WO2017002086A1 - 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

Info

Publication number
WO2017002086A1
WO2017002086A1 PCT/IB2016/053969 IB2016053969W WO2017002086A1 WO 2017002086 A1 WO2017002086 A1 WO 2017002086A1 IB 2016053969 W IB2016053969 W IB 2016053969W WO 2017002086 A1 WO2017002086 A1 WO 2017002086A1
Authority
WO
WIPO (PCT)
Prior art keywords
oxo
amino
octane
carboxamide
sulfooxy
Prior art date
Application number
PCT/IB2016/053969
Other languages
English (en)
Inventor
Vijaykumar Jagdishwar Patil
Ravikumar Tadiparthi
Velupillai LOGANANTHAN
Deepak Dekhane
Mohammad Usman Shaikh
Satish BIRAJDAR
Prashant Ratnakar JOSHI
Mahesh Vithalbhai Patel
Original Assignee
Wockhardt Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Wockhardt Limited filed Critical Wockhardt Limited
Publication of WO2017002086A1 publication Critical patent/WO2017002086A1/fr

Links

Classifications

    • 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 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 OR 3 , NR 3 R 4 , SR 3 , SOR 3 , S0 2 R 3 , CN, halogen, COOR 3 , CONR3R4, NR3COR4, or NR3CONR4R5,
  • R 2 is:
  • cycloalkyl optionally substituted with one or more substituents independently selected from OR 3 , NR3R4, SR 3 , SOR 3 , S0 2 R 3 , CN, (CH 2 )nNR 3 R4, halogen, COOR3, CONR3R4, NR3COR4 or NR3CONR4R5,
  • heterocycloalkyl optionally substituted with one or more substituents independently selected from OR 3 , NR 3 R4, SR 3 , SOR 3 , S0 2 R 3 , CN, (CH 2 ) n NR 3 R4, halogen, COOR3, CONR3R4, NR3COR or NR3CONR4R5,
  • aryl optionally substituted with one or more substituents independently selected from OR3, NR3R4, SR 3 , SOR3, SO2R3, CN, (CH 2 ) n NR 3 R4, halogen, COOR3, CONR3R4, NR3COR4 or NR3CONR4R5 or
  • heteroaryl optionally substituted with one or more substituents independently selected from OR 3 , NR3R4, SR 3 , SOR 3 , S0 2 R 3 , CN, (CH 2 ) n NR 3 R4, halogen, COOR3, CONR3R4, NR3COR4 or NR3CONR4R5;
  • R 3 , R4 and R5 are each independently:
  • Ci-C 6 alkyl (b) Ci-C 6 alkyl; n is 0, 1,2 or 3;
  • M is hydrogen or a cation.
  • 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 bicyclic nitrogen containing compounds having antibacterial properties.
  • C1-C6 alkyl refers to branched or unbranched acyclic hydrocarbon radical with 1 to 6 carbon atoms.
  • Typical non-limiting examples of “C1-C 6 alkyl” include methyl, ethyl, n-propyl, iso-propyl, «-butyl, sec-butyl, / ' so-butyl, ieri-butyl, w-pentyl, z ' so-pentyl, ierf-pentyl, neopentyl, sec-pentyl, 3-pentyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3- dimethylbutyl and the like.
  • C1-C6 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, CONH2, 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 14 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 14 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 aziridinyl, 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 ira «s-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. (/. 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. nitrogen atoms) as well as 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 compounds can form acidic salts (formed with inorganic and/or organic acids), as well as basic salts (formed with inorganic and/or organic bases).
  • 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.
  • suitable 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.
  • 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-ierf-butyl dicarbonate.
  • TB AHS refers to tetrabutylammonium hydrogen sulfate.
  • cation includes Na, K, Mg, Ca, NH 4 "1" , (CH 3 CH 2 )3N and the like.
  • Ri is:
  • Ci-Ce alkyl optionally substituted with one or more substituents independently selected from OR 3 , NR3R4, SR 3 , SOR 3 , S0 2 R 3 , CN, halogen, COOR 3 , CONR3R4, NR3COR4, or NR3CONR4R5,
  • R 2 is:
  • cycloalkyl optionally substituted with one or more substituents independently selected from OR 3 , NR3R4, SR 3 , SOR 3 , S0 2 R 3 , CN, (CH 2 ) n NR 3 R4, halogen, COOR3, CONR3R4, NR3COR4 or NR3CONR4R5,
  • heterocycloalkyl optionally substituted with one or more substituents independently selected from OR 3 , NR3R4, SR 3 , SOR 3 , S0 2 R 3 , CN, (CH 2 ) n NR 3 R4, halogen, COOR3, CONR3R4, NR3COR4 or NR3CONR4R5,
  • aryl optionally substituted with one or more substituents independently selected from OR 3 , NR3R4, SR 3 , SOR 3 , S0 2 R 3 , CN, (CH 2 ) n NR 3 R4, halogen, COOR 3 , CONR3R4, NR 3 COR4 or NR3CONR4R5 or
  • heteroaryl optionally substituted with one or more substituents independently selected from OR 3 , NR3R4, SR 3 , SOR 3 , S0 2 R 3 , CN, (CH 2 ) n NR 3 R4, halogen, COOR3, CONR3R4, NR3COR4 or NR3CONR4R5;
  • R 3 , R4 and R5 are each independently:
  • Ci-C 6 alkyl (b) Ci-C 6 alkyl; n is 0, 1,2 or 3;
  • 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 Scheme 1.
  • 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) 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), ⁇ , -carbonyldiimidazole, di-ieri-butyldicarbonate, acetic anhydride, ethyl chloro formate, 2-ethoxy- l- ethoxycarbonyl- l ,2-dihydroquinoline (EDDQ), 1 -hydro xybenzotriazole (HOBt), ⁇ - hydroxysuccin
  • 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 (prepared as per the procedure disclosed in WO2014135929)] 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 are N-methyl morpholine, N- methyl pyrrolidine, N-ethyl diisopropylamine and the like.
  • Typical, non-limiting examples of coupling reagent are EDC.HC1, HOBt, 2-(lH-benzotriazole-l-yl)- l, l,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 hydrolyzed 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 1 hour to about 24 hours to obtain a compound of Formula (VI).
  • the compound of Formula (VI) is reacted with a hydroxyl amine 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 temperature of about 15°C to about 35°C for about 10 hours to about 24 hours to obtain a compound of Formula (VIII).
  • Typical, non-limiting examples of coupling reagent are EDC.HC1, 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 water, dimethylformamide, dimethylacetamide and the like.
  • the compound of Formula (VI) is reacted with a compound of Formula (VII) in presence of EDC.HC1 and HOBt at temperature of about 25°C for about 16 hours to obtain a compound of Formula (VIII).
  • the compound of Formula (VIII) is debenzylated by subjecting it for hydrogenolysis by using hydrogen source in presence of transition metal catalyst in a suitable solvent such as methanol, ethanol, methanol dichloro methane mixture, dimethylformamide dichloro methane mixture, ethyl acetate, tetrahydrofuran, or ethyl acetate and tetrahydrofuran mixture at a temperature ranging from about 10 °C to about 60°C for about 1 hour to about 14 hour to provide a compound of Formula (IX).
  • a suitable solvent such as methanol, ethanol, methanol dichloro methane mixture, dimethylformamide dichloro methane mixture, ethyl acetate, tetrahydrofuran, or ethyl acetate and tetrahydrofuran mixture at a temperature ranging from about 10 °C to about 60°C for about 1 hour to about 14 hour to provide a compound of Formula (IX).
  • Typical, non-limiting examples of hydrogen source include hydrogen gas, ammonium formate, cyclohexene, lithium -liquid ammonia, ammonia - fe/ -butanol, sodium - liquid ammonia - tert- butanol, triethyl silyl hydride and the like.
  • Typical, non-limiting examples of transition metal catalyst include 5% palladium on carbon, 10% palladium on carbon, 20% palladium hydroxide on carbon, Raney-Nickel and the like.
  • 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 3 to 5 hours 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 such as pyridine, dichloro methane or N,N-dimethylformamide, at a temperature ranging from about 0°C to about 80°C for about 1 hour to about 48 hours.
  • suitable solvent such as pyridine, dichloro methane or N,N-dimethylformamide
  • sulfonating reagent include sulfur trioxide pyridine complex, sulfur trioxide trimethylamine complex, sulfur trioxide triethylamine complex, sulfur trioxide NN-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.
  • compound of Formula (IX) is reacted with sulfur trioxide pyridine complex in presence of pyridine at a temperature of about 25°C 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 hydrogen sulfate (TBAHS), wherein obtained sulfonic acid compound is converted to corresponding tetrabutylammonium salt of Formula (X).
  • TSAHS tetrabutylammonium hydrogen sulfate
  • 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 treated 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 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).
  • compounds according to invention are isolated as pharmaceutically acceptable salts.
  • compounds according to invention are isolated as sodium salts, wherein a compound of Formula (X) is dissolved in suitable solvent and passed through cation exchange resin.
  • compound of Formula (X) is dissolved in 10% tetrahydrofuran: water mixture and then passed through the column packed with cation exchange resin such as Dowex 50WX8 200 Sodium resin, Indion 225 Sodium resin and the like.
  • compound of Formula (X) is dissolved in suitable solvent such as acetone, tetrahydrofuran, ethanol, isopropanol, acetonitrile, and the like, or a mixture thereof; and treated with sodium ethylhexanoate or potassium ethylhexanoate to provide corresponding sodium or potassium salt of a compound of Formula (I).
  • suitable solvent such as acetone, tetrahydrofuran, ethanol, isopropanol, acetonitrile, and the like, or a mixture thereof.
  • 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.
  • 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.
  • the pharmaceutical 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.
  • the pharmaceutical 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 3 Synthesis of lithium (2S)-2-( ⁇ [(2S,5/f)-6-(benzyloxy)-7-oxo-l,6- diazabicyclo[3.2.1]oct-2-yl]carbonyl ⁇ amino)propanoate:
  • ester compound (8.48 g, 23 mmol) in tetrahydrofuran (84 ml), was added drop-wise a solution lithium hydroxide (0.98 g, 23 mmol) in 16 ml of water at 0°C under stirring. Stirring was continued further for 2 hour at 0°C. The resulting solution was diluted with a mixture of ethyl acetate (84 ml) and water (68 ml) and stirred for 5 minutes. The organic layer was separated and the aqueous layer was taken for next step as such
  • Step 4 Synthesis of (25,5/f)-6-(benzyloxy)-7-oxo-/V-[(25)-l-oxo-l- ⁇ [iert-butyl (25)-pyrrolidin-2- ylmethoxy]amino ⁇ propan-2-yl-l-carboxylate]-l,6-diazabicyclo[3.2.1]octane-2-carboxamide:
  • the crude product was purified by column chromatography using silica gel (60-120 mesh size) and by carrying elution with a mixture of ethyl acetate: hexane (20:80) and evaporation of the combined fractions gave 3.5 g of the titled product as white solid 3.5 g in 29% yield.
  • Step 5 Synthesis of (25,5 ?)-6-hydroxy-7-oxo- ⁇ -[(25)-l-oxo-l- ⁇ [1 ⁇ 2ri-butyl (25)-pyrrolidin-2- ylmethoxy]amino ⁇ propan-2-yl-l-carboxylate]-l,6-diazabicyclo[3.2.1]octane-2-carboxamide:
  • Step 6 Synthesis of tetrabutylammonium salt of (25,5R)-6-(sulfooxy)-7-oxo- V-[(25)-l-oxo-l- ⁇ [fert-butyl (2S)-pyrrolidin-2-ylmethoxy]amino ⁇ propan-2-yl-l-carboxylate]-l,6-diazabicyclo
  • Step 7 Synthesis of (25,5 ?)-6-(sulfooxy)-7-oxo-A f -[(25)-l-oxo-l- ⁇ [(25)-pyrrolidin-2-ylmethoxy] amino ⁇ propan-2-yl-l-carboxylate]-l,6-diazabicyclo[3.2.1]octane-2-carboxamide
  • MIC Minimum Inhibitory Concentration
  • the Table 3 shows the MIC values of Ceftazidime in presence of compounds according to the invention (at 4 ⁇ g/ml) 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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/IB2016/053969 2015-07-02 2016-07-01 Composés bicycliques contenant de l'azote et leur utilisation dans le traitement d'infections bactériennes WO2017002086A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2544MU2015 2015-07-02
IN2544/MUM/2015 2015-07-02

Publications (1)

Publication Number Publication Date
WO2017002086A1 true WO2017002086A1 (fr) 2017-01-05

Family

ID=56550924

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2016/053969 WO2017002086A1 (fr) 2015-07-02 2016-07-01 Composés bicycliques contenant de l'azote et leur utilisation dans le traitement d'infections bactériennes

Country Status (1)

Country Link
WO (1) WO2017002086A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111171052A (zh) * 2020-03-04 2020-05-19 刀鹏 一种盐酸头孢吡肟的合成方法
US11905286B2 (en) 2018-08-09 2024-02-20 Antabio Sas Diazabicyclooctanones as inhibitors of serine beta-lactamases

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002010172A1 (fr) 2000-08-01 2002-02-07 Aventis Pharma Sa Composes azabicycliques, leur preparation et leur utilisation comme medicaments, notamment comme anti-bacteriens
WO2013030733A1 (fr) * 2011-08-27 2013-03-07 Wockhardt Limited Dérivés 1,6-diazabicyclo[3,2,1]octane-7-one et leur utilisation dans le traitement d'infections bactériennes
WO2014033560A1 (fr) * 2012-08-25 2014-03-06 Wockhardt Limited Dérivés de 1,6-diazabicyclo[3,2,1]octan-7-one et leur utilisation dans le traitement d'infections bactériennes
WO2014135929A1 (fr) 2013-03-08 2014-09-12 Wockhardt Limited Sel de sodium de l'acide (2s, 5r)-6-benzyloxy-7-oxo-1,6-diaza-bicyclo [3.2.1] octane-2-carboxylique et sa préparation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002010172A1 (fr) 2000-08-01 2002-02-07 Aventis Pharma Sa Composes azabicycliques, leur preparation et leur utilisation comme medicaments, notamment comme anti-bacteriens
WO2013030733A1 (fr) * 2011-08-27 2013-03-07 Wockhardt Limited Dérivés 1,6-diazabicyclo[3,2,1]octane-7-one et leur utilisation dans le traitement d'infections bactériennes
WO2014033560A1 (fr) * 2012-08-25 2014-03-06 Wockhardt Limited Dérivés de 1,6-diazabicyclo[3,2,1]octan-7-one et leur utilisation dans le traitement d'infections bactériennes
WO2014135929A1 (fr) 2013-03-08 2014-09-12 Wockhardt Limited Sel de sodium de l'acide (2s, 5r)-6-benzyloxy-7-oxo-1,6-diaza-bicyclo [3.2.1] octane-2-carboxylique et sa préparation

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
"Clinical and Laboratory Standards Institute (CLSI), Performance Standards for Antimicrobial Susceptibility Testing", 20T INFORMATIONAL SUPPLEMENT, M 100-S20, vol. 30, no. 1, 2010
"Clinical and Laboratory Standards Institute (CLSI), Performance Standards for Antimicrobial Susceptibility Testing", 20TH INFORMATIONAL SUPPLEMENT, M 100-S20, vol. 30, no. 1, 2010
COATES ET AL., BR. J. PHARMACOL., vol. 152, no. 8, 2007, pages 1147 - 1154
GILMAN ET AL.: "Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th ed.", 1990, PERGAMON PRESS
GWYNN ET AL.: "Annals of the New York Academy of Sciences", vol. 1213, 2010, pages: 5 - 19
S. M. BERGE ET AL., J. PHARMACEUTICAL SCIENCES, vol. 66, 1977, pages 1 - 19

Cited By (2)

* Cited by examiner, † Cited by third party
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
CN111171052A (zh) * 2020-03-04 2020-05-19 刀鹏 一种盐酸头孢吡肟的合成方法

Similar Documents

Publication Publication Date Title
EP2748165B1 (fr) Dérivés 1,6-diazabicyclo[3,2,1]octane-7-one et leur utilisation dans le traitement d'infections bactériennes
CA2846107C (fr) Composes azotes et leur utilisation
WO2016116788A1 (fr) Composés bicycliques contenant de l'azote et leur utilisation dans le traitement d'infections bactériennes
US9822115B2 (en) Nitrogen containing compounds and their use as antibacterial agents
WO2016128867A1 (fr) Composés contenant de l'azétidinone et leur utilisation dans le traitement d'infections bactériennes
US10501464B2 (en) 7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide containing compounds and their use in treating bacterial infections
WO2017081615A1 (fr) 7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1] octane contenant des composés et leur utilisation dans le traitement d'infections bactériennes
EP3055311B1 (fr) Composés azotés et leur utilisation
WO2017002089A1 (fr) Composés bicycliques contenant de l'azote et leur utilisation dans le traitement d'infections bactériennes
WO2017002086A1 (fr) Composés bicycliques contenant de l'azote et leur utilisation dans le traitement d'infections bactériennes
WO2017037607A1 (fr) Dérivés de (2s,5r)-6-(sulfonyl)-7-oxo -1,6-diazabicyclo [3.2.1] octane-2-carboxamide substitués par (aminométhylidène)amino à activité antibactérienne
WO2017216764A1 (fr) Dérivés de n-(alcanoyl)-7-oxo-6-sulfooxy-1,6-diazabicyclo[3.2.1]octane-2-carbonylhydrazide et leur utilisation comme agents antibactériens
WO2017002087A1 (fr) Composés bicycliques contenant de l'azote et leur utilisation dans le traitement d'infections bactériennes
WO2017002083A1 (fr) Composés bicycliques contenant de l'azote et leur utilisation dans le traitement d'infections bactériennes
WO2017216763A1 (fr) Dérivés de n-phénylalcoxy-7-oxo-6-sulfooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide et leur utilisation en tant qu'agents antibactériens
US10500195B2 (en) Antibacterial compounds
WO2017060826A1 (fr) Composés d'acide acétique difluoro-(carbamoyl-1,6-diaza-bicyclo[3.2.1]oct-6-yloxy 2-substitué) et leur utilisation dans le traitement d'infections bactériennes
NZ616542B2 (en) 1,6-diazabicyclo[3,2,1]octan-7-one derivatives and their use in the treatment of bacterial infections

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16744529

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16744529

Country of ref document: EP

Kind code of ref document: A1