NZ618286B2 - Nitrogen containing compounds suitable for preventing or treating bacterial infections - Google Patents

Abstract

Disclosed is trans-7-oxo-6-(sulphoxy)-1,6-diazabicyclo[3,2,1]octane-2-carbonitrile and its salts of formula (I), wherein M is a cation selected from hydrogen, sodium, or potassium. Also disclosed is the use of compounds of formula (I) for treating or preventing bacterial infections, particularly bacterial infections caused by bacterial producing beta-lactamase enzymes. terial infections caused by bacterial producing beta-lactamase enzymes.

Description

EN CONTAINING COMPOUNDS LE FOR PREVENTING OR TREATING BACTERIAL INFECTIONS FIELD OF THE INVENTION The ion relates to nitrogen containing compounds, their preparation and their use in preventing or treating bacterial infections.

BACKGROUND OF THE INVENTION Emergence of bacterial resistance to known cterial agents is ng a major challenge in treating ial infections. One way forward to treat bacterial infections, and especially those caused by resistant bacteria, is to develop newer antibacterial agents that can overcome the bacterial resistance. Coates et al. (Br. J. Pharmacol. 2007; 152(8), 1147–1154.) have reviewed novel ches to developing new antibiotics. However, the development of new cterial agents is a challenging task. For example, Gwynn et al. (Annals of the New York Academy of Sciences, 2010, 1213: 5–19) have reviewed the challenges in discovery of antibacterial agents.

Another approach to overcome the bacterial ance to known antibacterial agents is to target the bacterial mechanisms, which helps it acquiring and maintaining the resistance.

For example, several bacteria are known to produce enzymes (beta-lactamase enzymes) that hydrolyze the beta-lactam ring in a typical beta-lactam antibacterial agent. Once the betalactam ring is hydrolyzed, the antibacterial agents become ineffective against those bacteria.

Bacteria are known to produce several types of beta-lactamase enzymes. Depending on their amino-acid sequence homologies, the beta-lactamase enzymes are broadly classified into four classes: A, B, C and D (Ambler R. P., Phil. Trans. R. Soc. Lon., B289, 321—331, 1980).

Beta-lactamase enzymes belonging to classes A, C and D use serine as the active site to facilitate catalysis, whereas those ing to class B contain one or more metal ions (e.g. zinc ions) at the active site to facilitate the beta-lactam cleavage.

Several compounds, generally known as beta-lactamase inhibitors, are capable of inhibiting activity of one or more beta-lactamase s, thereby restoring the efficacy of conventional beta-lactam antibacterial agents. Typical examples of beta-lactamase inhibitors include sulbactam, tazobactam and clavulanic acid. Drawz et al. (Clinical Microbiology Reviews, Jan. 2010, Volume 23(1), p. 160–201) have reviewed the subject of actamase inhibition. US Patent No. 592 discloses several heterocyclic compounds and their use as antibacterial agents.

The inventors have surprisingly discovered nitrogen containing compounds that are useful in preventing or treating bacterial infections SUMMARY OF THE INVENTION Accordingly there are provided en containing compounds, methods for preparation of these compounds, pharmaceutical compositions comprising these compounds, and method for preventing or ng bacterial infection in a t using these compounds.

In one l aspect, there are provided compounds of Formula (I): N Formula (I) A—N\ /303M 0 O or a stereoisomer or a pharmaceutically acceptable salt thereof; wherein M is a cation.

In another general aspect, there are provided pharmaceutical compositions comprising a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof.

In another general aspect, there is provided a method for preventing or treating ial infection in a subject, said method comprising administering to said subject a pharmaceutically effective amount of a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof.

In another general aspect, there is provided a method for preventing or treating a bacterial infection in a subject, said infection being caused by ia ing one or more actamase enzymes, wherein the method ses stering to said subject a pharmaceutically effective amount of a compound of Formula (I) or a stereoisomer or a ceutically acceptable salt thereof.

In another general aspect, there is provided a method for preventing or treating bacterial infection in a subject, said method comprising administering to said subject a pharmaceutically effective amount of a pharmaceutical composition comprising a compound of Formula (I) or a isomer or a pharmaceutically acceptable salt thereof.

In yet another general aspect, there is provided a method for preventing or treating a bacterial ion in a subject, said infection being caused by bacteria producing one or more beta-lactamase enzymes, wherein the method comprises stering to said subject a pharmaceutically effective amount of a pharmaceutical composition comprising a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt f.

In another general aspect, there are provided pharmaceutical itions comprising: (a) a compound of Formula (I), or a stereoisomer or a ceutically acceptable salt thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable salt f.

In another general , there is provided a method for preventing or treating a bacterial infection in a subject, said method comprising administering to said subject a pharmaceutically effective amount of: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically able salt thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable salt thereof.

In yet another general aspect, there is provided a method for preventing or treating a bacterial infection in a subject, said infection being caused by bacteria producing one or more beta-lactamase enzymes, said method comprising administering to said t a pharmaceutically ive amount of: (a) a compound of Formula (I) or a stereoisomer or a ceutically acceptable salt thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable salt thereof.

In another general aspect, there are ed s for increasing antibacterial effectiveness of a antibacterial agent in a subject, said method comprising co-administering said antibacterial agent or a pharmaceutically acceptable salt thereof with a pharmaceutically effective amount of a nd of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof.

In another general aspect, there is provided use of a nd according to the invention for the manufacture of a medicament for preventing or treating bacterial infection in a subject.

In another general aspect, there is provided use of a ceutical composition according to the invention for the cture of a medicament for preventing or treating bacterial infection in a subject.

In another general aspect, there is provided use of: (a) a compound of Formula (I) ing to the invention or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing or treating a bacterial infection in a subject.

In another general , there is provided use of a compound of Formula (I) according to the invention, or a stereoisomer or a pharmaceutically able salt thereof for the manufacture of a medicament for increasing antibacterial effectiveness of an cterial agent in a subject.

The s of one or more embodiments of the invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the following description including claims.

DETAILED PTION OF THE INVENTION Reference will now be made to the exemplary embodiments, and specific ge will be used herein to describe the same. It should nevertheless be understood that no limitation of the scope of the invention is thereby intended. Alterations and further modifications of the inventive features illustrated herein, and additional applications of the principles of the invention as illustrated herein, which would occur to one skilled in the relevant art and having possession of this disclosure, are to be considered within the scope of the invention. It must be noted that, as used in this ication and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. All references including s, patent applications, and literature cited in the specification are expressly incorporated herein by reference in their entirety.

The inventors have surprisingly discovered novel nitrogen containing compounds having cterial properties.

The term “stereoisomers” as used herein refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of their atoms or groups in space. The compounds of Formula (I) may n asymmetric or chiral s and, therefore, exist in different stereoisomeric forms. It is intended, unless specified otherwise, that all stereoisomeric forms of the compounds of Formula (I) as well as es thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers (including cis and trans-forms), as well as mixtures thereof, are ed within the scope of the invention. In general, a reference to a compound is intended to cover it’s stereoisomers and mixture of s stereoisomers.

The term “pharmaceutically acceptable salt” as used herein refers to one or more salts of a given compound which possesses the desired pharmacological ty of the free compound and which are neither ically nor otherwise rable. In general, the “pharmaceutically acceptable salts” refer to salts that are suitable for use in t with the tissues of human and animals without undue ty, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. (J. Pharmaceutical Sciences, 66: 1-19, 1977), incorporated herein by reference in its entirety, describes various pharmaceutically acceptable salts in details.

In general, the compounds according to the invention contain basic (e.g. nitrogen atoms) as well as acid moieties (e.g. compounds of Formula (I) wherein M is a hydrogen). A person of skills in the art would appreciate that such compounds, therefore, can form acidic 2012/054706 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 e, the basic moiety can be converted to its salt by treating a compound with a suitable amount of acid. Typical, non-limiting es of such suitable acids include hydrochloric acid, trifluoroacetic acid, methanesulphonic acid, or the like. Alternatively, the acid moiety may be converted into its salt by treating with a suitable base. Typical non- limiting examples of such bases include sodium ate, sodium onate, potassium carbonate, potassium bicarbonate or the like. In case of compounds containing more than functional groups capable of being ted into salt, each such onal may be converted to salt independently. For example, in case of compounds containing two basic nitrogen atoms, one basic nitrogen can form salt with one acid while the other basic nitrogen can form salt with another acid. Some compounds according to the invention contain both, acidic as well as basic moieties, and thus can form inner salts or corresponding zwitterions. In general, all pharmaceutically acceptable salt forms of compounds of Formula (1) according to ion including acid addition salts, base addition salts, zwitterions or the like are contemplated to be within the scope of the present invention and are generically referred to as pharmaceutically acceptable salts.

The term "infection" or “bacterial infection” as used herein includes presence of bacteria, in or on a subject, which, if its growth were ted, would result in a t to the subject. As such, the term "infection" in addition to referring to the presence of bacteria also refers to normal flora, which are not desirable. The term "infection" includes infection caused by bacteria.

The term “treat”, “treating” or “treatment” as used herein refers to administering 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 treating a t who is not yet infected, but who is susceptible to, or otherwise at a risk of infection (preventing the bacterial infection). The term "therapeutic treatment" refers to administering treatment to a subject already suffering from infection. The terms “treat”, “treating” or “treatment” as used herein also refer to administering compositions or one or more of pharmaceutically active ingredients discussed herein, with or without additional pharmaceutically active or inert ingredients, in order to: (i) reduce or ate either a ial ion or one or more symptoms of the bacterial infection, or (ii) retard the progression of a bacterial infection or of one or more ms of the bacterial infection, or (iii) reduce the severity of a bacterial infection or of one or more ms of the bacterial infection, or (iv) suppress the al manifestation of a bacterial infection, or (v) suppress the station of adverse symptoms of the bacterial infection.

The term “pharmaceutically effective amount" or “therapeutically effective amount" or “effective amount” as used herein refers to an amount, which has a therapeutic effect or is the amount required to produce a eutic effect in a subject. For example, a therapeutically or pharmaceutically effective amount of an antibacterial agent or a pharmaceutical composition is the amount of the antibacterial agent or the pharmaceutical composition ed to produce a desired therapeutic effect as may be judged by clinical trial results, model animal infection studies, and/or in vitro s (e.g. in agar or broth media).

The pharmaceutically effective amount depends on several factors, including but not limited to, the microorganism (e.g. bacteria) involved, teristics of the subject (for example height, weight, sex, age and medical history), severity of infection and the particular type of the antibacterial agent used. For prophylactic treatments, a therapeutically or prophylactically effective amount is that amount which would be effective in preventing a microbial (e.g. bacterial) infection.

The term "administration" or "administering" includes delivery of a composition or one or more pharmaceutically active ingredients to a subject, including for example, by any appropriate s, which serves to r the composition or it’s active ingredients or other pharmaceutically active ients to the site of the infection. The method of administration may vary depending on various factors, such as for example, the components of the pharmaceutical ition or the type/nature of the pharmaceutically active or inert ingredients, the site of the potential or actual ion, the microorganism involved, severity of the infection, age and al condition of the subject and a like. Some non-limiting examples of ways to administer a ition or a pharmaceutically active ingredient to a subject according to this invention includes oral, intravenous, topical, intrarespiratory, intraperitoneal, intramuscular, parenteral, sublingual, transdermal, intranasal, aerosol, intraocular, intratracheal, intrarectal, vaginal, gene gun, dermal patch, eye drop, ear drop or ash. In case of a pharmaceutical composition comprising more than one ingredient (active or inert), one of way of administering such composition is by admixing the ingredients (e. g. in the form of a suitable unit dosage form such as tablet, capsule, solution, powder and a like) and then administering the dosage form. Alternatively, the ingredients may also be administered separately (simultaneously or one after the other) as long as these ingredients reach cial therapeutic levels such that the ition as a whole provides a synergistic and/or desired .

The term "growt " as used herein refers to a growth of one or more rganisms and es reproduction or population expansion of the microorganism (e.g. bacteria). The term also includes maintenance of on-going metabolic processes of a microorganism, including processes that keep the microorganism alive.

The term, “effectiveness” as used herein refers to ability of a treatment or a composition or one or more pharmaceutically active ingredients to produce a desired biological effect in a subject. For example, the term acterial effectiveness” of a composition or a antibacterial agent refers to the ability of the composition or the antibacterial agent to prevent or treat the ial (e.g. bacterial) infection in a subject.

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.

The term “antibacterial agent” as used herein refers to any substance, compound or a combination of substances or a combination compounds capable of: (i) inhibiting, reducing or preventing growth of bacteria; (ii) inhibiting or reducing ability of a bacteria to e infection in a t; or (iii) ting or reducing ability of ia to multiply or remain infective in the environment. The term "antibacterial agent" also refers to compounds capable of decreasing infectivity or virulence of bacteria.

The term "beta-lactam antibacterial agent" as used herein refers to compounds with antibacterial properties and containing a beta-lactam nucleus in their molecular structure.

The term “beta-lactamase” as used herein refers to any enzyme or protein or any other substance that breaks down a beta-lactam ring. The term “beta-lactamase” includes enzymes that are produced by bacteria and have the ability to hydrolyze the beta-lactam ring in a beta- lactam compound, either partially or completely.

The term "beta-lactamase inhibitor” as used herein refers to a compound capable of inhibiting activity of one or more beta-lactamase enzymes, either partially or completely.

The term “pharmaceutically inert ingredient” or “carrier" or "excipient" refers to a compound or material used to facilitate administration of a compound, for example, to increase the solubility of the compound. Solid rs include, e.g., starch, lactose, dicalcium ate, sucrose, and kaolin. Liquid carriers include, e.g., sterile water, saline, buffers, non-ionic surfactants, and edible oils such as oil, peanut and sesame oils. In addition, various adjuvant commonly used in the art may be included. These and other such compounds are described in the literature, e.g., in the Merck Index, Merck & Company, Rahway, N.J. erations for the inclusion of s components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press., which is incorporated herein by reference in its entirety.

The term "subject" as used herein refers to vertebrate or invertebrate, including a . The term “subject” es human, animal, a bird, a fish, or an amphibian.

Typical, non-limiting examples of a "subject" includes humans, cats, dogs, horses, sheep, bovine cows, pigs, lambs, rats, mice and guinea pigs.

The term “Ceftolozane” as used herein refers to a compound also known as CXA-lOl (CAS Registry No.: 3; Chemical Name: (6R,7R)[(5-amino{ [(2- aminoethyl)carbamoyl]amino } - 1 l- 1 H-pyrazol-Z-ium-2—yl)methyl] ({ (ZZ)(5 - amino-l,2,4-thiadiazol-3—yl)-2—[(l-carboxy-l- methyl ethoxy)imino]acetyl}amino)oxo thia-l-azabicyclo[4.2.0]oct-2—ene-2—carboxylate). A reference to Ceftolozane is intended to include its pharmaceutically acceptable salts, pro-drugs, metabolites, esters, ethers, hydrates, rphs, solvates, complexes, enantiomers, adducts and its any other pharmaceutically acceptable derivative In one general aspect, there are ed compounds of Formula (I): NC 0| Formula (I) N 80 M \O/ 3 or a stereoisomer or a ceutically acceptable salt thereof; wherein M is a cation.

In general, the compounds of the invention can be prepared according to the general procedures given in Schemes l to 3. A person of skills in the art would iate that the described methods can be varied or optimized further to provide the desired and related compounds. In the following procedures, all variables are as defined above.

In another general aspect, there are ed pharmaceutical compositions comprising a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof.

In another general aspect, there is ed a method for preventing or treating bacterial infection in a subject, said method sing administering to said subject a pharmaceutically effective amount of a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof.

In another general aspect, there is provided a method for preventing or treating a ial infection in a t, said infection being caused by ia producing one or more beta-lactamase enzymes, wherein the method comprises administering to said subject a pharmaceutically effective amount of a nd of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof.

In another general , there is provided a method for preventing or treating bacterial infection in a subject, said method comprising administering to said subject a pharmaceutically effective amount of a pharmaceutical composition comprising a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt f.

In yet another general aspect, there is provided a method for preventing or ng a bacterial infection in a subject, said infection being caused by bacteria producing one or more beta-lactamase enzymes, wherein the method comprises administering to said subject a pharmaceutically effective amount of a ceutical composition comprising a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof.

WO 38330 Scheme 1 BnOHN o BnOHN/l, BnOHN/l’ ,, a OH , _,b (l N COOBn N COOBn COOBn H o n I—Z Boc “ Ilb .anHN/fifjv N/l, BnOHN/fi = BnOHN e o, N w~~ NH2~~ (1 I 0%“ o I o o [it COOH BOC Boc Boc VI Boc V IV NC,” N\ fi/O 0 0—8/ o 0—350 \ \ OM ON(Bu)4 a: Base,water,RT;b:Boc-anhydride,TEA,DMAP,DCM ,RT; c:LiOH, acetone; d: Pivaloyl chloride, TEA; e. Ammonia(g); f:Trif|uoroacetic anhydride,TEA,DCM g: TFA,DCM; h: Triphosgene,TEA,DMAP,DCM; i:H2, Pd/C; j:SOS-DMF; k: Tetrabutyl ammonium acetate, DCM; I: Dowex 50WX8 200 Na+ resin WO 38330 COOH A b A _, fl —> O —> CONH H 800 | II III IV BnON Of 9J1 N\ f I e ‘— <— O‘. <— A H CN CI Hi}! CN /8\ Hi}! CN 0 CN Boo Boo Elioc VI” V” VI BnOHN/l/ j NC,“ Scheme-I I“ N N N CN IX ONa a: Water, reflux,24h; b:1-Hydroxybenzotriazole ammonium salt, DCC,DMF; c: Boc-anhydride,TEA,DMAP,DCM ,RT; d:Trif|uoroacetic anhydride,TEA, DCM; e:TMSO|, NaH,DMSO,THF, -10°C 1hr; f: O-Benzyl hydroxyl HCI, EtOAc 60°C,2.5hr; g: Methane sulphonic acid, ethyl acetate,40°C; h:.KHCOS, water, 55°C; i: sodium triacetoxy borohydride, STABH, H2804; j: Triphosgene,TEA,DMAP,DCM; Scheme-1: further steps as depicted in scheme-1 B ONn , ,,, BnON N \ g f e O ( <— O I N CONH2 N CONH2 0' e + H H H'fl CONH2 /s my CONH2 BOC \ V” VI NC,” NC"~ HZNoch, .

' Scheme-I N —> N N —> E O )—N \ 0 O 0—8: 0 \OBn OBn ONa a: Water, reflux,24h; b:1-Hydroxybenzotriazo|e ammonium salt, DCC,DMF; c: Boc-anhydride,TEA,DMAP,DCM ,rt; d:TMSO|, NaH,DMSO,THF, -10°C1hr; e: O-Benzyl hydroxyl amine.HCI, EtOAc 60°C, 2.5hr; f: Methane sulphonic acid, ethyl e,40°C g:.KHCOS, water, 55°C; 9: sodium triacetoxy borohydride, STABH, H2804; h: sgene,TEA,DMAP,DCM; i: Trifluoroacetic anhydride, TEA, DCM; Scheme-1: further steps as depicted in -1 In some embodiments, the compound of formula (I), wherein M is sodium, was prepared using a general procedure described in Scheme 1. Typically, (S) (benzyloxyamino)-piperidine-2—carboxylic acid benzyl ester oxalate salt (11) was converted into the free base by treating with a suitable base at RT to obtain the compound (Ila). This on reaction with Boc anhydride in the ce of a base and suitable catalyst like DMAP, at temperatures g from —5 to 40°C was obtained the compound (IIb). This compound on ysis with a base like lithium hydroxide at temp from -5 to 25°C gave trans benzyloxyamino-piperidine-l,2—dicarboxylic acid-l-tertbutyl ester compound (III).

The compound (III), was reacted with acid chloride such as pivaloyl chloride in the presence of suitable base such as yl line, ylamine or diisopropyl ethylamine in a solvent such as dichloromethane, tetrahydrofuran, 1,4 dioxane or chloroform, at a temperature ranging from -5 to 35°C, for about 1 to 2 hours to provide anhydride (IV).

The anhydride (IV) was subsequently treated with a gas at a temperature ranging from -50 to 5°C, for about 0.5 to 2 hours to provide amide ediate compound (V).

Dehydration of the intermediate compound (V) was effected by treating intermediate (V) with trifluoroacetic anhydride, in a solvent such as toluene, chloroform, tetrahydrofuran, or dichloromethane, at a temperature ranging from -5 to 35°C, for about 1 to 24 hours to provide nitrile intermediate compound (VI).

The intermediate compound (VI) was deprotected to e intermediate compound (VII), using deprotecting agent such as trifluoro acetic acid or hydrochloric acid in a solvent such as dichloromethane, form, acetonitrile or water, at a temperature g from — to 50°C, for about 1 to 24 hours. The cyclization of intermediate nd (VII) was achieved by treating intermediate VII using reagent such as phosgene solution or diphosgene or triphosgene, in a solvent such as e, chloroform, acetonitrile, and in the presence of base such as triethyl amine or diisopropyl ethyl amine, at a temperature ranging from -5 to 50°C, for about 1 to 24 hours to provide cyclized intermediate compound (VIII).

The cyclized intermediate compound (VIII) was subjected for hydrogenolysis by using a catalyst such as 5% or 10% palladium on carbon, or 20% palladium ide on carbon, in the presence of hydrogen source such as en gas, ammonium formate, formic acid or exene, in a solvent such as methanol, ethanol, methanol-dichloromethane e, or N,N dimethyl formamide-dichloromethane mixture at a temperature ranging from to 60°C for about 1 to 24 hours to provide N-hydroxy intermediate compound (IX).

The intermediate compound (IX) was sulfonated by reacting it with a sulfonating reagent such as pyridine sulfur trioxide complex, or N,N-dimethyl formamide sulfur trioxide complex in a solvent such as ne, methyl formamide, dichloromethane or mixture thereof at a temperature ranging from —5 to 50°C, for about 0.5 to 24 hours to provide pyridine salt of sulfonic acid (X) which subsequently was treated with utyl ammonium acetate to provide tetrabutylammonium salt of sulfonic acid ediate compound (XI).

The compound of invention was isolated as a sodium salt by passing intermediate compound (XI) through sodium form of Dowex 50WX8 200 resin in aqueous tetrahydrofuran ed by evaporation of solvent fractions under reduced pressure to obtain the compound I, wherein M is sodium.

Alternatively this compound can be prepared by treating the compound XI with ethyl sodium hexanoate (when M=Na) in a solvent like acetone, ethyl acetate, tetrahydrofuran, ethanol, isopropanol, at temperatures from RT to 80°C.

Various polymorphs of these compounds (where M=Na) have been prepared In another general aspect, there are provided pharmaceutical compositions 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 salt thereof.

In another general aspect, there is provided a method for ting or treating a bacterial infection in a subject, said method comprising administering to said subject a pharmaceutically effective amount of: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable salt thereof.

In yet another l aspect, there is provided a method for preventing or treating a bacterial infection in a subject, said ion being caused by ia producing one or more beta-lactamase enzymes, said method comprising administering to said subject a pharmaceutically effective amount of: (a) a nd of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable salt thereof.

In another general aspect, there are provided methods for increasing cterial effectiveness of a antibacterial agent in a subject, said method comprising co-administering said antibacterial agent or a pharmaceutically acceptable salt thereof with a pharmaceutically effective amount of a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof.

In some embodiments, the compositions and methods according to the invention use compounds of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof in combination with at least one cterial agent. A Wide variety of antibacterial agents can be used. Typical, non-limiting examples of antibacterial agents include one or more of antibacterial compounds generally classified as Aminoglycosides, Ansamycins, ephems, Cephalosporins, Cephamycins, Lincosamides, Lipopeptides, Macrolides, Monobactams, Nitrofurans, Penicillins, Polypeptides, ones, Sulfonamides, Tetracyclines, Oxazolidinone and the like.

Typical, non-limiting es of Aminoglycoside antibacterial agents include Amikacin, Gentamicin, Kanamycin, in, Netilmicin, Tobramycin, Paromomycin, Arbekacin, Streptomycin, Apramycin and the like.

Typical, non-limiting examples of Ansamycin antibacterial agents include Geldanamycin, Herbimycin and the like.

Typical, non-limiting examples of Carbacephem antibacterial agents include rbef and the like.

Typical, non-limiting examples of Carbapenem antibacterial agents include Ertapenem, Doripenem, Imipenem, Meropenem and the like.

Typical, non-limiting examples of Cephalosporin and Cephamycin antibacterial agents e Cefazolin, Cefacetrile, Cefadroxil, Cefalexin, Cefaloglycin, nium, Cefaloridine, Cefalotin, Cefapirin, Cefatrizine, Cefazedone, flur, Cefradine, Cefroxadine, Ceftezole, Cefaclor, Cefamandole, Cefminox, Cefonicid, Ceforanide, Cefotiam, Cefprozil, Cefbuperazone, Cefuroxime, Cefuzonam, Cephamycin, tin, Cefotetan, azole, Carbacephem, Cefixime, Ceftazidime, Ceftriaxone, Cefcapene, Cefdaloxime, Cefdinir, Cefditoren, Cefetamet, Cefmenoxime, Cefodizime, razone, Cefotaxime, Cefpimizole, Cefpiramide, oxime, Cefsulodin, Cefteram, Ceftibuten, Ceftiolene, Ceftizoxime, Oxacephem, Cefepime, Cefozopran, Cefpirome, Cefquinome, Ceftobiprole, Ceftiofur, Cefquinome, cin, CXA-lOl, oline, Ceftobiprole etc.

Typical, non-limiting examples of Lincosamide antibacterial agents include Clindamycin, Lincomycin and the like.

Typical, non-limiting examples of Macrolide antibacterial agents include omycin, Clarithromycin, Dirithromycin, Erythromycin, Roxithromycin, Troleandomycin, Telithromycin, nomycin and the like.

Typical, non-limiting examples of ctam antibacterial agents include Aztreonam and the like.

Typical, non-limiting examples of Nitrofuran antibacterial agents include Furazolidone, urantoin and the like.

Typical, non-limiting examples of Penicillin antibacterial agents include Amoxicillin, Ampicillin, Azlocillin, Carbenicillin, Cloxacillin, Dicloxacillin, Flucloxacillin, Mezlocillin, Methicillin, Nafcillin, Oxacillin, Penicillin G, Penicillin V, Piperacillin, Temocillin, Ticarcillin and the like.

Typical, non-limiting examples of Polypeptide antibacterial agents include Bacitracin, Colistin, Polymyxin B and the like.

Typical, non-limiting examples of Quinolone antibacterial agents e Ciprofloxacin, Enoxacin, Gatifloxacin, Levofloxacin, Lomefloxacin, Moxifloxacin, Nalidixic acid, Norfloxacin, Ofloxacin, Trovafloxacin, Grepafloxacin, Sparfloxacin, Temafloxacin and the like. l, non-limiting examples of amide antibacterial agents include Mafenide, Sulfonamidochrysoidine, etamide, Sulfadiazine, Sulfamethizole, Sulfamethoxazole, Sulfasalazine, oxazole, Trimethoprim and the like.

Typical, non-limiting examples of Tetracycline antibacterial agents include Demeclocycline, Doxycycline, Minocycline, Oxytetracycline, Tetracycline, Tigecycline and the like.

Typical, non-limiting examples of Oxazolidinone antibacterial agents include Linezolid, Ranbezolid, Torezolid, Radezolid etc.

The pharmaceutical compositions according to the invention may include one or more pharmaceutically able carriers or ents or the like, Typical, non-limiting examples of such carriers or ent include mannitol, lactose, starch, magnesium stearate, sodium saccharine, , cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, g agents, emulsifying agents, lizing agents, pH buffering agents, lubricants, stabilizing agents, binding agents etc.

The pharmaceutical compositions according to this invention can exist in various forms. In some embodiments, the ceutical 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 on of a compatible reconstitution diluent prior to parenteral stration. miting example of such a compatible reconstitution diluent includes water.

In some other embodiments, the pharmaceutical itions according to the invention are in the form of a frozen composition that can be diluted with a compatible diluent prior to parenteral administration.

In some other embodiments, the pharmaceutical compositions ing to the invention are in the form ready to use for parenteral administration.

In the methods ing to the invention, the pharmaceutical composition and/or other pharmaceutically active ingredients disclosed herein may be administered by any appropriate method, which serves to deliver the composition or its constituents or the active ients to the desired site. The method of administration can vary depending on various factors, such as for example, the components of the pharmaceutical composition and nature of the active ingredients, the site of the potential or actual infection, the microorganism (e. g. bacteria) involved, ty of infection, age and physical condition of the subject. Some non- limiting examples of administering the composition to a subject ing to this invention include oral, intravenous, topical, intrarespiratory, intraperitoneal, intramuscular, parenteral, sublingual, transdermal, intranasal, aerosol, cular, intratracheal, intrarectal, vaginal, gene gun, dermal patch, eye drop, ear drop or mouthwash.

The compositions according to the ion can be ated into various dosage forms wherein the active ingredients and/or excipients may be t either together (e.g. as an admixture) or as separate components. When the various ingredients in the ition are formulated as a mixture, such composition can be delivered by administering such a mixture. The composition or dosage form wherein the ingredients do not come as a e, but come as separate components, such composition/dosage form may be administered in several ways. In one possible way, the ingredients may be mixed in the desired proportions and the mixture is then administered as required. Alternatively, the components or the ingredients (active or inert) may be separately administered (simultaneously or one after the other) in appropriate proportion so as to achieve the same or equivalent therapeutic level or effect as would have been achieved by administration of the equivalent mixture.

Similarly, in the methods according to the invention, the active ingredients disclosed herein may be administered to a subject in several ways depending on the requirements. In some embodiments, the active ingredients are admixed in appropriate amounts and then the admixture is administered to a t. In some other embodiments, the active ingredients are administered separately. Since the invention contemplates that the active ingredients agents may be administered separately, the invention further provides for combining separate pharmaceutical compositions in kit form. The kit may comprise one or more separate pharmaceutical compositions, each comprising one or more active ingredients. Each of such separate compositions may be present in a separate container such as a bottle, vial, syringes, boxes, bags, and the like. lly, the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are ably administered in different dosage forms (e.g., oral and parenteral) ore are administered at different dosage intervals. When the active ingredients are administered separately, they may be administered simultaneously or sequentially.

The pharmaceutical composition or the active ingredients according to the t invention may be formulated into a variety of dosage forms. Typical, non-limiting examples of dosage forms e solid, semi-solid, liquid and aerosol dosage forms; such as tablets, capsules, powders, solutions, sions, suppositories, ls, granules, emulsions, syrups, elixirs and a like.

In general, the pharmaceutical compositions and method disclosed 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 be less or not susceptible to one or more of known cterial agents or their known compositions. Some non-limiting examples of such bacteria known to have developed resistance to various cterial agents include Acinetobacter, E. coli, Pseudomonas aeruginosa, lococcus aureus, Enterobacter, Klebsiella, Citrobacter and a like. Other non-limiting examples of infections that may be prevented or treated using the compositions and/or methods of the invention include: skin and soft tissue ions, febrile neutropenia, urinary tract infection, intraabdominal infections, respiratory tract infections, pneumonia (nosocomial), bacteremia meningitis, surgical, ions etc.

Surprisingly, the compounds, itions and methods according to the invention are also effective in ting or treating bacterial infections that are caused by bacteria producing one or more beta-lactamase enzymes. The ability of itions and methods according to the present invention to treat such resistant bacteria with typical beta-lactam antibiotics ents a significant improvement in the art.

In general, the compounds of Formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof according to invention are also useful in increasing antibacterial effectiveness of a antibacterial agent in a subject. The antibacterial effectiveness one or more antibacterial agents may increased, for example, by co-administering said antibacterial agent or a pharmaceutically acceptable salt thereof with a pharmaceutically effective amount of a compound of Formula (I) or a stereoisomer or a pharmaceutically able salt thereof according to the invention.

It will be y apparent to one skilled in the art that varying substitutions and modifications may be made to the invention sed herein without departing from the scope and spirit of the invention. For example, those skilled in the art will recognize that the invention may be ced using a variety of different compounds within the described c descriptions.

EXAMPLES The following examples illustrate the ments of the ion that are presently best known. However, it is to be understood that the following are only exemplary or illustrative of the application of the principles of the present invention. Numerous modifications and alternative compositions, methods, and systems may be devised by those d in the art without departing from the spirit and scope of the present invention. The appended claims are intended to cover such modifications and arrangements. Thus, while the present ion has been described above with particularity, the following examples provide further detail in connection with what are presently deemed to be the most practical and preferred embodiments of the invention.

Pre aration of Sodium salt of transoxo sul hox -l 6-diazabic clo 3.2.1 e-2— carbonitrile I Ste 1: Pre aration of se and — Boc rotection BnOHN/I BnOHN/IIQH NaHCOB BnOHN/Il 80% _> TEA DMAP '(Nj:COOBn OH water COOBn N COOBn H Ila Ilb The oxalate salt 11 (30g, 0.0697moles) was partitioned between water (300ml), and ethyl acetate (300ml) followed by addition of sodium bicarbonate (ll.7gm, 0.139moles) under stirring. After lhr the organic layer was separated and the aqueous layer was extracted with ethyl acetate (150ml). The combined organic layer was washed with water (150ml) then brine (150ml), dried (over NaZSO4) and the solvent ated under reduced pressure to obtain the free base IIa, 24gm.

To a cooled (5-100C solution of the free base (24g, 0.0705moles) in DCM (240ml) were added ylamine (19.68ml, 0.14lmoles), Boc anhydride (17.8ml, 0.0775moles) under stirring. After 30min. was added DMAP m, 0.00705moles) and the resulting solution was allowed to warm to room temperature and stirred for a further l6hrs. The on mixture was diluted with saturated aqueous ammonium chloride on (10ml), stirred well and the DCM layer was separated, washed with water (10ml) and finally with brine (10ml). The solvent was evaporated under reduced pressure and the residue chromatographed on a column of silica gel (60-120 mesh). Elution with mixtures of ethyl e: hexane 25-50% and concentration of the combined fractions gave the product as a colorless oil, 25gm(yield: 80%).

MS: 439 [M+]; MF: C26H33N05; MW: 439.

Step 2: Hydrolysis of Benzyl ester BnOHN/I(l LiOHAcetone BnOHN/g N COOBn GAO N COOH X of)? To a solution of the nd IIb (25gm, 0.0567moles) in acetone (500ml), at 0 0C, was added lithium hydroxide solution (3.81gm, 0.0908moles in mixture of 228.6ml water and 76.2 ml acetone) drop-wise under vigorous stirring. The on mixture was allowed to warm to RT and stirring continued further for 5hrs. The ing mixture was cooled to 0 °C and pH adjusted to 8 to 8.5 with 2N HCl (~10ml). The reaction mixture was diluted with brine (75ml) and toluene (250ml) under stirring, and after 10 minutes the organic layer was separated. The s layer was re-extracted with toluene (2 X 120ml). The aqueous layer was acidified to pH 3-4 by using 2N HCl and the solution extracted with ethyl acetate (3X200ml).,The combined organic layer was washed with water (200ml), and brine (200ml), dried (over )and the solvent evaporated under reduced pressure to obtain the product as a thick oil, 21g, (quantitative yield).

MS: 349(M+); MF: C19H27N05; MW: 349 Step 3: Conversion of Acid to Amide Snow/”(l BnOHN/I’ BnOHN/l’ Pivaloyl chloride, NH N COOH TEA N 0% NHso) N O O 0*00 O ogNOO X X X ”I IV V To a stirred on of compound IV (21 gm, 0.06moles) in DCM (210ml) at 0°C was added TEA (25.12ml, 0.18moles) followed by slow addition of Pivaloyl chloride (11.07ml, 0.09moles). The resulting mixture was stirred further for 1.5hrs. The on mixture was cooled to —40°C and dry ammonia gas was bubbled through the reaction mixture for 30 min.

The reaction mixture was allowed to warm to RT and the suspended white solid was filtered off. The solvent was evaporated under reduced pressure and the residue chromatographed on a column of silica gel (60-120 mesh). Elution with a mixture of acetone: hexane system (1:4) and concentration of the combined solvents gave the t, as thick oil, 10.2gm (yield: 49%) MS: 348[M+], MF: C19H28N204; MW: 348.

Step 4: sion of Amide to Cyano BnOHN/,, NH TFAA, TEA i 2 N /N 0 2° 0*0 To a cooled (0°C) and stirred on of compound VI (10.2gm, 0.0286moles) in DCM (306ml) was added ylamine (17.99ml, 1.289moles) and followed by the slow addition of Trifluoro acetic ide (12.08gm, 0.0573moles). The resulting solution was allowed to warm to RT and d for a further 6h. The reaction mixture was washed water (3*100ml), Saturated ammonium chloride solution (100ml) and brine (100ml). The organic layer was dried (NazSO4) and the solvent evaporated under reduced pressure. The residue was chromatographed on a column of silica gel (60-120 mesh) using a mixture of Acetone: Hexane (1:19). tration of the combined fractions gave the product, as a white solid, 9.7gm (yield - quantitative).

MS: 331(M+), MF: C18H25N303; MW: 331 Step 5: Deprotection of Cyano BnOHN/I’ BnOHN/, TFA, DCM N / é UV/N VI VII To a chilled (-l5°C) and stirred solution of nd VII (6gm,) in DCM ) was added Trifluoro acetic acid (12ml) and the mixture was allowed to warm to RT. The reaction mixture was stirred for a further 4hrs. The solvent was ated under reduced pressure at 40$ 5°C and the e diluted with aqueous sat. sodium bicarbonate solution (60ml) and the mixture extracted with DCM (2 X 60ml). The combined extracts were washed with water (60ml), dried (over sodium sulphate) and evaporated under reduced pressure at 35$ 5°C to obtain 4.2gm of compound VIII.

Step 6: Formation of lic compound Triphosgene, TEA, BHOHN/I, NC/l DMAP,DCM N IQN H / H.

O O V“ VIII b To the cooled (0- 5°C) and stirred solution of compound VIII (4.2gm) in acetonitrile (63ml) was added triethyl amine (5.28ml) followed by a slow addition of a solution of Triphosgene (l.9gm) in Acetonitrile (16.8ml). Stirring was further continued for 30min. followed by addition of Dimethyl amino pyridine (0.178gm). The reaction e was allowed to warm to RT and stirred for further l6hrs. A aqueous sat. solution of sodium bicarbonate (33.6ml) was added to the reaction mixture and the resulting mixture d for 30min. The mixture was concentrated to 1/3rd volume under reduced pressure. The residue was diluted with water (42ml) and the resulting mixture extracted with DCM (2 X 42ml). The solvent was evaporated under reduced pressure and the residue purified over a column of silica-gel (60 —120 mesh). Elution with a 1:4 mixture of acetone: hexane and tration of the combined fractions gave the t as white solid, 2.3g (yield: 48%).

MS. 314(M+), MF, C16H18N403; MW, 314 Step 7: Synthesis of TBA sulfate salt NC,” N01,, NC, Pd/C NC": SOBDMF complex TBAA " N ——> N —) 0—) N J—N. N N‘ oé—N‘ A—N‘ I? 0 OH VIII IX X X' To a on of benzyl compound VIII (6 gm, 0.0233 mol) in a 1:1 mixture of DCM (30 ml)& DMF (30 n11), was added 1.5 gm of dry 10% Palladium charcoal and the mixture was hydrogenated under 3 kg Hydrogen pressure for 3 hour at 25-30°C.The reaction e was filtered through micron filter to remove catalyst and the filtrate concentrated under d pressure to obtain the debenzylated compound IX.

The debenzylated compound (IX) was dissolved in N,N’-Dimethyl formamide (30 ml) under argon atmosphere and the solution cooled to 0°C. DMF: S03 (4.26 gm, 0.0278mol) was added to the cooled solution and the stirring continued further for 30 min at 0°C. The mixture was then allowed to warm to RT and stirred for 1 hour. TLC showed complete conversion of N-Hydroxy nd to product X.

The on containing the sulfate(X) was re-cooled to 0°C and a solution of Tetra butyl ammonium acetate (9 gm, 0.0301mol dissolved in 30ml water) was added to it. The reaction mixture was allowed to warm to 25°C and stirred for 1 hour. The volatiles were removed under reduced pressure and residue was co-evaporated with 2X50 ml Xylene to remove traces of N,N’-Dimethyl formamide. The residue was partitioned between a 1:1 mixture of water and dichloromethane (120ml). The aqueous layer was re-extracted with dichloromethane (30 ml). The combined organic extracts were washed with water (2x30ml), brine (30 ml). And dried over NazSO4 and the t evaporated under d re to obtain the crude TBA sulfate (5.2 gm). Crude compound was triturated with hexane (2X30 ml) & dried on rotavapor under 4mmHg pressure to obtain the TBA salt (XI), 5.0 g, yield- 44%.

Mass: 246 (M-H) of sulfate M.W: 488, M.F: N4OSS.

Step 8: Synthesis of Sodium salt of trans0X0(sulphoxy)-1,6-diazabicyclo[3.2.1]- 0ctanecarbonitrile I XI | The TBA sulfate (4.4g, 0.009mol) was dissolved in 5% THF in water (2ml) and the solution was passed h column (45cm length and 2.0cm diameter) packed with Dowex 50WX8 200 Na+ resin. The column was eluted with 5% THF-water mixture (100ml). The combined fractions were evaporated under reduced pressure (4 mmHg) to obtain the product as white semi-solid, 1.5 gm, yield: 62%.

MS: 246 (M-H) of sulfate; M.W.: 269; M.F.: C7H8N305SNa, 1H NMR (DMSO):8 4.54 (d, 1H), 4.06 (s, 1H), 3.22 (m, 2H), 1.96 (m, 2H), 1.84 (m, 2H).

The X-ray powder diffraction pattern of various polymorphs of this compound, when crystallized from ent solvents is given in Figure 1 to 6 (description given below) Figure 1 is X-ray diffraction pattern of rph I of Sodium salt of transoxo oxy)-1,6-diazabicyclo[3.2.1]—octanecarbonitrile when crystallized from acetone.

Figure 2 is X-ray diffraction pattern of Polymorph II of Sodium salt of transoxo (sulphoxy)-1,6-diazabicyclo[3.2.1]—octanecarbonitrile when crystallized from ethanol.

Figure 3 is X-ray diffraction pattern of Polymorph III of Sodium salt of transoxo (sulphoxy)-1,6-diazabicyclo[3.2.1]—octanecarbonitrile when crystallized from water.

Figure 4 is X-ray diffraction pattern of rph IV of Sodium salt of transoxo- 6-(sulphoxy)-1,6-diazabicyclo[3.2.1]—octanecarbonitrile when crystallized from acetonitrile.

Figure 5 is X-ray diffraction pattern of Polymorph V of Sodium salt of transoxo oxy)-1,6-diazabicyclo[3.2.1]—octanecarbonitrile when crystallized from toluene.

Figure 6 is X-ray ction n of Polymorph VI of Sodium salt of transoxo- 6-(sulphoxy)-1,6-diazabicyclo[3.2.1]—octanecarbonitrile when crystallized from tetrahydrofuran. ical Activity Data The biological activity of representative compounds of the invention against various bacterial strains (in combination with another antibacterial agent) was investigated. In a typical study, overnight grown bacterial es were diluted appropriately and inoculated on the agar media containing doubling dilutions of the antibiotics. Observation for growth or no growth was performed after 16-20 hours of incubation at 35 i 2°C in ambient air. The l procedure was performed as per Clinical and Laboratory Standards Institute (CLSI) recommendations (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 1 and 2.

Table 1 details potencies of idime in combination of representative compound according to the invention (compound of formula (I) wherein M is sodium) against various MDR (Multi Drug Resistant) egative strains producing Class A, C and D beta- lactamase enzymes. The activities are expressed as MICs l). For comparison, the activity of various other known beta-lactamase inhibitors such as clavulanic acid, tazobactam, MK-7655, and NXL-104 are also provided. As can be seen, the use of compounds according to the invention significantly lowered the MIC values of the antibacterial agent (e.g. in this case Ceftazidime). The results also suggest the compounds according the ion increase antibacterial effectiveness of an antibacterial agent when said antibacterial agent is co- administered with a pharmaceutically effective amount of a compound of a (I) or a stereoisomer or a pharmaceutically acceptable salt thereof.

Table 1.Comparative activity of compound of Formula (I) (wherein M is sodium) against Class A, Class C and Class D ESBL producing s in combination with Ceftazidime MICs in mcg/ml Ceftazidime Sodium salt of Strains + + transoxo Control + + Clavulanic MK (sulphoxy)-1,6- TaZObaCtam NXL104 acid 7655 diazabicyclo[3. ctane-2— carbonitrile K. pneumoniae ATCC 700603 E. coli NCTC 13351 E.coli NCTC 13352 E. coli M 50 E.coli B 89 anni NCTC 1 3 301 A.baumanni NCTC 13304 A.baumanni NCTC 13305 All the inhibitors were tested at 4 mcg/ml at which they did not show their own, stand alone antibacterial activity Table 2 details data corresponsing to a combination of nem with a compound of Formula (I), wherein M is sodium, against Class D ESBL producing strains. Class D ESBLs producing pathogens that confer a high degree of resistance to carbapenems are a eutic problem in the al settings since extremely limited treatment options are available to treat them. As can be seen, the use of compounds according to the invention significantly lowered the MIC values of the antibacterial agent (e.g. in this case Meropenem).

The results also suggest the compounds according the invention increase antibacterial effectiveness of an antibacterial agent when said cterial agent is co-administered with a pharmaceutically effective amount of a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof.

Table 2. Comparative activity of WCK 4234 against Class D ESBL producing strains in combination with Meropenem MICs in mcg/ml Meropenem ESBL Sodium salt of Strains Type + + + transoxo l Clavulanic MK NXL (sulphoxy)-1,6- Tazobactam acid 7655 104 diazabicyclo[3. ctane carbonitrile A.baumanni 32 32 32 32 16 4 NCTC 13301 Class D ESBL A.baumanni 32 32 32 32 16 NCTC 13304 A.baumanni 8 8 8 8 8 2 NCTC 13305 All the inhibitors were tested at 4 mcg/ml at which they did not show their own, stand alone antibacterial activity.

Where the terms “comprise”, “comprises”, “comprised” or “comprising” are used in this ication , they are to be interpreted as specifying the presence of the stated features, integers, steps or components referred to, but not to de the presence or addition of one or more other feature, r, step, component or group thereof.

Further, any prior art reference or statement provided in the specification is not to be taken as an admission that such art constitutes, or is to be understood as constituting, part of the common general knowledge.

Claims (20)

The Claims defining the invention are as follows:

1. A compound of Formula (I): N Formula (I) N SO3M O O or a stereoisomer or a pharmaceutically acceptable salt thereof; wherein M is a cation.

2. The compound according to Claim 1, wherein M is hydrogen, sodium or potassium.

3. A pharmaceutical composition comprising a compound according to Claim 1 or Claim 2.

4. Use of a compound according to Claim 1 or Claim 2 for the manufacture of a medicament for preventing or treating bacterial infection in a subject.

5. The use according to Claim 4, wherein said infection is caused by bacteria producing one or more beta-lactamase enzymes.

6. Use of a pharmaceutical ition ing to Claim 3 for the manufacture of a ment for preventing or treating bacterial infection in a subject.

7. The use according to Claim 6, wherein said infection is caused by bacteria producing one or more beta-lactamase enzymes.

8. The pharmaceutical composition according to Claim 3, further comprising at least one antibacterial agent or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical composition according to Claim 8, wherein the antibacterial agent is a beta-lactam antibacterial agent.

10. The pharmaceutical composition according to Claim 8, wherein said cterial agent is ed from the group consisting of penicillins, penems, enems, cephalosporins, and ctams.

11. The ceutical composition according to Claim 8, wherein the antibacterial agent is a cephalosporin otic selected from the group consisting of cephalothin, cephaloridine, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cephradine, ceftizoxime, cefoxitin, cephacetrile, cefotiam, xime, cefsulodin, cefoperazone, ceftizoxime, cefmenoxime, cefmetazole, cephaloglycin, cefonicid, cefodizime, cefpirome, ceftazidime, axone, cefpiramide, erazone, cefozopran, cefepime, cefoselis, cefluprenam, cefuzonam, izole, cefclidin, cefixime, ceftibuten, cefdinir, cefpodoxime axetil, cefpodoxime proxetil, cefteram pivoxil, cefetamet pivoxil, cefcapene pivoxil or cefditoren l, cefuroxime, cefuroxime axetil, loracarbacef, ceftaroline, ceftolozane and latamoxef.

12. The pharmaceutical composition according to Claim 8, n the antibacterial agent is ed from the group consisting of ceftazidime, cefepime, cefpirome, piperacillin, ertapenem, doripenem, meropenem, imipenem, ceftaroline and ceftolozane.

13. Use of: (a) a nd of Formula (I) according to Claim 1 or a stereoisomer or a ceutically acceptable salt thereof, and (b) at least one cterial agent or a pharmaceutically acceptable salt f for the manufacture of a medicament for preventing or treating a bacterial infection in a subject.

14. The use according to Claim 13, wherein said infection is caused by bacteria producing one or more beta-lactamase enzymes.

15. Use of a compound of Formula (I) ing to Claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for increasing antibacterial effectiveness of an cterial agent in a subject.

16. The use according to any of Claims 13 to 15, wherein the antibacterial agent is a beta-lactam antibacterial agent.

17. The use according to any of Claims 13 to 15, n said antibacterial agent is selected from the group consisting of penicillins, penems, carbapenems, cephalosporins, and monobactams.

18. The use according to any of Claims 13 to 15, wherein the antibacterial agent is a cephalosporin antibiotic selected from the group consisting of cephalothin, cephaloridine, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cephradine, ceftizoxime, cefoxitin, etrile, cefotiam, cefotaxime, cefsulodin, cefoperazone, ceftizoxime, cefmenoxime, cefmetazole, cephaloglycin, cefonicid, cefodizime, cefpirome, ceftazidime, ceifriaxone, cefpiramide, cefbuperazone, cefozopran, cefepime, cefoselis, cefluprenam, cefuzonam, cefpimizole, cefclidin, cefixime, ceftibuten, cefdinir, cefpodoxime axetil, cefpodoxime proxetil, cefteram l, cefetamet pivoxil, cefcapene pivoxil or cefditoren l, cefuroxime, cefuroxime axetil, loracarbacef, ceftaroline, ceftolozane and latamoxef.

19. The use according to any of Claims 13 to 15, wherein the cterial agent is selected from the group consisting of ceftazidime, cefepime, cefpirome, piperacillin, ertapenem, doripenem, meropenem, imipenem, ceftaroline and ceftolozane.

20. The compound according to Claim 1, substantially as hereinbefore described with reference to the accompanying Examples and/or