WO2022047790A1 - Composés bicycliques substitués par amidine, leur préparation, leur utilisation comme agents antibactériens et inhibiteurs de bêta-lactamase - Google Patents

Composés bicycliques substitués par amidine, leur préparation, leur utilisation comme agents antibactériens et inhibiteurs de bêta-lactamase Download PDF

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Publication number
WO2022047790A1
WO2022047790A1 PCT/CN2020/113787 CN2020113787W WO2022047790A1 WO 2022047790 A1 WO2022047790 A1 WO 2022047790A1 CN 2020113787 W CN2020113787 W CN 2020113787W WO 2022047790 A1 WO2022047790 A1 WO 2022047790A1
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Prior art keywords
oxo
diazabicyclo
octan
carbamimidoyl
hydrogen sulfate
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PCT/CN2020/113787
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English (en)
Inventor
Zhixiang Yang
Haikang YANG
Jinbo JI
Jian Sun
Yuanyu GAO
Dong TANG
Jingwen JI
Lijuan ZHAI
Yangxiu MU
Zafar Iqbal
Lili He
Yuanbai LIU
Rui JIANG
Koko MYO
Zawmin THU
Xueqin Ma
Jianqiang Yu
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Ningxia Academy Of Agriculture And Forestry Sciences
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Priority to PCT/CN2020/113787 priority Critical patent/WO2022047790A1/fr
Publication of WO2022047790A1 publication Critical patent/WO2022047790A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • 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
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to amidine substituted bicyclic compounds, 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.
  • the compounds of the present invention are ⁇ -lactamase inhibiting or non- ⁇ -lactamase inhibiting (i.e., some of the present invention by themselves would directly inhibit ⁇ -lactamase enzymatic function, and others of compounds of the present invention by themselves would not inhibit some ⁇ -lactamase enzymatic function though they provide synergy and increased potency of activity in combination with antibiotics, e.g., ⁇ -lactam antibiotics or non- ⁇ -lactam antibiotics) .
  • the present invention is concerned with methods for overcoming antibiotic resistance caused by ⁇ -lactamase producing bacteria, the method of preparation of the amidine substituted bicyclic compounds, pharmaceutical compositions containing the amidine substituted bicyclic compounds, methods of treatment, uses of the compounds, and other subject matter.
  • ⁇ -lactamases are enzymes that catalyze the hydrolysis of the ⁇ -lactam ring, which inactivates the antibacterial activity of the ⁇ -lactam antibiotic and allow the bacterial to become resistant. Inhibition of the ⁇ -lactamase with a ⁇ -lactamases inhibitor slows or prevents degradation of the ⁇ -lactam antibiotic and restores ⁇ -lactam antibiotic susceptibility to ⁇ -lactamase producing bacteria.
  • the compounds of the present invention are new and the structural features are significantly distinct from the compounds described in the patent references cited above.
  • 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.
  • 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
  • reference to specified compounds “modified in that they have been deuterated” refers to compounds prepared by modifying the specified compounds so that one or more hydrogen atoms in the compound 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:
  • C 1-6 straight or branched chain alkyl which is optionally substituted.
  • Non-limiting examples of such compounds are:
  • 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.
  • some compounds of formula (I) when they contain a basic group such as NH, NH 2 or pyridine and the like may form an inner, zwitterionic salt with OSO 3 H; such inner salts are also included in this invention.
  • 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 , I,
  • 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 NHCH 3 , –CH 2 N (CH 3 ) 2 , –CH 2 CH 2 NHCH 3 , –CH 2 CH 2 N (CH 3 ) 2 ,
  • Substituted sulfonamide such as —SO 2 NHCH 3 , –SO 2 NHCH 2 CH 3 , –SO 2 NHPr i , –SO 2 NHBu t ,
  • 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
  • sterile solutions of the active ingredient are usually prepared and the pH of the solutions are suitably adjusted and buffered.
  • Suitable solvents include saline solution (e.g., 0.9%NaCl solution) and apyrogenic sterile water.
  • Pharmaceutical 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.
  • the administered daily dose varies according to the illness treated, and the administration route. However in most instances, an effective dose (e.g., in some instances, ⁇ -lactamase inhibiting dose) of 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.
  • 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 bicyclic amide (II) to bicyclic 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 unsubstituted amidine (IV) can be prepared by reacting NH 4 Cl with he nitrile (III) , and the substituted amidine (IV) can be prepared by substituting an appropriately substituted amine (NH 2 -Y) to the nitrile (III) in presence of a suitable reagent.
  • the suitable reagents useful for carrying out this step include, but are not limited to trimethylaluminum, or triethylaluminum, or trifluoromethanesulfonate, or Lanthanum (III) 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 dichloromethane, chloroform, toluene, dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and the like.
  • the reaction is normally carried out at a temperature of from about 0 °C to about 100 °C. 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 (V) may be prepared by putting a protection groups (p) on the substituted amidine (IV) .
  • the protecting group can be Boc (tert-butoxycarbonyl) , Cbz (benzyloxycarbonyl) , trifluoroacetyl and the like.
  • the intermediate (V) could be converted to compound (VI) 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 V. 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 (V) , 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 (VI) can be purified by silica gel column chromatography or in many cases can be directly carried out to the next step without further purification.
  • Sulfation of the intermediate (VI) can be achieved using a sulfating reagent (e.g., pyridine-SO 3 complex, NMe 3 -SO 3 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) .
  • pyridine-SO 3 complex can be added to a solution of the intermediate (VI) in a solvent in 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 not limited to, pyridine, tetrahydrofuran, isopropyl alcohol and water, dimethyl formamide, dimethylacetamide, acetonitrile, dichloromethane, and the like.
  • the transformation can be carried out at from 0 °C to 40 °C, and more preferably at room temperature.
  • the product (VII) can be isolated by standard procedure that is by filtering the reaction mixture, concentrating the filtrate, which was directly used for next step without further purification. Sometime the filtrate concentrated may need to purified silica gel column chromatography to give desired compound (VII) .
  • the compound of formula (I) can be achieved by treating the intermediate (VII) with an acid to remove protecting group when the intermediate (VII) containing protection group, such as Boc. and the like, or the compound of formula (I) can also be achieved by treating the intermediate (VII) with an base to remove protecting group when the intermediate (VII) containing protection group, such as trifluoacetyl and the like.
  • Suitable acids include trifluoroacetic acid, methanesulfonic acid, trifluoromethane sulfonic acid, formic acid and the like.
  • Suitable bases include K 2 CO 3 , Na 2 CO 3 , NaOH, KOH, LiOH and the like
  • the treatment is suitably conducted at a temperature in a range from about -10 °C to about 100 °C 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 (I) are normal silica gel chromatograph, perp. HPLC, HP20 chromatograph, inon exchange resin and the like.
  • Preparative HPLC was performed on an Agilent 1260 Infinity II System on Agilent 10 prep-C18 250x21.2 mm column, using an acetonitrile/aqueous 0.1%trifluoroacetic acid gradient, or an acetonitrile/aqueous 0.1%formic acid gradient, or an acetonitrile/water at 22°C.
  • Mass spectra were performed on an Agilent 1260II-6125 Separation Module using either ES - or ES + ionization modes.
  • Step 3 Synthesis of tert-butyl ( (Z) -amino ( (2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octan-2-yl) methylene) carbamate (1_2)
  • Step 4 Synthesis of tert-butyl ( (Z) -amino ( (2S, 5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octan-2-yl) methylene) carbamate (1_3)
  • Step 5 Synthesis of (2S, 5R) -2- ( (Z) -N’ - (tert-butoxycarbonyl) carbamimidoly) -7-oxo-1, 6-diazabicyclo [3.2.1] octan-6-yl) hydrogen sulfate as pyridine salt (1_4)
  • Step 6 Synthesis of sodium (2S, 5R) -2-carbamimidoyl-7-oxo-1, 6-diazabicyclo [3.2.1] octan-6-yl sulfate (example 1)
  • Step 1 Synthesis of (2S, 5R) -6- (benzyloxy) -N-methyl-7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboximidamide (2_1)
  • Step 2 Synthesis of tert-butyl ( (Z) - ( (2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octan-2-yl) (methylamino) methylene) carbamate (2_2)
  • Step 3 Synthesis of tert-butyl ( (Z) - ( (2S, 5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octan-2-yl) (methylamino) methylene) carbamate (2_3)
  • Step 4 Synthesis of (2S, 5R) -2- ( (Z) -N’ - (tert-butoxycarbonyl) -N-methylcarbamimidoly) -7-oxo-1, 6-diazabicyclo [3.2.1] octan-6-yl) hydrogen sulfate pyridine salt (2_4)
  • Step 5 Synthesis of sodium (2S, 5R) -2- (N-methylcarbamimidoyl) -7-oxo-1, 6-diazabicyclo [3.2.1] octan-6-yl sulfate (example 2)
  • Step 1 Synthesis of (2S, 5R) -6- (benzyloxy) -N-ethyl-7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboximidamide (3_1)
  • Step 2 Synthesis of tert-butyl ( (Z) - ( (2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octan-2-yl) (ethylamino) methylene) carbamate (3_2)
  • Step 3 Synthesis of tert-butyl ( (Z) - (ethylamino) ( (2S, 5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octan-2-yl) methylene) carbamate (3_3)
  • Step 4 Synthesis of (2S, 5R) -2- ( (Z) -N'- (tert-butoxycarbonyl) -N-ethylcarbamimidoyl) -7-oxo-1, 6-diazabicyclo [3.2.1] octan-6-yl hydrogen sulfate (3_4)
  • Step 5 Synthesis of (2S, 5R) -2- (N-ethylcarbamimidoyl) -7-oxo-1, 6-diazabicyclo [3.2.1] octan-6-yl hydrogen sulfate (example 3)
  • Step 1 Synthesis of N- (2- ( (2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboximidamido) ethylacetamide (4_1)
  • Trifluoromethanesulfonate 0.60 mL, 3.31 mmol
  • N- (2-aminoethyl) acetamide (1.02 g, 10.00 mmol) were added to a solution of III (1.67 g, 6.50 mmol) in anhydrous THF (20 mL) at 0 °C.
  • the reaction mixture was stirred at room temperature for 3.5 days, concentrated, diluted with CH 2 Cl 2 (80 mL) , washed with water (20 mL) , brine (15 mL) and dried over Na 2 SO 4 .
  • the filtrate was concentrated and purified by flash column chromatography using 2-5%MeOH in CH 2 CH 2 to give the title compound 4_1 (1.11 g, 47%) as a white foam.
  • Step 2 Synthesis of tert-butyl ( (Z) - ( (2-acetamidoethyl) amino ( (2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octan-2-yl) methylene) carbamate (4_2)
  • Step 3 Synthesis of tert-butyl ( (Z) - ( (2-acetamidoethyl) amino ( (2S, 5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octan-2-yl) methylene) carbamate (4_3)
  • Step 4 Synthesis of (2S, 5R) -2- ( (Z) -N- (2-acetamidoethyl) -N’ - (tert-butoxycarbonyl) carbamimidoly) -7-oxo-1, 6-diazabicyclo [3.2.1] octan-6-yl) hydrogen sulfate as pyridine salt (4_4)
  • Step 5 Synthesis of sodium (2S, 5R) -2- (N- (2-acetamidoethyl) carbamimidoly) -7-oxo-1, 6-diazabicyclo [3.2.1] octan-6-yl sulfate (example 4)
  • Step 1 Synthesis of ethyl 4- ( (2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboximidamido) piperidine-1-caboxylate (5_1)
  • Step 2 Synthesis of ethyl 4- ( (2S, 5R, E) -6- (benzyloxy) -7-oxo-N’ - (2, 2, 2-trifluoroacetyl) -1, 6-diazabicyclo [3.2.1] octane-2-carboximidamido) piperidine-1-caboxylate (5_2)
  • Step 3 Synthesis of ethyl 4- ( (2S, 5R, E) -6-hydroxy-7-oxo-N’ - (2, 2, 2-trifluoroacetyl) -1, 6-diazabicyclo [3.2.1] octane-2-carboximidamido) piperidine-1-caboxylate (5_3)
  • Step 4 Synthesis of ethyl 4- ( (2S, 5R, E) -7-oxo-6- (sulfooxy) -N’ - (2, 2, 2-trifluoroacetyl) -1, 6-diazabicyclo [3.2.1] octane-2-carboximidamido) piperidine-1-caboxylate as pyridine salt (5_4)
  • Step 5 Synthesis of sodium (2S, 5R) -2- (N- (1-ethylcarbonyl) piperidin-4-yl) carbamimidoyl) -7-oxo-1, 6-diazabicyclo [3.2.1] octan-6-yl sulfate (example 5)
  • Step 1 Synthesis of (2S, 5R) -6- (benzyloxy) -7-oxo-N- (pyridin-3-ylmethyl) -1, 6-diazabicyclo [3.2.1] octane-2-carboximidamide (6_1)
  • Step 2 Synthesis of tert-butyl ( (Z) - ( (2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octan-2-yl) ( (pyridin-3-ylmethyl) amino) methylene) carbamate (6_2)
  • Step 3 Synthesis of tert-butyl ( (Z) - ( (2S, 5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octan-2-yl) ( (pyridin-3-ylmethyl) amino) methylene) carbamate (6_3)
  • Step 4 Synthesis of (2S, 5R) -2- ( (Z) -N’ - (tert-butoxycarbonyl) -N- (pyridin-3-ylmethyl) carbamimidoly) -7-oxo-1, 6-diazabicyclo [3.2.1] octan-6-yl) hydrogen sulfate as pyridine salt (6_4)
  • Step 5 Synthesis of sodium (2S, 5R) -7-oxo-2- (N- (pyridin-3-ylmethyl) carbamimidoyl) -1, 6-diazabicyclo [3.2.1] octan-6-yl sulfate (example 6)
  • Step 1 Synthesis of (2S, 5R) -6- (benzyloxy) -N-cyclopropyl-7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboximidamide (7_1)
  • Step 2 Synthesis of tert-butyl ( (E) - ( (2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octan-2-yl) (cyclopropylamino) methylene) carbamate (7_2)
  • Step 3 Synthesis of tert-butyl ( (E) - (cyclopropylamino) ( (2S, 5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octan-2-yl) methylene) carbamate (7_3)
  • Step 4 Synthesis of (2S, 5R) -2- ( (E) -N'- (tert-butoxycarbonyl) -N-cyclopropylcarbamimidoyl) -7-oxo-1, 6-diazabicyclo [3.2.1] octan-6-yl sulfate trimethyl amaine salt (7_4)
  • NMe 3 complex (0.20 g, 1.43 mmol) was added to a solution of compound 7_3 (0.30 g, 0.93 mmol) and TEA (2 mL) in THF/water (each 10 mL) . The mixture was stirred overnight, concentrated to dryness under reduced pressure to give the title compound 7_4 (0.53 g, crude) as a pale yellow foam.
  • LC-MS analysis: [M-H] - 403.2.
  • Step 5 Synthesis of sodium (2S, 5R) -2- (N-cyclopropylcarbamimidoyl) -7-oxo-1, 6-diazabicyclo [3.2.1] octan-6-yl sulfate (example 7)
  • Step 1 Synthesis of (2S, 5R) -6- (benzyloxy) -7-oxo-N- ( (tetrahydro-2H-pyran-4-yl) methyl) -1, 6-diazabicyclo [3.2.1] octane-2-carboximidamide (8_1)
  • Step 2 Synthesis of tert-butyl ( (E) - ( (2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octan-2-yl) ( ( (tetrahydro-2H-pyran-4-yl) methyl) amino) methylene) carbamate (8_2)
  • Step 3 Synthesis of tert-butyl ( (E) - ( (2S, 5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octan-2-yl) ( ( (tetrahydro-2H-pyran-4-yl) methyl) amino) methylene) carbamate (8_3)
  • Step 4 Synthesis of tert-butyl ( (E) - ( (2S, 5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octan-2-yl) ( ( (tetrahydro-2H-pyran-4-yl) methyl) amino) methylene) carbamate (8_4)
  • NMe 3 complex (0.11 g, 0.78 mmol) was added to a solution of compound 8_3 (0.20 g, 0.52 mmol) and TEA (1 mL) in THF and water (each 10 mL) . The mixture was stirred overnight, concentrated to dryness under reduced pressure to give a residue, which was purified by Dowex-50wx Na + resin, using water as an elution solvent to give the desired compound 8_4 (198 mg, 81%) as a white powder.
  • Step 5 Synthesis of sodium (2S, 5R) -7-oxo-2- (N- ( (tetrahydro-2H-pyran-4-yl) methyl) carbamimidoyl) -1, 6-diazabicyclo [3.2.1] octan-6-yl sulfate (example 8)
  • Step 1 Synthesis of tert-butyl (3R) -3- ( (2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboximidamido) pyrrolidine-1-carboxylate (9_1)
  • Step 2 Synthesis of tert-butyl (3R) -3- ( (2S, 5R, Z) -6- (benzyloxy) -N'- (tert-butoxycarbonyl) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboximidamido) pyrrolidine-1-carboxylate (9_2)
  • Step 3 Synthesis of tert-butyl (3R) -3- ( (2S, 5R, Z) -N'- (tert-butoxycarbonyl) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboximidamido) pyrrolidine-1-carboxylate (9_3)
  • Step 4 Synthesis of (3R) -3- ( (2S, 5R, Z) -N'- (tert-butoxycarbonyl) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carboximidamido) pyrrolidine-1-carboxylate (9_4)
  • Step 5 Synthesis of sodium (2S, 5R) -7-oxo-2- (N- ( (R) -pyrrolidin-3-yl) carbamimidoyl) -1, 6-diazabicyclo [3.2.1] octan-6-yl sulfate (example 9)
  • Meropenam was 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 compoumds; 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. the lowest concentration of the test compound that inhibited visible growth of the bacteria, was recorded.
  • 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 Antibacterial activity of example 1 to example 9 (Ex. 1 to Ex. 9, MIC, mg/L)
  • Table 3 Synergy of the inhibitor example 1 to example 9 (4 mg/L) in combination with meropenam (MER, 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 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 meropenam with and without ⁇ -lactamase inhibitor was initiated and the survival ratio monitored for 5 days twice daily.
  • the dosing regimen used are meropenam alone (doses of 512, 1024 &2048 mg/kg of body weight) and meropenam plus ⁇ -lactamase inhibitor at ratio of 2: 1, 4: 1, 8: 1, 16: 1 &32: 1 (meropenam 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 meropenam and inhibitor at a ratio of 2/1 &4/1 demonstrated efficacy with significant 3 to 6 log reduction in lung counts compared to meropenam 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

L'invention concerne des composés bicycliques substitués par amidine qui sont des inhibiteurs de β-lactamase, pour le traitement d'infections bactériennes, notamment d'une infection provoquée par des organismes résistants aux médicaments, y compris des organismes multirésistants aux médicaments. L'invention concerne également des composés de formule (I) : ou leurs sels pharmaceutiquement acceptables, les valeurs de M et de Y étant telles que définies dans la description.
PCT/CN2020/113787 2020-09-07 2020-09-07 Composés bicycliques substitués par amidine, leur préparation, leur utilisation comme agents antibactériens et inhibiteurs de bêta-lactamase WO2022047790A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050020572A1 (en) * 2002-01-28 2005-01-27 Aventis Pharma S.A. Heterocyclic compounds as inhibitors of beta-lactamases
WO2009091856A2 (fr) * 2008-01-18 2009-07-23 Merck & Co., Inc. Inhibiteurs de bêta-lactamase
WO2013030735A1 (fr) * 2011-08-30 2013-03-07 Wockhardt Limited Dérivés 1,6-diazabicyclo[3,2,1]octane-7-one et leur utilisation dans le traitent d'infections bactériennes
US20130296555A1 (en) * 2012-03-30 2013-11-07 Cubist Pharmaceuticals, Inc. Beta-lactamase inhibitors
US20150203503A1 (en) * 2012-08-25 2015-07-23 Wockhardt Limited 1,6- diazabicyclo [3,2,1] octan-7-one derivatives and their use in the treatment of bacterial infections

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Publication number Priority date Publication date Assignee Title
US20050020572A1 (en) * 2002-01-28 2005-01-27 Aventis Pharma S.A. Heterocyclic compounds as inhibitors of beta-lactamases
WO2009091856A2 (fr) * 2008-01-18 2009-07-23 Merck & Co., Inc. Inhibiteurs de bêta-lactamase
WO2013030735A1 (fr) * 2011-08-30 2013-03-07 Wockhardt Limited Dérivés 1,6-diazabicyclo[3,2,1]octane-7-one et leur utilisation dans le traitent d'infections bactériennes
US20130296555A1 (en) * 2012-03-30 2013-11-07 Cubist Pharmaceuticals, Inc. Beta-lactamase inhibitors
US20150203503A1 (en) * 2012-08-25 2015-07-23 Wockhardt Limited 1,6- diazabicyclo [3,2,1] octan-7-one derivatives and their use in the treatment of bacterial infections

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GAO YUANYU, LIU YUANBAI, IQBAL ZAFAR, SUN JIAN, JI JINBO, ZHAI LIJUAN, TANG DONG, JI JINGWEN, HE LILI, MU YANGXIU, YANG HAIKANG, Y: "Amidine Derivatives of Avibactam: Synthesis and In Vitro β‐Lactamase Inhibition Activity", CHEMISTRYSELECT, WILEY - V C H VERLAG GMBH & CO. KGAA, DE, vol. 6, no. 5, 4 February 2021 (2021-02-04), DE , pages 1174 - 1178, XP055907438, ISSN: 2365-6549, DOI: 10.1002/slct.202004620 *
IQBAL ZAFAR, ZHAI LIJUAN, GAO YUANYU, TANG DONG, MA XUEQIN, JI JINBO, SUN JIAN, JI JINGWEN, LIU YUANBAI, JIANG RUI, MU YANGXIU, HE: "β-Lactamase inhibition profile of new amidine-substituted diazabicyclooctanes", BEILSTEIN JOURNAL OF ORGANIC CHEMISTRY, BIOMED CENTRAL, LONDON, GB, vol. 17, 1 January 2021 (2021-01-01), GB , pages 711 - 718, XP055907439, ISSN: 1860-5397, DOI: 10.3762/bjoc.17.60 *

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