1,6-diazabicyclo [3,2,1] octan-7-one derivatives and pharmaceutical compositions comprising them

专利摘要:
1,6-DIAZABICIC DERIVATIVES [3,2,1] OCTAN-7-ONA, ITS USES FOR THE PREVENTION OR TREATMENT OF BACTERIAL INFECTION, AS WELL AS PHARMACEUTICAL COMPOSITIONS. The present invention relates to compounds of Formula (I), their preparation and use in the prevention or treatment of bacterial infection.
公开号:BR112013028813B1
申请号:R112013028813-2
申请日:2012-08-24
公开日:2020-10-20
发明作者:Mahesh Vithalbhai Patel；Prasad Keshav Deshpande；Satish Bhawasar；Sachin Bhagwat；Mohammad Alam Jafri；Amit MISHRA；Laxmikant Pavase；Sunil Gupta；Rajesh Kale；Sanjeev Joshi
申请人:Wockhardt Limited；
IPC主号:

专利说明:

RELATED PATENT APPLICATIONS
[0001] This application claims the benefit of Indian Provisional Patent Application No. 2412 / MUM / 2011 filed on August 27, 2011, the disclosures of which are incorporated herein by reference in their entirety as if completely rewritten herein. All references, including patents, patent applications and literature cited in the specification are hereby expressly incorporated by reference in their entirety. FIELD OF THE INVENTION
[0002] The invention relates to nitrogen-containing compounds, their preparation and their use in the prevention and / or treatment of bacterial infections. BACKGROUND OF THE INVENTION
[0003] The emergence of bacterial resistance to known antibacterial agents is increasingly an important challenge in the treatment of bacterial infections. A direct way to treat bacterial infections, and especially those caused by resistant bacteria, is to develop new antibacterial agents that can overcome bacterial resistance. Coates et al. (Br. J. Pharmacol. 2007; 152 (8), 1147-1154.) Reviewed new approaches to the development of new antibiotics. However, the development of new antibacterial agents is a difficult task. For example, Gwynn et al. (Annals of the New York Academy of Sciences, 2010, 1213: 5-19) analyzed the challenges in the discovery of antibacterial agents.
[0004] 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 for preventing and / or treating bacterial infections, including those caused by bacteria that are resistant to known antibacterial agents.
[0005] The inventors surprisingly discovered nitrogen-containing compounds with antibacterial properties. SUMMARY OF THE INVENTION
[0006] In this way, nitrogen containing compounds are provided, methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods for the prevention or treatment of bacterial infection in an individual using these compounds.
[0007] In a general aspect, compounds of Formula (I) are provided:
or a stereoisomer or a pharmaceutically acceptable salt thereof; where: Ri is: (a) hydrogen, (b) (CO) n-R3, (C) COOR4, OR (d) COCH2COR3 n is 0, 1 or 2; R2 is: (a) SO3M, (b) SO2NH2, (C) PO3M, (d) CH2COOM, (e) CF2COOM, (f) CHFCOOM, or (g) CF3; M is hydrogen or a cation; R3 is: (a) hydrogen, (b) Ci-Ce alkyl optionally substituted by one or more substituents independently selected from halogen, R5, CN, COORÕ, CONR6R7, NR6R7, NR5COR8, NR5CONR6R7, heterocyclyl, heteroaryl, cycloalkyl or aryl , (c) CN, (d) NR6R7, (e) CONR6R7, (f) NHCONR6R7, (g) aryl optionally substituted by one or more substituents independently selected from Ci-Ce alkyl, Rs, NR3R7, halogen, CN, CONR6R7, SO2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl, or NHCONR6R7, (h) heterocyclyl optionally substituted by one or more substituents independently selected from Ci-Ce alkyl, Rs, NR6R7, halogen, CN, CONR6R7, SO2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl, NHC (NH) NR3R7, or NHCONR6R7, (i) heteroaryl optionally substituted by one or more substituents independently selected from Ci-Ce alkyl, Rs, NR6R7, halogen, CN, CONR6R7, SO2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl, or NHCONR6R7, (j) cycloal chyl optionally substituted by one or more substituents independently selected from Ci-Ce alkyl, Rs, NReR , halogen, CN, CONReR , SO2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl, or NHCONReR , (k) cycloalkyl substituted by Ci-Cβ alkyl wherein Ci-Cβ alkyl is additionally substituted by one or more substituents independently selected from ORs, NReR , halogen, CN, or CONReR , or (l) OR8; R4 is: (a) hydrogen, (b) Ci-Ce alkyl optionally substituted by one or more substituents independently selected from halogen, Rs, CN, COORs, CONReR , NReR , NR5COR8, heterocyclyl, heteroaryl, cycloalkyl or aryl , (c) aryl optionally substituted by one or more substituents independently selected from Ci-Ce alkyl, Rs, NReR , halogen, CN, CONReR , Sθ2_alkyl, Sθ2-aryl, OSO2-alkyl, OSO2-aryl, or NHCONReR , (d) heterocyclyl optionally substituted by one or more substituents independently selected from Ci-Cβ alkyl, Rs, NRβR7, halogen, CN, CONReR , Sθ2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl, or NHCONReR , (e) heteroaryl optionally substituted by one or more substituents independently selected from Ci-Cβ alkyl, Rs, NR6R , halogen, CN, CONReR , Sθ2-alkyl, SO2-aryl, OSO2-alkyl, OSO2 -aryl, or NHCONReR , or (f) cycloalkyl optionally substituted by one or more independent substituents selected from Ci-Cβ alkyl, Rs, NReR , halogen, CN, CONReR , SO2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl, or NHCONR6R ; R5 and Rs are each independently: (a) hydrogen, or (b) Ci-Cθ alkyl optionally substituted by one or more substituents independently selected from halogen, CN, CONReRz, NReR , heterocyclyl, heteroaryl, cycloalkyl or aryl; R6 and R are each independently: (a) hydrogen, (b) Ci-Cθ alkyl optionally substituted by one or more substituents independently selected from halogen, Rs, CN, COOR5, CONR5R8, NR5Rδ, NRsCORs, heterocyclyl, heteroaryl, cycloalkyl or aryl , (c) aryl optionally substituted by one or more substituents independently selected from Ci-Cδ alkyl, Rs, NR5Rs, halogen, CN, CONRsRs, SO2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl, or NHCONRsRs , (d) heterocyclyl optionally substituted by one or more substituents independently selected from Ci-Cδ alkyl, Rs, NR5Rs, halogen, CN, CONRsRs, SO2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl, or NHCONRsRs , (e) heteroaryl optionally substituted by one or more substituents independently selected from Ci-Cδ alkyl, Rs, NR5Rs, halogen, CN, CONRsRs, SO2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl, or NHCONRsRs , (f) cycloalkyl optionally substituted by one or more s substituents independently selected from Ci-Cδ alkyl, Rs, NRsRs, halogen, CN, CONRsRs, SO2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl, or NHCONRsRs, or (g) Rβ and R7 are placed together to form a four to seven-membered ring.
[0008] In another general aspect, pharmaceutical compositions are provided comprising a compound of Formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
[0009] In another general aspect, a method is provided for the prevention or treatment of 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 of the same or a pharmaceutically acceptable salt thereof.
[00010] In another general aspect, a method is provided for the prevention or treatment of a bacterial infection in an individual, said infection being caused by bacteria that produce one or more of the beta-lactamase enzymes, wherein the method comprises administering to said individual a pharmaceutically effective amount of a compound of Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
[00011] In another general aspect, a method is provided for the prevention or treatment of 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 thereof or a pharmaceutically acceptable salt thereof.
[00012] In yet another general aspect, a method is provided for the prevention or treatment of a bacterial infection in an individual, said infection being caused by bacteria that produce one or more of the 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 thereof or a pharmaceutically acceptable salt thereof.
[00013] In another general aspect, pharmaceutical compositions are provided comprising: (a) a compound of Formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and (b) at least one beta-inhibitor lactamase selected from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof.
[00014] In another general aspect, pharmaceutical compositions are provided comprising: (a) a compound of Formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
[00015] In another general aspect, pharmaceutical compositions are provided comprising: (a) a compound of Formula (I), or a stereoisomer thereof 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.
[00016] In another general aspect, a method is provided for the prevention or treatment of 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.
[00017] In yet another general aspect, a method is provided for the prevention or treatment of a bacterial infection in an individual, said infection being caused by bacteria that produce one or more of the 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 thereof or a pharmaceutically acceptable salt thereof, and (b) at least one beta inhibitor -lactamase selected from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof.
[00018] In another general aspect, a method is provided for the prevention or treatment of 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 antibacterial agent or a pharmaceutically acceptable derivative thereof.
[00019] In yet another general aspect, a method is provided for the prevention or treatment of a bacterial infection in an individual, said infection being caused by bacteria that produce one or more of the 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 thereof or a pharmaceutically acceptable salt thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
[00020] In another general aspect, a method is provided for the prevention or treatment of 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.
[00021] In yet another general aspect, a method is provided for the prevention or treatment of a bacterial infection in an individual, said infection being caused by bacteria that produce one or more of the 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 thereof or a pharmaceutically acceptable salt thereof, (b) at least one beta-inhibitor lactamase 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.
[00022] In another general aspect, a method is provided for the prevention or treatment of 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 thereof 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.
[00023] In yet another general aspect, a method is provided for the prevention or treatment of a bacterial infection in an individual, said infection being caused by bacteria that produce one or more of the 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 thereof or a pharmaceutically acceptable salt thereof, and (b) at least one beta-lactamase inhibitor selected from from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof.
[00024] In another general aspect, a method is provided for the prevention or treatment of 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 thereof or a pharmaceutically acceptable salt thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
[00025] In yet another general aspect, a method is provided for the prevention or treatment of a bacterial infection in an individual, said infection being caused by bacteria that produce one or more of the 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 thereof or a pharmaceutically acceptable salt thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative the same.
[00026] In another general aspect, a method is provided for the prevention or treatment of 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 thereof 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) the least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
[00027] In yet another general aspect, a method is provided for the prevention or treatment of a bacterial infection in an individual, said infection being caused by bacteria that produce one or more of the 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 thereof or a pharmaceutically acceptable salt thereof, (b) at least one beta-lactamase inhibitor selected from of sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof, and (c) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
[00028] In another general aspect, methods are provided to increase the antibacterial effectiveness of an antibacterial agent in an 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 thereof or a pharmaceutically acceptable salt thereof.
[00029] Details of one or more embodiments of the invention are presented in the description below. Other features, objects and advantages of the invention will be apparent from the following description including claims. DETAILED DESCRIPTION OF THE INVENTION
[00030] Reference will now be made to the exemplary modalities, and specific language will be used here to describe them. However, it should be understood that no limitation on the scope of the invention is thus intended. Changes and other modifications to the characteristics of the invention illustrated herein, and other applications of the principles of the invention, as illustrated here, which would occur to a person skilled in the relevant art and possession of the present description, should be considered within the scope of the invention. It should be noted that, as used in this specification and the appended claims, the singular forms "one / one", and "the one /" include plural referents unless the content clearly dictates otherwise. All references, including patents, patent applications and literature cited in the specification are hereby expressly incorporated by reference in their entirety.
[00031] The inventors have surprisingly discovered new compounds containing nitrogen, having antibacterial properties.
[00032] The term "Ci-Cealkyl" as used herein refers to acyclic, linear or branched hydrocarbon radicals having 1 to 6 carbon atoms. Typical non-limiting examples of "Ci-Ce" include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl and the like. The "Ci-Ce" can be unsubstituted, or substituted by one or more substituents. Typical non-limiting examples of such substituents include halogen, alkoxy, CN, COOH, CONH2, OH, -NH2, -NHCOCH3, cycloalkyl, heterocyclyl, heteroaryl, aryl and the like.
[00033] The term "cycloalkyl" as used herein refers to three to seven-membered cyclic hydrocarbon radicals. The cycloalkyl group may optionally incorporate one or more double or triple bonds, or a combination of double bonds and triple bonds, but which is not aromatic. Typical non-limiting examples of cycloalkyl groups include cyclopropane, cyclobutane, cyclopentane, cyclohexane, and cyclohexane -heptane. Cycloalkyl can be unsubstituted, or substituted by one or more substituents. Typical non-limiting examples of such substituents include C1-C6 alkyl, halogen, alkoxy, CN, COOH, CONH2, OH, NH2, NHCOCH3, heterocyclyl, heteroaryl, aryl, SO2-alkyl, SO2-aryl, OSO2-alkyl, -OSO2- arila and the like.
[00034] The term "heterocyclyl" as used herein refers to a four to seven-membered cycloalkyl group containing one or more heteroatoms selected from nitrogen, oxygen or sulfur. The heterocycloalkyl group may optionally incorporate one or more double or triple bonds, or a combination of double bonds and triple bonds, but which is not aromatic. Typical non-limiting examples of heterocycloalkyl groups include azetidine, pyrrolidine, 2-oxo-pyrrolidine, imidazolidine-2-one, piperidine, oxazine, thiazine, piperazine, piperazine-2,3-dione, morpholine, thiamorpholine, azapane and the like. Heterocycloalkyl can be unsubstituted or substituted by one or more substituents. Typical non-limiting examples of such substituents include C1-C6 alkyl, halogen, alkoxy, CN, COOH, CONH2, OH, NH2, NHCOCH3, heterocyclyl, heteroaryl, aryl, SO2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl and the like.
[00035] The term "aryl" as used herein refers to monocyclic or polycyclic aromatic hydrocarbons. Non-limiting examples of typical aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, phenanthrenyl and the like. The aryl group can be unsubstituted, or substituted by one or more substituents. Typical non-limiting examples of such substituents include C1-C6 alkyl, halogen, alkoxy, CN, COOH, CONH2, OH, NH2, NHCOCH3, heterocyclyl, heteroaryl, aryl, SO2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl and the like.
[00036] The term "heteroaryl" as used herein refers to a monocyclic or polycyclic aromatic hydrocarbon group in which one or more carbon atoms have been replaced by 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. A typical non-limiting example of heteroaryl groups includes 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 by one or more substituents. Typical non-limiting examples of such substituents include C1-C6 alkyl, halogen, alkoxy, CN, COOH, CONH2, OH, NH2, NHCOCH3, heterocyclyl, heteroaryl, aryl, SO2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl and the like.
[00037] The term "stereoisomers", as used herein, refers to compounds that have identical chemical composition, but differ in terms of 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. Unless otherwise specified, it is intended that all stereoisomeric forms of the compounds of Formula (I), as well as their mixtures, including racemic mixtures, form part of the present invention. In addition, all geometric and positional isomers, (including cis and trans forms), as well as their mixtures, are also included in the scope of the invention. In general, a reference to a compound is intended to cover its stereoisomers and mixtures of various stereoisomers.
[00038] The term used here as "optionally substituted" means that substitution is optional and therefore includes both unsubstituted and substituted atoms and portions. A "substituted" atom or moiety indicates that any hydrogen in the designated atom or moiety can be substituted by a selection of the indicated substituent group, provided that the normal valence of the designated atom or moiety is not exceeded and that the substitution results in a stable compound.
[00039] The term "pharmaceutically acceptable salt" as used herein refers to one or more salts of a given compound, which have the desired pharmacological activity of the free compound and which are neither biologically nor otherwise undesirable. In general, "pharmaceutically acceptable salts" refer to salts that are suitable for use in contact with the tissues of humans and animals without toxicity, irritation, allergic response and the like, and are commensurable with a reasonable risk / benefit 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.
[00040] In general, the compounds according to the invention contain basic portions (for example, nitrogen atoms), as well as acidic (for example, compounds of Formula (I) in which M is hydrogen). A person skilled in the art will appreciate that such compounds, therefore, 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, the basic portion can be converted to its salt by treating a compound with an appropriate amount of acid. Typical non-limiting examples of such suitable acids include hydrochloric acid, trifluoroacetic acid, methanesulfonic acid, or the like. Alternatively, the acidic portion can be converted to its salt by treatment 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 the salt independently. For example, in the case of compounds that contain two basic nitrogen atoms, one basic nitrogen atom can form a salt with the acid, while the other basic nitrogen atom can form salt with another acid. Some compounds according to the invention contain both the basic and acidic moieties and thus can form internal salts or corresponding zwitterions. In general, all forms of pharmaceutically acceptable salts of the compounds of Formula (I) according to the invention including their acid addition salts, base addition salts, zwitterions or the like, are contemplated to be within the scope of the present invention and are generally referred to as pharmaceutically acceptable salts.
[00041] The term "halogen" or "halo", as used herein, refers to chlorine, bromine, fluorine or iodine.
[00042] The term "infection" or "bacterial infection", as used herein, includes the presence of bacteria, on or on an individual which, if their growth were inhibited, would result in a benefit to the individual. As such, the term "infection" in addition to the reference to the presence of bacteria also refers to normal flora, which is not desirable. The term "infection" includes infection caused by bacteria.
[00043] The term "treat", "treating" or "treatment" as used herein refers to the administration of a medicament, 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 having an infection (preventing bacterial infection). The term "therapeutic treatment" refers to administering treatment to a patient who is already suffering from infection. The terms "treat", "treating" or "treatment" as used herein, also refer to administering compositions or one or more pharmaceutically active ingredients discussed herein, with or without additional pharmaceutically active or 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 progression of a bacterial infection or one or more symptoms of the bacterial infection, or (iii) decrease 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 appearance of adverse symptoms of the bacterial infection.
[00044] The term "pharmaceutically effective amount" or "therapeutically effective amount" or "effective amount" as used herein refers to an amount that has a therapeutic effect or is the amount necessary to produce a therapeutic effect in an individual . For example, a therapeutic or pharmaceutically effective amount of an antibacterial agent or a pharmaceutical composition is the amount of antibacterial agent or pharmaceutical composition needed to produce a desired therapeutic effect, as can be assessed by the results of clinical trials, infection studies in models animals, and / or in vitro studies (for example, in agar or broth media). The pharmaceutically effective amount depends on several factors, including, but not limited to, the microorganism (eg, bacteria) involved, characteristics of the individual (eg, height, weight, sex, age and medical history), severity of infection and the particular type of antibacterial agent used. For prophylactic treatments, a therapeutic or prophylactically effective amount is the amount that is effective in preventing a microbial (eg, bacterial) infection.
[00045] The term "administration" or "administering" includes the delivery of a composition or one or more pharmaceutically active ingredients to an individual, including, for example, by any suitable method, which serves to provide the composition or its ingredients active ingredients or other pharmaceutically active ingredients at the site of infection. 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, the severity of the infection , the age and physical condition of the individual and the like. Some non-limiting examples of ways to administer a composition or a pharmaceutically active ingredient to an individual according to the present invention include oral, intravenous, topical, intrarespiratory, intraperitoneal, intramuscular, parenteral, sublingual, transdermal, intranasal, aerosol, intraocular, intratracheal, intrarectal, vaginal, gene device, dermal patch, eye drops, ear drops or mouthwash. In the case of a pharmaceutical composition comprising more than one ingredient (active or inert), one way of administering such a composition is by mixing the ingredients (for 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 also be administered separately (simultaneously or one after the other) while these ingredients achieve beneficial therapeutic levels such that the composition as a whole provides a synergistic and / or desired effect.
[00046] The term "growth" as used herein refers to the growth of one or more microorganisms and includes the reproduction or expansion of the population of microorganisms (for example, bacteria). The term also includes the maintenance of a microorganism's ongoing metabolic processes, including the processes that keep the microorganism alive.
[00047] The term "efficacy", as used herein, refers to the ability of a treatment or composition, or one or more pharmaceutically active ingredients to produce a desired biological effect on an individual. For example, the term "antibacterial efficacy" of a composition or an antibacterial agent refers to the ability of the composition or antibacterial agent to prevent or treat microbial (e.g., bacterial) infection in an individual.
[00048] The term "synergistic" or "synergy" as used herein refers to the interaction of two or more agents so that their combined effect is greater than their individual effects.
[00049] The term "antibacterial agent" as used herein refers to any substance, compound or a combination of substances or a combination of compounds capable of: (i) inhibiting, reducing or preventing the growth of bacteria, (ii) inhibit or reduce the ability of a bacterium to produce infection in an individual, or (iii) inhibit or reduce the ability of the bacteria to multiply or remain infectious in the environment. The term "antibacterial agent" also refers to compounds capable of decreasing the bacterial infectivity or virulence.
[00050] The term "beta-lactam antibacterial agent" as used herein refers to compounds with antibacterial properties and which contain a beta-lactam nucleus in their molecular structure.
[00051] The term "beta-lactamase" as used herein 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 has the ability to hydrolyze the beta-lactam ring into a beta-lactam compound, partially or completely.
[00052] The term "beta-lactamase inhibitor" as used herein refers to a compound capable of inhibiting the activity of one or more beta-lactamase enzymes, partially or completely.
[00053] The term "pharmaceutically inert ingredient" or "carrier" or "excipient" refers to a compound or material used to facilitate the administration of a compound, including, for example, increasing the compound's solubility. Examples, typical non-limiting of solid vehicles include, starch, lactose, dicalcium phosphate, sucrose, kaolin and so on. Typical non-limiting examples of liquid vehicles include sterile water, saline, buffers, nonionic surfactants, and edible oils such as peanut oil and sesame oils 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, NJ). Considerations for including various components in pharmaceutical compositions are described, for example, in Gilman et al. (Eds.) (1990); Goodman and Gilman: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, which is hereby incorporated by reference in its entirety.
[00054] The term "individual" as used herein refers to vertebrates or invertebrates, including a mammal. The term "individual" includes human, animal, bird, fish, or amphibian. Typical non-limiting examples of an "individual" include humans, cats, dogs, horses, sheep, cows, oxen, pigs, sheep, mice and guinea pigs.
[00055] The term "pharmaceutically acceptable derivative" as used herein refers to and includes any pharmaceutically acceptable salt, prodrugs and metabolites, esters, ethers, hydrates, polymorphs, solvates, complexes, enanciomers or adducts of a compound described herein which , after administration to an individual, are able to supply (directly or indirectly) the precursor compound. For example, the term "antibacterial agent or a pharmaceutically acceptable derivative thereof" includes all derivatives of the antibacterial agent (for example, salt, prodrugs, metabolites, esters, ethers, hydrates, polymorphs, solvates, complexes, enanciomers or adducts) that , after administration to an individual, are able to supply (directly or indirectly) the antibacterial compound.
[00056] In general, the term "cation" includes Na, K, Mg, Ca, NH4 +, (CH3CH2) 3N +, etc.
[00057] In a general aspect, compounds of formula (I) are provided:
or a stereoisomer or a pharmaceutically acceptable salt thereof; where: Ri is: (a) hydrogen, (b) (CO) n-R3, (c) COOR4, or (d) COCH2COR3 n is 0, 1 or 2; R2 is: (a) SO3M, (b) SO2NH2, (C) PO3M, (d) CH2COOM, (e) CF2COOM, (f) CHFCOOM, or (g) CF3; M is hydrogen or a cation; R3 is: (a) hydrogen, (b) Ci-Cθ alkyl optionally substituted by one or more substituents independently selected from halogen, R5, CN, COOR5, CONReR , NR6R7I NR5COR8, NR5CONR6R7, heterocyclyl, heteroaryl, cycloalkyl or aryl , (c) CN, (d) NR6R7, (e) CONR6R7, (f) NHCONR6R7, (g) aryl optionally substituted by one or more substituents independently selected from Ci-Ce alkyl, Rs, NR6R7, halogen, CN, CONR6R7, SO2-alkyl, SCh-aryl, OSO2-alkyl, OSO2-aryl, or NHCONReR7, (h) heterocyclyl optionally substituted by one or more substituents independently selected from Ci-Ce alkyl, Rs, NR6R7, halogen, CN, CONR6R7, SO2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl, NHC (NH) NReR7, or NHCONReR7, (i) heteroaryl optionally substituted by one or more substituents independently selected from CI-CΘ alkyl, Rs, NR8R7, halogen, CN, CONReR7, SO2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl, or NHCONR8R7, (j) cic loalkyl optionally substituted by one or more substituents independently selected from Ci-Ce alkyl, Rs, NR8R7, halogen, CN, CONReR7, Sθ2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl, or NHCONReR7, (k) cycloalkyl substituted by Ci-Ce alkyl in which CI-CΘ alkyl is additionally substituted by one or more substituents independently selected from ORs, NR8R7, halogen, CN, or CONReR7, or (1) OR8; R4 is: (a) hydrogen, (b) Ci-Ce alkyl optionally substituted by one or more substituents independently selected from halogen, Rs, CN, COOR5, CONR6R7, NR6R7, NR5COR8, heterocyclyl, heteroaryl, cycloalkyl or aryl, ( c) aryl optionally substituted by one or more substituents independently selected from Ci-Ce alkyl, Rs, NReR , halogen, CN, CONReR , Sθ2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl, or NHCONRβR , (d) heterocyclyl optionally substituted by one or more substituents independently selected from Ci-Ce alkyl, Rs, NReR , halogen, CN, CONReR , Sθ2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl , or NHCONRβR , (e) heteroaryl optionally substituted by one or more substituents independently selected from Ci-Ce alkyl, Rs, NReR , halogen, CN, CONReR , Sθ2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl, or NHCONRβR , or (f) cycloalkyl optionally substituted by one or more independent substituents selected from Ci-Ce alkyl, Rs, NReR , halogen, CN, CONR6R , Sθ2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl, or NHCONRβR ; R5eR8 are each independently: (a) hydrogen, or (b) C1-Cβ alkyl optionally substituted by one or more substituents independently selected from halogen, CN, CONReR , NReR , heterocyclyl, heteroaryl, cycloalkyl or aryl; (c) and R are each independently: (a) hydrogen, (b) C1-Cβ alkyl optionally substituted by one or more substituents independently selected from halogen, R5, CN, COOR5, CONRsRs, NR5R8, NR5COR8, heterocyclyl, heteroaryl, cycloalkyl or aryl , (c) aryl optionally substituted by one or more substituents independently selected from Ci-Cβ alkyl, Rs. NRsRs, halogen, CN, CONRsRs, Sθ2-alkyl, Sθ2-aryl, OSO2-alkyl, OSO2-aryl, or NHCONRsRs, (d) heterocyclyl optionally substituted by one or more substituents independently selected from Ci-Cs alkyl, Rs, NRsRs, halogen, CN, CONRsRs, Sθ2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl, or NHCONRsRs, (e) heteroaryl optionally substituted by one or more substituents independently selected from Ci-Cs alkyl, Rs, NRsRs, halogen, CN, CONRsRs, SO2-alkyl, SO2_aryl, OSO2-alkyl, OSO2-aryl, or NHCONRsRs, (f) cycloalkyl optionally substituted by one or more substituents independently selected from Ci-Cs alkyl, Rs, NRsRs, halogen, CN, CONRsRs, Sθ2-alkyl, SO2-aryl, OSO2-alkyl, OSO2-aryl, or NHCONRsRs, or (g) Rs and R are placed together to form a four to seven-membered ring.
[00058] Typical non-limiting examples of compounds according to the invention include: mono- [2- (N '- [(S) -pyrrolidin-2-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza- bicycles [3.2.1] oct-6-yl] ester of trans-sulfuric acid; trans- [2- (N '- ((R) -piperidin-3-carbonyl) -hydrazinocarbonyl) -7- oxo-1,6-diaza-bicycl [3.2.1] oct-6-yl] ester -sulfuric; trans- [2- (N '- [(R) -pyrrolidin-3-carbonyl] -hydrazinocarbonyl) -7- oxo-1,6-diaza-bicycl [3.2.1] oct-6-yl] ester -sulfuric; trans- {7-oxo-2- [N '- ((R) -piperidin-3-carbonyl) - hydrazinocarbonyl] -1,6-diaza-bicyclo [3.2.1] -oct-6-yloxy} -acetic acid ; trans-difluoro- {7-oxo-2- [N '- ((R) -piperidin-3-carbonyl) - hydrazinocarbonyl] -1,6-diaza-bicyclo [3.2.1] -oct-6-yloxy acid} -acetic; mono- [2-hydrazinocarbonyl-7-oxo-1,6-diaza-bicyclo [3.2.1] oct-6-yl] ester of trans-sulfuric acid; mono- [2- (N '- (amino-acetyl) -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicyclo [3.2.1] oct-6-yl] trans-sulfuric acid ester; mono- [2- (N '- (3-amino-propioyl) -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicyclo [3.2.1] oct-6-yl] ester of trans-sulfuric acid; mono- [2- (N '- (4-amino-butanoyl) -hydrazinocarbonyl) -7-oxo- 1.6-diaza-bicyclo [3.2.1] oct-6-yl] trans-sulfuric acid ester; mono- [2- (N '- ((2S) -2-amino-3-hydroxy-propioyl) -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycle [3.2.1] oct-6-yl] trans-sulfuric acid ester; mono- [2- (N '- [(2S, 4S) -4-fluoro-pyrrolidin-2-carbonyl] - hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycle [3.2.1] oct-6- il] trans-sulfuric acid ester; mono- [2- (N '- [(2S, 4R) -4-methoxy-pyrrolidin-2-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycle [3.2.1] oct-6- il] trans-sulfuric acid ester; mono- [2- (N '- (piperidin-4-carbonyl) -hydrazinocarbonyl) -7-oxo- 1,6-diaza-bicyclo [3.2.1] oct-6-yl] ester of trans-sulfuric acid; trans- [2- (N '- ((RS) -piperidin-3-carbonyl) -hydrazinocarbonyl) -7- oxo-1,6-diaza-bicycl [3.2.1] oct-6-yl] ester -sulfuric; trans- [2- (N '- ((S) -piperidin-3-carbonyl) -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycl [3.2.1] oct-6-yl] ester -sulfuric; trans- [2- (N '- ((RS) -piperidin-2-carbonyl) -hydrazinocarbonyl) -7- oxo-1,6-diaza-bicycl [3.2.1] oct-6-yl] ester -sulfuric; trans- [2- (N '- ((S) -piperidin-2-carbonyl) -hydrazinocarbonyl) -7- oxo-1,6-diaza-bicyclo [3.2.1] oct-6-yl] ester -sulfuric; trans- [2- (N '- ((R) -piperidin-2-carbonyl) -hydrazinocarbonyl) -7- oxo-1,6-diaza-bicyclo [3.2.1] oct-6-yl] ester -sulfuric; mono- [2- (N '- (piperazin-4-yl-acetyl) -hydrazinocarbonyl) -7-oxo- 1.7-diaza-bicyclo [3.2.1] oct-6-yl] trans-sulfuric acid ester; mono- [2- (N '- ((RS) -1-amino-1-phenyl-acetyl) -hydrazinocarbonyl) - 7-oxo-1,6-diaza-bicycle [3.2.1] oct-6-yl] trans-sulfuric acid ester; trans- [2- (N '- ((RS) -3-amino-butanoyl) -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicyclo [3.2.1] oct-6-yl] ester -sulfuric; mono- [2- (N '- (3-amino-2,2-dimethyl-propioyl) -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicyclo [3.2.1] oct-6-yl] ester trans-sulfuric acid; trans- [2- (N '- (1-aminomethyl-cyclopropan-1-carbonyl) -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycl [3.2.1] oct-6-yl] ester -sulfuric; trans- [2- (N '- (2-amino-4-carboxamido-butanoyl) -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicyclo [3.2.1] oct-6-yl] ester -sulfuric; mono- [2- (N '- (5-amino-pentanoyl) -hydrazinocarbonyl) -7-oxo-1.8-diaza-bicyclo [3.2.1] oct-6-yl] trans-sulfuric acid ester; mono- [2- (N '- ((2S) -2,6-diaminohexanoyl) -hydrazinocarbonyl) - 7-oxo-1,6-diaza-bicyclo [3.2.1] oct-6-yl] ester of trans-sulfuric acid;
[00059] mono- [2- (N '- ((2-aminoethoxy) -acetyl) -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicyclo [3.2.1] oct-6-yl] acid ester trans-sulfuric; mono- [2- (N '- [azetidin-3-carbonyl] -hydrazinocarbonyl) -7-oxo- 1.9-diaza-bicyclo [3.2.1] oct-6-yl] trans-sulfuric acid ester; mono- [2- (N '- [yrrolidin-1-carbonyl] -hydrazinocarbonyl) -7-oxo- 1.10-iaza-bicyclo [3.2.1] oct-6-yl] trans-sulfuric acid ester; trans- [2- (N '- [(R) -pyrrolidin-2-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycl [3.2.1] oct-6-yl] ester -sulfuric; mono- [2- (N '- [((S) -3-pyrrolidin-2-yl) -propionyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycle [3.2.1] oct-6- il] trans-sulfuric acid ester; trans- [2- (N '- [(RS) -pyrrolidin-3-carbonyl] -hydrazinocarbonyl) -7- oxo-1,6-diaza-bicycl [3.2.1] oct-6-yl] ester -sulfuric; trans- [2- (N '- [(S) -pyrrolidin-3-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycl [3.2.1] oct-6-yl] ester -sulfuric; mono- [2- (N '- [(2S, 4R) -4-hydroxy-pyrrolidin-2-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycle [.2.1] oct-6-yl ] trans-sulfuric acid ester; mono- [2- (N '- [(2S, 4S) -4-amino-pyrrolidin-2-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycle [3.2.1] oct-6- il] trans-sulfuric acid ester; mono- [2- (N '- [(2S, 4S) -4-guanidino-pyrrolidin-2-carbonyl] - hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycle [3.2.1] oct-6- il] trans-sulfuric acid ester; mono- [2- (N '- [(RS) -3-piperidin-2-yl-propionyl] - hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycle [3.2.1] oct-6-yl] trans-sulfuric acid ester; trans- [2- (N '- ((RS) -piperazin-2-carbonyl) -hydrazinocarbonyl) - 7-oxo-1,6-diaza-bicycl [3.2.1] oct-6-yl] ester -sulfuric; trans- [2- (N '- ((S) -morpholin-3-carbonyl) -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycl [3.2.1] oct-6-yl] ester -sulfuric; mono- [2- (N '- (3-oxo-3-piperazin-1-yl-propionyl) -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycle [3.2.1] oct-6-yl] trans-sulfuric acid ester; mono- [2- (N '- ((RS) -1-amino-1-pyridin-2-yl-acetyl) -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycle [3.2.1] oct- 6-yl] trans-sulfuric acid ester; trans mono- [2- (N '- (2-amino-thiazol-4-carbonyl) -hydrazinocarbonyl) - 7-oxo-1,6-diaza-bicycl [3.2.1] oct-6-yl] ester -sulfuric; Sodium salt of mono- [2- (N '- (cyano-acetyl) -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicyclo [3.2.1] oct-6-yl] trans-sulfuric acid ester ; Trans-N '- tert-butyl ester sodium salt (7-oxo-6-sulfo-oxy-1,6-diaza-bicyclo [3.2.1] octane-2-carboxylic acid) - hydrazinecarboxylic; Sodium salt of mono- [2- (N '- (morpholin-4-yl-acetyl) -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycl [3.2.1] oct-6-yl] ester trans-sulfuric acid; Sodium salt of mono- [2- (N '- (6-carboxamido-pyridin-2-carbonyl) -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycle [3.2.1] oct-6-yl] trans-sulfuric acid ester; Sodium salt of mono- [2- (N '- (morpholin-4-oxo-carbonyl) -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicyclo [3.2.1] oct-6-yl] ester trans-sulfuric acid; Sodium salt of mono- [2- (N '- [(S) -1-carbamoyl-pyrrolidin-2-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycle [3.2.1] oct- 6-yl] trans-sulfuric acid ester; Sodium salt of mono- [2- (N '- [(2S, 4S) -1-carbamoyl-4-fluoro-pyrrolidin-2-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycle [ 3.2.1] oct-6-yl] trans-sulfuric acid ester; Sodium salt of mono- [2- (N '- [(S) -1-methanesulfonyl-pyrrolidin-2-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycle [3.2.1] oct- 6-yl] trans-sulfuric acid ester; Trans mono- [2- (N '- (cyano-dimethyl-acetyl) -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicyclo [3.2.1] oct-6-yl] trans acid ester -sulfuric; Sodium salt of mono- [2- (N '- [(S) -5-oxo-pyrrolidin-2-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycle [3.2.1] oct- 6-yl] trans-sulfuric acid ester; or a stereoisomer or a pharmaceutically acceptable salt thereof.
[00060] In general, the compounds of the invention can be prepared according to the following procedures (Scheme 1). A person skilled in the art will appreciate that the methods described can be varied or further optimized to provide the desired and related compounds. In the following procedures, all variables are as defined above.
[00061] As described in Scheme 1, trans-6-benzyloxy-7-oxo-1,6-diaza-bicyclo [3.2.1] octane-2-carboxylic acid (1-A), which is described in the PCT International Publication No. WO 2009/091856, was reacted with corresponding acid hydrazides in the presence of a suitable coupling agent, such as EDC hydrochloride; or dicyclohexylcarbodiimide (DCC), in a 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).
[00062] 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 hydrogen source (such as hydrogen gas, ammonium formate, cyclohexene) in a suitable solvent (such as methanol, ethanol, a mixture of methanol-dichloromethane, or a mixture of N, N dimethyl formamide - dichloromethane) at a temperature ranging from about 25 ° C to 60 ° C for about 1 to 14 hours to obtain intermediate compound (1c).

[00063] The intermediate compound (1c) was sulfonated by reaction with a sulfonating reagent (such as sulfur trioxide complex - pyridine or, sulfur trioxide complex - N, 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 pyridine, a salt of sulfonic acid which, when treated with tetrabutyl ammonium sulfate, provided tetrabutylammonium salt sulfonic acid, as an intermediate compound (1d).
[00064] Some compounds according to the invention were isolated as zwitterions, by treating the intermediate compound (1d) with trifluoroacetic acid, in a suitable solvent (such as dichloromethane, chloroform or acetonitrile) at a temperature between about from -10 ° C to 40 ° C for about 1 to 14 hours, especially when R in the intermediate compound (1d) contained amine function protected by tert-butoxycarbonyl.
[00065] Some other compounds according to the invention were isolated as a corresponding sodium salt, passing the intermediate compound (1 d), sodium form through 200C Aberlite resin in a tetrahydrofuran - water mixture followed by evaporation of the solvent under vacuum.

[00066] As described in Scheme 2, the hydroxyl intermediate (1c) obtained according to scheme 1, was subjected to alkylation with the alkylating agent (for example, ethyl bromoacetate, ethyl fluoroacetate or ethyl difluoroacetate) in the presence of an base (such as potassium carbonate, diisopropylethylamine or triethylamine) in a suitable solvent (such as N, N dimethylformamide, N, N dimethyl acetamide or N-methyl pyrrolidine) to obtain the O-alkylated compound (2d).
[00067] The compound (2d) was subjected to hydrolysis in the presence of a base (such as lithium hydroxide or potassium hydroxide) in a suitable solvent (such as aqueous tetrahydrofuran, aqueous dioxane) to provide the compound of Formula ( I) after adjusting the pH.
[00068] Optionally, if R1 bears amine function protected with the Boc group, then it was removed in an additional deprotection step, using a suitable deprotecting agent (such as trifluoroacetic acid or HF pyridine) in a solvent (such as dichloromethane, chloroform or acetonitrile) to provide the compound of Formula (I).
[00069] In some embodiments, pharmaceutical compositions are provided comprising a compound of Formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
[00070] In some other embodiments, a method is provided for the prevention or treatment of 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 of the same or a pharmaceutically acceptable salt thereof.
[00071] In some embodiments, a method is provided for the prevention or treatment of a bacterial infection in an individual, said infection being caused by bacteria that produce one or more of the beta-lactamase enzymes, wherein the method comprises administration to the said individual of a pharmaceutically effective amount of a compound of Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
[00072] In some other embodiments, a method is provided for the prevention or treatment of 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 thereof or a pharmaceutically acceptable salt thereof.
[00073] In some other embodiments, a method is provided for the prevention or treatment of a bacterial infection in an individual, said infection being caused by bacteria that produce one or more of the beta-lactamase enzymes, wherein the method comprises administration said individual of a pharmaceutically effective amount of a pharmaceutical composition comprising a compound of Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
[00074] In some embodiments, pharmaceutical compositions are provided comprising: (a) a compound of Formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and (b) at least one selected beta-lactamase inhibitor from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof.
[00075] In some other embodiments, pharmaceutical compositions are provided comprising: (a) a compound of Formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and (b) at least one antibacterial agent or derivative pharmaceutically acceptable product.
[00076] In some other embodiments, pharmaceutical compositions are provided comprising: (a) a compound of Formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, (b) at least one selected beta-lactamase inhibitor from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof, and (c) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
[00077] In some other embodiments, a method is provided for the prevention or treatment of 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.
[00078] In some other embodiments, a method is provided for the prevention or treatment of a bacterial infection in an individual, said infection being caused by bacteria that produce one or more of the beta-lactamase enzymes, wherein the method comprises administration said individual of a pharmaceutically effective amount of a pharmaceutical composition comprising: (a) a compound of Formula (I), or a stereoisomer thereof 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.
[00079] In some other embodiments, a method is provided for the prevention or treatment of 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 antibacterial agent or a pharmaceutically acceptable derivative thereof.
[00080] In some other embodiments, a method is provided for the prevention or treatment of a bacterial infection in an individual, said infection being caused by bacteria that produce one or more of the beta-lactamase enzymes, wherein the method comprises administration said individual of a pharmaceutically effective amount of a pharmaceutical composition comprising: (a) a compound of Formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and (b) at least one antibacterial agent or derivative pharmaceutically acceptable product.
[00081] In some other embodiments, a method is provided for the prevention or treatment of 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.
[00082] In some other embodiments, a method is provided for the prevention or treatment of a bacterial infection in an individual, said infection being caused by bacteria that produce one or more of the beta-lactamase enzymes, wherein the method comprises administration said individual of a pharmaceutically effective amount of a pharmaceutical composition comprising: (a) a compound of Formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, (b) at least one selected beta-lactamase inhibitor from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof and (c) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
[00083] In some other embodiments, a method is provided for the prevention or treatment of 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 thereof 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.
[00084] In some other embodiments, a method is provided for the prevention or treatment of a bacterial infection in an individual, said infection being caused by bacteria that produce one or more of the beta-lactamase enzymes, wherein the method comprises administration said individual of a pharmaceutically effective amount of: (a) a compound of Formula (I), or a stereoisomer thereof 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.
[00085] In some other embodiments, a method is provided for the prevention or treatment of 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 thereof or a pharmaceutically acceptable salt thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
[00086] In some other embodiments, a method is provided for the prevention or treatment of a bacterial infection in an individual, said infection being caused by bacteria that produce one or more of the beta-lactamase enzymes, wherein the method comprises administration said individual of a pharmaceutically effective amount of: (a) a compound of Formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof .
[00087] In some other embodiments, a method is provided for the prevention or treatment of 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 thereof 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 an antibacterial agent or a pharmaceutically acceptable derivative thereof.
[00088] In some other embodiments, a method is provided for the prevention or treatment of a bacterial infection in an individual, said infection being caused by bacteria that produce one or more of the beta-lactamase enzymes, wherein the method comprises administration said individual of a pharmaceutically effective amount of: (a) a compound of Formula (I), or a stereoisomer thereof 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.
[00089] In some embodiments, pharmaceutical compositions are provided comprising: (a) mono- [2- (N '- [(R) - piperidin-3-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza- bicyclo [3.2.1] oct-6-yl] trans-sulfuric acid ester or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and (b) sulbactam or a pharmaceutically acceptable derivative thereof.
[00090] In some other embodiments, a method is provided for the prevention or treatment of a bacterial infection in an individual, said method comprising administering to said individual a pharmaceutically effective amount of: (a) mono- [2- ( N '- [(R) -piperidine-3-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicyclo [3.2.1] oct-6-yl] -ester of trans-sulfuric acid or a stereoisomer of the same or a pharmaceutically acceptable salt thereof, and (b) sulbactam or a pharmaceutically acceptable derivative thereof.
[00091] In some other embodiments, a method is provided for the prevention or treatment of a bacterial infection in an individual, said infection being caused by bacteria that produce one or more of the beta-lactamase enzymes, said method comprising administration to the said individual of a pharmaceutically effective amount of: (a) mono- [2- (N '- [(R) - piperidine-3-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycles [3.2. 1] oct-6-yl] -ester of trans-sulfuric acid or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and (b) sulbactam or a pharmaceutically acceptable derivative thereof.
[00092] In some other embodiments, a method is provided for the prevention or treatment of bacterial infection in an individual, said method comprising administering to said individual a pharmaceutically effective amount of a pharmaceutical composition comprising: (a) mono- [ 2- (N '- [(R) - piperidine-3-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicyclo [3.2.1] oct-6-yl] -ester of trans-sulfuric acid or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and, (b) sulbactam or a pharmaceutically acceptable derivative thereof.
[00093] In some embodiments, a method is provided for the prevention or treatment of a bacterial infection in an individual, said infection being caused by bacteria that produce one or more of the beta-lactamase enzymes, wherein the method comprises administration to the said individual of a pharmaceutically effective amount of a drug composition comprising: (a) mono- [2- (N '- [(R) -piperidine-3-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza- bicyclo [3.2.1] oct-6-yl] -ester of trans-sulfuric acid or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and (b) sulbactam or a pharmaceutically acceptable derivative thereof.
[00094] In some embodiments, pharmaceutical compositions are provided comprising: (a) mono- [2- (N '- [(R) - pyrrolidin-3-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza- bicyclo [3.2.1] oct-6-yl] -ester of trans-sulfuric acid or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and (b) sulbactam or a pharmaceutically acceptable derivative thereof.
[00095] In some other embodiments, a method is provided for the prevention or treatment of a bacterial infection in an individual, said method comprising administering to said individual a pharmaceutically effective amount of: (a) mono- [2- ( N '- [(R) -pyrrolidin-3-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicyclo [3.2.1] oct-6-yl] -ester of trans-sulfuric acid or a stereoisomer of the same or a pharmaceutically acceptable salt thereof, and (b) sulbactam or a pharmaceutically acceptable derivative thereof.
[00096] In some other embodiments, a method is provided for the prevention or treatment of a bacterial infection in an individual, said infection being caused by bacteria that produce one or more of the beta-lactamase enzymes, said method comprising administration to the said individual of a pharmaceutically effective amount of: (a) mono- [2- (N '- [(R) - pyrrolidin-3-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycles [3.2. 1] oct-6-yl] -ester of trans-sulfuric acid or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and (b) sulbactam or a pharmaceutically acceptable derivative thereof.
[00097] In some other embodiments, a method is provided for the prevention or treatment of bacterial infection in an individual, said method comprising administering to said individual a pharmaceutically effective amount of a pharmaceutical composition comprising: (a) mono- [ 2- (N '- [(R) - pyrrolidin-3-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicyclo [3.2.1] oct-6-yl] -ester of trans-sulfuric acid or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and, (b) sulbactam or a pharmaceutically acceptable derivative thereof.
[00098] In some embodiments, a method is provided for the prevention or treatment of a bacterial infection in an individual, said infection being caused by bacteria that produce one or more of the beta-lactamase enzymes, wherein the method comprises administration to the said individual of a pharmaceutically effective amount of a drug composition comprising: (a) mono- [2- (N '- [(R) -pyrrolidin-3-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza- bicyclo [3.2.1] oct-6-yl] -ester of trans-sulfuric acid or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and (b) sulbactam or a pharmaceutically acceptable derivative thereof.
[00099] In some embodiments, methods are provided for increasing the antibacterial effectiveness of an antibacterial agent in an 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.
[000100] In some embodiments, the compositions and methods according to the invention use the compounds of Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in combination with at least one antibacterial agent or a pharmaceutically derived acceptable value. A wide variety of antibacterial agents can be used. Non-limiting examples of typical antibacterial agents include one or more of the antibacterial compounds generally classified as aminoglycosides, ansamycins, carbacefems, cephalosporins, cephamycins, lincosamides, lipopeptides, macrolides, nitrofurans, monobactams, penicillins, polypeptides, quinolones, sulfonamines and oxonolidines, tetracidines and sulfonamides, tetracidines, sulfonamides and tetraacids. .
[000101] Typical non-limiting examples of antibacterial Aminoglycoside agents include Amikacin, Gentamycin, Kanamycin, Neomycin, Netylmycin Tobramycin, Paromomycin, Arbecacin, Streptomycin, AMP and the like.
[000102] Non-limiting examples, typical of Ansamycin antibacterial agents include Geldanamycin, Herbimycin and the like.
[000103] Typical non-limiting examples of antibacterial agents of Carbacefem include Loracarbef and the like.
[000104] Typical non-limiting examples of antibacterial Carbapenem agents include Ertapenem, Doripenem, Imipenem, Meropenem and the like.
[000105] Typical non-limiting examples of Cefamycin and Cephalosporin antibacterial agents include Cefazolin, Cefacetril, Cefadroxil, Cefalexina, Cefaloglycin, Cefalonio, Cefaloridina, Cefalotina, Cefapirina, Cefatrizina, Cefazadina, Cefazadona, Cefazadona, Cefazadona, Cefazadona , Cefonicida, Ceforanida, Cefotiam, Cefprozil, Cefbuperazone, Cefuroxime, Cefuzonam, Cefamycin, Cefoxitin, Cefotetan, Cefmetazol, Carbacefem, Cefixime, Ceftazone, Ceftrimexamine, Cefixime, Cefoxime, Cefoxime, Cefoxime , Cefpiramide, Cefpodoxima, Cefsulodina, Cefteram, Ceftibuteno, Ceftioleno, Ceftizoxima, Oxacefem, Cefepime, Cefozopran, Cefpirome, Cefquinoma, Ceftobiprol, Ceftiofur, Cefquinoma, Cefovecina, CXA-101, CXA-101.
[000106] Typical non-limiting examples of Lincosamide antibacterial agents include Clindamycin, Lincomycin and the like.
[000107] Typical non-limiting examples of Macrolide antibacterial agents include Azithromycin, Clarithromycin, Dirithromycin, Erythromycin, Roxithromycin, Troleandomycin, Telithromycin, Spectinomycin, Solithromycin and the like.
[000108] Non-limiting examples, typical of Monobactam antibacterial agents include Aztreonam and the like.
[000109] Typical non-limiting examples of Nitrofuran antibacterial agents include Furazolidone, Nitrofurantoin and the like.
[000110] Non-limiting examples, typical of antibacterial agents of Penicillin include Amoxicillin, Ampicillin, Azlocillin, Carbenicillin, Cloxacillin, Dicloxacillin, Mezlocillin, Methicillin, Nafcilin, Oxacillin, Penicillin G, Penicillin, Ticillin, Ticillin, Ticillin and Ticillin,
[000111] Typical non-limiting examples of antibacterial Polypeptide agents include Bacitracin, Colistin, Polymyxin B and the like.
[000112] Typical non-limiting examples of Quinolone antibacterial agents include Ciprofloxacin, Enoxacin, Gatifloxacin, Levofloxacin, Lomefloxacin, Moxifloxacin, Nalidixic acid, Levonadifloxacin, Norfloxacin, Ofloxacin, Trovpafloxacin, Trovafloxacin, Trovafloxacin, Trovafloxacin, Trovafloxacin, Trovpaflacac
[000113] Non-limiting examples, typical of antibacterial Sulfonamide agents include Mafenide, Sulfonamidochisoidina, Sulfacetamida, Sulfadiazina, Sulfametizol, Sulfametoxazol, Sulfasalazina, Sulfisoxazol, Trimetoprim and the like.
[000114] Typical non-limiting examples of antibacterial Tetracycline agents include Demeclocycline, Doxycycline, Minocycline, Oxytetracycline, Tetracycline, Tigecycline and the like.
[000115] Typical non-limiting examples of Oxazolidinone antibacterial agents include Tedizolid, Linezolid, Ranbezolid, Torezolid, Radezolid etc.
[000116] The pharmaceutical compositions according to the invention can include one or more pharmaceutically acceptable vehicles or excipients and the like, typical, non-limiting examples of such vehicles or excipients include mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc , cellulose, croscarmellose sodium, glucose, gelatin, sucrose, magnesium carbonate, wetting agents, emulsifying agents, solubilizing agents, pH buffering agents, lubricants, stabilizing agents, binding agents, etc.
[000117] 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 diluent compatible with the reconstitution prior to parenteral administration. A non-limiting example of such a compatible reconstitution diluent includes water.
[000118] 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.
[000119] In some other embodiments, the pharmaceutical compositions according to the invention are in ready-to-use form for parenteral administration.
[000120] In the methods according to the invention, the pharmaceutical composition and / or other pharmaceutically active ingredients disclosed herein can be administered by any suitable method, which serves to deliver the composition or its components 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 the nature of the active ingredients, the location of the potential or actual infection, the microorganism (eg bacteria) involved, the severity of the infection, the age and physical condition of the individual. Some non-limiting examples of administering the composition to an individual according to this invention include the oral, intravenous, topical, intraspiratory, intraperitoneal, intramuscular, parenteral, sublingual, transdermal, intranasal, aerosol, intraocular, intratracheal, intrarectal, vaginal, routes. gene device, skin patch, eye drops, ear drops or mouthwash.
[000121] The compositions according to the invention can be formulated in various dosage forms in which the active ingredients and / or excipients can be present either together (for example, as a mixture) or as separate components. When the various ingredients in the composition are formulated as a mixture, that composition can be delivered 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, as a composition / dosage form can be administered in several ways. In a possible form, the ingredients can be mixed in the desired proportions and the mixture is then administered as needed. Alternatively, the components or ingredients (active or inert) can be administered separately (simultaneously or one after the other), in an appropriate proportion, in order to achieve the same therapeutic or equivalent level or effect that would have been achieved by administering the equivalent mixture. .
[000122] Likewise, in the methods according to the invention, the active ingredients disclosed herein can be administered to a patient in several ways, depending on the needs. In some embodiments, the active ingredients are mixed in suitable amounts and then the mixture is administered to an individual. In some other embodiments, the active ingredients are administered separately. Since the invention contemplates that the active ingredient agents can be administered separately, the invention further 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 bottle, vial, syringe, box, bag and the like. Typically, the kit comprises instructions 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.
[000123] The pharmaceutical composition or active ingredients according to the present invention can be formulated in a variety of dosage forms. Typical non-limiting 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.
[000124] In general, the pharmaceutical compositions and methods described herein are useful in preventing or treating bacterial infections. Advantageously, the compositions and methods disclosed herein are also effective in preventing or treating infections caused by bacteria that are considered to be inferior or not sensitive to one or more of the known antibacterial agents or their known compositions. Some non-limiting examples of such bacteria known to have developed resistance to various antibacterial agents include Acinetobacter, E. coli, Pseudomonas aeruginosa, Staphylococcus aureus, Enterobacter, Klebsiella, Citrobacter and the like. Other non-limiting examples of infections that can be prevented or treated with 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), bacteremia, surgical meningitis, infections, etc.
[000125] Surprisingly, the compounds, compositions and methods according to the invention are also effective in preventing or treating bacterial infections caused by bacteria that produce one or more of the beta-lactamase enzymes. The ability of the compositions and methods according to the present invention to treat such resistant bacteria with typical beta-lactam antibiotics represents a significant improvement in the field.
[000126] In general, compounds of Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to the invention are also useful for increasing the antibacterial effectiveness 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 derivative thereof, with a pharmaceutically effective amount of a compound of Formula (I) or a stereoisomer of the same or a salt pharmaceutically acceptable product according to the invention.
[000127] It will be readily apparent to one skilled in the art that various substitutions and modifications can be made to the invention described herein 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 in the general descriptions described. EXAMPLES
[000128] The following examples illustrate the modalities of the invention that are currently best known. However, it should be understood that the following are only illustrative examples or application of the principles of the present invention. Numerous alternative modifications and compositions, methods and systems can be designed 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 arrangements. Thus, although the present invention has been described above with particularity, the following examples provide more details, in connection with what are presently considered the most practical and preferred embodiments of the invention. Example-1 Mono- [2- (N '- [(S) -pyrrolidin-2-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycle [3.2.1] oct-6-ill ester of trans-sulfuric acid

[000129] Step-1: Preparation of trans-2- acid tert-butyl ester [N'- (6-benzyloxy-7-oxo-1,6-diaza-bicyclo [3.2.1] octane-2-carbonyl) - hydrazinocarbonyl] - (S) -pyrrolidin-1-carboxylic:
[000130] To a clear solution of trans-6-benzyloxy-7-oxo-1,6-diaza-bicyclo [3.2.1] octane-2-carboxylic acid (15 g, 0.054 mol) in N, N-dimethyl formamide (150 ml), EDC hydrochloride (15.57 g, 0.082 mol) was added followed by HOBt (11.0 g, 0.082 mol) at about 25 ° C to 35 ° C, with stirring. The reaction mixture was stirred for 15 minutes and a solution of (S) -N- tert-butoxycarbonyl-pyrrolidin-2-carboxylic acid hydrazide (14.93 g, 0.065 mol) dissolved in N, N-dimethyl formamide (75 ml), followed by N, N-diisopropylethylamine (28.4 ml, 0.163 mol) were added. The reaction mixture was stirred at a temperature between 25 ° C to 35 ° C for 16 hours. The reaction mixture was poured under stirring in 10% aqueous citric acid solution (2250 ml). The resulting mixture was extracted with diethyl ether (1000 ml x 3). The combined organic layer was washed with water (1000 ml) followed by a brine solution (500 ml) and dried over sodium sulfate. Concentration of the organic layer under vacuum gave the crude residue in 13 gm of quantity. The residue was purified using silica gel column chromatography to provide the product tert-butyl acid ester (trans-2- [N '- (6-benzyloxy-7-oxo-1,6-diaza-bicycles [3.2.1 ] octane-2-carbonyl) -hydrazinocarbonyl] - (S) -pyrrolidin-1 - carboxylic acid in 6.3 g of white powder.
[000131] Analysis: MS (ES +) C24H33N5O6 = 488.1 (M +1);
[000132] H1RMN (DMSO-d6) = 9.86 (br d, 1H), 9.75 (br d, 1H), 7.34- 7.44 (m, 5H), 4.92 (dd, 2H ), 4.07-4.10 (m, 1H), 3.78-3.82 (m, 1H), 3.68 (br d, 1H), 3.20-3.25 (m, 3H) , 2.87 (br d, 1H), 1.62-2.10 (m, 8H), 1.34 (s, 9H).
[000133] Step-2: Preparation of trans-2- [N '- (6-hydroxy-7-oxo-1,6-diaza-bicyclo [3.2.1] octane-2-carbonyl) tert-butyl ester] - hydrazinocarbonyl] - (S) -pyrrolidin-1-carboxylic:
[000134] To a clear solution of the product from step-1 (3.0 g, 6.15 mmol) in methanol (30 ml) was added 10% palladium on carbon (300 mg). The suspension was stirred under atmospheric pressure of hydrogen at a temperature of about 30 ° C for 2 hours. The catalyst was filtered over a bed of celite and the bed containing the catalyst was washed with additional methanol (10 ml) and dichloromethane (10 ml). The filtrate was concentrated in vacuo to provide a white powder, which was triturated with diethyl ether to provide 2- [N '- (6-hydroxy-7-oxo-1,6-diaza-bicyclo) tert-butyl ester [3.2 .1] octane-2-carbonyl) -hydrazinocarbonyl] - (S) -pyrrolidin-1-carboxylic as a white powder in the amount of 2.00 g in 82% yield.
[000135] Analysis: MS (ES +) C17H27N5O6 = 398.0 (M + 1);
[000136] H1RMN (DMSO-d6) = 9.82 (d, 1H), 9.70-9.80 (m, 2H), 4.08- 4.15 (m, 1H), 3.4.0 -3.78 (m, 1H), 3.59 (br s, 1H), 3.17-3.40 (m, 3H), 2.97 (br d, 1H), 1.55-2.15 (m, 8H), 1.35 (s, 9H).
[000137] Step-3: Preparation of tetrabutylammonium salt of trans-2- [N '- (6-sulfo-oxy-7-oxo-1,6-diaza-bicycles) tert-butyl ester [3.2.1] octane-2-carbonyl) -hydrazinocarbonyl] - (S) -pyrrolidin-1 - carboxylic:
[000138] The product obtained in Step 2 (2.00 g, 5.03 mmols) was dissolved in pyridine (40 ml) and to the clear solution was added pyridine - sulfur trioxide complex (4.03 g, 25.18 mmols). The suspension was stirred at a temperature of 25 ° C to 35 ° C overnight. The suspension was filtered and the solids were washed with dichloromethane (25 ml x 2). The filtrate was evaporated in vacuo and the residue was stirred in 0.5 N aqueous potassium dihydrogen phosphate solution (200 ml) for 0.5 hour. The solution was washed with ethyl acetate (100 ml x 4) and the layers were separated. To the aqueous layer, tetrabutylammonium sulfate (1.71 g, 5.03 mmol) was added and stirred for four hours at about 25 ° C. The mixture was extracted with dichloromethane (100 ml x 2). The combined organic extract was washed with brine (50 ml) and dried over sodium sulfate and evaporated in vacuo to provide a solid, which was triturated with diethyl ether and filtered to provide a white powder, as a product of step -3 (salt of trans-2- [N '- tert-butyl ester tetrabutylammonium (6-sulfo-oxy-7-oxo-1,6-diaza-bicyclo [3.2.1] octane-2-carbonyl) -hydrazinocarbonyl] - ( S) -pyrrolidin-1 - carboxylic), in 3.0 g of quantity (83% yield).
[000139] Analysis: MS (ES-) Ci7H26N5OgS.N (C4Hg) 4 as a salt = 476.0 (M-1) as a free sulfonic acid;
[000140] H1RMN (CDCh) = 9.13 (br s, 1H), 8.49 (br s, 1H), 4.35 (br s, 2H), 3.98 (d, 1H), 3.24- 3.50 (m, 10H), 3.13 (br d, 1H), 2.35 (dd, 2H), 2.16 (br s, 2H), 1.91-2.01 (m, 4H) , 1.61-1.70 (m, 10H), 1.40-1.48 (m, 17H), 0.98-1.02 (m, 12H).
[000141] Step-4: Mono- [2- (N '- [(S) -pyrrolidin-2-carbonyl] - hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycle [3.2.1] oct-6 -yl] trans-sulfuric acid ester
[000142] To the powder obtained in step 3 (3.0 g, 4.17 mmols), a solution of trifluoroacetic acid (7 ml) in dichloromethane (7 ml) was added slowly through a syringe at a temperature of -5 ° C over a period of 5 minutes. The mixture was kept under stirring for 1 hour. The solvents were removed below 40 ° C under high vacuum to provide a residue, which was triturated with diethyl ether (50 ml x 5) and each time diethyl ether was decanted. The white solid obtained was further triturated with acetonitrile (100 ml x 2). The resulting solid was stirred in dichloromethane (100 ml) and the suspension was filtered. The solid was dried under vacuum to provide the title compound of the invention (mono- [2- (N '- [(S) -pyrrolidin-2-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycle [3.2.1] oct-6-yl] ester of trans-sulfuric acid) In the amount of 1.2 g (59% yield).
[000143] Analysis: MS (ES-) C12H19N5O7S = 376.2 (M-1) as a free sulfonic acid;
[000144] H1RMN (DMSO-d6) = 10.39 (br s, 1H), 10.15 (s, 1H), 8.96 (br s, 2H), 4.19 (t, 1H), 4, 03 (br s, 1H), 3.86 (d, 1H), 3.16-3.25 (m, 3H), 3.02 (br d, 1H), 2.27-2.33 (m, 1H), 1.92-2.23 (m, 1H), 1.84-1.90 (m, 4H), 1.69-1.75 (m, 1H), 1.54-1.62 ( m, 1H). Example-2 Mono- [2- (N '- [(R) -piperidin-3-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycle [3,2,1] oct-6-yl ] trans-sulfuric acid ester

[000145] Step-1: Preparation of trans-3- [N'- (6-benzyloxy-7-oxo-1,6-diaza-bicyclo [3.2.1] octane-2-carbonyl) tert-butyl ester] - hydrazinocarbonyl] - (R) -piperidin-1-carboxylic:
[000146] Using the procedure described in Step-1 of Example 1, supra, and using trans-6-benzyloxy-7-oxo-1,6-diaza-bicyclo [3.2.1] octane -2-carboxylic acid (25 g ; 0.084 mol), N, N-dimethyl formamide (625 ml), EDC hydrochloride (24 g, 0.126 mol), HOBt (16.96 g, 0.126 mol), (R) -N-tert-butoxycarbonyl acid hydrazide -piperidine-3-carboxylic (21.40 g, 0.088 mol) to provide the title compound in an amount of 17.0 gm, 41% yield as a white solid.
[000147] Analysis: MS (ES +) C25H35N5O6 = 502.1 (M + 1);
[000148] H1RMN (CDCI3) = 8.40 (br s, 1H), 7.34-7.44 (m, 5H), 5.05 (d, 1H), 4.90 (d, 1H), 4 .00 (br d, 1H), 3.82 (br s, 1H), 3.30 (br s, 1H), 3.16-3.21 (m, 1H), 3.06 (br d, 1H ), 2.42 (br s, 1H), 2.29-2.34 (m, 1H), 1.18-2.02 (m, 4H), 1.60-1.75 (m, 4H) , 1.45-1.55 (m, 2H), 1.44 (s, 9H).
[000149] Step-2: Preparation of trans-3- [N'- (6-hydroxy-7-oxo-1,6-diaza-bicyclo [3,2,1] octane-2- tert-butyl ester] carbonyl) - hydrazinocarbonyl] - (R) -piperidin-1-carboxylic.
[000150] Using the procedure described in Step 2 of Example 1, supra, and using trans-3- [N '- (6-benzyloxy-7-oxo- 1,6-diaza-bicyclo tert-butyl ester] [3.2 .1] octane-2-carbonyl) -hydrazinocarbonyl] - (R) - piperidin-1-carboxylic (16.5 g, 0.033 mol), methanol (170 ml) and 10% palladium on carbon (3.5 g) to provide the title compound in the amount of 13.5 gm as a pale pink solid, which was used for the next reaction immediately.
[000151] Analysis: MS (ES +) C18H29N5O6 = 411.1 (M + 1);
[000152] Step-3: Preparation of tetrabutylammonium salt of trans-3- [N '- (6-sulfo-oxy-7-oxo-1,6-diaza-bicyclo-tert-butyl ester) [3.2.1] octane-2-carbonyl) -hydrazinocarbonyl] - (R) -piperidin-1 - carboxylic
[000153] Using the procedure described in Step 3 of Example 1, supra, and using trans-3- [N '- (6-hydroxy-7-oxo-1,6-diaza-bicyclo tert-butyl ester] [3.2 .1] octane-2-carbonyl) -hydrazinocarbonyl] - (R) -piperidin-1 - carboxylic (13.5 g, 0.033 mol), pyridine (70 ml) and sulfur trioxide - pyridine complex (26.11 g , 0.164 mol), 0.5 N of aqueous potassium dihydrogen phosphate solution (400 ml) and tetrabutylammonium sulfate (9.74 g, 0.033 mol) to provide the title compound with 25 gm amount as a solid yellowish, with a quantitative yield.
[000154] Analysis: MS (ES-) C18H28N5O9S.N (C4H9) 4 as a salt = 490.0 (M-1) as a free sulfonic acid;
[000155] Step-4: Mono- [2- (N '- [(R) -piperidin-3-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycle [3.2.1] oct-6 -il] trans-sulfonic acid ester
[000156] Using the procedure described in Step 4 of Example 1 above, and using the tetrabutylammonium salt of trans-3- [N '- (6-sulfo-oxy-7-oxo-1,6-tert-butyl ester) -diaza-bicyclo [3.2.1] octane-2-carbonyl) - hydrazinocarbonyl] - (R) -piperidin-1-carboxylic (24 g, 0.032 mmol), dichloromethane (60 ml) and trifluoroacetic acid (60 ml) to provide the title compound in quantity of 10 gm of a white solid, 79% yield
[000157] Analysis: MS (ES -) = C13H21N5O7S = 390.2 (M-1) as a free sulfonic acid;
[000158] H1RMN (DMSO-d6) = 9.97 (d, 2H), 8.32 (br s, 2H), 4.00 (br s, 1H), 3.81 (d, 1H), 3, 10-3.22 (m, 3H), 2.97-3.02 (m, 2H), 2.86-2.91 (m, 1H), 2.65-2.66 (m, 1H), 1.97-2.03 (m, 1H), 1.57-1.88 (m, 7H).
[000159] [a] D25 = -32.6 °, (c 0.5, water). Example-3 Mono- [2- (N '- [(R) -pyrrolidin-3-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicyclo [3.2.1] oct-6-yl] ester of trans-sulfuric acid

[000160] Step-1: Preparation of trans-3- [N '- (6-benzyloxy-7-oxo-1,6-diaza-bicyclo [3.2.1] octane-2-carbonyl tert-butyl ester] ) - hydrazinocarbonyl] - (R) -pyrrolidin-1-carboxylic:

[000161] Using the procedure described in Step-1 of Example 1, and using trans-6-benzyloxy-7-oxo-1,6-diaza-bicyclo [3.2.1] octane-2-carboxylic acid (15.7 g , 0.057 mol), N, N-dimethyl formamide (390 ml), hydrochloride (13.7 g, 11.94 g, 43% yield as a white solid).
[000162] Analysis: MS (ES +) C24H33N5O6 = 488.2 (M + 1);
[000163] H1RMN (CDCI3), exchange D2O = 7.30-7.39 (m, 5H), 4.85 (s, 2H), 3.77 (d, 1H), 3.68 (br s, 1H ), 3.39-3.41 (m, 1H), 3.17-3.26 (m, 3H), 3.01 (d, 1H), 2.90-2.92 (m, 2H), 1.97-2.03 (m, 2H), 1.79-1.89 (m, 2H), 1.66-1.70 (m, 1H), 1.55-1.57 (m, 1 H), 1.32 (s, 9H).
[000164] Step-2: Preparation of trans-3- [N'- (6-hydroxy-7-oxo-1,6-diaza-bicyclo [3.2.1] octane-2-carbonyl) tert-butyl ester] - hydrazinocarbonyl] - (R) -pyrrolidin-1-carboxylic
[000165] Using the procedure described in Step 2 of Example 1, and using trans-3- [N '- (6-benzyloxy-7-oxo-1,6-diaza-bicyclo tert-butyl ester] [3.2.1 ] octane-2-carbonyl) -hydrazinocarbonyl] - (R) -pyrrolidin-1 - carboxylic (11.5 g, 0.024 mol), methanol (115 ml) and 10% palladium on carbon (3.0 g) to provide the title compound in the amount of 9.5 g of a pale brown solid and was used for the next reaction immediately.
[000166] Analysis: MS (ES +) C17H27N5O6 = 398.2 (M + 1);
[000167] Step-3: Preparation of tetrabutylammonium salt of trans-3- [N '- (6-sulfo-oxy-7-oxo-1,6-diaza-bicycles) tert-butyl ester [3,2, 1] octane-2-carbonyl) -hydrazinocarbonyl] - (R) -pyrrolidin-1 - carboxylic:
[000168] Using the procedure described in Step 3 of Example 1, and using trans-3- [N '- (6-hydroxy-7-oxo-1,6-diaza-bicyclo tert-butyl ester] [3.2.1 ] octane-2-carbonyl) -hydrazinocarbonyl] - (R) -pyrrolidin-1 - carboxylic (9.5 g, 0.024 mol), pyridine (95 ml) and sulfur trioxide - pyridine complex (19.08 g, 0 , 12 mol), 0.5 N of aqueous potassium dihydrogen phosphate solution (300 ml) and tetrabutylammonium sulfate (8.15 g, 0.024 mol) to provide the title compound in the amount of 15.3 g of a yellowish solid, in 87% yield.
[000169] Analysis: MS (ES-) C17H26N5O9S.N (C4H9) 4 as a salt = 476.1 (M-1) as a free sulfonic acid;
[000170] H1RMN (DMSO-d6) = 9.82 (d, 2H), 3.97 (br s, 1H), 3.79 (d, 1H), 3.42-3.44 (m, 1H) , 3.00-3.18 (m, 10H), 2.65-2.97 (m, 2H), 1.98-2.01 (m, 2H), 1.74-1.83 (m, 2H), 1.63-1.72 (m, 1H), 1.38-1.55 (m, 9H), 1.33 (s, 9H), 1.24-1.28 (m. 8H) , 0.91-0.99 (m, 12H).
[000171] Step-4: Mono- [2- (N '- [(R) -pyrrolidin-3-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycle [3.2.1] oct-6 -il] trans-sulfonic acid ester:
[000172] Using the procedure described in Step 4 of Example 1, and using the tetrabutylammonium salt of trans-3- [N '- (6-sulfo-oxy-7-oxo-1,6-) tert-butyl ester diaza-bicyclo [3.2.1] octane-2-carbonyl) - hydrazinocarbonyl] - (R) -pyrrolidin-1-carboxylic (15 g, 0.021 mmol), dichloromethane (37 ml) and trifluoroacetic acid (37 ml) to provide the title compound in an amount of 7.7 g of a white solid.
[000173] Analysis: MS (ES-) = C12H19N5O7S = 376.1 (M-1) as a free sulfonic acid;
[000174] H1RMN (DMSO-d6) = 10.04 (s, 1H), 9.96 (s, 1H), 8.79 (br s, 1H), 8.68 (br s, 1H), 4, 00 (br s, 1H), 3.82 (d, 1H), 3.18-3.32 (m, 4H), 3.08-3.12 (m, 1H), 3.00 (br d, 1H), 2.05-2.29 (m, 1H), 1.96-2.05 (m, 2H), 1.84-1.87 (m, 1H), 1.69-1.73 ( m, 1H), 1.56-1.67 (m, 1H) .. [a] D25 = -44.2 °, (c 0.5, water). Example-4 trans- [7-oxo-2- [N '- ((R) -piperidin-3-carbonyl) -hydrazinocarbonyl] -1,6-diaza-bicyclo [3,2,1] -oct-6 -yloxy} -acetic

[000175] Step-1: Preparation of trans-3- {N '- (6-ethoxycarbonylmethoxy-7-oxo-1,6-diaza-bicyclo [3.2.1] octane-2-carbonyl) tert-butyl ester -hydrazinocarbonyl} - (R) -piperidin-1-carboxylic:
[000176] The intermediate compound tert-butyl ester of trans-3- [N '- (6-hydroxy-7-oxo-1,6-diaza-bicyclo [3.2.1] octane-2-carbonyl) - hydrazinocarbonyl] - (R) -piperidin-1-carboxylic (4.0 g, 9.73 mmol), obtained in Step-2 of Example 2) was dissolved in DMF (12 ml) and to the clear solution was added potassium carbonate (1 , 61 g, 11.6 mmols) followed by ethyl bromine acetate (1.2 ml, 10.0 mmols) with stirring and the suspension was stirred for 18 hours at about 25 ° C. The reaction was monitored by TLC. DMF was evaporated in vacuo to provide a residue. The residue was purified by silica gel column chromatography to provide the intermediate title compound of Step-1 in the amount of 2.6 g as a solid in 53.7% yield.
[000177] Analysis: MS (+) = C22H35N5O8 = 498.1 (M + 1);
[000178] H1RMN (CDCl3) = 8.45 (br s, 2H), 4.58 (s, 2H), 4.19-4.27 (m, 2H), 4.02-4.12 (m, 2H), 3.25 (br d, 1H), 3.15 (br d, 1H), 2.38 (br s, 1H), 2.35 (dd, 1H), 2.15-2.20 ( m, 1H), 1.79-2.02 (m, 4H), 1.67-1.77 (m, 4H), 1.44-1.51 (m, 11H), 1.28 (t, 3H).
[000179] Step-2: Preparation of trans-3- {N'- (6-carboxymethoxy-7-oxo-1,6-diaza-bicyclo [3.2.1] octane-2-carbonyl) tert-butyl ester] - hydrazinocarbonyl} - (R) -piperidin-1-carboxylic:
[000180] To a clear solution of trans-3- {N '- (6-ethoxycarbonylmethoxy-7-oxo-1,6-diaza-bicyclo [3.2.1] octane-2-carbonyl) tert-butyl ester] - hydrazinocarbonyl} - (R) -piperidin-1-carboxylic (600 mg, 1.20 mmol) in tetrahydrofuran (32 ml) and water (12 ml) lithium hydroxide (43.2 mg, 1.8 mmol) was added ) at 0 ° C. The reaction mixture was stirred for 3 hours and was neutralized to pH 6 by adding 1 N of aqueous potassium hydrogen sulfate. It was extracted with ethyl acetate (3 x 25 ml). The layers were separated and the aqueous layer was acidified with 1 N of potassium hydrogen sulfate at pH 1 and extracted with ethyl acetate (3 x 25 ml). The organic layer was dried over sodium sulfate and evaporated to dryness in vacuo to provide 160 mg of the title intermediate as a solid in 27% yield.
[000181] Analysis: MS (ES +) = C20H31N5O8 = 470.1 (M + 1)
[000182] H1RMN (CDCl3) = 8.40 (br s, 2H), 4.67 (d, 1H), 4.52 (d, 1H), 4.07-4.14 (m, 2H), 3 , 95 (br s, 1H), 3.43 (br d, 1H), 3.19 (br d, 1H), 2.47 (br s, 1H), 2.39 (dd, 1H), 2, 09-2.13 (m, 2H), 1.77-2.00 (m, 4H), 1.68-1.77 (m, 2H), 1.45-1.51 (m, 11H). .
[000183] Step-3: Trans- {7-oxo-2- [N '- ((R) -piperidin-3-carbonyl) - hydrazinocarbonyl] -1,6-diaza-bicyclo [3.2.1] -oct -6-yloxy} -acetic:
[000184] To a clear solution of trans-3- {N '- (6-carboxymethoxy-7-oxo-1,6-diaza-bicyclo [3.2.1] octane-2-carbonyl) tert-butyl ester - hydrazinocarbonyl} - (R) -piperidin-1-carboxylic (150 mg, 0.32 mmol) in dichloromethane (2 ml), trifluoroacetic acid was added, with stirring at -10 ° C. The reaction mixture was stirred for about 1 hour at -10 ° C and the solvents were evaporated in vacuo to provide a residue. The residue was triturated successively with diethyl ether (25 ml) and acetonitrile (25 ml) and the solvents were decanted to provide a solid which was dried under vacuum, to provide 59 mg of the title compound in 50% yield.
[000185] Analysis: MS (ES -) = C15H23N5O6 = 368.0 (M-1)
[000186] H1RMN (DMSO-d6) = 9.97 (br s, 2H), 4.48 (d, 1H), 4.29 (d, 1H), 3.91 (s, 1H), 3.83 (d, 1H), 3.36 (q, 1H), 3.11 - 3.21 (m, 4H), 2.84 - 3.01 (m, 3H), 2.66 (br s, 1H) , 1.90-2.05 (m, 3H), 1.69-1.76 (m, 2H), 1.59-1.66 (m, 3H). Example-5 Trans-difluoro- {7-oxo-2- [N '- ((R) -piperidin-3-carbonyl) -hydrazino carbonill-1,6-diaza-bicyclo [3.2.1] -oct-6 -yloxy} -acetic

[000187] Using the procedure described in Example 4, and using bromoethyl difluoroacetate (2.0 g, 10.0 mmols) in place of bromoethyl acetate, the title compound was prepared in the amount of 30 mg in the form of a solid.
[000188] Analysis: MS (ES +) = C15H21F2N5O6 = 406.2 (M + 1)
[000189] H1RMN (DMSO-d6) = 10.99 (d, 2H), 8.59 (br s, 2H), 3.89- 4.00 (m, 2H), 3.13-3.31 ( m, 4H), 2.95-3.07 (m, 2H), 2.81-2.88 (m, 1H), 2.62-2.78 (m, 1H), 1.97-2, 05 (m, 1H), 1-84-1.95 (m, 1H), 1.72-1.79 (m, 2H), 1.59-1.64 (m, 3H).
[000190] Compounds 6-42 (Table 1) were prepared using the procedure as described in Example 1 and using corresponding -R1CONHNH2, instead of (S) -N-tert-butoxycarbonyl-pyrrolidin-2-carboxylic acid hydrazide.














Example- 43 Sodium salt of mono- [2- (N '- (cyano-acetyl) -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicyclo [3.2.1] oct-6-yl] acid ester trans-sulfuric

[000191] Mono- [2- (N '- (cyanoacetyl) -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicyclo [3.2.1] oct-6-yl] -ester tetrabutylammonium salt trans-sulfuric acid (600 mg, obtained using the procedure described in Step-1 to Step-3 of Example 1 (using acetic cyano in place of (S) -N-tert-butoxycarbonyl-pyrrolidine-2-carboxylic acid hydrazide) was placed in tetrahydrofuran and 1: 9 water mixture (10 ml) and slowly passed through freshly activated Amberlite 200C resin in the form of sodium (100 gm). The column was eluted with 10% water mixture in tetrahydrofuran. The fractions were analyzed by TLC and the desired fractions were evaporated to remove the volatile solvent under vacuum below 40 ° C. The aqueous layer was then washed with dichloromethane (25 ml_2) and the layers were separated. aqueous solution was concentrated in vacuo below 40 ° C to obtain the residue, which was azeotroped with acetone and triturated with diethyl ether to provide a suspension. was filtered to provide the title compound (mono- [2 -. (N'- (2-cyano-acetyl) -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicyclo [3,2 , 1] oct-6-yl] -ester of trans-sulfuric acid) in 300 mg amount and 81% yield.
[000192] Analysis: MS (ES-) CwH ^ NsOySNa, 346.2 (M-1) as a free sulfonic acid;
[000193] H1RMN (DMSO-d6) = 10.2 (s, 1H), 10.05 (s, 1H), 3.99 (s, 1H), 3.82 (d, 1H), 3.72 ( s, 1H), 3.36 (s, 1H), 3.14 (br d, 1H), 2.99 (d, 1H), 1.98-2.03 (m, 1H), 1.75- 1.84 (m, 1H), 1.56-1.72 (m, 2H).
[000194] Compounds 44-52 (Table 2) used a procedure described in Example-16 and using corresponding R1CONHNH2 in place of acetic acid hydrazide.




[000195] Compounds of the invention from Examples 1 to 52 were prepared using (S) -pyrroglutamic acid as a starting compound. The absolute stereochemistry is, therefore, a (2S, 5R) 7-oxo- 1,6-diaza-bicyclo [3.2.1] octane ring. Thus, the compound of Example-2, mono- [2- (N '- [(R) -piperidin-3-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycle [3.2.1] oct -6-yl] trans-sulfuric acid ester has absolute stereochemistry as mono- [2- (N '- [(R) -piperidin-3-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza- bicycles [3.2.1] oct-6-yl] (2S, 5R) -sulfuric acid ester. Alternatively, if the starting compound used is (R) -pyrroglutamic acid, the resulting compounds will have stereochemistry (2R, 5S) in the 7-oxo-1,6-diaza-bicyclo [3.2.1] octane ring. A reference to a compound according to the invention also includes corresponding compounds having stereochemistry (2S, 5R) and (2R, 5S). Biological activity
[000196] The biological activity of representative compounds according to the invention against various bacterial strains has been investigated. In a typical study, cultures of bacteria grown overnight were diluted appropriately and inoculated onto agar media containing dilutions of test compounds. Observation for growth or no growth was performed after 16-20 hours of incubation at 35 ± 2 ° C in room air. The general procedure was performed according to the recommendations of the Clinical and Laboratory Standards Institute (CLSI), Performance Standards for Antimicrobial Susceptibility Testing, 20th Informational Supplement, M 100 - S20, Volume 30, No. 1, 2010). The results of these studies are summarized in Tables 3 to 8.
[000197] Table 3 details the antibacterial activity of representative compounds according to the invention against various strains of E. coli (NCTC 13351, M 50 and 7 MP) that express ESBL (Beta Lactamases of Extended Spectrum).



[000198] Tables 4 and 5 provide antibacterial activity of representative compounds according to the invention against various gram-negative bacterial strains resistant to various drugs (MDR) expressing various BLEEs. Activities are expressed as MIC (mcg / ml). For comparison, the activity of several known antibacterial agents (for example, Ceftazidime, Aztreonam, Imipenem, Ciprofloxacin and Tigecycline) is also included. As can be seen, the representative compounds according to the invention exhibit antibacterial activity against several strains of MDR. The data in Tables 4 and 5 also indicate that the compounds according to the invention exhibit potent activity against a wide variety of bacteria, even against those that produce different types of beta-lactamase enzymes. In general, the activity of the compounds according to the invention against various beta-lactamase that produce bacterial strains is even better than the other antibacterial agents currently used in clinical practice for the treatment of such infections.
[000199] The antibacterial activity of representative compounds according to the invention was also investigated in combination with at least one antibacterial agent, using the study protocol above and the results are given in Table 6. As can be seen, the use of compounds according to the invention significantly reduced the MIC values of the antibacterial agent (for example, in this case, Ceftazidime). The results also suggest that the compounds according to the invention increase the antibacterial effectiveness of the antibacterial agent, when said antibacterial agent is co-administered with a pharmaceutically effective amount of a compound of Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt the same.
[000200] The antibacterial activity of representative compounds according to the invention was also investigated in combination with a beta-lactamase inhibitor, using the study protocol above and the results are shown in Table 7. As can be seen, the compounds of according to the invention in combination with a beta-lactam inhibitor exhibited excellent antibacterial activity against various bacterial strains. For example, a combination comprising the compound of Example 2 (and also Example 3) according to the invention in combination with sulbactam exhibited much higher MIC values compared to when they were used alone. The results also suggest that the compounds according to the invention in combination with a beta-lactam inhibitor can be effectively used in the prevention or treatment of a bacterial infection in an individual, including infections caused by bacteria that produce one or more of the enzymes beta-lactamase.
[000201] The antibacterial activity of representative compounds according to the invention was also investigated in combination with a beta-lactamase inhibitor and an antibacterial agent, using the study protocol above and the results are shown in Table 8. As can be seen , the compounds according to the invention in combination with at least one beta-lactam inhibitor and at least one antibacterial agent exhibited excellent antibacterial activity against several bacterial strains. For example, a combination comprising the compound of Example 2 (and also Example 3) according to the invention in combination with sulbactam and Cefepime exhibited better MIC values when compared to when they were used alone. The results also suggest that the compounds according to the invention in combination with at least one beta-lactam inhibitor and at least one antibacterial agent can be effectively used in the prevention or treatment of a bacterial infection in an individual, including infections caused by bacteria that produce one or more beta-lactamase enzymes.







Note: The MICs of each of the compounds of Example 1, 2, 3, 5, 8, 9 and 14 when used alone (in the absence of Ceftazidime) are> 32 mcg / ml.

权利要求:
Claims (16)
[0001]
1. Compound, characterized by the fact that it presents the formula (I):
[0002]
2. Compound according to claim 1, characterized by the fact that it is selected from: mono- [2- (N '- [(S) -pyrrolidin-2-carbonyl] -hydrazinocarbonyl) -7- oxo- 1,6-diaza-bicyclo [3.2.1] oct-6-yl] ester of trans-sulfuric acid; trans- [2- (N '- ((R) -piperidin-3-carbonyl) -hydrazinocarbonyl) -7- oxo-1,6-diaza-bicycl [3.2.1] oct-6-yl] ester -sulfuric; trans- [2- (N '- [(R) -pyrrolidin-3-carbonyl] -hydrazinocarbonyl) -7- oxo-1,6-diaza-bicycl [3.2.1] oct-6-yl] ester -sulfuric; mono- [2- (N '- [(2S, 4S) -4-fluoro-pyrrolidin-2-carbonyl] - hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycle [3.2.1] oct-6- il] trans-sulfuric acid ester; mono- [2- (N '- [(2S, 4R) -4-methoxy-pyrrolidin-2-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycle [3.2.1] oct-6- il] trans-sulfuric acid ester; mono- [2- (N '- (piperidin-4-carbonyl) -hydrazinocarbonyl) -7-oxo- 1,6-diaza-bicyclo [3.2.1] oct-6-yl] ester of trans-sulfuric acid; trans- [2- (N '- ((RS) -piperidin-3-carbonyl) -hydrazinocarbonyl) -7- oxo-1,6-diaza-bicycl [3.2.1] oct-6-yl] ester -sulfuric; trans- [2- (N '- ((S) -piperidin-3-carbonyl) -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycl [3.2.1] oct-6-yl] ester -sulfuric; trans- [2- (N '- ((RS) -piperidin-2-carbonyl) -hydrazinocarbonyl) -7- oxo-1,6-diaza-bicycl [3.2.1] oct-6-yl] ester -sulfuric; trans- [2- (N '- ((S) -piperidin-2-carbonyl) -hydrazinocarbonyl) -7- oxo-1,6-diaza-bicyclo [3.2.1] oct-6-yl] ester -sulfuric; trans- [2- (N '- ((R) -piperidin-2-carbonyl) -hydrazinocarbonyl) -7- oxo-1,6-diaza-bicyclo [3.2.1] oct-6-yl] ester -sulfuric; mono- [2- (N '- [azetidin-3-carbonyl] -hydrazinocarbonyl) -7-oxo- 1,6-diaza-bicyclo [3.2.1] oct-6-yl] trans-sulfuric acid ester; mono- [2- (N '- [pyrrolidin-1-carbonyl] -hydrazinocarbonyl) -7-oxo- 1,6-diaza-bicyclo [3.2.1] oct-6-yl] trans-sulfuric acid ester; trans- [2- (N '- [(R) -pyrrolidin-2-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycl [3.2.1] oct-6-yl] ester -sulfuric; trans- [2- (N '- [(RS) -pyrrolidin-3-carbonyl] -hydrazinocarbonyl) -7- oxo-1,6-diaza-bicycl [3.2.1] oct-6-yl] ester -sulfuric; trans- [2- (N '- [(S) -pyrrolidin-3-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycl [3.2.1] oct-6-yl] ester -sulfuric; mono- [2- (N '- [(2S, 4R) -4-hydroxy-pyrrolidin-2-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycle [3.2.1] oct-6- il] trans-sulfuric acid ester; mono- [2- (N '- [(2S, 4S) -4-amino-pyrrolidin-2-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycle [3.2.1] oct-6- il] trans-sulfuric acid ester; mono- [2- (N '- [(2S, 4S) -4-guanidino-pyrrolidin-2-carbonyl] - hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycle [3.2.1] oct-6- il] trans-sulfuric acid ester; trans- [2- (N '- ((RS) -piperazin-2-carbonyl) -hydrazinocarbonyl) - 7-oxo-1,6-diaza-bicycl [3.2.1] oct-6-yl] ester -sulfuric; trans- [2- (N '- ((S) -morpholin-3-carbonyl) -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycl [3.2.1] oct-6-yl] ester -sulfuric; or a stereoisomer or a pharmaceutically acceptable salt thereof.
[0003]
3. Compound according to claim 1, characterized by the fact that it is selected from: Sodium salt of mono- [2- (N '- [(S) -1-carbamoyl-pyrrolidin-2-carbonyl] -hydrazinocarbonyl ) -7-oxo-1,6-diaza-bicyclo [3.2.1] oct-6-yl] trans-sulfuric acid ester; Sodium salt of mono- [2- (N '- [(2S, 4S) -1-carbamoyl-4-fluoro-pyrrolidin-2-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycle [ 3.2.1] oct-6-yl] trans-sulfuric acid ester; Sodium salt of mono- [2- (N '- [(S) -1-methanesulfonyl-pyrrolidin-2-carbonyl] -hydrazinocarbonyl) -7-oxo-1,6-diaza-bicycle [3.2.1] oct- 6-yl] trans-sulfuric acid ester; or a stereoisomer thereof.
[0004]
4. Pharmaceutical composition, characterized by the fact that it comprises a compound, as defined in any one of claims 1 to 3.
[0005]
5. Pharmaceutical composition according to claim 4, characterized by the fact that it further comprises a beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid or a pharmaceutically acceptable salt thereof.
[0006]
6. Pharmaceutical composition according to claim 4 or 5, characterized in that it further comprises an antibacterial agent or a pharmaceutically acceptable salt thereof.
[0007]
7. Pharmaceutical composition according to claim 6, characterized by the fact that the antibacterial agent is selected from the group consisting of aminoglycosides, ansamycins, carbacefems, cephalosporins, cephamycins, lincosamides, lipopeptides, macrolides, monobactams, nitrofurans, penicillins, polypeptides, quinolones, sulfonamides, tetracyclines or oxazolidinone antibacterial agents.
[0008]
8. Pharmaceutical composition according to claim 6, characterized by the fact that the antibacterial agent is a beta-lactam antibacterial agent.
[0009]
9. Pharmaceutical composition according to claim 6, characterized by the fact that said antibacterial agent is selected from a group consisting of penicillins, penems, carbapenems, cephalosporins and monobactams.
[0010]
10. Pharmaceutical composition according to claim 6, characterized by the fact that the antibacterial agent is a cephalosporin antibiotic selected from a group consisting of cephalothin, cephaloridine, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cefradine, cefizoxime, cefizoxime, cefizoxime, cefizoxime, cefizoxime, cefizoxime, cefacetril, cefotiam, cefotaxime, cefsulodine, cefoperazone, ceftizoxime, cefmenoxime, cefmetazole, cefaloglycine, cefonicid, cefodizime, cefpiroma, ceftazidime, ceifriaxone, cefpiram, cefpamexam, cefpamexam, cefdinir, cefpodoxime axetila, cefpodoxime proxetila, cefteram pivoxila, cefetamet pivoxila, cefcapene pivoxila or cefditoren pivoxila, cefuroxime, cefuroxime, loracarbacef, ceftaroline and latamoxef.
[0011]
11. Pharmaceutical composition according to claim 6, characterized by the fact that the antibacterial agent is selected from a group consisting of ceftazidime, cefepime, cefpiroma, piperacillin doripenem, meropenem, imipenem, ceftaroline and ceftolozano.
[0012]
12. Pharmaceutical composition according to claim 6, characterized by the fact that the antibacterial agent is selected from the group consisting of aminoglycosides, ansamycins, carbacefems, cephalosporins, cephamycins, lincosamides, lipopeptides, macrolides, monobactams, nitrofurans, penicillins, polypeptides, quinolones, sulfonamides, tetracyclines or oxazolidinone antibacterial agents.
[0013]
13. Pharmaceutical composition according to claim 5, characterized by the fact that it comprises: (a) mono- [2- (N '- [(R) -piperidine-3-carbonyl] -hydrazinocarbonyl) -7-oxo-1, 6-diaza-bicyclo [3.2.1] oct-6-yl] -ester of trans-sulfuric acid or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) sulbactam or a pharmaceutically acceptable salt thereof.
[0014]
14. Pharmaceutical composition according to claim 5, characterized by the fact that it comprises: (a) mono- [2- (N '- [(R) -pyrrolidin-3-carbonyl] -hydrazinocarbonyl) - 7-oxo-1, 6-diaza-bicyclo [3.2.1] oct-6-yl] -ester of trans-sulfuric acid or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) sulbactam or a pharmaceutically acceptable salt thereof.
[0015]
15. Pharmaceutical composition according to claim 6, characterized by the fact that it comprises: (a) mono- [2- (N '- ((R) -piperidin-3-carbonyl) -hydrazinocarbonyl) - 7-oxo-1, 6-diaza-bicyclo [3.2.1] oct-6-yl] ester of trans-sulfuric acid or a stereoisomer or a pharmaceutically acceptable salt thereof; and (b) cefepime or a pharmaceutically acceptable salt thereof.
[0016]
16. Pharmaceutical composition according to claim 6, characterized by the fact that it comprises: (a) mono- [2- (N '- [(R) -pyrrolidin-3-carbonyl] -hydrazinocarbonyl) - 7-oxo-1, 6-diaza-bicyclo [3.2.1] oct-6-yl] ester of trans-sulfuric acid or a stereoisomer or a pharmaceutically acceptable salt thereof; and (b) cefepime or a pharmaceutically acceptable salt thereof.

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同族专利:

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EP2748165B1|2016-11-02|

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ZA201307631B|2014-12-23|

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WO2013030733A1|2013-03-07|

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PT2748165T|2016-12-28|

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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]|

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2018-03-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2019-03-19| 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 |

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2019-07-16| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|

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2019-11-19| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|

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2020-03-31| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2020-10-20| 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 24/08/2012, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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IN2412MU2011|2011-08-27|

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IN2412/MUM/2011|2011-08-27|

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PCT/IB2012/054290|WO2013030733A1|2011-08-27|2012-08-24|1,6- diazabicyclo [3,2,1] octan-7-one derivatives and their use in the treatment of bacterial infections|

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