U.S. patent application number 15/027790 was filed with the patent office on 2016-09-08 for nitrogen containing compounds and their use.
The applicant listed for this patent is WOCKHARDT LIMITED. Invention is credited to Sachin BHAGWAT, Satish BHAWSAR, Prasad Keshav DESHPANDE, Mahesh Vithalbhai PATEL, Shivaji Sampatrao PAWAR, Ravindra Dattatraya YEOLE.
Application Number | 20160257684 15/027790 |
Document ID | / |
Family ID | 51945946 |
Filed Date | 2016-09-08 |
United States Patent
Application |
20160257684 |
Kind Code |
A1 |
DESHPANDE; Prasad Keshav ;
et al. |
September 8, 2016 |
NITROGEN CONTAINING COMPOUNDS AND THEIR USE
Abstract
Compound of Formula (I), its preparation and use in preventing
or treating bacterial infection is disclosed. Formula (I)
##STR00001##
Inventors: |
DESHPANDE; Prasad Keshav;
(Aurangabad 431003,, IN) ; PAWAR; Shivaji Sampatrao;
(Aurangabad 423702,, IN) ; BHAWSAR; Satish;
(Aurangabad 431005,, IN) ; YEOLE; Ravindra
Dattatraya; (Aurangabad 431003,, IN) ; BHAGWAT;
Sachin; (Aurangabad, IN) ; PATEL; Mahesh
Vithalbhai; (Aurangabad 3,, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
WOCKHARDT LIMITED |
Aurangabad |
|
IN |
|
|
Family ID: |
51945946 |
Appl. No.: |
15/027790 |
Filed: |
October 10, 2014 |
PCT Filed: |
October 10, 2014 |
PCT NO: |
PCT/IB2014/065195 |
371 Date: |
April 7, 2016 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 31/00 20180101;
A61K 31/546 20130101; C07D 471/08 20130101; A61K 31/407 20130101;
A61K 31/439 20130101; A61P 31/04 20180101; A61K 45/06 20130101 |
International
Class: |
C07D 471/08 20060101
C07D471/08; A61K 45/06 20060101 A61K045/06; A61K 31/439 20060101
A61K031/439; A61K 31/546 20060101 A61K031/546; A61K 31/407 20060101
A61K031/407 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 11, 2013 |
IN |
3216/MUM/2013 |
Claims
1-29. (canceled)
30. A compound of Formula (I): ##STR00023## or a stereoisomer or a
pharmaceutically acceptable derivative thereof; wherein M is a
cation.
31. The compound according to claim 30, wherein M is hydrogen,
sodium or potassium.
32. The compound according to claim 30, which is (2S,
5R)-6-sulfooxy-2-(aminomethyl)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane
or a stereoisomer or a pharmaceutically acceptable derivative
thereof.
33. A method for treating bacterial infection in a subject, the
method comprising administering to the subject a pharmaceutically
effective amount of a compound according to claim 30.
34. The method according to claim 33, wherein the infection is
caused by bacteria producing one or more beta-lactamase
enzymes.
35. A pharmaceutical composition for treating bacterial infection,
wherein the composition comprises a compound according to claim
30.
36. The pharmaceutical composition according to claim 35, further
comprising at least one beta-lactamase inhibitor or a
pharmaceutically acceptable derivative thereof.
37. The pharmaceutical composition according to claim 35, further
comprising at least one antibacterial agent or a pharmaceutically
acceptable derivative thereof.
38. The pharmaceutical composition according to claim 37, further
comprising at least one beta-lactamase inhibitor or a
pharmaceutically acceptable derivative thereof.
39. The pharmaceutical composition according to claim 36, wherein
the beta-lactamase inhibitor is selected from the group consisting
of Sulbactam, Tazobactam, Clavulanic acid, or a pharmaceutically
acceptable derivative thereof.
40. The pharmaceutical composition according to claim 37, wherein
the antibacterial agent is selected from a group consisting of
Aminoglycosides, Ansamycins, Carbacephems, Cephalosporins,
Cephamycins, Lincosamides, Lipopepetides, Macrolidees, Monobactams,
Nitrofuran, Penems, Carbapenems, Penicillins, Polypeptide,
Quinolones, Sulfonamides, Tetracyclines, and Oxazolidinone
antibacterial agents.
41. The pharmaceutical composition according to claim 37, wherein
the antibacterial agent is a beta lactam antibacterial agent.
42. The pharmaceutical composition according to claim 37, 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,
Cefpiramide, 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.
43. The pharmaceutical composition according to claim 37, wherein
the antibacterial agent is selected from the group consisting of
Cetazidime, Cefepime, Cefpirome, Piperacillin, Ertapenem,
Doripenem, Meropenem, Imipenem, Ceftraroline, and Ceftolozane.
44. The pharmaceutical composition according to claim 36,
comprising (a) (2S,
5R)-6-sulfooxy-2-(aminomethyl)-7-oxo-1,6-diaza-bicyclo
[3.2.1]octane or a stereoisomer or a pharmaceutically acceptable
derivative thereof, and (b) Sulbactam or a pharmaceutically
acceptable derivative thereof.
45. A method for treating bacterial infection in a subject, wherein
the method comprising administering to the subject a
pharmaceutically effective amount of: (a) a compound of Formula (I)
according to claim 30 or a stereoisomer or a pharmaceutically
acceptable derivative thereof, and (b) at least one beta-lactamase
inhibitor or a pharmaceutically acceptable derivative thereof.
46. A method for treating bacterial infection in a subject, wherein
the method comprising administering to the subject a
pharmaceutically effective amount of: (a) a compound of Formula (I)
according to claim 30 or a stereoisomer or a pharmaceutically
acceptable derivative thereof, and (b) at least one antibacterial
agent or a pharmaceutically acceptable derivative thereof.
47. A method for treating bacterial infection in a subject, wherein
the method comprising administering to the subject a
pharmaceutically effective amount of: (a) a compound of Formula (I)
according to claim 30 or a stereoisomer or a pharmaceutically
acceptable derivative thereof, (b) at least one beta-lactamase
inhibitor or a pharmaceutically acceptable derivative thereof and
(c) at least one antibacterial agent or a pharmaceutically
acceptable derivative thereof.
48. A method for increasing antibacterial effectiveness of an
antibacterial agent in a subject, wherein the method comprising
co-administering the antibacterial agent or a pharmaceutically
acceptable derivative thereof with a pharmaceutically effective
amount of a compound of Formula (I) according to claim 30, or a
stereoisomer or a pharmaceutically acceptable derivative
thereof.
49. A process for preparation of (2S,
5R)-6-sulfooxy-2-(aminomethyl)-7-oxo-1,6-diaza-bicyclo
[3.2.1]octane of Formula (XI), wherein the process comprising:
##STR00024## (a) Converting a compound of Formula (II) to a
compound of Formula (III); ##STR00025## (b) Reacting a compound of
Formula (III) with p-nitrophenyl sulfonyl chloride in presence of a
base to obtain a compound of Formula (IV); ##STR00026## (c)
Reacting a compound of Formula (IV) with sodium azide to obtain a
compound of Formula (V); ##STR00027## (d) Converting a compound of
Formula (V) to a compound of Formula (VI); ##STR00028## (e)
Hydrogenolysis of a compound of Formula (VI) to obtain a compound
of Formula (VII); ##STR00029## (f) Reacting a compound of Formula
(VII) with sulfonating agent, followed by a reaction with
tetrabutyl ammonium hydrogen sulfate to obtain a compound of
Formula (VIII); ##STR00030## (g) Converting a compound of Formula
(VIII) to a compound of Formula (IX); ##STR00031## (h) Reacting a
compound of Formula (IX) with trifluoroacetic acid in suitable
solvent to obtain a compound of Formula (X); and ##STR00032## (i)
Converting a compound of Formula (X) to a compound of Formula (XI).
Description
[0001] This application claims benefit of Indian Patent Application
No. 3216/MUM/2013 filed on Oct. 11, 2013, the disclosures of which
are incorporated herein by reference in its entirety as if fully
rewritten herein.
FIELD OF THE INVENTION
[0002] The invention relates to nitrogen containing compounds,
their preparation and their use in preventing or treating
infections.
BACKGROUND OF THE INVENTION
[0003] Emergence of bacterial resistance to known antibacterial
agents is becoming a major challenge in treating bacterial
infections. One way forward to treat bacterial infections, and
especially those caused by resistant bacteria, is to develop newer
antibacterial agents that can overcome the bacterial resistance.
Coates et al. (Br. J. Pharmacol. 2007; 152(8), 1147-1154.) have
reviewed novel approaches to developing new antibiotics. However,
the development of new antibacterial agents is a challenging task.
For example, Gwynn et al. (Annals of the New York Academy of
Sciences, 2010, 1213: 5-19) have reviewed the challenges in
discovery of antibacterial agents.
[0004] Another approach to overcome the bacterial resistance to
known antibacterial agents is to target the bacterial mechanisms,
which helps it acquire and maintain the resistance. For example,
several bacteria are known to produce enzymes (beta-lactamase
enzymes) that hydrolyze the beta-lactam ring in a typical
beta-lactam antibacterial agent. Once the beta-lactam ring is
hydrolyzed, the antibacterial agents become ineffective against
those bacteria. Several compounds, generally known as
beta-lactamase inhibitors, are capable of inhibiting activity of
one or more beta-lactamase enzymes, thereby restoring the efficacy
of conventional beta-lactam antibacterial agents. Typical examples
of beta-lactamase inhibitors include Sulbactam, Tazobactam and
Clavulanic acid. Drawz et al. (Clinical Microbiology Reviews,
January 2010, Volume 23(1), p. 160-201) have reviewed the subject
of beta-lactamase inhibition. U.S. Pat. No. 7,112,592 and US Patent
Application No. 20100092443 disclose several compounds containing
heterocyclic core and their use as antibacterial agents. The
inventors have now surprisingly discovered nitrogen containing
compounds having antibacterial activity.
SUMMARY OF THE INVENTION
[0005] Accordingly, there are provided nitrogen containing
compounds, methods for preparation of these compounds,
pharmaceutical compositions comprising these compounds, and method
for preventing or treating bacterial infection in a subject using
these compounds.
[0006] In one general aspect, there are provided compounds of
Formula (I)
##STR00002##
or a stereoisomer or a pharmaceutically acceptable derivative
thereof; wherein M is a cation.
[0007] In another general aspect, there are provided pharmaceutical
compositions comprising a compound of Formula (I) or a stereoisomer
or a pharmaceutically acceptable derivative thereof.
[0008] In another general aspect, there is provided a method for
preventing or treating bacterial infection in a subject, said
method comprising administering to said subject a pharmaceutically
effective amount of a compound of Formula (I) or a stereoisomer or
a pharmaceutically acceptable derivative thereof. In another
general aspect, there is provided a method for preventing or
treating a bacterial infection in a subject, said infection being
caused by bacteria producing one or more beta-lactamase enzymes,
said method comprising administering to said subject a
pharmaceutically effective amount of a compound of Formula (I) or a
stereoisomer or a pharmaceutically acceptable derivative
thereof.
[0009] In another general aspect, there is provided a method for
preventing or treating bacterial infection in a subject, said
method comprising administering to said subject a pharmaceutically
effective amount of a pharmaceutical composition comprising a
compound of Formula (I) or a stereoisomer or a pharmaceutically
acceptable derivative thereof.
[0010] 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-lactamase 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, and (b) at least
one beta-lactamase inhibitor or a pharmaceutically acceptable
derivative thereof, and (c) at least one antibacterial agent or a
pharmaceutically acceptable derivative thereof.
[0011] In another general aspect, there is provided a method for
preventing or treating bacterial infection in a subject, said
method comprising administering to said subject a pharmaceutically
effective amount of a pharmaceutical composition comprising: (a) a
compound of Formula (I) or a stereoisomer or a pharmaceutically
acceptable derivative thereof, and (b) at least one beta-lactamase
inhibitor or a pharmaceutically acceptable derivative thereof.
[0012] In another general aspect, there is provided a method for
preventing or treating bacterial infection in a subject, said
method comprising administering to said subject a pharmaceutically
effective amount of: (a) a compound of Formula (I) or a
stereoisomer or a pharmaceutically acceptable derivative thereof
and (b) at least one antibacterial agent or a pharmaceutically
acceptable derivative thereof.
[0013] In another general aspect, there is provided a method for
preventing or treating bacterial infection in a subject, said
method comprising administering to said subject a pharmaceutically
effective amount of: (a) a compound of Formula (I) or a
stereoisomer or a pharmaceutically acceptable derivative thereof,
(b) at least one beta-lactamase inhibitor or a pharmaceutically
acceptable derivative thereof, and (c) at least one antibacterial
agent or a pharmaceutically acceptable derivative thereof.
[0014] 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 pharmaceutically effective amount of a compound of
Formula (I) or a stereoisomer or a pharmaceutically acceptable
derivative thereof.
[0015] 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
[0016] 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 including the 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.
[0017] The inventors have surprisingly discovered novel nitrogen
containing compounds having antibacterial properties.
[0018] 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,
within the scope of the invention. In general, a reference to a
compound is intended to cover its stereoisomers and mixture of
various stereoisomers.
[0019] The term "pharmaceutically acceptable derivative" as used
herein refers to and includes any pharmaceutically acceptable salt,
pro-drug, metabolite, ester, ether, hydrate, polymorph, solvate,
complexe and adduct of a compound described herein which, upon
administration to a subject, is capable of providing (directly or
indirectly) the parent compound. For example, the term
"antibacterial agent or a pharmaceutically acceptable derivative
thereof" includes all derivatives of the antibacterial agent (such
as salts, pro-drugs, metabolites, esters, ethers, hydrates,
polymorphs, solvates, complexes and adducts) which, upon
administration to a subject, are capable of providing (directly or
indirectly) the antibacterial agent.
[0020] 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
term "pharmaceutically acceptable salts" refer to salts that are
suitable for use in contact with the tissues of human and animals
without undue toxicity, irritation, allergic response and the like,
and are commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable salts are well known in the art. For
example, S. M. Berge, et al. (J. Pharmaceutical Sciences, 66; 1-19,
1977), incorporated herein by reference in its entirety, describes
various pharmaceutically acceptable salts in details.
[0021] In general, the compounds according to the invention contain
basic (e.g. nitrogen atoms) as well as acid moieties (e.g.
compounds of Formula (I) wherein M is hydrogen). A person of skills
in the art would appreciate that such compounds, therefore, can
form acidic salts (formed with inorganic and/or organic acids), as
well as basic salts (formed with inorganic and/or organic bases).
Such salts can be prepared using procedures described in the art.
For example, the basic moiety can be converted to its salt by
treating a compound with a suitable amount of acid. Typical,
non-limiting examples of such suitable acids include hydrochloric
acid, trifluoroacetic acid, methanesulphonic acid or the like.
Alternatively, the acid moiety may be converted into its salt by
treating with a suitable base. Typical non-limiting examples of
such bases include sodium carbonate, sodium bicarbonate, potassium
carbonate, potassium bicarbonate or the like. In case of compounds
containing more than one functional group capable of being
converted into salt, each such functional group may be converted to
corresponding 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.
[0022] The term "OBn" as used herein refers to benzyloxy.
[0023] 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 presence of normal floras, which are not
desirable. The term "infection" includes infection caused by
bacteria.
[0024] The term "treat", "treating" or "treatment" as used herein
refers to administering a medicament, including a pharmaceutical
composition, or one or more pharmaceutically active ingredients,
for prophylactic and/or therapeutic purposes. The term
"prophylactic treatment" refers to treating a subject who is not
yet infected, but who is susceptible to, or otherwise at a risk of
infection (preventing the bacterial infection). The term
"therapeutic treatment" refers to administering treatment to a
subject already suffering from infection. The terms "treat",
"treating" or "treatment" as used herein also refer to
administering compositions or one or more of pharmaceutically
active ingredients discussed herein, with or without additional
pharmaceutically active or inert ingredients, in order to: (i)
reduce or eliminate either a bacterial infection or one or more
symptoms of the bacterial infection, or (ii) retard the progression
of a bacterial infection or 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.
[0025] 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.
[0026] 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 ingredients (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.
[0027] 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 "growth"
also includes maintenance of on-going metabolic processes of a
microorganism, including the processes that keep the microorganism
alive.
[0028] 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.
[0029] The term "antibacterial agent" as used herein refers to any
substance, compound or a combination of substances or a combination
of compounds capable of: (i) inhibiting, reducing or preventing
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.
[0030] 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.
[0031] 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. Typical, non-limiting examples of solid
carriers include, starch, lactose, dicalcium phosphate, sucrose,
and kaolin. Typical, non-limiting examples of liquid carriers
include sterile water, saline, buffers, non-ionic surfactants, and
edible oils such as peanut oil and sesame oils. In addition,
various adjuvants commonly used in the art may also 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, 8.sup.th Ed., Pergamon Press., which is incorporated
herein by reference in its entirety.
[0032] 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.
[0033] In one general aspect, there are provided compounds of
Formula (I)
##STR00003##
or a stereoisomer or a pharmaceutically acceptable derivative
thereof; wherein M is a cation.
[0034] In general, the term "cation" includes H, Na, K, Mg, Ca,
NH.sub.4.sup.+, (CH.sub.3CH.sub.2).sub.3N.sup.+ and the like. In
another general aspect, there is provided a compound of Formula
(I), wherein M is H, Na, K, Mg, Ca, NH.sub.4.sup.+, or
(CH.sub.3CH.sub.2).sub.3N.sup.+.
[0035] In one general aspect, there is provided a compound of
Formula (XI), chemically known as (2S,
5R)-6-sulfooxy-2-(aminomethyl)-7-oxo-1,6-diaza-bicyclo
[3.2.1]octane or a stereoisomer or a pharmaceutically acceptable
derivative thereof.
[0036] In general, the compounds of the invention can be prepared
according to the general procedure given in Scheme 1. 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.
[0037] In some embodiments, the compound of Formula (I), wherein M
is hydrogen, was prepared using a general procedure described in
Scheme 1. In some embodiments, there is provided a process for the
preparation of (2S,
5R)-6-sulfooxy-2-(aminomethyl)-7-oxo-1,6-diaza-bicyclo
[3.2.1]octane of Formula (XI) or a stereoisomer or a
pharmaceutically acceptable derivative thereof,
##STR00004##
comprising:
[0038] (a) Converting a compound of Formula (II) to a compound of
Formula (III);
##STR00005##
[0039] (b) Reacting a compound of Formula (III) with
p-nitrophenylsulfonyl chloride in presence of a base to obtain a
compound of Formula (IV);
##STR00006##
[0040] (c) Reacting a compound of Formula (IV) with sodium azide to
obtain a compound of Formula (V);
##STR00007##
[0041] (d) Converting a compound of Formula (V) to a compound of
Formula (VI);
##STR00008##
[0042] (e) Hydrogenolysis of a compound of Formula (VI) to obtain a
compound of Formula (VII);
##STR00009##
[0043] (f) Reacting a compound of Formula (VII) with sulfonating
agent, followed by a reaction with tetrabutylammonium hydrogen
sulfate to obtain a compound of Formula (VIII);
##STR00010##
[0044] (g) Converting a compound of Formula (VIII) to a compound of
Formula (IX);
##STR00011##
[0045] (h) Reacting compound of Formula (IX) with trifluoroacetic
acid in suitable solvent to obtain a compound of Formula (X);
and
##STR00012##
[0046] (i) Converting a compound of Formula (X) to a compound of
Formula (XI).
[0047] Typically, sodium salt of (2S, 5R)
trans-6-benzyloxy-7-oxo-1,
6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (II) was first
treated with a suitable base such as N-methyl morpholine and a
suitable formylating agent such as ethyl chloroformate (ClCOOEt) to
produce the corresponding mixed anhydride which was subsequently
reduced using sodium borohydride to provide an alcoholic compound
(III), (2S, 5R)-2-(hydroxymethyl)-6-(benzyloxy)-7-oxo-1,
6-diaza-bicyclo[3.2.1]octane.
[0048] The hydroxyl group of the compound of Formula (III) was
condensed with p-nitrophenyl sulfonyl chloride
(p-NO.sub.2PhSO.sub.2Cl) in presence of a suitable base such as
triethylamine and a suitable solvent such as dichloromethane to
provide (2S, 5R)-2-(4-nitrophenylsulfonate
methyl)-6-(benzyloxy)-7-oxo-1, 6-diaza-bicyclo [3.2.1] octane (IV).
The sulfonate compound of Formula (IV) was reacted with sodium
azide (NaN.sub.3), wherein the sulfonate group was displaced with
the azide group to provide the compound (2S,
5R)-2-(azidomethyl)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]
octane (V).
[0049] The compound (V) was reacted with triphenylphosphine
(PPh.sub.3) in a suitable solvent such as tetrahydrofuran followed
by addition of a catalytic amount of water to provide corresponding
amine. This amino compound was further treated in situ with
di-tert-butyl dicarbonate ((Boc).sub.2O) in presence of a suitable
base such as triethylamine to provide an amino protected compound,
(2S, 5R)-2-(tert-butoxycarbonylaminomethyl)-6-benzyloxy-7-oxo-1,
6-diaza-bicyclo[3.2.1] octane (VI). The intermediate compound of
Formula (VI) was subjected to hydrogenolysis using a catalyst such
as 5% or 10% Palladium on carbon in presence of a hydrogen source
such as hydrogen gas and in a suitable solvent such as methanol to
provide debenzylated compound, (2S,
5R)-2-(tert-butoxycarbonylaminomethy)-6-hydroxy-7-oxo-1,6-diaza-bicyclo[3-
.2.1]octane (VII).
[0050] The hydroxyl function in the compound of Formula (VII) was
further reacted with a suitable sulfonating agent such as sulfur
trioxide-pyridine complex (SO.sub.3Py complex) or sulfur
trioxide-dimethylformamide complex; in a suitable solvent such as
dichloromethane and in presence of a suitable base such as
triethylamine (Et.sub.3N) to provide the corresponding sulfate
ester pyridinium intermediate. This intermediate was further
reacted with tetrabutyl ammonium hydrogen sulfate to provide
tetrabutyl ammonium salt (2S, 5R)-6-sulfooxy-2-(tert-butoxy
carbonyl aminomethyl)-7-oxo-1, 6-diaza-bicyclo[3.2.1]octane
(VIII).
[0051] The compound of the Formula (VIII) was dissolved in a
suitable solvent such as 10% tetrahydrofuran:water mixture and was
passed through the column packed with Dowex 50WX8 200 Na.sup.+
resin to provide sodium salt of (2S, 5R)-6-sulfoxy-2-(tert-butoxy
carbonyl aminomethyl)-7-oxo-1, 6-diaza-bicyclo[3.2.1]octane
(IX).
##STR00013##
[0052] The compound of Formula (IX) was reacted with
trifluoroacetic acid in a suitable solvent such as dichloromethane
to provide trifluoroacetic acid and sodium salt of
6-sulfooxy-2-(amino methyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane
(X). This trifluoroacetic acid and sodium salt (X) was further
treated with water isopropyl alcohol mixture to obtain zwitterion
form, (2S,
5R)-6-sulfooxy-2-(aminomethyl)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane
(XI).
[0053] In some embodiments, there is provided a process for the
preparation of (2S,
5R)-6-sulfooxy-2-(aminomethyl)-7-oxo-1,6-diaza-bicyclo
[3.2.1]octane of Formula (XI), comprising:
##STR00014##
[0054] (a) Reacting a compound of Formula (II) with ethyl
chloroformate in presence of N-methyl morpholine followed by
treating with sodium borohydride to obtain a compound of Formula
(III);
##STR00015##
[0055] (b) Reacting a compound of Formula (III) with p-nitrophenyl
sulfonyl chloride in presence of triethylamine to obtain a compound
of Formula (IV);
##STR00016##
[0056] (c) Reacting a compound of Formula (IV) with sodium azide to
obtain a compound of Formula (V);
##STR00017##
[0057] (d) Reacting a compound of Formula (V) with
triphenylphosphine, followed by treating with di-tert-butyl
dicarbonate to obtain a compound of Formula (VI);
##STR00018##
[0058] (e) Hydrogenolysis of a compound of Formula (VI) in presence
of palladium on carbon catalyst and hydrogen gas to obtain a
compound of Formula (VII);
##STR00019##
[0059] (f) Reacting a compound of Formula (VII) with sulfur
trioxide-pyridine complex, followed by a reaction with tetrabutyl
ammonium hydrogen sulfate to obtain a compound of Formula
(VIII);
##STR00020##
[0060] (g) Passing a solution of a compound of Formula (VIII)
through a column packed with sodium resin to obtain a compound of
Formula (IX);
##STR00021##
[0061] (h) Reacting a compound of Formula (IX) with trifluoroacetic
acid in suitable solvent to obtain a compound of Formula (X);
and
##STR00022##
[0062] (i) Converting a compound of Formula (X) to a compound of
Formula (XI) by treating with water isopropyl mixture.
[0063] In some embodiments, there are provided pharmaceutical
compositions comprising a compound of Formula (I) or a stereoisomer
or a pharmaceutically acceptable derivative thereof.
[0064] In some embodiments, there is provided a compound of Formula
(X) having purity of more than 97% as determined by HPLC. In some
embodiments, there is provided a pharmaceutical composition
comprising a compound of Formula (X) having purity more than 97% as
determined by HPLC. In some embodiments, there is provided a
compound of Formula (XI) having purity of more than 99% as
determined by HPLC. In some embodiments, there is provided a
pharmaceutical composition comprising a compound of Formula (XI)
having purity more than 99% as determined by HPLC.
[0065] In some other embodiments, there is provided a method for
preventing or treating bacterial infection in a subject, said
method comprising administering to said subject a pharmaceutically
effective amount of a compound of Formula (I) or a stereoisomer or
a pharmaceutically acceptable derivative thereof. In some
embodiments, there is provided a method for preventing or treating
a bacterial infection in a subject, said infection being caused by
bacteria producing one or more beta-lactamase enzymes, said method
comprising administering to said subject a pharmaceutically
effective amount of a compound of Formula (I) or a stereoisomer or
a pharmaceutically acceptable derivative thereof.
[0066] In some other embodiments, there is provided a method for
preventing or treating bacterial infection in a subject, said
method comprising administering to said subject a pharmaceutically
effective amount of a pharmaceutical composition comprising a
compound of Formula (I) or a stereoisomer or a pharmaceutically
acceptable derivative thereof. In some other embodiments, there is
provided a method for preventing or treating bacterial infection in
a subject, said infection being caused by bacteria producing one or
more beta-lactamase enzymes, said method comprising administering
to said subject a pharmaceutically effective amount of a
pharmaceutical composition comprising a compound of Formula (I) or
a stereoisomer or a pharmaceutically acceptable derivative
thereof.
[0067] In some 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 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, (b) at least one
beta-lactamase inhibitor or a pharmaceutically acceptable
derivative thereof, and (c) at least one antibacterial agent or a
pharmaceutically acceptable derivative thereof.
[0068] In some other embodiments, there is provided a method for
preventing or treating bacterial infection in a subject, said
method comprising administering to said subject a pharmaceutically
effective amount of a pharmaceutical composition comprising: (a) a
compound of Formula (I) or a stereoisomer or a pharmaceutically
acceptable derivative thereof, and (b) at least one beta-lactamase
inhibitor or a pharmaceutically acceptable derivative thereof.
[0069] In some other embodiments, there is provided a method for
preventing or treating bacterial infection in a subject, said
method comprising administering to said subject a pharmaceutically
effective amount of a pharmaceutical composition comprising: (a) a
compound of Formula (I) or a stereoisomer or a pharmaceutically
acceptable derivative thereof, and (b) at least one antibacterial
agent or a pharmaceutically acceptable derivative thereof.
[0070] In some other embodiments, there is provided a method for
preventing or treating bacterial infection in a subject, said
method comprising administering to said subject a pharmaceutically
effective amount of a pharmaceutical composition comprising: (a) a
compound of Formula (I) or a stereoisomer or a pharmaceutically
acceptable derivative thereof, (b) at least one beta-lactamase
inhibitor or a pharmaceutically acceptable derivative thereof, and
(c) at least one antibacterial agent or a pharmaceutically
acceptable derivative thereof.
[0071] In some other embodiments, there is provided a method for
preventing or treating bacterial infection in a subject, said
method comprising administering to said subject a pharmaceutically
effective amount of: (a) a compound of Formula (I), or a
stereoisomer or a pharmaceutically acceptable derivative thereof,
and (b) at least one beta-lactamase inhibitor or a pharmaceutically
acceptable derivative thereof.
[0072] In some other embodiments, there is provided a method for
preventing or treating bacterial infection in a subject, said
method comprising administering to said subject a pharmaceutically
effective amount of: (a) a compound of Formula (I) or a
stereoisomer or a pharmaceutically acceptable derivative thereof,
and (b) at least one antibacterial agent or a pharmaceutically
acceptable derivative thereof.
[0073] In some other embodiments, there is provided a method for
preventing or treating bacterial infection in a subject, said
method comprising administering to said subject a pharmaceutically
effective amount of: (a) a compound of Formula (I) or a
stereoisomer or a pharmaceutically acceptable derivative thereof,
(b) at least one beta-lactamase inhibitor or a pharmaceutically
acceptable derivative thereof, and (c) at least one antibacterial
agent or a pharmaceutically acceptable derivative thereof.
[0074] In some embodiments, there is provided a method for
preventing or treating bacterial infection in a subject, said
infection being caused by bacteria producing one or more
beta-lactamase enzymes, said method comprising administering to
said subject a pharmaceutically effective amount of a compound
according to invention, or combination of a compound according to
invention with atleast one beta-lactamase inhibitor, or combination
of a compound according to invention with atleast one antibacterial
agent, or combination of a compound according to invention with
atleast one beta-lactamase inhibitor and atleast one antibacterial
agent. In some embodiments, there is provided a method for
preventing or treating bacterial infection in a subject, said
infection being caused by bacteria producing one or more
beta-lactamase enzymes, said method comprising administering to
said subject a pharmaceutically effective amount of a
pharmaceutical composition according to present invention.
[0075] In some embodiments, there are provided pharmaceutical
compositions comprising: (a) (2S,
5R)-6-sulfooxy-2-(aminomethyl)-7-oxo-1,6-diaza-bicyclo[3.2.1]
octane or a stereoisomer or a pharmaceutically acceptable
derivative thereof, and (b) Sulbactam or a pharmaceutically
acceptable derivative thereof.
[0076] In some other embodiments, there is provided a method for
preventing or treating bacterial infection in a subject, said
method comprising administering to said subject a pharmaceutically
effective amount of: (a) (2S,
5R)-6-sulfooxy-2-(aminomethyl)-7-oxo-1,6-diaza-bicyclo[3.2.1]
octane or a stereoisomer or a pharmaceutically acceptable
derivative thereof, and (b) Sulbactam or a pharmaceutically
acceptable derivative thereof.
[0077] In some other embodiments, there is provided a method for
preventing or treating bacterial infection in a subject, said
infection being caused by bacteria producing one or more
beta-lactamase enzymes, said method comprising administering to
said subject a pharmaceutically effective amount of: (a) (2S,
5R)-6-sulfooxy-2-(aminomethyl)-7-oxo-1,6-diaza-bicyclo[3.2.1]
octane or a stereoisomer or a pharmaceutically acceptable
derivative thereof, and (b) Sulbactam or a pharmaceutically
acceptable derivative thereof.
[0078] In some other embodiments, there is provided a method for
preventing or treating bacterial infection in a subject, said
method comprising administering to said subject a pharmaceutically
effective amount of a pharmaceutical composition comprising: (a)
(2S, 5R)-6-sulfooxy-2-(aminomethyl)-7-oxo-1,6-diaza-bicyclo[3.2.1]
octane or a stereoisomer or a pharmaceutically acceptable
derivative thereof, and (b) Sulbactam or a pharmaceutically
acceptable derivative thereof.
[0079] In some embodiments, there is provided a method for
preventing or treating bacterial infection in a subject, said
infection being caused by bacteria producing one or more
beta-lactamase enzymes, said method comprising administering to
said subject a pharmaceutically effective amount of a
pharmaceutical composition comprising: (a) (2S,
5R)-6-sulfooxy-2-(aminomethyl)-7-oxo-1,6-diaza-bicyclo[3.2.1]
octane or a stereoisomer or a pharmaceutically acceptable
derivative thereof, and (b) Sulbactam or a pharmaceutically
acceptable derivative thereof.
[0080] In some embodiments, there are provided methods for
increasing antibacterial effectiveness of a antibacterial agent in
a subject, said method comprising co-administering said
antibacterial agent or a pharmaceutically acceptable derivative
thereof with a pharmaceutically effective amount of a compound of
Formula (I) or a stereoisomer or a pharmaceutically acceptable
derivative thereof.
[0081] 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.
[0082] 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.
[0083] 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.
[0084] 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.
[0085] 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.
[0086] 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 inhibitors include
Sulbactam, Tazobactam or Clavulanic acid and the like.
[0087] 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 and the like.
[0088] The pharmaceutical compositions according to this invention
can exist in various forms. In some embodiments, the pharmaceutical
composition is in the form of a powder or a solution. In some other
embodiments, the pharmaceutical compositions according to the
invention are in the form of a powder that can be reconstituted by
addition of a compatible reconstitution diluent prior to parenteral
administration. Non-limiting example of such a compatible
reconstitution diluent includes water. In some other embodiments,
the pharmaceutical compositions according to the invention are in
the form of a frozen composition that can be diluted with a
compatible diluent prior to parenteral administration. In some
other embodiments, the pharmaceutical compositions according to the
invention are in the form ready to use for parenteral
administration.
[0089] 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, 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.
[0090] 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.
[0091] 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 one after the other.
[0092] 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.
[0093] In general, the pharmaceutical compositions and methods
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, intra-abdominal infections,
respiratory tract infections, pneumonia (nosocomial), bacteremia
meningitis, surgical, infections and the like.
[0094] Surprisingly, the compounds, compositions and methods
according to the invention are also effective in preventing or
treating bacterial infections that are caused by bacteria producing
one or more beta-lactamase enzymes. The ability of compositions and
methods according to the present invention to treat such resistant
bacteria with typical beta-lactam antibacterial agents represents a
significant improvement in the art.
[0095] 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 gents may be increased,
for example, by co-administering said antibacterial agents or a
pharmaceutically acceptable derivative thereof with a
pharmaceutically effective amount of a compound of Formula (I) or a
stereoisomer or a pharmaceutically acceptable derivative thereof
according to the invention.
[0096] 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
[0097] 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.
Synthesis of (2S, 5R)-6-sulfooxy-2-(aminomethyl)-7-oxo-1,
6-diaza-bicyclo [13.2.1]octane (XI)
Step 1: Preparation of (2S,
5R)-6-(benzyloxy)-2-(hydroxymethyl)-7-oxo-1,
6-diaza-bicyclo[3.2.1]octane (III)
[0098] The sodium salt of (2S, 5R)-6-benzyloxy-7-oxo-1,
6-diaza-bicyclo [3.2.1] octane-2-carboxylic acid (II) (50 g, 0.16
moles, prepared as per the procedure described in Indian Patent
Application No. 699/MUM/2013) was suspended in tetrahydrofuran (500
ml). To the suspension was added N-methyl morpholine (18.4 ml, 0.16
moles) under stirring. The reaction mixture was cooled to about
-10.degree. C. and ethyl chloroformate was added via addition
funnel and stirred for 1 hour at about -10.degree. C. To the
reaction mixture was added NaBH.sub.4 (9.56 g, 0.25 moles) in lots
under stirring. The reaction was monitored with the help of thin
layer chromatography (TLC). After completion of reaction, water
(500 ml) followed by ethyl acetate (500 ml) was added to the
reaction mass. The reaction mixture was stirred for 30 minutes and
the layers were separated. Organic layer was washed with brine (200
ml). The solvent was evaporated under vacuum to dryness to provide
43 g of (2S,
5R)-6-(benzyloxy)-2-(hydroxymethyl)-7-oxo-1,6-diaza-bicyclo[3.2.1]
octane (III) as a pale yellow oil (99% yield).
[0099] Analysis:
[0100] Mass: 263.2 [M+1]; for Molecular Formula:
C.sub.14H.sub.18N.sub.2O.sub.3; and Molecular Weight: 262.3.
[0101] .sup.1H NMR (CDCl.sub.3): .delta. 7.28-7.49 (m, 5H), 4.96
(dd, 2H), 4.10-4.16 (m, 1H), 3.60-3.74 (m, 3H), 3.55-3.59 (m, 2H),
1.92-2.02 (m, 2H), 1.54-1.58 (m, 2H), 1.36-1.41 (m, 1H).
Step 2: Preparation of (2S, 5R)-6-(benzyloxy)-2-(4-nitophenyl
sulfonyloxy-methyl)-7-oxo-1, 6-diaza-bicyclo[3.2.1]octane (IV)
[0102] Solution of (2S,
5R)-6-(benzyloxy)-2-(hydroxymethyl)-7-oxo-1, 6-diaza-bicyclo
[3.2.1]octane (24 g, 0.091 moles) in dichloromethane (240 ml) was
cooled to about 10.degree. C. To the above solution, triethylamine
(38.2 ml, 0.274 moles) followed by p-nitrophenylsulfonyl chloride
were added. This reaction mixture was stirred for 2 hours at the
same temperature and then quenched with water (200 ml). The
reaction mixture was stirred for 15 minutes and the layers were
separated. Organic layer was washed with brine (200 ml). The
solvent was evaporated under vacuum to yield 35.3 g of (2S,
5R)-2-(4-nitophenyl
sulfonyloxy-methyl)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo [3.2.1]
octane (IV) as a pale yellow solid, (85% yield).
[0103] Analysis:
[0104] Mass: 448.2 [M+1]; for Molecular Formula:
C.sub.20H.sub.21N.sub.3O.sub.7S and Molecular Weight: 447.5.
[0105] .sup.1H NMR (CDCl.sub.3): .delta. 8.39 (d, 2H), 8.11 (d,
2H), 7.35-7.40 (m, 5H), 5.00 (dd, 2H), 3.73-4.21 (m, 2H), 3.33 (m,
1H), 2.98-3.16 (m, 3H), 1.70-2.00 (m, 2H), 1.51-1.61 (m, 2H).
Step 3: Preparation of (2S,
5R)-6-(benzyloxy)-2-(azidomethyl)-7-oxo-1, 6-diaza-bicyclo [3.2.1]
octane (V)
[0106] To a solution of (2S, 5R)-6-(benzyloxy)-2-(4-nitophenyl
sulfonyloxy-methyl)-7-oxo-1,6-diaza-bicyclo [3.2.1] octane (30 g,
0.067 moles) in N, N-dimethyl formamide (150 ml), was added
NaN.sub.3 (8.7 g, 0.134 moles) and reaction mixture was heated at
about 65.degree. C. for 4 hours. After completion of reaction on
TLC, the reaction mixture was cooled to about 25.degree. to
30.degree. C., and water (750 ml) followed by ethyl acetate (300
ml) were added. The reaction mass was stirred for 15 minutes. The
organic layer was separated and washed with water (200 ml) followed
by brine (200 ml). The solvent was evaporated under vacuum to
provide 14 g of (2S,
5R)-2-(azidomethyl)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo [3.2.1]
octane (V) as a solid, (72% yield).
[0107] Analysis:
[0108] Mass: 288.1 [M+1]; for Molecular Formula:
C.sub.14H.sub.17N.sub.5O.sub.2; and Molecular Weight: 287.3.
[0109] .sup.1H NMR (CDCl.sub.3): .delta. 7.28-7.42 (m, 5H), 4.94
(dd, 2H), 3.48-3.57 (m, 2H), 3.29-3.33 (m, 2H), 2.92 (d, 2H),
1.93-2.02 (m, 2H), 1.41-1.59 (m, 2H).
Step 4: Preparation of (2S,
5R)-6-benzyloxy-2-(tert-butoxycarbonylaminomethyl)-7-oxo-1,
6-diaza-bicyclo [3.2.1] octane (VI)
[0110] To a solution of (2S,
5R)-6-(benzyloxy)-2-(azidomethyl)-7-oxo-1,
6-diaza-bicyclo[3.2.1]octane (13 g, 0.045 moles) in tetrahydrofuran
(130 ml), was added triphenylposphine (23.7 g, 0.19 moles) and
reaction mixture was stirred for 12 hours at about 25-30.degree. C.
To the reaction mixture, water (1 ml) was added and it was stirred
for 2 hours at about 25-30.degree. C. After 2 hours, triethylamine
(19 ml, 0.135 moles) followed by di-tert-butylpyrocarbonate (20.5
ml, 0.95 moles) were added and the mixture was stirred for 4 hours
at about 25-30.degree. C. After completion of reaction monitored by
TLC, water (130 ml) followed by ethyl acetate (130 ml) were added,
and the reaction mass was stirred for 15 minutes. The organic layer
was separated and washed with brine (200 ml). The solvent was
evaporated under vacuum and the residue was purified by using
silica gel (60-120 mesh) column chromatography by using a mixture
of ethyl acetate:hexane (2:8) to provide 8 g of (2S,
5R)-6-benzylozy-2-(tert-butoxycarbonylaminomethyl)-7-oxo-1,6-diaza-bicycl-
o [3.2.1] octane (VI) as solid, (49% yield.
[0111] Analysis:
[0112] Mass: 362.1 [M+1]; for Molecular Formula:
C.sub.19H.sub.27N.sub.3O.sub.4 and Molecular Weight: 361.4.
[0113] .sup.1H NMR (CDCl.sub.3): .delta. 7.28-7.45 (m, 5H), 5.03
(d, 1H), 4.97 (bs, 1H), 4.89 (d, 1H), 3.43-3.46 (m, 1H), 3.26-3.36
(m, 3H), 2.84-2.96 (m, 2H), 1.94-2.04 (m, 3H), 1.57-1.61 (m, 1H),
1.42 (s, 9H).
Step 5: Preparation of (2S,
5R)-6-hydroxy-2-(tert-butoxycarbonylaminomethyl)-7-oxo-1,
6-diaza-bicyclo [3.2.1] octane (VII)
[0114] To a solution of (2S,
5R)-6-benzylozy-2-(tert-butoxycarbonylaminomethyl)-7-oxo-1,6-diaza-bicycl-
o[3.2.1]octane (8 g, 0.022 moles) in methanol (60 ml), was added
10% palladium on charcoal and the mixture was hydrogenated under 60
psi pressure of hydrogen gas for 3 hours at about 25-30.degree. C.
The reaction mixture was filtered through celite bed filter to
remove the catalyst and the filtrate was concentrated under vacuum
to obtain 6 g of (2S,
5R)-6-hydroxy-2-(tert-butoxycarbonylaminomethyl)-7-oxo-1,6-diaza-bic-
yclo [3.2.1] octane (VII) as white solid, (100% yield).
[0115] Analysis:
[0116] Mass: 272.1 [M+1]; for Molecular Formula:
C.sub.12H.sub.21N.sub.3O.sub.4; and Molecular Weight: 271.3.
[0117] .sup.1H NMR (CDCl.sub.3): .delta. 4.92 (bs, 1H), 3.29-3.73
(m, 3H), 2.75-2.98 (m, 2H), 2.35-2.65 (m, 3H), 1.96-2.02 (m, 2H),
1.67-1.73 (m, 1H), 1.47 (s, 9H).
Step 6: Preparation of Tetrabutylammonium salt of (2S,
5R)-6-sulfooxy-2-(tert-butoxycarbonylaminomethyl)-7-oxo-1,
6-diaza-bicyclo [3.2.1] octane (VIII)
[0118] To a solution of (2S,
5R)-6-hydroxy-2-(tert-butoxycarbonylaminomethyl)-7-oxo-1,6-diaza-bicyclo[-
3.2.1]octane (6 g, 0.022 moles) in dichloromethane (60 ml) under
argon atmosphere, was added triethylamine (9.2 ml, 0.066 moles)
followed by sulfur trioxide-pyridine complex (7 g, 0.044 moles)
under stirring at about 30.degree. C. The reaction mixture was
stirred for 2 hours and then poured into 0.5 N potassium dihydrogen
phosphate buffer solution (120 ml). Organic layer was separated and
discarded. To the aqueous layer solid tetrabutylammonium hydrogen
sulfate (6.75 g, 0.0.19 moles) was added and stirred for 2 hours at
about 30.degree. C. The reaction mixture was extracted with
dichloromethane (60 ml.times.2). The layers were separated. The
combined organic layer was evaporated under vacuum below 40.degree.
C. to provide 10 g of tetrabutylammonium salt of (2S,
5R)-6-sulfooxy-2-(tertbutoxycarbonylaminomethyl)-7-oxo-1,6-diaza-bicyclo[-
3.2.1]octane (VIII) as a white solid, (87% yield).
[0119] Analysis:
[0120] Mass: (M-1): 350.1 as a free sulfonic acid; for Molecular
Formula: C.sub.12H.sub.21N.sub.3O.sub.7S.N(C.sub.4H.sub.9).sub.4;
and Molecular Weight: 592.9.
[0121] .sup.1H NMR (CDCl.sub.3): .delta. 4.94 (bs, 1H), 3.28-3.37
(m, 11H), 2.72-2.95 (m, 3H), 2.32-2.64 (m, 3H), 1.62-1.78 (m, 11H),
1.40-1.49 (m, 16H), 0.98-1.02 (m, 12H).
Step 7: Preparation of Sodium salt of (2S,
5R)-6-sulfooxy-2-(tert-butoxycarbonyl aminomethyl)-7-oxo-1,
6-diaza-bicyclo[3.2.1]octane (IX)
[0122] The tetrabutylammonium salt of (2S,
5R)-6-sulfooxy-2-(tert-butoxycarbonyl
aminomethyl)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane (9 g) was
dissolved in 10% tetrahydrofuran:water and the solution was passed
through column (45 cm length and 2.0 cm diameter) packed with Dowex
50WX8 200 Na.sup.+ resin. The column was eluted with 10%
tetrahydrofuran:water mixture (250 ml). The combined fractions
having compound were evaporated under vacuum (4 mm Hg) to obtain
2.9 g of sodium salt of (2S, 5R)-6-sulfooxy-2-(tert-butoxycarbonyl
aminomethyl)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane (IX) as white
solid, (72% yield). The intermediate was used for next
reaction.
[0123] Analysis:
[0124] Mass: (M-1): 373.1 as a free sulfonic acid; for Molecular
Formula: C.sub.12H.sub.20N.sub.3O.sub.7SNa; and Molecular Weight:
374.74.
Step 8: Preparation of Sodium and trifluoroacetate salt of (2S,
5R)-6-sulfooxy-2-(aminomethyl)-7-oxo-1,
6-diaza-bicyclo[3.2.1]octane (X)
[0125] The sodium salt of (2S,
5R)-6-sulfooxy-2-(tert-butoxycarbonylaminomethyl)-7-oxo-1,6-diaza-bicyclo-
[3.2.1]octane (2.4 g, 0.006 moles) was suspended in dichloromethane
(6 ml) and to the reaction mixture was slowly added trifluoroacetic
acid (6 ml) at about 0-5.degree. C. The reaction mixture was
stirred between about 0-5.degree. C. for additional 2 hours. The
solvent and excess trifluoroacetic acid was evaporated under vacuum
below 40.degree. C. to approximately 1/3 of its original volume to
provide pale yellow oily residue. This oily residue was triturated
with diethyl ether and ether was decanted (40 ml.times.2). The
crude solid was again triturated with dichloromethane (40
ml.times.2) and solvents were decanted. The final solid was dried
under vacuum below 40.degree. C. to furnish 2.2 g of sodium and
trifluoroacetic acid salt of (2S,
5R)-6-sulfooxy-2-(aminomethyl)-7-oxo-1,6-diaza-bicyclo
[3.2.1]octane (X) (90% yield).
[0126] Analysis:
[0127] Mass: (M-1): 250.1 as a free sulfonic acid; for Molecular
Formula: C.sub.7H.sub.13N.sub.3O.sub.5SNa CF.sub.3COO; and
Molecular Weight: 387.26.
[0128] .sup.1H NMR (DMSO-d6): .delta. 7.82 (br s, 3H), 4.00 (d,
1H), 3.35-3.40 (m, 3H), 2.28-2.91 (m, 2H), 1.74-1.79 (m, 3H),
1.44-1.47 (m, 1H); and
[0129] Purity as determined by HPLC: 97.64%.
Step 9: Preparation of (2S,
5R)-6-sulfooxy-2-(aminomethyl)-7-oxo-1,6-diaza-bicyclo[3.2.1]
octane (XI)
[0130] Sodium and trifluoroacetic acid salt of (2S,
5R)-6-sulfooxy-2-(aminomethyl)-7-oxo 1,6-diaza-bicyclo[3.2.1]octane
(2 g, 0.005 moles) was dissolved in distilled water (2 ml) and to
the clear solution, was slowly added isopropyl alcohol (14 ml) at
about 25.degree. C. The reaction mixture was stirred for 12 hours.
The precipitate was filtered under suction to provide a solid,
which was dried under vacuum below 40.degree. C. to furnish 1.2 g
of (2S,
5R)-6-sulfooxy-2-(aminomethyl)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane
(XI) (92% yield).
[0131] Analysis:
[0132] Mass: 252 (M+1), 250 (M-1); for Molecular Formula:
C.sub.7H.sub.14N.sub.3O.sub.5S; and Molecular Weight: 251.3.
[0133] .sup.1H NMR (DMSO-d6): .delta. 7.78 (br s, 3H), 4.24 (s,
1H), 3.62-3.65 (m, 1H), 3.20-3.42 (m, 4H), 2.00-2.18 (m, 2H),
1.81-1.98 (m, 1H), 1.60-1.65 (m, 1H);
[0134] .sup.13C NMR (D.sub.2O): 18, 20, 40, 43, 56, 60, 171;
and
[0135] Purity as determined by HPLC: 99.77%.
Biological Activity Data
[0136] 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.degree. 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, 20.sup.th Informational Supplement, M
100-S20, Volume 30, No. 1, 2010). The results of these studies are
summarized in Table 1 and 2, wherein the antibacterial activity is
expressed as minimum inhibitory concentration (MIC). Table 1 shows
the antibacterial activity profile of (2S,
5R)-6-sulfooxy-2-(aminomethyl)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane
(Compound XI) in comparison to known antibacterial agents. The
Compound (XI), which is the free zwitterionic form of Compound (X),
was also studied for the antibacterial activity profile. The
Compound (XI) exhibits good antibacterial activity against
resistant ESBL strains of K. pneumoniae, E. coli and P. aeruginosa.
The activity profile of the Compound (XI) was found to be better
than Ceftazidime and Cefepime against all tested strains. The
Compound (XI) also exhibited better activity than Imipenem against
resistant ESBL strains K. pneumoniae and P. aeruginosa.
[0137] The antibacterial activity of the Compound (XI) was also
studied in combination with other beta-lactam antibacterial agents.
Data in Table 2 shows the results of the ESBL enzyme inhibition in
presence of Compound (XI) in combination with Ceftazidime. Results
obtained using Ceftazidime alone were used as control. The
antibacterial activity of the combination of Compound (XI) (4
.mu.g/ml) and Ceftazidime was compared with (i) combination of
Cetftazidime and Avibactam (4 .mu.g/ml); and (ii) Imipenem alone.
The results showed that the combination of the Compound (XI) and
Ceftazidime exhibited good antibacterial activity against resistant
bacterial strains. The presence of Compound (XI) in combination
with Ceftazidime significantly lowered the MIC values of
Ceftazidime alone. From the results in Table 2, it appears that the
combination comprising Compound (XI) and Ceftazidime exhibited
synergism and showed potent antibacterial inhibition against those
resistant bacterial strains where Ceftazidime alone was found to be
ineffective.
TABLE-US-00001 TABLE 1 Antibacterial Activity of the
(2S,5R)-6-sulfooxy-2-(aminomethyl)- 7-oxo-1,6-diaza-bicyclo
[3.2.1]octane (Compound XI) in comparison with other antibacterial
agents. MIC (.mu.g/ml) Organism Compound Sr. (Strain) ESBL
Ceftazidime Cefepime Imipenem (XI) 1. E. coli CTXM-15 >32 >32
0.25 1 (NCTC 13353) 2. E. coli TEM 10 >32 2 0.25 2 (NCTC 13352)
3. K. pneumoniae KPC >32 >32 16 1 (H521) 4. E. coli SHV,
>32 16 1 4 (7MP) CMY 5. K. pneumoniae NDM, >32 >32 16 1
(S48) SHV 6. P. aeruginosa VIM >32 >32 16 8 (MBL18)
TABLE-US-00002 TABLE 2 Antibacterial Activity of
(2S,5R)-6-sulfooxy-2-(aminomethyl)-7-oxo-1,6-diaza- bicyclo [3.2.1]
octane (Compound XI) in combination with Ceftazidime. MIC
(.mu.g/ml) Ceftazidime +Compound (XI) +Avibactam Sr. Strains ESBL
Control (4 .mu.g/ml ) (4 .mu.g/ml) Imipenem 1. K. pneumoniae SHV-18
16 0.03 0.5 0.12 ATCC 700603 2 E. coli CMY-2 >32 .ltoreq.0.015 1
0.25 H483 3. K. pneumoniae TEM-1, >32 2 1 2 J101 SHV-12, OMP 4.
K. pneumoniae TEM-1, >32 4 0.5 8 J102 SHV-5, OMP
* * * * *