FIELD OF THE INVENTION

The invention relates to nitrogen containing compounds  use of these compounds as antibacterial agents  compositions comprising them and processes for their preparation.

BACKGROUND OF THE INVENTION

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

Several antibacterial agents have been described in the prior art (for example  see PCT International 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.

The inventors have surprisingly discovered nitrogen containing compounds with antibacterial properties.

SUMMARY OF THE INVENTION

Accordingly there are provided nitrogen containing compounds  methods for preparation of these compounds  pharmaceutical compositions comprising these compounds  and method for preventing or treating bacterial infection in a subject using these compounds.

In one general aspect  there are provided compounds of Formula (I):

or a stereoisomer or a pharmaceutically acceptable salt thereof;

wherein:
Q is heteroaryl  or
Q is a –CO-NH-NH-CO- group  wherein R1 and bicyclic moiety are attached to carbonyl function present in –CO-NH-NH-CO- group 

R1 is:

(a) hydrogen 
(b) C1-C6 alkyl 
(c) heterocyclyl
(d) (CO)n-R3  or
(e) COOR4 

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) C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen  OR5  CN  COOR5  CONR6R7  NR6R7  NR5COR8  NR5CONR6R7  heterocyclyl  heteroaryl  cycloalkyl or aryl 
(c) CN 
(d) NR6R7 
(e) CONR6R7 
(f) NHCONR6R7 
(g) aryl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR6R7  halogen  CN  CONR6R7  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR6R7 
(h) heterocyclyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR6R7  halogen  CN  CONR6R7  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR6R7 
(i) heteroaryl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR6R7  halogen  CN  CONR6R7  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR6R7 
(j) cycloalkyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR6R7  halogen  CN  CONR6R7  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR6R7 
(k) cycloalkyl substituted with C1-C6 alkyl wherein C1-C6 alkyl is further substituted with one or more substituents independently selected from OR5  NR6R7  halogen  CN  or CONR6R7  or
(l) OR8;

R4 is:

(a) hydrogen 
(b) C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen  OR5  CN  COOR5  CONR6R7  NR6R7  NR5COR8  heterocyclyl  heteroaryl  cycloalkyl or aryl 
(c) aryl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR6R7  halogen  CN  CONR6R7  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR6R7 
(d) heterocyclyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR6R7  halogen  CN  CONR6R7  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR6R7 
(e) heteroaryl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR6R7  halogen  CN  CONR6R7  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR6R7  or
(f) cycloalkyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR6R7  halogen  CN  CONR6R7  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR6R7;

R5 and R8 are each independently:

(a) hydrogen  or
(b) C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen  CN  CONR6R7  NR6R7  heterocyclyl  heteroaryl  cycloalkyl or aryl;

R6 and R7 are each independently:

(a) hydrogen 
(b) C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen  OR5  CN  COOR5  CONR5R8  NR5R8  NR5COR8  heterocyclyl  heteroaryl  cycloalkyl or aryl 
(c) aryl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR5R8  halogen  CN  CONR5R8  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR5R8 
(d) heterocyclyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR5R8  halogen  CN  CONR5R8  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR5R8 
(e) heteroaryl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR5R8  halogen  CN  CONR5R8  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR5R8 
(f) cycloalkyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR5R8  halogen  CN  CONR5R8  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR5R8  or
(g) R6 and R7 are joined together to form a four to seven member ring.

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 bacterial 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 bacteria producing one or more beta-lactamase enzymes  wherein the method comprises 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 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 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  wherein the method comprises 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 thereof.

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 beta-lactamase inhibitor selected from sulbactam  tazobactam  clavulanic acid  or a pharmaceutically acceptable derivative thereof.

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 derivative thereof.

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  (b) at least one beta-lactamase inhibitor selected from sulbactam  tazobactam  clavulanic acid  or a pharmaceutically acceptable derivative thereof  and (c) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.

In another general aspect  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) 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.

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  wherein the method comprises administering to said subject a pharmaceutically effective amount of a pharmaceutical composition comprising: (a) a compound of Formula (I)  or a stereoisomer or a pharmaceutically acceptable salt thereof  and (b) at least one beta-lactamase inhibitor selected from sulbactam  tazobactam  clavulanic acid  or a pharmaceutically acceptable derivative 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) 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.

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  wherein the method comprises administering to said subject a pharmaceutically effective amount of a pharmaceutical composition comprising: (a) a compound of Formula (I)  or a stereoisomer or a pharmaceutically acceptable salt thereof  and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative 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) a compound of Formula (I)  or a stereoisomer or a pharmaceutically acceptable salt thereof  (b) at least one beta-lactamase inhibitor selected from sulbactam  tazobactam  clavulanic acid  or a pharmaceutically acceptable derivative thereof  and (c) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.

In 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  wherein the method comprises administering to said subject a pharmaceutically effective amount of a pharmaceutical composition comprising: (a) a compound of Formula (I)  or a stereoisomer or a pharmaceutically acceptable salt thereof  (b) at least one beta-lactamase inhibitor selected from sulbactam  tazobactam  clavulanic acid  or a pharmaceutically acceptable derivative thereof  and (c) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.

In another general aspect  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) 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.

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  wherein the method comprises 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 beta-lactamase inhibitor selected from sulbactam  tazobactam  clavulanic acid  or a pharmaceutically acceptable derivative 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) 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.

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  wherein the method comprises 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 derivative 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) a compound of Formula (I)  or a stereoisomer or a pharmaceutically acceptable salt thereof  (b) at least one beta-lactamase inhibitor selected from sulbactam  tazobactam  clavulanic acid  or a pharmaceutically acceptable derivative thereof  and (c) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.

In 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  wherein the method comprises administering to said subject a pharmaceutically effective amount of: (a) a compound of Formula (I)  or a stereoisomer or a pharmaceutically acceptable salt thereof  (b) at least one beta-lactamase inhibitor selected from sulbactam  tazobactam  clavulanic acid  or a pharmaceutically acceptable derivative thereof  and (c) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.

In another general aspect  there are provided methods for increasing antibacterial effectiveness of a antibacterial agent in a subject  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.

The details 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 DESCRIPTION OF THE INVENTION

Reference will now be made to the exemplary embodiments  and specific language 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 specification and the appended claims  the singular forms "a " "an " and "the" include plural referents unless the content clearly dictates otherwise. All references including patents  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 antibacterial properties.

The term “C1-C6 alkyl” as used herein refers to branched or unbranched acyclic hydrocarbon radical with 1 to 6 carbon atoms. Typical  non-limiting examples of “C1-C6 alkyl” include methyl  ethyl  n-propyl  iso-propyl  n-butyl  iso-butyl  tert-butyl  n-pentyl  iso-pentyl  n-hexyl and the like. The “C1-C6 alkyl” may be unsubstituted  or substituted with 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.

The term “cycloalkyl” as used herein refers to three to seven member cyclic hydrocarbon radicals. The cycloalkyl group optionally incorporates one or more double or triple bonds  or a combination of double bonds and triple bonds  but which is not aromatic. Typical  non-limiting examples of cycloalkyl groups include cyclopropane  cyclobutane  cyclopentane  cyclohexane  and cycloheptane. The cycloalkyl may be unsubstituted  or substituted with 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.

The term “heterocyclyl” as used herein refers to four to seven member cycloalkyl group containing one or more heteroatoms selected from nitrogen  oxygen or sulfur. The heterocycloalkyl group optionally incorporates one or more double or triple bonds  or a combination of double bonds and triple bonds  but which is not aromatic. Typical  non-limiting examples of heterocycloalkyl groups include azetidine  pyrrolidine  2-oxo-pyrrolidine  imidazolidin-2-one  piperidine  oxazine  thiazine  piperazine  piperazin-2 3-dione  morpholine  thiamorpholine  azapane  and the like. The heterocycloalkyl may be unsubstituted  or substituted with 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.

The term “aryl” as used herein refers to a monocyclic or polycyclic aromatic hydrocarbon. Typical  non-limiting examples of aryl groups include phenyl  naphthyl  anthracenyl  fluorenyl  phenanthrenyl  and the like. The aryl group may be unsubstituted  or substituted with 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.

The term “heteroaryl” as used herein refers to a monocyclic or polycyclic aromatic hydrocarbon group wherein one or more carbon atoms have been replaced with heteroatoms selected from nitrogen  oxygen  and sulfur. If the heteroaryl group contains more than one heteroatom  the heteroatoms may be the same or different. Typical  non-limiting example of heteroaryl groups include 1 2 4-oxadiazol  1 3 4-oxadiazol  1 3 4-thiadiazol  1 2 3 4-tetrazol  1 3-oxazol  1 3-thiazole  pyridine  pyrimidine  pyrazine  pyridazine  furan  pyrrol  thiophene  imidazole  pyrazole  benzofuran  benzothiophene  benzimidazole  benzoxazole  benzothiazole  thiazole  and the like. The heteroaryl group may be unsubstituted  or substituted with 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.

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 contain asymmetric or chiral centers and  therefore  exist in different stereoisomeric forms. It is intended  unless specified otherwise  that all stereoisomeric forms of the compounds of Formula (I) as well as mixtures thereof  including racemic mixtures  form part of the present invention. In addition  the present invention embraces all geometric and positional isomers (including cis and trans-forms)  as well as mixtures thereof  are embraced within the scope of the invention. In general  a reference to a compound is intended to cover its stereoisomers and mixture of various stereoisomers.

The term “optionally substituted” as used herein means that substitution is optional and therefore includes both unsubstituted and substituted atoms and moieties. A “substituted” atom or moiety indicates that any hydrogen on the designated atom or moiety can be replaced with a selection from the indicated substituent group  provided that the normal valency of the designated atom or moiety is not exceeded  and that the substitution results in a stable compound.

The term “pharmaceutically acceptable salt” as used herein refers to one or more salts of a given compound which possesses the desired pharmacological activity of the free compound and which are neither biologically nor otherwise undesirable. In general  the “pharmaceutically acceptable salts” refer to salts that are suitable for use in contact with the tissues of human and animals without undue toxicity  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 hydrogen). A person of skills in the art would appreciate that such compounds  therefore  can form acidic salts (formed with inorganic and/or organic acids)  as well as basic salts (formed with inorganic and/or organic bases). Such salts can be prepared using procedures described in the art. For example  the basic moiety can be converted to its salt by treating a compound with a suitable amount of acid. Typical  non-limiting examples 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 carbonate  sodium bicarbonate  potassium carbonate  potassium bicarbonate or the like. In case of compounds containing more than one functional groups capable of being converted into salt  each such functional group 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 (I) according to invention 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 "halogen" or "halo" as used herein refers to chlorine  bromine  fluorine  or iodine.

The term "infection" or “bacterial infection” as used herein includes presence of bacteria  in or on a subject  which  if its growth were inhibited  would result in a benefit to the subject. As such  the term "infection" in addition to referring to the presence of bacteria also refers to normal flora  which is 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 subject 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 eliminate either a bacterial infection or one or more symptoms of the bacterial infection  or (ii) retard the progression of a bacterial infection or of one or more symptoms of the bacterial infection  or (iii) reduce the severity of a bacterial infection or of one or more symptoms of the bacterial infection  or (iv) suppress the clinical manifestation of a bacterial infection  or (v) suppress the manifestation of adverse symptoms of the bacterial infection.

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 therapeutic 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 required to produce a desired therapeutic effect as may be judged by clinical trial results  model animal infection studies  and/or in vitro studies (e.g. in agar or broth media). The pharmaceutically effective amount depends on several factors  including but not limited to  the microorganism (e.g. bacteria) involved  characteristics 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 methods  which serves to deliver the composition or its active ingredients or other pharmaceutically active ingredients 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 composition or the nature of the pharmaceutically active or inert ingredients  the site of the potential or actual infection  the microorganism involved  severity of the infection  age and physical condition of the subject and a like. Some non-limiting examples of ways to administer a composition or a pharmaceutically active ingredient to a subject according to this invention 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 mouthwash. 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 beneficial therapeutic levels such that the composition as a whole provides a synergistic and/or desired effect.

The term "growth" as used herein refers to a growth of one or more microorganisms and includes 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 “antibacterial effectiveness” of a composition or an antibacterial agent refers to the ability of the composition or the antibacterial agent to prevent or treat the microbial (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 produce infection in a subject; or (iii) inhibiting or reducing ability of bacteria 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  including for example  to increase the solubility of the compound. Typical  non-limiting examples of solid carriers include  starch  lactose  dicalcium phosphate  sucrose  and kaolin and so on. Typical  non-limiting examples of liquid carriers include  sterile water  saline  buffers  non-ionic surfactants  and edible oils such as oil  peanut and sesame oils and so on. In addition  various adjuvants commonly used in the art may be included. These and other such compounds are described in the literature  for example  in the Merck Index (Merck & Company  Rahway  N.J.). Considerations for inclusion of various components in pharmaceutical compositions are described  for example  in Gilman et al. (Eds.) (1990); Goodman and Gilman""s: The Pharmacological Basis of Therapeutics  8th Ed.  Pergamon Press.  which is incorporated herein by reference in its entirety.

The term "subject" as used herein refers to vertebrate or invertebrate  including a mammal. The term “subject” includes 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 “pharmaceutically acceptable derivative” as used herein refers to and includes any pharmaceutically acceptable salt  pro-drugs  metabolites  esters  ethers  hydrates  polymorphs  solvates  complexes  enantiomers or adducts of a compound described herein which  upon administration to a subject  is capable of providing (directly or indirectly) the parent compound. For example  the term “antibacterial agent or a pharmaceutically acceptable derivative thereof” includes all derivatives of the antibacterial agent (such as salt  pro-drugs  metabolites  esters  ethers  hydrates  polymorphs  solvates  complexes  enantiomers or adducts) which  upon administration to a subject  is capable of providing (directly or indirectly) the antibacterial compound.

In general  the term “cation” includes Na  K  Mg  Ca  NH4+  (CH3CH2)3N+ etc.

In one general aspect  there are provided compounds of Formula (I):

or a stereoisomer or a pharmaceutically acceptable salt thereof;
wherein:

Q is heteroaryl  or
Q is a –CO-NH-NH-CO- group  wherein R1 and bicyclic moiety are attached to carbonyl function present in –CO-NH-NH-CO- group 

R1 is:

(a) hydrogen 
(b) C1-C6 alkyl 
(c) heterocyclyl
(d) (CO)n-R3  or
(e) COOR4 

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) C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen  OR5  CN  COOR5  CONR6R7  NR6R7  NR5COR8  NR5CONR6R7  heterocyclyl  heteroaryl  cycloalkyl or aryl 
(c) CN 
(d) NR6R7 
(e) CONR6R7 
(f) NHCONR6R7 
(g) aryl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR6R7  halogen  CN  CONR6R7  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR6R7 
(h) heterocyclyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR6R7  halogen  CN  CONR6R7  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR6R7 
(i) heteroaryl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR6R7  halogen  CN  CONR6R7  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR6R7 
(j) cycloalkyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR6R7  halogen  CN  CONR6R7  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR6R7 
(k) cycloalkyl substituted with C1-C6 alkyl wherein C1-C6 alkyl is further substituted with one or more substituents independently selected from OR5  NR6R7  halogen  CN  or CONR6R7  or
(l) OR8;

R4 is:

(a) hydrogen 
(b) C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen  OR5  CN  COOR5  CONR6R7  NR6R7  NR5COR8  heterocyclyl  heteroaryl  cycloalkyl or aryl 
(c) aryl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR6R7  halogen  CN  CONR6R7  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR6R7 
(d) heterocyclyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR6R7  halogen  CN  CONR6R7  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR6R7 
(e) heteroaryl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR6R7  halogen  CN  CONR6R7  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR6R7  or
(f) cycloalkyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR6R7  halogen  CN  CONR6R7  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR6R7;

R5 and R8 are each independently:

(a) hydrogen  or
(b) C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen  CN  CONR6R7  NR6R7  heterocyclyl  heteroaryl  cycloalkyl or aryl;

R6 and R7 are each independently:

(a) hydrogen 
(b) C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen  OR5  CN  COOR5  CONR5R8  NR5R8  NR5COR8  heterocyclyl  heteroaryl  cycloalkyl or aryl 
(c) aryl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR5R8  halogen  CN  CONR5R8  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR5R8 
(d) heterocyclyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR5R8  halogen  CN  CONR5R8  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR5R8 
(e) heteroaryl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR5R8  halogen  CN  CONR5R8  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR5R8 
(f) cycloalkyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR5R8  halogen  CN  CONR5R8  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR5R8  or
(g) R6 and R7 are joined together to form a four to seven member ring.

Typical non-limiting examples of compounds according to the invention include:

trans-Sodium salt of sulfuric acid mono-{5-methyl-7-(-5-methyl-[1 3 4]oxadiazol-2-yl)-9-oxo-4 5 8 10-tetraaza-tricyclo[6.2.1.0*2 6*]undeca-2(6) 3-dien-10-yl}ester;

trans-Sodium salt of N’-{5-Methyl-9-oxo-10-sulfooxy-4 5 8 10-tetraaza-tricyclo [6.2.1.0*2 6]undeca-2(6) 3-diene-7-carbonyl}-hydrazine carboxylic acid tert-butyl ester;

trans-Sulfuric acid mono-{7-[N’-(2-amino-acetyl)-hydrazinocarbonyl]-5-methyl-9-oxo-4 5 8 10-tetraaza-tricyclo[6.2.1.0*2 6*]undeca-2(6) 3-dien-10-yl}ester;

trans-Sulfuric acid mono-{7-[N’-(3-amino-propionyl)-hydrazinocarbonyl]-5-methyl-9-oxo-4 5 8 10-tetraaza-tricyclo[6.2.1.0*2 6*]undeca-2(6) 3-dien-10-yl}ester;

trans-Sulfuric acid mono-{5-methyl-9-oxo-7-[N’-((S)-pyrrolidine-2-carbonyl)-hydrazinocarbonyl]-4 5 8 10-tetraaza-tricycl0[6.2.1.0*2 6*]undeca-2(6) 3-dien-10-yl}-ester;

trans-Sulfuric acid mono-{5-methyl-9-oxo-7-[N’-((R)-pyrrolidine-3-carbonyl)-hydrazinocarbonyl]-4 5 8 10-tetraaza-tricycl0[6.2.1.0*2 6*]undeca-2(6) 3-dien-10-yl}-ester;

trans-Sulfuric acid mono-{5-methyl-9-oxo-7-[N’-((R)-piperidine-3-carbonyl)-hydrazinocarbonyl]-4 5 8 10-tetraaza-tricycl0[6.2.1.0*2 6*]undeca-2(6) 3-dien-10-yl}-ester;

or a stereoisomer or a pharmaceutically acceptable salt thereof;

In general  the compounds of the invention can be prepared according to the following procedures. A person of skills in the art would appreciate 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.

General Procedure

A) Synthesis of compounds containing 1 3 4-oxdiazole groups:

In general  the compounds  according to the invention containing 1 3 4-oxadiazole group were prepared using a procedure given in Scheme-1.

As per Scheme-1  trans-10-benzyloxy-5-methyl-9-oxo-4 5 8 10-tetraaza-tricyclo [6.2.1.0*2 6*] undeca-2(6) 3-diene-7-carboxylic acid (1a) was reacted with corresponding suitable acid hydride (1b) in the presence of coupling agent [such as EDC hydrochloride  dicyclohexylcarbodiimide (DCC)  or pivalyl chloride] in a suitable solvent (such as N N dimethyl formamide  N N dimethyl acetamide  1 4 dioxane) at a temperature ranging from about -15°C to 60°C for about 1 to 24 hours to provide intermediate (1c).

The cyclization of intermediate (1c) was effected by treating intermediate (1b) with a reagent (such as p-toluene sulfonyl chloride  p-nitrobenzene sulfonyl chloride  methane sulfonyl chloride)  in a suitable solvent (such as toluene  chloroform  dichloromethane  N N-dimethyl formamide)  at a temperature ranging from 25°C to 110°C for about 1 to 14 hours to provide to provide 1 3 4-oxadiazole intermediate (1d).

The 1 3 4-oxadiazole intermediate (1d) was subjected for hydrogenolysis by using catalyst (such as 5% or 10% palladium on carbon  20% palladium hydroxide on carbon) in the presence of hydrogen source (such as hydrogen gas  ammonium formate  or cyclohexene)  in a solvent (such as methanol  ethanol  methanol dichloromethane mixture  or N N dimethyl formamide dichloromethane mixture)  at a temperature ranging from 25°C to 60°C  for about 1 to 14 hours to provide intermediate (1e).

The intermediate (1e) was sulfonated by reacting it with sulfonating reagent (such as pyridine sulfur trioxide complex  sulfur trioxide N N-dimethyl formamide complex)  in a suitable solvent (such as pyridine  N N-dimethyl formamide)  at a temperature ranging from 25°C to 80°C for about 1 to 24 hours to provide pyridine salt of sulfonic acid which later was treated with tetrabutyl ammonium sulfate to provide tetrabutylammonium salt of sulfonic acid as an intermediate (1f).

Some compounds according to the invention were isolated as a zwitterions  by treating intermediate compound (1f) with trifluoroacetic acid  in a suitable solvent (such as dichloromethane  chloroform  acetonitrile) at a temperature ranging from -15°C to 40°C for about 0.5 to 14 hours  especially when R1 in intermediate compound (1f) contained tert-butoxycarbonyl protected amine function.

Some other compounds according to the invention were isolated as a sodium salt  by passing intermediate compound (1f) through sodium form of sodium form of Amberlite 200C resin or sodium form of Amberlite IR120 resin in mixture of tetrahydrofuran-water mixture followed by evaporation of the solvent under vacuum.

As described in Scheme-2  trans-10-benzyloxy-5-methyl-9-oxo-4 5 8 10-tetraaza-tricyclo[6.2.1.0*2 6*] undeca-2(6) 3-diene-7-carboxylic acid (1a) was reacted with corresponding suitable acid hydride (1b) in the presence of coupling agent [such as EDC hydrochloride  dicyclohexylcarbodiimide (DCC)  or pivalyl chloride]  in a suitable solvent (such as N N dimethyl formamide  N N dimethyl acetamide  or 1 4 dioxane)  at a temperature ranging from -15° C to 60° C for 1 to 24 hours to provide intermediate (1c).

The intermediate compound (1c) was subjected for hydrogenolysis in presence of a suitable catalyst (such as 5% or 10% palladium on carbon  or 20% palladium hydroxide on carbon) in presence of hydrogen source (such as hydrogen gas  ammonium formate  cyclohexene) in a suitable solvent (such as methanol  ethanol  methanol-dichloromethane mixture  or N N dimethyl formamide-dichloromethane mixture) at a temperature ranging from 25°C to 60°C for about 1 to 14 hours to obtain intermediate compound (2d).

The intermediate compound (2d) was sulfonated by reacting it with sulfonating reagent (such as sulfur trioxide-pyridine complex  or sulfur trioxide-N N-dimethyl formamide complex) 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 salt of sulfonic acid which when treated with tetrabutyl ammonium sulfate provided terabutylammonium salt of sulfonic acid as an intermediate compound (2e).

Some compounds according to the invention were isolated as a zwitterions  by treating intermediate compound (2e) with trifluoroacetic acid  in a suitable solvent (such as dichloromethane  chloroform  acetonitrile) at a temperature ranging from -15°C to 40°C for about 0.5 to 14 hours  especially when R1 in intermediate compound (1e) contained tert-butoxycarbonyl protected amine function.

Some other compounds according to the invention were isolated as a sodium salt  by passing intermediate compound (2e) through sodium form of sodium form of Aberlite 200C resin or sodium form of Amberlite IR120 resin in mixture of tetrahydrofuran-water mixture followed by evaporation of the solvent under vacuum.

In some embodiments  there are provided pharmaceutical compositions comprising a compound of Formula (I)  or a stereoisomer or a pharmaceutically acceptable salt thereof.

In some other embodiments  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 compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof.

In some embodiments  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  wherein the method comprises administering to said subject a pharmaceutically effective amount of a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof.

In some other embodiments  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 thereof.

In some other embodiments  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  wherein the method comprises 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 thereof.

In some embodiments  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 beta-lactamase inhibitor selected from sulbactam  tazobactam  clavulanic acid  or a pharmaceutically acceptable derivative thereof.

In some other embodiments  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 derivative thereof.

In some other embodiments  there are provided pharmaceutical compositions comprising: (a) a compound of Formula (I)  or a stereoisomer or a pharmaceutically acceptable salt thereof  (b) at least one beta-lactamase inhibitor selected from sulbactam  tazobactam  clavulanic acid  or a pharmaceutically acceptable derivative thereof  and (c) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.

In some other embodiments  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) 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.

In some other embodiments  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  wherein the method comprises administering to said subject a pharmaceutically effective amount of a pharmaceutical composition comprising: (a) a compound of Formula (I)  or a stereoisomer or a pharmaceutically acceptable salt thereof  and (b) at least one beta-lactamase inhibitor selected from sulbactam  tazobactam  clavulanic acid  or a pharmaceutically acceptable derivative thereof.

In some other embodiments  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) 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.

In some other embodiments  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  wherein the method comprises administering to said subject a pharmaceutically effective amount of a pharmaceutical composition comprising: (a) a compound of Formula (I)  or a stereoisomer or a pharmaceutically acceptable salt thereof  and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.

In some other embodiments  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) a compound of Formula (I)  or a stereoisomer or a pharmaceutically acceptable salt thereof  (b) at least one beta-lactamase inhibitor selected from sulbactam  tazobactam  clavulanic acid  or a pharmaceutically acceptable derivative thereof  and (c) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.

In some other embodiments  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  wherein the method comprises administering to said subject a pharmaceutically effective amount of a pharmaceutical composition comprising: (a) a compound of Formula (I)  or a stereoisomer or a pharmaceutically acceptable salt thereof  (b) at least one beta-lactamase inhibitor selected from sulbactam  tazobactam  clavulanic acid  or a pharmaceutically acceptable derivative thereof  and (c) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.

In some other embodiments  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) 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.

In some other embodiments  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  wherein the method comprises 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 beta-lactamase inhibitor selected from sulbactam  tazobactam  clavulanic acid  or a pharmaceutically acceptable derivative thereof.

In some other embodiments  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) 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.

In some other embodiments  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  wherein the method comprises 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 derivative thereof.

In some other embodiments  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) a compound of Formula (I)  or a stereoisomer or a pharmaceutically acceptable salt thereof  (b) at least one beta-lactamase inhibitor selected from sulbactam  tazobactam  clavulanic acid  or a pharmaceutically acceptable derivative thereof  and (c) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.

In some other embodiments  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  wherein the method comprises administering to said subject a pharmaceutically effective amount of: (a) a compound of Formula (I)  or a stereoisomer or a pharmaceutically acceptable salt thereof  (b) at least one beta-lactamase inhibitor selected from sulbactam  tazobactam  clavulanic acid  or a pharmaceutically acceptable derivative thereof  and (c) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.

In some embodiments  there are provided methods for increasing antibacterial effectiveness of a antibacterial agent in a subject  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.

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

Typical  non-limiting examples of Aminoglycoside antibacterial agents include Amikacin  Gentamicin  Kanamycin  Neomycin  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 Loracarbef 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 include Cefazolin  Cefacetrile  Cefadroxil  Cefalexin  Cefaloglycin  Cefalonium  Cefaloridine  Cefalotin  Cefapirin  Cefatrizine  Cefazedone  Cefazaflur  Cefradine  Cefroxadine  Ceftezole  Cefaclor  Cefamandole  Cefminox  Cefonicid  Ceforanide  Cefotiam  Cefprozil  Cefbuperazone  Cefuroxime  Cefuzonam  Cephamycin  Cefoxitin  Cefotetan  Cefmetazole  Carbacephem  Cefixime  Ceftazidime  Ceftriaxone  Cefcapene  Cefdaloxime  Cefdinir  Cefditoren  Cefetamet  Cefmenoxime  Cefodizime  Cefoperazone  Cefotaxime  Cefpimizole  Cefpiramide  Cefpodoxime  Cefsulodin  Cefteram  Ceftibuten  Ceftiolene  Ceftizoxime  Oxacephem  Cefepime  Cefozopran  Cefpirome  Cefquinome  Ceftobiprole  Ceftiofur  Cefquinome  Cefovecin  CXA-101  Ceftaroline  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 Azithromycin  Clarithromycin  Dirithromycin  Erythromycin  Roxithromycin  Troleandomycin  Telithromycin  Spectinomycin  Solithromycin and the like.

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

Typical  non-limiting examples of Nitrofuran antibacterial agents include Furazolidone  Nitrofurantoin 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 include Ciprofloxacin  Enoxacin  Gatifloxacin  Levofloxacin  Lomefloxacin  Moxifloxacin  Nalidixic acid  Levonadifloxacin  Norfloxacin  Ofloxacin  Trovafloxacin  Grepafloxacin  Sparfloxacin  Temafloxacin and the like.

Typical  non-limiting examples of Sulfonamide antibacterial agents include Mafenide  Sulfonamidochrysoidine  Sulfacetamide  Sulfadiazine  Sulfamethizole  Sulfamethoxazole  Sulfasalazine  Sulfisoxazole  Trimethoprim and the like.
Typical  non-limiting examples of Tetracycline antibacterial agents include Demeclocycline  Doxycycline  Minocycline  Oxytetracycline  Tetracycline  Tigecycline and the like.

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

The pharmaceutical compositions according to the invention may include one or more pharmaceutically acceptable carriers or excipients or the like  Typical  non-limiting examples of such carriers or excipient include mannitol  lactose  starch  magnesium stearate  sodium saccharine  talcum  cellulose  sodium crosscarmellose  glucose  gelatin  sucrose  magnesium carbonate  wetting agents  emulsifying agents  solubilizing agents  pH buffering agents  lubricants  stabilizing agents  binding agents etc.

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 addition of a compatible reconstitution diluent prior to parenteral administration. Non-limiting example of such a compatible reconstitution diluent includes water.

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.

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

In the methods according 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 ingredients to the desired site. The method of administration can vary depending on various factors  such as for example  the components of the pharmaceutical composition and nature of the active ingredients  the site of the potential or actual infection  the microorganism (e.g. bacteria) involved  severity of infection  age and physical condition of the subject. Some non-limiting examples of administering the composition to a subject according to this invention include oral  intravenous  topical  intrarespiratory  intraperitoneal  intramuscular  parenteral  sublingual  transdermal  intranasal  aerosol  intraocular  intratracheal  intrarectal  vaginal  gene gun  dermal patch  eye drop  ear drop or mouthwash.

The compositions according to the invention can be formulated into various dosage forms wherein the active ingredients and/or excipients may be present either together (e.g. as an admixture) or as separate components. When the various ingredients in the composition 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 mixture  but come as separate components  such composition/dosage form may be administered in several ways. In one possible way  the ingredients may be mixed in the desired proportions and the mixture is then administered as required. Alternatively  the components or the ingredients (active or inert) may be separately administered (simultaneously or one after the other) in appropriate proportion so as to achieve the same or equivalent therapeutic level or effect as would have been achieved by administration of the equivalent mixture.

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 subject. 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. Typically  the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g.  oral and parenteral) or 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 present invention may be formulated into 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 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 to be less or not susceptible to one or more of known antibacterial agents or their known compositions. Some non-limiting examples of such bacteria known to have developed resistance to various antibacterial agents include Acinetobacter  E. coli  Pseudomonas aeruginosa  Staphylococcus aureus  Enterobacter  Klebsiella  Citrobacter and a like. 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 infections  febrile neutropenia  urinary tract infection  intraabdominal infections  respiratory tract infections  pneumonia (nosocomial)  bacteremia meningitis  surgical  infections etc.

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

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 of 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 acceptable salt thereof according to the invention.

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed 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 practiced using a variety of different compounds within the described generic descriptions.

EXAMPLES

The following examples illustrate the embodiments of the invention 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 skilled 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 invention 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.

Preparation-1

Preparation of trans-10-benzyloxy-5-methyl-9-oxo-4 5 8 10-tetraaza-tricyclo [6.2.1.0*2 6*]undeca-2(6) 3-diene-7-carboxylic acid:

To a 2 Lit three neck round bottom flask equipped with overhead stirrer  thermometer pocket and addition funnel was charged trans-10-benzyloxy-5-methyl-9-oxo-4 5 8 10-tetraaza-tricyclo[6.2.1.0*2 6*]undeca-2(6) 3-diene-7-carboxylic acid methyl ester (18 gm  0.0526 mol  prepared as per the procedure described in US 2010/0092443 A1) followed by acetone (360 ml). The stirring was started to provide a clear solution. The reaction mixture was cooled to -20 ° C and the addition of a solution of lithium hydroxide (3.53 gm  0.842 mol) pre dissolved in water (211 ml) and acetone (70 ml) was started for next 2.5 hr. As the addition was completed  the mixture stirred for additional 1 h and the pH of reaction mixture was adjusted between 8 to 8.5 by using 2N aqueous hydrochloric acid under stirring at -20°C.

The mixture was allowed to warm at room temperature and saturated aqueous brine solution (100 ml) was added. The reaction mixture was extracted with toluene (1 X 500 ml) followed by (2 X 250 ml). The organic layer was separated and the pH of aqueous layer was adjusted between 2 to 2.5 by using 2N aqueous hydrochloric acid. The resultant solution was extracted with dichloromethane (3X 500 ml)  dried over sodium sulfate and distilled under vacuum by maintaining temperature below 35° C to provide tile compound in 9 gm quantity in 52% yield. This compound was used immediately for the next reactions due to stability issues.

Analysis: MS (ES-) C16H16N4O4 = 327.1 (M-1);
H1NMR (DMSO-d6) = 7.36-7.42 (m  6H)  6.56 (br s  1H)  5.19 (s  1H)  4.97 (d  1H)  4.82 (d  1H)  3.96 (d  1H)  3.79 (s  3H)  3.43 (dd  1H)  3.15 (d  1H).

Example -1

trans-Sodium salt of sulfuric acid mono-{5-methyl-7-(-5-methyl-[1 3 4]oxadiazol-2-yl)-9-oxo-4 5 8 10-tetraaza-tricyclo[6.2.1.0*2 6*]undeca-2(6) 3-dien-10-yl}ester

Step-1: trans-10-benzyloxy-5-methyl-9-oxo-4 5 8 10-tetraaza-tricyclo[6.2.1.0*2 6*]undeca-2(6) 3-diene-7-carboxylic acid N’-acetyl hydrazide:

To a 100 ml single neck round bottom flask equipped with magnetic stirrer was charged a solution of trans-10-benzyloxy-5-methyl-9-oxo-4 5 8 10-tetraaza-tricyclo[6.2.1.0*2 6*] undeca-2(6) 3-diene-7-carboxylic acid (4.5 gm  0.0137 mol  prepared as per preparation-1) in N  N dimethyl formamide (50 ml) followed by hydroxybenzotriazole (2.72 gm  0.0205 mol)  EDC hydrochloride (3.93 gm  0.0205 mol)  acetic acid hydrazide (1.52 gm  0.0205 mol) and diisopropyl ethylamine (7.27 ml  0.0411 mol) at 25° C under stirring. The reaction mixture was stirred for 19 h. The reaction mixture was quenched with water (250 ml) and extracted with dichloromethane (2X 250 ml). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to provide a residue which was purified by on 100-200 mesh silica gel column using 3% methanol in chloroform to provide titled intermediate compound in 0.650 gm quantity (12.3% yield).

Analysis: MS (ES-) C18H20N6O4 = 383.0 (M-1);

H1NMR (DMSO-d6) = 10.32 (s  1H)  9.89 (s  1H)  7.32-7.41 (m  6H)  5.26 (s  1H)  4.81-4.92 (dd  2H)  4.53 (d  1H)  3.70 (s  3H)  3.44 (d  1H)  3.25-3.29 (m  1H)  1.83 (s  3H).

Step-2: trans-10-benzyloxy-5-methyl-7-(5-methyl-[1  3 4]oxadiazol-2-yl)-4 5 8 10-tetraaza-tricyclo[6.2.1.0*2 6*]undeca-2(6) 3-dien-9-one:

To a single neck round bottom flask equipped with magnetic stirrer was charged a solution of trans-10-benzyloxy-5-methyl-9-oxo-4 5 8 10-tetraaza-tricyclo [6.2.1.0*2 6*] undeca-2(6) 3-diene-7-carboxylic acid N’-acetyl hydrazide (650 mg  1.692 mmol) in N N-dimethyl formamide (15 ml) followed by diisopropyl ethylamine (0.9 ml  5.078 mmol) and p-toluene sulfonylchloride (484 mg  2.538 mmol) under stirring at 25 ° C. The reaction mixture was stirred at 100° C for 2 h. The solvent was evaporated below 50° C under vacuum to provide a residue. The residue was purified on 100-200 mesh silica gel column using 70% ethyl acetate in dichloromethane to provide pure 320 mg title intermediate compound in 51.5% yield.

Analysis: MS (ES+) C18H18N6O3 = 367.0 (M+1);

Step-3: trans-10-hydroxy-5-methyl-7-(5-methyl-[1  3 4]oxadiazol-2-yl)-4 5 8 10-tetraaza-tricyclo[6.2.1.0*2 6*]undeca-2(6) 3-dien-9-one:

To a 100 ml single neck round bottom flask equipped with magnetic stirrer was charged a solution of trans-10-benzyloxy-5-methyl-7-(5-methyl-[1  3 4]oxadiazol-2-yl)-4 5 8 10-tetraaza-tricyclo[6.2.1.0*2 6*]undeca-2(6) 3-dien-9-one (320 mg  0.874 mmol) in methanol (20 ml) followed by 10% palladium on carbon (200 mg) at 35° C. The reaction mixture was stirred at 35° C under 1 atm. hydrogen pressure for 2.5 h. The catalyst was filter under suction over a celite bed. The bed was washed with dichloromethane (20 ml). The filtrate was evaporated under vacuum below 35° C to provide a residue as titled intermediate compound in 232 mg quantity (96.2% yield)  it was used as it such for further reaction.
Analysis: MS (ES+) C11H12N6O3 = 277.0 (M+1);

Step-4: Tetrabutyl ammonium salt of trans-sulfuric acid mono{5-methyl-7-(5-methyl-[1  3 4]oxadiazol-2-yl)-9-oxo-4 5 8 10-tetraaza-tricyclo[6.2.1.0*2 6*]undeca-2(6) 3-dien-10-yl}ester:

To a100 ml single neck round bottom flask equipped with magnetic stirrer was charged a solution of trans-10-hydroxy-5-methyl-7-(5-methyl-[1  3 4]oxadiazol-2-yl)-4 5 8 10-tetraaza-tricyclo[6.2.1.0*2 6*]undeca-2(6) 3-dien-9-one (232 mg  0.840 mmol) in pyridine (15 ml)  followed by pyridine sulfur trioxide complex (670 mg  4.202 mmol) under stirring. The reaction mixture was stirred for 15 h at 35° C. The solvent was evaporated under vacuum blow 40° C to provide a residue and the residue was stirred in 0.5N aqueous potassium dihydrogen phosphate solution (50 ml) for 1 h. The resulting solution was extracted with dichloromethane (2 X 50 ml). To the aqueous layer was added tetrabutyl ammonium hydrogen sulfate (286 mg  0.840 mmol) and the mixture was stirred for 3.5 h at 25° C. Tit was extracted with dichloromethane (2 X 50 ml). Combined organic layer was dried over sodium sulfate and evaporated under vacuum to provide titled intermediate compound in 280 mg quantity (55.7% yield).

Analysis: MS (ES-) C11H11N6O6S. N(C4H9)4 = 354.9 (M-1) as a free sulfonic acid;

Step-5: trans-Sodium salt of sulfuric acid mono-{5-methyl-7-(-5-methyl-[1 3 4]oxadiazol-2-yl)-9-oxo-4 5 8 10-tetraaza-tricyclo[6.2.1.0*2 6*]undeca-2(6) 3-dien-10-yl}ester:
A column was packed with Amberlite IR 120 Na resin (20 gm) using 10% tetrahydrofuran in water. Tetrabutyl ammonium salt of trans-sulfuric acid mono{5-methyl-7-(5-methyl-[1  3 4]oxadiazol-2-yl)-9-oxo-4 5 8 10-tetraaza-tricyclo[6.2.1.0*2 6*]undeca-2(6) 3-dien-10-yl}ester (280 mg  0.468 mmol) was dissolved in tetrahydrofuran (30 ml) and loaded on column. It was further eluted with 10% tetrahydrofuran and water mixture. Fraction containing compound were collected and evaporated under reduced pressure below 40° C to remove tetrahydrofuran. The remaining aqueous layer was extracted with dichloromethane (2 X 50 ml). The aqueous layer was evaporated to dryness under vacuum below 40° C to provide a residue. The residue was triturated with acetone (2X 25 ml) to provide a compound of invention in 100 mg quantity (60.2% yield).

Analysis: MS (ES-) C11H11N6O6SNa = 354.9 (M-1) as a free sulfonic acid;

H1NMR (DMSO-d6  D2O exchange) = 7.48 (s  1H)  6.06 (s  1H)  4.75 (d  1H)  3.48 (s  3H)  3.42 (s  3H)  3.36-3.3.39 (m  1H)  3.04 (d  1H).

Example -2

trans-Sodium salt of N’-{5-methyl-9-oxo-10-sulfooxy-4 5 8 10-tetraaza-tricyclo[6.2.1.0*2 6]undeca-2(6) 3-diene-7-carbonyl}-hydrazine carboxylic acid tert-butyl ester

The titled compound of invention was prepared in 165 mg quantity by using hydrazinecarboxylic acid tert-butyl ester (2.71 gm) in the place of acetic acid hydrazide and using the procedure described in steps 1  3  4 and 5 of example-1

Analysis: MS (ES+) C14H19N6O8SNa = 433.0 (M+1) as a free sulfonic acid;

H1NMR (DMSO-d6) = 10.22 (s  1H)  8.92 (s  1H)  7.36 (s  1H)  5.20 (s  1H)  4.69 (d  1H)  4.00-4.03 (m  1H)  3.70 (s  3H)  3.35-3.44 (m  2H)  1.38 (s  9H).

Example -3

trans-Sulfuric acid mono-{7-[N’-(3-amino-propionyl)-hydrazinocarbonyl]-5-methyl-9-oxo-4 5 8 10-tetraaza-tricyclo[6.2.1.0*2 6*]undeca-2(6) 3-dien-10-yl}ester

Step-1: trans-{3-[N’-(10-Benzyloxy-5-methyl-9-oxo-4 5 8 10-tetraaza-tricyclo [6.2.1.0*2 6*] undeca-2(6) 3-diene-7-carbonyl)-hydrazino]-3-oxo-propyl}-carbamic acid tert-butyl ester:

To a 100 ml round bottom flask equipped with magnetic stirrer was charged a solution of trans-10-benzyloxy-5-methyl-9-oxo-4 5 8 10-tetraaza-tricyclo[6.2.1.0*2 6*] undeca-2(6) 3-diene-7-carboxylic acid (2.8 gm  0.0085 mol  prepared as per preparation-1) in N N dimethyl formamide (30 ml) followed by hydroxybenzotriazole (1.72 gm  0.0128 mol)  EDC hydrochloride (2.44 gm  0.0128 mol)  (2-hydrazinocarbonyl-ethyl)-carbamic acid tert-butyl ester (2.6 gm  0.0128 mol) and diisopropyl ethylamine (4.53 ml  0.0256 mol) at 25° C under stirring. The reaction mixture was stirred for 20 h. The reaction mixture was quenched with water (150 ml) and extracted with dichloromethane (2X 150 ml). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to provide a residue which was purified by on 60-120 mesh silica gel column using 15% acetone in hexane to provide titled intermediate compound in 0.750 gm quantity (11.4% yield).
Analysis: MS (ES-) C24H31N7O6 = 512.3 (M-1).

Step-2: trans-{3-[N’-(10-Hydroxy-5-methyl-9-oxo-4 5 8 10-tetraaza-tricyclo [6.2.1.0*2 6*] undeca-2(6) 3-diene-7-carbonyl)-hydrazino]-3-oxo-propyl}-carbamic acid tert-butyl ester:

To a 50 ml single neck round bottom flask equipped with magnetic stirrer was charged a solution of trans-{3-[N’-(10-benzyloxy-5-methyl-9-oxo-4 5 8 10-tetraaza-tricyclo [6.2.1.0*2 6*]undeca-2(6) 3-diene-7-carbonyl)-hydrazino]-3-oxo-propyl}-carbamic acid tert-butyl ester (750 mg  1.461 mmol) in methanol (20 ml) followed by 10% palladium on carbon (200 mg) at 35° C. The reaction mixture was stirred at 35° C under 1 atm hydrogen pressure for 3.5 h. The catalyst was filter under suction over a celite bed. The bed was washed with dichloromethane (30 ml). The filtrate was evaporated under vacuum below 35° C to provide a residue. The residue was purified on 60-120 mesh silica gel column using 6% methanol in chloroform to provide titled intermediate compound in 400 mg quantity (64.7% yield)  it was used immediately for the next reaction.

Analysis: MS (ES-) C17H25N7O6 = 422.1 (M-1).

Step-3: Tetrabutyl ammonium salt of trans-{3-[N’-(5-methyl-9-oxo-10-sulfooxy-4 5 8 10-tetraaza-tricyclo [6.2.1.0*2 6*]undeca-2(6) 3-diene-7-carbonyl)-hydrazino]-3-oxo-propyl}-carbamic acid tert-butyl ester:

To a 50 ml single neck round bottom flask equipped with magnetic stirrer was charged a solution of trans-{3-[N’-(10-hydroxy-5-methyl-9-oxo-4 5 8 10-tetraaza-tricyclo [6.2.1.0*2 6*]undeca-2(6) 3-diene-7-carbonyl)-hydrazino]-3-oxo-propyl}-carbamic acid tert-butyl ester (400 mg  0.946 mmol) in pyridine (15 ml)  followed by pyridine sulfur trioxide complex (751 mg  4.728 mmol) under stirring. The reaction mixture was stirred for 18 h at 35° C. The solvent was evaporated under vacuum blow 40° C to provide a residue and the residue was stirred in 0.5N aqueous potassium dihydrogen phosphate solution (50 ml) for 1 h. The resulting solution was extracted with dichloromethane (2 X 50 ml). To the aqueous layer was added tetrabutyl ammonium hydrogen sulfate (321 mg  0.946 mmol) and the mixture was stirred for 3 h at 25° C. To it was extracted with dichloromethane (2 X 50 ml). Combined organic layer was dried over sodium sulfate and evaporated under vacuum to provide titled intermediate compound in 300 mg quantity (42.5% yield).

Analysis: MS (ES-) C17H24N7O9S. N(C4H9)4 = 502.0 (M-1) as a free sulfonic acid.

Step-4: trans-Sulfuric acid mono-{7-[N’-(3-amino-propionyl)-hydrazinocarbonyl]-5-methyl-9-oxo-4 5 8 10-tetraaza-tricyclo[6.2.1.0*2 6*]undeca-2(6) 3-dien-10-yl}ester:

To a 50 ml round bottom flask equipped with magnetic stirrer was charged a solution of tetrabutyl ammonium salt of trans-{3-[N’-(5-methyl-9-oxo-10-sulfooxy-4 5 8 10-tetraaza-tricyclo [6.2.1.0*2 6*]undeca-2(6) 3-diene-7-carbonyl)-hydrazino]-3-oxo-propyl}-carbamic acid tert-butyl ester (300 mg. 0.402 mmol) in dichloromethane (5 ml). The solution was cooled to -10° C under stirring and to it was added trifluoroacetic acid (5 ml) dropwisely. The reaction mixture was stirred at -10° C for 2 h. Solvents were evaporated under vacuum below 30° C and the residue was triturated successively with diethyl ether (2 X 25 ml)  acetonitrile ((2 X 25 ml) and dichloromethane (2 X 25 ml) to provide suspension. Each time solvents were decanted. The solid was dried in the flask under vacuum below 35° C to provide titled compound of the invention as a off-white solid in 100 mg quantity (62.1% yield).
Analysis: MS (ES-) C12H17N7O7S = 401.9 (M-1) as a free sulfonic acid;
H1NMR (DMSO-d6  D2O exchange) = 7.40 (s  1H)  5.29 (s  1H)  4.72 (d  1H)  3.67 (s  3H)  3.44-3.48 (m  1H)  3.40 (s  1H)  3.31 (br d  1H)  3.00 (t  2H)2.52-2.55 (m  2H).

Example-4

trans-Sulfuric acid mono-{5-methyl-9-oxo-7-[N’-((R)-piperidine-3-carbonyl)-hydrazinocarbonyl]-4 5 8 10-tetraaza-tricycl0[6.2.1.0*2 6*]undeca-2(6) 3-dien-10-yl}-ester;

The titled compound of invention was prepared in 120 mg quantity by using (R)-piperidine -3-carboxylic acid hydrazide (3.11 gm  0.0128 mol) in the place of (2-hydrazinocarbonyl-ethyl)-carbamic acid tert-butyl ester and using the procedure described in example-3.

Analysis: MS (ES-) C15H21N7O7S = 442.2 (M-1) as a free sulfonic acid;

H1NMR (DMSO-d6  D2O exchange) = 7.41 (s  1H)  5.29 (d  1H)  5.72 (d  1H)  3.67 (s  3H)  3.48 (br d  1H)  3.28 (br d  1H) 3.18 (br d  1H)  3.04-3.12 (m  1H)  2.72-3.00 (m  1H)  2.82-2.88 (m  1H)  2.64-2.72 (m  1H)  1.86-1.94 (m  1H)  1.74-1.82 (m  1H)  1.58-1.64 (m  3H).

Example-5

trans-Sulfuric acid mono-{7-[N’-(2-amino-acetyl)-hydrazinocarbonyl]-5-methyl-9-oxo-4 5 8 10-tetraaza-tricyclo[6.2.1.0*2 6*]undeca-2(6) 3-dien-10-yl}ester

The titled compound of invention was prepared in 92 mg quantity by using amino acetic acid hydrazide (2.49 gm  0.0128 mol) in the place of (2-hydrazinocarbonyl-ethyl)-carbamic acid tert-butyl ester and using the procedure described in example-3.
Analysis: MS (ES-) C11H15N7O7S = 388.0 (M-1) as a free sulfonic acid;
H1NMR (DMSO-d6) = 10.70 (s  1H)  10.40 (s  1H)  7.90-8.20 (m  3H)  7.4 (s  1H)  5.37 (s  1H)  4.77 (s  1H)  3.92-4.10 (m  2H)  3.75 (s  3H)  3.60-3.80 (m  2H).

Example-6

trans-Sulfuric acid mono-{5-methyl-9-oxo-7-[N’-((R)-pyrrolidine-3-carbonyl)-hydrazinocarbonyl]-4 5 8 10-tetraaza-tricycl0[6.2.1.0*2 6*]undeca-2(6) 3-dien-10-yl}-ester;

The titled compound of invention was prepared in 118 mg quantity by using (R)-pyrrolidine-3-carboxylic acid hydrazide (2.93 gm  0.0128 mol) in the place of (2-hydrazinocarbonyl-ethyl)-carbamic acid tert-butyl ester and using the procedure described in example-3.

Analysis: MS (ES-) C14H19N7O7S = 427.9 (M-1) as a free sulfonic acid;
H1NMR (DMSO-d6) = 10.46 (d  1H)  10.22 (s  1H)  8.73 (br d  2H)  7.37 (s  1H)  5.32 (d  1H)  4.71 (d  1H)  3.72 (s  3H)  3.38-3.48 (m  3H)  3.05-3.25 (m  4H)  2.15-2.20 (m  2H)  1.96-2.01 (m  2H).
Example-7

trans-Sulfuric acid mono-{5-methyl-9-oxo-7-[N’-((S)-pyrrolidine-2-carbonyl)-hydrazinocarbonyl]-4 5 8 10-tetraaza-tricycl0[6.2.1.0*2 6*]undeca-2(6) 3-dien-10-yl}-ester

The titled compound of invention was prepared in 108 mg quantity by using (S)-pyrrolidine-2-carboxylic acid hydrazide (2.93 gm  0.0128 mol) in the place of (2-hydrazinocarbonyl-ethyl)-carbamic acid tert-butyl ester and using the procedure described in example-3.

Analysis: MS (ES-) C14H19N7O7S = 428.0 (M-1) as a free sulfonic acid;

H1NMR (DMSO-d6) = 10.65 (d  1H)  10.56(s  1H)  9.17 (br s  1H)  8.74 (br s  1H)  7.38 (s  1H)  5.36 (d  1H)  4.72 (d  1H)  3.21 (br s  1H)  3.15-3.45 (br m  7H)  2.24-2.27 (m  2H)  1.82-1.88 (m  4H).

Biological Activity

The biological activity of representative compounds according to the invention against various bacterial strains was investigated. In a typical study  overnight grown bacterial cultures were diluted appropriately and inoculated on the agar media containing doubling dilutions of the test compounds. Observation for growth or no growth was performed after 16-20 hours of incubation at 35 ± 2°C in ambient air. The overall 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).

Table 1 describes antibacterial activity of representative compounds according to the invention against various Multi Drug Resistant (MDR) Gram-negative bacterial strains expressing various ESBLs. The activities are expressed as MICs (mcg/ml). For comparison  the activity of several known antibacterial agents (for example  Ceftazidime  Aztreonam  Imipenem  Ciprofloxacin and Tigecycline) are also included. As can be seen  the representative compounds according to the invention exhibit antibacterial activity against various MDR strains.

Table 1. Comparative antibacterial activity of representative compounds according to the invention against various Multi Drug Resistant (MDR) Gram negative strains (expressed as MICs (mcg/ml).
Sr. Compound Ceftazidime Ciprofloxacin Tigecycline Compound according to
Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7
1. E. ColiW 13353 32 > 32 1 16 > 32 4 4 16 2 4
2. E. ColiW 13351 32 0.5 1 32 > 32 8 8 32 4 16
3. E. ColiW 13352 > 32 0.12 0.25 16 > 32 16 16 16 8 32
4. E. ColiM 50 > 32 > 32 0.5 16 > 32 8 8 16 4 16
5. E. ColiH 483 > 32 > 32 0.25 16 > 32 > 32 > 32 16 4 > 32
6. K. pneumoniaeH 521 > 32 32 2 > 32 > 32 32 32 32 32 > 32
7. K. pneumoniaeH 523 > 32 8 8 32 > 32 16 16 16 32 > 32
8. K. pneumoniaeH 525 > 32 32 2 16 > 32 32 16 16 16 > 32
9. K. pneumoniaeS-48 > 32 > 32 1 > 32 > 32 32 16 > 32 16 32
10. K. pneumoniae13439 > 32 > 32 4 > 32 > 32 > 32 > 32 > 32 > 32 > 32
11. E. ColiM-44 > 32 > 32 0.25 > 32 > 32 > 32 > 32 > 32 > 32 > 32
12. P. aeruginosaM 1251 1 0.5 16 > 32 > 32 > 32 > 32 > 32 > 32 > 32

CLAIMS

1. A compound of Formula (I)

or a stereoisomer or a pharmaceutically acceptable salt thereof;

Wherein:
Q is heteroaryl  or
Q is a –CO-NH-NH-CO- group  wherein R1 and bicyclic moiety are attached to carbonyl function present in –CO-NH-NH-CO- group 

R1 is:

(a) hydrogen 
(b) C1-C6 alkyl 
(c) heterocyclyl
(d) (CO)n-R3  or
(e) COOR4 

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) C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen  OR5  CN  COOR5  CONR6R7  NR6R7  NR5COR8  NR5CONR6R7  heterocyclyl  heteroaryl  cycloalkyl or aryl 
(c) CN 
(d) NR6R7 
(e) CONR6R7 
(f) NHCONR6R7 
(g) aryl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR6R7  halogen  CN  CONR6R7  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR6R7 
(h) heterocyclyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR6R7  halogen  CN  CONR6R7  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR6R7 
(i) heteroaryl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR6R7  halogen  CN  CONR6R7  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR6R7 
(j) cycloalkyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR6R7  halogen  CN  CONR6R7  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR6R7 
(k) cycloalkyl substituted with C1-C6 alkyl wherein C1-C6 alkyl is further substituted with one or more substituents independently selected from OR5  NR6R7  halogen  CN  or CONR6R7  or
(l) OR8;

R4 is:

(a) hydrogen 
(b) C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen  OR5  CN  COOR5  CONR6R7  NR6R7  NR5COR8  heterocyclyl  heteroaryl  cycloalkyl or aryl 
(c) aryl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR6R7  halogen  CN  CONR6R7  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR6R7 
(d) heterocyclyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR6R7  halogen  CN  CONR6R7  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR6R7 
(e) heteroaryl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR6R7  halogen  CN  CONR6R7  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR6R7  or
(f) cycloalkyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR6R7  halogen  CN  CONR6R7  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR6R7;

R5 and R8 are each independently:

(a) hydrogen  or
(b) C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen  CN  CONR6R7  NR6R7  heterocyclyl  heteroaryl  cycloalkyl or aryl;

R6 and R7 are each independently:

(a) hydrogen 
(b) C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen  OR5  CN  COOR5  CONR5R8  NR5R8  NR5COR8  heterocyclyl  heteroaryl  cycloalkyl or aryl 
(c) aryl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR5R8  halogen  CN  CONR5R8  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR5R8 
(d) heterocyclyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR5R8  halogen  CN  CONR5R8  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR5R8 
(e) heteroaryl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR5R8  halogen  CN  CONR5R8  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR5R8 
(f) cycloalkyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl  OR5  NR5R8  halogen  CN  CONR5R8  SO2-alkyl  SO2-aryl  OSO2-alkyl  OSO2-aryl  or NHCONR5R8  or
(g) R6 and R7 are joined together to form a four to seven member ring.

2. A compound according Claim 1  selected from:

trans-Sulfuric acid mono-{7-[N’-(2-amino-acetyl)-hydrazinocarbonyl]-5-methyl-9-oxo-4 5 8 10-tetraaza-tricyclo[6.2.1.0*2 6*]undeca-2(6) 3-dien-10-yl}ester;

trans-Sulfuric acid mono-{7-[N’-(3-amino-propionyl)-hydrazinocarbonyl]-5-methyl-9-oxo-4 5 8 10-tetraaza-tricyclo[6.2.1.0*2 6*]undeca-2(6) 3-dien-10-yl}ester;

trans-Sulfuric acid mono-{5-methyl-9-oxo-7-[N’-((S)-pyrrolidine-2-carbonyl)-hydrazinocarbonyl]-4 5 8 10-tetraaza-tricycl0[6.2.1.0*2 6*]undeca-2(6) 3-dien-10-yl}-ester;

trans-Sulfuric acid mono-{5-methyl-9-oxo-7-[N’-((R)-pyrrolidine-3-carbonyl)-hydrazinocarbonyl]-4 5 8 10-tetraaza-tricycl0[6.2.1.0*2 6*]undeca-2(6) 3-dien-10-yl}-ester;

trans-Sulfuric acid mono-{5-methyl-9-oxo-7-[N’-((R)-piperidine-3-carbonyl)-hydrazinocarbonyl]-4 5 8 10-tetraaza-tricycl0[6.2.1.0*2 6*]undeca-2(6) 3-dien-10-yl}-ester;

or a stereoisomer or a pharmaceutically acceptable salt thereof.

3. A compound according Claim 1  selected from:

trans-Sodium salt of sulfuric acid mono-{5-methyl-7-(-5-methyl-[1 3 4]oxadiazol-2-yl)-9-oxo-4 5 8 10-tetraaza-tricyclo[6.2.1.0*2 6*]undeca-2(6) 3-dien-10-yl}ester;

trans-Sodium salt of N’-{5-Methyl-9-oxo-10-sulfooxy-4 5 8 10-tetraaza-tricyclo[6.2.1.0*2 6]undeca-2(6) 3-diene-7-carbonyl}-hydrazine carboxylic acid tert-butyl ester;

or a stereoisomer thereof.

4. A pharmaceutical composition comprising a compound according to any of the Claims 1 to 3.

5. A method for preventing or treating bacterial infection in a subject  said method comprising administering to said subject a pharmaceutically effective amount of a compound according to any of the Claims 1 to 3.

6. 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  wherein the method comprises administering to said subject a pharmaceutically effective amount of a compound according to any of the Claims 1 to 3.

7. A pharmaceutical composition according to Claim 4  further comprising at least one beta-lactamase inhibitor selected from sulbactam  tazobactam  clavulanic acid  or a pharmaceutically acceptable derivative thereof.

8. A pharmaceutical composition according to Claim 4 or 7  further comprising at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.

9. 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 according to Claim 4  7 or 8.

10. 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  wherein the method comprises administering to said subject a pharmaceutically effective amount of a pharmaceutical composition according to Claim 4  7 or 8.

11. 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) according to Claim 1 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.

12. 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 subject a pharmaceutically effective amount of: (a) a compound of Formula (I) according to Claim 1 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.

13. 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) according to Claim 1 or a stereoisomer or a pharmaceutically acceptable salt thereof  and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.

14. 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 subject a pharmaceutically effective amount of: (a) a compound of Formula (I) according to Claim 1 or a stereoisomer or a pharmaceutically acceptable salt thereof  and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.

15. 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) according to Claim 1 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.

16. 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 subject a pharmaceutically effective amount of: (a) a compound of Formula (I) according to Claim 1 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.

17. A method for increasing antibacterial effectiveness of a antibacterial agent in a subject  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) according to Claim 1  or a stereoisomer or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition according to Claim 8 or a method according to any of the Claims 9  10  13  14  15  16 or 17  wherein the antibacterial agent is selected from a group consisting of aminoglycosides  ansamycins  carbacephems  cephalosporins  cephamycins  lincosamides  lipopeptides  macrolides  monobactams  nitrofurans  penicillins  polypeptides  quinolones  sulfonamides  tetracyclines  or oxazolidinone antibacterial agents.

19. A pharmaceutical composition according to Claim 8 or a method according to any of the Claims 9  10  13  14  15  16 or 17  wherein the antibacterial agent is a beta-lactam antibacterial agent.

20. A pharmaceutical composition according to Claim 8 or a method according to any of the Claims 9  10  13  14  15  16 or 17  wherein said antibacterial agent is selected from a group consisting of penicillins  penems  carbapenems  cephalosporins  and monobactams.

21. A pharmaceutical composition according to Claim 8 or a method according to any of the Claims 9  10  13  14  15  16 or 17  wherein the antibacterial agent is a cephalosporin antibiotic selected from a group consisting of cephalothin  cephaloridine  cefaclor  cefadroxil  cefamandole  cefazolin  cephalexin  cephradine  ceftizoxime  cefoxitin  cephacetrile  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 pivoxil  cefetamet pivoxil  cefcapene pivoxil or cefditoren pivoxil  cefuroxime  cefuroxime axetil  loracarbacef  ceftaroline and latamoxef.

22. A pharmaceutical composition according to Claim 8 or a method according to any of the Claims 9  10  13  14  15  16 or 17  wherein the antibacterial agent is selected from a group consisting of ceftazidime  cefepime  cefpirome  piperacillin doripenem  meropenem  imipenem  ceftaroline and ceftolozane.

23. A pharmaceutical composition according to Claim 8 or a method according to any of the Claims 9  10  13  14  15  16 or 17  wherein the antibacterial agent is selected from a group consisting of aminoglycosides  ansamycins  carbacephems  cephalosporins  cephamycins  lincosamides  lipopeptides  macrolides  monobactams  nitrofurans  penicillins  polypeptides  quinolones  sulfonamides  tetracyclines  or oxazolidinone antibacterial agents.