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
January 21, 2014, the disclosures of which are incorporated herein by reference in its entirety as
fully rewritten herein.
FIELD OF THE INVENTION
The invention relates to nitrogen containing compounds, their preparation and their
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), 1147-1154.) have reviewed novel approaches
to developing new antibiotics. However, the development of new antibacterial agents is a challenging
task. For example, Gwynn et al. {Annals of the New YorkAcademy 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 the use in treatment of bacterial
infections (for example, see Patent Application Nos. PCT/IB2012/054296, PCT/IB2012/054290,
US20130225554, PCT/US2010/060923, PCT/EP20 10/067647, PCT/US2010/052109,
PCT/US2010/048109, PCT/GB2009/050609, PCT/EP2009/056178, PCT/US2009/041200,
PCT/IB20 13/053092 and PCT/IB2012054706). 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:
cycloalkyl optionally substituted with one or more substituents independently
selected from Ci-C 6 alkyl, halogen, CN, OR3, NR3R4, or CONR3R4, or
(b) heterocycloalkyl optionally substituted with one or more substituents
independently selected from Ci-C 6 alkyl, halogen, CN, OR3, NR3R4, or
(a) S03M,
(b) CF2COOM,
(c) CHFCOOM,
(d) CH2COOM,
(e) CF3;
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(Ci-C6 alkyl), NH(Ci-C 6 alkyl), N(Ci-C 6
alkyl)2, CONH(Ci-C 6 alkyl), CON(Ci-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 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
beta-lactamase 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 betalactamase
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 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.
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, n-propyl, iso-propyl, n-butyl, sec-butyl, z' -butyl, ieri-butyl, n-pentyl, z'so-pentyl, ieri-pentyl,
neopentyl, -pentyl, 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, non-limiting examples of such substituents include halogen, alkoxy, CN, SH,
COOH, COOCi-C 6alkyl, CONH2, OH, NH2, NHCOCH3, cycloalkyl, heterocycloalkyl, 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-Cealkyl,
CONH2, OH, NH2, NHCOCH3, heterocycloalkyl, heteroaryl, aryl, S0 2-alkyl, S0 2-aryl, OS0 2-alkyl,
OS0 2-aryl and the like.
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, nonlimiting
examples of such substituents include Ci-C 6 alkyl, halogen, alkoxy, CN, COOH, CONH2, OH,
NH2, NHCOCH3, heteroaryl, aryl, S0 2-alkyl, S0 2-aryl, 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, NHCOCH3, 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, benzimidazolyl, benzoxazolyl, benzoisoxazolyl,
benzothiazolyl, benzotriazolyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, acridinyl, naphthothienyl,
thianthrenyl, chromenyl, xanthenyl, phenoxathienyl, indolizinyl,indazolyl, phthalazinyl,
naphthyridinyl, qinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, beta-carbolinyl, 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,
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 "heteroaryl" refers to a monocyclic or polycyclic aromatic
hydrocarbon radical containing up to 14 ring atoms.
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 ra -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. J. 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 "halogen" or "halo" as used herein includes chlorine, bromine, fluorine or iodine.
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 ie/t-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 aztreonamby 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, N¾ +, (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:
cycloalkyl optionally substituted with one or more substituents independently
selected from Ci-C 6 alkyl, halogen, CN, OR3, NR3R4, or CONR3R4, or
(b) heterocycloalkyl optionally substituted with one or more substituents
independently selected from Ci-C6 alkyl, halogen, CN, OR3, NR3R4, or
(a) S0 3M,
(b) CF2COOM,
(c) CHFCOOM,
(d) CH2COOM,
(e) CF3;
R3 and R4 are each independently:
hydrogen, or
Ci-C 6 alkyl optionally substituted with one or more substitutents independently
selected from halogen, CN, OH, 0(Ci-C 6 alkyl), NH(Ci-C 6 alkyl), N(Ci-C 6
alkyl)2, CONH(Ci-C 6 alkyl), CON(Ci-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,57?)-sulfuric acid mono-{2 -[N '-(2-(S)-pyrrolidin-2-yl-acetyl)-hydrazinocarbonyl]-7-oxol,
6-diaza-bicyclo[3.2.1] oct-6-yl} ester;
(2S,57?)-sulfuric acid mono-{2 -[N '-(2-azetidin-3-yl-acetyl)-hydrazinocarbonyl]-7-oxo-l,6-
diaza-bicyclo[3.2.1] oct-6-yl} ester;
(2S,57?)-sulfuric acid mono-{2 -[N '-(2-(S)-piperidin-2-yl-acetyl)-hydrazinocarbonyl]-7-oxo-l,6-
diaza-bicyclo[3.2.1] oct-6-yl} ester;
(2S,57?)-sulfuric acid mono-{2 -[N '-(2-(7?)-piperidin-2-yl-acetyl)-hydrazinocarbonyl]-7-oxo-l,6-
diaza-bicyclo[3.2.1] oct-6-yl} ester;
(2S,57?)-sulfuric acid mono-{2 -[N '-(2-(S)-piperidin-3-yl-acetyl)-hydrazinocarbonyl]-7-oxo-l,6-
diaza-bicyclo[3.2.1] oct-6-yl} ester;
(2S,57?)-sulfuric acid mono-{2-[N'-(2-piperidin-4-yl-acetyl)-hydrazinocarbonyl]-7-oxo-l,6-
diaza-bicyclo[3.2.1] oct-6-yl} ester;
(2S,57?)-sulfuric acid mono-{2 -[N '-(2-(7?S)-piperazin-2-yl-acetyl)-hydrazinocarbonyl]-7-oxol,
6-diaza-bicyclo[3.2.1] oct-6-yl} ester;
or a stereoisomer, or a pharmaceutically acceptable derivative 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
Formula (I):
Formula (I)
or a stereoisomer or a pharmaceutically acceptable derivative thereof;
wherein
Ri is :
(a) cycloalkyl optionally substituted with one or more substituents independently
selected from Ci-C 6 alkyl, halogen, CN, OR3, NR3R4, or CONR3R4, or
(b) heterocycloalkyl optionally substituted with one or more substituents
independently selected from Ci-C 6 alkyl, halogen, CN, OR3, NR3R4, or CONR3R4 ;
R2 is -S0 3M;
R3 and R4 are each independently:
(c) hydrogen, or
(d) Ci-C 6 alkyl optionally substituted with one or more substitutents independently
selected from halogen, CN, OH, 0(Ci-C 6 alkyl), NH(Ci-C 6 alkyl), N(Ci-C 6
alkyl)2, CONH(Ci-C 6 alkyl), CON(Ci-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 to obtain a com ound of Formula (Ic);
(b) hydrogeno lysis of a compound of Formula (Ic) to obtain a compound of Formula (Id);
(Id)
(c) sulfonating a compound of Formula (Id), followed by the treatment with tetrabutyl
ammonium hydrogen sulfate to obtain a compound of Formula (Ie); and
(le)
(d) converting a compound of Formula (Ie) to obtain a compound of Formula (I).
In general, 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 hour 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 18
hour to obtain a compound of Formula (Ic).
The compound of Formula (Ic) 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 hour to
obtain a compound of Formula (Id). In some embodiments, compound of Formula (Ic) is converted to
a compound of Formula (Id) in presence of 10% palladium on carbon and hydrogen at a temperature of
about 25°C for about 2 hours.
Compound of of Formula (I) ,
wherein R2 is S0 3M
Scheme-1
The compound of Formula (Id) 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 to 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 (le). In some embodiments, compound of Formula (Id) is
sulfonated in presence of sulfur trioxide-pyridine complex at a temperature of about 25°C for about 1
to 24 hours. The sulphonated compound is further treated with tetrabutylammonium hydrogen sulfate
to provide a compound of Formula (le).
Some compounds according to invention are isolated as zwitterions, by treating a compound of
Formula (le) 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 (le) is treated with trifluoro acetic acid in presence of
dichloromethane at a temperature of about -10°C for about 0.5 to 14 hours to obtain a compound of
Formula (I), wherein R2 is -SO 3M.
Some other compounds according to the invention are isolated as a corresponding sodium salt,
by passing intermediate compound of Formula (Ie) through sodium form of Amberlite 200C resin in a
tetrahydrofuran-water mixture followed by evaporation of the solvent under vacuum.
The compounds according to invention wherein R2 is selected from CF2COOM or CHFCOOM
or CH2COOM were prepared by general reaction scheme as described in Scheme-2. The hydroxyl
intermediate (Id) obtained as per Scheme- 1, is subjected to alkylation with an alkylating agent (Ila)
such as ethyl-bromoacetate, ethyl-bromofluoroacetate, or ethyl-bromodifluoroacetate, in presence of a
base such as potassium carbonate, dnsopropylethylamine 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 Ri 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 trifluoro acetic 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 betalactamase
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 betalactamase
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 betalactamase
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 -[N'-(2-(S)-pyrrolidin-2-yl-acetyl)-hydrazinocarbonyl]-7-oxo-l,6-diazabicyclo[
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,57?)-sulfuric acid mono-{2 -[N'-(2-(S)-pyrrolidin-2-yl-acetyl)-hydrazinocarbonyl]-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)
(2S,57?)-sulfuric acid mono-{2 -[N'-(2-(S)-pyrrolidin-2-yl-acetyl)-hydrazinocarbonyl]-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,57?)-sulfuric acid mono-{2 -[N'-(2-(S)-pyrrolidin-2-yl-acetyl)-hydrazinocarbonyl]-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)
(2S,57?)-sulfuric acid mono-{2 -[N '-(2-(S)-pyrroUdin-2-yl-acetyl)-hydrazinocarbonyl]-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)
(2S,57?)-sulfuric acid mono-{2 -[N '-(2-(S)-pyrroUdin-2-yl-acetyl)-hydrazinocarbonyl]-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 (2S,57?)-sulfuric acid mono-{2 -[N '-(2-(S)-pyrrolidin-2-yl-acetyl)-
hydrazinocarbonyl]-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) (2S,57?)-sulfuric acid mono-{2 -[N '-(2-(S)-pyrrolidin-2-yl-acetyl)-
hydrazinocarbonyl]-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) (2S,57?)-sulfuric acid mono-{2 -[N '-(2-(S)-pyrrolidin-2-yl-acetyl)-
hydrazinocarbonyl]-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) (2S,57?)-sulfuric acid mono-{2 -[N '-(2-(S)-pyrrolidin-2-yl-acetyl)-
hydrazinocarbonyl]-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) (2S,57?)-sulfuric acid mono-{2 -[N '-(2-(S)-pyrrolidin-2-yl-acetyl)-
hydrazinocarbonyl]-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,57?)-sulfuric acid mono-{2 -[N '-(2-(S)-pyrrolidin-2-yl-acetyl)-
hydrazinocarbonyl]-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 (2S,57?)-sulfuric acid
mono-{2 -[N '-(2-(S)-pyrroUdin-2-yl-acetyl)-hydrazinocarbonyl]-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,57?)-sulfuric acid
mono-{2 -[N '-(2-(S)-pyrroUdin-2-yl-acetyl)-hydrazinocarbonyl]-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 betalactamase
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) (2S,57?)-sulfuric acid
mono-{2 -[N '-(2-(S)-pyrroUdin-2-yl-acetyl)-hydrazinocarbonyl]-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 betalactamase
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) ((2S,57?)-sulfuric acid
mono-{2 -[N '-(2-(S)-pyrroUdin-2-yl-acetyl)-hydrazinocarbonyl]-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) (2S,57?)-sulfuric acid
mono-{2 -[N '-(2-(S)-pyrroUdin-2-yl-acetyl)-hydrazinocarbonyl]-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-
yl} ester 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) (2S,57?)-sulfuric acid
mono-{2 -[N '-(2-(S)-pyrroUdin-2-yl-acetyl)-hydrazinocarbonyl]-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-
yl} ester 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, troleandomycin,
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,
non-limiting examples of sulfonamide antibacterial agents include mafenide, sulfonamidochrysoidine,
sulfacetamide, sulfadiazine, sulfamethizole, sulfamethoxazole, sulfasalazine, sulfisoxazole,
trimethoprim and the like. Typical, non-limiting examples of tetracycline antibacterial agents include
demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline, tigecycline and the like.
Typical non-limiting examples of oxazolidinone 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 are provided methods for preventing or treating a bacterial
infection in a subject, said infection being caused by bacteria producing one or more beta-lactamase
enzymes, said methods comprising administering to said subject a compound of Formula (I). In some
other embodiments, there are provided methods for preventing or treating a bacterial infection in a
subject, said infection being caused by bacteria producing one or more beta-lactamase enzymes, said
methods comprising administering to said subject a pharmaceutical composition comprising compound
of Formula (I).
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
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.
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
Synthesis of (25,5/f)-Sulfuric acid mono-{2-[N '-(2-(5)-pyrrolidin-2-yl-acetyl)-
hydrazinocarbonyl]-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl} ester:
Step-1 : Preparation of (25,5/f)-2 -{N '-[2-(5 )-N-t rt -butoxycarbonyl-pyrrolidin-2-yl-acetyl]-
hydrazinocarbonyl}-6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1] octane:
To a clear solution of sodium salt of (2S,57?)-6-benzyloxy-7-oxo-l, 6-diazabicyclo[
3.2.1]octane-2-carboxylic acid (31.5 g, 0.106 mol) (prepared according to the process
disclosed in PCT/IB20 13/059264) in water (500 ml), was added EDC hydrochloride (30.4 g, 0.159
mol), followed by HOBt (14.3 gm, 0.106 mol) at about 25°C under stirring. The reaction mixture was
stirred for 15 minutes and a solution of (S)-(N-tert-butoxycarbonyl-pyrrolidin-2-yl)-acetic acid
hydrazide (26 g, 0.106 mol) dissolved in water (150 ml) was added. The reaction mixture was stirred at
25°C for 18 hour. The precipitated solid was filtered, washed with water (650 ml) and dried under
reduced pressure. The residue was suspended in water (650 ml) and stirred at 45°C for 3 hour. The
reaction mixture was filtered and the solid was washed with water (650 ml). The solid was dried under
reduced pressure and dissolved in dichloromethane (1000 ml). The organic layer was dried over
anhydrous sodium sulphate, filtered and evaporated to obtain 40 g of (2 ,5 )-[2-(N '-[(S )-N -tertbutoxycarbonyl-
pyrrolidin-2-yl-methylcarbonyl] -hydrazinocarbonyl)-6-benzyloxy-7-oxo- 1,6-diazabicyclo[
3.2.1] octane, in 75% yield.
Analysis:
Mass: 502.4 (M+l), for Molecular Formula of C25H35N5O6;
1H NMR (DMSO-d 6) : d 9.89 (br d, 2H), 7.33-7.44 (m, 5H), 4.90-4.96 (m, 2H), 3.92-3.96 (m,
1H), 3.80 (d, 1H), 3.69 (s, 1 H), 3.26 (s, 2H), 3.23 (d, 1H), 2.90 (d, 1H), 1.99-2.11 (m, 2H), 1.60-1.95
(m, 8H), 1.38 (s, 9H).
Step-2: Preparation of (25,5/f)-2 -{N '-[2-(5 )-N-t rt -butoxycarbonyl-pyrrolidin-2-yl-acetyl]-
hydrazinocarbonyl}-6-hydroxy-7-oxo-l,6-diaza-bicyclo[3.2.1] octane:
To a clear solution of (2 ,5 )-[2-(N '-[(S )-N -ieri-butoxycarbonyl-pyrrolidin-2-ylmethylcarbonyl]-
hydrazinocarbonyl)-6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1]octane (30 g, 0.0598
mol) in methanol (250 ml), 10% palladium on carbon (3 gm) was added at 25°C. The reaction mixture
was stirred under 150 psi hydrogen pressure at 25°C for 2 hour. The catalyst was filtered under suction
over a celite bed. The bed was washed with methanol (125 ml). The combined filtrate was evaporated
under vacuum below 35°C to provide 24.5 g of (2 ,5 )-[2-(N '-[(S )-N -ieri-butoxycarbonyl-pyrrolidin-
2-yl-methylcarbonyl]-hydrazinocarbonyl)-6-hydroxy-7-oxo-l,6-diaza-bicyclo[3.2.1] octane, in 99%
yield. It was used as such for further reaction.
Analysis:
Mass: 410.3 (M-l), for Molecular Formula of Cis N O ;
1H NMR (DMSO-d 6) : d 9.76 (br s, 2H), 3.90-3.97 (m, 1H), 3.75 (d, 1H), 3.60 (s, 1H), 3.30 (s,
2H), 3.19 (d, 1H), 2.97 (d, 1H), 2.00-2.17 (m, 2H), 1.50-1.88 9m, 8H), 1.38 (s, 9H).
Step-3: Preparation of tetrabutyl ammonium salt of (25,5/f)-2 -{N '-[2-(5 )-N-t rt-butoxycarbonylpyrrolidin-
2-yl-acetyl]-hydrazinocarbonyl}-6-sulphooxy-7-oxo-l,6-diaza-bicyclo[3.2.1] octane:
To a 1 L single neck round bottom flask equipped with magnetic stirrer was charged a solution
of (2S,5R)-[2-(N'-[(S)-N-tert-butoxycarbonyl-pyrroUdin-2-yl-methylcarbonyl]-hydrazinocarbonyl)-6-
hydroxy-7-oxo-l,6-diaza-bicyclo[3.2.1] octane (24.5 g, 0.0596 mol) in dichloromethane (250 ml),
followed by triethylamine (25 ml, 0.178 mol) and pyridine sulfur trioxide complex (19 gm, 0.119 mol)
under stirring. The reaction mixture was stirred for 2 hours at 25°C. The solvent was evaporated under
vacuum below 40°C to provide a residue which was stirred in 0.5 N aqueous potassium dihydrogen
phosphate solution (500 ml) for 1 hour. The resulting solution was extracted successively with ethyl
acetate (500 ml) and a mixture of ethyl acetate (250 ml) and dichloro methane (125 ml). To the aqueous
layer was added tetrabutyl ammonium hydrogen sulfate (18.21 gm, 0.0536 mol) and the mixture was
stirred for 15 hour at 25°C. The precipitated sohd was filtered under reduced pressure and dried under
vacuum to provide 25 g of tetrabutyl ammonium salt of (2S,5R)-[2-(N'-[(S)-N-tert-butoxycarbonylpyrroUdin-
2-yl-methylcarbonyl] -hydrazinocarbonyl)-6-sulfooxy-7-oxo- 1,6-diaza-bicyclo [3.2.1]
octane, in 57% yield.
Analysis:
Mass: 490.3 (M-l) as a free sulfonic acid, for Molecular Formula of C1 H2 N5O S. N(C4H )4;
H NMR (CDCI3): d 8.70 (s, 1H), 8.54 (s, 1H), 4.30 (br s, 1H), 4.09-4.15 (m, 1H), 3.97 (d, 1H),
3.23-3.40 (m, 10H), 3.16 (d, 1H), 2.73-2.81 (m, 1H), 2.28-2.42 (m, 2H), 2.10-2.20 (m, 1H), 1.98-2.09
(m, 1H), 1.75-1.96 (m, 7H), 1.57-1.73 (m, 8H), 1.45-1.52 (m, 16H), 0.99 (t, 12H).
Step-4 : Preparation of (25,5/f)-sulfuric acid mono-{2-[N '-(2-(5)-pyrrolidin-2-yl-acetyl)-
hydrazinocarbonyl]-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl} ester:
To a 250 ml round bottom flask equipped with magnetic stirrer was charged a solution of
tetrabutyl ammonium salt of (2S,5R)-[2-(N'-[(S)-N-tert-butoxycarbonyl-pyrroUdin-2-ylmethylcarbonyl]-
hydrazinocarbonyl)-6-sulfooxy-7-oxo-l,6-diaza-bicyclo[3.2.1] octane (24 g, 0.033
mol) in dichloro methane (60 ml). The solution was cooled to -10 °C under stirring and to it was added
trifluoro acetic acid (60 ml) drop wise. The reaction mixture was stirred at -10 °C for 2 hour. Solvents
were evaporated under vacuum and the residue was taken in diethyl ether (360 ml) and stirred for 1
hour. The mixture was filtered; the sohd was washed with diethyl ether (120 ml) and dried under
reduced pressure. Acetone (360 ml) was added to the sohd and the pH of the solution was adjusted
from initial pH 3 to pH 6.5 by addition of 10% solution of sodium 2-ethyl hexanoate in acetone. The
reaction mixture was filtered; the sohd was washed with acetone (120 ml) and dried under reduced
pressure. The sohd (13 g) was dissolved in water (13 ml) and 2-propanal (91 ml) was added under
stirring. The reaction mixture was stirred for 18 hour, filtered and the sohd was washed with a mixture
of water (6.5 ml) and 2-propanol (45.5 ml). The sohd was dried under reduced pressure to obtain 10.2
g of compound of invention as (2S,5R)-sulfuric acid mono-[2-(N'-[(S)-pyrroUdin-2-ylmethylcarbonyl]-
hydrazinocarbonyl)-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl] ester in 79% yield.
Analysis:
Mass: 390.1 (M-l), for Molecular Formula of Ci3H2iN50 7S;
1H NMR (DMSO-d6, D20 exchange): d 4.00 (br s, 1H), 3.83 (d, 1H), 3.60-3.66 (m, 1H), 3.17
(d, 1H), 3.10 (t, 2H), 2.90-3.07 (m, 1H), 2.53-2.64 (m, 2H), 1.98-2.11 9m, 2H), 1.67-1.89 (m, 4H),
1.50-1.62 (m, 2H).
Compounds 2 to 7 (Table 1) were prepared using the procedure described in Example- 1 and
using corresponding R1CH 2-C0NHNH 2, in the place of ( )-(N -ieri-butoxycarbonyl-pyrroUdin-2-yl)-
acetic acid hydrazide.
Formula (I)

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, M07-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 the compounds of Formula (I) were much lower in comparison to the standards (imipenem
and ceftazidime). Therefore, the results of Table 2 suggests that the compounds of invention exhibited
good antibacterial activity against the multidrug resistant gram negative strains.
Table 3 details the antibacterial activity of representive compound of Formula (I), (25,5i?)-sulfuric
acid mono-{2-[V-(2-(5)-pyrrolidin-2-yl-acetyl)-hydrazinocarbonyl]-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-
yl} ester (Compound of Example 1), against various Multi Drug Resistant (MDR) Gram-negative
bacterial strains. The activities are expressed as Minimum Inhibitory Concentrations (MICs) (mcg/ml). As
can be seen in Table 3, the MIC values obtained for compound of Example No. 1 were found to be lower
than those obtained for avibactam. Hence, (2S,5i?)-sulfuric acid mono-{2 -[N'-(2-(S)-pyrrolidin-2-ylacetyl)-
hydrazinocarbonyl]-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl} ester (compound of Example No. 1)
exhibited good antibacterial activity against various Multi Drug Resistant (MDR) Gram-negative bacterial
strains.
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.
Table 4. Beta-lactamase enzyme inhibition activity of representative compounds
according to invention (expressed as IC (u ))
Compound Class A Class C Class D
K. pneumoniae E. coli M50 A. baumannii NCTC
ATCC 700603 (CMY/DHA) 13301 (OXA 23)
(SHV 18)
Avibactam 0.098 0.146 9.735
Clavulanic acid 0.021 >10 >10
Example 1 0.08 0.06 2.389
Example 2 0.097 0.103 6.187
Example 3 0.074 0.052 2.111
Example 4 0.170 0.056 2.93
Example 5 0.16 0.03 1.73
Example 6 0.06 0.037 1.615
Example 7 0.067 0.070 2.842
The Table 5 provides the beta-lactamase enzyme inhibition activity of (2S,5i?)-sulfuric acid mono-
{2-[N '-(2-(5)-pyrrolidin-2-yl-acetyl)-hydrazinocarbonyl]-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl} ester
(compound of Example 1), against Multi Drug Resistant Gram-negative bacterial strains expressing
various ESBLs. As can be seen from the data of Table 5, the IC50 values obtained for compound of
Example 1 were significantly lower than those obtained for avibactam and clavulanic acid. The compound
of Example 1 exhibited potent antibacterial activity against wide variety of bacterial strains producing
different types of beta-lactamase enzymes including those of Class A, Class C and Class D.
Determination of antibacterial activity of combinations according to invention: In a typical
experiment, two sets of plates containing growth media (Molten Mueller Hilton Agar) and bacterial strains
were prepared. One set of plates was taken as control (without ceftazidime) and other set contained
ceftazidime. The media was allowed to solidify and wells were punched later, into which varying
concentrations of compounds according to the invention were poured. A two-fold serial dilution range of
each of the compounds according to invention was prepared and 50 mΐ of each of the dilution was added
into the punched well. The plates were then incubated at 37°C for 18 hours in BOD incubator and
diameters of zone of inhibition were measured after the completion of the incubation.
The Table 6 provides the antibacterial activity of the combination comprising compounds
according to invention and ceftazidime. The compounds according to invention were tested at 0.12, 0.25,
0.5 and 1 mg/well. As can be seen from the results of the Table 6 the diameter to zone of inhibition
significantly increased in presence of ceftazidime. The compounds according to invention exhibited
synergistic antibacterial activity in presence of ceftazidime.
The results of Tables 1 to 6 clearly demonstrate potent antibacterial activity of compounds
according to invention, even against highly resistant gram negative bacteria producing ESBLs. Thus, the
compounds of Formula (I) has tremendous beneficial effect in inhibiting highly resistant bacterial strains
demonstrating the noteworthy therapeutic advance in the treatment of infections caused by such
pathogens.
A compound of Fo
Formula (I)
or a stereoisomer or a pharmaceutically acceptable derivative thereof;
wherein:
Ri is:
(a) cycloalkyl optionally substituted with one or more substituents independently
selected from Ci-C 6 alkyl, halogen, CN, OR3, NR3R4, or CONR3R4, or
(b) heterocycloalkyl 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(Ci-C 6 alkyl), NH(Ci-C 6 alkyl), N(Ci-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:
(2S,5i?)-sulfuric acid mono- { -[ T-(2-(5)-pyrrolidin-2-yl-acetyl)-hydrazinocarbonyl] -7-oxo- 1,6-
diaza-bicyclo[3.2.1] oct-6-yl} ester;
(25,5i?)-sulfuric acid mono-{2 -[N '-(2-azetidin-3-yl-acetyl)-hydrazinocarbonyl]-7-oxo-l,6-diazabicyclo[
3.2.1] oct-6-yl} ester;
(25,5i?)-sulfuric acid mono-{2 -[N '-(2-(5)-piperidin-2-yl-acetyl)-hydrazinocarbonyl]-7-oxo-l,6-
diaza-bicyclo[3.2.1] oct-6-yl} ester;
(25,5i?)-sulfuric acid mono-{2 -[N '-(2-(i?)-piperidin-2-yl-acetyl)-hydrazinocarbonyl]-7-oxo-l,6-
diaza-bicyclo[3.2.1] oct-6-yl} ester;
(2S,5R)-sulfuric acid mono-{2 -[N '-(2-(5)-piperidin-3-yl-acetyl)-hydrazinocarbonyl]-7-oxo-l,6-
diaza-bicyclo[3.2.1] oct-6-yl} ester;
(2S,5i?)-sulfuric acid mono-{2 -[N'-(2-piperidin-4-yl-acetyl)-hydrazinocarbonyl]-7-oxo-l,6-diazabicyclo[
3.2.1] oct-6-yl} ester;
(2S,5i?)-sulfuric acid mono-{2-[N'-(2-(i?5)-piperazin-2-yl-acetyl)-hydrazinocarbonyl]-7-oxo-l,6-
diaza-bicyclo[3.2.1] oct-6-yl} ester;
or a stereoisomer or a pharmaceutically acceptable derivative thereof.
3. A pharmaceutical composition comprising a compound according to any one of the Claims
1 or 2.
4. A pharmaceutical composition comprising (25,5i?)-sulfuric acid mono-{2 -[N'-(2-(5)-
pyrrolidin-2-yl-acetyl)-hydrazinocarbonyl]-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl} ester or a
stereoisomer or a pharmaceutically acceptable derivative thereof.
5. A pharmaceutical composition according to any one of the Claims 3 or 4, further comprising
at least one beta-lactamase inhibitor, or a pharmaceutically acceptable derivative thereof.
6. A pharmaceutical composition according to Claim 5, wherein the beta-lactamase inhibitor is
selected from the group consisting of sulbactam, tazobactam, clavulanic acid, avibactam, or a
pharmaceutically acceptable derivative thereof
7. A pharmaceutical composition according to any one of the Claims 3 to 6, further comprising
at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
8. A pharmaceutical composition according to Claim 7, 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.
9. A pharmaceutical composition according to Claim 7, wherein the antibacterial agent is a
beta-lactam antibacterial agent.
10. A pharmaceutical composition according to Claim 7, wherein said antibacterial agent is
selected from a group consisting of penicillins, penems, carbapenems, cephalosporins, and monobactams.
11. A pharmaceutical composition according to Claim 7, 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, cefmenoxime, cefmetazole, cepfaloglycin, cefonicid, cefodizime,
cefpirome, ceftazidime, ceftriaxone, , cefbuperazone, cefozopran, cefepime, cefoselis,
cefluprenam, cefuzonam, cefpimizole, cefclidin, cefixime, ceftibuten, cefdinir, cefpodoxime auxetil,
cefpodoxime proxetil, cefteram pivoxil, cefetamet pivoxil, cefcapene pivoxil, cefditoren pivoxel,
cefuroxime, cefuroxime auxetil, loracarbacef, ceftaroline, ceftolozane and latamoxef.
12. A pharmaceutical composition according to Claim 5, comprising (a) (25,5i?)-sulfuric acid
mono-{2 -[N'-(2-(5)-pyrrolidin-2-yl-acetyl)-hydrazinocarbonyl]-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl}
ester, or a stereoisomer, or a pharmaceutically acceptable derivative thereof, and (b) sulbactam, or a
pharmaceutically acceptable derivative thereof.
13. A pharmaceutical composition according to Claim 7, comprising: (a) (2S,5i?)-sulfuric acid
mono-{2-[N '-(2-(5)-pyrrolidin-2-yl-acetyl)-hydrazinocarbonyl]-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.
14. A pharmaceutical composition according to any one of the Claims 3 to 13 for use in
treatment or prevention of a bacterial infection.
15. 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 or 2.
16. 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 3 to 13.
17. 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 the Claims 1 or 2, and (b)
at least one beta-lactamase inhibitor or a pharmaceutically acceptable derivative thereof.
18. 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 the Claims 1 or 2, and (b) at least one
antibacterial agent or a pharmaceutically acceptable derivative thereof.
19. 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 the Claims 1 or 2.
20. A method for preventing or treating a bacterial infection in a subject according to Claim 15,
wherein the said method comprises administering to said subject (25,5i?)-sulfuric acid mono-{2 -[N '-(2-
(5)-pyrrolidin-2-yl-acetyl)-hydrazinocarbonyl]-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 according to Claim 17,
wherein the said method comprises administering to said subject: (a) (25,5i?)-sulfuric acid mono-{2-[N'-
(2-(5)-pyrrolidin-2-yl-acetyl)-hydrazinocarbonyl]-7-oxo-l,6-diaza-bicyclo[3.2.1] oct-6-yl} ester, or a
stereoisomer, or a pharmaceutically acceptable derivative thereof, and (b) sulbactam, or a
pharmaceutically acceptable derivative thereof.
22. A method for preventing or treating a bacterial infection in a subject according to Claim 18,
wherein the said method comprises administering to said subject: (a) (25,5i?)-sulfuric acid mono-{2-[N '-(2-
(5)-pyrrolidin-2-yl-acetyl)-hydrazinocarbonyl]-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.
23. A process for the preparation of a compound of Formula (I),
Formula (I)
wherein,
Ri is:
(a) cycloalkyl optionally substituted with one or more substituents independently
selected from Ci-C 6 alkyl, halogen, CN, OR3, NR3R4, or CONR3R4, or
(b) heterocycloalkyl optionally substituted with one or more substituents independently
selected from Ci-C 6 alkyl, halogen, CN, OR3, NR3R4, or CONR3R4;
R2 is -S0 3M,
R3 and R4 are each independently:
(e) hydrogen, or
(f) 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(Ci-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 a coupling
agent, to obtain a com ound of Formula (Ic);
(b) hydrogenolysis of a compound of Formula (Ic) to obtain a compound of Formula (Id);
(Id) (le)
(c) sulfonating a compound of Formula (Id), followed by the treatment with tetrabutyl
ammonium sulfate, to obtain a compound of Formula (Ie) and
(d) converting a compound of Formula (Ie) to obtain a compound of Formula (I).
24. The process according to Claim 23, wherein the coupling agent in step (a) is selected from
l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-hydroxybenzotriazole, dicyclohexyl
carbodiimde or pivalyl chloride.
25. The process according to Claim 23, wherein the sulfonation in step (c) is carried in
presence of sulfur trioxide-pyridine complex or sulfur trioxide-N N-dimethylformamide complex.