WO2017002089A1 - Composés bicycliques contenant de l'azote et leur utilisation dans le traitement d'infections bactériennes - Google Patents

Composés bicycliques contenant de l'azote et leur utilisation dans le traitement d'infections bactériennes Download PDF

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Publication number
WO2017002089A1
WO2017002089A1 PCT/IB2016/053974 IB2016053974W WO2017002089A1 WO 2017002089 A1 WO2017002089 A1 WO 2017002089A1 IB 2016053974 W IB2016053974 W IB 2016053974W WO 2017002089 A1 WO2017002089 A1 WO 2017002089A1
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Prior art keywords
oxo
octane
diazabicyclo
sulfooxy
carboxamide
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PCT/IB2016/053974
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English (en)
Inventor
Vijaykumar Jagdishwar Patil
Ravikumar Tadiparthi
Velupillai LOGANANTHAN
Deepak Dekhane
Mohammad Usman Shaikh
Satish BIRAJDAR
Mangesh PAWAR
Piyush Ambalal PATEL
Prashant Ratnakar JOSHI
Mahesh Vithalbhai Patel
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Wockhardt Limited
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Publication of WO2017002089A1 publication Critical patent/WO2017002089A1/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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the invention relates to nitrogen containing bicyclic compounds, their preparation and their use in preventing or treating infections.
  • Emergence of bacterial resistance to known antibacterial agents is becoming a major challenge in treating bacterial infections.
  • One way forward to treat bacterial infections, and especially those caused by resistant bacteria, is to develop newer antibacterial agents that can overcome the bacterial resistant.
  • Coates et al. ⁇ Br. J. Pharmacol. 2007; 152(8), 1147-1154.) have reviewed novel approaches to developing new antibiotics.
  • the development of new antibacterial agents is a challenging task. For example, Gwynn et al. ⁇ Annals of the New York Academy of Sciences, 2010, 1213: 5-19) have reviewed the challenges in discovery of antibacterial agents.
  • the inventors have now surprisingly discovered novel nitrogen containing bicyclic compounds having antibacterial activity.
  • nitrogen containing bicyclic compounds methods for preparation of these compounds, pharmaceutical compositions comprising these compounds, and methods for preventing or treating bacterial infection in a subject using these compounds.
  • Ri is:
  • Ci-C 6 alkyl optionally substituted with one or more substituents independently selected from OR4, NR4R5, SR4, SOR4, SO2R4, CN, halogen, COOR4, CONR4R5, NR4COR5, or NR4CONR5R6,
  • R 2 and R 3 are each independently:
  • cycloalkyl optionally substituted with one or more substituents independently selected from OR4, NR4R5, SR4, SOR4, SO2R4, CN, (CH 2 ) m NR4R 5 , halogen, COOR4, CONR4R5, NR4COR5 or NR4CONR5R6,
  • heterocycloalkyl optionally substituted with one or more substituents independently selected from OR4, NR4R5, SR4, SOR4, SO2R4, CN, (CH 2 ) m NR4R 5 , halogen, COOR4, CONR4R5, NR4COR5 or NR4CONR5R6,
  • aryl optionally substituted with one or more substituents independently selected from OR4, NR4R5, SR4, SOR4, SO2R4, CN, (CH 2 ) m NR4R 5 , halogen, COOR4, CONR4R5, NR4COR5 or NR4CONR5R6,
  • heteroaryl optionally substituted with one or more substituents independently selected from OR4, NR4R5, SR4, SOR4, SO2R4, CN, (CH 2 ) m NR4R 5 , halogen, COOR4, CONR4R5, NR4COR5 or NR4CONR5R6 or
  • R 4 , R 5 and R 6 are each independently:
  • Ci-C 6 alkyl (b) Ci-C 6 alkyl; n is 0,1,2 or 3;
  • n 1 to 6;
  • M is hydrogen or a cation.
  • pharmaceutical compositions comprising a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable derivative thereof.
  • a method for preventing or treating a bacterial infection in a subject comprising administering to said subject a pharmaceutically effective amount of a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable derivative thereof.
  • a method for preventing or treating a bacterial infection in a subject comprising administering to said subject a pharmaceutically effective amount of a pharmaceutical composition comprising a compound of Formula (I), or a stereoisomer, or a pharmaceutically acceptable derivative thereof.
  • compositions comprising: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable derivative thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
  • a method for preventing or treating a bacterial infection in a subject comprising administering to said subject a pharmaceutically effective amount of a pharmaceutical composition comprising: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable derivative thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
  • a method for preventing or treating a bacterial infection in a subject comprising administering to said subject a pharmaceutically effective amount of: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable derivative thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
  • a method of inhibiting beta-lactamase enzymes comprising administering a pharmaceutically effective amount of a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable derivative thereof.
  • a method of inhibiting beta-lactamase enzymes comprising administering a pharmaceutically effective amount of a pharmaceutical composition comprising a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable derivative thereof.
  • a method for increasing antibacterial effectiveness of an antibacterial agent in a subject comprising co-administering said antibacterial agent or a pharmaceutically acceptable derivative thereof with a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable derivative thereof.
  • the inventors have surprisingly discovered novel nitrogen containing bicyclic compounds having antibacterial properties.
  • Ci-C 6 alkyl refers to branched or unbranched acyclic hydrocarbon radical with 1 to 6 carbon atoms.
  • Typical non-limiting examples of "Ci-C 6 alkyl” include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, z ' so-butyl, tert-butyl, n-pentyl, z ' so-pentyl, ieri-pentyl, neopentyl, sec-pentyl, 3-pentyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3- dimethylbutyl and the like.
  • Ci-C 6 alkyl may be unsubstituted, or substituted with one or more substituents.
  • substituents include halogen, alkoxy, CN, SH, COOH, COOCi-C 6 alkyl, CONH 2 , OH, NH 2 , NHCOCH 3 , cycloalkyl, heterocycloalkyl, heteroaryl, aryl and the like.
  • cycloalkyl refers to three to seven member cyclic hydrocarbon radicals.
  • the cycloalkyl group optionally incorporates one or more double or triple bonds, or a combination of double or triple bonds, but which is not aromatic.
  • Typical, non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • the cycloalkyl may be unsubstituted, or substituted with one or more substituents.
  • substituents include Ci-C 6 alkyl, halogen, alkoxy, CN, SH, COOH, COOCi-Cealkyl, CONH 2 , OH, NH 2 , NHCOCH 3 , heterocycloalkyl, heteroaryl, aryl, S0 2 -alkyl, S0 2 -aryl, OS0 2 -alkyl, OS0 2 -aryl and the like.
  • aryl refers to a monocyclic or polycyclic aromatic hydrocarbon. Typical, non-limiting examples of aryl groups include phenyl, naphthyl, anthracenyl, flourenyl, phenanthrenyl, indenyl and the like. The aryl group may be unsubstituted, or substituted with one or more substituents.
  • substituents include C1-C6 alkyl, halogen, alkoxy, CN, COOH, CONH 2 , OH, NH 2 , NHCOCH 3 , heterocycloalkyl, heteroaryl, aryl, S0 2 -alkyl, S0 2 -aryl, OS0 2 -alkyl, OS0 2 -aryl and the like.
  • aryl refers to a monocyclic or polycyclic aromatic hydrocarbon radical containing up to twenty ring atoms. In some embodiments, the term “aryl” refers to six to fourteen membered monocyclic or polycyclic aromatic hydrocarbon radical.
  • heteroaryl refers to a monocyclic or polycyclic aromatic hydrocarbon group wherein one or more carbon atoms have been replaced with heteroatoms selected from nitrogen, oxygen, and sulfur. If the heteroaryl group contains more than one heteroatom, the heteroatoms may be the same or different.
  • heteroaryl groups include pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, pyrrolyl, thienyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazonyl, isoxazolyl, oxadiazolyl, oxatriazolyl, isothiazolyl, thiatriazolyl, thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, tetrazinyl, thiatriazinyl, imidazolinyl
  • the heteroaryl group may be unsubstituted, or substituted with one or more substituents.
  • substituents include Ci-C 6 alkyl, halogen, alkoxy, CN, COOH, CONH 2 , OH, SH, SCH 3 , NH 2 , NHCOCH 3 , heterocycloalkyl, heteroaryl, aryl, S0 2 -alkyl, S0 2 -aryl, OS0 2 -alkyl, OS0 2 -aryl and the like.
  • the term "heteroaryl” refers to a monocyclic or polycyclic aromatic hydrocarbon radical containing up to twenty ring atoms. In some embodiments, the term “heteroaryl” refers to five to fourteen membered monocyclic or polycyclic aromatic hydrocarbon radical.
  • heterocycloalkyl refers to three to seven member cycloalkyl group containing one or more heteroatoms selected from nitrogen, oxygen or sulfur.
  • the heterocycloalkyl group optionally incorporates one or more double or triple bonds, or a combination of double bonds and triple bonds, but which is not aromatic.
  • heterocycloalkyl groups include azridinyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, imidazolidin-2-one-yl, piperidinyl, oxazinyl, thiazinyl, piperazinyl, piperazin-2,3-dione-yl, morpholinyl, thiomorpholinyl, azepanyl, and the like.
  • the heterocycloalkyl may be unsubstituted, or substituted with one or more substituents.
  • substituents include Ci-C 6 alkyl, halogen, alkoxy, CN, COOH, CONH 2 , OH, NH 2 , NHCOCH 3 , heteroaryl, aryl, S0 2 -alkyl, S0 2 -aryl, OS0 2 -aryl and the like.
  • halogen or halo as used herein refers to chlorine, bromine, fluorine or iodine.
  • stereoisomers refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of their atoms or groups in space.
  • the compounds of Formula (I) may contain asymmetric or chiral centers and, therefore, exist in different stereoisomeric forms. It is intended, unless specified otherwise, that all stereoisomeric forms of the compounds of Formula (I) as well as mixtures thereof, including racemic mixtures, form part of the present invention.
  • the present invention embraces all geometric and positional isomers (including cis and irans-forms), as well as mixtures thereof, are embraced within the scope of the invention.
  • a reference to a compound is intended to cover its stereoisomers and mixture of various stereoisomers.
  • substitution is optional and therefore includes both unsubstituted and substituted atoms and moieties.
  • a "substituted" atom or moiety indicates that any hydrogen on the designated atom or moiety can be replaced with a selection from the indicated substituent group, provided that the normal valency of the designated atom or moiety is not exceeded, and that the substitution results in a stable compound.
  • pharmaceutically acceptable derivative refers to and includes any pharmaceutically acceptable salt, pro-drug, metabolite, ester, ether, hydrate, polymorph, solvate, complex, and adduct of a compound described herein which, upon administration to a subject, is capable of providing (directly or indirectly) the parent compound.
  • antibacterial agent or a pharmaceutically acceptable derivative thereof includes all derivatives of the antibacterial agent (such as salts, pro-drugs, metabolites, esters, ethers, hydrates, polymorphs, solvates, complexes, and adducts) which, upon administration to a subject, are capable of providing (directly or indirectly) the antibacterial agent.
  • pharmaceutically acceptable salt refers to one or more salts of a given compound which possesses the desired pharmacological activity of the free compound and which are neither biologically nor otherwise undesirable.
  • pharmaceutically acceptable salts refer to salts that are suitable for use in contact with the tissues of human and animals without undue toxicity, irrigation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. (J. Pharmaceutical Sciences, 66; 1-19, 1977), incorporated herein by reference in its entirety, describes various pharmaceutical acceptable salts in details.
  • the compounds according to the invention contain basic (e.g.
  • acid moieties e.g. compounds of Formula (I) wherein M is hydrogen
  • acid moieties e.g. compounds of Formula (I) wherein M is hydrogen
  • Such salts can be prepared using procedures described in the art.
  • the basic moiety can be converted to its salt by treating a compound with a suitable amount of acid.
  • suitable acids include hydrochloric acid, trifluoro acetic acid, methanesulphonic acid or the like.
  • the acid moiety may be converted into its salt by treating with a suitable base.
  • Typical non-limiting examples of such bases include sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium ethylhexanoate, potassium ethylhexanoate or the like.
  • each such functional group may be converted to salt independently.
  • one of the basic nitrogen can form salt with one acid while the other basic nitrogen can form salt with another acid.
  • Some compounds according to the invention contain both acidic as well as basic moieties, and thus can form inner salts or corresponding zwitterions.
  • infection or "bacterial infection” as used herein includes presence of bacteria, in or on a subject, which, if its growth were inhibited, would result in a benefit to the subject.
  • infection in addition to referring to the presence of bacteria also refers to presence of other floras, which are not desirable.
  • infection includes infection caused by bacteria.
  • treat refers to administration of a medicament, including a pharmaceutical composition, or one or more pharmaceutically active ingredients, for prophylactic and/or therapeutic purposes.
  • prophylactic treatment refers to treating a subject who is not yet infected, but who is susceptible to, or otherwise at a risk of infection (preventing the bacterial infection).
  • therapeutic treatment refers to administering treatment to a subject already suffering from infection.
  • treat also refer to administering compositions, or one or more of pharmaceutically active ingredients discussed herein, with or without additional pharmaceutically active or inert ingredients, in order to: (i) reduce or eliminate either a bacterial infection, or one or more symptoms of a bacterial infection, or (ii) retard progression of a bacterial infection, or one or more symptoms of a bacterial infection, or (iii) reduce severity of a bacterial infection, or one or more symptoms of a bacterial infection, or (iv) suppress clinical manifestation of a bacterial infection, or (v) suppress manifestation of adverse symptoms of a bacterial infection.
  • a “therapeutically effective amount” or “pharmaceutically effective amount” or “effective amount” as used herein refer to an amount, which has a therapeutic effect or is the amount required to produce a therapeutic effect in a subject.
  • a “therapeutically effective amount” or “pharmaceutically effective amount” or “effective amount” of an antibacterial agent or a pharmaceutical composition is the amount of the antibacterial agent or the pharmaceutical composition required to produce a desired therapeutic effect as may be judged by clinical trial results, model animal infection studies, and/or in vitro studies (e.g. in agar or broth media).
  • Such effective amount depends on several factors, including but not limited to, the microorganism (e.g.
  • a prophylactically effective amount is that amount which would be effective in preventing the bacterial infection.
  • administration refers to and includes delivery of a composition, or one or more pharmaceutically active ingredients to a subject, including for example, by any appropriate method, which serves to deliver the composition or its active ingredients or other pharmaceutically active ingredients to the site of infection.
  • the method of administration may vary depending on various factors, such as for example, the components of the pharmaceutical composition or type/nature of the pharmaceutically active or inert ingredients, site of the potential or actual infection, the microorganism involved, severity of the infection, age and physical condition of the subject and a like.
  • Some non-limiting examples of ways to administer a composition or a pharmaceutically active ingredient to a subject according to this invention include oral, intravenous, topical, intrarespiratory, intraperitoneal, intramuscular, parenteral, sublingual, transdermal, intranasal, aerosol, intraocular, intratracheal, intrarectal, vaginal, gene gun, dermal patch, eye drop and mouthwash.
  • a pharmaceutical composition comprising more than one ingredients (active or inert)
  • one of the ways of administering such composition is by admixing the ingredients (e.g. in the form of a suitable unit dosage form such as tablet, capsule, solution, powder or a like) and then administering the dosage form.
  • the ingredients may also be administered separately (simultaneously or one after the other) as long as these ingredients reach beneficial therapeutic levels such that the composition as a whole provides a synergistic and/or desired effect.
  • growth refers to a growth of one or more microorganisms and includes reproduction or population expansion of the microorganism (e.g. bacteria).
  • growth also includes maintenance of on-going metabolic processes of the microorganism, including the processes that keep the microorganism alive.
  • an antibacterial effectiveness refers to the ability of the composition or the antibacterial agent to prevent or treat bacterial infection in a subject.
  • antibacterial agent refers to any substance, compound, a combination of substances, or a combination of compounds capable of: (i) inhibiting, reducing or preventing growth of bacteria; (ii) inhibiting or reducing ability of a bacteria to produce infection in a subject; or (iii) inhibiting or reducing ability of bacteria to multiply or remain infective in the environment.
  • antibacterial agent also refers to compounds capable of decreasing infectivity or virulence of bacteria.
  • beta-lactamase or "beta-lactamase enzyme” as used herein refers to any enzyme or protein or any other substance that breaks down a beta-lactam ring.
  • beta-lactamase includes enzymes that are produced by bacteria and have the ability to hydrolyze the beta-lactam ring in a beta-lactam compound, either partially or completely.
  • beta-lactamase inhibitor refers to a compound capable of inhibiting activity of one or more beta-lactamase enzymes, either partially or completely.
  • pharmaceutically inert ingredient or “carrier” or “excipient” refers to and includes compounds or materials used to facilitate administration of a compound, for example, to increase the solubility of the compound.
  • solid carriers include starch, lactose, dicalcium phosphate, sucrose, and kaolin.
  • Typical, non-limiting examples of liquid carriers include sterile water, saline, buffers, non-ionic surfactants, and edible oils.
  • various adjuvants commonly used in the art may also be included. These and other such compounds are described in literature, e.g., in the Merck Index (Merck & Company, Rahway, N.J.).
  • subject refers to vertebrate or invertebrate, including a mammal.
  • subject includes human, animal, a bird, a fish, or an amphibian.
  • Typical, non-limiting examples of a “subject” include humans, cats, dogs, horses, sheep, bovine cows, pigs, lambs, rats, mice and guinea pigs.
  • EDC l-ethyl-3-(3-dimethylamino propyl)carbodiimide
  • HOBt refers to 1-hydroxybenzotriazole.
  • Boc anhydride refers to di-ie/t-butyl dicarbonate.
  • TFA trifluoro acetic acid
  • TBAA tetrabutylammonium acetate
  • cation includes Na, K, Mg, Ca, NH 4 + , (CH 3 CH 2 ) 3 N and the like.
  • Ri is:
  • Ci-C 6 alkyl optionally substituted with one or more substituents independently selected from OR4, NR4R5, SR4, SOR4, SO2R4, CN, halogen, COOR4, CONR4R5, NR4COR5, or NR4CONR5R6,
  • R 2 and R 3 are each independently:
  • cycloalkyl optionally substituted with one or more substituents independently selected from OR4, NR4R5, SR4, SOR4, SO2R4, CN, (CH 2 ) m NR4R 5 , halogen, COOR4, CONR4R5, NR4COR5 or NR4CONR5R6,
  • heterocycloalkyl optionally substituted with one or more substituents independently selected from OR4, NR4R5, SR4, SOR4, SO2R4, CN, (CH 2 ) m NR4R 5 , halogen, COOR4, CONR4R5, NR4COR5 or NR4CONR5R6,
  • aryl optionally substituted with one or more substituents independently selected from OR4, NR4R5, SR4, SOR4, SO2R4, CN, (CH 2 ) m NR4R 5 , halogen, COOR4, CONR4R5, NR4COR5 or NR4CONR5R6,
  • heteroaryl optionally substituted with one or more substituents independently selected from OR4, NR4R5, SR4, SOR4, SO2R4, CN, (CH 2 ) m NR4R 5 , halogen, COOR4, CONR4R5, NR4COR5 or NR4CONR5R6 or
  • R 4 , R 5 and R 6 are each independently:
  • Ci-C 6 alkyl (b) Ci-C 6 alkyl; n is 0, 1,2 or 3;
  • n 1 to 6;
  • M is hydrogen or a cation.
  • Typical, non-limiting examples of compounds according to the invention include:
  • non-limiting examples of compounds according to the invention include:
  • the compounds of the invention can be prepared according to the general procedure given in Schemes 1 and 2.
  • a person of skills in the art would appreciate that the described method can be varied or optimized further to provide the desired and related compounds.
  • all variables are as defined above.
  • a compound of Formula (I), wherein A is NHCOR 2 can be prepared by the general procedure as described in Scheme 1.
  • a compound of Formula (II) is first treated with a suitable carboxyl group activating reagent, followed by treatment with esterifying agent to obtain a compound of Formula (III).
  • carboxyl group activating compounds include thionyl chloride, oxalyl chloride, phosphorous trichloride, phosphorous oxychloride, phosphorous pentachloride, a-bromoacetyl bromide, pivaloyl chloride, diphenylphosphonic azide dicyclohexylcarbodiimide, diisopropylcarbodiimide, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl), 1, 1 '-carbonyldiimidazole, di-ie/t-butyldicarbonate, acetic anhydride, ethyl chloroformate, 2-ethoxy- l-ethoxycarbonyl- l,2-dihydroquinoline (EDDQ), 1 -hydro xybenzotriazole (HOBt), N-hydroxysuccinimi
  • a compound of Formula (III) is coupled with a compound of Formula (IV) [(2S,5R)-6- benzyloxy-7-oxo- l,6-diazabicyclo[3.2.1]octane-2-carboxylic acid sodium salt] in presence of a base, coupling agent and a solvent at a temperature of about 15°C to about 35°C for about 10 hours to about 24 hours to obtain a coupled compound of Formula (V).
  • base include N-methyl morpholine, N-methyl pyrrolidine, N-ethyl diisopropylamine and the like.
  • Typical, non-limiting examples of coupling reagent are EDC.HCl, HOBt, 2-(lH-Benzotriazole- l-yl)- l, 1,3,3- tetramethyluronium hexafluorophosphate (HBTU), l-[Bis(dimethylamino)methylene]- lH- l,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) or a mixture thereof.
  • Typical, non- limiting examples of solvent include dimethylformamide, dimethylacetamide and the like.
  • the compound of Formula (V) is hydro lyzed to obtain a compound of Formula (VI).
  • compound of Formula (V) is hydrolyzed with a suitable reagent such as lithium hydroxide in presence of a suitable solvent such as water, tetrahydrofuran, and the like or a mixture thereof at a temperature of about 15°C to about 35°C for about 10 hours to about 24 hours to obtain a compound of Formula (VI).
  • the compound of Formula (VI) is reacted with a hydrazide compound of Formula (VII) to obtain a compound of Formula (VIII).
  • the compound of Formula (VI) is reacted with a compound of Formula (VII) in presence of a coupling agent and a solvent at about - 10°C to about 40°C for about 1 hour to about 25 hour to obtain a compound of Formula (VIII).
  • Typical, non-limiting examples of coupling reagent include EDC.HCl, HOBt, 2-(lH-benzotriazole- l-yl)- l, l,3,3-tetramethyluronium hexafluoropho sphate (HB TU) , ( 1 - [bis(dimethy lamino ) methylene] - 1 H- 1 ,2, 3 -triazo lo [4 , 5 -b] pyridinium 3-oxid hexafluoropho sphate) (HATU) or a mixture thereof.
  • Typical, non-limiting examples of solvent include dimethylformamide, dimethylacetamide and the like.
  • the compound of Formula (VIII) is debenzylated by carrying out hydrogenolysis in presence of hydrogen source, transition metal catalyst and a suitable solvent at a temperature ranging from about 10°C to about 60°C for about 1 hour to about 14 hours to provide a compound of Formula (IX).
  • hydrogen source include hydrogen gas, ammonium formate, cyclohexene, lithium -liquid ammonia, ammonia - ie/t-butanol, sodium - liquid ammonia - tert- butanol, triethyl silyl hydride and the like.
  • transition metal catalyst include 5% palladium on carbon, 10% palladium on carbon, 20% palladium hydroxide on carbon, Raney-Nickel and the like.
  • solvent include methanol, ethanol, dichloromethane, dimethylformamide, ethyl acetate, tetrahydrofuran, and the like or a mixture thereof.
  • compound of Formula (VIII) is treated with 10% palladium on carbon in presence of hydrogen gas and suitable solvent and at temperature of about 25°C for about 5 hour to provide a compound of Formula (IX).
  • the solvent used in conversion of a compound of Formula (VIII) to a compound of Formula (IX) is methanol.
  • the compound of Formula (IX) is sulfonated by reacting with suitable sulfonating reagent in a suitable solvent at a temperature ranging from about 0°C to about 80°C for about 1 hour to about 24 hours.
  • suitable sulfonating reagent include sulfur trioxide pyridine complex, sulfur trioxide trimethylamine complex, sulfur trioxide triethylamine complex, sulfur trioxide N,N- dimethylaniline complex, sulfur trioxide 2-methylpyridine complex, sulfur trioxide dioxane complex, sulfur trioxide thioxane complex, sulfur trioxide dimethyl sulfide complex, sulfur trioxide dimethylsulfoxide complex, sulfur trioxide N,N-dimethylformamide complex and the like.
  • solvent examples include pyridine, dichloromethane, dimethylformamide and the like.
  • compound of Formula (IX) is reacted with dimethylformamide sulfur trioxide complex in presence of pyridine and dichloromethane at a temperature of about 10°C for about 1 hour to provide the sulfonated compound.
  • the obtained sulfonated compound is converted into corresponding tetrabutylammonium salt of Formula (X).
  • the sulfonated compound is treated with tetrabutylammonium acetate (TBAA) to provide tetrabutylammonium salt of sulfonic acid compound of Formula (X).
  • TBAA tetrabutylammonium acetate
  • the compound according to the invention is then isolated as zwitterions, by removing the protecting groups of compound of Formula (X).
  • the compound of Formula (X) is reacted with suitable deprotecting agent such as trifluoro acetic acid in presence of a suitable solvent such as dichloromethane, chloroform or acetonitrile, at a temperature ranging from about -15°C to about 40°C for about 0.5 hour to about 14 hours.
  • suitable deprotecting agent such as trifluoro acetic acid
  • a suitable solvent such as dichloromethane, chloroform or acetonitrile
  • compound of Formula (X) is treated with trifluoro acetic acid in presence of dichloromethane at temperature of about 0°C to about -10°C for about 1 hour to provide a compound of Formula (I).
  • a compound of Formula (I), wherein A is NHCOR 2 can be prepared by the general procedure as described in Scheme 2.
  • the compound of Formula (VI) is obtained by adopting a reaction sequence similar to as disclosed in Scheme 1.
  • the compound of Formula (VI) is coupled with protected hydrazine (XI) to obtain a compound of Formula (XII).
  • the compound of Formula (XII) is debenzylated to obtain a hydro xyl containing compound of Formula (XIII).
  • the compound of Formula (XIII) is sulphonated, followed by conversion to tetrabutylammonium salt to obtain a compound of Formula (XIV).
  • the compound of Formula (XIV) is deprotected to obtain a compound of Formula (XV).
  • the compound of Formula (XV) is then coupled with a carboxylic acid compound of Formula (XVI) in presence of a coupling agent at temperature of about 0°C to about 40°C to obtain a compound of Formula (X). Finally, protecting groups in a compound of Formula (XVII) are removed to obtain a compound of Formula (I).
  • the hydrazine compound of Formula (XV) is reacted with an aldehyde compound of Formula (XVIa) to obtain a hydrazone compound of Formula (XVII).
  • the compounds according to the invention are either isolated as zwitterions or as corresponding pharmaceutically acceptable salts.
  • the compounds according to invention are isolated as corresponding pharmaceutically acceptable salts by passing solution of a compound of Formula (X) or a compound of Formula (XVII) in suitable solvent through a cation exchange resin.
  • a compound of Formula (X)or a compound of Formula (XVII) is dissolved in suitable solvent such as 10% tetrahydrofuran: water mixture and is passed through the column packed with Dowex 50WX8 200 Na resin or through Indion 225 Na resin to provide sodium salt of a compound of Formula (I).
  • a compound of Formula (X) or a compound of Formula (XVII) is dissolved in suitable solvent such as acetone, tetrahydrofuran, ethanol, isopropanol, acetonitrile or a mixture thereof, and thereby treating with sodium ethylhexanoate or potassium ethylhexanoate to provide sodium or potassium salt of compound of Formula (I).
  • suitable solvent such as acetone, tetrahydrofuran, ethanol, isopropanol, acetonitrile or a mixture thereof
  • compound of Formula (I) having azepane ring moeity are also prepared.
  • the starting reaction compounds containing azepane ring are synthesized by a general procedure as described in Scheme 3.
  • Azepane-2-carboxylic acid (XVIII) is treated with a suitable nitrogen protecting group such as Boc anhydride to obtain a compound of Formula (XIX).
  • the racemic compound of Formula (XIX) is further separated to obtain a compound of Formula (XXI) and a compound of Formula (XXIV).
  • compositions comprising a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof.
  • compositions comprising: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, and (b) at least one beta- lactamase inhibitor or a pharmaceutically acceptable derivative thereof.
  • compositions comprising: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, and (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, avibactam or a pharmaceutically acceptable derivative thereof.
  • compositions comprising: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
  • compositions comprising: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, and (b) at least one antibacterial agent selected from cefepime, cefpirome, ceftaroline, ceftazidime, ceftolozane or a pharmaceutically acceptable derivative thereof.
  • compositions comprising: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, (b) at least one beta-lacatamse inhibitor or a pharmaceutically acceptable derivative thereof, and (c) at least one antibacterial agent, or a pharmaceutically acceptable derivative thereof.
  • methods for preventing or treating a bacterial infection in a subject comprising administering to said subject a pharmaceutical composition comprising a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof.
  • methods for preventing or treating a bacterial infection in a subject comprising administering to said subject a pharmaceutical composition comprising: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable derivative thereof and (b) at least one beta-lactamase inhibitor or pharmaceutically acceptable derivative thereof.
  • methods for preventing or treating a bacterial infection in a subject comprising administering to said subject a pharmaceutical composition comprising: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable derivative thereof and (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, avibactam, or pharmaceutically acceptable derivative thereof.
  • methods for preventing or treating a bacterial infection in a subject comprising administering to said subject a pharmaceutical composition comprising: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
  • methods for preventing or treating a bacterial infection in a subject comprising administering to said subject a pharmaceutical composition comprising: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, and (b) at least one antibacterial agent selected from selected from cefepime, cefpirome, ceftaroline, ceftazidime, ceftolozane or a pharmaceutically acceptable derivative thereof.
  • methods for preventing or treating a bacterial infection in a subject comprising administering to said subject a pharmaceutical composition comprising: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, (b) at least one beta-lactamase inhibitor or pharmaceutically acceptable derivative thereof and (c) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
  • methods for preventing or treating a bacterial infection in a subject comprising administering to said subject a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof.
  • methods for preventing or treating a bacterial infection in a subject comprising administering to said subject: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, (b) at least one beta- lactamase inhibitor or pharmaceutically acceptable derivative thereof.
  • methods for preventing or treating a bacterial infection in a subject comprising administering to said subject: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, (b) at least one beta- lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, avibactam, or pharmaceutically acceptable derivative thereof.
  • methods for preventing or treating a bacterial infection in a subject comprising administering to said subject: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, (b) at least one antibacterial agent or pharmaceutically acceptable derivative thereof.
  • methods for preventing or treating a bacterial infection in a subject comprising administering to said subject: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, (b) at least one antibacterial agent selected from selected from cefepime, cefpirome, ceftaroline, ceftazidime, ceftolozane or pharmaceutically acceptable derivative thereof.
  • methods for preventing or treating a bacterial infection in a subject comprising administering to said subject: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, (b) at least one beta- lactamase inhibitor or pharmaceutically acceptable derivative thereof, and (c) at least one antibacterial agent or pharmaceutically acceptable derivative thereof.
  • compositions and methods according to the invention use compounds of Formula (I), or a stereoisomer or a pharmaceutically acceptable derivative thereof in combination with at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
  • antibacterial agents can be used.
  • antibacterial agents include one or more of antibacterial compounds generally classified as aminoglycosides, ansamycins, carbacephems, cephalosporins, cephamycins, lincosamides, lipopeptides, macrolides, monobactams, nitrofurans, penicillins, polypeptides, quinolones, penems, carbapenems, sulfonamides, tetracyclines, oxazolidinone and the like.
  • aminoglycoside antibacterial agents include amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin, arbekacin, streptomycin, apramycin and the like.
  • aminoglycoside antibacterial agents include amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin, arbekacin, streptomycin, apramycin and the like.
  • ansamycin antibacterial agents include geldanamycin, herbimycin and the like.
  • carbacephem antibacterial agents include loracarbef and the like.
  • carbapenem antibacterial agents include ertapenem, doripenem, imipenem, meropenem and the like.
  • cephalosporin and cephamycin antibacterial agents include cefazolin, cefacetrile, cefadroxil, cefalexin, cefaloglycin, cefalonium, cefaloridine, cefalotin, cefapirin, cefatrizine, cefazedone, cefazaflur, cefradine, cefroxadine, ceftezole, cefaclor, cefamandole, cefminox, cefonicid, ceforanide, cefotiam, cefprozil, cefbuperazone, cefuroxime, cefuzonam, cephamycin, cefoxitin, cefotetan, cefmetazole, carbacephem, cefixime, ceftazidime, ceftriaxone, cefcapene, cefdaloxime, cefdinir, cefditoren, cefetamet, cefmen
  • Lincosamide antibacterial agents include clindamycin, lincomycin and the like.
  • macrolide antibacterial agents include azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, spectinomycin, solithromycin and the like.
  • monobactam antibacterial agents include aztreonam and the like.
  • nitrofuran antibacterial agents include furazolidone, nitrofurantoin and the like.
  • penicillin antibacterial agents include amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, temocillin, ticarcillin and the like.
  • polypeptide antibacterial agents include bacitracin, colistin, polymyxin B and the like.
  • quinolone antibacterial agents include ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, levonadifloxacin, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, temafloxacin and the like.
  • Sulfonamide antibacterial agents include Mafenide, Sulfonamidochrysoidine, sulfacetamide, sulfadiazine, sulfamethizole, sulfamethoxazole, sulfasalazine, sulfisoxazole, trimethoprim and the like.
  • Typical, non-limiting examples of tetracycline antibacterial agents include demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline, tigecycline and the like.
  • oxazolidinone antibacterial agents include tedizolid, linezolid, ranbezolid, torezolid, radezolid and the like.
  • the pharmaceutical compositions according to the invention may include one or more pharmaceutically acceptable carriers or excipients or the like, Typical, non-limiting examples of such carriers or excipient include mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, wetting agents, emulsifying agents, solubilizing agents, pH buffering agents, lubricants, stabilizing agents, binding agents etc.
  • compositions according to the present invention are administered orally or parenterally.
  • compositions according to this invention can exist in various forms.
  • the pharmaceutical composition is in the form of a powder or a solution.
  • the pharmaceutical compositions according to the invention are in the form of a powder that can be reconstituted by addition of a compatible reconstitution diluent prior to parenteral administration.
  • a compatible reconstitution diluent includes water.
  • the pharmaceutical compositions according to the invention are in the form of a frozen composition that can be diluted with a compatible diluent prior to parenteral administration.
  • compositions according to the invention are in the form ready to use for oral or parenteral administration.
  • the pharmaceutical composition and/or other pharmaceutically active ingredients disclosed herein may be administered by any appropriate method, which serves to deliver the composition or its constituents or the active ingredients to the desired site.
  • the method of administration can vary depending on various factors, such as for example, the components of the pharmaceutical composition and nature of the active ingredients, the site of the potential or actual infection, the microorganism (e.g. bacteria) involved, severity of infection, age and physical condition of the subject.
  • the microorganism e.g. bacteria
  • compositions to a subject according to this invention include oral, intravenous, topical, intrarespiratory, intraperitoneal, intramuscular, parenteral, sublingual, transdermal, intranasal, aerosol, intraocular, intratracheal, intrarectal, vaginal, gene gun, dermal patch, eye drop, ear drop or mouthwash.
  • compositions according to the invention can be formulated into various dosage forms wherein the active ingredients and/or excipients may be present either together (e.g. as an admixture) or as separate components.
  • the various ingredients in the composition are formulated as a mixture, such composition can be delivered by administering such a mixture to a subject using any suitable route of administration.
  • pharmaceutical compositions according to the invention may also be formulated into a dosage form wherein one or more ingredients (active or inactive ingredients) are present as separate components.
  • the composition or dosage form wherein the ingredients do not come as a mixture, but come as separate components, such composition/dosage form may be administered in several ways. In one possible way, the ingredients may be mixed in the desired proportions and the mixture is then administered as required. Alternatively, the components or the ingredients (active or inert) may be separately administered (simultaneously or one after the other) in appropriate proportion so as to achieve the same or equivalent therapeutic level or effect as would have been achieved by administration of the equivalent mixture.
  • compositions according to the invention are formulated into a dosage form such that the compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, and the antibacterial agent or a pharmaceutically acceptable derivative thereof, are present in the composition as admixture or as a separate components.
  • pharmaceutical compositions according to the invention are formulated into a dosage form such that the compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, and the antibacterial agent or a pharmaceutically acceptable derivative thereof, are present in the composition as separate components.
  • the active ingredients disclosed herein may be administered to a subject in several ways depending on the requirements.
  • the active ingredients are admixed in appropriate amounts and then the admixture is administered to a subject.
  • the active ingredients are administered separately.
  • the invention further provides for combining separate pharmaceutical compositions in kit form.
  • the kit may comprise one or more separate pharmaceutical compositions, each comprising one or more active ingredients. Each of such separate compositions may be present in a separate container such as a bottle, vial, syringes, boxes, bags, and the like.
  • the kit comprises directions for the administration of the separate components.
  • the kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral) ore are administered at different dosage intervals.
  • the active ingredients are administered separately, they may be administered simultaneously or sequentially.
  • compositions or the active ingredients according to the present invention may be formulated into a variety of dosage forms.
  • dosage forms include solid, semi-solid, liquid and aerosol dosage forms; such as tablets, capsules, powders, solutions, suspensions, suppositories, aerosols, granules, emulsions, syrups, elixirs and a like.
  • compositions and methods disclosed herein are useful in preventing or treating bacterial infections.
  • compositions and methods disclosed herein are also effective in preventing or treating infections caused by bacteria that are considered be less or not susceptible to one or more of known antibacterial agents or their known compositions.
  • Some non-limiting examples of such bacteria known to have developed resistance to various antibacterial agents include Acinetobacter, E. coli, Pseudomonas aeruginosa, Staphylococcus aureus, Enterobacter, Klebsiella, Citrobacter and a like.
  • infections that may be prevented or treated using the compositions and/or methods of the invention include: skin and soft tissue infections, febrile neutropenia, urinary tract infection, intraabdominal infections, respiratory tract infections, pneumonia (nosocomial), bacteremia meningitis, surgical, infections etc.
  • compositions and methods according to the invention are also effective in preventing or treating bacterial infections that are caused by bacteria producing one or more beta-lactamase enzymes.
  • the ability of compositions and methods according to the present invention to treat such resistant bacteria with typical beta-lactam antibiotics represents a significant improvement in the art.
  • a method of inhibiting beta-lactamase enzymes comprising administering a pharmaceutically effective amount of a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable derivative thereof.
  • a method of inhibiting beta-lactamase enzymes comprising administering a pharmaceutically effective amount of a pharmaceutical composition comprising a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable derivative thereof.
  • a method for preventing or treating a bacterial infection in a subject comprising administering to said subject a pharmaceutically effective amount of a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable derivative thereof.
  • the compounds of Formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof according to invention are also useful in increasing antibacterial effectiveness of antibacterial agent in a subject.
  • the antibacterial effectiveness of one or more antibacterial agents may increased, for example, by co- administering said antibacterial agent or a pharmaceutically acceptable derivative thereof with a pharmaceutically effective amount of a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof according to the invention.
  • a method for increasing antibacterial effectiveness of the antibacterial agent in a subject comprising co- administering said antibacterial agent or a pharmaceutically acceptable derivative thereof with a of a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable derivative thereof.
  • Step 1 Preparation of l-(tert-butoxycarbonyl)-azepane-2-carboxylic acid (XIX): To a stirred solution of a mixture of water (15 ml) and tetrahydrofuran (25 ml) were added azepane-2-carboxylic acid (Prepared as per procedure given in patent US20110212942) (2.5 g, 17.48 mmol) and potassium carbonate (6.03 g, 43.7 mmol) followed by drop-wise addition of Boc anhydride (7.6 g, 34.9 mmol) over a period of 30 minutes at 25-30°C. The reaction mixture was stirred further for 16 hours.
  • azepane-2-carboxylic acid Prepared as per procedure given in patent US20110212942
  • the resulting mixture was diluted with ethyl acetate (25 ml) and the organic layer was separated.
  • the aqueous layer was acidified to pH ⁇ 2 using 5% aqueous potassium hydrogen sulpahte (KHS0 4 ) and the resulting mixture extracted with ethyl acetate (2 x 25 ml).
  • the combined extracts were dried over anhydrous sodium sulfate.
  • the solvents were evaporated under reduced pressure to obtain 3.5 g of 1- (ieri-butoxycarbonyl)-azepane-2-carboxylic acid (XIX) as a white solid in 82% yield.
  • Step 2 Preparation of salt of l-(tert-butoxycarbonyl)-azepane-2-carboxylic acid and (R)-a- methyl benzyl amine: A stirred solution of l-(ieri-butoxycarbonyl)-azepane-2-carboxylic acid (48.5 g, 199.5 mmol) in acetone (728 ml) was charged R-methylbenzyl amine (24.5 g, 199.5 mmol) and the stirring continued further for 3 hours. The separated solid was filtered on buckner funnel and the residue washed with 2 x 50 ml acetone.
  • Step 3 Preparation of (R)-l-(tert-butoxycarbonyl)-azepane-2-carboxylic acid (XXI): A biphasic mixture of dichloromethane (310 ml) and water (310 ml) was charged the salt of ⁇ R)- ⁇ - ⁇ tert- butoxycarbonyl)-azepane-2-carboxylic acid and ( ?)-a-methyl benzyl amine (XXa; 31 g; 85 mmol). The resulting biphasic solution was then acidified by addition of an aqueous solution of potassium hydrogen sulphate to pH ⁇ 2.
  • Step 1 Preparation of (S)-l-(tert-butoxycarbonyl)-azepane-2-carboxylic acid (XXII): To a stirred biphasic mixture of dichloromethane (350 ml) and water (350 ml) was charged salt of ⁇ S)- ⁇ - ⁇ tert- butoxycarbonyl)-azepane-2-carboxylic acid and ?-a-methyl benzyl amine (XXb) (35 g 85 mmol). The biphasic solution was then acidified by addition of potassium hydrogen sulfate to pH ⁇ 2. The dichloromethane layer was separated and the aqueous layer re-extracted with dichloromethane (350 ml).
  • Step 2 Preparation of salt of (S)-l-(tert-butoxycarbonyl)-azepane-2-carboxylic acid and (S)-a- methyl benzyl amine (XXIII): To a stirred solution of (5)-l-(ieri-butoxycarbonyl)-azepane-2- carboxylic acid (22 g, 90.5 mmol) in acetone (220 ml) was charged S- - methyl benzyl amine (10.95 g, 90.5 mmol) at room temperature. Stirring was further continued for 3 more hours and then the separated solid filtered on buckner funnel under suction and the solid washed with 2 x 40 ml of acetone.
  • Step 3 Preparation of_(S)-l-(tert-butoxycarbonyl)-azepane-2-carboxylic acid (XXIV): To a stirred biphasic mixture of dichloromethane (240 ml) and water (240 ml) was charged salt of ⁇ S)- ⁇ - ⁇ tert- butoxycarbonyl)-azepane-2-carboxylic acid and (S)-a-methyl benzyl amine (24 g 65.9 mmol) at room temperature. The resulting biphasic solution was then acidified with potassium hydrogen sulfate to pH ⁇ 2. The dichloromethane layer was separated and water layer re-extracted with dichloromethane (240 ml).
  • Step 1 Synthesis of (25)-4-amino-2-[ ⁇ 9H-fluoren-9yl-methanol ⁇ amino]-4-oxobutanoic acid: To a stirred solution of L-aspragine monohydrate (25 g, 166.6 mmol) in 1 : 1 mixture of water (250 ml) and tetrahydrofuran (250 ml) was added sodium bicarbonate (28 g, 333.3 mmol) in one portion followed by addition of N-(9-fluorenylmethoxycarbonyloxy)succinimide (61.78 g, 183.3 mmol). The resulting mixture was stirred at room temperature. The reaction was monitored by mass spectrometry.
  • reaction mixture was acidified to pH of 1 by addition of 5% potassium hydrogen sulphate solution in water.
  • the separated solid was filtered under suction and the obtained solid was further washed with 2 x 250 ml water and dried under reduced pressure to obtain 50 g of the titled product as white solid in 74% yield.
  • Step 2 Synthesis of (25)-3-amino-2-[ ⁇ 9H-fluoren-9yl-methanol ⁇ amino]propanoic acid hydrochloride salt: To suspension of (25)-4-amino-2- [ ⁇ 9H- fluoren-9yl- methanol ⁇ amino] -4- oxobutanoic acid (30g, 84.74 mmoles) in a mixture of water (10 ml) and N,N'-dimethylformamide (25 ml) was added iodobenzene diacetate ( 32.74 g, 101.6 mmol) at 0°C under stirring.
  • reaction mixture was stirred at 0°C for 10 minutes and pyridine (20.4 ml, 254 mmoles) was added. The progress of reaction was monitored by mass spectrometry. After the completion of reaction, the reaction mixture was concentrated under reduced pressure (4 mm Hg) and residue was diluted with 2N hydrochloric acid (25 ml). The aqueous reaction mixture was extracted with 2 x 25 ml diethyl ether. The aqueous layer was then concentrated under reduced pressure (4 mm Hg) to obtain 15.2 g of the titled product as a white solid 49% yield.
  • Step 3 Synthesis of (25)-3[ ⁇ tert-butoxycarbonyl ⁇ -amino]-2-[ ⁇ 9H-fluoren-9yl-methanol ⁇ amino] propanoic acid: To a (25)-3-amino-2-[ ⁇ 9H-fluoren-9yl-methanol ⁇ amino]propanoic acid as hydrochloride salt (15 g, 41.3 mmoles) in a 1: 1 mixture of water (150 mL) and tetrahydrofuran (150 ml) was added solid sodium bicarbonate (6.95g, 82.7 mmol) at 0°C under stirring. Boc anhydride (10.82 g, 49.6 mmol) was added drop-wise to it.
  • the reaction mixture was allowed to warm to room temperature and stirred for 16 hours.
  • the reaction mixture was extracted with 250 ml of diethyl ether.
  • the aqueous layer was acidified to pH of 1 by addition of 5% potassium hydrogen sulphate solution followed by extraction with 2 x 250 ml ethyl acetate and 250 ml dichloromethane.
  • the combined extracts were dried over anhydrous sodium sulphate and the solvent evaporated under reduced pressure to obtain the 13.08 g of titled product, as a white solid in 67% yield.
  • Step 4 Synthesis of ethyl (25)-3[ ⁇ tert-butoxycarbonyl ⁇ -amino]-2-[ ⁇ 9H-fluoren-9yl- methanol ⁇ amino]propanoate: To a solution of (25)-3[ ⁇ ieri-butoxycarbonyl ⁇ -amino]-2-[ ⁇ 9H-fluoren- 9yl-methanol ⁇ amino] propanoic acid (13 g, 30.5 mmol) in N,N'-dimethylformamide (130 ml) was added potassium carbonate (4.63 g, 33.5 mmol). The resulting mixture was cooled to 0°C and ethyl iodide (7.14 g, 45.7 mmol) was added drop-wise.
  • the reaction mixture was allowed to warm to room temperature and stirred at ambient temperature for 16 hours.
  • the resulting mixture was diluted with water (700 ml).
  • the resulting mixture was extracted with 3 x 250 ml of ethyl acetate.
  • the combined extracts were dried over anhydrous sodium sulphate and the solvent evaporated under reduced pressure to provide 10.5 g of the titled product as oil in 76% yield.
  • Step 5 Synthesis of ethyl (2S)-2-amino-3-[ ⁇ tert-butoxycarbonyl ⁇ -amino]propanoate: To a solution of ethyl (25)-3[ ⁇ ieri-butoxycarbonyl ⁇ -amino]-2-[ ⁇ 9H-fluoren-9-yl-methanol ⁇ amino] propanoate (10 g, 22.0 mmol) in dichloromethane (200 ml) was added piperidine (3.74 g, 44.0 mmol). The reaction mixture was stirred at ambient temperature. The progress of reaction was monitored by mass spectrometry. After completion of reaction, the reaction mixture was concentrated under reduced pressure and residue was diluted with 200 ml of 5% potassium hydrogen sulphate.
  • the resulting mixture was extracted with 2 x 150 ml of ethyl acetate.
  • the aqueous layer was basified with solid sodium bicarbonate and extracted with 2 x 50 ml of dichloromethane.
  • the combined dichloromethane extracts were dried over anhydrous sodium sulphate and the solvent was evaporated under reduced pressure to provide 4.1 g of the titled product as oil in 76% yield.
  • Step 6 Synthesis of ethyl (25)-3-[ ⁇ tert-butoxycarbonyl ⁇ -amino]2-( ⁇ [2S,5R)-6-benzyloxy-7-oxo- l,6diazabicyclo[3.2.1]oct-2yl]carbonyl ⁇ amino)propanoate: To a solution of (25,5 ?)-6-benzyloxy-7- oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxylic acid sodium salt (5.65 g, 18.9 mmol) in N,N'dimethylformamide (25 ml) was added ethyl (25)-2-amino-3-[ ⁇ ieri-butoxycarbonyl ⁇ - amino]propanoate (4 g, 17.2 mmol).
  • Step 7 Synthesis of (25,5/f)-N-[(25)-3-[ ⁇ tert-butoxycarbonyl ⁇ -amino]-l-[ ⁇ tert-butyl-(3/?)-3- (hydrazinylcarbonyl)piperidine-l-carboxylate)-l-oxopropan-2-yl]-6-benzyloxy-7-oxo-l,6- diazabicyclo [3.2.1]octane-2-carboxamide: To a stirred solution of ethyl (25)-3-[ ⁇ ieri- butoxycarbonyl ⁇ -amino]2-( ⁇ [25,5 ?)-6-benzyloxy-7-oxo- l,6diazabicyclo[3.2.1]oct-2yl]carbonyl ⁇ amino)propanoate (1 g, 2.0 mmol) in tetrahydrofuran (10 ml) was added a solution of lithium hydroxide monohydrate (100 mg, 2.2 mmol)
  • reaction was monitored by thin layer chromatography (acetone: hexane 1 : 1). After the completion of reaction, the mixture was diluted with 10 ml of diethyl ether and stirred further for 10 minutes. Organic layer was separated. To the aqueous layer were added successively EDC.HC1 (857 mg, 4.48 mmol), ieri-butyl- (3 ?)-3-(hydrazinylcarbonyl)piperidine- l-carboxylate (500 mg, 2.0 mmol)( prepared as per Patent WO 2013/030733) followed by addition of hydroxyl benzotriazole (275 mg, 2.0 mmol). The resulting mixture was stirred at room temperature for 16 hours. The completion of reaction was monitored by mass spectrometry.
  • reaction mixture was extracted with 2 x 20 ml of ethyl acetate.
  • the combined extracts were dried over anhydrous sodium sulphate and the solvent evaporated under reduced pressure to get crude product (-900 mg).
  • This crude product was purified by column chromatography over silica gel (100-200 mesh ) and was eluted with a v/v 1 : 1 mixture of hexane: acetone (5:5) and evaporation of the solvent from the combined fractions gave the 600 mg of the titled product as white solid in 42% yield.
  • Step 8 Synthesis of (25,5/f)-N-[(25)-3-[ ⁇ tert-butoxycarbonyl ⁇ -amino]-l-[ ⁇ tertbutyl-(3/?)-3-
  • reaction mass was stirred at the same temperature for 30 minutes and allowed to warm to room temperature. After 2 hours of stirring, to the resulting reaction mass was added a solution of tetrabutylammonium acetate (316 mg, 1.04 mmol) in water (1.2 ml). After 2 hours the solvent from the reaction mixture was evaporated under reduced pressure to obtain an oily residue. The oily mass was co-evaporated with xylene (2x10 ml) to obtain thick mass. This mass was partitioned between a 1: 1 mixture of dichloro methane (50 ml) and water (50 ml). The organic layer was separated and the aqueous layer re-extracted with dichloromethane (50 ml).
  • Step 9 Synthesis of (2S,5R)-N-[(2S)-3-amino-l-[(3R)-3-(hydrazinylcarbonyl) piperidine]-l- oxopropan-2-yl]-6-sulfooxy-7-oxo-l,6diazabicyclo[3.2.1]octane-2-carboxamide trifluoroacetic acid salt: To a stirred solution of (25,5 ?)-N-[(25)-3-[ ⁇ ieri-butoxycarbonyl ⁇ -amino]-l-[ ⁇ ieri-butyl- (3 ?)-3-(hydrazinylcarbonyl)piperidine-l-carboxylate)-l-oxopropan-2-yl]-6-sulfooxy-7-oxo-l,6- diazabicyclo [3.2.1]octane-2-carboxamide tetrabutylammonium salt (610 mg, 0.652 mmol) in dich
  • the resulting mass was further stirred at same temperature for 1 hour. The progress of reaction was monitored by mass spectrometry. After complete consumption of starting material the resulting mixture was concentrated under reduced pressure to obtain oily residue. To this was added 10 ml of acetonitrile and the mixture stirred well and solvent evaporated under reduced pressure to remove traces of trifluoroactetic acid. The resulting oily residue was diluted with 25 ml of diethyl ether and stirred for 30 minutes. The ether layer was removed by decantation from the precipitated solid. This procedure was repeated twice again with diethyl ether (2 x 25 ml). The solid thus obtained was filtered and washed with fresh diethyl ether (2 x 25 ml).
  • Methyl (7?)-2-(benzyloxycarbonyl) amino-3-hydroxypropanoate was prepared by procedure described by Iwashita, Masazumi et al from Journal of Medicinal Chemistry, 52(19), 5837-5863; 2009.
  • Step 3 Synthesis of methyl 2-(((benzyloxy)carbonyl)amino)-3- (methoxymethoxy) propanoate: Methyl 2-(((benzyloxy)carbonyl)amino)-3-(methoxymethoxy)propanoate was prepared according to PCT International Patent Application No. 2013064231.
  • Step 4 Synthesis of (25)-2- ⁇ [(benzyloxy) carbonyl] amino ⁇ -3- (methoxymethoxy) propanoic acid lithium salt: A solution of lithium hydroxide (1.26 g, 0.030 mol) in (15 ml) of water was added slowly to a stirred solution of methyl 2-(((benzyloxy)carbonyl)amino)-3-(methoxymethoxy) propanoate (5.96 g, 0.020 mol) in tetrahydrofuran (60 ml) at 0°C. The stirring was continued further for 2 hour at same temperature. The solvent was evaporated under reduced pressure to obtain the titled product which was taken for next step without workup.
  • Step 5 Synthesis of 3-[N'-(2-benzyloxycarbonylamino-3-methoxymethoxy-propionyl)- hydrazinocarbonyl]-piperidine-l-carboxylic acid tert-butyl ester: To a stirred solution of (2S)-2- ⁇ [(benzyloxy)carbonyl]amino ⁇ -3-(methoxymethoxy)propanoic acid lithium salt (5.78 g, 0.020 mol) in N, N-dimethylformamide (25 ml) were successively added HOBt (2.7 g, 0.020 mol), EDC hydrochloride (7.69 g, 0.040 mol) and N-methylmorpholine ( 4.08 g, 0.040 mol) at 25°C.
  • Step 6 Synthesis of 3-[N'-(2-amino-3-methoxymethoxy-propionyl)-hydrazinocarbonyl]- piperidine-l-carboxylic acid tert-butyl ester: To a solution of 3-[N-(2-benzyloxycarbonylamino-3- methoxymethoxy-propionyl)-hydrazinocarbonyl]-piperidine-l-carboxylic acid tert-butyl ester (5 g, 0.0098 mol) in methanol (50 ml) was added 10% palladium on carbon (500 mg) and the suspension was stirred under atmospheric hydrogen pressure at a temperature of about 25 °C for 2 hours.
  • the catalyst was filtered over a celite bed and catalyst containing bed was washed with additional methanol (50 ml). The filtrate was concentrated under reduced pressure to provide a white foam, which was triturated with diethyl ether (10ml) to provide 3.5 g of the titled product as semi solid in 95% yield.
  • Step 7 Synthesis of 3-(N'- ⁇ 2-[(6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1]octane-2- carbonyl)-amino]-3-methoxymethoxy-propionyl ⁇ -hydrazinocarbonyl)-piperidine-l-carboxylic acid tert-butyl ester: To a stirred solution of trans-6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1]octane- 2-carboxylic acid sodium salt (prepared as per the procedure disclosed in WO2014135929) (2.79 g, 0.00936 mol) in N, N-dimethylformamide (5 ml), were added successively HOBt (1.26 g, 0.00936 mol), EDC hydrochloride (3.59 g, 0.0187 mol) and N-methylmorpholine (1.91 g, 0.0187 mol) at 25°
  • reaction mixture was stirred for 15 minutes and a solution of 3-[N-(2-amino-3- methoxymethoxy-propionyl)-hydrazinocarbonyl]-piperidine-l-carboxylic acid tert-butyl ester (3.5 g, 0.00936 mol) dissolved in N, N-dimethylformamide (2 ml) was added in small portions.
  • the reaction mixture was stirred at 25 °C for 18 hours and the resulting mixture was poured into water (100 ml), stirred well and the mixture extracted with ethyl acetate ( 2 x 100 ml). The ethyl acetate layer was washed with water (100 ml) and brine (50 ml).
  • Step 8 Synthesis of 3-(N'- ⁇ 2-[(6-hydroxy-7-oxo-l,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)- amino]-3-methoxymethoxy-propionyl ⁇ -hydrazinocarbonyl)-piperidine-l-carboxylic acid tert- butyl ester:To a solution of 3-(N'- ⁇ 2-[(6-benzyloxy-7-oxo- l,6-diaza-bicyclo[3.2.1]octane-2- carbonyl)-amino]-3-methoxymethoxy-propionyl ⁇ -hydrazinocarbonyl)-piperidine- l-carboxylic acid tert-butyX ester (2.5 g, 0.0039 mol) in methanol (25 ml) was added 10% palladium on carbon (250 mg).
  • the suspension was stirred under atmospheric hydrogen pressure at a temperature of about 25°C for 2 hours.
  • the catalyst was filtered over a celite bed and catalyst containing bed was washed with additional methanol (25 ml).
  • the filtrate was concentrated under reduced pressure to provide white foam, which was triturated with diethyl ether (5 ml) to obtain 2 g of the titled product in 93% yield.
  • Step 9 & Step 10 Synthesis of tetrabutylammonium salt of 3-(N'- ⁇ 3-methoxymethoxy-2-[(7-oxo- 6-sulfooxy-l,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)-amino]-propionyl ⁇ -hydrazinocarbonyl)- piperidine-l-carboxylic acid tert-butyl ester: 3-(V- ⁇ 2-[(6-Hydroxy-7-oxo- l,6-diaza- bicyclo[3.2.1]octane-2-carbonyl)-amino]-3-methoxy methoxy-propionylj-hydrazinocarbonyl)- piperidine- l-carboxylic acid tert-butyX ester (2.0 g, 0.00368 mol) was dissolved in pyridine (10 ml) and to the stirred clear solution was added pyridine
  • Step 11 Synthesis of sulfuric acid mono-(2- ⁇ l-hydroxymethyl-2-oxo-2-[N'-(piperidine-3- carbonyl)-hydrazino]-ethylcarbamoyl ⁇ -7-oxo-l,6-diaza-bicyclo[3.2.1]oct-6-yl) ester: To a cooled (- 10°C), stirred solution of tetrabutylammonium salt of 3-(N'- ⁇ 3-methoxymethoxy-2-[(7-oxo-6- sulfooxy- l,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)-amino]-propionyl ⁇ -hydrazinocarbonyl)- piperidine- l-carboxylic acid tert-butyl ester (950 mg, 0.00109 mol) in dichloromethane (5 ml) was added trifluoro acetic acid (5 ml) drop-wise
  • Step 1 Synthesis of ethyl aminoacetate hydrochloride: To the solution of glycine (40 g, 0.53 mol) in ethanol (400 ml), thionyl chloride (158.49 g, 1.33 mol) was added at 0°C under stirring. The solution was then allowed to warm to room temperature and stirred further for 16 hours. The completion of the reaction was monitored with thin layer chromatography. The resulting reaction mixture was concentrated under reduced pressure and the residual oil was diluted with diethyl ether (200 ml) and the mixture stirred for 15 minutes and the separated solid was filtered and the residue was washed with additional diethyl ether (40 ml). The solid obtained was dried under reduced pressure to obtain 62 g of the titled product as a white solid in 84% yield.
  • Step 2 Synthesis of ethyl ( ⁇ [(25,5/f)-6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]oct-2- yl]carbonyl ⁇ amino)acetate: EDC.HC1 (96.05 g, 0.50 mol), N,N-diisopropylethylamine (129.90 g, 1.0 mol) and HOBT (45.26 g, 0.33 mol) were added successively to a stirred solution of (25,5R)-6- benzyloxy-7-oxo- l,6-diazabicyclo[3.2.1]octane-2-carboxylic acid sodium salt (100 g, 0.33 mol) in dimethyl formamide (1 L) at 25°C.
  • Step 3 Synthesis of lithium ( ⁇ [(25,5/f)-6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]oct-2- yl]carbonyl ⁇ amino)acetate: A solution of lithium hydroxide (4.0 g, 96 mmol) in 70 ml of water was added slowly to stirred solution of above obtained ester compound of step 2 (35 g, 96 mmol) in tetrahydrofuran (350 ml) at 0°C. After stirring for 1 hour at 0°C, the thin layer chromatography indicated the completion of the reaction.
  • Step 4 Synthesis of tert-butyl 2-[( ⁇ [(25,5/f)-6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]oct-2- yl]carbonyl ⁇ amino)acetyl]hydrazinecarboxylate: EDC.HC1 (40.68 g, 213 mmol), and HOBT (13.07 g, 96 mmol) were added to the stirred solution of above obtained lithium salt compound (water layer from step 3) (32.85 g, 96 mmol) at room temperature.
  • Step 5 Synthesis of tert-butyl 2-[( ⁇ [(2S,5R)-6-hydroxy-7-oxo-l,6-diazabicyclo[3.2.1]oct-2- yl]carbonyl ⁇ amino)acetyl]hydrazinecarboxylate: To a solution of above obtained compound (24 g, 53 mmol) in methanol (240 ml) was added 10% palladium over carbon (50% wet) (2.4 g) and was hydrogenated under hydrogen balloon pressure under stirring for 3 hours at 25°C. The completion of the reaction was monitored by thin layer chromatography. After completion, the resulting mixture was filtered through celite bed and the residue washed with 50 ml of methanol. The filtrate was evaporated under reduced pressure to obtain 18.16 g of the titled product as white solid in 95% yield.
  • Step 6 Synthesis of tetrabutylammonium salt of [tert-butyl 2-[( ⁇ [(25,5/f)-6-sulfooxy-7-oxo-l,6- diazabicyclo[3.2.1]oct-2-yl]carbonyl ⁇ amino)acetyl]hydrazinecarboxylate] : Pyridine sulphur trioxide complex (42.66 g, 268 mmol) was added to a stirred solution of hydroxy compound obtained in step-5 (18.16 g, 53 mmol) in pyridine (190 ml) under argon atmosphere at 25°C. Stirring was continued further for 16 hours at 25°C until thin layer chromatography indicated the completion of reaction.
  • Step 7 Synthesis of (25,5/f)-N-(2-hydrazinyl-2-oxoethyl)-7-oxo-6-(sulfooxy)-l,6-diazabicyclo
  • Step 1 Synthesis of tetrabutylammonium salt of (25,5/f)-N- ⁇ 2-[(2E/Z)-2-(2,4- dimethoxybenzylidenehydrazino]-2-oxoethyl ⁇ -7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2- carboxamide: To a stirred solution of 2,4 dimethoxy benzaldehyde (0.542 g, 3.3 mmol) in tetrahydrofuran (10 ml.), was added N, N-diisopropyl ethyl amine (1.0 g, 7.0 mmol) followed by the addition of (25,5 ?)-N-(2-hydrazino-2-oxoethyl)-7-oxo-6-(sulfooxy)- l,6-diazabicyclo [3.2.1 ]octane-2- carbox
  • Step-2 Synthesis of sodium salt of (25,5/f)-N- ⁇ 2-[(2E/Z)-2-(2,4-dimethoxybenzylidenehydrazino]- 2-oxoethyl ⁇ -7-oxo-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2-carboxamide: A solution of tetrabutyl ammonium salt of (25,5 ?)-N- ⁇ 2-[(2E/Z)-2-(2,4-dimethoxybenzylidenehydrazino]-2- oxoethyl ⁇ -7-oxo-6-(sulfooxy)- l,6-diazabicyclo[3.2.1]octane-2-carboxamide (1 g) in tetrahydrofuran (2 ml) diluted to 20 ml using water and passed through INDION 225 Na ION exchange resin with 10% tetrahydrofuran in water as
  • MIC Minimum Inhibitory Concentration
  • the combinations of compounds according to present invention were also tested for their antibacterial activity in combination with Ceftazidime against various bacterial strains.
  • the plates were poured with MHA containing doubling concentration range of Ceftazidime in combination with constant concentration (4 ⁇ / ⁇ 1) of representative compounds of Formula (I).
  • the Table 3 shows the MIC values of Ceftazidime in presence of compounds according to the invention (at 4 ⁇ / ⁇ 1) against various bacterial strains. As shown in Table 3, the MIC value of Ceftazidime was significantly lowered in presence of compounds according to the invention.
  • Example 18 >32 >32 >32 8 >32 >32 >32 .
  • Example 19 >32 >32 >32 32 >32 >32 .
  • Example 20 >32 >32 >32 >32 >32 >32 .
  • Example 21 >32 >32 >32 32 >32 >32 .
  • Example 22 >32 >32 >32 >32 >32 .
  • Example 23 >32 >32 >32 32 >32 >32 .
  • Example 24 >32 >32 >32 32 >32 >32 >32 .
  • Example 25 >32 >32 >32 >32 >32 .
  • Example 26 >32 >32 >32 16 >32 >32 >32 .
  • Example 27 >32 >32 16 >32 >32 >32 >32 .
  • Example 28 >32 >32 >32 16 >32 >32 >32 .
  • Example 29 >32 >32 >32 >32 >32 >32 >32 .

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Abstract

L'invention concerne des composés de formule (I), leur préparation et leur utilisation pour la prévention ou le traitement d'une infection bactérienne.
PCT/IB2016/053974 2015-07-02 2016-07-01 Composés bicycliques contenant de l'azote et leur utilisation dans le traitement d'infections bactériennes WO2017002089A1 (fr)

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JP2022553002A (ja) * 2019-10-18 2022-12-21 ウォックハート リミテッド 窒素含有二環式化合物
WO2024007883A1 (fr) * 2022-07-05 2024-01-11 福安药业集团重庆三禾兴医药科技有限公司 Classe de dérivés conjugués de thiazolamine-diazabicyclooctanone et leur utilisation
US11905286B2 (en) 2018-08-09 2024-02-20 Antabio Sas Diazabicyclooctanones as inhibitors of serine beta-lactamases

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Publication number Priority date Publication date Assignee Title
US11905286B2 (en) 2018-08-09 2024-02-20 Antabio Sas Diazabicyclooctanones as inhibitors of serine beta-lactamases
JP2022553002A (ja) * 2019-10-18 2022-12-21 ウォックハート リミテッド 窒素含有二環式化合物
JP7286879B2 (ja) 2019-10-18 2023-06-05 ウォックハート リミテッド 窒素含有二環式化合物
WO2024007883A1 (fr) * 2022-07-05 2024-01-11 福安药业集团重庆三禾兴医药科技有限公司 Classe de dérivés conjugués de thiazolamine-diazabicyclooctanone et leur utilisation

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