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    abstract patent of invention: "derivatives of 1,6-diazabicyclo [3,2,1] octan-7-one and its use in the treatment of bacterial infections". the present invention to compounds of formula (i), their preparation and use in the prevention or treatment of bacterial infections are described.
    公开号:BR112015003592B1
    申请号:R112015003592
    申请日:2013-04-19
    公开日:2020-04-14
    发明作者:Kale Amol；Dond Bharat；Dekhane Deepak；Velupillai Loganathan；Vithalbhai Patel Mahesh；Pawar Mangesh；Usman Shaikh Mohammad；Ambalal Patel Piyush；Dixit Prasad；Tadiparthi Ravikumar；Bhagwat Sachin；Shrimant Birajdar Satish；Maurya Sushilkumar；Jagdishwar Patil Vijaykumar
    申请人:Wockhardt Ltd；
    IPC主号:
    专利说明:

    Descriptive Report of the Patent of Invention for DERIVATIVES OF 1,6-DIAZABYCLE [3,2,1] OCTAN-7-ONA AND ITS USE IN THE TREATMENT OF BACTERIAL INFECTIONS.
    FIELD OF THE INVENTION [001] The present invention relates to compounds containing nitrogen, use of these compounds as antibacterial agents, compositions comprising them and processes for their preparation.
    BACKGROUND OF THE INVENTION [002] The emergence of bacterial resistance to known antibacterial agents is becoming a major challenge in the treatment of bacterial infections. One way forward for treating bacterial infections, and especially those caused by resistant bacteria, is to develop newer antibacterial agents that can overcome bacterial resistance. Coates et al. (Br. J. Pharmacol. 2007; 152 (8), 1147-1154.) Has new methods reviewed to develop new antibiotics. However, 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) has reviewed the challenges in the discovery of antibacterial agents.
    [003] Various antibacterial agents have been described in the prior art (for example, see International PCT Application Nos. PCT / US2010 / 060923, PCT / EP2010 / 067647, PCT / US2010 / 052109, PCT / US2010 / 048109, PCT / GB2009 / 050609 , PCT / EP2009 / 056178 and PCT / US2009 / 041200). However, there remains a need for potent antibacterial agents to prevent and / or treat bacterial infections, including those caused by bacteria that are resistant to known antibacterial agents.
    [004] The inventors have surprisingly discovered nitrogen-containing compounds with antibacterial properties.
    2/62
    SUMMARY OF THE INVENTION [005] Consequently, nitrogen containing compounds are provided, methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and method for preventing or treating bacterial infection in an individual using these compounds.
    [006] In a general aspect, compounds of Formula (I) are provided:
    O
    R3
    R1
    Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof;
    on what:
    R1 is:
    (a) SO3M, (b) SO2NH2, (c) PO3M, (d) CH2COOM, (e) CF2COOM, (f) CHFCOOM, or (g) CF3;
    M is hydrogen or a cation;
    R2 is:
    (a) hydrogen, (b) (CH2) „- R3, or (c) COOR3, n is 0, 1 or 2;
    R3 is:
    (a) hydrogen,
    3/62 (b) C1-C 6 alkyl optionally substituted with one or more substituents independently selected from halogen, OR5, CN, COOR5, CONR6R7, NR6R7, NR5COR8, NR5CONR6R7 heterocyclyl, heteroaryl, cycloalkyl or aryl, (c) CN , (d) NR6R7, (e) CONR6R7, (f) NHCONR6R7, (g) aryl optionally substituted with one or more substituents independently selected from C1-C 6 alkyl, OR5, NR6R7, halogen, CN, CONR6R7, SO2- alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl, or NHCONR6R7, (h) heterocyclyl optionally substituted with one or more substituents independently selected from C1-C 6 alkyl, OR5, NR6R7, halogen, CN, CONR6R7, SO2-alkyl , SO2-aryl, OSO2-alkyl, OSO2-aryl, or NHCONR6R7, (i) heteroaryl optionally substituted with one or more substituents independently selected from C1-C 6 alkyl, OR5, NR6R7, halogen, CN, CONR6R7, SO2- alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl, or NHCONR6R7, (j) cycloalkyl option substituted with one or more substituents independently selected from C1-C 6 alkyl, OR5, NR6R7, halogen, CN, CONR6R7, SO2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl, or NHCONR6R7, (k) cycloalkyl substituted with C1-C 6 alkyl wherein C1C6 alkyl is also substituted with one or more substituents independently selected from OR5, NR6R7, halogen, CN, or CONR6R7, or (1) OR8;
    R4 is:
    4/62 (a) hydrogen, (b) C1-C 6 alkyl optionally substituted with one or more substituents independently selected from halogen, OR5, CN, COOR5, CONR6R7, NR6R7, NR5COR8, heterocyclyl, heteroaryl, cycloalkyl or aryl, (c) aryl optionally substituted with one or more substituents independently selected from C1-C 6 alkyl, OR5, NR6R7, halogen, CN, CONR6R7, SO2-alkyl, SO2-aryl, OSO2alkyl, OSO2-aryl, or NHCONR6R7, ( d) heterocyclyl optionally substituted with one or more substituents independently selected from C1-C 6 alkyl, OR5, NR6R7, halogen, CN, CONR6R7, SO2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl, or NHCONR6R7, (e) heteroaryl optionally substituted with one or more substituents independently selected from C1-C 6 alkyl, OR5, NR6R7, halogen, CN, CONR6R7, SO2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl, or NHCONR6R7 , or (f) cycloalkyl optionally substituted with one or more sub constituents independently selected from C1-C 6 alkyl, OR5, NR6R7, halogen, CN, CONR6R7, SO2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl, or NHCONR6R7;
    R5 and R8 are each independently:
    (a) hydrogen, or (b) C1-C 6 alkyl optionally substituted with one or more substituents independently selected from halogen, CN, CONR6R7, NR6R7, heterocyclyl, heteroaryl, cycloalkyl or aryl;
    R 6 and R7 are each independently:
    (a) hydrogen,
    5/62 (b) C1-C 6 alkyl optionally substituted with one or more substituents independently selected from halogen, OR 5 , CN, COOR5, CONR5R8, NR5R8, NR5COR8, heterocyclyl, heteroaryl, cycloalkyl or aryl, (c) aryl optionally substituted with one or more substituents independently selected from C1-C 6 alkyl, OR5, NR5R8, halogen, CN, CONR5R8, SO2-alkyl, SO2-aryl, OSO2alkyl, OSO2-aryl, or NHCONR5R8, (d) optionally heterocyclyl substituted with one or more substituents independently selected from C1-C 6 alkyl, OR5, NR5R8, halogen, CN, CONR5R8, SO2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl, or NHCONR5R8, (e) heteroaryl optionally substituted with one or more substituents independently selected from C1-C 6 alkyl, OR5, NR5R8, halogen, CN, CONR5R8, SO2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl, or NHCONR5R8, (f) cycloalkyl optionally substituted with one or more substituents independently selected from C1-C 6 alkyl, OR5, NR5R8, halogen, CN, CONR5R8, SO2-alkyl, SO2-aryl, OSO 2 -alkyl, OSO 2 -aryl, or NHCONR5R8, or (g) R 6 and R7 are joined together to form a four to seven-membered ring.
    [007] In another general aspect, pharmaceutical compositions are provided comprising a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof.
    [008] In another general aspect, a method is provided to prevent or treat bacterial infection in an individual, said method comprising administering to said individual a pharmaceutically effective amount of a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt the same.
    6/62 [009] In another general aspect, a method is provided to prevent or treat a bacterial infection in an individual, said infection being caused by bacteria producing one or more beta-lactamase enzymes, wherein the method comprises administering to the said individual a pharmaceutically effective amount of a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof.
    In another general aspect, a method is provided to prevent or treat bacterial infection in an individual, said method comprising administering to said individual a pharmaceutically effective amount of a pharmaceutical composition comprising a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof.
    [0011] In yet another general aspect, a method is provided to prevent or treat a bacterial infection in an individual, said infection being caused by bacteria producing one or more beta-lactamase enzymes, wherein the method comprises administering to said individual a pharmaceutically effective amount of a pharmaceutical composition comprising a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof.
    [0012] In another general aspect, pharmaceutical compositions are provided comprising: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one beta-lactamase inhibitor selected from among sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof.
    [0013] In another general aspect, pharmaceutical compositions are provided comprising: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, and
    7/62 (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
    [0014] In another general aspect, pharmaceutical compositions are provided comprising: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, (b) at least one beta-lactamase inhibitor selected from sulbactam , tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof, and (c) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
    In another general aspect, a method for preventing or treating bacterial infection in an individual is provided, said method comprising administering to said individual a pharmaceutically effective amount of a pharmaceutical composition comprising: (a) a compound of Formula (I) , or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof.
    [0016] In yet another general aspect, a method is provided to prevent or treat a bacterial infection in an individual, said infection being caused by bacteria producing one or more beta-lactamase enzymes, wherein the method comprises administering to said individual a pharmaceutically effective amount of a pharmaceutical composition comprising: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof.
    [0017] In another general aspect, a method is provided to prevent or treat bacterial infection in an individual, said method
    8/62 comprising administering to said individual a pharmaceutically effective amount of a pharmaceutical composition comprising: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
    [0018] In yet another general aspect, a method is provided to prevent or treat a bacterial infection in an individual, said infection being caused by bacteria producing one or more beta-lactamase enzymes, wherein the method comprises administering to said individual a pharmaceutically effective amount of a pharmaceutical composition comprising: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
    [0019] In another general aspect, a method is provided to prevent or treat bacterial infection in an individual, said method comprising administering to said individual a pharmaceutically effective amount of a pharmaceutical composition comprising: (a) a compound of Formula (I) , or a stereoisomer or a pharmaceutically acceptable salt thereof, (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof, and (c) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
    [0020] In yet another general aspect, a method is provided to prevent or treat a bacterial infection in an individual, said infection being caused by bacteria producing one or more beta-lactamase enzymes, wherein the method comprises administering to said individual a pharmaceutically effective amount of a
    9/62 pharmaceutical composition comprising: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof, and (c) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof. [0021] In another general aspect, a method is provided to prevent or treat bacterial infection in an individual, said method comprising administering to said individual a pharmaceutically effective amount of: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof.
    [0022] In yet another general aspect, a method is provided to prevent or treat a bacterial infection in an individual, said infection being caused by bacteria producing one or more beta-lactamase enzymes, wherein the method comprises administering to said individual a pharmaceutically effective amount of: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof. [0023] In another general aspect, a method is provided to prevent or treat bacterial infection in an individual, said method comprising administering to said individual a pharmaceutically effective amount of: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
    10/62 [0024] In yet another general aspect, a method is provided to prevent or treat a bacterial infection in an individual, said infection being caused by bacteria producing one or more beta-lactamase enzymes, wherein the method comprises administering to said individual a pharmaceutically effective amount of: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
    [0025] In another general aspect, a method is provided to prevent or treat bacterial infection in an individual, said method comprising administering to said individual a pharmaceutically effective amount of: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof, and (c) at least one antibacterial agent or pharmaceutically acceptable derivative the same.
    [0026] In yet another general aspect, a method is provided to prevent or treat a bacterial infection in an individual, said infection being caused by bacteria producing one or more beta-lactamase enzymes, wherein the method comprises administering to said individual a pharmaceutically effective amount of: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically derived of the same, and (c) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
    [0027] In another general aspect, methods are provided to increase the antibacterial effectiveness of an antibacterial agent in a
    11/62 individual, said method comprising 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.
    [0028] Details of one or more embodiments of the invention are mentioned in the description below. Other aspects, objectives and advantages of the invention will be apparent from the following description including the claims.
    DETAILED DESCRIPTION OF THE INVENTION [0029] Reference will now be made to the exemplary modalities, and the specific language will be used here to describe them. However, it should be understood that no limitation on the scope of the invention is therefore intended. Changes and other modifications to the inventive aspects illustrated here, and additional requests for the principles of the invention as illustrated here, which would occur to someone skilled in the relevant art and possessing this description, should be considered within the scope of the invention. It should be noted that, when used in these specifications and the appended claims, the singular forms one, one, and a / o include plural referents unless the content clearly dictates otherwise. All references including patents, patent applications, and the literature cited in the specification are expressly incorporated herein by reference in their entirety.
    [0030] The inventors have surprisingly described new nitrogen-containing compounds having antibacterial properties.
    [0031] The term "C1-C6 alkyl" when used here refers to the acyclic branched or unbranched hydrocarbon radical with 1 to 6 carbon atoms. Non-limiting, typical examples of “C1-C 6 alkyl” include methyl, ethyl, n-propyl, / so-propyl, n-butyl, / so-butyl, tert
    12/62 butyl, n-pentyl, / so-pentyl, n-hexyl and the like. The "C1-C 6 alkyl" can be unsubstituted or substituted with one or more substituents. Typical non-limiting examples of such substituents include halogen, alkoxy, CN, COOH, CONH 2 , OH, -NH 2 , -NHCOCH3, cycloalkyl, heterocyclyl, heteroaryl, aryl and the like.
    [0032] The term cycloalkyl when used here refers to the cyclic hydrocarbon radicals of three to seven members. The cycloalkyl group optionally incorporates one or more double or triple bonds, or a combination of double bonds and triple bonds, however, which is not aromatic. Non-limiting examples typical of cycloalkyl groups include cyclopropane, cyclobutane, cyclopentane, cyclohexane, and cycloheptane. Cycloalkyl can be unsubstituted, or substituted with one or more substituents. Non-limiting, typical examples of such substituents include C1-C 6 alkyl, halogen, alkoxy, CN, COOH, CONH 2 , OH, NH 2 , NHCOCH3, heterocyclyl, heteroaryl, aryl, SO 2 alkyl, SO 2 -aryl, OSO 2 -alkyl, -OSO 2 -aryl, and the like.
    [0033] The term heterocyclyl when used here refers to the 4- to 7-membered 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, however, which is not aromatic. Non-limiting examples typical of heterocycloalkyl groups include azetidine, pyrrolidine, 2oxo-pyrrolidine, imidazolidin-2-one, piperidine, oxazin, thiazine, piperazine, piperazin-2,3-dione, morpholine, thiamorpholine, azapane, and the like. Heterocycloalkyl can be unsubstituted, or substituted with one or more substituents. Non-limiting, typical examples of such substituents include C1-C 6 alkyl, halogen, alkoxy, CN, COOH, CONH 2 , OH, NH 2 , NHCOCH3, heterocyclyl, heteroaryl, aryl, SO 2 -alkyl, SO 2 aryl, OSO 2 -alkyl, OSO 2 -aryl, and the like.
    13/62 [0034] The term aryl when used here refers to a monocyclic or polycyclic aromatic hydrocarbon. Non-limiting, typical examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, phenanthrenyl, and the like. The aryl group can be unsubstituted, or substituted with one or more substituents. Non-limiting, typical examples of such substituents include C1-C 6 alkyl, halogen, alkoxy, CN, COOH, CONH2, OH, NH 2 , NHCOCH3, heterocyclyl, heteroaryl, aryl, SO 2 -alkyl, SO 2 -aryl, OSO 2 -alkyl, OSO 2 -aryl, and the like. [0035] The term heteroaryl when used here refers to a monocyclic or polycyclic aromatic hydrocarbon group in which 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 hetero atoms can be the same or different. Non-limiting example, typical of heteroaryl groups include 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole,
    1,2,3,4-tetrazole, 1,3-oxazole, 1,3-thiazole, pyridine, pyrimidine, pyrazine, pyridazine, furan, pyrrole, thiophene, imidazole, pyrazole, benzofuran, benzothiophene, benzimidazole, benzoxazole, benzothiazole, thiazole, and the like. The heteroaryl group can be unsubstituted, or substituted with one or more substituents. Non-limiting, typical examples of such substituents include C1-C6 alkyl, halogen, alkoxy, CN, COOH, CONH2, OH, NH2, NHCOCH3, heterocyclyl, heteroaryl, aryl, SO2-alkyl, SO2-aryl, OSO 2 -alkyl, OSO 2- aryl, and the like.
    [0036] The term stereoisomers when used here refers to compounds that have identical chemical constitution, however, differ with respect to the arrangement of their atoms or groups in space. The compounds of Formula (I) can contain asymmetric or chiral centers and, therefore, exist in different stereoisomeric forms. It is intended, unless otherwise specified, that all stereoisomeric forms of the compounds of Formula (I) as well as
    14/62 mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention encompasses all geometric and positional isomers (including cis and trans forms), as well as mixtures thereof, within the scope of the invention. In general, a reference to a compound is intended to encompass its stereoisomers and mixture of various stereoisomers. [0037] The term optionally substituted when used here means that substitution is optional and therefore includes unsubstituted and substituted atoms and portions. A substituted atom or moiety indicates that any hydrogen in the designated atom or moiety can be substituted with a selection from the indicated substituent group, as long as the normal valence of the designated atom or moiety is not exceeded, and the substitution results in a compound stable.
    [0038] The term pharmaceutically acceptable salt when used herein refers to one or more salts of a particular compound that have the desired pharmacological activity of the free compound and that are not biologically or otherwise undesirable. In general, pharmaceutically acceptable salts refer to salts that are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic response, and the like, and are commensurable 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 pharmaceutically acceptable salts in detail.
    [0039] In general, the compounds according to the invention contain basic moieties (for example, nitrogen atoms) as well as acidic moieties (for example, compounds of Formula (I) in which M is hydrogen). A person experienced in the art would appreciate that such
    Therefore, 15/62 compounds can form acid 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. For example, basic portions can be converted to their salt by treating a compound with an appropriate amount of acid. Non-limiting, typical examples of such suitable acids include hydrochloric acid, trifluoroacetic acid, methanesulfonic acid, or the like. Alternatively, the acidic portions can be converted to their salt by treating them with a suitable base. Typical non-limiting examples of such bases include sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate or the like. In the case of compounds containing more than one functional group capable of being converted to salt, each such functional group can be converted to salt independently. For example, in the case of compounds that contain two basic nitrogen atoms, one 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 also contain acidic as well as basic moieties, and thus can form corresponding internal salts or zwitterions. In general, all forms of pharmaceutically acceptable salt of compounds of Formula (I) according to the invention including acid addition salts, base addition salts, zwitterions or the like are considered to be within the scope of the present invention and are generally called pharmaceutically acceptable salts.
    [0040] The term halogen or halo when used here refers to chlorine, bromine, fluorine or iodine.
    [0041] The term infection or bacterial infection when used here includes the presence of bacteria, on or in an individual which, if its growth was inhibited, would result in a benefit to the individual.
    16/62
    As such, the term infection, in addition to referring in the same way to the presence of bacteria, refers to normal flora that is not desirable. The term infection includes infection caused by bacteria.
    [0042] The term treat, treating or treatment when used herein refers to the administration of a drug, including a pharmaceutical composition, or one or more pharmaceutically active ingredients, for prophylactic and / or therapeutic purposes. The term prophylactic treatment refers to the treatment of an individual who is not yet infected, but who is susceptible to, or otherwise at risk of infection (preventing bacterial infection). The term therapeutic treatment refers to the administration of treatment to an individual who is already suffering from infection. The terms treat, treating or treatment when used in the same manner here refer to the administration of compositions or one or more of the pharmaceutically active ingredients discussed here, with or without additional active or pharmaceutically inert ingredients, in order to: (i) reduce or eliminate a bacterial infection or one or more symptoms of the bacterial infection, or (ii) slow the progress of a bacterial infection or one or more symptoms of the bacterial infection, or (iii) reduce the severity of a bacterial infection or one or more symptoms of the bacterial infection, or (iv) suppress the clinical manifestation of a bacterial infection, or (v) suppress the manifestation of adverse symptoms of the bacterial infection.
    [0043] The term pharmaceutically effective amount or therapeutically effective amount or effective amount when used herein refers to an amount that has a therapeutic effect or is the amount required to produce a therapeutic effect in an individual. For example, a therapeutically or pharmaceutically effective amount of the antibacterial agent or a pharmaceutical composition is that the amount of the antibacterial agent or the composition
    17/62 pharmaceutical product required to produce a desired therapeutic effect as can be judged by results of clinical trial, model animal infection studies, and / or in vitro studies (for example, on agar or broth media). The pharmaceutically effective amount depends on several factors, including, but not limited to, microorganism (eg, bacteria) involved, characteristics of the individual (eg, health, weight, sex, age and medical history), severity of infection, and the particular type of antibacterial agent used. For prophylactic treatments, a therapeutically or prophylactically effective amount is that amount that would be effective in preventing a microbial (for example, bacterial) infection.
    [0044] The term administration or administering includes the release of a composition or one or more pharmaceutically active ingredients to an individual, including, for example, by any appropriate method, which serve to release the composition or its active ingredients or other pharmaceutically active ingredients to the infection site. The method of administration can vary, depending on several factors, such as, for example, the components of the pharmaceutical composition or the nature of the pharmaceutically active or inert ingredients, the site of the potential or actual infection, the microorganism involved, severity of the infection , age and physical condition of the individual and similar. Some non-limiting examples of ways to administer a composition or a pharmaceutically active ingredient to an individual according to this invention include oral, intravenous, topical, inter-respiratory, intraperitoneal, intramuscular, parenteral, sublingual, transdermal, intranasal, aerosol, intraocular, intratracheal, intrarectal, vaginal, gene gun, dermal patch, eye drops, ear drops or mouthwashes. In the case of a pharmaceutical composition that comprises more than one ingredient (active or inert), one way of administering that composition is by mixing the ingredients (eg
    18/62 example, in the form of a suitable unit dosage form such as a tablet, capsule, solution, powder and the like) and then administering the dosage form. Alternatively, the ingredients can be administered in the same way 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.
    [0045] The term growth when used here refers to the growth of one or more microorganisms and includes the reproduction or expansion of the microorganism's population (for example, bacteria). The term also includes the maintenance of a microorganism's ongoing metabolic processes, including the processes that keep the microorganism alive.
    [0046] The term, efficacy when used herein refers to the ability of a treatment or a composition or one or more pharmaceutically active ingredients to produce a desired biological effect on an individual. For example, the term antibacterial effectiveness of a composition or an antibacterial agent refers to the ability of the composition or the antibacterial agent to prevent or treat microbial (e.g., bacterial) infection in an individual.
    [0047] The term synergistic or synergy when used here refers to the interaction of two or more agents so that their combined effect is greater than their individual effects.
    [0048] The term antibacterial agent when used herein refers to any substance, compound or combination of substances or a combination compound capable of: (i) inhibiting, reducing or preventing the growth of bacteria; (ii) inhibiting or reducing the ability of a bacterium to produce infection in an individual; or (iii) inhibit or reduce the ability of bacteria to multiply or remain infectious in the environment. The term antibacterial agent refers to the
    19/62 similarly to compounds capable of decreasing the infectivity or virulence of bacteria.
    [0049] The term beta-lactam antibacterial agent when used here refers to compounds with antibacterial properties and containing a beta-lactam nucleus in its molecular structure. [0050] The term beta-lactamase when used here refers to any enzyme or protein or any other substance that breaks a beta-lactam ring. The term beta-lactamase includes enzymes that are produced by bacteria and have the ability to hydrolyze the beta-lactam ring in a beta-lactam compound, partially or completely.
    [0051] The term beta-lactamase inhibitor when used herein refers to a compound capable of inhibiting the activity of one or more beta-lactamase enzymes, partially or completely.
    [0052] The term pharmaceutically inert ingredient or vehicle or excipient refers to a compound or material used to facilitate the administration of a compound, including, for example, increasing the solubility of the compound. Non-limiting, typical examples of solid vehicles include: gum, lactose, dicalcium phosphate, sucrose, and kaolin and so on. Non-limiting examples, typical of liquid vehicles, include: sterile water, saline, buffers, non-ionic surfactants, and edible oils such as oil, peanut and sesame oil and so on. In addition, various adjuvants commonly used in the art can be included. These and other such compounds are described in the literature, for example, in the Merck Index (Merck & Company, Rahway, N.J.). Considerations for including various components in pharmaceutical compositions are described, for example, in Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press., Which is hereby incorporated by reference in its entirety.
    20/62 [0053] The term individual when used herein refers to vertebrate or invertebrate, including a mammal. The term individual includes human, animal, bird, fish, or amphibian. Non-limiting, typical examples of an individual include humans, cats, dogs, horses, sheep, cows, pigs, lambs, rats, mice and guinea pigs.
    [0054] The term pharmaceutically acceptable derivative when used herein refers to and includes any pharmaceutically acceptable salt, prodrugs, metabolites, esters, ethers, hydrates, polymorphs, solvates, complexes, enantiomers or adduct of a compound described herein which administration to an individual, is capable of supplying (directly or indirectly) the parent compound. For example, the term antibacterial agent or a pharmaceutically acceptable derivative thereof includes all derivatives of the antibacterial agent (such as salt, prodrugs, metabolites, esters, ethers, hydrates, polymorphs, solvates, complexes, enantiomers or adducts) that, on administration to an individual, it is able to supply (directly or indirectly) the antibacterial compound.
    [0055] In general, the term cation includes Na, K, Mg, Ca, NH4 + , (CH 3 CH 2 ) 3 N + etc.
    [0056] In a general aspect, compounds of Formula (I) are provided:
    Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof;
    on what:
    R1 is:
    (a) SO3M,
    21/62 (b) SO2NH2, (c) PO3M, (d) CH2COOM, (e) CF2COOM, (f) CHFCOOM, or (g) CF3;
    M is hydrogen or a cation;
    R 2 is:
    (a) hydrogen, (b) (CH2) „- R3, or (c) COOR3, n is 0, 1 or 2;
    R3 is:
    (a) hydrogen, (b) C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen, OR5, CN, COOR5, CONR6R7, NR6R7, NR5COR8, NR5CONR6R7 heterocyclyl, heteroaryl, cycloalkyl or aryl, (c) CN, (d) NR6R7, (e) CONR6R7, (f) NHCONR6R7, (g) aryl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, OR5, NR6R7, halogen, CN, CONR6R7, SO2- alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl, or NHCONR6R7, (h) heterocyclyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, OR5, NR6R7, halogen, CN, CONR6R7, SO2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl, or NHCONR6R7,
    22/62 (i) heteroaryl optionally substituted with one or more substituents independently selected from C1-C 6 alkyl, OR5, NR6R7, halogen, CN, CONR6R7, SO 2 -alkyl, SO 2 -aryl, OSO2-alkyl, OSO2 -aryl, or NHCONR6R7, (j) cycloalkyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, OR5, NR6R7, halogen, CN, CONR6R7, SO2-alkyl, SO2-aryl, OSO2-alkyl, OSO2 -aryl, or NHCONR6R7, (k) cycloalkyl substituted with C1-C 6 alkyl where C1C6 alkyl is also substituted with one or more substituents independently selected from OR5, NR6R7, halogen, CN, or CONR6R7, or (l) OR8 ;
    R4 is:
    (a) hydrogen, (b) C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen, OR5, CN, COOR5, CONR6R7, NR6R7, NR5COR8, heterocyclyl, heteroaryl, cycloalkyl or aryl, (c) aryl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, OR5, NR6R7, halogen, CN, CONR6R7, SO2-alkyl, SO2-aryl, OSO2alkyl, OSO2-aryl, or NHCONR6R7, (d) optionally substituted heterocyclyl with one or more substituents independently selected from C1-C6 alkyl, OR5, NR6R7, halogen, CN, CONR6R7, SO2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl, or NHCONR6R7, (e) optionally substituted heteroaryl with one or more substituents independently selected from C1-C6 here
    23/62 la, OR 5 , NR 6 R 7 , halogen, CN, CONR 6 R 7 , SO 2 -alkyl, SO 2 -aryl, OSO 2 -alkyl, OSO 2 -aryl, or NHCONR 6 R 7 , or ( f) cycloalkyl optionally substituted with one or more substituents independently selected from C1-C 6 alkyl, OR5, NR6R7, halogen, CN, CONR6R7, SO2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl, or NHCONR6R7;
    R 5 and R8 are each independently:
    (a) hydrogen, or (b) C1-C 6 alkyl optionally substituted with one or more substituents independently selected from halogen, CN, CONR6R7, NR6R7, heterocyclyl, heteroaryl, cycloalkyl or aryl;
    R 6 and R 7 are each independently:
    (a) hydrogen, (b) C1-C 6 alkyl optionally substituted with one or more substituents independently selected from halogen, OR5, CN, COOR5, CONR5R8, NR5R8, NR5COR8, heterocyclyl, heteroaryl, cycloalkyl or aryl, (c) aryl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, OR5, NR5R8, halogen, CN, CONR5R8, SO2-alkyl, SO2-aryl, OSO2alkyl, OSO2-aryl, or NHCONR5R8, (d) optionally heterocyclyl substituted with one or more substituents independently selected from C1-C6 alkyl, OR5, NR5R8, halogen, CN, CONR5R8, SO2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl, or NHCONR5R8, (e) optionally heteroaryl substituted with one or more substituents independently selected from C1-C6 alkyl, OR5, NR5R8, halogen, CN, CONR5R8, SO2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl, or NHCONR5R8,
    24/62 (f) cycloalkyl optionally substituted with one or more substituents independently selected from C1-C 6 alkyl, OR5, NR5R8, halogen, CN, CONR5R8, SO 2 -alkyl, SO 2 -aryl, OSO 2 -alkyl, OSO 2 -aryl, or NHCONR5R8, or (g) R 6 and R7 are joined together to form a four to seven membered ring.
    [0057] Non-limiting examples, typical of compounds according to the invention include:
    (2S, 5R) -7-oxo-N - [(2S) -pyrrolidin-2-ylmethyloxy] -6- (sulphoxy) -
    1,6-diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -7-oxo-N - [(2R) -pyrrolidin-2-ylmethyloxy] -6- (sulphoxy) -
    1,6-diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -7-oxo-N - [(3S) -pyrrolidin-3-ylmethyloxy] -6- (sulphoxy) -
    1,6-diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -7-oxo-N - [(3R) -pyrrolidin-3-ylmethyloxy] -6- (sulphoxy) -
    1,6-diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -N - {[(2S, 4R) -4-hydroxyl-pyrrolidin-2-yl] methyloxy} -7-oxo-
    6- (sulfo-oxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -N - {[(2S, 4R) -4-cyano-pyrrolidin-2-yl] methyloxy} -7-oxo-6 (sulphoxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -N - {[(5R) -5-cyanopyrrolidin-2-yl] methyloxy} -7-oxo-6 (sulphoxy) -1,6-diazabicyclo [3.2.1] octane-2- carboxamide;
    (2S, 5R) -N - {[(SR) -5-cyanopyrrolidin-2-yl] methyloxy} -7-oxo-6 (sulphoxy) -1,6-diazabicyclo [3.2.1] octane-2- carboxamide;
    (2S, 5R) -N - {[(2S, 4R) -4-trifluoroacetylamino-pyrrolidin-2yl] methyloxy} -7-oxo-6- (sulphoxy) -1,6-diazabicyclo [3.2.1] octane -2carboxamide;
    (2S, 5R) -N - {[(2S) -1-carbamimidoyl-pyrrolidin-2-yl] methyloxy} -7oxo-6- (sulphoxy) -1,6-diazabicyclo [3.2.1] octane-2 -carboxamide;
    25/62 (2S, 5R) -7-oxo-N- {1 - [(2S) -pyrrolidin-2-yl] ethyloxy} -6- (sulphoxy) -
    1,6-diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -7-oxo-N - {[(2S) -5-oxopyrrolidin-2-yl] methyloxy} -6- (sulphoxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide ;
    (2S, 5R) -N - [(2S) -azetidin-2-ylmethyloxy] -7-oxo-6- (sulphoxy) -1,6 diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -N - [(2R) -azetidin-2-ylmethyloxy] -7-oxo-6- (sulphoxy) -1,6 diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -7-oxo-N- (piperidin-4-ylmethyloxy) -6- (sulphoxy) -1,6 diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -7-oxo-N - (((3R, S) -piperidin-3-ylmethyloxy) -6- (sulfo-oxy) -
    1,6-diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -7-oxo-N - (((2R, S) piperidin-2-ylmethyloxy) -6- (sulfo-oxy) -
    1,6-diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -7-oxo-N - ((2S) piperidin-2-ylmethyloxy) -6- (sulphoxy) -
    1,6-diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -7-oxo-N - ((2S) piperidin-2-ylmethyloxy) -6- (sulphoxy) -
    1,6-diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -7-oxo-N- {1 - [(2S) -piperidin-2-yl] ethyloxy} -6- (sulphoxy) -
    1,6-diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -N- (azepan-2-ylmethyloxy) -7-oxo-6- (sulpho-oxy) -1,6 diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S) -N- (2,3-dihydro-1H-indol-2-ylmethyloxy) -7-oxo-6- (sulphoxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -N - {[(2R, S) -1,2,3,4-tetrahydro-quinolin-2-yl] methyloxy} -
    7-oxo-6- (sulfo-oxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -N - {[(3S) -1,2,3,4-tetrahydro-isquinolin-3-yl] methyloxy} 7-oxo-6- (sulphoxy) -1,6- diazabicyclo [3.2.1] octane-2-carboxamide;
    26/62 (2S, 5R) -N - {[(4S) -1-methyl-1,4,5,6-tetrahydropyrrolo [3,4-
    c] pyrazol-4-yl] methoxy} -7-oxo-6- (sulfo-oxy) -1,6-diazabicyclo [3.2.1] octane2-carboxamide;
    (2S, 5R) -N - {[(4S) -1 H-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol4-yl] methyloxy} -7-oxo-6- (sulfo -oxy) -1,6-diazabicyclo [3.2.1] octane-2carboxamide;
    (2S) -N - [(4,5-dihydroxy-1,4-di-idropyridin-2-yl) methyloxy] -7-oxo6- (sulphoxy) -1,6-diazabicyclo [3.2.1 ] octane-2-carboxamide;
    (2S, 5R) -7-oxo-N - {[(4S) -2- (2-hydroxyphenyl) -4,5-dihydro-1,3oxazol-4-yl] methyloxy} -6- (sulfo- oxy) -1,6-diazabicyclo [3.2.1] octane-2carboxamide;
    (2S, 5R) -7-oxo-N - {[(4S) -2 - ((2S) -pyrrolidin-2-yl) -4,5-dihydro-
    1,3-oxazol-4-yl] methyloxy} -6- (sulfo-oxy) -1,6-diazabicyclo [3.2.1] octane-2carboxamide;
    (2S, 5R) -7-oxo-N - [(3R, S) -pyrrolidin-3-yloxy] -6- (sulphoxy) -1,6 diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -7-oxo-N - [(3S) -pyrrolidin-3-yloxy] -6- (sulphoxy) -1,6 diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -7-oxo-N - [(3R) -pyrrolidin-3-yloxy] -6- (sulphoxy) -1,6 diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -N - {[(3R, 5S) -5-cyanopyrrolidin-3-yl] oxy} -7-oxo-6- (sulphoxy) -1,6-diazabicyclo [3.2.1] octane-2 -carboxamide;
    (2S, 5R) -N - {[(3S, 5S) -5-cyanopyrrolidin-3-yl] oxy} -7-oxo-6- (sulphoxy) -1,6-diazabicyclo [3.2.1] octane-2 -carboxamide;
    (2S, 5R) -N - {[(3R, 5S) -5-carbamoylpyrrolidin-3-yl] oxy} -7-oxo-6 (sulfo-oxy) -1,6-diazabicyclo [3.2.1] octane- 2-carboxamide;
    (2S, 5R) -N- (azetidin-3-yloxy) -7-oxo-6- (sulpho-oxy) -1,6 diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -N-methyloxy-7-oxo-N- (piperidin-2-ylmethyl) -6- (sulphoxy) -
    1,6-diazabicyclo [3.2.1] octane-2-carboxamide;
    27/62 (2S, 5R) -N-methyloxy-7-oxo-N- (piperidin-3-ylmethyl) -6- (sulphoxy) -
    1,6-diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -N-methyloxy-7-oxo-N- (pyrrolidin-2-ylmethyl) -6- (sulphoxy) -
    1,6-diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -N - [(2S) -azetidin-2-ylmethyl] -N-hydroxy-7-oxo-6- (sulphoxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -N-hydroxy-7-oxo-N - [(2S) -pyrrolidin-2-ylmethyl] -6- (sulphoxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -N-hydroxy-7-oxo-N - [(2S) -piperidin-2-ylmethyl] -6- (sulphoxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -N - [(2S) -azepan-2-ylmethyl] -N-hydroxy-7-oxo-6- (sulphoxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -N - [(2R) -azetidin-2-ylmethyl] -N-hydroxy-7-oxo-6- (sulphoxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -N-hydroxy-7-oxo-N - [(2R) -pyrrolidin-2-ylmethyl] -6- (sulphoxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -N-hydroxy-7-oxo-N - [(2R) -piperidin-2-ylmethyl] -6- (sulphoxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -N - [(2R) -azepan-2-ylmethyl] -N-hydroxy-7-oxo-6- (sulphoxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide;
    or a stereoisomer or a pharmaceutically acceptable salt thereof.
    [0058] Non-limiting examples, typical of various salt forms of the compounds according to the invention include:
    (2S, 5R) -N - [(2S) -azetidin-2-ylmethyl] -N-hydroxy-7oxo-6- (sulpho-oxy) -1,6-diazabicyclo [3.2.1] octane-2 sodium salt -carboxamide;
    (2S, 5R) -N-hydroxy-7-oxo-N - [(2S) -pyrrolidin-2ylmethyl] -6- (sulfo-oxy) -1,6-diazabicyclo [3.2.1] octane-2 sodium salt -carboxamide;
    (2S, 5R) -N-hydroxy-7-oxo-N - [(2S) -piperidin-2ylmethyl] -6- (sulfo-oxy) -1,6-diazabicyclo [3.2.1] octane-2 sodium salt -carboxamide;
    28/62
    (2S, 5R) -N - [(2S) -azepan-2-ylmethyl] -N-hydroxy-7oxo-6- (sulpho-oxy) -1,6-diazabicyclo [3.2.1] octane-2 sodium salt -carboxamide;
    (2S, 5R) -N - [(2R) -azetidin-2-ylmethyl] -N-hydroxy7-oxo-6- (sulpho-oxy) -1,6-diazabicyclo [3.2.1] octane-2 sodium salt -carboxamide;
    (2S, 5R) -N-hydroxy-7-oxo-N - [(2R) -pyrrolidin-2ylmethyl] -6- (sulfo-oxy) -1,6-diazabicyclo [3.2.1] octane-2 sodium salt -carboxamide;
    (2S, 5R) -N-hydroxy-7-oxo-N - [(2R) -piperidin-2ylmethyl] -6- (sulfo-oxy) -1,6-diazabicyclo [3.2.1] octane-2 sodium salt -carboxamide;
    (2S, 5R) -N - [(2R) -azepan-2-ylmethyl] -N-hydroxy-7oxo-6- (sulpho-oxy) -1,6-diazabicyclo [3.2.1] octane-2 sodium salt -carboxamide;
    (2S, 5R) -7-oxo-N - [(2S) -pyrrolidin-2-ylmethyloxy] 6- (sulpho-oxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide sodium salt;
    (2S, 5R) -7-oxo-N - [(2R) -pyrrolidin-2-ylmethyloxy] 6- (sulphoxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide sodium salt;
    (2S, 5R) -7-oxo-N - [(3S) -pyrrolidin-3-ylmethyloxy] 6- (sulpho-oxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide sodium salt;
    (2S, 5R) -7-oxo-N - [(3R) -pyrrolidin-3-ylmethyloxy] 6- (sulphoxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide sodium salt;
    (2S, 5R) -N - {[(2S, 4R) -4-hydroxyl-pyrrolidin-2yl] methyloxy} -7-oxo-6- (sulphoxy) -1,6-diazabicycle [3.2. 1] octane-2carboxamide;
    (2S, 5R) -N - {[(2S, 4R) -4-cyanol-pyrrolidin-2yl] methyloxy} -7-oxo-6- (sulphoxy) -1,6-diazabicycle [3.2. 1] octane-2carboxamide;
    (2S, 5R) -N - {[(5R) -5-cyanopyrrolidin-2yl] methyl salt} -7-oxo-6- (sulfo-oxy) -1,6-diazabicyclo [3.2.1] octane- 2carboxamide;
    (2S, 5R) -N - {[(SR) -5-cyanopyrrolidin-2yl] methyl salt} -7-oxo-6- (sulpho-oxy) -1,6-diazabicyclo [3.2.1] octane- 2carboxamide;
    29/62
    (2S, 5R) -N - {[(2S, 4R) -4-trifluoroacetylaminopyrrolidin-2-yl] methyloxy} -7-oxo-6- (sulphoxy) -1,6-diazabicycle [3.2. 1] octane2-carboxamide;
    (2S, 5R) -N - {[(2S) -1-carbamimidoyl-pyrrolidin-2yl] methyloxy} -7-oxo-6- (sulphoxy) -1,6-diazabicyclo [3.2.1] octane-2carboxamide;
    (2S, 5R) -7-oxo-N- {1 - [(2S) -pyrrolidin-2-yl] ethyloxy} 6- (sulphoxy) -1,6-diazabicyclo [3.2.1] octane sodium salt -2-carboxamide;
    (2S, 5R) -7-oxo-N - {[(2S) -5-oxopyrrolidin-2yl] methyloxy} -6- (sulphoxy) -1,6-diazabicyclo [3.2.1] octane- 2-carboxamide;
    (2S, 5R) -N - [(2S) -azetidin-2-ylmethyloxy] -7-oxo-6 (sulphoxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide sodium salt;
    (2S, 5R) -N - [(2R) -azetidin-2-ylmethyloxy] -7-oxo-6 (sulfo-oxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide sodium salt;
    (2S, 5R) -7-oxo-N- (piperidin-4-ylmethyloxy) -6 (sulphoxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide sodium salt;
    (2S, 5R) -7-oxo-N - ((3R, S) -piperidin-3ylmethyloxy) -6- (sulpho-oxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide sodium salt ;
    (2S, 5R) -7-oxo-N - ((2R, S) piperidin-2-ylmethyloxy) 6- (sulpho-oxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide sodium salt ;
    (2S, 5R) -7-oxo-N - ((2S) piperidin-2-ylmethyloxy) -6 (sulfo-oxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide sodium salt;
    (2S, 5R) -7-oxo-N - ((2S) piperidin-2-ylmethyloxy) -6 (sulfo-oxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide sodium salt;
    (2S, 5R) -7-oxo-N- {1 - [(2S) -piperidin-2-yl] ethyloxy} 6- (sulphoxy) -1,6-diazabicyclo [3.2.1] octane sodium salt -2-carboxamide;
    (2S, 5R) -N- (azepan-2-ylmethyloxy) -7-oxo-6 (sulphoxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide sodium salt;
    (2S) -N- (2,3-dihydro-1H-indol-2-ylmethyloxy) -7oxo-6- (sulphoxy) -1,6-diazabicyclo [3.2.1] octane-2 sodium salt -carboxamide;
    30/62
    (2S, 5R) -N - {[(2R, S) -1,2,3,4-tetrahydroquinolin-2-yl] methyloxy} -7-oxo-6- (sulfo-oxy) - sodium salt - 1,6-diazabicyclo [3.2.1] octane2-carboxamide;
    (2S, 5R) -N - {[(3S) -1,2,3,4-tetrahydroisquinolin-3-yl] methyloxy} -7-oxo-6- (sulphoxy) -1 -1 sodium salt, 6diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -N - {[(4S) -1-methyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-4-yl] methoxy} -7-oxo- 6- (sulfo-oxy) -1,6 diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -N - {[(4S) -1H-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-4-yl] methyloxy} -7-oxo-6- (sulfo-oxy) -1,6 diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S) -N - [(4,5-dihydroxy-1,4-dihydropyridin-2yl) methyloxy] -7-oxo-6- (sulphoxy) -1,6-diazabicyclo [ 3.2.1] octane-2carboxamide;
    (2S, 5R) -7-oxo-N - {[(4S) -2- (2-hydroxyphenyl) -4,5dihydro-1,3-oxazol-4-yl] methyloxy} -6- (sulfo-oxy) -1,6 diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -7-oxo-N - {[(4S) -2 - ((2S) -pyrrolidin-2-yl) - sodium salt -
    4,5-dihydro-1,3-oxazol-4-yl] methyloxy} -6- (sulphoxy) -1,6 diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -7-oxo-N - [(3R, S) -pyrrolidin-3-yloxy] -6 (sulfo-oxy) -1,6-diazabicyclo [3.2.1] octane-2- sodium salt carboxamide;
    (2S, 5R) -7-oxo-N - [(3S) -pyrrolidin-3-yloxy] -6 (sulfo-oxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide sodium salt;
    (2S, 5R) -7-oxo-N - [(3R) -pyrrolidin-3-yloxy] -6 (sulfo-oxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide sodium salt;
    (2S, 5R) -N - {[(3R, 5S) -5-cyanopyrrolidin-3-yl] oxy} 7-oxo-6- (sulfo-oxy) -1,6-diazabicyclo [3.2.1 ] octane-2-carboxamide;
    31/62
    (2S, 5R) -N - {[(3S, 5S) -5-cyanopyrrolidin-3-yl] oxy} 7-oxo-6- (sulfo-oxy) -1,6-diazabicyclo [3.2.1 ] octane-2-carboxamide;
    (2S, 5R) -N - {[(3R, 5S) -5-carbamoylpyrrolidin-3yl] oxy} -7-oxo-6- (sulfo-oxy) -1,6-diazabicycle [3.2.1] octane-2-carboxamide;
    (2S, 5R) -N- (azetidin-3-yloxy) -7-oxo-6- (sulphoxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide sodium salt;
    (2S, 5R) -N-methyloxy-7-oxo-N- (piperidin-2ylmethyl) -6- (sulphoxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide sodium salt;
    (2S, 5R) -N-methyloxy-7-oxo-N- (piperidin-3ylmethyl) -6- (sulphoxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide sodium salt;
    (2S, 5R) -N-methyloxy-7-oxo-N- (pyrrolidin-2ylmethyl) -6- (sulfo-oxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide sodium salt;
    (2S, 5R) -N- (2-aminoethyloxy) 7-oxo-6- (sulphoxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide trifluoroacetic acid salt;
    (2S, 5R) -N- (2carbamimidamidoethyloxy) -7-oxo-6- (sulphoxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide trifluoroacetic acid salt;
    (2S, 5R) -N- (3 aminopropyloxy) -7-oxo-6- (sulphoxy) -1,6-diazabicyclo [3.2.1] octane-2carboxamide trifluoroacetic acid salt;
    (2S, 5R) -N - {[(2S) -2,5 diaminopentyl] oxy} -7-oxo-6- (sulpho-oxy) -1,6-diazabicyclo [3.2.1] octane- trifluoroacetic acid salt 2carboxamide;
    (2S, 5R) -N - {[(2S, 4R) -4aminopyrrolidin-2-yl] methyloxy} -7-oxo-6- (sulphoxy) -1,6-diazabicyclo [3.2.1] trifluoroacetic acid salt octane-2-carboxamide;
    (2S, 5R) -7-oxo-N - [(2S) piperazin-2-ylmethyloxy] -6- (sulphoxy) -1,6-diazabicyclo [3.2.1] octane-2carboxamide trifluoroacetic acid salt;
    32/62
    (2S, 5R) -N-methyloxy-7-oxo-N (piperazin-2-ylmethyl) -6- (sulphoxy) -1,6-diazabicyclo [3.2.1] octane-2carboxamide trifluoroacetic acid salt;
    (2S, 5R) -N-methoxy-N-methyl-7-oxo-6- (sulfo-oxy) - sodium salt -
    1,6-diazabicyclo [3.2.1] octane-2-carboxamide;
    (2S, 5R) -N-methoxy-7-oxo-6- (sulpho-oxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide sodium salt;
    (2S, 5R) -N-hydroxy-7-oxo-6- (sulpho-oxy) -1,6-diazabicyclo [3.2.1] octane-2-carboxamide sodium salt;
    (2S, 5R) -N - [(1-methyl-1H-pyrazol-5-yl) methyloxy] -7oxo-6- (sulpho-oxy) -1,6-diazabicyclo [3.2.1] octane- sodium salt 2-carboxamide;
    (2S, 5R) -N-hydroxy-N-methyl-7-oxo-6- (sulfo-oxy) - sodium salt -
    1,6-diazabicyclo [3.2.1] octane-2-carboxamide;
    or a stereoisomer thereof.
    [0059] In general, the compounds of the invention can be prepared according to the following procedures. A person skilled in the art would appreciate that the methods described can be varied or optimized as well to provide the desired and related compounds. In the following procedures, all variables are as defined above.
    [0060] As described in Scheme-1, trans-6-benzyloxy-7oxo-1,6-diaza-bicyclo [3.2.1] octane-2-carboxylic acid (1a), which is described in PCT International Publication No. WO 2009/091856, was reacted with corresponding substituted hydroxylamines in the presence of a suitable coupling agent such as EDC hydrochloride, or dicyclohexylcarbodiimide (DCC) in a suitable solvent such as N, N dimethyl formamide; N, N dimethyl acetamide; 1.4 dioxane; chloroform; dichloromethane; or dichloroethane at a temperature ranging from -15 ° C to 60 ° C for about 1 to 24 hours to obtain the intermediate compound (1b).
    33/62
    O
    HO
    O, O. Λ
    R3 N
    R2
    O
    R3
    Formation of sodium salt „o„ Λ
    R3 N
    R2
    Sulphonating agent then BU4NHSO4
    Ο Λ
    R3 N
    R2
    OSO 3 NBu 4
    1d
    1c O
    O
    R = H or Na 'oso 3 r
    OH
    CF3COOH (when R2, R3 contains t-Boc-amino group)
    Scheme 1 [0061] The intermediate compound (1b) was subjected to hydrogenolysis in the presence of a suitable catalyst (for example, 5% or 10% palladium on carbon, or 20% palladium hydroxide on carbon) in the presence of a source of hydrogen (such as hydrogen gas, ammonium formate, cyclohexene) in a suitable solvent (such as methanol, ethanol, methanol-dichloromethane mixture, or N, N dimethyl formamide-dichloromethane mixture) at a temperature ranging from 25 ° C to 60 ° C for about 1 to 14 hours to obtain the intermediate compound (1c).
    [0062] The intermediate compound (1c) was sulfonated by reacting it with a sulfonation reagent (such as sulfur pyridine trioxide complex, or sulfur trioxide-N complex, N-dimethyl formamide) in a suitable solvent (such as pyridine , N, N-dimethyl formamide) at a temperature ranging from about 25 ° C to 90 ° C for about 1 to 24 hours to obtain sulfonic acid pyridine salt which when treated with tetrabutyl ammonium sulfate provided tetrabutylammonium salt of sulfonic acid as an intermediate compound (1d).
    34/62 [0063] Some compounds according to the invention were isolated as zwitterions, the intermediate compound (1d) being treated with trifluoroacetic acid, in a suitable solvent (such as dichloromethane, chloroform, acetonitrile) at a temperature ranging from - 10 ° C to 40 ° C for about 1 to 14 hours, especially when R in the intermediate compound (1d) contained the amine function protected by tert-butoxycarbonyl.
    [0064] Some other compounds according to the invention were isolated as a sodium salt, passing a solution of the intermediate compound (1d) through a column of sodium form of Amberlite resin 200C in a mixture of tetrahydrofuran-water followed by evaporation of solvent under vacuum.
    [0065] The required substituted hydroxyl amines were prepared as shown in Scheme-2 as described in Synthesis 6824 (1976) and US patent 5,120,849 (1992), OH
    R3
    DEAD, TPP, RT
    H 2 N-NH 2 __, ONH 2
    R3 2 [0066] In some embodiments, pharmaceutical compositions are provided comprising a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof.
    [0067] In some other embodiments, a method is provided to prevent or treat bacterial infection in an individual, said method comprising administering to said individual a pharmaceutically effective amount of a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt the same.
    [0068] In some embodiments, a method is provided to prevent or treat a bacterial infection in an individual, said infection being caused by bacteria producing one or more beta-lactamase enzymes, wherein the method comprises administering to the
    35/62 said individual a pharmaceutically effective amount of a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof.
    [0069] In some other embodiments, a method is provided to prevent or treat bacterial infection in an individual, said method comprising administering to said individual a pharmaceutically effective amount of a pharmaceutical composition comprising a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof.
    [0070] In some other embodiments, a method is provided to prevent or treat a bacterial infection in an individual, said infection being caused by bacteria producing one or more beta-lactamase enzymes, wherein the method comprises administering to said individual an pharmaceutically effective amount of a pharmaceutical composition comprising a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof.
    [0071] In some embodiments, pharmaceutical compositions are provided comprising: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one beta-lactamase inhibitor selected from sulbactam , tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof.
    [0072] In some other embodiments, pharmaceutical compositions are provided comprising: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative the same.
    [0073] In some other embodiments, pharmaceutical compositions are provided comprising: (a) a compound of Formula (I),
    36/62 or a stereoisomer or a pharmaceutically acceptable salt thereof, (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof, and (c) at least one agent antibacterial or a pharmaceutically acceptable derivative thereof. [0074] In some other embodiments, a method is provided to prevent or treat bacterial infection in an individual, said method comprising administering to said individual a pharmaceutically effective amount of a pharmaceutical composition comprising: (a) a compound of Formula (I) , or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof.
    [0075] In some other embodiments, a method is provided to prevent or treat a bacterial infection in an individual, said infection being caused by bacteria producing one or more beta-lactamase enzymes, wherein the method comprises administering to said individual an pharmaceutically effective amount of a pharmaceutical composition comprising: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof.
    [0076] In some other embodiments, a method is provided to prevent or treat bacterial infection in an individual, said method comprising administering to said individual a pharmaceutically effective amount of a pharmaceutical composition comprising: (a) a compound of Formula (I) , or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at
    37/62 minus an antibacterial agent or a pharmaceutically acceptable derivative thereof.
    [0077] In some other embodiments, a method is provided to prevent or treat a bacterial infection in an individual, said infection being caused by bacteria producing one or more beta-lactamase enzymes, wherein the method comprises administering to said individual an pharmaceutically effective amount of a pharmaceutical composition comprising: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
    [0078] In some other embodiments, a method is provided to prevent or treat bacterial infection in an individual, said method comprising administering to said individual a pharmaceutically effective amount of a pharmaceutical composition comprising: (a) a compound of Formula (I) , or a stereoisomer or a pharmaceutically acceptable salt thereof, (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof, and (c) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
    [0079] In some other embodiments, a method is provided to prevent or treat a bacterial infection in an individual, said infection being caused by bacteria producing one or more beta-lactamase enzymes, wherein the method comprises administering to said individual an pharmaceutically effective amount of a pharmaceutical composition comprising: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid
    38/62 co, or a pharmaceutically acceptable derivative thereof, and (c) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
    [0080] In some other embodiments, a method is provided to prevent or treat bacterial infection in an individual, said method comprising administering to said individual a pharmaceutically effective amount of: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof.
    [0081] In some other embodiments, a method is provided to prevent or treat a bacterial infection in an individual, said infection being caused by bacteria producing one or more beta-lactamase enzymes, wherein the method comprises administering to said individual an pharmaceutically effective amount of: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof.
    [0082] In some other embodiments, a method is provided to prevent or treat bacterial infection in an individual, said method comprising administering to said individual a pharmaceutically effective amount of: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
    [0083] In some other modalities, a method is provided to prevent or treat a bacterial infection in an individual, the
    Said infection being caused by bacteria producing one or more beta-lactamase enzymes, wherein the method comprises administering to said individual a pharmaceutically effective amount of: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
    [0084] In some other embodiments, a method is provided to prevent or treat bacterial infection in an individual, said method comprising administering to said individual a pharmaceutically effective amount of: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof, and (c) at least one antibacterial agent or pharmaceutically acceptable derivative the same.
    [0085] In some other embodiments, a method is provided to prevent or treat a bacterial infection in an individual, said infection being caused by bacteria producing one or more beta-lactamase enzymes, wherein the method comprises administering to said individual an pharmaceutically effective amount of: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, or a derivative pharmaceutically acceptable thereto, and (c) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
    [0086] In some embodiments, methods are provided to increase the antibacterial effectiveness of an antibacterial agent in an individual, said method comprising co-administering said
    40/62 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.
    [0087] In some embodiments, the compositions and methods according to the invention use compounds of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof in combination with at least one antibacterial agent or a pharmaceutically acceptable derivative thereof. A wide variety of antibacterial agents can be used. Typical, non-limiting examples of antibacterial agents include one or more of antibacterial compounds generally classified as aminoglycosides, Ansamycins, Carbacefens, Cephalosporins, Cefamycins, Lincosamides, Lipopeptides, Macrolides, Monobactans, Nitrofurans, Penicillins, Polypeptides, Quinolones, Quinolonas, Sulkinonidases, Quinolonas, similar.
    [0088] Non-limiting examples, typical of Aminoglycoside antibacterial agents include Amikacin, Gentamycin, Kanamycin, Neomycin, Netylmycin, Tobramycin, Paromomycin, Arbecacin, Streptomycin, Apramycin and the like.
    [0089] Non-limiting examples, typical of Ansamycin antibacterial agents include Geldanamycin, Herbimycin and the like.
    [0090] Non-limiting examples, typical of Carbacefem antibacterial agents include Loracarbefe and the like.
    [0091] Non-limiting examples typical of Carbapenem antibacterial agents include Ertapenem, Doripenem, Imipenem, Meropenem and the like.
    [0092] Non-limiting examples, typical of Cephalosporin and Cefamycin antibacterial agents include Cefazolin, Cefacetril, Cefadroxila, Cefalexina, Cefaloglicina, Cefalonio, Cefaloridina, Cefalotina,
    41/62
    Cefapyrine, Cefatrizine, Cefazedlone, Cefazaflur, Cefradin, Cefroxadine, Ceftezol, Cefaclor, Cefamandol, Cefminox, Cefonicide, Ceforanide, Cefotiam, Cefprozila, Cefbefazine, Cefbefazone, Cefbuperzone, Cefbefazone Cefcapene, Cefdaloxime, Cefdinir, Cefditoren, Cefetamethox, Cefmenoxime, Cefodizime, Cefoperazone, Cefotaxime, Cefpimizole, Cefpiramide, Cefpodoxime, Cefsulodyne, Cefteram, Cefibutime, Cefypozepine, Cefypozepine, Cefoxime, Cefoxime, Cefoxime, Cefoxime, Cefoxime Cefovecin, CXA-101, Ceftaroline, Ceftobiprol etc.
    [0093] Non-limiting examples, typical of antibiotic agents of Lincosamide include Clindamycin, Lincomycin and the like.
    [0094] Non-limiting examples, typical of Macrolide antibacterial agents include Azithromycin, Clarithromycin, Dirithromycin, Erythromycin, Roxithromycin, Troleandomycin, Telithromycin, Spectinomycin, Solithromycin and the like.
    [0095] Non-limiting examples, typical of Monobactam antibacterial agents include Aztreonam and the like.
    [0096] Non-limiting examples, typical of antibacterial Nitrofuran agents include Furazolidone, Nitrofurantoin and the like.
    [0097] Non-limiting examples, typical of Penicillin antibacterial agents include Amoxicillin, Ampicillin, Azlocillin, Carbenicillin, Cloxacillin, Dicloxacillin, Flucloxacillin, Mezlocillin, Methicillin, Nafcilin, Oxyacillin, Penicillin, Tilicillin, Penicillin, Tilicillin, Penicillin, Piacillin, Penicillin, Penicillin, Penicillin,
    [0098] Non-limiting examples, typical of antibacterial Polypeptide agents include Bacitracin, Colistin, Polymyxin B and the like.
    [0099] Non-limiting examples, typical of Quinolone antibacterial agents include Ciprofloxacin, Enoxacin, Gatifloxacin, Levo
    42/62 floxacin, Lomefloxacin, Moxifloxacin, Nalidixic acid, Levonadifloxacin, Norfloxacin, Ofloxacin, Trovafloxacin, Grepafloxacin, Sparfloxacin, Temafloxacin and the like.
    [00100] Non-limiting examples, typical of Sulfonamide antibacterial agents include Mafenide, Sulfonamidocrisoidina, Sulfacetamida, Sulfadiazina, Sulfametizol, Sulfametoxazol, Sulfasalazina, Sulfisoxazol, Trimetoprim and the like.
    [00101] Non-limiting examples, typical of Tetracycline antibacterial agents include Demeclocycline, Doxycycline, Minocycline, Oxytetracycline, Tetracycline, Tigecycline and the like.
    [00102] Non-limiting examples, typical of Oxazolidinone antibacterial agents include Tedizolid, Linezolid, Ranbezolid, Torezolid, Radezolid, etc.
    [00103] The pharmaceutical compositions according to the invention can include one or more pharmaceutically acceptable diluents or excipients or the like. Non-limiting, typical examples of such diluents or excipients include mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, magnesium carbonate, wetting agents, emulsifying agents, agents solubilizing agents, pH buffering agents, lubricants, stabilizing agents, binding agents etc.
    [00104] The pharmaceutical compositions according to this invention can exist in various forms. In some embodiments, the pharmaceutical composition is in the form of a powder or a solution. In some other embodiments, the pharmaceutical compositions according to the invention are in the form of a powder that can be reconstituted by adding a compatible reconstitution diluent prior to parenteral administration. Non-limiting examples of such a compatible reconstitution diluent include water.
    [00105] In some other embodiments, 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.
    [00106] In some other embodiments, the pharmaceutical compositions according to the invention are in ready-to-use form for parenteral administration.
    [00107] In the methods according to the invention, the pharmaceutical composition and / or other pharmaceutically active ingredients described herein can be administered by any appropriate method, which serves to release the composition or its constituents or the active ingredients to the desired site. The method of administration can vary depending on several 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 micro-organism (eg, bacteria) involved, severity of infection, age and physical condition of the individual. Some non-limiting examples of administering the composition to an individual according to this invention include oral, intravenous, topical, intraspiratory, intraperitoneal, intramuscular, parenteral, sublingual, transdermal, intranasal, aerosol, intraocular, intratracheal, intrarectal, vaginal, gene gun , dermal plaster, eye drops, ear drops or mouthwashes.
    [00108] The compositions according to the invention can be formulated in various dosage forms in which the active ingredients and / or excipients can be present together (for example, as a mixture) or as separate components. When the various ingredients in the composition are formulated as a mixture, such a composition can be released by administering such a mixture. The composition or dosage form in which the ingredients do not come as a mixture, but come as separate components, such as
    44/62 composition / dosage form can be administered in several ways. In a possible way, the ingredients can be mixed in the desired proportions and the mixture is then administered when required. Alternatively, the components or ingredients (active or inert) can be administered separately (simultaneously or one after the other) in an appropriate proportion to obtain the same or equivalent therapeutic level or the effect would have been obtained by administering the equivalent mixture.
    [00109] Similarly, in the methods according to the invention, the active ingredients described here can be administered to an individual in several ways depending on the requirements. In some embodiments, the active ingredients are mixed in appropriate amounts and then the mixture is administered to an individual. In some other embodiments, the active ingredients are administered separately. Since the invention considers that the active ingredient agents can be administered separately, the invention also provides the combination of separate pharmaceutical compositions in kit form. The kit can comprise one or more separate pharmaceutical compositions, each comprising one or more active ingredients. Each of such separate compositions can be present in a separate container such as a vial, vial, syringe, box, pouch, and the like. Typically, 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 (for example, oral and parenteral) or are administered at different dosage intervals. When the active ingredients are administered separately, they can be administered simultaneously or sequentially.
    45/62 [00110] The pharmaceutical composition or active ingredients according to the present invention can be formulated in a variety of dosage forms. Non-limiting, typical examples of 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 the like.
    [00111] In general, the pharmaceutical compositions and methods described here are useful in preventing or treating bacterial infections. Advantageously, the compositions and methods described herein are likewise effective in preventing or treating infections caused by bacteria that should be considered less or not susceptible to one or more of the known antibacterial agents or their known compositions. Some non-limiting examples of such known bacteria having developed resistance to various antibacterial agents include Acinetobacter, E. coli, Pseudomonas aeruginosa, Staphylococcus aureus, Enterobacter, Klebsiella, Citrobacter and the like. Other non-limiting examples of infections that can be prevented or treated using the compositions and / or methods of the invention include: skin and soft tissue infections, febrile neutropenia, urinary tract infection, intra-abdominal infections, respiratory tract infections, pneumonia ( nosocomial), bacterial meningitis, surgical infections, etc.
    [00112] Surprisingly, the compounds, compositions and methods according to the invention are likewise effective in preventing or treating bacterial infections that are caused by bacteria producing one or more beta-lactamase enzymes. The ability of the compositions and methods according to the present invention to treat such resistant bacteria with typical betalactam antibiotics represents a significant improvement in the art.
    46/62 [00113] In general, the compounds of Formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof according to the invention are likewise useful in increasing the antibacterial efficacy of an antibacterial agent in an individual. The antibacterial effectiveness of one or more antibacterial agents can be increased, for example, by co-administering said antibacterial agent or a pharmaceutically acceptable salt thereof with a pharmaceutically effective amount of a compound of Formula (I) or a stereoisomer or a pharmaceutically salt acceptable value according to the invention.
    [00114] It will be readily apparent to someone skilled in the art that various substitutions and modifications can be made to the invention described here without departing from the scope and spirit of the invention. For example, those skilled in the art will recognize that the invention can be practiced using a variety of different compounds within the generic descriptions described.
    EXAMPLES [00115] The following examples illustrate the modalities of the invention that are now better known. However, it should be understood that the following are only exemplary or illustrative of the application of the principles of the present invention. Numerous modifications and alternative compositions, methods and systems can be devised by those skilled in the art without departing from the spirit and scope of the present invention. The attached claims are intended to cover such modifications and provisions. Thus, while the present invention has been described above with particularity, the following examples provide more details with respect to what is now judged to be the most practical and preferred embodiments of the invention. Example-1
    47/62 (2S, 5R) -7-oxo-N - [(2S) -pyrrolidin-2-ylmethyloxy] -6- (sulphoxy) -1,6 diazabicyclo [3.2.1] octane-2-carboxamide
    Side chain preparation: tert-butyl (2S) -2 [(aminooxy) methyl] pyrrolidine-1 carboxylate:
    N H
    THF
    DEAD, TPP, RT


    H 2 N-NH 2
    Et ° H
    N
    ° nh 2
    Step-1 [00116] A solution of DEAD (17.14 ml, 1.092 mol) in THF (366 ml) was cooled to -10 ° C and to this was added a TPP solution slowly (22.49 gm, 1.092 mmol) in THF (36 ml). After stirring for 45 minutes below -10 ° C, a solution of tert-butyl (2S) -2- (hydroxymethyl) pyrrolidine-1-carboxylate (12.2 gm, 0.606 mol) in THF (36 ml) was added and after stirring for 5 minutes, a solution of N-Hydroxyphthalimide (9.88 gm, 0.606 mol) in THF (122 ml) was added. The resulting mixture was allowed to warm to RT and stirring was also continued. After 16 hours, the solvent was evaporated under reduced pressure, and the residue diluted with ethyl acetate (250 ml), and the ethyl acetate layer washed with saturated aqueous sodium bicarbonate solution. (1x122 ml), water (1x122 ml) and Brine (1x61 ml). The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel. Elution with 12% Acetone in hexane, and the concentration of the combined fractions produced the product as a pale yellow oil, 20.6 gm in
    98% yield.
    Analyze:
    48/62
    Mass: 347.3 (M + H) for MW-346.39 and MF- Ci 8 H 22 N 2 O 5
    Step-II:
    [00117] In a solution of Phthalimide (4 gm, 0.115 mol) in ethanol (60 ml), hydrazine hydrate (0.84 ml, 0.173 mol) in TA was added. After stirring for 1 hour, the insolubles were filtered off. The filtrate was concentrated under reduced pressure, and the residue was diluted with DCM (40 ml). The DCM layer was washed with water (2x40 ml) and brine (1x40 ml). The solvent was evaporated under reduced pressure to obtain 2.4 gm of residue. This was used as such for the next coupling reaction.
    Coupling reaction
    Step-1: Preparation of (2S, 5R) -2 - [(6benzyloxy-7-oxo-1,6-diaza-bicyclo [3.2.1] octane-2-carbonyl) methyloxycarbamoyl] - ( 2S) -pyrrolidine-1-carboxylic:

    O.
    nh 2
    the ho
    O
    OBn edc.hci, hobt, nmm, dmf, rt
    O O n
    O
    OBn [00118] In a clear solution of (2S, 5R) -6- (benzyloxy) -7-oxo-
    1,6-diazabicyclo [3.2.1] octane-2-carboxylic (3.06 gm, 0.111 mol) in N, N-dimethylformamide (24 ml), HOBt (1.49 gm, 0.111 mol) was added followed by hydrochloride of EDC (3.18 gm, 0.166 mol) and NMM (3.39, 0.333 mol) at approximately 25 ° C to 35 ° C with stirring. The reaction mixture was stirred for 15 minutes, and a 2-amino-oxymethyl- (S) -pyrrolidine-1-carboxylic acid solution (2.4 gm, 0.100 mol) dissolved in N, N-dimethylformamide (15 ml). The reaction mixture was stirred at a temperature between 25 ° C to 35 ° C for 16 hours, and the resulting mixture was poured into water (120 ml) and extracted from the mixture with Ethyl acetate (3 x 25 ml). The ethyl acetate layer was washed with water (1 x 100 ml) and brine (1 x 50 ml). The solvent was
    49/62 evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel. Elution with 10% acetone in hexane and concentration of the combined fractions produced the product as a white solid, 2.1 gm, 64% yield.
    Analyze:
    Mass: 475.4 (M + H) for MW-474.56 and MF - C24H34N4O6 1 H NMR: Solvent (CDCl 3 ): 10.16 (s, 1H), 7.43-7.35 (m, 5H ), 5.06-4.88 (dd, 2H), 4.12 (s, 1H), 3.94 -, 393 (d, 2H), 3.83 (unresolved s, 1H), 3.75 -3.73 (m, 1H), 3.37-3.28 (dt, 2H), 3.02-2.86 (dd, 2H), 2.29-2.25 (m, 1H), 1 , 99-1.82 (m, 5H), 1.75-1.61 (m, 2H), 1.45 (s, 9H).
    Step-2: Preparation of tetrabutylammonium salt of tert-butyl acid ester (2S, 5R) -2 - [(6-sulfo-oxy-7-oxo-1,6-diaza-bicyclo [3.2.1] octane- 2carbonyl) -methyloxycarbamoyl] - (2S) -pyrrolidine-1-carboxylic:

    O
    O_ Á, N Ϊ N
    The OBn
    H 2 -Pd / C, DMF, DCM.
    O
    O ° n A
    SO3.DMF, DMF

    O
    OSO 3 NBu 4 [00119] A solution of the benzyl compound (2.1 g, mmol) in a 1: 1 mixture of DMF: DCM (5 ml), was hydrogenated in 10% Pd / C (125 mg) in 1 atmosphere Hydrogen balloon. After stirring for 4 hours, the reaction mixture was filtered over celite. The filtrate was concentrated under reduced pressure, and the residue obtained was dissolved in fresh DMF (2.5 ml) and cooled to 10 ° C. SO3.DMF complex (193 mg, 12.6 mmol) was added, and the reaction mixture was allowed to warm to RT. After stirring RM at RT for 1.5 hours, TBAA (379 mg, 12.6 mmol) in water (1.25 ml) was added to the reaction mixture, and stirring was also continued for 2 hours. The volatiles were removed by high vacuum distillation, and the residue coevaporated with xylene (2X25 ml) to remove traces of DMF. The residue obtained was diluted with water (20 ml) and extracted with DCM (3X20 ml). The combined DCM layer was washed with water (2 x 20 ml). The layer of
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    DCM was dried, and the solvent evaporated under reduced pressure. The crude residue was triturated with Diethyl ether (3X25 ml) to obtain the product as a white solid, 610 mg, 82% yield.
    Analyze:
    Mass: 463.4 (MH) for MW-705.96 and MF - C 3 3H 6 3N 5 O 9 S.
    1 H NMR: Solvent (CDCl 3 ): 10.2 (s, 1H), 4.35 (s, 1H), 4.14 (s, 1H), 3.91-3.92 (d, 2H), 3.74 (m, 1H), 3.36-3.27 (m, 10H), 2.96-2.88 (dd, 2H), 2.31-2.26 (m, 2H), 2, 19-1.98 (m, 2H), 1.95-1.70 (m, 4H), 1.68-1.62 (p, 8H), 1.49-1.40 (m, 17H), 1.02-0.98 (t, 12H).
    Step-3: Preparation of (2S, 5R) -7-oxo-N - [(2S) -pyrrolidin-2-ylmethyloxy] -6 (sulfo-oxy) -1,6-diazabicyclo [3.2.1] octane-2 -carboxamide:

    O O N
    O
    TFA, DCM, -10 ° C
    O O N
    OSO3NBu4
    O
    N.
    OSO2OH [00120] In a cooled solution (-10 ° C) of TBA compound (300 mg, 4.2 mmol) in DCM (2.5 ml) TFA (2.5 ml) was added. After stirring for 30 min. at -10 ° C, the solvent was evaporated under reduced pressure. The obtained residue was triturated with diethyl ether to obtain the white solid. The solid was washed with diethyl ether (3X25 ml), Acetonitrile (2X25 ml) and DCM (2X25 ml). And the residual solid dried under reduced pressure (4 mmHg), to obtain the product as a 140 mg white solid, 91% yield.
    Analyze:
    Mass: 363.2 (MH) for MW - 364.37 and MF- C 12 H 20 N 4 O 7 S.
    1 H NMR: Solvent (DMSO-D6): 11.73 (s, 1H), 8.62-8.83 (d, 2H), 3.884.00 (m, 3H), 3.74-3.81 ( m, 2H), 3.19 (t, 2H), 2.94-3.04 (dd, 2H), 1,962.03 (m, 2H), 1.80-1.92 (m, 3H), 1 , 54-1.73 (m, 3H).
    [00121] Examples 2 to 39 (Table 1) were prepared using the procedure described as in Example-1 and using corresponding R1CH2ONH2, in place of 2-amino-oxymethyl- (S) 51/62 pyrrolidine acid t-butyl ester -1-carboxylic. These compounds were isolated as zwitterions.
    R3
    The J,
    N i
    R2
    OSO 3 H [00122] Examples 40 to 45 (Table 2) were prepared using the procedure described as in Example-1 and using corresponding R1CH 2 ONH 2 , in place of 2-amino-oxymethyl acid t-butyl ester (S ) -pyrrolidine-1-carboxylic. These compounds were isolated as salts of trifluoroacetic acid.
    O
    R3
    O, N i
    R2
    N.
    O
    OSO 3 Na [00123] Examples 46 to 50 (Table 3) were prepared using the procedure described as in Example-1 and using corresponding R1CH 2 ONH 2 , instead of 2-amino-oxymethyl acid t-butyl ester (S ) -pyrrolidine-1-carboxylic. These compounds were isolated as sodium salts.
    [00124] Procedure: A solution of the intermediate sulfate compound (1d) was passed through a column of sodium form of Amberlite 200C resin in the mixture of tetrahydrofuran-water followed by evaporation of the solvent from the combined fractions under reduced pressure (4 mmHg ).
    Table 1. Example No. R1 R2 R3 1H-NMR (DMSO-d6) / D2O,δ values Mass (ES-1) as free acid (MF)
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    1. SO2OH H / H (DMSO-Ó6): δ 11.73 (s, 1H), 8.62-8.83 (d, 2H), 3.88-4.00 (m, 3H), 3.74-3.81 ( m, 2H), 3.19 (t, 2H), 2.94-3.04 (dd, 2H), 1.96-2.03 (m, 2H), 1,801.92 (m, 3H), 1 , 54-1.73 (m, 3H), 363.1(C12H20N4O7S) 2. SO2OH H / H (DMSO-d6): δ 11.72 (br s, 1H), 8.88 (br s, 1H), 8.60 (br s, 1H), 3.88-4.04 (m, 3H), 3.72-3.84 (m, 2H), 2.96-3.28 (m, 4H), 1.52 -2.10 (s, 8H), 363.1 (M-1) C 12 H 20 N 4 O 7 S 3. SO2OH H H ' N CX ^ (DMSO-d6): δ 11.50 (br s, 1H), 8.60 (br s, 2H), 3.98-4.02 (m, 1H), 3.68-3.82 (m, 3H), 3.303.40 (m, 1H), 2.96-3.26 (m, 5H), 2.54-2.60 (m, 1H), 1,942.08 (m, 2H), 1.84 -1.88 (m, 1H), 1.64 -1.78 (s, 3H), 363.1 (M-1) C 12 H 20 N 4 O 7 S 4. SO2OH H H-N0., (DMSO-d6): δ 11.50 (br s, 1H),8.60 (br s, 2H), 3.98-4.02 (m,1H), 3.69-3.84 (m, 3H), 2.96-3.36 (m, 6H), 2.54-2.60 (m,1H), 1.94-2.08 (m, 2H), 1.82-1.90 (m, 1H), 1.60 -1.72 (s, 3H), 363.1 (M-1) C 12 H 20 N 4 O 7 S 5. SO2OH H HOH379.1(C12H20N4O8S) 6. SO2OH H NCH388.1(C13H19N5O7S)
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    7. SO2OH H H388.1(C13H19N5O7S) 8. SO2OH H n ^ NG H388.1(C13H19N5O7S) 9. SO2OH H f f H γΛΛ o / 1 'N ^ * H (DMSO-Ó6): δ 11.6 (s, 1H), 9.75 (d, 1H), 8.91-9.21 (bs, 2H), 4.40-4.46 (q, 1H) , 4.02 (s, 2H), 3.86 (bs, 1H), 3.52-3.79 (d, 1H), 3.47-3.49 (t, 1H), 3,123.19 (m , 2H), 3.02-3.052 (d, 1H), 2.94-2.96 (d, 1H), 2.382.45 (m, 1H) 2.003-2.054 (m, 1H), 1.87-1 , 89 (m, 1H), 1,581.74 (m, 2H), 1.54-1.58 (m, 2H), [ES -] 473.9[ES +] 476.0 (C14H20N5O8SF3) 10. SO2OH H hn Ah 2 (DMSO-de) δ: 10.9 (s, 1H),7.65 (d, 3H), 4.23 (s, 1H), 4.403 (m, 2H), 3.87-3.92 (m, 2H), 3.70-3.74 (dd, 1H) , 3.47-3.50 (m, 1H), 2.91-3.02 (dd, 2H), 1.83-1.89 (m, 6H), 1.65-1.67 (m, 2H), 405.15(C13H22N6O7S) 11. SO2OH H CVr H 1 (DMSO-de): 12.04 (bs, 1H), 8.42-9.20 (bs, 2H), 4.09 (bs, 1H), 4.01 (s, 1H), 3.83 ( m, 1H), 3.67 (m, 1H), 3.21 (m, 2H), 2.92-3.03 (m, 2H), 1.692.05 (m, 8H), 1.23-1 , 24 (d, 3H), [ES - ] 377.0, [ES +] 379.0 (C13H22N4O7S) 12. SO2OH H O = <1 V N - ^ »<H377.1(C12H18N4O8S) -
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    13. SO2OH H N — I>H350.1 (M + 1)(C11H18N4O7S) 14. SO2OH H HI350.1 (M + 1)(C11H18N4O7S) 15. SO2OH H k nOl> (DMSO-Ó6) δ 11.37 (s, 1H), 8.39 (bs, 1H), 8.1 (bs, 1H), 3.98 (s, 1H), 3.67-3.68 ( d, 2H), 3.64-3.69 (d, 2H), 3.24-3.27 (d, 1H), 3.07-3.12 2.99(s, 2H), 2.8-2.89 (m, 2H), 1.851.96 (m, 4H), 1.65-1.67 (m, 2H), 1.55 (m, 1H), 1.28-1.36 (m, 2H), [ES -] 377.2[ES +] 379.1 (C13H23N4O7S) 16. SO2OH H /1H (DMSO-de): δ 11.43 (s, 1H), 8.48-8.50 (d, 1H), 8.24-8.27 (d, 1H), 3.99 (s, 1H) , 3.61-3.73 (m, 3H), 3.34-3.37 (m, 2H), 3.16-3.21 (m, 2H), 2.99 (s, 2H), 2 , 68-2.77 (m, 3H), 1,852.00 (m, 4H), 1.65-1.79 (m, 4H), 1.53-1.58 (m, 2H), 1,201.30 (m, 2H), 378.40(C13H22N4O7S) 17. SO2OH H / (DMSO-de): δ 11.85 (br s, 1H), 11.77 (br s, 1H), 8.47 (br s, 1H), 4.00-4.04 (m, 1H), 3.803.95 (m, 3H), 2.76-3.18 (m, 4H), 1.98-2.06 (m, 1H), 1.841.94 (m, 1H), 1.62-1, 80 (m, 5H), 1.28-1.60 (m, 4H), 377.2 (M-1)(C13H22N4O7S) 18. SO2OH H tQh ' (DMSO-de): δ 11.78 (s, 1H), 8.36-8.60 (m, 2H), 3.76-4.06 (m, 4H), 2.70-3.06 ( m, 4H), 1.98-2.04 (m, 1H), 1.84-1.92 (m, 1H), 1.62-1.80 (m, 5H), 1.28-1, 60 (m, 4H), 377.0 (M-1)(C13H22N4O7S)
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    19. SO2OH H(DMSO-Ó6): δ 11.90 (s, 1H), 8.40-8.60 (m, 2H), 3.76-4.06 (m, 4H), 2.70-3.06 ( m, 4H), 1.98-2.04 (m, 2H), 1.84-1.92 (m, 1H), 1.62-1.80 (m, 5H), 1.28-1, 60 (m, 4H), 379.0 (M + 1) (C13H22N4O7S) 20. SO2OH H(DMSO-de): δ 11.78 (s, 1H), 8.16-8.60 (m, 2H), 3.98-4.03 (m, 3H), 3.78-3.80 ( d, 1H), 3.23-3.28 (m, 4H), 2.85-3.06 (m, 4H), 1.94-2.05 (m, 2H), 1.57-1, 87 (m, 8H), 1.30-1.49 (m, 3H), 1.15-1.24 (m, 4H), 391.0 (M-1) (C14H24N4O7S) 21. SO2OH H 391.2 (M-1) (C14H24N4O7S) 22. SO2OH H H (DMSO-to D2O exchange): δ 11.5 (M, 1H), 7.128-7.012 (m, 2H), 6.76 (m, 2H), 4.12 (m,1H) 3.98 (s, 1H), 3.90-3.73 (m, 3H), 3.14-3.08 (dd, 2H), 2.99 (d, 2H), 2.78- 2.72 (m,1H) 2.00-1.98 (m, 1H), 1.85 (m, 1H), 1.71-1.66 (m, 2H), 411.3 (M-1)413.3 (M + 1)(C16H20N4O7S) 23. SO2OH H QXH (exchange of DMSO-from, D2O): δ 6.96-6.99 (m, 2H), 6.68-6.73 (m, 2H), 3.98 (d, 1H), 3.90 ( dd, 1H) 3.72-3.77 (m, 2H), 3,453.55 (m, 1H), 3.05 (d, 1H), 2.91 (dd, 1H), 2.66-2, 71 (m, 2H), 1.97-2.04 (m, 1H), 1,851.88 (m, 2H), 1.65-1.71 (m, 2H), 1.53-1.58 ( m, 1H), 425.2 (M-1)427.2 (M + 1)(C17H22N4O7S) 24. SO2OH H(DMSO-de): δ 11.91 (s, 1H),9.18 (br s, 1H), 7.19-7.27 (m, 425.0 (M-1) (C17H22N4O7S)
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    4H), 4.33 (dd, 2H), 3.83-4.11 (m, 4H), 2.99-3.08 (m, 2H),2.94 (d, 1H), 2.83 (dd, 1H), 2.02-2.05 (m, 1H), 1.86-1.90 (m, 1H), 1.65-1, 76 (m, 2H),25. SO2OH H Vk/H (DMSO-de): δ 11.86 (br s, 1H),9.90 (br s, 1H), 7.29 (s, 1H),4.89 (dd, 1H), 4.46 (dd, 2H),4.12 (dd, 1H), 4.01-4.05 (m,2H), 3.83 (d, 1H), 3.75 (s, 3H),2.98 (dd, 2H), 1.96-2.06 (m,1H), 1.86-1.99 (m, 1H) 1.63-1.77 (m, 2H), 415.1 (M-1)417.1 (M + 1)(C14H20N6O7S) 26. SO2OH H h 'nA n ^ À / H401.1 (M-1)403.1 (M + 1)(C13H18N6O7S) 27. SO2OH H OHHO. „ANH404.2 (M-1) (C13H17N4O9S) 28. SO2OH H The V-OH) = NO ^^ Xy (DMSO-to D2O exchange) δ 7.50-7.52 (m, 1H), 7.33-7.37 (m, 1H), 6.91-6.94 (m, 2H), 4, 25-4.31 (m, 3H), 4.15-4.17 (m, 1H) 3.97-4.05 (m, 2H), 3.05-2.95 (dd, 3H), 2 , 05-, 97 (m, 2H), 1.82-1.85 (m, 3H), 1.66-1.62 (m, 2H), 457.2 (M + 1) (C17H20N4O9S) 29. SO2OH H Ν '- / H ) = N O ^ / ^ y (DMSO-to D2O exchange) δ 7.41 (d, 1H), 4.20-4.14 (m, 3H), 4.02-3.99 (m, 2H), 3.86-3.82 (dd, 1H) 3.75-3.74 (m, 1H), 3.68-3.64 (dd, 1H), 3.213.02 (m, 4H) 2.93-2.90 (d, 1H) 432.1 (M-1)434.2 (M + 1)(C15H23N5O8S)
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    2.24-2.19 (m, 2H), 2.00-1.68(m, 7H)30. SO2OH H / H (D2O): δ 4.733 (m, 1H), 4.107 (d, 1H), 4.001 (d, 1H), 3.5163.481 (d, 1H), 3.371 (4H, m), 3.240-3.210 (d, 1H), 2.2582.220 (1H, m), 2.1301.936 (3H, m), 1.8971.712 (2H, m), 350.9 (M + 1)(C11H18N4O7S) 31. SO2OH H / H350.9 (M + 1) (C11H18N4O7S) 32. SO2OH H %1 H350.9 (M + 1) (C11H18N4O7S) 33. SO2OH H VX *N-JH (DMSO-de): δ 11.62 (s, 1H),9.77 (bs, 1H), 4.802-4.83 (q,1H), 4.68 (s, 1H), 4.001 (s, 1H), 3.78-3.79 (d, 1H), 3.56-3.59 (d,1H), 3.12-3.16 (m, 1H), 3.07 (s, 2H), 2.55-2.61 (m, 1H), 2.43-2.44 (d, 1H) , 2.40-2.41 (d,1H), 1.97-1.99 (m, 1H), 1.86-1.975 (m, 1H), 1.66-1.71 (m, 2H), [ES -] 373.9[ES +] 376.0(C12H17N5O7S) 34. SO2OH H N '> LApN-JH[ES -] 373.9[ES +] 376.0(C12H17N5O7S) 35. SO2OH H h 2 n / 'J'! ' The Ν'-J H (DMSO-de): δ 11.38 (s, 1H), 9.44 (bs, 1H), 8.49 (bs, 1H), 7.90 (s, 1H), 7.70 (s, 1H ), 4.63 (s, 1H), 4.20 (s, 1H), 3.99 (s, [ES -] 391.8[ES +] 394.1(C12H19N5O8S)
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    1H), 3.77-3.78 (d, 1H), 3.543.57 (d, 1H), 3.02-3.14 (m,1H), 2.99-3.02 (d, 1H), 2.92-2.95 (d, 1H), 2.55-2.60 (m,1H), 2.10-2.11 (d, 1H), 2.052.067 (m, 1H), 1.85 (m, 1H), 1.61-1.72 (m, 1H), 1.55-1H),36 SO2OH H N— 1 h ' (DMSO-de): δ 11.8 (bs, 1H), 8.85 (bs, 1H), 8.52 (bs, 1H), 4.73 (m, 1H), 4.17 (m, 2H ), 4.00 (m, 3H), 3.79 (d, 1H), 2.91-3.02 (m, 2H), 2.00 (m, 1H), 1.86 (m, 1H) , 1.64-1.71 (m, 2H), [ES +] 336.9(C10H16N4O7S) 37. SO2OH 1 *H CH3 (DMSO-de): δ 8.2-8.24 (d, 2H), 4.02 (s, 1H), 3.730 (m, 1H), 3.561 (s, 3H), 3.18-3.37 (m, 3H), 2.72-2.78 (m, 3H), 2.48-2.56 (m, 2H), 1.95-1.96 (m, 2H), 1.726-1.787 (m , 3H), 1.55-1.59 (m, 2H), 1.07-1.17 (m, 2H), 392.42(C14H24N4O7S) 38. SO2OHCH3 (DMSO-de): δ 8.4 (bs, 1H), 8.08 (bs, 1H), 4.31 (bs, 1H), 4.01 (s, 1H), 3,6,2-3 , 72 (m, 4H), 3.44-3.48 (m, 1H), 3.23 (bs, 3H), 2.97 (d, 1H), 2.84 (bs, 2H), 1, 76-1.89 (m, 6H), 1.22-1.33 (m, 2H), [ES -] 391.3[ES +] 393.3(C14H24N4O7S) 39. SO2OH N '-' ^ C/ t.H CH3 (DMSO-de): δ 8.95 (bs, 1H),8.38 (bs, 1H), 4.33 (m, 1H), 4.03 (m, 2H), 3.65-3.90 (m, 5H), 3.00-3.24 (m, 4H), 2,032.09 (m, 1H), 1.73-1.91 (m, 5H), 1.26-1.31 (m, 2H), [ES - ] 377.3, [ES + ] 379.2 (C13H22N4O7S)
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    Table-2 40. SO2OH H ,, .CF3COOH H 3 H ' N ^ (DMSO-Ó6): δ 11.64 (s, 1H),7.78 (bs, 3H), 4.01 (s, 1H),3.95 (t, 2H), 3.82 (d, 1H),2.95-3.02 (m, 3H), 2.92 (d,1H), 1.89-2.04 (m, 1H), 1.85-1.88 (m, 1H), 1.61 to 1.75 (m,2H), 323.1(C9H16N4O7S) 41. SO2OH H .CF3COOH hn ^ nh 2 N. ^ £ / H (DMSO-d6): δ 8.18 (t, 1H), 7.59 (bs, 5H), 3.98 (s, 1H), 3.81 (t, 2H), 3.74 (d, 1H ), 3.38 (t, 2H), 2.99-3.02 (d, 1H), 2.82-2.85 (d, 1H), 2.052.08 (dd, 1H), 1.84- 1.86 (m, 1H), 1.56-1.69 (m, 2H), 365.1(C10H18N6O7S) 42. SO2OH H .CF3COOHH j1 ___.NH (DMSO-d6): δ 11.63 (s, 1H),7.72 (bs, 3H), 4.00 (s, 1H),3.88 (t, 2H), 3.75 (d, 1H), 2.95-3.00 (m, 4H), 1.99 (d,1H), 1.78-1.92 (m, 3H), 1.62-1.73 (m, 2H), 337(C10H18N4O7S) 43. SO2OH H .CF3COOH H '' h h N ^ (DMSO-d6): δ11.79 (br, 1H), 7.94-7.663 (br, 5H), 4.02 (s, 1H), 3.94(m, 1H), 3.81 (m, 1H), 3.05-2.95 (dd, 2H), 2.75 (m, 2H), 2.06-1.88 (m, 2H),1.68 (m, 2H), 1.50 (m, 4H), 1.35 (m, 2H), (M-H, 394 (-SO3H) (C13H26N5O7S, C2O2F3) 44. SO2OH H H 2 n .CF3COOH HH (DMSO-d6): δ 9.00 (bs, 2H), 8.05 (bs, 3H), 3.98-4.07 (m, 3H), 3.80-3.84 (1, 2H) , 3,453.50 (dd, 1H), 3.15-3.20 (m, 1H), 3.03-3.06 (d, 1H), 2,932.96 (d, 1H), 2.41-2 , 47 (m, 1H), 2.01-2.05 (m, 1H), 1.881.90 (m, 1H), 1.52-1.75 (m, 6 H), 378.2(C12H21N5O7S) (DMSO-d6): δ 11.9 (s, 1H),9.00 (bs, 2H), 3.94-4.02 (s, [ES - ] 378.2,
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    45. SO2OH H H .cf 3 cooh ^ N ^^ V 1 ~ H 1H), 3.79-3.80 (m, 1H), 3.44-3.59 (m, 4H), 3.03-3.16 (m, 4H), 2.99 (s, 2H) , 1.992.03 (m, 1H), 1.88-1.91 (m, 1H), 1.65-1.75 (m, 2H), 1.531.55 (m, 1H), 1.26-1 , 32 (m, 1H), [ES +] 380.1 for free amineC12H21N5O7S, C2HO2F3 46. SO2OH H .CF3COOHN1 "H CH3 (DMSO-d6): δ 8.2-9.6 (bs, 3H), 4.38 (m, 1H), 4.01 (m, 2H), 3.69 (m, 4H), 3,333.58 (m, 4H), 2.92-3.31 (m, 5H), 2.70-2.91 (m, 1H), 1.501.95 (m, 4H), C13H24N5O7S, C2O2F3 [ES - ] 392.2, [ES +] 394.3
    Table-3 47. SO2ONa CH3 CH3 (DMSO-d6): δ 4.38 (m, 1H), 4.15-4.20 (m, 2H), 3.58-3.78 (m, 4H), 3.15-3.42 ( m, 4H), 1.83-2.048 (m, 4H) [ES '] 308.1, [ES +] 310.1 for free acid (C9H14N3O7S,At) 48. SO2ONa H CH3 (DMSO-d6): δ 11.39 (s, 1H),3.97 (s, 1H), 3.66 (d, 1H),3.57 (s, 3H), 2.99 (dd, 2H), 1.95-1.97 (m, 1H), 1.79-1.88 (m, 1H), 1.62-1, 72 (m, 2H), 294 for free acidC8H12N3O7S,At 49. SO2ONa H H (D2O): δ 4.10-4.22 (m, 2H), 3.52-3.64 (m, 1H), 3.22-3.26 (m, 1H), 1.70-2, 10 (s, 4H), 280.01 (M-1)C7H11N3O7S 50. SO2ONa H Il II -1 (DMSO-d6 D2O exchange): δ7.32 (d, 1H), 6.29 (d, 1H),4.83 (s, 2H), 3.95-3.91 (m, 4H) 3.76-3.66 (m, 2H), 2.98-2.88 (dd, 2H), 1.95-1.93 (m, 1H), 1.82 (m, 1H), 1.67-1.62(m, 2H), 374.2 (M-1) 376.3 (M + 1) (C 12 H 16 N 5 O 7 S, Na) 51. SO2ONa CH3 H294 for free acidC8H12N3O7S,At
    61/62
    Biological Activity [00125] The biological activity of representative compounds according to the invention against various bacterial strains has been investigated. In a typical study, bacterial cultures grown overnight were diluted appropriately and inoculated on agar media containing double dilutions of the test compounds. Observation for growth or no growth was performed after 16-20 hours of incubation at 35 ± 2 ° C in room air. The total procedure was performed according to the recommendations of the Clinical and Laboratory Standards Institute (CLSI) (Clinical and Laboratory Standards Institute (CLSI), Performance Standards for Antimicrobial Susceptibility Testing, 20th Informational Supplement, M 100 - S20, Volume 30, No. 1, 2010). [00126] Table 4 describes the antibacterial activity of representative compounds according to the invention against various Multiple Drug Resistant Gram-negative bacterial strains (MDR) expressing various ESBLs. Activities are expressed as MICs (mcg / ml). For comparison, the activity of several known antibacterial agents (for example, Ceftazidime, Aztreonam, Imipenem, Ciprofloxacino and Tigecycline) is likewise included. As can be seen, the representative compounds according to the invention exhibit antibacterial activity against various strains of MDR.
    Table 4. Comparative antibacterial activity of representative compounds according to the invention against multiple strains Multiple Gram-Resistant Gram-negative (MDR) strains (expressed as MICs (mcg / ml). Sir Compound ESBL Class A ESBL Class C P. aeruginosa E. ColiW13353 E. ColiW13351 E. ColiW13352 E. ColiM 50 E. ColiH 483 Ps21 Ps32 1. Ceftazidime 32 32 > 32 > 32 > 32 > 32 > 32 2. Aztreonam > 32 > 32 > 32 > 32 > 32 8 8 3. Imipenem 0.25 0.25 0.25 0.5 1 > 32 > 32 4. Ciprofloxacino > 32 0.5 0.12 > 32 > 32 32 0.12 5. Tigecycline 1 1 0.25 0.5 0.5 16 16 6. Example 1 0.5 1 1 0.5 > 32 > 32 > 32 7. Example 2 1 2 2 1 > 32 > 32 > 32
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    8. Example 3 8 16 16 8 > 32 > 32 > 32 9. Example 4 8 8 8 8 > 32 > 32 > 32 10. Example 17 0.5 1 1 0.5 > 32 > 32 > 32 11. Example 18 0.5 1 1 1 > 32 > 32 > 32 12. Example 19 4 8 16 8 > 32 > 32 > 32 13. Example 30 4 8 8 4 > 32 > 32 > 32 14. Example 33 4 4 > 32 4 > 32 > 32 > 32 15. Example 35 4 16 8 8 > 32 > 32 > 32
    1/3
    权利要求:
    Claims (7)
    [1]
    1. Compound, characterized by the fact that it presents the
    Formula (I)

    [2]
    2. Compound, according to claim 1, characterized by the fact that it is selected from:

    [3]
    3. Compound, according to claim 1, characterized by the fact that it is selected from:

    [4]
    4. Pharmaceutical composition, characterized by the fact that it comprises a compound, as defined in any one of claims 1 to 3.
    [5]
    Compound according to any one of claims 1 to 3, characterized in that it is for use as an antibacterial agent.
    [6]
    6. Use of a compound, as defined in any of claims 1 to 3, characterized by the fact that it is for the preparation of a pharmaceutical composition for prevention or
    Petition 870200002794, of 01/07/2020, p. 5/11
    3/3 treatment of bacterial infection in an individual, and said infection caused by bacteria produces one or more beta-lactamase enzymes.
    [7]
    7. Use of a composition, as defined in claim 4, characterized by the fact that it is for the preparation of a medicine for the prevention or treatment of bacterial infection in an individual, said infection being caused by bacteria that produce one or more of beta-lactamase enzymes.
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    同族专利:
    公开号 | 公开日
    JP6329147B2|2018-05-23|
    EP2961751B1|2018-03-21|
    CA2881169A1|2014-03-06|
    AU2013308127A1|2014-07-10|
    BR112015003592A2|2017-07-04|
    AU2015205914A1|2015-08-20|
    CN104768951A|2015-07-08|
    JP2017128617A|2017-07-27|
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    CA2881169C|2020-06-16|
    US10519155B2|2019-12-31|
    RU2614418C2|2017-03-28|
    EP3360877B1|2021-02-17|
    RU2015110500A|2016-10-10|
    ES2672100T3|2018-06-12|
    US9732081B2|2017-08-15|
    EP2961751A1|2016-01-06|
    US20160311822A1|2016-10-27|
    NZ626314A|2017-02-24|
    CN104768951B|2018-03-23|
    EP3360877A1|2018-08-15|
    JP2015526501A|2015-09-10|
    MX368346B|2019-09-27|
    KR101946107B1|2019-02-08|
    AU2013308127B2|2015-08-13|
    US20150203503A1|2015-07-23|
    ZA201500970B|2016-10-26|
    US20200071328A1|2020-03-05|
    US20180170930A1|2018-06-21|
    AU2015205914B2|2016-07-28|
    US20160213655A1|2016-07-28|
    KR20150046066A|2015-04-29|
    JP6386132B2|2018-09-05|
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    法律状态:
    2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2018-03-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-02-12| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |
    2019-05-28| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|
    2019-10-22| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|
    2020-02-27| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2020-04-14| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 19/04/2013, OBSERVADAS AS CONDICOES LEGAIS. |
    2022-02-15| B21F| Lapse acc. art. 78, item iv - on non-payment of the annual fees in time|Free format text: REFERENTE A 9A ANUIDADE. |
    优先权:
    申请号 | 申请日 | 专利标题
    IN2471MU2012|2012-08-25|
    PCT/IB2013/053092|WO2014033560A1|2012-08-25|2013-04-19|1,6- diazabicyclo [3,2,1] octan- 7- one derivatives and their use in the treatment of bacterial infections|
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