperature of from about 0 °C to 40 °C, and preferably at room temperature under nitrogen.
  • R 1 when R 1 is methyl or ethyl group, the compound of formula (Ia) can be achieved by treatment of the key intermediate (V) directly with sodium methoxide or sodium ethoxide in an suitable organic solvent.
  • the compound of formula (Ia or Ib) also can be achieved by removing protecting group when the compound (Ia or Ib) containing protection group, such as Boc., and the like.
  • the treatment is suitably conducted at a temperature in a range from about -10 °C to room temperature and is typically conducted at a temperature in a range of from about 0 °C to about 35 °C.
  • Suitable purification methods for the final compound of formula (Ia or Ib) are a preparative HPLC, or HP20 chromatograph, or inon exchange resin and the like.
  • DIPEA N, N-diisopropylethylamine
  • Preparative HPLC was performed on an Agilent 1260 Infinity II System on Agilent 10 prep-C18 250 ⁇ 21.2 mm column, using an acetonitrile/aqueous 0.1%trifluoroacetic acid gradient, or an acetonitrile/aqueous 0.1%formic acid gradient at 22°C.
  • Mass spectra were performed on an Agilent 1260II-6125 Separation Module using either ES - or ES + ionization modes.
  • Step 1 Synthesis of (2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carbonitrile (A-2)
  • TFAA 0.3 g, 1.4 mmol
  • A-1 0.2 g, 0.7 mmol, prepared according to Org. Process Res. Dev. 2016, 20, 1799-1805
  • TEA 0.7 g, 7.0 mmol
  • DCM 5 mL
  • the resulting reaction mixture was heated at 35 °C for 3 hours, and then concentrated under reduced pressure.
  • the residue was extracted with ethyl acetate, washed with water, brine, dried over Na 2 SO 4 and filtrated.
  • Step 3 Synthesis of triethylamine (2S, 5R) -2-cyano-7-oxo-1, 6-diazabicyclo [3.2.1] octan-6-yl sulfate (B5_1)
  • Imipenem as a test antibiotic compound was dissolved in DMSO, and then diluted in microbial growth medium (Mueller-Hinton Broth II, cation adjusted) resulting in a final concention range of 0.125-64 mg/L in serial two-fold dilution. In all cases the filnal DMSO concentraion was less than 0.5%.
  • Bacteria were added to 96-well microtitre plates containing the serial two-fold dilutions of the compounds; the final cell density was appoximately 5x10 5 colony forming units/mL (CFU/mL) . Plates were incubated at 37 °C for 18-24 hours and read visually. The MIC, i.e.
  • test compound that inhibited visible growth of the bacteria.
  • the same assay conditions were used when the compounds of present invention alone, avibactam (as a control) alone, and as a combination with test imipenem was tested for minmum inhibitory concentration (MIC, mg/L) . While test imipenem was serially diluted as descrribed above, a constant concentration of both avibactam and the present invention of 4 mg/L was used.
  • Bacterial strains that were used to evaluate the antimicrobial activity using the MIC determination included but were not limited to E. coli clinical isolate (strain 1) , E. coli 8739 (strain 2) , K. pneumoniae clinical isolate (strain 3) , K. pneumoniae 700603 (strain 4) , E. cloacae clinical isolate (strain 5) , E. cloacae 700323 (strain 6) , A. baumannii clinical isolate (strain 7) , A. baumannii 19606 (strain 8) , P. aeruginosa clinical isolate (strain 9) , P. aeruginosa 9027 (strain 10) .
  • Table 2 Synergy of the inhibitor example 1 to example 14 (4 mg/L) in combination with imipenem (IMI, AVI and Ex. 1 to Ex. 4, MIC, mg/L)
  • Table 3 Antibacterial activity of example 1 to example 14 (AVI and Ex. 1 to Ex. 7, MIC, mg/L)
  • the inhibitory activities of present compounds against various enzymes are measured by spectrophotometric assay using 490 nM and using nitrocefin as a substrate [J. Antimicrob. Chemother., 28, pp 775-776 (1991) ] .
  • the concentration of inhibitor (IC 50 ) which inhibits by 50%the reaction of hydrolysis of nitrocefin by the enzyme is determined.
  • Efficacy of the ⁇ -lactamase inhibitors can be evaluated in combination with ceftazidime aztreonam, meropenem, imipenem and other class of carbapenems and cephalosporins in murine infection models such as septicemia, pneumonia and thigh infection models (Ref: Andrea Endimiani et. al. Antimicrobial Agents and Chemotherapy, January 2011, page 82-85) .
  • murine acute lethal septicemia model mice were infected by the intraperitoneal injection of the clinical strains resulting in death of the untreated controls within 24-48 hours.
  • a single subcutaneous dose of meropenem with and without ⁇ -lactamase inhibitor was initiated and the survival ratio monitored for 5 days twice daily.
  • the dosing regimen used are meropenem alone (doses of 512, 1024 &2048 mg/kg of body weight) and meropenem plus ⁇ -lactamase inhibitor at ratio of 2: 1, 4: 1, 8: 1, 16: 1 &32: 1 (meropenem doses were 4, 8, 16, 32 &64 mg/kg for each ratio) .
  • the median effective dose for 50%protective dose (ED 50 ) of animals was determined by a computerized program of Probit analysis. Survival rates stratified for different dosing regimen were also obtained.
  • ED 50 50%protective dose
  • mice were used and intratracheally infected with Klebsiella pneumoniae strains. Mice in this model developed bacteraemia pneumoniae and fatal disease within 2 to 4 days with lung bacterial burden at 16-18 hours post infection of 10 11 to 10 13 CFU/gm lung.
  • Treatment with meropenem and inhibitor at a ratio of 2/1 &4/1 demonstrated efficacy with significant 3 to 6 log reduction in lung counts compared to meropenem alone and was relevant to the clinical situation.
  • Human testing of the ⁇ -lactamase inhibitor can be conducted in combination with partner antibiotic at a set ratio utilizing standard clinical development practice.

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Abstract

La présente divulgation concerne de nouveaux inhibiteurs de β-lactamase, pour le traitement d'infections bactériennes en combinaison avec des antibiotiques β-lactames, y compris une infection provoquée par des organismes pharmacorésistants et en particulier des organismes multirésistants à des médicaments. De façon spécifique, la présente Invention concerne des composés selon la formule (I) ou des sels pharmaceutiquement acceptables de ceux-ci. Dans cette formule, M, X et R sont tels que définis dans la description.
PCT/CN2021/122965 2021-10-11 2021-10-11 Nouveaux composés bicycliques à substitution carbimidate et leur utilisation en tant qu'inhibiteurs de bêta-lactamase WO2023060369A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1655781A (zh) * 2002-01-28 2005-08-17 安万特医药股份有限公司 具有β－内酰胺酶抑制剂活性的新的杂环化合物
WO2014141132A1 (fr) * 2013-03-14 2014-09-18 Naeja Pharmaceutical Inc. Nouveaux composés hétérocycliques et leur utilisation en tant qu'agents antibactériens et inhibiteurs de β-lactamase
US20140288051A1 (en) * 2011-12-02 2014-09-25 Naeja Pharmaceutical Inc. Bicyclic compounds and their use as antibacterial agents and beta-lactamase inhibitors
CN104334559A (zh) * 2012-05-30 2015-02-04 明治制果药业株式会社 新型β-内酰胺酶抑制剂及其制备方法
CN105801579A (zh) * 2014-12-31 2016-07-27 卢来春 一种β-内酰胺酶抑制剂
WO2016128867A1 (fr) * 2015-02-12 2016-08-18 Wockhardt Limited Composés contenant de l'azétidinone et leur utilisation dans le traitement d'infections bactériennes
JP2020023484A (ja) * 2018-07-26 2020-02-13 Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社 β−ラクタマーゼ阻害剤

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1655781A (zh) * 2002-01-28 2005-08-17 安万特医药股份有限公司 具有β－内酰胺酶抑制剂活性的新的杂环化合物
US20140288051A1 (en) * 2011-12-02 2014-09-25 Naeja Pharmaceutical Inc. Bicyclic compounds and their use as antibacterial agents and beta-lactamase inhibitors
CN104334559A (zh) * 2012-05-30 2015-02-04 明治制果药业株式会社 新型β-内酰胺酶抑制剂及其制备方法
WO2014141132A1 (fr) * 2013-03-14 2014-09-18 Naeja Pharmaceutical Inc. Nouveaux composés hétérocycliques et leur utilisation en tant qu'agents antibactériens et inhibiteurs de β-lactamase
CN105801579A (zh) * 2014-12-31 2016-07-27 卢来春 一种β-内酰胺酶抑制剂
WO2016128867A1 (fr) * 2015-02-12 2016-08-18 Wockhardt Limited Composés contenant de l'azétidinone et leur utilisation dans le traitement d'infections bactériennes
JP2020023484A (ja) * 2018-07-26 2020-02-13 Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社 β−ラクタマーゼ阻害剤

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