2-(1 ,3,4-OXADIAZOL-2-YL)-7-OXO-1 ,6-DIAZABICYCLO[3.2.1 ]OCTANE
DERIVATIVES AND THEIR USE AS ANTIBACTERIAL AGENTS
RELATED PATENT APPLICATIONS
This application claims priority to Indian Patent Application No. 192/MUM/2014 filed on January
21, 2014, the disclosures of which are incorporated herein by reference in its entirety as if fully rewritten
herein.
FIELD OF THE INVENTION
The invention relates to nitrogen containing compounds, their preparation and their use in
preventing or treating infections.
BACKGROUND OF 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 resistant. Coates
et al. (Br. J. Pharmacol. 2007; 152(8), 1147-1 154.) 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 discovery of antibacterial agents.
Several compounds have been described in the prior art for use in treatment of bacterial infections
(for example, see Patent Application Nos. PCT/IB20 12/054296, PCT/IB20 12/054290, US20130225554,
PCT/US2010/060923, PCT/EP20 10/067647, PCT/US20 10/052 109, PCT/US20 10/048 109,
PCT/GB2009/050609, PCT/EP2009/056178, PCT/US2009/041200, PCT/US20 13/034562,
PCT/US2013/034589, PCT/IB20 13/053092 and PCT/IB20 12054706). 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 now surprisingly discovered novel nitrogen containing compounds having
potent antibacterial activity.
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 a bacterial infection in a subject using these compounds.
In one general aspect, there are provided compounds of Formula (I):
Formula (I)
or a stereoisomer or a pharmaceutically acceptable derivative thereof;
wherein:
Ri is:
(a) Ci-C 6 alkyl optionally substituted with one or more substituents independently
selected from Ci-C 6 alkyl, halogen, CN, OR3, NR3R4, CONR3R4, cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl;
(b) heterocycloalkyl optionally substituted with one or more substituents independently
selected from Ci-C 6 alkyl, halogen, CN, OR3, NR3R4, or CONR3R4;
(c) aryl optionally substituted with one or more substituents independently
selected from Ci-C 6 alkyl, halogen, CN, OR3, NR3R4, or CONR3R4; or
(d) heteroaryl optionally substituted with one or more substituents independently
selected from Ci-C 6 alkyl, halogen, CN, OR3, NR3R4, or CONR3R4;
R2 is:
(a) S0 3M,
(b) CF2COOM,
(c) CHFCOOM,
(d) CH2COOM, or
(e) CF ;
R3 and R4 are each independently:
(a) hydrogen, or
(b) Ci-C 6 alkyl optionally substituted with one or more substitutents independently
selected from halogen, CN, OH, 0 ( -C6 alkyl), NH(Ci-C 6 alkyl), N(d-C 6 alkyl)2,
CONH(Ci-C 6 alkyl), CON(d-C 6 alkyl)2, cycloalkyl, heterocycloalkyl, aryl or
heteroaryl;
M is hydrogen or a cation.
In another general aspect, there are provided pharmaceutical compositions comprising a compound
of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof.
In another general aspect, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject a compound of Formula (I)
or a stereoisomer or a pharmaceutically acceptable derivative thereof.
In yet another general aspect, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject a pharmaceutical
composition comprising a compound of Formula (I) or a stereoisomer 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 derivative thereof, and (b) at
least one beta-lacatamse inhibitor 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 derivative 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 derivative thereof, (b) at
least one beta-lacatamse inhibitor or a pharmaceutically acceptable derivative thereof, and (c) at least one
antibacterial agent or a pharmaceutically acceptable derivative thereof.
In another general aspect, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject a pharmaceutical
composition comprising: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically
acceptable derivative thereof, and (b) at least one beta-lactamase inhibitor or a pharmaceutically
acceptable derivative thereof.
In another general aspect, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject a pharmaceutical
composition comprising: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically
acceptable derivative thereof, and (b) at least one antibacterial agent or pharmaceutically acceptable
derivative thereof.
In another aspect, there are provided methods for preventing or treating a bacterial infection in a
subject, said methods comprising administering to said subject a pharmaceutical composition comprising:
(a) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, (b)
at least one beta-lactamase inhibitor or pharmaceutically acceptable derivative thereof, and (c) at least one
antibacterial agent or a pharmaceutically acceptable derivative thereof.
In another general aspect, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject: (a) a compound of Formula
(I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, and (b) at least one betalactamase
inhibitor or pharmaceutically acceptable derivative thereof.
In another general aspect, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject: (a) a compound of Formula
(I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, and (b) at least one antibacterial
agent or pharmaceutically acceptable derivative thereof.
In another general aspect, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject: (a) a compound of Formula
(I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, (b) at least one beta-lactamase
inhibitor or pharmaceutically acceptable derivative thereof, and (c) at least one antibacterial agent or
pharmaceutically acceptable derivative thereof.
In another general aspect, there are provided methods for increasing antibacterial effectiveness of
an antibacterial agent in a subject, said methods comprising co-administering said antibacterial agent, or a
pharmaceutically acceptable derivative thereof, with a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof.
The 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, 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 "Ci-C 6 alkyl" as used herein refers to branched or unbranched acyclic hydrocarbon
radical with 1 to 6 carbon atoms. Typical non-limiting examples of "Ci-C 6 alkyl" include methyl, ethyl, npropyl,
iso-propyl, n-butyl, sec-butyl, -butyl, tert-buty\, n-pentyl, -pentyl, r -pentyl, neopentyl, secpentyl,
3-pentyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and the
like. The "Ci-C 6 alkyl" may be unsubstituted, or substituted with one or more substituents. Typical, nonlimiting
examples of such substituents include halogen, alkoxy, CN, SH, COOH, COOCi-Cealkyl,
CONH2, OH, NH2, NHCOCH3, cycloalkyl, heterocyclo alkyl, 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 or triple bonds, but which is not aromatic. Typical, non-limiting examples of cycloalkyl groups
include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The cycloalkyl may be
unsubstituted, or substituted with one or more substituents. Typical, non-limiting examples of such
substituents include Ci-C 6 alkyl, halogen, alkoxy, CN, SH, COOH, COOCi-C 6alkyl, CONH2, OH, NH2,
NHCOCH 3, heterocycloalkyl, heteroaryl, aryl, S0 2-alkyl, S0 2-aryl, OS0 2-alkyl, OS0 2-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, indenyl 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, NHCOCH 3, heterocycloalkyl, heteroaryl, aryl, S0 2-alkyl, S0 2-aryl,
OS0 2-alkyl, OS0 2-aryl and the like. In some embodiments, the term "aryl" refers to a monocyclic or
polycyclic aromatic hydrocarbon radical containing up to 14 ring atoms.
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 pyridyl, pyrimidinyl,
pyrazinyl, pyridazinyl, triazinyl, furanyl, pyrrolyl, thienyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxazolyl,
thiazolyl, imidazolyl, pyrazolyl, triazonyl, isoxazolyl, oxadiazolyl, oxatriazolyl, isothiazolyl, thiatriazolyl,
thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, tetrazinyl, thiatriazinyl,
oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, tetrazolo-pyridazinyl,
purinyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzothiophenyl, carbazolyl, benzirnidazolyl,
benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzotriazolyl, indolyl, isoindolyl, quinolinyl,
isoquinolinyl, acridinyl, naphthothienyl, thianthrenyl, chromenyl, xanthenyl, phenoxathienyl,
indolizinyl,indazolyl, phthalazinyl, naphthyridinyl, qinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, betacarbolinyl,
phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl 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, SH,
SCH3, NH2, NHCOCH3, heterocycloalkyl, heteroaryl, aryl, S0 2-alkyl, S0 2-aryl, OS0 2-alkyl, OS0 2-aryl
and the like. In some embodiments, the term "heteroaryl" refers to a monocyclic or polycyclic aromatic
hydrocarbon radical containing up to 14 ring atoms.
The term "heterocycloalkyl" 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 example of heterocycloalkyl groups include
azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, imidazolidin-2-one-yl, piperidinyl, oxazinyl, thiazinyl,
piperazinyl, piperazin-2,3-dione-yl, morpholinyl, thiomorpholinyl, azepanyl, and the like. The
heterocycloalkyl may be unsubstituted, or substituted with one or more substituents. Typical, non-limiting
examples of such substituents include Ci-C 6 alkyl, halogen, alkoxy, CN, COOH, CONH2, OH, NH2,
NHCOCH 3, heteroaryl, aryl, S0 2-alkyl, S0 2-aryl, OS0 2-aryl and the like.
The term "halogen" or halo as used herein refers to chlorine, bromine, fluorine or iodine.
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 the 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 derivative" as used herein refers to and includes any
pharmaceutically acceptable salt, pro-drugs, metabolites, esters, ethers, hydrates, polymorphs, solvates,
complexes 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 or a
pharmaceutically acceptable derivative thereof includes all derivatives of the antibacterial agent (such as
salt, prodrugs, metabolites, esters, ethers, hydrates, polymorphs, solvates, complexes or adducts) which,
upon administration to a subject, is capable of providing (directly or indirectly) the antibacterial
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,
irrigation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. ( .
Pharmaceutical Sciences, 66; 1-19, 1977), incorporated herein by reference in its entirety, describes
various pharmaceutical acceptable salts in details.
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, trifluoro acetic 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 group 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 of the 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 compound 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 "OBn" as used herein refers to benzyloxy.
The term "EDC" as used herein refers to l-ethyl-3-(3-dimethylamino propyl)carbodiimide.
The term "HOBt" as used herein refers to 1-hydroxybenzotriazole.
The term "Boc" as used herein refers to teri-butyloxycarbonyl
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 floras, which are not
desirable. The term "infection" includes infection caused by bacteria.
The term "treat", "treating" or "treatment" as used herein refers to administering a medicament,
including a pharmaceutical composition, or one or more pharmaceutically active ingredients, for
prophylactic and/or therapeutic purposes. The term "prophylactic treatment" refers to treating a 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 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 type/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 or mouthwash. In case of a pharmaceutical
composition comprising more than one ingredient (active or inert), one of the 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 or 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 the 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 "Extended spectrum beta-lactamase or ESBL" as used herein includes those betalactamase
enzymes which are capable of conferring bacterial resistance to the penicillins, first-, second-,
and third-generation cephalosporins, and aztreonam by hydrolysis of these antibiotics.
The term "pharmaceutically inert ingredient" or "carrier" or "excipient" refers to a compound or
material used to facilitate administration of a compound, for example, to increase the solubility of the
compound. Solid carriers include, e.g., starch, lactose, dicalcium phosphate, sucrose, and kaolin. Liquid
carriers include, e.g., sterile water, saline, buffers, non-ionic surfactants, and edible oils such as oil peanut
and sesame oils. In addition, various adjuvants commonly used in the art may be included. These and
other such compounds are described in the literature, e.g., in the Merck Index, Merck & Company,
Rahway, N.J. Considerations for the inclusion of various components in pharmaceutical compositions are
described, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman' s : The Pharmacological Basis of
Therapeutics, 8th Ed., Pergamon Press., which is incorporated herein by reference in its entirety.
The term "subject" as used herein refers to vertebrate or invertebrate, including a 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.
In general, the term "cation" includes H, Na, K, Mg, Ca, NH4
+, (CH3CH2)3N+ etc.
In one general aspect, there are provided compounds of Formula (I):
Formula (I)
or a stereoisomer or a pharmaceutically acceptable derivative thereof;
wherein:
Ri is:
(a) Ci-C 6 alkyl optionally substituted with one or more substituents independently
selected from Ci-C 6 alkyl, halogen, CN, OR3, NR R4 , CONR3R4 , cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl;
(b) heterocycloalkyl optionally substituted with one or more substituents independently
selected from Ci-C 6 alkyl, halogen, CN, OR3, NR3R4 , or CONR3R4 ;
aryl optionally substituted with one or more substituents independently
selected from Ci-C 6 alkyl, halogen, CN, OR3, NR3R4 , or CONR3R4 ; or
heteroaryl optionally substituted with one or more substituents independently
selected from Ci-C 6 alkyl, halogen, CN, OR3, NR3R4 , or CONR3R4 ;
R2 is:
(a) S0 3M,
(b) CF2COOM,
(c) CHFCOOM,
(d) CH2COOM, or
(e) CF ;
R3 and R4 are each independently:
(a) hydrogen, or
(b) Ci-C 6 alkyl optionally substituted with one or more substitutents independently
selected from halogen, CN, OH, 0 ( -C6 alkyl), NH(Ci-C 6 alkyl), N(d-C 6 alkyl)2,
CONH(Ci-C 6 alkyl), CON(d-C 6 alkyl)2, cycloalkyl, heterocycloalkyl, aryl or
heteroaryl;
M is hydrogen or a cation.
Typical non-limiting examples of compounds according to the invention include:
(2S,5i?)-sulfuric acid mono-[2-(5-azetidin-3-ylmethyl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[
3.2.1] oct-6-yl] ester;
(25,5i?)-sulfuric acid mono-[2-(5-(5)-pyrrolidin-2-ylmethyl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-
diaza-bicyclo[3.2.1] oct-6-yl] ester;
(25,5i?)-sulfuric acid mono-[2-(5-piperidin-4-ylmethyl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[
3.2.1] oct-6-yl] ester;
(25,5i?)-sulfuric acid mono-[2-(5-(i?5)-piperazin-2-ylmethyl- [l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-
diaza-bicyclo[3.2.1] oct-6-yl] ester;
(25,5i?)-sulfuric acid mono-[2-(5-benzyl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diaza-bicyclo[3.2.1]
oct-6-yl] ester;
(25,5i?)-sulfuric acid mono-[2-(5-phenyl-ethyl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[
3.2.1] oct-6-yl] ester;
(2S,5i?)-sulfuric acid mono- {2-[5-(3-phenyl-propyl)-[ 1,3,4]-oxadiazol-2-yl]-7-oxo- 1,6-diazabicyclo[
3.2.1] oct-6-yl} ester;
(2S,5i?)-sulfuric acid mono-[2-(5-benzhydryl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[
3.2.1] oct-6-yl] ester;
(2S,5i?)-sulfuric acid mono- {2-[5-(2,2-diphenyl-ethyl)-[ 1,3,4]-oxadiazol-2-yl]-7-oxo- 1,6-diazabicyclo[
3.2.1] oct-6-yl} ester;
(2S,5i?)-sulfuric acid mono- {2-[5-(4-chloro-benzyl)-[ 1,3,4]-oxadiazol-2-yl]-7-oxo- 1,6-diazabicyclo[
3.2.1] oct-6-yl} ester;
(2S,5i?)-sulfuric acid mono- {2-[5-(4-amino-benzyl)-[ 1,3,4]-oxadiazol-2-yl]-7-oxo- 1,6-diazabicyclo[
3.2.1] oct-6-yl} ester;
(2S,5i?)-sulfuric acid mono-{2-[5-(4-dimethylamino-benzyl)-[l,3,4]-oxadiazol-2-yl]-7-oxo-l,6-
diaza-bicyclo[3.2.1] oct-6-yl} ester;
(2S,5i?)-sulfuric acid mono- {2-[5-(4-hydroxy-benzyl)-[ 1,3,4]-oxadiazol-2-yl]-7-oxo- 1,6-diazabicyclo[
3.2.1] oct-6-yl} ester;
(2S,5i?)-sulfuric acid mono- {2-[5-(4-methoxy-benzyl)-[ 1,3,4]-oxadiazol-2-yl]-7-oxo- 1,6-diazabicyclo[
3.2.1] oct-6-yl} ester;
or a stereoisomer or a pharmaceutically acceptable derivative thereof.
In some embodiments, typical non-limiting examples of compounds according to the invention
include:
sodium salt of (25,5i?)-sulfuric acid mono-[2-(5-azetidin-3-ylmethyl-[l,3,4]-oxadiazol-2-yl)-7-
oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl] ester;
sodium salt of (25,5i?)-sulfuric acid mono-[2-(5-(5)-pyrrolidin-2-ylmethyl-[l,3,4]-oxadiazol-2-
yl)-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl] ester;
sodium salt of (25,5i?)-sulfuric acid mono-[2-(5-piperidin-4-ylmethyl-[l,3,4]-oxadiazol-2-yl)-7-
oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl] ester;
trifluoro acetic acid salt of (25,5i?)-sulfuric acid mono-[2-(5-(i?5)-piperazin-2-ylmethyl- [1,3,4]-
oxadiazol-2-yl)-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl] ester;
sodium salt of (25,5i?)-sulfuric acid mono-[2-(5-benzyl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[
3.2.1] oct-6-yl] ester;
sodium salt of (25,5i?)-sulfuric acid mono-[2-(5-phenyl-ethyl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-
diaza-bicyclo[3.2.1] oct-6-yl] ester;
sodium salt of (25,5i?)-sulfuric acid mono-{2-[5-(3-phenyl-propyl)-[l,3,4]-oxadiazol-2-yl]-7-oxol,
6-diaza-bicyclo[3.2.1] oct-6-yl} ester;
sodium salt of (2S,5i?)-sulfuric acid mono-[2-(5-benzhydryl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-
diaza-bicyclo[3.2.1] oct-6-yl] ester;
sodium salt of (2S,5i?)-sulfuric acid mono-{2-[5-(2,2-diphenyl-ethyl)-[l,3,4]-oxadiazol-2-yl]-7-
oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl} ester;
sodium salt of (2S,5i?)-sulfuric acid mono-{2-[5-(4-chloro-benzyl)-[l,3,4]-oxadiazol-2-yl]-7-oxol,
6-diaza-bicyclo[3.2.1] oct-6-yl} ester;
sodium salt of (2S,5i?)-sulfuric acid mono-{2-[5-(4-amino-benzyl)-[l,3,4]-oxadiazol-2-yl]-7-oxol,
6-diaza-bicyclo[3.2.1] oct-6-yl} ester;
sodium salt of (2S,5i?)-sulfuric acid mono-{2-[5-(4-dimethylamino-benzyl)-[l,3,4]-oxadiazol-2-
yl]-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl} ester;
sodium salt of (2S,5i?)-sulfuric acid mono-{2-[5-(4-hydroxy-benzyl)-[l,3,4]-oxadiazol-2-yl]-7-
oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl} ester;
sodium salt of (2S,5i?)-sulfuric acid mono-{2-[5-(4-methoxy-benzyl)-[l,3,4]-oxadiazol-2-yl]-7-
oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl} ester;
or a stereoisomer thereof.
In general, the compounds of the invention can be prepared according to the general procedures
given in Schemes 1 and 2. A person of skills in the art would appreciate that the described method can be
varied or optimized further to provide the desired and related compounds. In the following procedures, all
variables are as defined above.
In some embodiments, there is provided a process for preparation of compounds of Formula (I):
Formula (I)
or a stereoisomer or a pharmaceutically acceptable derivative thereof;
wherein
Ri is as defined earlier elsewhere in the text;
R2 is -SO 3M;
said process comprising:
(a) reacting a compound of Formula (la) with R1CONHNH 2 (lb) in presence of coupling agent
to obtain a compound of Formula (Ic);
cyclizing a compound of Formula (Ic) to obtain a compound of Formula (Id);
(c) hydrogenolysis of a compound of Formula (Id) to obtain a compound of Formula (Ie);
(le)
(d) sulfonating a compound of Formula (Ie), followed by the treatment with tetrabutyl
ammonium hydrogen sulfate to obtain a compound of Formula (If); and
converting a compound of Formula (If) to obtain a compound of Formula (I).
In general, the compounds of Formula (I), wherein R2 is -SO 3M, are prepared as described in
Scheme-1. Typically, sodium salt of 6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid
(la), is reacted with suitable acid hydrazides (lb) in presence of a suitable coupling agent such as EDC
hydrochloride, HOBt, dicyclohexylcarodiimide (DCC), pivalyl chloride and the like, in suitable solvent
such as water, N N-dimethylformamide, N N-dimethylacetamide, or 1,4-dioxane, at a temperature ranging
from about -15°C to 60°C for about 1 hour to 24 hours to obtain a compound of Formula (Ic). In some
embodiments, compound of Formula (la) is reacted with a compound of Formula (lb) in presence of EDC
hydrochloride and HOBt at a temperature of about 25°C for about 1 hour to 24 hours to obtain a
compound of Formula (Ic).
The compound of Formula (Ic) is cyclized by treating it with a suitable reagent such as p -
toluenesulfonyl chloride, j?-nitrobenzenesulfonyl chloride or methanesulfonyl chloride, in a suitable
solvent such as toluene, chloroform, dichloromethane, or N N-dimethylformamide, at a temperature
ranging from about 25°C to about 110°C, for about 1 hour to 14 hours to provide l,3,4-oxadiazol-2-yl
compound of Formula (Id). In some embodiments, cyclization of a compound of Formula (Ic) was carried
by treating with p-toluenesulfonyl chloride, in presence of N,N-dimethylformamide at a temperature
ranging from about 55° to about 100°C for about 1 hour to 14 hours to provide l,3,4-oxadiazol-2-yl
compound of Formula (Id).
The compound of Formula (Id) is subjected to hydrogenolysis in presence of a suitable catalyst
such as 5% or 10% palladium on carbon, 20% palladium hydroxide on carbon, in presence of suitable
hydrogen source such as hydrogen gas, ammonium formate, or cyclohexene, in presence of a suitable
solvent such as methanol, ethanol, methanol-dichloromethane mixture, or N N-dimethylformamidedichloromethane
mixture, at a temperature ranging from about 25°C to 60°C for about 1 to 14 hours to
obtain a compound of Formula (le). In some embodiments, compound of Formula (Id) is converted to a
compound of Formula (le) in presence of 10% palladium on carbon and hydrogen at a temperature of
about 25°C for about 1 hour to about 14 hours.
The compound of Formula (le) is sulfonated by reacting with a suitable sulfonating reagent such as
sulfur trioxide-pyridine complex, or sulfur trioxide-N,N-dimethylformamide complex, in presence of a
suitable solvent such as pyridine, or N N-dimethyl formamide, at a temperature ranging from about 25°C
to 90°C for about 1 hour to about 24 hours to obtain corresponding pyridine salt of sulfonic acid. This is
further treated with suitable reagent such as tetrabutylammonium acetate, tetrabutylammonium hydrogen
sulfate, tetrabutylammonium sulfate and the like to provide tetrabutylammonium salt of sulfonic acid as a
compound of Formula (If). In some embodiments, compound of Formula (le) is sulfonated in presence of
sulfur trioxide-pyridine complex at a temperature of about 25°C for about 1 hour to about 24 hours. The
sulphonated compound is further treated with tetrabutylammonium hydrogen sulfate to provide a
compound of Formula (If).
Some compounds according to invention are isolated as zwitterions, by treating a compound of
Formula (If) with trifluoro acetic acid, in a suitable solvent such as dichloromethane, chloroform, or
acetonitrile, at a temperature ranging from about -15°C to 40°C for about 0.5 to 14 hours. In some
embodiments, compound of Formula (If) is treated with trifluoroacetic acid in presence of
dichloromethane at a temperature of about -10°C for about 2 hours to obtain a compound of Formula (I),
wherein R2 is -S0 3M.
Some other compounds according to the invention are isolated as a corresponding sodium salt, by
passing intermediate compound of Formula (If) through sodium form of Amberlite 200C resin in a
tetrahydrofuran-water mixture followed by evaporation of the solvent under vacuum.
Compound of Formula (I),
(if) wherein R2 is -S0 3M
Scheme-1
The compounds according to invention wherein R2 is selected from CF2COOM or CHFCOOM or
CH2COOM are prepared by general reaction scheme as described in Scheme-2. The hydroxyl intermediate
(Ie) obtained as per Scheme-1, is subjected to alkylation with an alkylating agent (Ila) such as ethylbromoacetate,
ethyl-bromofluoro acetate, or ethyl-bromodifluoro acetate, in presence of a base such as
potassium carbonate, diisopropylethylamine or triethylamine, in a suitable solvent such as N,N-dimethyl
formamide, N,N-dimethylacetamide or N-methyl pyrrolidine, to provide O-alkylated compound (lib).
The compound of Formula (lib) is subjected for hydrolysis in presence of a base such as lithium
hydroxide or potassium hydroxide, in a suitable solvent such as aqueous tetrahydrofuran or aqueous
dioxane, to provide compound of Formula (I). Optionally, if R i bears amine function protected with Boc
group, then it is removed with an additional step of deprotection by using a suitable deprotecting agent
(such as trifluoroacetic acid or hydrogen fluoride-pyridine) in a suitable solvent such as dichloromethane,
chloroform or acetonitrile, to provide a compound of Formula (I), wherein, R2 is selected from CF2COOM
or CHFCOOM or CH2COOM.
i) Ester hydrolysis
ii) Boc deprotection
Compound of Formula (I) , wherein
R2 is -CA2COOH and
A is H or F
Scheme-2
In some embodiments, there are provided pharmaceutical compositions comprising a compound of
Formula (I) or a stereoisomer 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 derivative thereof, and (b) at
least one beta-lactamase inhibitor 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 derivative thereof, and (b) at
least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, avibactam 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 derivative 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 derivative thereof, and (b) at
least one antibacterial agent selected from cefepime, cefpirome, ceftaroline, ceftazidime, ceftalozane 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 derivative thereof, (b) at
least one beta-lacatamse inhibitor or a pharmaceutically acceptable derivative thereof, and (c) at least one
antibacterial agent, or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject a pharmaceutical
composition comprising a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable
derivative thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject a pharmaceutical
composition comprising: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically
acceptable derivative thereof and (b) at least one beta-lactamase inhibitor or pharmaceutically acceptable
derivative thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject a pharmaceutical
composition comprising: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically
acceptable derivative thereof and (b) at least one beta-lactamase inhibitor selected from sulbactam,
tazobactam, clavulanic acid, avibactam, or pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject a pharmaceutical
composition comprising: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically
acceptable derivative thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable
derivative thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject a pharmaceutical
composition comprising: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically
acceptable derivative thereof, and (b) at least one antibacterial agent selected from selected from
cefepime, cefpirome, ceftaroline, ceftazidime, ceftalozane or a pharmaceutically acceptable derivative
thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject a pharmaceutical
composition comprising: (a) a compound of Formula (I) or a stereoisomer or a pharmaceutically
acceptable derivative thereof, (b) at least one beta-lactamase inhibitor or pharmaceutically acceptable
derivative thereof and (c) at least one antibacterial agent or a pharmaceutically acceptable derivative
thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said method comprising administering to said subject a compound of Formula (I) or
a stereoisomer or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject: (a) a compound of Formula
(I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, (b) at least one beta-lactamase
inhibitor or pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject: (a) a compound of Formula
(I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, (b) at least one beta-lactamase
inhibitor selected from sulbactam, tazobactam, clavulanic acid, avibactam, or pharmaceutically acceptable
derivative thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject: (a) a compound of Formula
(I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, (b) at least one antibacterial
agent or pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject: (a) a compound of Formula
(I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, (b) at least one antibacterial
agent selected from selected from cefepime, cefpirome, ceftaroline, ceftazidime, ceftalozane or
pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject: (a) a compound of Formula
(I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, (b) at least one beta-lactamase
inhibitor or pharmaceutically acceptable derivative thereof, and (c) at least one antibacterial agent or
pharmaceutically acceptable derivative thereof.
In some embodiments, there are provided pharmaceutical compositions comprising (2S,5R)-
sulfuric acid mono-[2-(5-benzhydryl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl]
ester or a stereoisomer or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided pharmaceutical compositions comprising: (a)
(2S,5i?)-sulfuric acid mono-[2-(5-benzhydryl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-
6-yl] ester or a stereoisomer or a pharmaceutically acceptable derivative thereof, and (b) at least one betalactamase
inhibitor or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided pharmaceutical compositions comprising: (a)
(25,5i?)-sulfuric acid mono-[2-(5-benzhydryl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-
6-yl] ester or a stereoisomer or a pharmaceutically acceptable derivative thereof, and (b) at least one betalactamase
inhibitor selected from sulbactam, tazobactam, clavulanic acid, avibactam or a pharmaceutically
acceptable derivative thereof.
In some other embodiments, there are provided pharmaceutical compositions comprising: (a)
(25,5i?)-sulfuric acid mono-[2-(5-benzhydryl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-
6-yl] ester or a stereoisomer or a pharmaceutically acceptable derivative 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)
(25,5i?)-sulfuric acid mono-[2-(5-benzhydryl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-
6-yl] ester or a stereoisomer or a pharmaceutically acceptable derivative thereof, and (b) at least one
antibacterial agent selected from cefepime, cefpirome, ceftaroline, ceftazidime, ceftalozane or a
pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided pharmaceutical compositions comprising: (a)
(2S,5i?)-sulfuric acid mono-[2-(5-benzhydryl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-
6-yl] ester or a stereoisomer or a pharmaceutically acceptable derivative thereof, (b) at least one betalacatamse
inhibitor or a pharmaceutically acceptable derivative thereof, and (c) at least one antibacterial
agent, or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject a pharmaceutical
composition comprising (25,5i?)-sulfuric acid mono-[2-(5-benzhydryl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-
diaza-bicyclo[3.2.1] oct-6-yl] ester or a stereoisomer or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject a pharmaceutical
composition comprising: (a) (25,5i?)-sulfuric acid mono- [2-(5-benzhydryl-[ 1,3,4]-oxadiazo l-2-yl)-7-oxol,
6-diaza-bicyclo[3.2.1] oct-6-yl] ester or a stereoisomer or a pharmaceutically acceptable derivative
thereof and (b) at least one beta-lactamase inhibitor or pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject a pharmaceutical
composition comprising: (a) (25,5i?)-sulfuric acid mono- [2-(5-benzhydryl-[ 1,3,4]-oxadiazo l-2-yl)-7-oxol,
6-diaza-bicyclo[3.2.1] oct-6-yl] ester or a stereoisomer or a pharmaceutically acceptable derivative
thereof and (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid,
avibactam, or pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject a pharmaceutical
composition comprising: (a) (25,5i?)-sulfuric acid mono- [2-(5-benzhydryl-[ 1,3,4]-oxadiazo l-2-yl)-7-oxol,
6-diaza-bicyclo[3.2.1] oct-6-yl] ester or a stereoisomer or a pharmaceutically acceptable derivative
thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject a pharmaceutical
composition comprising: (a) (25,5i?)-sulfuric acid mono- [2-(5-benzhydryl-[ 1,3,4]-oxadiazo l-2-yl)-7-oxol,
6-diaza-bicyclo[3.2.1] oct-6-yl] ester or a stereoisomer or a pharmaceutically acceptable derivative
thereof, and (b) at least one antibacterial agent selected from selected from cefepime, cefpirome,
ceftaroline, ceftazidime, ceftalozane or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject a pharmaceutical
composition comprising: (a) (25,5i?)-sulfuric acid mono- [2-(5-benzhydryl-[ 1,3,4]-oxadiazo l-2-yl)-7-oxol,
6-diaza-bicyclo[3.2.1] oct-6-yl] ester or a stereoisomer or a pharmaceutically acceptable derivative
thereof, (b) at least one beta-lactamase inhibitor or pharmaceutically acceptable derivative thereof and (c)
at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said method comprising administering to said subject (25,5i?)-sulfuric acid mono-
[2-(5-benzhydryl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl] ester or a stereoisomer
or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject: (a) (2S,5i?)-sulfuric acid
mono-[2-(5-benzhydryl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl] ester or a
stereoisomer or a pharmaceutically acceptable derivative thereof, (b) at least one beta-lactamase inhibitor
or pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject: (a) (25,5i?)-sulfuric acid
mono-[2-(5-benzhydryl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl] ester or a
stereoisomer or a pharmaceutically acceptable derivative thereof, (b) at least one beta-lactamase inhibitor
selected from sulbactam, tazobactam, clavulanic acid, avibactam, or pharmaceutically acceptable
derivative thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject: (a) (25,5i?)-sulfuric acid
mono-[2-(5-benzhydryl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl] ester or a
stereoisomer or a pharmaceutically acceptable derivative thereof, (b) at least one antibacterial agent or
pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject: (a) (25,5i?)-sulfuric acid
mono-[2-(5-benzhydryl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl] ester or a
stereoisomer or a pharmaceutically acceptable derivative thereof, (b) at least one antibacterial agent
selected from selected from cefepime, cefpirome, ceftaroline, ceftazidime, ceftalozane or
pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject: (a) (25,5i?)-sulfuric acid
mono-[2-(5-benzhydryl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl] ester or a
stereoisomer or a pharmaceutically acceptable derivative thereof, (b) at least one beta-lactamase inhibitor
or pharmaceutically acceptable derivative thereof, and (c) at least one antibacterial agent or
pharmaceutically acceptable derivative thereof.
In some embodiments, there are provided pharmaceutical compositions comprising (2S,5R)-
sulfuric acid mono-[2-(5-(4-hydroxybenzyl)-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-
yl] ester or a stereoisomer or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided pharmaceutical compositions comprising: (a)
(25,5i?)-sulfuric acid mono-[2-(5-(4-hydroxybenzyl)-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[
3.2.1] oct-6-yl] ester or a stereoisomer or a pharmaceutically acceptable derivative thereof, and (b)
at least one beta-lactamase inhibitor or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided pharmaceutical compositions comprising: (a)
(25,5i?)-sulfuric acid mono-[2-(5-(4-hydroxybenzyl)-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[
3.2.1] oct-6-yl] ester or a stereoisomer or a pharmaceutically acceptable derivative thereof, and (b)
at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, avibactam or a
pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided pharmaceutical compositions comprising: (a)
(2S,5i?)-sulfuric acid mono-[2-(5-(4-hydroxybenzyl)-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[
3.2.1] oct-6-yl] ester or a stereoisomer or a pharmaceutically acceptable derivative 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)
(25,5i?)-sulfuric acid mono-[2-(5-(4-hydroxybenzyl)-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[
3.2.1] oct-6-yl] ester or a stereoisomer or a pharmaceutically acceptable derivative thereof, and (b)
at least one antibacterial agent selected from cefepime, cefpirome, ceftaroline, ceftazidime, ceftalozane or
a pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided pharmaceutical compositions comprising: (a)
(25,5i?)-sulfuric acid mono-[2-(5-(4-hydroxybenzyl)-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[
3.2.1] oct-6-yl] ester or a stereoisomer or a pharmaceutically acceptable derivative thereof, (b) at
least one beta-lacatamse inhibitor or a pharmaceutically acceptable derivative thereof, and (c) at least one
antibacterial agent, or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject a pharmaceutical
composition comprising (25,5i?)-sulfuric acid mono-[2-(5-(4-hydroxybenzyl)-[l,3,4]-oxadiazol-2-yl)-7-
oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl] ester or a stereoisomer or a pharmaceutically acceptable derivative
thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject a pharmaceutical
composition comprising: (a) (25,5i?)-sulfuric acid mono-[2-(5-(4-hydroxybenzyl)-[l,3,4]-oxadiazol-2-yl)-
7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl] ester or a stereoisomer or a pharmaceutically acceptable
derivative thereof and (b) at least one beta-lactamase inhibitor or pharmaceutically acceptable derivative
thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject a pharmaceutical
composition comprising: (a) (25,5i?)-sulfuric acid mono-[2-(5-(4-hydroxybenzyl)-[l,3,4]-oxadiazol-2-yl)-
7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl] ester or a stereoisomer or a pharmaceutically acceptable
derivative thereof and (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam,
clavulanic acid, avibactam, or pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject a pharmaceutical
composition comprising: (a) (25,5i?)-sulfuric acid mono-[2-(5-(4-hydroxybenzyl)-[l,3,4]-oxadiazol-2-yl)-
7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl] ester or a stereoisomer or a pharmaceutically acceptable
derivative thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative
thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject a pharmaceutical
composition comprising: (a) (25,5i?)-sulfuric acid mono-[2-(5-(4-hydroxybenzyl)-[l,3,4]-oxadiazol-2-yl)-
7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl] ester or a stereoisomer or a pharmaceutically acceptable
derivative thereof, and (b) at least one antibacterial agent selected from selected from cefepime,
cefpirome, ceftaroline, ceftazidime, ceftalozane or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject a pharmaceutical
composition comprising: (a) (2S,5i?)-sulfuric acid mono-[2-(5-(4-hydroxybenzyl)-[l,3,4]-oxadiazol-2-yl)-
7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl] ester or a stereoisomer or a pharmaceutically acceptable
derivative thereof, (b) at least one beta-lactamase inhibitor or pharmaceutically acceptable derivative
thereof and (c) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said method comprising administering to said subject (25,5i?)-sulfuric acid mono-
[2-(5-(4-hydroxybenzyl)-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl] ester or a
stereoisomer or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject: (a) (25,5i?)-sulfuric acid
mono-[2-(5-(4-hydroxybenzyl)-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl] ester or a
stereoisomer or a pharmaceutically acceptable derivative thereof, (b) at least one beta-lactamase inhibitor
or pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject: (a) (25,5i?)-sulfuric acid
mono-[2-(5-(4-hydroxybenzyl)-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl] ester or a
stereoisomer or a pharmaceutically acceptable derivative thereof, (b) at least one beta-lactamase inhibitor
selected from sulbactam, tazobactam, clavulanic acid, avibactam, or pharmaceutically acceptable
derivative thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject: (a) (25,5i?)-sulfuric acid
mono-[2-(5-(4-hydroxybenzyl)-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl] ester or a
stereoisomer or a pharmaceutically acceptable derivative thereof, (b) at least one antibacterial agent or
pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject: (a) (25,5i?)-sulfuric acid
mono-[2-(5-(4-hydroxybenzyl)-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl] ester or a
stereoisomer or a pharmaceutically acceptable derivative thereof, (b) at least one antibacterial agent
selected from selected from cefepime, cefpirome, ceftaroline, ceftazidime, ceftalozane or
pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided methods for preventing or treating a bacterial
infection in a subject, said methods comprising administering to said subject: (a) (25,5i?)-sulfuric acid
mono-[2-(5-(4-hydroxybenzyl)-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl] ester or a
stereoisomer or a pharmaceutically acceptable derivative thereof, (b) at least one beta-lactamase inhibitor
or pharmaceutically acceptable derivative thereof, and (c) at least one antibacterial agent or
pharmaceutically acceptable derivative thereof.
In some embodiments, the compositions and methods according to the invention use compounds of
Formula (I), or a stereoisomer, or a pharmaceutically acceptable derivative thereof, in combination with at
least one antibacterial agent. 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 carbapenam
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, cefiolene, ceftizoxime, oxacephem, cefepime, cefozopran,
cefpirome, cefquinome, ceftobiprole, cetiofur, cefquinome, cefovecin, CXA-101, ceftaroline, ceftobiprole,
cefoselis, cefluprenam, cefclidin, loracarbacef, ceftolozane, latamoxef and the like.
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, telithromycin,
spectinomycin 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, colistin,
polymyxin B 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,
norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, temafloxacin and the like. Typical, nonlimiting
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 anti-bacterial agents include linezolid, ranbezolid, torezolid, radezolid and the
like. Typical non-limiting examples of beta-lactamase inhibitor include sulbactam, tazobactam, clavulanic
acid, avibactam and the like.
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 excipients 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, preservatives, 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 oral or 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 the 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. In some embodiments, compounds and compositions
according to invention are administered orally or parenterally.
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 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 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 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, pharmaceutical compositions and methods according to the
invention are useful in treatment or prevention of infections caused by resistant bacteria. The compounds,
compositions and methods according to the invention are also useful in treatment or prevention of
infections caused by bacteria producing one or more beta-lactamase enzymes including those producing
extended spectrum beta-lactamase enzymes.
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 compound of Formula (I). 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 pharmaceutical composition comprising compound of Formula
( -
In general, the compounds of Formula (I) or a stereoisomer or pharmaceutically acceptable
derivative thereof according to invention are also useful in increasing antibacterial effectiveness of an
antibacterial agent in a subject. The antibacterial effectiveness of one or more antibacterial agents may be
increased, for example, by co- administering said antibacterial agents or a pharmaceutically acceptable
derivative thereof with a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable
derivative thereof according to the invention. In some other embodiments, there are provided methods for
increasing antibacterial effectiveness of an antibacterial agent in a subject, said method comprising co
administering said antibacterial agent or a pharmaceutically acceptable derivative thereof with a
compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof.
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.
Example-1
(25,5R)-Sulfuric acid mono-r2-(5-azetidin-3-ylmethyl-ri,3,41-oxadiazol-2-yl)-7-oxo-l,6-diazabicvclor3.2.11
oct-6-yll ester:
Step-1 : Preparation of (25,5R)-2-{N'-[2-(5 )-iV-tert-butoxycarbonyl-azetidin-2-yl-acetyl]-hydrazino
carbonyl}-6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1] octane:
To a solution of sodium (2S, 5R)-7-oxo-6-benzyloxy-l,6-diazabicyclo[3.2.1]octane-2-carboxylate
(8.45 g, 28.3 mmol) (prepared according to the process disclosed in PCT/IB20 13/059264) in water (100
ml) was added 3-(N-feri-butoxycarbonyl-azetidin-3-yl)-acetic acid hydrazide (5.9 g, 25.7 mmol), EDC
hydrochloride (7.47 g, 38.6 mmol) and N-hydroxybenzotriazole (3.47 g, 25.7 mmol) at 25°C to 35°C
under stirring. The reaction mixture was stirred for 18 hours. Precipitated solid was filtered under suction
and washed with water (100 ml). It was dried to provide 10.01 g of (25,5R)-2-{N '-[2-(S -N-fertbutoxycarbonyl-
azetidin-2-yl-acetyl]-hydrazinocarbonyl}-6-benzyloxy-7-oxo-l,6-diaza-bicyclo [3.2.1]
octane in 80% yield.
Analysis:
Mass: 486.4 (M-l), for Molecular Formula of C24H33N5O6;
Purity as determined by HPLC: 89.90%.
Step-2 : Preparation of (25,5R)-2-(5 -( V-tert-butoxycarbonylazetidin-3-yl)-methyl-[l,3,4]-oxadiazol-2-
yl)-6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1] octane:
To a solution of (25,5i?)-2-{N '-[2-(5 )-N-ieri-butoxycarbonyl-azetidin-2-yl-acetyl]-
hydrazinocarbonyl}-6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1] octane (4 gm, 8.21 mmol) in chloroform
(70 ml) was added p-toluenesulfonylchloride (2.34 gm, 12.3 mmol) followed by dnsopropylethylamine
(4.4 ml, 24.6 mmol). The reaction mixture was heated under stirring at 75°C for 18 hours. The reaction
mixture was concentrated under vacuum and the resulting mass was purified by using silica gel column
chromatography, to provide (25,5i?)-2-(5 -(N-ieri-butoxycarbonylazetidin-3-yl)-methyl-[l,3,4]-oxadiazol-
2-yl)-6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1] octane in 3.3 g quantity in 86% yield as a solid.
Analysis:
Mass: 470.4 (M+l), for Molecular Formula of C H iN O ;
1H NMR: (CDCb): d 7.36-7.44 (m, 5H), 5.08 (d, 1H), 4.93 (d, 1H), 4.68-4.71 (m, 1H), 4.10-4.15
(m, 2H), 3.68-3-72 (m, 2H), 3.37 (s, 1H), 3.13-3.15 (m, 2H), 2.90-3.11 (m, 2H), 2.77 (d, 1H), 2.25-2.31
(m, 2H), 2.10-2.19 (m, 1H), 1.87-1.97 (m, 1H), 1.43 (s, 9H).
Step-3: Preparation of (25,5R)-2-(5-(iV-tert-butoxycarbonylazetidin-3-yl)-methyl-[l,3,4]-oxadiazol-2-
yl)-6-hydroxy-7-oxo-l,6-diaza-bicyclo[3.2.1] octane:
To the solution of (25,5i?)-2-(5 -(N -ieri-butoxycarbonylazetidin-3-yl)-methyl-[l,3,4]-oxadiazol-2-
yl)-6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1] octane ( 3.3 g, 7.0 rnmol) in methanol (35 ml) was
subjected to catalytic hydrogenolysis using 10% palladium on charcoal (350 mg) under atmospheric
hydrogen gas pressure at 25°C to 35°C for 2 hours. The reaction mixture was filtered through celite bed
and was washed with methanol (30 ml). The filtrate was concentrated under vacuum below 35°C to
provide 2.7 g of (25,5i?)-2-(5 -(N -ieri-butoxycarbonylazetidin-3-yl)-methyl-[l,3,4]-oxadiazol-2-yl)-6-
hydroxy-7-oxo-l,6-diaza-bicyclo[3.2.1] octane, which was used immediately for the next reaction.
Analysis:
Mass: 378.4 (M-l), for Molecular Formula of C H N O .
Step-4: Preparation of tetrabutylammonium salt of (2S,5R)-2-(5- V- rt-butoxycarbonylazetidin-3-
yl)-methyl-[l,3,4]-oxadiazol-2-yl)-6-sulphooxy-7-oxo-l,6-diaza-bicyclo[3.2.1] octane:
To a solution of (25,5i?)-2-(5 -(N -ieri-butoxycarbonylazetidin-3-yl)-methyl-[l,3,4]-oxadiazol-2-yl)-
6-hydroxy-7-oxo-l,6-diaza-bicyclo[3.2.1] octane (2.7 gm, 7.12 mmol) in dichloromethane (50 ml) was
added triethylamine (5 ml, 35 mmol) followed by sulfur trioxide pyridine complex (2.26 g 14.2 mmol)
under stirring at 25°C to 35°C. The reaction mixture was stirred for 2 hours. To the reaction mixture was
added aqueous 0.5 N potassium dihydrogen phosphate solution (100 ml). It was stirred for about 30
minutes and tetrabutyl ammonium hydrogen sulfate (2.17 gm 6.4 mmol) was added. It was stirred for 2
hours. Layers were separated and organic layer was concentrated under vacuum to provide a crude mass,
which was purified by silica gel column chromatography to furnish 2.1 g of tetrabutylammonium salt of
(25,5i?)-2-(5 -(N -ieri-butoxycarbonylazetidin-3-yl)-methyl-[ 1,3,4]-oxadiazol-2-yl)-6-sulphooxy-7-oxo- 1,6-
diaza-bicyclo[3.2.1] octane as solid in 43% yield.
Analysis:
Mass: 458.3 (M-l), as a free sulfonic acid, for Molecular Formula of C17H25N5O8S. N(C4H )4;
Purity as determined by HPLC: 94.87%.
Step-5 : Preparation of (25,5R)-sulfuric acid mono-[2-(5-azetidin-3-ylmethyl-[l,3,4]-oxadiazol-2-yl)-
7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl] ester:
To the solution of tetrabutylammonium salt of (25,5i?)-2-(5 -(N -feri-butoxycarbonylazetidin-3-yl)-
methyl-[l,3,4]-oxadiazol-2-yl)-6-sulphooxy-7-oxo-l,6-diaza-bicyclo[3.2.1] octane (1.0 g, 2.2 mmol) in
dichloromethane (5 ml) was charged trifluoroacetic acid (5 ml) with syringe at -10°C under stirring. The
reaction mixture was stirred for 1 hour. The mixture was evaporated under vacuum by maintaining
temperature below 35°C, to provide a residue, which was suspended in diethyl ether (25 ml) twice. The
suspension was filtered and the solid was suspended further in dichloromethane (50 ml) and stirred for 30
minutes. The suspension was filtered and dried to afford the 310 mg of (25,5i?)-sulfuric acid mono-[2-(5-
azetidin-3-ylmethyl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl] ester as a solid in
60% yield.
Analysis:
Mass: 358.2 (M-l), for Molecular Formula of C H N O S;
1H NMR (DMSO-d6): d 8.50 (br s, IH), 8.62 br s, IH), 4.60 (d, IH), 4.05 (s, 3H), 3.82-3.84 (m,
IH), 3.21-3.27 (m, 4H), 2.93-2.96 (m, IH), 2.75 (d, IH), 2.12-2.17 (m, IH), 1.96-2.05 (m, 2H), 1.82-1.88
(m, IH).
The representative compounds of Formula (I)-Compounds 2 to 14 (Table 1) were prepared by
using the procedure described in Example- 1 and by using corresponding acid hydrazide in the step- 1.
Formula (I)
The sodium salt of the compound of the invention was obtained by loading tetrabutyl ammonium
salt as obtained in step-4 of Example- 1, on freshly activated Amberlite-IR 120 sodium resin column, and
by eluting with tetrahydrofuran water mixture (10:90). The required fractions were concentrated under
vacuum to deliver sodium salt of invention.

BIOLOGICAL ACTIVITY DATA
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.
Observations for growth or no growth was performed after 16-20 hours of incubation at 35±2°C in the
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 07-A9, Volume 32, No. 2, 2012).
Molten Mueller Hinton Agar (BD, USA) containing serial dilutions of each antibacterial agent were
poured on to the plates and allowed to solidify. Appropriate suspensions from the freshly grown cultures
were prepared in normal saline so that about 104 CFU/spot of the organism was delivered on to the drug
containing agar plates using automated multipoint inoculator (Mast, UK). The plates were incubated in
Biochemical oxygen demand (BOD) incubator at 37 °C for 18 hours and then examined for growth.
Table 2 details the antibacterial activity of representative compounds according to invention,
against various Multi Drug Resistant (MDR) Gram-negative bacterial strains. . The strains selected for
study included E.coli NCTC 13353 producing CTX-M15 and OXA-1 beta-lactamase enzymes;
K.pneumoniae H521 producing KPC, SHV, TEM beta-lactamase enzymes; and K.pneumoniae S48
producing NDM, SHV, TEM beta-lactamase enzymes. The activities are expressed as Minimum
Inhibitory Concentrations (MICs) (mcg/ml). The antibacterial activity profile of representative compounds
according to invention were compared against known antibacterial agent such as imipenem and
ceftazidime. As can be seen, the MIC values for representative compounds of Formula (I) were
comparitively higher in comparison to the standards (imipenem and ceftazidime). Therefore, the results of
Table 2 suggests that the compounds of invention when used alone exhibited lesser antibacterial activity
against the multidrug resistant gram negative strains.
Table 3 details the antibacterial activity of representative compound of Formula (I), sodium salt of
(2S,5i?)-sulfuric acid mono-[2-(5-benzyl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl]
ester (Compound of Example 5), against various Multi Drug Resistant (MDR) Gram-negative bacterial
strains. The activities are expressed as Minimum Inhibitory Concentrations (MICs) (mcg/ml). The
antibacterial activity profile of Compound of Example 5 was compared with avibactam. As can be seen
from the data, Compound of Example 5 exhibited antibacterial activity in comparison to avibactam.
Determination of enzyme inhibition activity: IC50 is concentration of the compound required to
inhibit 50% of enzymatic activity. IC50 values for various compounds was measured by adding Nitrocefin
(IOOmM, 5 min) to the preincubated mixture of crude enzyme and the compounds (37°C, 10 minutes).
Absorbance was measured at 485 nm by UV-spectrophotometer. The IC50 was calculated by plotting
absorbance against concentration through Sigmoidal dose response curve using Graph Pad software.
The Table 4 provides the beta-lactamase enzyme inhibition activity of representative compounds
of Formula (I), against Multi Drug Resistant Gram-negative bacterial strains expressing various ESBLs.
The enzyme inhibition was expressed as IC50. As can be seen from the data of Table 4, the beta-lactamase
enzyme inhibition values for the compounds according to invention were found to be lower than
avibactam and clavulanic acid. The compounds according to invention exhibited potent antibacterial
activity against wide variety of bacteria producing Class A, Class C and Class D types of beta-lactamase
enzymes. Surprisingly, the representative compounds according to invention exhibit even better than
avibactam and clavulanic acid.
xamp e - . .
Agar dilution MIC determination method: Agar dilution MIC was carried out in Muller Hinton
Agar (Difco, USA) according to the recommendations of CLSI (M07-A9). In short, the plates were poured
with a range of doubling increasing concentration of Ceftazidime and fixed 4mg/ml compound according
to invention containing MHA. The freshly overnight grown cultures were diluted in physiological saline
to deliver per spot 104 CFU. The plates were inoculated with a multipoint inoculator (Mast, UK) and
incubated at 35°C for 18 hours. MICs were read as the lowest concentration of drug that completely
inhibited visible bacterial growth as per CLSI guidelines. Table-5 provides the result of combination MIC
results.
The results of Table 5 show that the MIC values of Ceftazidime in presence of compounds
according to the invention (at 4mg/ml). As shown in Table 5, the MIC value of Ceftazidime was
significantly lowered in presence of representative compounds according to the invention. Thus
combination of a compound of Formula (I) and an antibacterial agent exhibited good antibacterial activity
against highly resistant bacterial strains.
The results of Tables 1 to 5 clearly demonstrate that the representative compounds of Formula (I)
exhibited potent beta-lactamase enzyme inhibition against Multi Drug Resistant Gram-negative bacterial
strains expressing highly resistant ESBLs. Thus, combination of compounds of Formula (I) with
antibacterial agents has tremendous beneficial effect in inhibiting highly resistant bacterial strains
demonstrating the noteworthy therapeutic advance in the treatment of infections caused by such
pathogens.
Table 5. Antibacterial activity of representative compounds according to the invention in combination with Ceftazidime.
K. pneumoniae E. coli E. coli Citrobactor spp K. pneumoniae Sr. Compounds
ATCC 700606 NCTC 13353 M 50 58 MP H521
1. Ceftazidime alone 32 32 > 32 16 > 32
Ceftazimime +
2. 1 0.25 1 0.12 2
Example 1 (4mcg/ml)
Ceftazidime +
3. 1 0.25 1 0.25 1
Example 4 (4mcg/ml)
Ceftazidime +
4. 4 0.25 4 0.5 32
Example 5 (4mcg/ml)
Ceftazidime +
5. 8 0.5 8 4 > 32
Example 6 (4mcg/ml)
Ceftazidime +
6. 8 0.5 8 4 > 32
Example 7 (4mcg/ml)
Ceftazidime +
7. 16 2 32 16 > 32
Example 8 (4mcg/ml)
Ceftazidime +
8. 8 4 32 16 > 32
Example 9 (4mcg/ml)
Ceftazidime +
9. 8 0.25 8 1 > 32
Example 10 (4mcg/ml)
Ceftazidime +
10. 4 0.25 2 0.5 16 Example 11 (4mcg/ml)
11. Ceftazidime + 8 1 16 4 > 32
Example 12 (4mcg/ml)
Ceftazidime +
12. 4 0.5 2 0.5 16 Example 13 (4mcg/ml)
Ceftazidime +
13. 32 0.25 8 0.5 > 32
Example 14 (4mcg/ml)
CLAIMS
1. A compound of Formula (I):
Formula (I)
or a stereoisomer or a pharmaceutically acceptable derivative thereof;
wherein:
Ri is
(a) Ci-C 6 alkyl optionally substituted with one or more substituents independently
selected from Ci-C 6 alkyl, halogen, CN, OR3, NR3R4, CONR3R4, cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl;
(b) heterocycloalkyl optionally substituted with one or more substituents independently
selected from Ci-C 6 alkyl, halogen, CN, OR3, NR3R4, or CONR3R4;
(c) aryl optionally substituted with one or more substituents independently
selected from Ci-C 6 alkyl, halogen, CN, OR3, NR3R4, or CONR3R4; or
(d) heteroaryl optionally substituted with one or more substituents independently
selected from Ci-C 6 alkyl, halogen, CN, OR3, NR3R4, or CONR3R4;
R2 is
(a) S0 3M,
(b) CF2COOM,
(c) CHFCOOM,
(d) CH2COOM, or
(e) CF ;
R3 and R4 are each independently:
(a) hydrogen, or
(b) Ci-C 6 alkyl optionally substituted with one or more substitutents independently
selected from halogen, CN, OH, 0 ( -C6 alkyl), NH(Ci-C 6 alkyl), N(d-C 6 alkyl)2,
CONH(Ci-C 6 alkyl), CON(d-C 6 alkyl)2, cycloalkyl, heterocycloalkyl, aryl or
heteroaryl;
M is hydrogen or a cation.
2. A compound according to Claim 1, selected from:
(25,5i?)-sulfuric acid mono-[2-(5-azetidin-3-ylmethyl-[ l ,3,4]-oxadiazol-2-yl)-7-oxo- l ,6-diazabicyclo[
3.2. 1] oct-6-yl] ester;
(25,5i?)-sulfuric acid mono-[2-(5-(5)-pyrrolidin-2-ylmethyl-[ l ,3,4]-oxadiazol-2-yl)-7-oxo- l ,6-
diaza-bicyclo[3.2. 1] oct-6-yl] ester;
(2S,5i?)-sulfuric acid mono-[2-(5-piperidin-4-ylmethyl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[
3.2.1] oct-6-yl] ester;
(2S,5i?)-sulfuric acid mono-[2-(5-(i?S)-piperazin-2-ylmethyl- [l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-
diaza-bicyclo[3.2.1] oct-6-yl] ester;
(2S,5i?)-sulfuric acid mono-[2-(5-benzyl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diaza-bicyclo[3.2.1]
oct-6-yl] ester;
(2S,5i?)-sulfuric acid mono-[2-(5-phenyl-ethyl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[
3.2.1] oct-6-yl] ester;
(2S,5i?)-sulfuric acid mono- {2-[5-(3-phenyl-propyl)-[ 1,3,4]-oxadiazol-2-yl]-7-oxo- 1,6-diazabicyclo[
3.2.1] oct-6-yl} ester;
(2S,5i?)-sulfuric acid mono-[2-(5-benzhydryl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[
3.2.1] oct-6-yl] ester;
(2S,5i?)-sulfuric acid mono- {2-[5-(2,2-diphenyl-ethyl)-[ 1,3,4]-oxadiazol-2-yl]-7-oxo- 1,6-diazabicyclo[
3.2.1] oct-6-yl} ester;
(2S,5i?)-sulfuric acid mono- {2-[5-(4-chloro-benzyl)-[ 1,3,4]-oxadiazol-2-yl]-7-oxo- 1,6-diazabicyclo[
3.2.1] oct-6-yl} ester;
(2S,5i?)-sulfuric acid mono- {2-[5-(4-amino-benzyl)-[ 1,3,4]-oxadiazol-2-yl]-7-oxo- 1,6-diazabicyclo[
3.2.1] oct-6-yl} ester;
(2S,5i?)-sulfuric acid mono-{2-[5-(4-dimethylamino-benzyl)-[l,3,4]-oxadiazol-2-yl]-7-oxo-l,6-
diaza-bicyclo[3.2.1] oct-6-yl} ester;
(25,5i?)-sulfuric acid mono- {2-[5-(4-hydroxy-benzyl)-[ 1,3,4]-oxadiazol-2-yl]-7-oxo- 1,6-diazabicyclo[
3.2.1] oct-6-yl} ester;
(25,5i?)-sulfuric acid mono- {2-[5-(4-methoxy-benzyl)-[ 1,3,4]-oxadiazol-2-yl]-7-oxo- 1,6-diazabicyclo[
3.2.1] oct-6-yl} ester;
or a stereoisomer or a pharmaceutically acceptable derivative thereof.
3. A compound according to Claim 1, selected from:
sodium salt of (25,5i?)-sulfuric acid mono-[2-(5-azetidin-3-ylmethyl-[l,3,4]-oxadiazol-2-yl)-7-
oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl] ester;
sodium salt of (25,5i?)-sulfuric acid mono-[2-(5-(5)-pyrrolidin-2-ylmethyl-[l,3,4]-oxadiazol-2-
yl)-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl] ester;
sodium salt of (25,5i?)-sulfuric acid mono-[2-(5-piperidin-4-ylmethyl-[l,3,4]-oxadiazol-2-yl)-7-
oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl] ester;
trifluoro acetic acid salt of (2S,5i?)-sulfuric acid mono-[2-(5-(i?S)-piperazin-2-ylmethyl- [1,3,4]-
oxadiazol-2-yl)-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl] ester;
sodium salt of (2S,5i?)-sulfuric acid mono-[2-(5-benzyl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[
3.2.1] oct-6-yl] ester;
sodium salt of (2S,5i?)-sulfuric acid mono-[2-(5-phenyl-ethyl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-
diaza-bicyclo[3.2.1] oct-6-yl] ester;
sodium salt of (2S,5i?)-sulfuric acid mono-{2-[5-(3-phenyl-propyl)-[l,3,4]-oxadiazol-2-yl]-7-oxol,
6-diaza-bicyclo[3.2.1] oct-6-yl} ester;
sodium salt of (2S,5i?)-sulfuric acid mono-[2-(5-benzhydryl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-
diaza-bicyclo[3.2.1] oct-6-yl] ester;
sodium salt of (2S,5i?)-sulfuric acid mono-{2-[5-(2,2-diphenyl-ethyl)-[l,3,4]-oxadiazol-2-yl]-7-
oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl} ester;
sodium salt of (2S,5i?)-sulfuric acid mono-{2-[5-(4-chloro-benzyl)-[l,3,4]-oxadiazol-2-yl]-7-oxol,
6-diaza-bicyclo[3.2.1] oct-6-yl} ester;
sodium salt of (2S,5i?)-sulfuric acid mono-{2-[5-(4-amino-benzyl)-[l,3,4]-oxadiazol-2-yl]-7-oxol,
6-diaza-bicyclo[3.2.1] oct-6-yl} ester;
sodium salt of (2S,5i?)-sulfuric acid mono-{2-[5-(4-dimethylamino-benzyl)-[l,3,4]-oxadiazol-2-
yl]-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl} ester;
sodium salt of (2S,5i?)-sulfuric acid mono-{2-[5-(4-hydroxy-benzyl)-[l,3,4]-oxadiazol-2-yl]-7-
oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl} ester;
sodium salt of (2S,5i?)-sulfuric acid mono-{2-[5-(4-methoxy-benzyl)-[l,3,4]-oxadiazol-2-yl]-7-
oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl} ester;
or a stereoisomer thereof.
4. A pharmaceutical composition comprising a compound according to any one of the Claims
1 to 3.
5. A pharmaceutical composition comprising (25,5i?)-sulfuric acid mono-[2-(5-benzhydryl-
[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl] ester or a stereoisomer or a
pharmaceutically acceptable derivative thereof.
6. A pharmaceutical composition comprising (25,5i?)-sulfuric acid mono-{2-[5-(4-hydroxybenzyl)-[
l,3,4]-oxadiazol-2-yl]-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl} ester or a stereoisomer or a
pharmaceutically acceptable derivative thereof.
7. A pharmaceutical composition according to any one of the Claims 4 to 6, further comprising
at least one beta-lactamase inhibitor, or a pharmaceutically acceptable derivative thereof.
8. A pharmaceutical composition according to Claims 7, wherein the beta-lactamase inhibitor is
selected from the group consisting of sulbactam, tazobactam, clavulanic acid, avibactam, or a
pharmaceutically acceptable derivative thereof.
9. A pharmaceutical composition according to any one of the Claims 4 to 8, further comprising
at least one antibacterial agent, or a pharmaceutically acceptable derivative thereof.
10. A pharmaceutical composition according to Claim 9, 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.
11. A pharmaceutical composition according to Claim 9, wherein the antibacterial agent is a
beta-lactam antibacterial agent.
12. A pharmaceutical composition according to Claim 9, wherein said antibacterial agent is
selected from a group consisting of penicillins, penems, carbapenems, cephalosporins, and monobactams.
13. A pharmaceutical composition according to Claim 9, wherein the antibacterial agent is a
cephalosporin antibiotic selected from the group consisting of cephalotin, cephaloridine, cefaclor,
cefadroxil, cefamandole, cefazolin, cefalexin, cefradine, ceftizoxime, cefoxitin, cephacetrile, cefotiam,
cefotaxime, cefsulodin, cefoperazone, cefinenoxime, cefmetazole, cepfaloglycin, cefonicid, cefodizime,
cefpirome, ceftazidime, ceftriaxone, cefpiramide, cefbuperazone, cefozopran, cefepime, cefoselis,
cefluprenam, cefuzonam, zoΐ , cefclidin, cefixime, ceftibuten, cefdinir, cefpodoxime auxetil,
cefpodoxime proxetil, cefteram pivoxil, cefetamet pivoxil, cefcapene pivoxil, cefditoren pivoxel,
cefuroxime, cefuroxime auxetil, loracarbacef, ceftaroline, ceftolozane and latamoxef.
14. A pharmaceutical composition according to Claim 9, comprising: (a) (2S,5i?)-sulfuric acid
mono-[2-(5-benzhydryl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl] ester, or a
stereoisomer or a pharmaceutically acceptable derivative thereof, and (b) at least one antibacterial agent
selected from cefepime, cefpirome, ceftaroline, ceftazidime, ceftalozane, or a pharmaceutically acceptable
derivative thereof.
15. A pharmaceutical composition according to Claim 9, comprising: (a) (25,5i?)-sulfuric acid
mono-{2-[5-(4-hydroxy-benzyl)-[l,3,4]-oxadiazol-2-yl]-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl} ester, or
a stereoisomer or a pharmaceutically acceptable derivative thereof, and (b) at least one antibacterial agent
selected from cefepime, cefpirome, ceftaroline, ceftazidime, ceftalozane or a pharmaceutically acceptable
derivative thereof.
16. A pharmaceutical composition according to any one of the Claims 4 to 15 for use in
treatment or prevention of a bacterial infection.
17. A method of preventing or treating a bacterial infection in a subject, said method comprising
administering to said subject a compound according to any one of the Claims 1 to 3.
18. A method for preventing or treating a bacterial infection in a subject, said method comprising
administering to said subject a pharmaceutical composition according to any one of the Claims 4 to 15.
19. A method of preventing or treating a bacterial infection in a subject, said method comprising
administering to said subject: (2S,5i?)-sulfuric acid mono-[2-(5-benzhydryl-[l,3,4]-oxadiazol-2-yl)-7-oxol,
6-diaza-bicyclo[3.2.1] oct-6-yl] ester, or a stereoisomer or a pharmaceutically acceptable derivative
thereof.
20. A method of preventing or treating a bacterial infection in a subject, said method comprising
administering to said subject: (25,5i?)-sulfuric acid mono-{2-[5-(4-hydroxy-benzyl)-[l,3,4]-oxadiazol-2-
yl]-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl} ester, or a stereoisomer or a pharmaceutically acceptable
derivative thereof.
21. A method for preventing or treating a bacterial infection in a subject, said method
comprising administering to said subject: (a) a compound according to any one of Claims 1 to 3, and (b) at
least one beta-lactamase inhibitor or a pharmaceutically acceptable derivative thereof.
22. A method for preventing or treating a bacterial infection in a subject, said method comprising
administering to said subject: (a) a compound according to any one of Claims 1 to 3, and (b) at least one
antibacterial agent or a pharmaceutically acceptable derivative thereof.
23. A method for increasing antibacterial effectiveness of an antibacterial agent in a subject,
said method comprising co-administering said antibacterial agent, or a pharmaceutically acceptable
derivative thereof, with a compound according to any one of Claims 1 to 3.
24. A method for preventing or treating a bacterial infection in a subject according to Claim 22,
wherein the said method comprising administering to said subject: (a) (25,5i?)-sulfuric acid mono-[2-(5-
benzhydryl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl] ester, and (b) at least one
antibacterial agent selected from cefepime, cefpirome, ceftaroline, ceftazidime, ceftalozane or a
pharmaceutically acceptable derivative thereof.
25. A method for preventing or treating a bacterial infection in a subject according to Claim 22,
wherein the said method comprising administering to said subject: (a) (25,5i?)-sulfuric acid mono-{2-[5-
(4-hydroxy-benzyl)-[l,3,4]-oxadiazol-2-yl]-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl} ester, and (b) at least
one antibacterial agent selected from cefepime, cefpirome, ceftaroline, ceftazidime, ceftalozane or a
pharmaceutically acceptable derivative thereof.
26. A process for the preparation of a compound of Formula (I),
Formula (I)
wherein, Ri is:
(a) Ci-C 6 alkyl optionally substituted with one or more substituents independently
selected from Ci-C 6 alkyl, halogen, CN, OR3, NR3R4, CONR3R4, cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl;
(b) heterocycloalkyl optionally substituted with one or more substituents independently
selected from Ci-C 6 alkyl, halogen, CN, OR3, NR3R4, or CONR3R4;
(c) aryl optionally substituted with one or more substituents independently
selected from Ci-C 6 alkyl, halogen, CN, OR3, NR3R4, or CONR3R4; or
(d) heteroaryl optionally substituted with one or more substituents independently
selected from Ci-C 6 alkyl, halogen, CN, OR3, NR3R4, or CONR3R4;
R2 is:
(a) S0 3M,
R3 and R4 are each independently:
(a) hydrogen, or
(b) Ci-C 6 alkyl optionally substituted with one or more substitutents independently
selected from halogen, CN, OH, 0 ( -C6 alkyl), NH(Ci-C 6 alkyl), N(d-C 6 alkyl)2,
CONH(Ci-C 6 alkyl), CON(d-C 6 alkyl)2, cycloalkyl, heterocycloalkyl, aryl or
heteroaryl;
M is hydrogen or a cation;
said process comprising:
(a) reacting a compound of Formula (la) with RiCONHNH 2 (lb) in presence of coupling agent
n a compound of Formula (Ic);
cyclizing a compound of Formula (Ic) to obtain a compound of Formula (Id);
(c) hydrogenolysis of a compound of Formula (Id) to obtain a compound of Formula (Ie);
(le)
(d) sulfonating a compound of Formula (Ie), followed by the treatment with tetrabutyl
ammonium hydrogen sulfate to obtain a compound of Formula (If); and
converting a compound of Formula (If) to obtain a compound of Formula (I).
27. The process according to Claim 26, wherein the coupling agent in step (a) is selected from
l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-hydroxybenzotriazole, dicyclohexyl
carbodiimde or pivalyl chloride.
28. The process according to Claim 26, wherein the sulfonation in step (d) is carried in
presence of sulfur trioxide-pyridine complex or sulfur trioxide-N, N-dimethylformamide complex.