U.S. patent application number 17/044517 was filed with the patent office on 2021-01-28 for substituted 2-aminobenzimidazoles analogs as antibiofilm agents.
The applicant listed for this patent is North Carolina State University, Ohio State Innovation Foundation. Invention is credited to John Gunn, William M. Huggins, Laura Kuo, Christian Melander.
Application Number | 20210023060 17/044517 |
Document ID | / |
Family ID | 1000005167301 |
Filed Date | 2021-01-28 |
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United States Patent
Application |
20210023060 |
Kind Code |
A1 |
Gunn; John ; et al. |
January 28, 2021 |
SUBSTITUTED 2-AMINOBENZIMIDAZOLES ANALOGS AS ANTIBIOFILM AGENTS
Abstract
In one aspect, the disclosure relates to compositions and
methods for dispersing exiting Salmonella biofilms and inhibiting
formation of Salmonella biofilms. In various aspects, the disclosed
compositions can be used in methods of treating a persistent
Salmonella infection, including an asymptomatic infection. Such
infections can colonize a variety of tissues, including the
gall-bladder. Also disclosed are methods of treating typhoid fever.
Also disclosed are methods for mitigating or preventing secondary
outbreaks of typhoid fever by treating asymptomatic subjects who
had been symptomatic for typhoid fever at a previous time. This
abstract is intended as a scanning tool for purposes of searching
in the particular art and is not intended to be limiting of the
present disclosure.
Inventors: |
Gunn; John; (Columbus,
OH) ; Kuo; Laura; (Columbus, OH) ; Melander;
Christian; (Raleigh, NC) ; Huggins; William M.;
(Raleigh, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Ohio State Innovation Foundation
North Carolina State University |
Columbus
Raleigh |
OH
NC |
US
US |
|
|
Family ID: |
1000005167301 |
Appl. No.: |
17/044517 |
Filed: |
April 3, 2019 |
PCT Filed: |
April 3, 2019 |
PCT NO: |
PCT/US2019/025683 |
371 Date: |
October 1, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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62651829 |
Apr 3, 2018 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/4184
20130101 |
International
Class: |
A61K 31/4184 20060101
A61K031/4184 |
Claims
1. A pharmaceutical composition comprising a therapeutically
effective amount of a compound having a structure represented by a
formula: ##STR00105## wherein R.sup.1 is selected from a C1-C12
alkyl, a C3-C12 cycloalkyl; and a substituted aryl; and wherein
R.sup.2 is selected from a C1-C12 alkyl, a C3-C12 cycloalkyl; and a
substituted aryl; or a pharmaceutically acceptable salt thereof;
and a pharmaceutically acceptable carrier.
2. The pharmaceutical composition of claim 1, wherein R.sup.1 is
selected from a C1-C12 alkyl and a substituted aryl.
3. The pharmaceutical composition of claim 0, wherein R.sup.1 is a
C1-C12 alkyl.
4. The pharmaceutical composition of claim 0, wherein R.sup.1 is a
C1-C6 alkyl.
5. The pharmaceutical composition of claim 0, wherein R.sup.1 is
selected from methyl, ethyl, propyl, isopropyl, tert-butyl,
sec-butyl, isobutyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl,
3,3-dimethylbutan-2-yl, and 2,3-dimethylbutan-2-yl.
6. The pharmaceutical composition of claim 0, wherein R.sup.1 is a
substituted aryl.
7. The pharmaceutical composition of claim 0, wherein R.sup.1 is a
structure represented by a formula: ##STR00106## wherein each of
R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d and R.sup.10e is
independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6
alkoxy, and C1-C6 haloalkyl, provided that at least one of
R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d and R.sup.10e is not
hydrogen.
8. The pharmaceutical composition of claim 0, wherein each of
R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d, R.sup.10e is
independently selected from hydrogen, halogen, C1-C6 alkyl, and
C1-C6 alkoxy, provided that two R.sup.10a, R.sup.10b, R.sup.10c,
R.sup.10d and R.sup.10e are hydrogen.
9. The pharmaceutical composition of claim 0, wherein each of
R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d and R.sup.10e is
independently selected from hydrogen, bromo, chloro, fluoro, C1-C3
alkyl, and C1-C3 alkoxy, provided that at least one of R.sup.10a,
R.sup.10b, R.sup.10c, R.sup.10d and R.sup.10e is not hydrogen.
10. The pharmaceutical composition of claim 0, wherein each of
R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d and R.sup.10e is
independently selected from hydrogen, bromo, chloro, C1-C3 alkyl,
and C1-C3 alkoxy, provided that at least one of R.sup.10a,
R.sup.10b, R.sup.10c, R.sup.10d and R.sup.10e is not hydrogen.
11. The pharmaceutical composition of claim 0, wherein each of
R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d and R.sup.10e is
independently selected from hydrogen, bromo, and chloro, provided
that at least one of R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d and
R.sup.10e is not hydrogen.
12. The pharmaceutical composition of claim 0, wherein each of
R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d and R.sup.10e is
independently selected from hydrogen, bromo, and chloro, provided
that two of R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d and
R.sup.10e are hydrogen.
13. The pharmaceutical composition of claim 0, wherein each of
R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d and R.sup.10e is
independently selected from hydrogen, bromo, and chloro, provided
that three of R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d and
R.sup.10e are hydrogen.
14. The pharmaceutical composition of claim 0, wherein each of
R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d, R.sup.10e is
independently selected from hydrogen, bromo, and chloro, provided
that four of R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d and
R.sup.10e are hydrogen.
15. The pharmaceutical composition of claim 0, wherein R.sup.1 is a
structure represented by a formula: ##STR00107## wherein each of
R.sup.10b and R.sup.10c is independently selected from halogen,
C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl.
16-19. (canceled)
20. The pharmaceutical composition of claim 0, wherein R.sup.1 is a
structure represented by a formula: ##STR00108## wherein each of
R.sup.10b and R.sup.10d is independently selected from halogen,
C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl.
21-24. (canceled)
25. The pharmaceutical composition of claim 0, wherein R.sup.1 is a
structure represented by a formula: ##STR00109## wherein R.sup.10c
is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6
haloalkyl.
26-29. (canceled)
30. The pharmaceutical composition of claim 1, present as:
##STR00110## ##STR00111## or a subgroup thereof.
31-32. (canceled)
33. A method for treating a Salmonella enterica clinical condition,
comprising administering to a subject in need thereof the
pharmaceutical composition of claim 1.
34-45. (canceled)
46. A method for inhibiting biofilm formation or dispersing a
biofilm in a subject comprising the step of administering to the
subject the pharmaceutical composition of claim 1.
47-58. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. 62/651,829, filed on Apr. 3, 2018, which is
incorporated herein by reference in its entirety.
BACKGROUND
[0002] A "biofilm" is a well known phenomenon and may be defined as
a population of prokaryotic cells growing on a surface and enclosed
in a self-produced matrix of extracellular polymeric material,
which mediates adhesion of the cells to each other and to surfaces.
Biofilms are not simply passive assemblages of cells that are stuck
to surfaces, but are structurally and dynamically complex
biological systems. As compared with cells that are planktonic in
nature, bacteria growing in biofilms exhibit a different phenotype
with respect to growth rate and gene transcription.
[0003] Biofilms may be involved in a significant percentage of
human microbial infections (Potera C. Forging a link between
biofilms and disease. Science 1999; 283:1837-8). Parsek and Singh
proposed four criteria for defining a biofilm etiology of an
infection: the pathogenic bacteria are surface associated or
adherent to a substratum; direct examination reveals bacteria in
clusters, encased in a matrix of bacterial or host constituents;
the infection is localized; and the infection is resistant to
antibiotic therapy despite the antibiotic sensitivity of the
constituent planktonic organisms (Parsek M R, Singh P K. Bacterial
biofilms: an emerging link to disease pathogenesis. Annu Rev
Microbiol 2003; 57:677-701).
[0004] Biofilm infections can be involved in the etiology of dental
caries, periodontal disease, cystic fibrosis (CF) airway
infections, native valve endocarditis, chronic bacterial
prostatitis, otitis media, and vaginal infections. Biofilm
microorganisms are also involved in implant-related infections, in
which adherent microbial populations form on the surfaces of
catheters, prosthetic heart valves, joint replacements, and other
devices (Donlan R M. Biofilms and device-associated infections.
Emerg Infect Dis 2001; 7:277-81).
[0005] The bacterium Salmonella enterica serovar Typhi (S. Typhi)
is the causative agent of typhoid fever, infecting and killing an
estimated 21 million and 200,000 individuals each year,
respectively. S. Typhi will persist in the gallbladder of 3-5% of
individuals, after resolution of the acute infection, through an
asymptomatic chronic carrier state, during which fecal shedding
allows the bacteria to spread. In this chronic carrier state, S.
Typhi forms biofilms--organized, multicellular communities
encapsulated in an extracellular matrix comprised of
polysaccharides, proteins, and extracellular DNA--on gallstones. It
is believe that the primary reservoir of bacteria in asymptomatic
chronic carriers is the gallbladder.
[0006] Despite advances in research directed to mitigating the
spread of infectious diseases associated with asymptomatic
carriers, e.g., biofilms associated with the gallbladder following
infection with Salmonella enterica serovar Typhi (S. Typhi), there
is still a scarcity of compounds that are both potent and
efficacious for the treatment of biofilms in such clinical
situations. These needs and other needs are satisfied by the
present disclosure.
SUMMARY
[0007] In accordance with the purpose(s) of the disclosure, as
embodied and broadly described herein, the disclosure, in one
aspect, relates to compositions and methods for dispersing
Salmonella biofilms. In various aspects, the disclosed compositions
can be used in methods of treating a persistent Salmonella
infection, including an asymptomatic infection. Such infections can
colonize a variety of tissues, including the gall-bladder. Also
disclosed are methods of treating typhoid fever. Also disclosed are
methods for mitigating or preventing secondary outbreaks of typhoid
fever by treating asymptomatic subjects who had been symptomatic
for typhoid fever at a previous time.
[0008] Disclosed are pharmaceutical compositions comprising a
therapeutically effective amount of a compound having a structure
represented by a formula:
##STR00001##
wherein R.sup.1 is selected from a C1-C12 alkyl, a C3-C12
cycloalkyl; and a substituted aryl; and wherein R.sup.2 is selected
from a C1-C12 alkyl, a C3-C12 cycloalkyl; and a substituted
aryl;
[0009] Also disclosed are methods for treatment of a Salmonella
enterica clinical condition, comprising administering to a subject
in need thereof a disclosed pharmaceutical composition.
[0010] Also disclosed are methods inhibiting formation of a biofilm
in a subject comprising the step of administering to the subject in
need thereof a disclosed pharmaceutical composition.
[0011] Also disclosed are methods for dispersing a biofilm in a
subject comprising the step of administering to the subject in need
thereof a disclosed pharmaceutical composition.
[0012] Also disclosed are uses of a disclosed pharmaceutical
composition.
[0013] Also disclosed are uses of a disclosed compound, or a
pharmaceutically acceptable salt thereof, in the manufacture of a
medicament for the treatment of of Salmonella enterica clinical
condition in a subject in need thereof.
[0014] Also disclosed are methods for the manufacture of a
medicament for the treatment of of Salmonella enterica clinical
condition in a subject in need thereof comprising combining at
least one disclosed compound, or a pharmaceutically acceptable salt
thereof with a pharmaceutically acceptable carrier or diluent.
[0015] Other systems, methods, features, and advantages of the
present disclosure will be or become apparent to one with skill in
the art upon examination of the following drawings and detailed
description. It is intended that all such additional systems,
methods, features, and advantages be included within this
description, be within the scope of the present disclosure, and be
protected by the accompanying claims. In addition, all optional and
preferred features and modifications of the described embodiments
are usable in all aspects of the disclosure taught herein.
Furthermore, the individual features of the dependent claims, as
well as all optional and preferred features and modifications of
the described embodiments are combinable and interchangeable with
one another.
BRIEF DESCRIPTION OF THE FIGURES
[0016] Many aspects of the present disclosure can be better
understood with reference to the following drawings. The components
in the drawings are not necessarily to scale, emphasis instead
being placed upon clearly illustrating the principles of the
present disclosure. Moreover, in the drawings, like reference
numerals designate corresponding parts throughout the several
views.
[0017] FIG. 1 shows a schematic representation of biofilm formation
and dispersal.
[0018] FIG. 2 shows molecular structures for representative
disclosed compounds.
[0019] FIGS. 3A-3B show representative data obtained from assays of
S. typhimurium biofilm formation and dispersal. FIG. 3A shows the
effect of 20 .mu.M of indicated compound (M4-M8) on inhibition of
formation of biofilms by S. typhimurium (JSG210) compared to
control treatment with 1% DMSO. FIG. 3B shows the effect of 20
.mu.M of indicated compound (M4-M8) on dispersal of biofilms formed
by S. typhimurium (JSG210) compared to control treatment with 1%
DMSO.
[0020] FIGS. 4A-4B show representative data obtained from assays of
S. typhimurium biofilm formation and dispersal versus concentration
of a representative disclosed compound. FIG. 4A shows the effect of
a representative disclosed compound, compound M4, on inhibition of
formation of biofilms by S. typhimurium (JSG210) at the indicated
concentrations. The EC.sub.50 value for inhibition of biofilm
formation was calculated from the data to be 8.1 .mu.M. FIG. 3B
shows the effect of a representative disclosed compound, compound
M4, on inhibition on dispersal of biofilms formed by S. typhimurium
(JSG210) at the indicated concentrations. The EC.sub.50 value for
inhibition of biofilm dispersal was calculated from the data to be
20.3 .mu.M.
[0021] FIGS. 5A-5B show representative toxicity data obtained for a
representative disclosed compound. FIG. 5A shows representative
data for a cell death assay using S. typhimurium (JSG210). Briefly,
S. typhimurium (JSG210) was grown in the presence of a
representative disclosed compound, compound M4, present at a
concentration of 10 .mu.M for 24 hours, followed by determination
of viability measured by drip plating at T=0, 2, 5, 15, 20, 24
hours. 3 biological replicates were tested. The data show that the
compound was not associated with any toxicity. FIG. 5B shows
representative data obtained in a toxicity assay using Galleria
mellonella larvae. Briefly, a representative disclosed compound,
compound M4, was injected into last left proleg of Galleria
mellonella larvae at 400 mg/kg and assessed at 24-hour intervals
over 5 days. The study was repeated 3 times using 10 larvae per
experiment group. The data show no significant toxicity in Galleria
mellonella larvae.
[0022] FIG. 6 shows representative data obtained from Rapid
Attachment Assay using newly generated JSG210 M4 mutants exposed to
a representative disclosed compound, compound M4. The effects in
these mutants was compared to WT JSG210 control.
[0023] FIG. 7 shows the structure of regions of modification in
Compound 1.
[0024] FIG. 8 shows the structure of compounds 10a-t with various
tail substitutions.
[0025] FIG. 9 shows growth curves for select compounds against S.
Typhimurium ATCC 14028
[0026] Additional advantages of the disclosure will be set forth in
part in the description which follows, and in part will be obvious
from the description, or can be learned by practice of the
disclosure. The advantages of the disclosure will be realized and
attained by means of the elements and combinations particularly
pointed out in the appended claims. It is to be understood that
both the foregoing general description and the following detailed
description are exemplary and explanatory only and are not
restrictive of the disclosure, as claimed.
DETAILED DESCRIPTION
[0027] Many modifications and other embodiments disclosed herein
will come to mind to one skilled in the art to which the disclosed
compositions and methods pertain having the benefit of the
teachings presented in the foregoing descriptions and the
associated drawings. Therefore, it is to be understood that the
disclosures are not to be limited to the specific embodiments
disclosed and that modifications and other embodiments are intended
to be included within the scope of the appended claims. The skilled
artisan will recognize many variants and adaptations of the aspects
described herein. These variants and adaptations are intended to be
included in the teachings of this disclosure and to be encompassed
by the claims herein.
[0028] Although specific terms are employed herein, they are used
in a generic and descriptive sense only and not for purposes of
limitation.
[0029] As will be apparent to those of skill in the art upon
reading this disclosure, each of the individual embodiments
described and illustrated herein has discrete components and
features which may be readily separated from or combined with the
features of any of the other several embodiments without departing
from the scope or spirit of the present disclosure.
[0030] Any recited method can be carried out in the order of events
recited or in any other order that is logically possible. That is,
unless otherwise expressly stated, it is in no way intended that
any method or aspect set forth herein be construed as requiring
that its steps be performed in a specific order. Accordingly, where
a method claim does not specifically state in the claims or
descriptions that the steps are to be limited to a specific order,
it is no way intended that an order be inferred, in any respect.
This holds for any possible non-express basis for interpretation,
including matters of logic with respect to arrangement of steps or
operational flow, plain meaning derived from grammatical
organization or punctuation, or the number or type of aspects
described in the specification.
[0031] All publications mentioned herein are incorporated herein by
reference to disclose and describe the methods and/or materials in
connection with which the publications are cited. The publications
discussed herein are provided solely for their disclosure prior to
the filing date of the present application. Nothing herein is to be
construed as an admission that the present invention is not
entitled to antedate such publication by virtue of prior invention.
Further, the dates of publication provided herein can be different
from the actual publication dates, which can require independent
confirmation.
[0032] While aspects of the present disclosure can be described and
claimed in a particular statutory class, such as the system
statutory class, this is for convenience only and one of skill in
the art will understand that each aspect of the present disclosure
can be described and claimed in any statutory class.
[0033] It is also to be understood that the terminology used herein
is for the purpose of describing particular aspects only and is not
intended to be limiting. Unless defined otherwise, all technical
and scientific terms used herein have the same meaning as commonly
understood by one of ordinary skill in the art to which the
disclosed compositions and methods belong. It will be further
understood that terms, such as those defined in commonly used
dictionaries, should be interpreted as having a meaning that is
consistent with their meaning in the context of the specification
and relevant art and should not be interpreted in an idealized or
overly formal sense unless expressly defined herein.
[0034] Prior to describing the various aspects of the present
disclosure, the following definitions are provided and should be
used unless otherwise indicated. Additional terms may be defined
elsewhere in the present disclosure.
A. Definitions
[0035] As used herein, "comprising" is to be interpreted as
specifying the presence of the stated features, integers, steps, or
components as referred to, but does not preclude the presence or
addition of one or more features, integers, steps, or components,
or groups thereof. Moreover, each of the terms "by", "comprising,"
"comprises", "comprised of," "including," "includes," "included,"
"involving," "involves," "involved," and "such as" are used in
their open, non-limiting sense and may be used interchangeably.
Further, the term "comprising" is intended to include examples and
aspects encompassed by the terms "consisting essentially of" and
"consisting of." Similarly, the term "consisting essentially of" is
intended to include examples encompassed by the term "consisting
of.
[0036] As used in the specification and the appended claims, the
singular forms "a," "an" and "the" include plural referents unless
the context clearly dictates otherwise. Thus, for example,
reference to "a biofilm," "a compound," or "a subject," including,
but not limited to, two or more such biofilms, compounds, or
subjects.
[0037] It should be noted that ratios, concentrations, amounts, and
other numerical data can be expressed herein in a range format. It
will be further understood that the endpoints of each of the ranges
are significant both in relation to the other endpoint, and
independently of the other endpoint. It is also understood that
there are a number of values disclosed herein, and that each value
is also herein disclosed as "about" that particular value in
addition to the value itself. For example, if the value "10" is
disclosed, then "about 10" is also disclosed. Ranges can be
expressed herein as from "about" one particular value, and/or to
"about" another particular value. Similarly, when values are
expressed as approximations, by use of the antecedent "about," it
will be understood that the particular value forms a further
aspect. For example, if the value "about 10" is disclosed, then
"10" is also disclosed.
[0038] Where a range is expressed, a further aspect includes from
the one particular value and/or to the other particular value.
Where a range of values is provided, it is understood that each
intervening value, to the tenth of the unit of the lower limit
unless the context clearly dictates otherwise, between the upper
and lower limit of that range and any other stated or intervening
value in that stated range, is encompassed within the disclosure.
The upper and lower limits of these smaller ranges may
independently be included in the smaller ranges and are also
encompassed within the disclosure, subject to any specifically
excluded limit in the stated range. Where the stated range includes
one or both of the limits, ranges excluding either or both of those
included limits are also included in the disclosure. For example,
where the stated range includes one or both of the limits, ranges
excluding either or both of those included limits are also included
in the disclosure, e.g. the phrase "x to y" includes the range from
`x` to `y` as well as the range greater than `x` and less than `y`.
The range can also be expressed as an upper limit, e.g. `about x,
y, z, or less` and should be interpreted to include the specific
ranges of `about x`, `about y`, and `about z` as well as the ranges
of `less than x`, less than y', and `less than z`. Likewise, the
phrase `about x, y, z, or greater` should be interpreted to include
the specific ranges of `about x`, `about y`, and `about z` as well
as the ranges of `greater than x`, greater than y', and `greater
than z`. In addition, the phrase "about `x` to `y`", where `x` and
`y` are numerical values, includes "about `x` to about `y`".
[0039] It is to be understood that such a range format is used for
convenience and brevity, and thus, should be interpreted in a
flexible manner to include not only the numerical values explicitly
recited as the limits of the range, but also to include all the
individual numerical values or sub-ranges encompassed within that
range as if each numerical value and sub-range is explicitly
recited. To illustrate, a numerical range of "about 0.1% to 5%"
should be interpreted to include not only the explicitly recited
values of about 0.1% to about 5%, but also include individual
values (e.g., about 1%, about 2%, about 3%, and about 4%) and the
sub-ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%;
about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other
possible sub-ranges) within the indicated range.
[0040] As used herein, "about," "approximately," "substantially,"
and the like, when used in connection with a numerical variable,
can generally refers to the value of the variable and to all values
of the variable that are within the experimental error (e.g.,
within the 95% confidence interval for the mean) or within +/-10%
of the indicated value, whichever is greater. As used herein, the
terms "about," "approximate," "at or about," and "substantially"
can mean that the amount or value in question can be the exact
value or a value that provides equivalent results or effects as
recited in the claims or taught herein. That is, it is understood
that amounts, sizes, formulations, parameters, and other quantities
and characteristics are not and need not be exact, but may be
approximate and/or larger or smaller, as desired, reflecting
tolerances, conversion factors, rounding off, measurement error and
the like, and other factors known to those of skill in the art such
that equivalent results or effects are obtained. In some
circumstances, the value that provides equivalent results or
effects cannot be reasonably determined. In general, an amount,
size, formulation, parameter or other quantity or characteristic is
"about," "approximate," or "at or about" whether or not expressly
stated to be such. It is understood that where "about,"
"approximate," or "at or about" is used before a quantitative
value, the parameter also includes the specific quantitative value
itself, unless specifically stated otherwise.
[0041] As used herein, the terms "optional" or "optionally" means
that the subsequently described event or circumstance can or cannot
occur, and that the description includes instances where said event
or circumstance occurs and instances where it does not.
[0042] As used herein, "administering" can refer to an
administration that is oral, topical, intravenous, subcutaneous,
transcutaneous, transdermal, intramuscular, intra-joint,
parenteral, intra-arteriole, intradermal, intraventricular,
intraosseous, intraocular, intracranial, intraperitoneal,
intralesional, intranasal, intracardiac, intraarticular,
intracavernous, intrathecal, intravireal, intracerebral, and
intracerebroventricular, intratympanic, intracochlear, rectal,
vaginal, by inhalation, by catheters, stents or via an implanted
reservoir or other device that administers, either actively or
passively (e.g. by diffusion) a composition the perivascular space
and adventitia. For example a medical device such as a stent can
contain a composition or formulation disposed on its surface, which
can then dissolve or be otherwise distributed to the surrounding
tissue and cells. The term "parenteral" can include subcutaneous,
intravenous, intramuscular, intra-articular, intra-synovial,
intrasternal, intrathecal, intrahepatic, intralesional, and
intracranial injections or infusion techniques. Administration can
be continuous or intermittent. In various aspects, a preparation
can be administered therapeutically; that is, administered to treat
an existing disease or condition. In further various aspects, a
preparation can be administered prophylactically; that is,
administered for prevention of a disease or condition.
[0043] As used herein, "therapeutic agent" can refer to any
substance, compound, molecule, and the like, which can be
biologically active or otherwise can induce a pharmacologic,
immunogenic, biologic and/or physiologic effect on a subject to
which it is administered to by local and/or systemic action. A
therapeutic agent can be a primary active agent, or in other words,
the component(s) of a composition to which the whole or part of the
effect of the composition is attributed. A therapeutic agent can be
a secondary therapeutic agent, or in other words, the component(s)
of a composition to which an additional part and/or other effect of
the composition is attributed. The term therefore encompasses those
compounds or chemicals traditionally regarded as drugs, vaccines,
and biopharmaceuticals including molecules such as proteins,
peptides, hormones, nucleic acids, gene constructs and the like.
Examples of therapeutic agents are described in well-known
literature references such as the Merck Index (14th edition), the
Physicians' Desk Reference (64th edition), and The Pharmacological
Basis of Therapeutics (12th edition), and they include, without
limitation, medicaments; vitamins; mineral supplements; substances
used for the treatment, prevention, diagnosis, cure or mitigation
of a disease or illness; substances that affect the structure or
function of the body, or pro-drugs, which become biologically
active or more active after they have been placed in a
physiological environment. For example, the term "therapeutic
agent" includes compounds or compositions for use in all of the
major therapeutic areas including, but not limited to, adjuvants;
anti-infectives such as antibiotics and antiviral agents;
analgesics and analgesic combinations, anorexics, anti-inflammatory
agents, anti-epileptics, local and general anesthetics, hypnotics,
sedatives, antipsychotic agents, neuroleptic agents,
antidepressants, anxiolytics, antagonists, neuron blocking agents,
anticholinergic and cholinomimetic agents, antimuscarinic and
muscarinic agents, antiadrenergics, antiarrhythmics,
antihypertensive agents, hormones, and nutrients, antiarthritics,
antiasthmatic agents, anticonvulsants, antihistamines,
antinauseants, antineoplastics, antipruritics, antipyretics;
antispasmodics, cardiovascular preparations (including calcium
channel blockers, beta-blockers, beta-agonists and antiarrythmics),
antihypertensives, diuretics, vasodilators; central nervous system
stimulants; cough and cold preparations; decongestants;
diagnostics; hormones; bone growth stimulants and bone resorption
inhibitors; immunosuppressives; muscle relaxants; psychostimulants;
sedatives; tranquilizers; proteins, peptides, and fragments thereof
(whether naturally occurring, chemically synthesized or
recombinantly produced); and nucleic acid molecules (polymeric
forms of two or more nucleotides, either ribonucleotides (RNA) or
deoxyribonucleotides (DNA) including both double- and
single-stranded molecules, gene constructs, expression vectors,
antisense molecules and the like), small molecules (e.g.,
doxorubicin) and other biologically active macromolecules such as,
for example, proteins and enzymes. The agent may be a biologically
active agent used in medical, including veterinary, applications
and in agriculture, such as with plants, as well as other areas.
The term therapeutic agent also includes without limitation,
medicaments; vitamins; mineral supplements; substances used for the
treatment, prevention, diagnosis, cure or mitigation of disease or
illness; or substances which affect the structure or function of
the body; or pro-drugs, which become biologically active or more
active after they have been placed in a predetermined physiological
environment.
[0044] As used herein, "kit" means a collection of at least two
components constituting the kit. Together, the components
constitute a functional unit for a given purpose. Individual member
components may be physically packaged together or separately. For
example, a kit comprising an instruction for using the kit may or
may not physically include the instruction with other individual
member components. Instead, the instruction can be supplied as a
separate member component, either in a paper form or an electronic
form which may be supplied on computer readable memory device or
downloaded from an internet website, or as recorded
presentation.
[0045] As used herein, "instruction(s)" means documents describing
relevant materials or methodologies pertaining to a kit. These
materials may include any combination of the following: background
information, list of components and their availability information
(purchase information, etc.), brief or detailed protocols for using
the kit, trouble-shooting, references, technical support, and any
other related documents. Instructions can be supplied with the kit
or as a separate member component, either as a paper form or an
electronic form which may be supplied on computer readable memory
device or downloaded from an internet website, or as recorded
presentation. Instructions can comprise one or multiple documents,
and are meant to include future updates.
[0046] As used herein, "attached" can refer to covalent or
non-covalent interaction between two or more molecules.
Non-covalent interactions can include ionic bonds, electrostatic
interactions, van der Walls forces, dipole-dipole interactions,
dipole-induced-dipole interactions, London dispersion forces,
hydrogen bonding, halogen bonding, electromagnetic interactions,
.pi.-.pi. interactions, cation-r interactions, anion-r
interactions, polar r-interactions, and hydrophobic effects.
[0047] As used interchangeably herein, "subject," "individual," or
"patient" can refer to a vertebrate organism, such as a mammal
(e.g. human). "Subject" can also refer to a cell, a population of
cells, a tissue, an organ, or an organism, preferably to human and
constituents thereof.
[0048] As used herein, the terms "treating" and "treatment" can
refer generally to obtaining a desired pharmacological and/or
physiological effect. The effect can be, but does not necessarily
have to be, prophylactic in terms of preventing or partially
preventing a disease, symptom or condition thereof, such as a
Salmonella enterica infection, Salmonella chronic carriage, and/or
a biofilm associated with a Salmonella enterica infection,
including an active infection or an asymptomatic infection. The
effect can be therapeutic in terms of a partial or complete cure of
a disease, condition, symptom or adverse effect attributed to the
disease, disorder, or condition. The term "treatment" as used
herein can include any treatment of a Salmonella enterica
infection, Salmonella chronic carriage, and/or a biofilm associated
with a Salmonella enterica infection in a subject, particularly a
human and can include any one or more of the following: (a)
preventing the disease from occurring in a subject which may be
predisposed to the disease but has not yet been diagnosed as having
it; (b) inhibiting the disease, i.e., arresting its development;
and (c) relieving the disease, i.e., mitigating or ameliorating the
disease and/or its symptoms or conditions. The term "treatment" as
used herein can refer to both therapeutic treatment alone,
prophylactic treatment alone, or both therapeutic and prophylactic
treatment. Those in need of treatment (subjects in need thereof)
can include those already with the disorder and/or those in which
the disorder is to be prevented. As used herein, the term
"treating", can include inhibiting the disease, disorder or
condition, e.g., impeding its progress; and relieving the disease,
disorder, or condition, e.g., causing regression of the disease,
disorder and/or condition. Treating the disease, disorder, or
condition can include ameliorating at least one symptom of the
particular disease, disorder, or condition, even if the underlying
pathophysiology is not affected, e.g., such as treating the pain of
a subject by administration of an analgesic agent even though such
agent does not treat the cause of the pain.
[0049] As used herein, "dose," "unit dose," or "dosage" can refer
to physically discrete units suitable for use in a subject, each
unit containing a predetermined quantity of a disclosed compound
and/or a pharmaceutical composition thereof calculated to produce
the desired response or responses in association with its
administration.
[0050] As used herein, "therapeutic" can refer to treating,
healing, and/or ameliorating a disease, disorder, condition, or
side effect, or to decreasing in the rate of advancement of a
disease, disorder, condition, or side effect.
[0051] As used herein, "effective amount" can refer to the amount
of a disclosed compound or pharmaceutical composition provided
herein that is sufficient to effect beneficial or desired
biological, emotional, medical, or clinical response of a cell,
tissue, system, animal, or human. An effective amount can be
administered in one or more administrations, applications, or
dosages. The term can also include within its scope amounts
effective to enhance or restore to substantially normal
physiological function.
[0052] As used herein, the term "therapeutically effective amount"
refers to an amount that is sufficient to achieve the desired
therapeutic result or to have an effect on undesired symptoms, but
is generally insufficient to cause adverse side effects. The
specific therapeutically effective dose level for any particular
patient will depend upon a variety of factors including the
disorder being treated and the severity of the disorder; the
specific composition employed; the age, body weight, general
health, sex and diet of the patient; the time of administration;
the route of administration; the rate of excretion of the specific
compound employed; the duration of the treatment; drugs used in
combination or coincidental with the specific compound employed and
like factors within the knowledge and expertise of the health
practitioner and which may be well known in the medical arts. In
the case of treating a particular disease or condition, in some
instances, the desired response can be inhibiting the progression
of the disease or condition. This may involve only slowing the
progression of the disease temporarily. However, in other
instances, it may be desirable to halt the progression of the
disease permanently. This can be monitored by routine diagnostic
methods known to one of ordinary skill in the art for any
particular disease. The desired response to treatment of the
disease or condition also can be delaying the onset or even
preventing the onset of the disease or condition.
[0053] For example, it is well within the skill of the art to start
doses of a compound at levels lower than those required to achieve
the desired therapeutic effect and to gradually increase the dosage
until the desired effect is achieved. If desired, the effective
daily dose can be divided into multiple doses for purposes of
administration. Consequently, single dose compositions can contain
such amounts or submultiples thereof to make up the daily dose. The
dosage can be adjusted by the individual physician in the event of
any contraindications. It is generally preferred that a maximum
dose of the pharmacological agents of the invention (alone or in
combination with other therapeutic agents) be used, that is, the
highest safe dose according to sound medical judgment. It will be
understood by those of ordinary skill in the art however, that a
patient may insist upon a lower dose or tolerable dose for medical
reasons, psychological reasons or for virtually any other
reasons.
[0054] A response to a therapeutically effective dose of a
disclosed compound and/or pharmaceutical composition, for example,
can be measured by determining the physiological effects of the
treatment or medication, such as the decrease or lack of disease
symptoms following administration of the treatment or
pharmacological agent. Other assays will be known to one of
ordinary skill in the art and can be employed for measuring the
level of the response. The amount of a treatment may be varied for
example by increasing or decreasing the amount of a disclosed
compound and/or pharmaceutical composition, by changing the
disclosed compound and/or pharmaceutical composition administered,
by changing the route of administration, by changing the dosage
timing and so on. Dosage can vary, and can be administered in one
or more dose administrations daily, for one or several days.
Guidance can be found in the literature for appropriate dosages for
given classes of pharmaceutical products.
[0055] As used herein, the term "prophylactically effective amount"
refers to an amount effective for preventing onset or initiation of
a disease or condition.
[0056] As used herein, the term "prevent" or "preventing" refers to
precluding, averting, obviating, forestalling, stopping, or
hindering something from happening, especially by advance action.
It is understood that where reduce, inhibit or prevent are used
herein, unless specifically indicated otherwise, the use of the
other two words is also expressly disclosed.
[0057] The term "pharmaceutically acceptable" describes a material
that is not biologically or otherwise undesirable, i.e., without
causing an unacceptable level of undesirable biological effects or
interacting in a deleterious manner.
[0058] The term "pharmaceutically acceptable salts", as used
herein, means salts of the active principal agents which are
prepared with acids or bases that are tolerated by a biological
system or tolerated by a subject or tolerated by a biological
system and tolerated by a subject when administered in a
therapeutically effective amount. When compounds of the present
disclosure contain relatively acidic functionalities, base addition
salts can be obtained by contacting the neutral form of such
compounds with a sufficient amount of the desired base, either neat
or in a suitable inert solvent. Examples of pharmaceutically
acceptable base addition salts include, but are not limited to;
sodium, potassium, calcium, ammonium, organic amino, magnesium
salt, lithium salt, strontium salt or a similar salt. When
compounds of the present disclosure contain relatively basic
functionalities, acid addition salts can be obtained by contacting
the neutral form of such compounds with a sufficient amount of the
desired acid, either neat or in a suitable inert solvent. Examples
of pharmaceutically acceptable acid addition salts include, but are
not limited to; those derived from inorganic acids like
hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic,
phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,
monohydrogensulfuric, hydriodic, or phosphorous acids and the like,
as well as the salts derived from relatively nontoxic organic acids
like acetic, propionic, isobutyric, maleic, malonic, benzoic,
succinic, suberic, fumaric, lactic, mandelic, phthalic,
benzenesulfonic, p-tolylsulfonic, citric, tartaric,
methanesulfonic, and the like. Also included are salts of amino
acids such as arginate and the like, and salts of organic acids
like glucuronic or galactunoric acids and the like.
[0059] The term "pharmaceutically acceptable ester" refers to
esters of compounds of the present disclosure which hydrolyze in
vivo and include those that break down readily in the human body to
leave the parent compound or a salt thereof. Examples of
pharmaceutically acceptable, non-toxic esters of the present
disclosure include C1-to-C6 alkyl esters and C5-to-C7 cycloalkyl
esters, although C1-to-C4 alkyl esters are preferred. Esters of
disclosed compounds can be prepared according to conventional
methods. Pharmaceutically acceptable esters can be appended onto
hydroxy groups by reaction of the compound that contains the
hydroxy group with acid and an alkylcarboxylic acid such as acetic
acid, or with acid and an arylcarboxylic acid such as benzoic acid.
In the case of compounds containing carboxylic acid groups, the
pharmaceutically acceptable esters are prepared from compounds
containing the carboxylic acid groups by reaction of the compound
with base such as triethylamine and an alkyl halide, for example
with methyl iodide, benzyl iodide, cyclopentyl iodide or alkyl
triflate. They also can be prepared by reaction of the compound
with an acid such as hydrochloric acid and an alcohol such as
ethanol or methanol.
[0060] The term "pharmaceutically acceptable amide" refers to
non-toxic amides of the present disclosure derived from ammonia,
primary C1-to-C6 alkyl amines and secondary C1-to-C6 dialkyl
amines. In the case of secondary amines, the amine can also be in
the form of a 5- or 6-membered heterocycle containing one nitrogen
atom. Amides derived from ammonia, C1-to-C3 alkyl primary amides
and C1-to-C2 dialkyl secondary amides are preferred. Amides of
disclosed compounds can be prepared according to conventional
methods. Pharmaceutically acceptable amides can be prepared from
compounds containing primary or secondary amine groups by reaction
of the compound that contains the amino group with an alkyl
anhydride, aryl anhydride, acyl halide, or aroyl halide. In the
case of compounds containing carboxylic acid groups, the
pharmaceutically acceptable amides are prepared from compounds
containing the carboxylic acid groups by reaction of the compound
with base such as triethylamine, a dehydrating agent such as
dicyclohexyl carbodiimide or carbonyl diimidazole, and an alkyl
amine, dialkylamine, for example with methylamine, diethylamine,
and piperidine. They also can be prepared by reaction of the
compound with an acid such as sulfuric acid and an alkylcarboxylic
acid such as acetic acid, or with acid and an arylcarboxylic acid
such as benzoic acid under dehydrating conditions such as with
molecular sieves added. The composition can contain a compound of
the present disclosure in the form of a pharmaceutically acceptable
prodrug.
[0061] The term "pharmaceutically acceptable prodrug" or "prodrug"
represents those prodrugs of the compounds of the present
disclosure which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response, and
the like, commensurate with a reasonable benefit/risk ratio, and
effective for their intended use. Prodrugs of the present
disclosure can be rapidly transformed in vivo to a parent compound
having a structure of a disclosed compound, for example, by
hydrolysis in blood. A thorough discussion is provided in T.
Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14
of the A.C.S. Symposium Series, and in Edward B. Roche, ed.,
Bioreversible Carriers in Drug Design, American Pharmaceutical
Association and Pergamon Press (1987).
[0062] As used herein, the term "derivative" refers to a compound
having a structure derived from the structure of a parent compound
(e.g., a compound disclosed herein) and whose structure is
sufficiently similar to those disclosed herein and based upon that
similarity, would be expected by one skilled in the art to exhibit
the same or similar activities and utilities as the claimed
compounds, or to induce, as a precursor, the same or similar
activities and utilities as the claimed compounds. Exemplary
derivatives include salts, esters, amides, salts of esters or
amides, and N-oxides of a parent compound.
[0063] The term "contacting" as used herein refers to bringing a
disclosed compound or pharmaceutical composition in proximity to a
cell, a target protein, or other biological entity together in such
a manner that the disclosed compound or pharmaceutical composition
can affect the activity of the a cell, target protein, or other
biological entity, either directly; i.e., by interacting with the
cell, target protein, or other biological entity itself, or
indirectly; i.e., by interacting with another molecule, co-factor,
factor, or protein on which the activity of the cell, target
protein, or other biological entity itself is dependent.
[0064] As used herein, nomenclature for compounds, including
organic compounds, can be given using common names, IUPAC, IUBMB,
or CAS recommendations for nomenclature. When one or more
stereochemical features are present, Cahn-Ingold-Prelog rules for
stereochemistry can be employed to designate stereochemical
priority, E/Z specification, and the like. One of skill in the art
can readily ascertain the structure of a compound if given a name,
either by systemic reduction of the compound structure using naming
conventions, or by commercially available software, such as
CHEMDRAW.TM. (Cambridgesoft Corporation, U.S.A.).
[0065] It is understood, that unless otherwise specified,
temperatures referred to herein are based on atmospheric pressure
(i.e. one atmosphere).
[0066] Described herein are compounds and pharmaceutical
compositions that have therapeutic or clinical utility. Also
described herein are methods of administering the disclosed
compounds or pharmaceutical compostions to a subject in need
thereof. In some aspects, the subject can have a Salmonella
enterica infection, Salmonella chronic carriage, and/or a biofilm
associated with a Salmonella enterica infection. Other
compositions, compounds, methods, features, and advantages of the
present disclosure will be or become apparent to one having
ordinary skill in the art upon examination of the following
drawings, detailed description, and examples. It is intended that
all such additional compositions, compounds, methods, features, and
advantages be included within this description, and be within the
scope of the present disclosure.
B. Compounds
[0067] In various aspects, a disclosed compound has a structure
represented by a formula:
##STR00002##
wherein R.sup.1 is selected from a C1-C12 alkyl, a C3-C12
cycloalkyl; and a substituted aryl; and wherein R.sup.2 is selected
from a C1-C12 alkyl, a C3-C12 cycloalkyl; and a substituted aryl;
or a pharmaceutically acceptable salt thereof.
[0068] In some aspects, R.sup.1 is selected from a C1-C12 alkyl and
a substituted aryl. Alternatively, R.sup.1 can be a C1-C12 alkyl.
In a further aspect, R.sup.1 is a C1-C6 alkyl. In a still further
aspect, R.sup.1 is selected from methyl, ethyl, propyl, isopropyl,
tert-butyl, sec-butyl, isobutyl, neopentyl, isopentyl, sec-pentyl,
tert-pentyl, 3,3-dimethylbutan-2-yl, and
2,3-dimethylbutan-2-yl.
[0069] In various aspects, R.sup.1 is a substituted aryl. For
example, R.sup.1 can be a structure represented by a formula:
##STR00003##
wherein each of R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d, and
R.sup.10e is independently selected from hydrogen, halogen, C1-C6
alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl, provided that at least
one of R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d, and R.sup.10e is
not hydrogen. In a further aspect, each of R.sup.10a, R.sup.10b,
R.sup.10c, R.sup.10d, and R.sup.10e is independently selected from
hydrogen, halogen, C1-C6 alkyl, and C1-C6 alkoxy, provided that two
R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d, and R.sup.10e are
hydrogen. In a still further aspect, each of R.sup.10a, R.sup.10b,
R.sup.10c, R.sup.10d, and R.sup.10e is independently selected from
hydrogen, bromo, chloro, fluoro, C1-C3 alkyl, and C1-C3 alkoxy,
provided that at least one of R.sup.10a, R.sup.10b, R.sup.10c,
R.sup.10d, and R.sup.10e is not hydrogen. In a yet further aspect,
each of R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d, and R.sup.10e
is independently selected from hydrogen, bromo, chloro, C1-C3
alkyl, and C1-C3 alkoxy, provided that at least one of R.sup.10a,
R.sup.10b, R.sup.10c, R.sup.10d, and R.sup.10e is not hydrogen. In
an even further aspect, each of R.sup.10a, R.sup.10b, R.sup.10c,
R.sup.10d, and R.sup.10e is independently selected from hydrogen,
bromo, and chloro, provided that at least one of R.sup.10a,
R.sup.10b, R.sup.10c, R.sup.10d, and R.sup.10e is not hydrogen. In
an yet further aspect, each of R.sup.10a, R.sup.10b, R.sup.10c,
R.sup.10d, and R.sup.10e is independently selected from hydrogen,
bromo, and chloro, provided that two of R.sup.10a, R.sup.10b,
R.sup.10c, R.sup.10d, and R.sup.10e are hydrogen. In a still
further aspect, R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d, and
R.sup.10e is independently selected from hydrogen, bromo, and
chloro, provided that three of R.sup.10a, R.sup.10b, R.sup.10c,
R.sup.10d, and R.sup.10e are hydrogen. In various further aspects,
each of R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d, and R.sup.10e
is independently selected from hydrogen, bromo, and chloro,
provided that four of R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d,
and R.sup.10e are hydrogen.
[0070] In a further aspect, R.sup.1 is a structure represented by a
formula:
##STR00004##
wherein each of R.sup.10b and R.sup.10c is independently selected
from halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl. In a
still further aspect, each of R.sup.10b and R.sup.10c is
independently selected from hydrogen, halogen, C1-C6 alkyl, and
C1-C6 alkoxy. In a yet further aspect, each of R.sup.10b and
R.sup.10c is independently selected from hydrogen, bromo, chloro,
fluoro, C1-C3 alkyl, and C1-C3 alkoxy. In an even further aspect,
each of R.sup.10b and R.sup.10c is independently selected from
hydrogen, bromo, chloro, C1-C3 alkyl, and C1-C3 alkoxy. In a still
further aspect, each of R.sup.10b and R.sup.10c is independently
selected from hydrogen, bromo, and chloro.
[0071] In a further aspect, R.sup.1 is a structure represented by a
formula:
##STR00005##
wherein each of R.sup.10b and R.sup.10d is independently selected
from halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl. In
various aspects, each of R.sup.10b and R.sup.10d is independently
selected from hydrogen, halogen, C1-C3 alkyl, and C1-C3 alkoxy. In
a further aspect, each of R.sup.10b and R.sup.10d is independently
selected from hydrogen, bromo, chloro, fluoro, C1-C3 alkyl, and
C1-C3 alkoxy. In a still further aspect, each of R.sup.10b and
R.sup.10d is independently selected from hydrogen, bromo, chloro,
C1-C3 alkyl, and C1-C3 alkoxy. In an even further aspect, each of
R.sup.10b and R.sup.10d is independently selected from hydrogen,
bromo, and chloro.
[0072] In various aspects, R.sup.1 is a structure represented by a
formula:
##STR00006##
wherein R.sup.10c is selected from halogen, C1-C6 alkyl, C1-C6
alkoxy, and C1-C6 haloalkyl. In a further aspect, R.sup.10c is
selected from hydrogen, halogen, C1-C6 alkyl, and C1-C6 alkoxy. In
a still further aspect, R.sup.10c is selected from hydrogen, bromo,
chloro, fluoro, C1-C3 alkyl, and C1-C3 alkoxy. In a yet further
aspect, R.sup.10c is selected from hydrogen, bromo, chloro, C1-C3
alkyl, and C1-C3 alkoxy. In an even further aspect, R.sup.10c is
selected from hydrogen, bromo, and chloro.
[0073] In various aspects, a disclosed compound has a structure
represented by a formula:
##STR00007##
[0074] In various aspects, a disclosed compound has a structure
represented by a formula:
##STR00008##
wherein each of R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d and
R.sup.10e is independently selected from hydrogen, halogen, C1-C6
alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl, provided that at least
one of R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d and R.sup.10e is
not hydrogen. In further aspect, each of R.sup.10a, R.sup.10b,
R.sup.10c, R.sup.10d, and R.sup.10e is independently selected from
hydrogen, halogen, C1-C6 alkyl, and C1-C6 alkoxy, provided that two
R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d, and R.sup.10e are
hydrogen. In a still further aspect, each of R.sup.10a, R.sup.10b,
R.sup.10c, R.sup.10d, and R.sup.10e is independently selected from
hydrogen, bromo, chloro, fluoro, C1-C3 alkyl, and C1-C3 alkoxy,
provided that at least one of R.sup.10a, R.sup.10b, R.sup.10c,
R.sup.10d, and R.sup.10e is not hydrogen. In a yet further aspect,
each of R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d and R.sup.10e is
independently selected from hydrogen, bromo, chloro, C1-C3 alkyl,
and C1-C3 alkoxy, provided that at least one of R.sup.10a,
R.sup.10b, R.sup.10c, R.sup.10d, and R.sup.10e is not hydrogen. In
an even further aspect, each of R.sup.10a, R.sup.10b, R.sup.10c,
R.sup.10d and R.sup.10e is independently selected from hydrogen,
bromo, and chloro, provided that at least one of R.sup.10a,
R.sup.10b, R.sup.10c, R.sup.10d, and R.sup.10e is not hydrogen. In
an yet further aspect, each of R.sup.10a, R.sup.10b, R.sup.10c,
R.sup.10d and R.sup.10e is independently selected from hydrogen,
bromo, and chloro, provided that two of R.sup.10a, R.sup.10b,
R.sup.10c, R.sup.10d, and R.sup.10e are hydrogen. In a still
further aspect, R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d,
R.sup.10e is independently selected from hydrogen, bromo, and
chloro, provided that three of R.sup.10a, R.sup.10b, R.sup.10c,
R.sup.10d and R.sup.10e are hydrogen. In various further aspects,
each of R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d, and R.sup.10e
is independently selected from hydrogen, bromo, and chloro,
provided that four of R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d,
and R.sup.10e are hydrogen.
[0075] In various aspects, a disclosed compound has a structure
represented by a formula:
##STR00009##
wherein each of R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d and
R.sup.10e is independently selected from hydrogen, halogen, C1-C6
alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl, provided that at least
one of R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d and R.sup.10e is
not hydrogen. In further aspect, each of R.sup.10a, R.sup.10b,
R.sup.10c, R.sup.10d, and R.sup.10e is independently selected from
hydrogen, halogen, C1-C6 alkyl, and C1-C6 alkoxy, provided that two
R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d, and R.sup.10e are
hydrogen. In a still further aspect, each of R.sup.10a, R.sup.10b,
R.sup.10c, R.sup.10d, and R.sup.10e is independently selected from
hydrogen, bromo, chloro, fluoro, C1-C3 alkyl, and C1-C3 alkoxy,
provided that at least one of R.sup.10a, R.sup.10b, R.sup.10c,
R.sup.10d, and R.sup.10e is not hydrogen. In a yet further aspect,
each of R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d, R.sup.10e is
independently selected from hydrogen, bromo, chloro, C1-C3 alkyl,
and C1-C3 alkoxy, provided that at least one of R.sup.10a,
R.sup.10b, R.sup.10c, R.sup.10d, and R.sup.10e is not hydrogen. In
an even further aspect, each of R.sup.10a, R.sup.10b, R.sup.10c,
R.sup.10d and R.sup.10e is independently selected from hydrogen,
bromo, and chloro, provided that at least one of R.sup.10a,
R.sup.10b, R.sup.10c, R.sup.10d, and R.sup.10e is not hydrogen. In
an yet further aspect, each of R.sup.10a, R.sup.10b, R.sup.10c,
R.sup.10d and R.sup.10e is independently selected from hydrogen,
bromo, and chloro, provided that two of R.sup.10a, R.sup.10b,
R.sup.10c, R.sup.10d, and R.sup.10e are hydrogen. In a still
further aspect, R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d,
R.sup.10e is independently selected from hydrogen, bromo, and
chloro, provided that three of R.sup.10a, R.sup.10b, R.sup.10c,
R.sup.10d, and R.sup.10e are hydrogen. In various further aspects,
each of R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d, and R.sup.10e
is independently selected from hydrogen, bromo, and chloro,
provided that four of R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d,
and R.sup.10e are hydrogen.
[0076] In various aspects, a disclosed compound has a structure
represented by a formula:
##STR00010##
wherein each of R.sup.10b and R.sup.10d is independently selected
from halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl. In
various aspects, each of R.sup.10b and R.sup.10d is independently
selected from hydrogen, halogen, C1-C3 alkyl, and C1-C3 alkoxy. In
a further aspect, each of R.sup.10b and R.sup.10d is independently
selected from hydrogen, bromo, chloro, fluoro, C1-C3 alkyl, and
C1-C3 alkoxy. In a still further aspect, each of R.sup.10b and
R.sup.10d is independently selected from hydrogen, bromo, chloro,
C1-C3 alkyl, and C1-C3 alkoxy. In an even further aspect, each of
R.sup.10b and R.sup.10d is independently selected from hydrogen,
bromo, and chloro.
[0077] In various aspects, a disclosed compound has a structure
represented by a formula:
##STR00011##
wherein each of R.sup.10b and R.sup.10d is independently selected
from halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl; and
wherein n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, and 12. In various aspects, each of R.sup.10b and R.sup.10d
is independently selected from hydrogen, halogen, C1-C3 alkyl, and
C1-C3 alkoxy. In a further aspect, each of R.sup.10b and R.sup.10d
is independently selected from hydrogen, bromo, chloro, fluoro,
C1-C3 alkyl, and C1-C3 alkoxy. In a still further aspect, each of
R.sup.10b and R.sup.10d is independently selected from hydrogen,
bromo, chloro, C1-C3 alkyl, and C1-C3 alkoxy. In an even further
aspect, each of R.sup.10b and R.sup.10d is independently selected
from hydrogen, bromo, and chloro.
[0078] In various aspects, a disclosed compound has a structure
represented by a formula:
##STR00012##
wherein each of R.sup.10b and R.sup.10c is independently selected
from halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl. In a
still further aspect, each of R.sup.10b and R.sup.10c is
independently selected from hydrogen, halogen, C1-C6 alkyl, and
C1-C6 alkoxy. In a yet further aspect, each of R.sup.10b and
R.sup.10c is independently selected from hydrogen, bromo, chloro,
fluoro, C1-C3 alkyl, and C1-C3 alkoxy. In an even further aspect,
each of R.sup.10b and R.sup.10c is independently selected from
hydrogen, bromo, chloro, C1-C3 alkyl, and C1-C3 alkoxy. In a still
further aspect, each of R.sup.10b and R.sup.10c is independently
selected from hydrogen, bromo, and chloro.
[0079] In various aspects, a disclosed compound has a structure
represented by a formula:
##STR00013##
wherein each of R.sup.10b and R.sup.10c is independently selected
from halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl; and
wherein n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, and 12. In a still further aspect, each of R.sup.10b and
R.sup.10c is independently selected from hydrogen, halogen, C1-C6
alkyl, and C1-C6 alkoxy. In a yet further aspect, each of R.sup.10b
and R.sup.10c is independently selected from hydrogen, bromo,
chloro, fluoro, C1-C3 alkyl, and C1-C3 alkoxy. In an even further
aspect, each of R.sup.10b and R.sup.10c is independently selected
from hydrogen, bromo, chloro, C1-C3 alkyl, and C1-C3 alkoxy. In a
still further aspect, each of R.sup.10b and R.sup.10c is
independently selected from hydrogen, bromo, and chloro.
[0080] In various aspects, a disclosed compound has a structure
represented by a formula:
##STR00014##
wherein R.sup.10c is selected from halogen, C1-C6 alkyl, C1-C6
alkoxy, and C1-C6 haloalkyl. In a further aspect, R.sup.10c is
selected from hydrogen, halogen, C1-C6 alkyl, and C1-C6 alkoxy. In
a still further aspect, R.sup.10c is selected from hydrogen, bromo,
chloro, fluoro, C1-C3 alkyl, and C1-C3 alkoxy. In a yet further
aspect, R.sup.10c is selected from hydrogen, bromo, chloro, C1-C3
alkyl, and C1-C3 alkoxy. In an even further aspect, R.sup.10c is
selected from hydrogen, bromo, and chloro.
[0081] In various aspects, a disclosed compound has a structure
represented by a formula:
##STR00015##
wherein R.sup.10c is selected from halogen, C1-C6 alkyl, C1-C6
alkoxy, and C1-C6 haloalkyl; and wherein n is an integer selected
from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12. In a further
aspect, R.sup.10c is selected from hydrogen, halogen, C1-C6 alkyl,
and C1-C6 alkoxy. In a still further aspect, R.sup.10c is selected
from hydrogen, bromo, chloro, fluoro, C1-C3 alkyl, and C1-C3
alkoxy. In a yet further aspect, R.sup.10c is selected from
hydrogen, bromo, chloro, C1-C3 alkyl, and C1-C3 alkoxy. In an even
further aspect, R.sup.10c is selected from hydrogen, bromo, and
chloro.
[0082] In various aspects, a disclosed compound has a structure
represented by a formula:
##STR00016##
wherein m is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, and 12.
[0083] In various aspects, a disclosed compound has a structure
represented by a formula:
##STR00017##
wherein m is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, and 12; and wherein n is an integer selected from 0, 1, 2,
3, 4, 5, 6, 7, 8, 9, 10, 11, and 12.
[0084] In various aspects, a disclosed compound has a structure
represented by a formula:
##STR00018##
wherein m is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, and 12; and wherein n is an integer selected from 0, 1, 2,
3, 4, 5, 6, 7, 8, 9, 10, 11, and 12.
[0085] In various aspects, a disclosed compound has a structure
represented by a formula:
##STR00019##
[0086] In various aspects, a disclosed compound has a structure
represented by a formula:
##STR00020##
wherein n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, and 12.
[0087] In various aspects, a disclosed compound has a structure
represented by a formula:
##STR00021##
wherein n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, and 12.
[0088] In various aspects, a disclosed compound has a structure
represented by a formula:
##STR00022##
wherein n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, and 12.
[0089] In various aspects, a disclosed compound has a structure
represented by a formula:
##STR00023##
wherein each of R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d and
R.sup.10e is independently selected from hydrogen, halogen, C1-C6
alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl, provided that at least
one of R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d and R.sup.10e is
not hydrogen. In further aspect, each of R.sup.10a, R.sup.10b,
R.sup.10c, R.sup.10d, and R.sup.10e is independently selected from
hydrogen, halogen, C1-C6 alkyl, and C1-C6 alkoxy, provided that two
R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d, and R.sup.10e are
hydrogen. In a still further aspect, each of R.sup.10a, R.sup.10b,
R.sup.10c, R.sup.10d, and R.sup.10e is independently selected from
hydrogen, bromo, chloro, fluoro, C1-C3 alkyl, and C1-C3 alkoxy,
provided that at least one of R.sup.10a, R.sup.10b, R.sup.10c,
R.sup.10d, and R.sup.10e is not hydrogen. In a yet further aspect,
each of R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d, and R.sup.10e
is independently selected from hydrogen, bromo, chloro, C1-C3
alkyl, and C1-C3 alkoxy, provided that at least one of R.sup.10a,
R.sup.10b, R.sup.10c, R.sup.10d, and R.sup.10e is not hydrogen. In
an even further aspect, each of R.sup.10a, R.sup.10b, R.sup.10c,
R.sup.10d and R.sup.10e is independently selected from hydrogen,
bromo, and chloro, provided that at least one of R.sup.10a,
R.sup.10b, R.sup.10c, R.sup.10d, and R.sup.10e is not hydrogen. In
an yet further aspect, each of R.sup.10a, R.sup.10b, R.sup.10c,
R.sup.10d and R.sup.10e is independently selected from hydrogen,
bromo, and chloro, provided that two of R.sup.10a, R.sup.10b,
R.sup.10c, R.sup.10d, and R.sup.10e are hydrogen. In a still
further aspect, R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d,
R.sup.10e is independently selected from hydrogen, bromo, and
chloro, provided that three of R.sup.10a, R.sup.10b, R.sup.10c,
R.sup.10d and R.sup.10e are hydrogen. In various further aspects,
each of R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d, and R.sup.10e
is independently selected from hydrogen, bromo, and chloro,
provided that four of R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d,
and R.sup.10e are hydrogen.
[0090] In various aspects, a disclosed compound has a structure
represented by a formula:
##STR00024##
wherein each of R.sup.10b and R.sup.10d is independently selected
from halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl; and
wherein n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, and 12. In various aspects, each of R.sup.10b and R.sup.10d
is independently selected from hydrogen, halogen, C1-C3 alkyl, and
C1-C3 alkoxy. In a further aspect, each of R.sup.10b and R.sup.10d
is independently selected from hydrogen, bromo, chloro, fluoro,
C1-C3 alkyl, and C1-C3 alkoxy. In a still further aspect, each of
R.sup.10b and R.sup.10d is independently selected from hydrogen,
bromo, chloro, C1-C3 alkyl, and C1-C3 alkoxy. In an even further
aspect, each of R.sup.10b and R.sup.10d is independently selected
from hydrogen, bromo, and chloro.
[0091] In various aspects, a disclosed compound has a structure
represented by a formula:
##STR00025##
wherein each of R.sup.10b and R.sup.10c is independently selected
from halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl; and
wherein n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, and 12. In a still further aspect, each of R.sup.10b and
R.sup.10c is independently selected from hydrogen, halogen, C1-C6
alkyl, and C1-C6 alkoxy. In a yet further aspect, each of R.sup.10b
and R.sup.10c is independently selected from hydrogen, bromo,
chloro, fluoro, C1-C3 alkyl, and C1-C3 alkoxy. In an even further
aspect, each of R.sup.10b and R.sup.10c is independently selected
from hydrogen, bromo, chloro, C1-C3 alkyl, and C1-C3 alkoxy. In a
still further aspect, each of R.sup.10b and R.sup.10c is
independently selected from hydrogen, bromo, and chloro.
[0092] In various aspects, a disclosed compound has a structure
represented by a formula:
##STR00026##
wherein R.sup.10c is selected from halogen, C1-C6 alkyl, C1-C6
alkoxy, and C1-C6 haloalkyl; and wherein n is an integer selected
from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12. In a further
aspect, R.sup.10c is selected from hydrogen, halogen, C1-C6 alkyl,
and C1-C6 alkoxy. In a still further aspect, R.sup.10c is selected
from hydrogen, bromo, chloro, fluoro, C1-C3 alkyl, and C1-C3
alkoxy. In a yet further aspect, R.sup.10c is selected from
hydrogen, bromo, chloro, C1-C3 alkyl, and C1-C3 alkoxy. In an even
further aspect, R.sup.10c is selected from hydrogen, bromo, and
chloro.
[0093] In various aspects, a disclosed compound can be present
as:
##STR00027## ##STR00028##
[0094] or a subgroup thereof.
[0095] In various aspects, it is contemplated herein that the
disclosed compounds further comprise their biosteric equivalents.
The term "bioisosteric equivalent" refers to compounds or groups
that possess near equal molecular shapes and volumes, approximately
the same distribution of electrons, and which exhibit similar
physical and biological properties. Examples of such equivalents
are: (i) fluorine vs. hydrogen, (ii) oxo vs. thia, (iii) hydroxyl
vs. amide, (iv) carbonyl vs. oxime, (v) carboxylate vs. tetrazole.
Examples of such bioisosteric replacements can be found in the
literature and examples of such are: (i) Burger A, Relation of
chemical structure and biological activity; in Medicinal Chemistry
Third ed., Burger A, ed.; Wiley-Interscience; New York, 1970,
64-80; (ii) Burger, A.; "Isosterism and bioisosterism in drug
design"; Prog. Drug Res. 1991, 37, 287-371; (iii) Burger A,
"Isosterism and bioanalogy in drug design", Med. Chem. Res. 1994,
4, 89-92; (iv) Clark R D, Ferguson A M, Cramer R D, "Bioisosterism
and molecular diversity", Perspect. Drug Discovery Des. 1998,
9/10/11, 213-224; (v) Koyanagi T, Haga T, "Bioisosterism in
agrochemicals", ACS Symp. Ser. 1995, 584, 15-24; (vi) Kubinyi H,
"Molecular similarities. Part 1. Chemical structure and biological
activity", Pharm. Unserer Zeit 1998, 27, 92-106; (vii) Lipinski C
A.; "Bioisosterism in drug design"; Annu. Rep. Med. Chem. 1986, 21,
283-91; (viii) Patani G A, LaVoie E J, "Bioisosterism: A rational
approach in drug design", Chem. Rev. (Washington, D.C.) 1996, 96,
3147-3176; (ix) Soskic V, Joksimovic J, "Bioisosteric approach in
the design of new dopaminergic/serotonergic ligands", Curr. Med.
Chem. 1998, 5, 493-512 (x) Thornber C W, "Isosterism and molecular
modification in drug design", Chem. Soc. Rev. 1979, 8, 563-80.
[0096] In further aspects, bioisosteres are atoms, ions, or
molecules in which the peripheral layers of electrons can be
considered substantially identical. The term bioisostere is usually
used to mean a portion of an overall molecule, as opposed to the
entire molecule itself. Bioisosteric replacement involves using one
bioisostere to replace another with the expectation of maintaining
or slightly modifying the biological activity of the first
bioisostere. The bioisosteres in this case are thus atoms or groups
of atoms having similar size, shape and electron density. Preferred
bioisosteres of esters, amides or carboxylic acids are compounds
containing two sites for hydrogen bond acceptance. In one
embodiment, the ester, amide or carboxylic acid bioisostere is a
5-membered monocyclic heteroaryl ring, such as an optionally
substituted 1H-imidazolyl, an optionally substituted oxazolyl,
1H-tetrazolyl, [1,2,4]triazolyl, or an optionally substituted
[1,2,4]oxadiazolyl.
[0097] In various aspects, it is contemplated herein that the
disclosed compounds further comprise their isotopically-labelled or
isotopically-substituted variants, i.e., compounds identical to
those described, but for the fact that one or more atoms are
replaced by an atom having an atomic mass or mass number different
from the atomic mass or mass number typically found in nature.
Examples of isotopes that can be incorporated into compounds of the
invention include isotopes of hydrogen, carbon, nitrogen, oxygen,
phosphorous, fluorine and chlorine, such as .sup.2H, .sup.3H,
.sup.13C, .sup.14C, .sup.15N, .sup.18O, .sup.17O, .sup.35S,
.sup.18F and .sup.36Cl, respectively. Compounds further comprise
prodrugs thereof, and pharmaceutically acceptable salts of said
compounds or of said prodrugs which contain the aforementioned
isotopes and/or other isotopes of other atoms are within the scope
of this invention. Certain isotopically-labelled compounds of the
present invention, for example those into which radioactive
isotopes such as .sup.3H and .sup.14C are incorporated, are useful
in drug and/or substrate tissue distribution assays. Tritiated,
i.e., .sup.3H, and carbon-14, i.e., .sup.14C, isotopes are
particularly preferred for their ease of preparation and
detectability. Further, substitution with heavier isotopes such as
deuterium, i.e., .sup.2H, can afford certain therapeutic advantages
resulting from greater metabolic stability, for example increased
in vivo half-life or reduced dosage requirements and, hence, may be
preferred in some circumstances. Isotopically labelled compounds of
the present invention and prodrugs thereof can generally be
prepared by carrying out the procedures below, by substituting a
readily available isotopically labelled reagent for a
non-isotopically labelled reagent.
[0098] In various aspects, the disclosed compounds can possess at
least one center of asymmetry, they can be present in the form of
their racemates, in the form of the pure enantiomers and/or
diastereomers or in the form of mixtures of these enantiomers
and/or diastereomers. The stereoisomers can be present in the
mixtures in any arbitrary proportions. In some aspects, provided
this is possible, the disclosed compounds can be present in the
form of the tautomers.
[0099] Thus, methods which are known per se can be used, for
example, to separate the disclosed compounds which possess one or
more chiral centers and occur as racemates into their optical
isomers, i.e., enantiomers or diastereomers. The separation can be
effected by means of column separation on chiral phases or by means
of recrystallization from an optically active solvent or using an
optically active acid or base or by means of derivatizing with an
optically active reagent, such as an optically active alcohol, and
subsequently cleaving off the residue.
[0100] In various aspects, the disclosed compounds can be in the
form of a co-crystal. The term "co-crystal" means a physical
association of two or more molecules which owe their stability
through non-covalent interaction. One or more components of this
molecular complex provide a stable framework in the crystalline
lattice. In certain instances, the guest molecules are incorporated
in the crystalline lattice as anhydrates or solvates, see e.g.
"Crystal Engineering of the Composition of Pharmaceutical Phases.
Do Pharmaceutical Co-crystals Represent a New Path to Improved
Medicines?" Almarasson, O., et. al., The Royal Society of
Chemistry, 1889-1896, 2004. Preferred co-crystals include
p-toluenesulfonic acid and benzenesulfonic acid.
[0101] The term "pharmaceutically acceptable co-crystal" means one
that is compatible with the other ingredients of the formulation
and not deleterious to the recipient thereof.
[0102] In a further aspect, the disclosed compounds can be isolated
as solvates and, in particular, as hydrates of a disclosed
compound, which can be obtained, for example, by crystallization
from a solvent or from aqueous solution. In this connection, one,
two, three or any arbitrary number of solvate or water molecules
can combine with the compounds according to the invention to form
solvates and hydrates.
[0103] The disclosed compounds can be used in the form of salts
derived from inorganic or organic acids. Pharmaceutically
acceptable salts include salts of acidic or basic groups present in
the disclosed compounds. Suitable pharmaceutically acceptable salts
include base addition salts, including alkali metal salts, e.g.,
sodium or potassium salts; alkaline earth metal salts, e.g.,
calcium or magnesium salts; and salts formed with suitable organic
ligands, e.g., quaternary ammonium salts, which may be similarly
prepared by reacting the drug compound with a suitable
pharmaceutically acceptable base. The salts can be prepared in situ
during the final isolation and purification of the compounds of the
present disclosure; or following final isolation by reacting a free
base function, such as a secondary or tertiary amine, of a
disclosed compound with a suitable inorganic or organic acid; or
reacting a free acid function, such as a carboxylic acid, of a
disclosed compound with a suitable inorganic or organic base.
[0104] Acidic addition salts can be prepared in situ during the
final isolation and purification of a disclosed compound, or
separately by reacting moieties comprising one or more nitrogen
groups with a suitable acid. In various aspects, acids which may be
employed to form pharmaceutically acceptable acid addition salts
include such inorganic acids as hydrochloric acid, sulphuric acid
and phosphoric acid and such organic acids as oxalic acid, maleic
acid, succinic acid and citric acid. In a further aspect, salts
further include, but are not limited, to the following:
hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate,
bisulfate, phosphate, acid phosphate, isonicotinate, acetate,
lactate, salicylate, citrate, tartrate, pantothenate, bitartrate,
ascorbate, succinate, maleate, gentisinate, fumarate, gluconate,
glucaronate, saccharate, formate, benzoate, glutamate,
methanesulfonate, ethanesulfonate, benzensulfonate,
p-toluenesulfonate, butyrate, camphorate, camphorsulfonate,
digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate,
fumarate, hydrochloride, 2-hydroxyethanesulfonate (isethionate),
nicotinate, 2-naphthalenesulfonate, oxalate, pectinate, persulfate,
3-phenylpropionate, picrate, pivalate, propionate, succinate,
tartrate, thiocyanate, phosphate, glutamate, bicarbonate,
undecanoate, and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Also, basic
nitrogen-containing groups can be quatemized with such agents as
lower alkyl halides, such as methyl, ethyl, propyl, and butyl
chloride, bromides, and iodides; dialkyl sulfates like dimethyl,
diethyl, dibutyl, and diamyl sulfates, long chain halides such as
decyl, lauryl, myristyl and stearyl chlorides, bromides and
iodides, aralkyl halides like benzyl and phenethyl bromides, and
others.
[0105] Basic addition salts can be prepared in situ during the
final isolation and purification of a disclosed compound, or
separately by reacting carboxylic acid moieties with a suitable
base such as the hydroxide, carbonate or bicarbonate of a
pharmaceutical acceptable metal cation or with ammonia, or an
organic primary, secondary or tertiary amine. Pharmaceutical
acceptable salts include, but are not limited to, cations based on
the alkali and alkaline earth metals, such as sodium, lithium,
potassium, calcium, magnesium, aluminum salts and the like, as well
as nontoxic ammonium, quaternary ammonium, and amine cations,
including, but not limited to ammonium, tetramethylammonium,
tetraethylammonium, methylamine, dimethylamine, trimethylamine,
triethylamine, ethylamine, and the like. Other representative
organic amines useful for the formation of base addition salts
include diethylamine, ethylenediamine, ethanolamine,
diethanolamine, piperazine and the like. In further aspects, bases
which may be used in the preparation of pharmaceutically acceptable
salts include the following: ammonia, L-arginine, benethamine,
benzathine, calcium hydroxide, choline, deanol, diethanolamine,
diethylamine, 2-(diethylamino)-ethanol, ethanolamine,
ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole,
L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine,
piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine,
secondary amine, sodium hydroxide, triethanolamine, tromethamine
and zinc hydroxide.
C. Pharmaceutical Compositions
[0106] In various aspects, the present disclosure relates to
pharmaceutical compositions comprising a therapeutically effective
amount of a disclosed compound, or a pharmaceutically acceptable
salt thereof, and a pharmaceutically acceptable carrier. In a
further aspect, the present disclosure relates to pharmaceutical
compositions comprising a therapeutically effective amount of at
least one disclosed compound or at least one disclosed product of a
method of making a compound, as well as pharmaceutically acceptable
salt, hydrate, solvate, or polymorph forms of the disclosed
compound or the disclosed product of a method of making
compound.
[0107] As used herein, "pharmaceutically-acceptable carriers" means
one or more of a pharmaceutically acceptable diluents,
preservatives, antioxidants, solubilizers, emulsifiers, coloring
agents, releasing agents, coating agents, sweetening, flavoring and
perfuming agents, and adjuvants. The disclosed pharmaceutical
compositions can be conveniently presented in unit dosage form and
prepared by any of the methods well known in the art of pharmacy
and pharmaceutical sciences.
[0108] In a further aspect, the disclosed pharmaceutical
compositions comprise a therapeutically effective amount of at
least one disclosed compound, at least one product of a disclosed
method, or a pharmaceutically acceptable salt thereof as an active
ingredient, a pharmaceutically acceptable carrier, optionally one
or more other therapeutic agent, and optionally one or more
adjuvant. The disclosed pharmaceutical compositions include those
suitable for oral, rectal, topical, pulmonary, nasal, and
parenteral administration, although the most suitable route in any
given case will depend on the particular host, and nature and
severity of the conditions for which the active ingredient is being
administered. In a further aspect, the disclosed pharmaceutical
composition can be formulated to allow administration orally,
nasally, via inhalation, parenterally, paracancerally,
transmucosally, transdermally, intramuscularly, intravenously,
intradermally, subcutaneously, intraperitonealy,
intraventricularly, intracranially and intratumorally.
[0109] As used herein, "parenteral administration" includes
administration by bolus injection or infusion, as well as
administration by intravenous, intramuscular, intraarterial,
intrathecal, intracapsular, intraorbital, intracardiac,
intradermal, intraperitoneal, transtracheal, subcutaneous,
subcuticular, intraarticular, subcapsular subarachnoid,
intraspinal, epidural and intrasternal injection and infusion.
[0110] In various aspects, the present disclosure also relates to a
pharmaceutical composition comprising a pharmaceutically acceptable
carrier or diluent and, as active ingredient, a therapeutically
effective amount of a disclosed compound, a product of a disclosed
method of making, a pharmaceutically acceptable salt, a hydrate
thereof, a solvate thereof, a polymorph thereof, or a
stereochemically isomeric form thereof. In a further aspect, a
disclosed compound, a product of a disclosed method of making, a
pharmaceutically acceptable salt, a hydrate thereof, a solvate
thereof, a polymorph thereof, or a stereochemically isomeric form
thereof, or any subgroup or combination thereof may be formulated
into various pharmaceutical forms for administration purposes.
[0111] Pharmaceutically acceptable salts can be prepared from
pharmaceutically acceptable non-toxic bases or acids. For
therapeutic use, salts of the disclosed compounds are those wherein
the counter ion is pharmaceutically acceptable. However, salts of
acids and bases which are non-pharmaceutically acceptable may also
find use, for example, in the preparation or purification of a
pharmaceutically acceptable compound. All salts, whether
pharmaceutically acceptable or not, are contemplated by the present
disclosure. Pharmaceutically acceptable acid and base addition
salts are meant to comprise the therapeutically active non-toxic
acid and base addition salt forms which the disclosed compounds are
able to form.
[0112] In various aspects, a disclosed compound comprising an
acidic group or moiety, e.g., a carboxylic acid group, can be used
to prepare a pharmaceutically acceptable salt. For example, such a
disclosed compound may comprise an isolation step comprising
treatment with a suitable inorganic or organic base. In some cases,
it may be desirable in practice to initially isolate a compound
from the reaction mixture as a pharmaceutically unacceptable salt
and then simply convert the latter back to the free acid compound
by treatment with an acidic reagent, and subsequently convert the
free acid to a pharmaceutically acceptable base addition salt.
These base addition salts can be readily prepared using
conventional techniques, e.g., by treating the corresponding acidic
compounds with an aqueous solution containing the desired
pharmacologically acceptable cations and then evaporating the
resulting solution to dryness, preferably under reduced pressure.
Alternatively, they also can be prepared by mixing lower alkanolic
solutions of the acidic compounds and the desired alkali metal
alkoxide together, and then evaporating the resulting solution to
dryness in the same manner as before.
[0113] Bases which can be used to prepare the pharmaceutically
acceptable base-addition salts of the base compounds are those
which can form non-toxic base-addition salts, i.e., salts
containing pharmacologically acceptable cations such as, alkali
metal cations (e.g., lithium, potassium and sodium), alkaline earth
metal cations (e.g., calcium and magnesium), ammonium or other
water-soluble amine addition salts such as
N-methylglucamine-(meglumine), lower alkanolammonium and other such
bases of organic amines. In a further aspect, derived from
pharmaceutically acceptable organic non-toxic bases include
primary, secondary, and tertiary amines, as well as cyclic amines
and substituted amines such as naturally occurring and synthesized
substituted amines. In various aspects, such pharmaceutically
acceptable organic non-toxic bases include, but are not limited to,
ammonia, methylamine, ethylamine, propylamine, isopropylamine, any
of the four butylamine isomers, betaine, caffeine, choline,
dimethylamine, diethylamine, diethanolamine, dipropylamine,
diisopropylamine, di-n-butylamine, N,N'-dibenzylethylenediamine,
pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine,
tripropylamine, tromethamine, 2-diethylaminoethanol,
2-dimethylaminoethanol, ethanolamine, quinuclidine, pyridine,
quinoline and isoquinoline; benzathine, N-methyl-D-glucamine,
ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,
glucosamine, methylglucamine, morpholine, piperazine, piperidine,
polyamine resins, procaine, purines, theobromine, hydrabamine
salts, and salts with amino acids such as, for example, histidine,
arginine, lysine and the like. The foregoing salt forms can be
converted by treatment with acid back into the free acid form.
[0114] In various aspects, a disclosed compound comprising a
protonatable group or moiety, e.g., an amino group, can be used to
prepare a pharmaceutically acceptable salt. For example, such a
disclosed compound may comprise an isolation step comprising
treatment with a suitable inorganic or organic acid. In some cases,
it may be desirable in practice to initially isolate a compound
from the reaction mixture as a pharmaceutically unacceptable salt
and then simply convert the latter back to the free base compound
by treatment with a basic reagent, and subsequently convert the
free base to a pharmaceutically acceptable acid addition salt.
These acid addition salts can be readily prepared using
conventional techniques, e.g., by treating the corresponding basic
compounds with an aqueous solution containing the desired
pharmacologically acceptable anions and then evaporating the
resulting solution to dryness, preferably under reduced pressure.
Alternatively, they also can be prepared by treating the free base
form of the disclosed compound with a suitable pharmaceutically
acceptable non-toxic inorganic or organic acid.
[0115] Acids which can be used to prepare the pharmaceutically
acceptable acid-addition salts of the base compounds are those
which can form non-toxic acid-addition salts, i.e., salts
containing pharmacologically acceptable anions formed from their
corresponding inorganic and organic acids. Exemplary, but
non-limiting, inorganic acids include hydrochloric hydrobromic,
sulfuric, nitric, phosphoric and the like. Exemplary, but
non-limiting, organic acids include acetic, benzenesulfonic,
benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric,
gluconic, glutamic, isethionic, lactic, maleic, malic,
mandelicmethanesulfonic, mucic, pamoic, pantothenic, succinic,
tartaric, p-toluenesulfonic acid and the like. In a further aspect,
the acid-addition salt comprises an anion formed from hydrobromic,
hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
[0116] In practice, the compounds of the present disclosure, or
pharmaceutically acceptable salts thereof, of the present
disclosure can be combined as the active ingredient in intimate
admixture with a pharmaceutical carrier according to conventional
pharmaceutical compounding techniques. The carrier can take a wide
variety of forms depending on the form of preparation desired for
administration, e.g., oral or parenteral (including intravenous).
Thus, the pharmaceutical compositions of the present disclosure can
be presented as discrete units suitable for oral administration
such as capsules, cachets or tablets each containing a
predetermined amount of the active ingredient. Further, the
compositions can be presented as a powder, as granules, as a
solution, as a suspension in an aqueous liquid, as a non-aqueous
liquid, as an oil-in-water emulsion or as a water-in-oil liquid
emulsion. In addition to the common dosage forms set out above, the
compounds of the present disclosure, and/or pharmaceutically
acceptable salt(s) thereof, can also be administered by controlled
release means and/or delivery devices. The compositions can be
prepared by any of the methods of pharmacy. In general, such
methods include a step of bringing into association the active
ingredient with the carrier that constitutes one or more necessary
ingredients. In general, the compositions are prepared by uniformly
and intimately admixing the active ingredient with liquid carriers
or finely divided solid carriers or both. The product can then be
conveniently shaped into the desired presentation.
[0117] It is especially advantageous to formulate the
aforementioned pharmaceutical compositions in unit dosage form for
ease of administration and uniformity of dosage. The term "unit
dosage form," as used herein, refers to physically discrete units
suitable as unitary dosages, each unit containing a predetermined
quantity of active ingredient calculated to produce the desired
therapeutic effect in association with the required pharmaceutical
carrier. That is, a "unit dosage form" is taken to mean a single
dose wherein all active and inactive ingredients are combined in a
suitable system, such that the patient or person administering the
drug to the patient can open a single container or package with the
entire dose contained therein, and does not have to mix any
components together from two or more containers or packages.
Typical examples of unit dosage forms are tablets (including scored
or coated tablets), capsules or pills for oral administration;
single dose vials for injectable solutions or suspension;
suppositories for rectal administration; powder packets; wafers;
and segregated multiples thereof. This list of unit dosage forms is
not intended to be limiting in any way, but merely to represent
typical examples of unit dosage forms.
[0118] The pharmaceutical compositions disclosed herein comprise a
compound of the present disclosure (or pharmaceutically acceptable
salts thereof) as an active ingredient, a pharmaceutically
acceptable carrier, and optionally one or more additional
therapeutic agents. In various aspects, the disclosed
pharmaceutical compositions can include a pharmaceutically
acceptable carrier and a disclosed compound, or a pharmaceutically
acceptable salt thereof. In a further aspect, a disclosed compound,
or pharmaceutically acceptable salt thereof, can also be included
in a pharmaceutical composition in combination with one or more
other therapeutically active compounds. The instant compositions
include compositions suitable for oral, rectal, topical, and
parenteral (including subcutaneous, intramuscular, and intravenous)
administration, although the most suitable route in any given case
will depend on the particular host, and nature and severity of the
conditions for which the active ingredient is being administered.
The pharmaceutical compositions can be conveniently presented in
unit dosage form and prepared by any of the methods well known in
the art of pharmacy.
[0119] Techniques and compositions for making dosage forms useful
for materials and methods described herein are described, for
example, in the following references: Modern Pharmaceutics,
Chapters 9 and 10 (Banker & Rhodes, Editors, 1979);
Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981);
Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition
(1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack
Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical
Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in
Pharmaceutical Sciences Vol 7. (David Ganderton, Trevor Jones,
James McGinity, Eds., 1995); Aqueous Polymeric Coatings for
Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences,
Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate
Carriers: Therapeutic Applications: Drugs and the Pharmaceutical
Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the
Gastrointestinal Tract (Ellis Horwood Books in the Biological
Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S.
Davis, Clive G. Wilson, Eds.); Modern Pharmaceutics Drugs and the
Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T.
Rhodes, Eds.).
[0120] The compounds described herein are typically to be
administered in admixture with suitable pharmaceutical diluents,
excipients, extenders, or carriers (termed herein as a
pharmaceutically acceptable carrier, or a carrier) suitably
selected with respect to the intended form of administration and as
consistent with conventional pharmaceutical practices. The
deliverable compound will be in a form suitable for oral, rectal,
topical, intravenous injection or parenteral administration.
Carriers include solids or liquids, and the type of carrier is
chosen based on the type of administration being used. The
compounds may be administered as a dosage that has a known quantity
of the compound.
[0121] Because of the ease in administration, oral administration
can be a preferred dosage form, and tablets and capsules represent
the most advantageous oral dosage unit forms in which case solid
pharmaceutical carriers are obviously employed. However, other
dosage forms may be suitable depending upon clinical population
(e.g., age and severity of clinical condition), solubility
properties of the specific disclosed compound used, and the like.
Accordingly, the disclosed compounds can be used in oral dosage
forms such as pills, powders, granules, elixirs, tinctures,
suspensions, syrups, and emulsions. In preparing the compositions
for oral dosage form, any convenient pharmaceutical media can be
employed. For example, water, glycols, oils, alcohols, flavoring
agents, preservatives, coloring agents and the like can be used to
form oral liquid preparations such as suspensions, elixirs and
solutions; while carriers such as starches, sugars,
microcrystalline cellulose, diluents, granulating agents,
lubricants, binders, disintegrating agents, and the like can be
used to form oral solid preparations such as powders, capsules and
tablets. Because of their ease of administration, tablets and
capsules are the preferred oral dosage units whereby solid
pharmaceutical carriers are employed. Optionally, tablets can be
coated by standard aqueous or nonaqueous techniques.
[0122] The disclosed pharmaceutical compositions in an oral dosage
form can comprise one or more pharmaceutical excipient and/or
additive. Non-limiting examples of suitable excipients and
additives include gelatin, natural sugars such as raw sugar or
lactose, lecithin, pectin, starches (for example corn starch or
amylose), dextran, polyvinyl pyrrolidone, polyvinyl acetate, gum
arabic, alginic acid, tylose, talcum, lycopodium, silica gel (for
example colloidal), cellulose, cellulose derivatives (for example
cellulose ethers in which the cellulose hydroxy groups are
partially etherified with lower saturated aliphatic alcohols and/or
lower saturated, aliphatic oxyalcohols, for example methyl
oxypropyl cellulose, methyl cellulose, hydroxypropyl methyl
cellulose, hydroxypropyl methyl cellulose phthalate), fatty acids
as well as magnesium, calcium or aluminum salts of fatty acids with
12 to 22 carbon atoms, in particular saturated (for example
stearates), emulsifiers, oils and fats, in particular vegetable
(for example, peanut oil, castor oil, olive oil, sesame oil,
cottonseed oil, corn oil, wheat germ oil, sunflower seed oil, cod
liver oil, in each case also optionally hydrated); glycerol esters
and polyglycerol esters of saturated fatty acids
C.sub.12H.sub.24O.sub.2 to C.sub.18H.sub.36O.sub.2 and their
mixtures, it being possible for the glycerol hydroxy groups to be
totally or also only partly esterified (for example mono-, di- and
triglycerides); pharmaceutically acceptable mono- or multivalent
alcohols and polyglycols such as polyethylene glycol and
derivatives thereof, esters of aliphatic saturated or unsaturated
fatty acids (2 to 22 carbon atoms, in particular 10-18 carbon
atoms) with monovalent aliphatic alcohols (1 to 20 carbon atoms) or
multivalent alcohols such as glycols, glycerol, diethylene glycol,
pentacrythritol, sorbitol, mannitol and the like, which may
optionally also be etherified, esters of citric acid with primary
alcohols, acetic acid, urea, benzyl benzoate, dioxolanes,
glyceroformals, tetrahydrofurfuryl alcohol, polyglycol ethers with
C1-C12-alcohols, dimethylacetamide, lactamides, lactates,
ethylcarbonates, silicones (in particular medium-viscous
polydimethyl siloxanes), calcium carbonate, sodium carbonate,
calcium phosphate, sodium phosphate, magnesium carbonate and the
like.
[0123] Other auxiliary substances useful in preparing an oral
dosage form are those which cause disintegration (so-called
disintegrants), such as: cross-linked polyvinyl pyrrolidone, sodium
carboxymethyl starch, sodium carboxymethyl cellulose or
microcrystalline cellulose. Conventional coating substances may
also be used to produce the oral dosage form. Those that may for
example be considered are: polymerizates as well as copolymerizates
of acrylic acid and/or methacrylic acid and/or their esters;
copolymerizates of acrylic and methacrylic acid esters with a lower
ammonium group content (for example EudragitR RS), copolymerizates
of acrylic and methacrylic acid esters and trimethyl ammonium
methacrylate (for example EudragitR RL); polyvinyl acetate; fats,
oils, waxes, fatty alcohols; hydroxypropyl methyl cellulose
phthalate or acetate succinate; cellulose acetate phthalate, starch
acetate phthalate as well as polyvinyl acetate phthalate, carboxy
methyl cellulose; methyl cellulose phthalate, methyl cellulose
succinate, -phthalate succinate as well as methyl cellulose
phthalic acid half ester; zein; ethyl cellulose as well as ethyl
cellulose succinate; shellac, gluten; ethylcarboxyethyl cellulose;
ethacrylate-maleic acid anhydride copolymer; maleic acid
anhydride-vinyl methyl ether copolymer; styrol-maleic acid
copolymerizate; 2-ethyl-hexyl-acrylate maleic acid anhydride;
crotonic acid-vinyl acetate copolymer; glutaminic acid/glutamic
acid ester copolymer; carboxymethylethylcellulose glycerol
monooctanoate; cellulose acetate succinate; polyarginine.
[0124] Plasticizing agents that may be considered as coating
substances in the disclosed oral dosage forms are: citric and
tartaric acid esters (acetyl-triethyl citrate, acetyl tributyl-,
tributyl-, triethyl-citrate); glycerol and glycerol esters
(glycerol diacetate, -triacetate, acetylated monoglycerides, castor
oil); phthalic acid esters (dibutyl-, diamyl-, diethyl-, dimethyl-,
dipropyl-phthalate), di-(2-methoxy- or 2-ethoxyethyl)-phthalate,
ethylphthalyl glycolate, butylphthalylethyl glycolate and
butylglycolate; alcohols (propylene glycol, polyethylene glycol of
various chain lengths), adipates (diethyladipate, di-(2-methoxy- or
2-ethoxyethyl)-adipate; benzophenone; diethyl- and diburylsebacate,
dibutylsuccinate, dibutyltartrate; diethylene glycol dipropionate;
ethyleneglycol diacetate, -dibutyrate, -dipropionate; tributyl
phosphate, tributyrin; polyethylene glycol sorbitan monooleate
(polysorbates such as Polysorbar 50); sorbitan monooleate.
[0125] Moreover, suitable binders, lubricants, disintegrating
agents, coloring agents, flavoring agents, flow-inducing agents,
and melting agents may be included as carriers. The pharmaceutical
carrier employed can be, for example, a solid, liquid, or gas.
Examples of solid carriers include, but are not limited to,
lactose, terra alba, sucrose, glucose, methylcellulose, dicalcium
phosphate, calcium sulfate, mannitol, sorbitol talc, starch,
gelatin, agar, pectin, acacia, magnesium stearate, and stearic
acid. Examples of liquid carriers are sugar syrup, peanut oil,
olive oil, and water. Examples of gaseous carriers include carbon
dioxide and nitrogen.
[0126] In various aspects, a binder can include, for example,
starch, gelatin, natural sugars such as glucose or beta-lactose,
corn sweeteners, natural and synthetic gums such as acacia,
tragacanth, or sodium alginate, carboxymethylcellulose,
polyethylene glycol, waxes, and the like. Lubricants used in these
dosage forms include sodium oleate, sodium stearate, magnesium
stearate, sodium benzoate, sodium acetate, sodium chloride, and the
like. In a further aspect, a disintegrator can include, for
example, starch, methyl cellulose, agar, bentonite, xanthan gum,
and the like.
[0127] In various aspects, an oral dosage form, such as a solid
dosage form, can comprise a disclosed compound that is attached to
polymers as targetable drug carriers or as a prodrug. Suitable
biodegradable polymers useful in achieving controlled release of a
drug include, for example, polylactic acid, polyglycolic acid,
copolymers of polylactic and polyglycolic acid, caprolactones,
polyhydroxy butyric acid, polyorthoesters, polyacetals,
polydihydropyrans, polycyanoacylates, and hydrogels, preferably
covalently crosslinked hydrogels.
[0128] Tablets may contain the active ingredient in admixture with
non-toxic pharmaceutically acceptable excipients which are suitable
for the manufacture of tablets. These excipients may be, for
example, inert diluents, such as calcium carbonate, sodium
carbonate, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example, corn starch, or
alginic acid; binding agents, for example starch, gelatin or
acacia, and lubricating agents, for example magnesium stearate,
stearic acid or talc. The tablets may be uncoated or they may be
coated by known techniques to delay disintegration and absorption
in the gastrointestinal tract and thereby provide a sustained
action over a longer period.
[0129] A tablet containing a disclosed compound can be prepared by
compression or molding, optionally with one or more accessory
ingredients or adjuvants. Compressed tablets can be prepared by
compressing, in a suitable machine, the active ingredient in a
free-flowing form such as powder or granules, optionally mixed with
a binder, lubricant, inert diluent, surface active or dispersing
agent. Molded tablets can be made by molding in a suitable machine,
a mixture of the powdered compound moistened with an inert liquid
diluent.
[0130] In various aspects, a solid oral dosage form, such as a
tablet, can be coated with an enteric coating to prevent ready
decomposition in the stomach. In various aspects, enteric coating
agents include, but are not limited to,
hydroxypropylmethylcellulose phthalate, methacrylic
acid-methacrylic acid ester copolymer, polyvinyl acetate-phthalate
and cellulose acetate phthalate. Akihiko Hasegawa "Application of
solid dispersions of Nifedipine with enteric coating agent to
prepare a sustained-release dosage form" Chem. Pharm. Bull.
33:1615-1619 (1985). Various enteric coating materials may be
selected on the basis of testing to achieve an enteric coated
dosage form designed ab initio to have a preferable combination of
dissolution time, coating thicknesses and diametral crushing
strength (e.g., see S. C. Porter et al. "The Properties of Enteric
Tablet Coatings Made From Polyvinyl Acetate-phthalate and Cellulose
acetate Phthalate", J. Pharm. Pharmacol. 22:42p (1970)). In a
further aspect, the enteric coating may comprise
hydroxypropyl-methylcellulose phthalate, methacrylic
acid-methacrylic acid ester copolymer, polyvinyl acetate-phthalate
and cellulose acetate phthalate.
[0131] In various aspects, an oral dosage form can be a solid
dispersion with a water soluble or a water insoluble carrier.
Examples of water soluble or water insoluble carrier include, but
are not limited to, polyethylene glycol, polyvinylpyrrolidone,
hydroxypropylmethyl-cellulose, phosphatidylcholine, polyoxyethylene
hydrogenated castor oil, hydroxypropylmethylcellulose phthalate,
carboxymethylethylcellulose, or hydroxypropylmethylcellulose, ethyl
cellulose, or stearic acid.
[0132] In various aspects, an oral dosage form can be in a liquid
dosage form, including those that are ingested, or alternatively,
administered as a mouth wash or gargle. For example, a liquid
dosage form can include aqueous suspensions, which contain the
active materials in admixture with excipients suitable for the
manufacture of aqueous suspensions. In addition, oily suspensions
may be formulated by suspending the active ingredient in a
vegetable oil, for example arachis oil, olive oil, sesame oil or
coconut oil, or in a mineral oil such as liquid paraffin. Oily
suspensions may also contain various excipients. The pharmaceutical
compositions of the present disclosure may also be in the form of
oil-in-water emulsions, which may also contain excipients such as
sweetening and flavoring agents.
[0133] For the preparation of solutions or suspensions it is, for
example, possible to use water, particularly sterile water, or
physiologically acceptable organic solvents, such as alcohols
(ethanol, propanol, isopropanol, 1,2-propylene glycol, polyglycols
and their derivatives, fatty alcohols, partial esters of glycerol),
oils (for example peanut oil, olive oil, sesame oil, almond oil,
sunflower oil, soya bean oil, castor oil, bovine hoof oil),
paraffins, dimethyl sulphoxide, triglycerides and the like.
[0134] In the case of a liquid dosage form such as a drinkable
solutions, the following substances may be used as stabilizers or
solubilizers: lower aliphatic mono- and multivalent alcohols with
2-4 carbon atoms, such as ethanol, n-propanol, glycerol,
polyethylene glycols with molecular weights between 200-600 (for
example 1 to 40% aqueous solution), diethylene glycol monoethyl
ether, 1,2-propylene glycol, organic amides, for example amides of
aliphatic C1-C6-carboxylic acids with ammonia or primary, secondary
or tertiary C1-C4-amines or C1-C4-hydroxy amines such as urea,
urethane, acetamide, N-methyl acetamide, N,N-diethyl acetamide,
N,N-dimethyl acetamide, lower aliphatic amines and diamines with
2-6 carbon atoms, such as ethylene diamine, hydroxyethyl
theophylline, tromethamine (for example as 0.1 to 20% aqueous
solution), aliphatic amino acids.
[0135] In preparing the disclosed liquid dosage form can comprise
solubilizers and emulsifiers such as the following non-limiting
examples can be used: polyvinyl pyrrolidone, sorbitan fatty acid
esters such as sorbitan trioleate, phosphatides such as lecithin,
acacia, tragacanth, polyoxyethylated sorbitan monooleate and other
ethoxylated fatty acid esters of sorbitan, polyoxyethylated fats,
polyoxyethylated oleotriglycerides, linolizated oleotriglycerides,
polyethylene oxide condensation products of fatty alcohols,
alkylphenols or fatty acids or also
1-methyl-3-(2-hydroxyethyl)imidazolidone-(2). In this context,
polyoxyethylated means that the substances in question contain
polyoxyethylene chains, the degree of polymerization of which
generally lies between 2 and 40 and in particular between 10 and
20. Polyoxyethylated substances of this kind may for example be
obtained by reaction of hydroxyl group-containing compounds (for
example mono- or diglycerides or unsaturated compounds such as
those containing oleic acid radicals) with ethylene oxide (for
example 40 Mol ethylene oxide per 1 Mol glyceride). Examples of
oleotriglycerides are olive oil, peanut oil, castor oil, sesame
oil, cottonseed oil, corn oil. See also Dr. H. P. Fiedler "Lexikon
der Hillsstoffe fur Pharmazie, Kostnetik und angrenzende Gebiete"
1971, pages 191-195.
[0136] In various aspects, a liquid dosage form can further
comprise preservatives, stabilizers, buffer substances, flavor
correcting agents, sweeteners, colorants, antioxidants and complex
formers and the like. Complex formers which may be for example be
considered are: chelate formers such as ethylene diamine
retrascetic acid, nitrilotriacetic acid, diethylene triamine
pentacetic acid and their salts.
[0137] It may optionally be necessary to stabilize a liquid dosage
form with physiologically acceptable bases or buffers to a pH range
of approximately 6 to 9. Preference may be given to as neutral or
weakly basic a pH value as possible (up to pH 8).
[0138] In order to enhance the solubility and/or the stability of a
disclosed compound in a disclosed liquid dosage form, a parenteral
injection form, or an intravenous injectable form, it can be
advantageous to employ .alpha.-, .beta.- or .gamma.-cyclodextrins
or their derivatives, in particular hydroxyalkyl substituted
cyclodextrins, e.g. 2-hydroxypropyl-.beta.-cyclodextrin or
sulfobutyl-.beta.-cyclodextrin. Also co-solvents such as alcohols
may improve the solubility and/or the stability of the compounds
according to the present disclosure in pharmaceutical
compositions.
[0139] In various aspects, a disclosed liquid dosage form, a
parenteral injection form, or an intravenous injectable form can
further comprise liposome delivery systems, such as small
unilamellar vesicles, large unilamellar vesicles, and multilamellar
vesicles. Liposomes can be formed from a variety of phospholipids,
such as cholesterol, stearylamine, or phosphatidylcholines.
[0140] Pharmaceutical compositions of the present disclosure
suitable injection, such as parenteral administration, such as
intravenous, intramuscular, or subcutaneous administration.
Pharmaceutical compositions for injection can be prepared as
solutions or suspensions of the active compounds in water. A
suitable surfactant can be included such as, for example,
hydroxypropylcellulose. Dispersions can also be prepared in
glycerol, liquid polyethylene glycols, and mixtures thereof in
oils. Further, a preservative can be included to prevent the
detrimental growth of microorganisms.
[0141] Pharmaceutical compositions of the present disclosure
suitable for parenteral administration can include sterile aqueous
or oleaginous solutions, suspensions, or dispersions. Furthermore,
the compositions can be in the form of sterile powders for the
extemporaneous preparation of such sterile injectable solutions or
dispersions. In some aspects, the final injectable form is sterile
and must be effectively fluid for use in a syringe. The
pharmaceutical compositions should be stable under the conditions
of manufacture and storage; thus, preferably should be preserved
against the contaminating action of microorganisms such as bacteria
and fungi. The carrier can be a solvent or dispersion medium
containing, for example, water, ethanol, polyol (e.g., glycerol,
propylene glycol and liquid polyethylene glycol), vegetable oils,
and suitable mixtures thereof.
[0142] Injectable solutions, for example, can be prepared in which
the carrier comprises saline solution, glucose solution or a
mixture of saline and glucose solution. Injectable suspensions may
also be prepared in which case appropriate liquid carriers,
suspending agents and the like may be employed. In some aspects, a
disclosed parenteral formulation can comprise about 0.01-0.1 M,
e.g. about 0.05 M, phosphate buffer. In a further aspect, a
disclosed parenteral formulation can comprise about 0.9%
saline.
[0143] In various aspects, a disclosed parenteral pharmaceutical
composition can comprise pharmaceutically acceptable carriers such
as aqueous or non-aqueous solutions, suspensions, and emulsions.
Examples of non-aqueous solvents are propylene glycol, polyethylene
glycol, vegetable oils such as olive oil, and injectable organic
esters such as ethyl oleate. Aqueous carriers include but not
limited to water, alcoholic/aqueous solutions, emulsions or
suspensions, including saline and buffered media. Parenteral
vehicles can include mannitol, normal serum albumin, sodium
chloride solution, Ringer's dextrose, dextrose and sodium chloride,
lactated Ringer's and fixed oils. Intravenous vehicles include
fluid and nutrient replenishers, electrolyte replenishers such as
those based on Ringer's dextrose, and the like. Preservatives and
other additives may also be present, such as, for example,
antimicrobials, antioxidants, collating agents, inert gases and the
like. In a further aspect, a disclosed parenteral pharmaceutical
composition can comprise may contain minor amounts of additives
such as substances that enhance isotonicity and chemical stability,
e.g., buffers and preservatives. Also contemplated for injectable
pharmaceutical compositions are solid form preparations that are
intended to be converted, shortly before use, to liquid form
preparations. Furthermore, other adjuvants can be included to
render the formulation isotonic with the blood of the subject or
patient.
[0144] In addition to the pharmaceutical compositions described
herein above, the disclosed compounds can also be formulated as a
depot preparation. Such long acting formulations can be
administered by implantation (e.g., subcutaneously or
intramuscularly) or by intramuscular injection. Thus, for example,
the compounds can be formulated with suitable polymeric or
hydrophobic materials (e.g., as an emulsion in an acceptable oil)
or ion exchange resins, or as sparingly soluble derivatives, e.g.,
as a sparingly soluble salt.
[0145] Pharmaceutical compositions of the present disclosure can be
in a form suitable for topical administration. As used herein, the
phrase "topical application" means administration onto a biological
surface, whereby the biological surface includes, for example, a
skin area (e.g., hands, forearms, elbows, legs, face, nails, anus
and genital areas) or a mucosal membrane. By selecting the
appropriate carrier and optionally other ingredients that can be
included in the composition, as is detailed herein below, the
compositions of the present disclosure may be formulated into any
form typically employed for topical application. A topical
pharmaceutical composition can be in a form of a cream, an
ointment, a paste, a gel, a lotion, milk, a suspension, an aerosol,
a spray, foam, a dusting powder, a pad, and a patch. Further, the
compositions can be in a form suitable for use in transdermal
devices. These formulations can be prepared, utilizing a compound
of the present disclosure, or pharmaceutically acceptable salts
thereof, via conventional processing methods. As an example, a
cream or ointment is prepared by mixing hydrophilic material and
water, together with about 5 wt % to about 10 wt % of the compound,
to produce a cream or ointment having a desired consistency.
[0146] In the compositions suitable for percutaneous
administration, the carrier optionally comprises a penetration
enhancing agent and/or a suitable wetting agent, optionally
combined with suitable additives of any nature in minor
proportions, which additives do not introduce a significant
deleterious effect on the skin. Said additives may facilitate the
administration to the skin and/or may be helpful for preparing the
desired compositions. These compositions may be administered in
various ways, e.g., as a transdermal patch, as a spot-on, as an
ointment.
[0147] Ointments are semisolid preparations, typically based on
petrolatum or petroleum derivatives. The specific ointment base to
be used is one that provides for optimum delivery for the active
agent chosen for a given formulation, and, preferably, provides for
other desired characteristics as well (e.g., emollience). As with
other carriers or vehicles, an ointment base should be inert,
stable, nonirritating and nonsensitizing. As explained in
Remington: The Science and Practice of Pharmacy, 19th Ed., Easton,
Pa.: Mack Publishing Co. (1995), pp. 1399-1404, ointment bases may
be grouped in four classes: oleaginous bases; emulsifiable bases;
emulsion bases; and water-soluble bases. Oleaginous ointment bases
include, for example, vegetable oils, fats obtained from animals,
and semisolid hydrocarbons obtained from petroleum. Emulsifiable
ointment bases, also known as absorbent ointment bases, contain
little or no water and include, for example, hydroxystearin
sulfate, anhydrous lanolin and hydrophilic petrolatum. Emulsion
ointment bases are either water-in-oil (W/O) emulsions or
oil-in-water (O/W) emulsions, and include, for example, cetyl
alcohol, glyceryl monostearate, lanolin and stearic acid. Preferred
water-soluble ointment bases are prepared from polyethylene glycols
of varying molecular weight.
[0148] Lotions are preparations that are to be applied to the skin
surface without friction. Lotions are typically liquid or
semiliquid preparations in which solid particles, including the
active agent, are present in a water or alcohol base. Lotions are
typically preferred for treating large body areas, due to the ease
of applying a more fluid composition. Lotions are typically
suspensions of solids, and oftentimes comprise a liquid oily
emulsion of the oil-in-water type. It is generally necessary that
the insoluble matter in a lotion be finely divided. Lotions
typically contain suspending agents to produce better dispersions
as well as compounds useful for localizing and holding the active
agent in contact with the skin, such as methylcellulose, sodium
carboxymethyl-cellulose, and the like.
[0149] Creams are viscous liquids or semisolid emulsions, either
oil-in-water or water-in-oil. Cream bases are typically
water-washable, and contain an oil phase, an emulsifier and an
aqueous phase. The oil phase, also called the "internal" phase, is
generally comprised of petrolatum and/or a fatty alcohol such as
cetyl or stearyl alcohol. The aqueous phase typically, although not
necessarily, exceeds the oil phase in volume, and generally
contains a humectant. The emulsifier in a cream formulation is
generally a nonionic, anionic, cationic or amphoteric surfactant.
Reference may be made to Remington: The Science and Practice of
Pharmacy, supra, for further information.
[0150] Pastes are semisolid dosage forms in which the bioactive
agent is suspended in a suitable base. Depending on the nature of
the base, pastes are divided between fatty pastes or those made
from a single-phase aqueous gel. The base in a fatty paste is
generally petrolatum, hydrophilic petrolatum and the like. The
pastes made from single-phase aqueous gels generally incorporate
carboxymethylcellulose or the like as a base. Additional reference
may be made to Remington: The Science and Practice of Pharmacy, for
further information.
[0151] Gel formulations are semisolid, suspension-type systems.
Single-phase gels contain organic macromolecules distributed
substantially uniformly throughout the carrier liquid, which is
typically aqueous, but also, preferably, contain an alcohol and,
optionally, an oil. Preferred organic macromolecules, i.e., gelling
agents, are crosslinked acrylic acid polymers such as the family of
carbomer polymers, e.g., carboxypolyalkylenes that may be obtained
commercially under the trademark Carbopol.TM.. Other types of
preferred polymers in this context are hydrophilic polymers such as
polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers
and polyvinylalcohol; modified cellulose, such as hydroxypropyl
cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose,
hydroxypropyl methylcellulose phthalate, and methyl cellulose; gums
such as tragacanth and xanthan gum; sodium alginate; and gelatin.
In order to prepare a uniform gel, dispersing agents such as
alcohol or glycerin can be added, or the gelling agent can be
dispersed by trituration, mechanical mixing or stirring, or
combinations thereof.
[0152] Sprays generally provide the active agent in an aqueous
and/or alcoholic solution which can be misted onto the skin for
delivery. Such sprays include those formulated to provide for
concentration of the active agent solution at the site of
administration following delivery, e.g., the spray solution can be
primarily composed of alcohol or other like volatile liquid in
which the active agent can be dissolved. Upon delivery to the skin,
the carrier evaporates, leaving concentrated active agent at the
site of administration.
[0153] Foam compositions are typically formulated in a single or
multiple phase liquid form and housed in a suitable container,
optionally together with a propellant which facilitates the
expulsion of the composition from the container, thus transforming
it into a foam upon application. Other foam forming techniques
include, for example the "Bag-in-a-can" formulation technique.
Compositions thus formulated typically contain a low-boiling
hydrocarbon, e.g., isopropane. Application and agitation of such a
composition at the body temperature cause the isopropane to
vaporize and generate the foam, in a manner similar to a
pressurized aerosol foaming system. Foams can be water-based or
aqueous alkanolic, but are typically formulated with high alcohol
content which, upon application to the skin of a user, quickly
evaporates, driving the active ingredient through the upper skin
layers to the site of treatment.
[0154] Skin patches typically comprise a backing, to which a
reservoir containing the active agent is attached. The reservoir
can be, for example, a pad in which the active agent or composition
is dispersed or soaked, or a liquid reservoir. Patches typically
further include a frontal water permeable adhesive, which adheres
and secures the device to the treated region. Silicone rubbers with
self-adhesiveness can alternatively be used. In both cases, a
protective permeable layer can be used to protect the adhesive side
of the patch prior to its use. Skin patches may further comprise a
removable cover, which serves for protecting it upon storage.
[0155] Examples of patch configuration which can be utilized with
the present disclosure include a single-layer or multi-layer
drug-in-adhesive systems which are characterized by the inclusion
of the drug directly within the skin-contacting adhesive. In such a
transdermal patch design, the adhesive not only serves to affix the
patch to the skin, but also serves as the formulation foundation,
containing the drug and all the excipients under a single backing
film. In the multi-layer drug-in-adhesive patch a membrane is
disposed between two distinct drug-in-adhesive layers or multiple
drug-in-adhesive layers are incorporated under a single backing
film.
[0156] Examples of pharmaceutically acceptable carriers that are
suitable for pharmaceutical compositions for topical applications
include carrier materials that are well-known for use in the
cosmetic and medical arts as bases for e.g., emulsions, creams,
aqueous solutions, oils, ointments, pastes, gels, lotions, milks,
foams, suspensions, aerosols and the like, depending on the final
form of the composition. Representative examples of suitable
carriers according to the present disclosure therefore include,
without limitation, water, liquid alcohols, liquid glycols, liquid
polyalkylene glycols, liquid esters, liquid amides, liquid protein
hydrolysates, liquid alkylated protein hydrolysates, liquid lanolin
and lanolin derivatives, and like materials commonly employed in
cosmetic and medicinal compositions. Other suitable carriers
according to the present disclosure include, without limitation,
alcohols, such as, for example, monohydric and polyhydric alcohols,
e.g., ethanol, isopropanol, glycerol, sorbitol, 2-methoxyethanol,
diethyleneglycol, ethylene glycol, hexyleneglycol, mannitol, and
propylene glycol; ethers such as diethyl or dipropyl ether;
polyethylene glycols and methoxypolyoxyethylenes (carbowaxes having
molecular weight ranging from 200 to 20,000); polyoxyethylene
glycerols, polyoxyethylene sorbitols, stearoyl diacetin, and the
like.
[0157] Topical compositions of the present disclosure can, if
desired, be presented in a pack or dispenser device, such as an
FDA-approved kit, which may contain one or more unit dosage forms
containing the active ingredient. The dispenser device may, for
example, comprise a tube. The pack or dispenser device may be
accompanied by instructions for administration. The pack or
dispenser device may also be accompanied by a notice in a form
prescribed by a governmental agency regulating the manufacture,
use, or sale of pharmaceuticals, which notice is reflective of
approval by the agency of the form of the compositions for human or
veterinary administration. Such notice, for example, may include
labeling approved by the U.S. Food and Drug Administration for
prescription drugs or of an approved product insert. Compositions
comprising the topical composition of the disclosure formulated in
a pharmaceutically acceptable carrier may also be prepared, placed
in an appropriate container, and labeled for treatment of an
indicated condition.
[0158] Another patch system configuration which can be used by the
present disclosure is a reservoir transdermal system design which
is characterized by the inclusion of a liquid compartment
containing a drug solution or suspension separated from the release
liner by a semi-permeable membrane and adhesive. The adhesive
component of this patch system can either be incorporated as a
continuous layer between the membrane and the release liner or in a
concentric configuration around the membrane. Yet another patch
system configuration which can be utilized by the present
disclosure is a matrix system design which is characterized by the
inclusion of a semisolid matrix containing a drug solution or
suspension which is in direct contact with the release liner. The
component responsible for skin adhesion is incorporated in an
overlay and forms a concentric configuration around the semisolid
matrix.
[0159] Pharmaceutical compositions of the present disclosure can be
in a form suitable for rectal administration wherein the carrier is
a solid. It is preferable that the mixture forms unit dose
suppositories. Suitable carriers include cocoa butter and other
materials commonly used in the art. The suppositories can be
conveniently formed by first admixing the composition with the
softened or melted carrier(s) followed by chilling and shaping in
molds.
[0160] Pharmaceutical compositions containing a compound of the
present disclosure, and/or pharmaceutically acceptable salts
thereof, can also be prepared in powder or liquid concentrate
form.
[0161] The pharmaceutical composition (or formulation) may be
packaged in a variety of ways. Generally, an article for
distribution includes a container that contains the pharmaceutical
composition in an appropriate form. Suitable containers are well
known to those skilled in the art and include materials such as
bottles (plastic and glass), sachets, foil blister packs, and the
like. The container may also include a tamper proof assemblage to
prevent indiscreet access to the contents of the package. In
addition, the container typically has deposited thereon a label
that describes the contents of the container and any appropriate
warnings or instructions.
[0162] The disclosed pharmaceutical compositions may, if desired,
be presented in a pack or dispenser device which may contain one or
more unit dosage forms containing the active ingredient. The pack
may for example comprise metal or plastic foil, such as a blister
pack. The pack or dispenser device may be accompanied by
instructions for administration. The pack or dispenser may also be
accompanied with a notice associated with the container in form
prescribed by a governmental agency regulating the manufacture,
use, or sale of pharmaceuticals, which notice is reflective of
approval by the agency of the form of the drug for human or
veterinary administration. Such notice, for example, may be the
labeling approved by the U.S. Food and Drug Administration for
prescription drugs, or the approved product insert. Pharmaceutical
compositions comprising a disclosed compound formulated in a
compatible pharmaceutical carrier may also be prepared, placed in
an appropriate container, and labeled for treatment of an indicated
condition.
[0163] The exact dosage and frequency of administration depends on
the particular disclosed compound, a product of a disclosed method
of making, a pharmaceutically acceptable salt, solvate, or
polymorph thereof, a hydrate thereof, a solvate thereof, a
polymorph thereof, or a stereochemically isomeric form thereof; the
particular condition being treated and the severity of the
condition being treated; various factors specific to the medical
history of the subject to whom the dosage is administered such as
the age; weight, sex, extent of disorder and general physical
condition of the particular subject, as well as other medication
the individual may be taking; as is well known to those skilled in
the art. Furthermore, it is evident that said effective daily
amount may be lowered or increased depending on the response of the
treated subject and/or depending on the evaluation of the physician
prescribing the compounds of the present disclosure.
[0164] Depending on the mode of administration, the pharmaceutical
composition will comprise from 0.05 to 99% by weight, preferably
from 0.1 to 70% by weight, more preferably from 0.1 to 50% by
weight of the active ingredient, and, from 1 to 99.95% by weight,
preferably from 30 to 99.9% by weight, more preferably from 50 to
99.9% by weight of a pharmaceutically acceptable carrier, all
percentages being based on the total weight of the composition.
[0165] In the treatment conditions which require of inhibiting
protein synthesis in a bacterial cell an appropriate dosage level
will generally be about 0.01 to 1000 mg per kg patient body weight
per day and can be administered in single or multiple doses. In
various aspects, the dosage level will be about 0.1 to about 500
mg/kg per day, about 0.1 to 250 mg/kg per day, or about 0.5 to 100
mg/kg per day. A suitable dosage level can be about 0.01 to 1000
mg/kg per day, about 0.01 to 500 mg/kg per day, about 0.01 to 250
mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50
mg/kg per day. Within this range the dosage can be 0.05 to 0.5, 0.5
to 5.0 or 5.0 to 50 mg/kg per day. For oral administration, the
compositions are preferably provided in the form of tablets
containing 1.0 to 1000 mg of the active ingredient, particularly
1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400,
500, 600, 750, 800, 900 and 1000 mg of the active ingredient for
the symptomatic adjustment of the dosage of the patient to be
treated. The compound can be administered on a regimen of 1 to 4
times per day, preferably once or twice per day. This dosing
regimen can be adjusted to provide the optimal therapeutic
response.
[0166] Such unit doses as described hereinabove and hereinafter can
be administered more than once a day, for example, 2, 3, 4, 5 or 6
times a day. In various aspects, such unit doses can be
administered 1 or 2 times per day, so that the total dosage for a
70 kg adult is in the range of 0.001 to about 15 mg per kg weight
of subject per administration. In a further aspect, dosage is 0.01
to about 1.5 mg per kg weight of subject per administration, and
such therapy can extend for a number of weeks or months, and in
some cases, years. It will be understood, however, that the
specific dose level for any particular patient will depend on a
variety of factors including the activity of the specific compound
employed; the age, body weight, general health, sex and diet of the
individual being treated; the time and route of administration; the
rate of excretion; other drugs that have previously been
administered; and the severity of the particular disease undergoing
therapy, as is well understood by those of skill in the area.
[0167] A typical dosage can be one 1 mg to about 100 mg tablet or 1
mg to about 300 mg taken once a day, or, multiple times per day, or
one time-release capsule or tablet taken once a day and containing
a proportionally higher content of active ingredient. The
time-release effect can be obtained by capsule materials that
dissolve at different pH values, by capsules that release slowly by
osmotic pressure, or by any other known means of controlled
release.
[0168] It can be necessary to use dosages outside these ranges in
some cases as will be apparent to those skilled in the art.
Further, it is noted that the clinician or treating physician will
know how and when to start, interrupt, adjust, or terminate therapy
in conjunction with individual patient response.
[0169] The present disclosure is further directed to a method for
the manufacture of a medicament for inhibiting protein synthesis in
a bacterial cell (e.g., treatment of one or more infectious
diseases associated with a bacterial infection) in mammals (e.g.,
humans) comprising combining one or more disclosed compounds,
products, or compositions with a pharmaceutically acceptable
carrier or diluent. Thus, in one aspect, the present disclosure
further relates to a method for manufacturing a medicament
comprising combining at least one disclosed compound or at least
one disclosed product with a pharmaceutically acceptable carrier or
diluent.
[0170] The disclosed pharmaceutical compositions can further
comprise other therapeutically active compounds, which are usually
applied in the treatment of the above mentioned pathological or
clinical conditions.
[0171] It is understood that the disclosed compositions can be
prepared from the disclosed compounds. It is also understood that
the disclosed compositions can be employed in the disclosed methods
of using.
[0172] As already mentioned, the present disclosure relates to a
pharmaceutical composition comprising a therapeutically effective
amount of a disclosed compound, a product of a disclosed method of
making, a pharmaceutically acceptable salt, a hydrate thereof, a
solvate thereof, a polymorph thereof, and a pharmaceutically
acceptable carrier. Additionally, the present disclosure relates to
a process for preparing such a pharmaceutical composition,
characterized in that a pharmaceutically acceptable carrier is
intimately mixed with a therapeutically effective amount of a
compound according to the present disclosure.
[0173] As already mentioned, the present disclosure also relates to
a pharmaceutical composition comprising a disclosed compound, a
product of a disclosed method of making, a pharmaceutically
acceptable salt, a hydrate thereof, a solvate thereof, a polymorph
thereof, and one or more other drugs in the treatment, prevention,
control, amelioration, or reduction of risk of diseases or
conditions for a disclosed compound or the other drugs may have
utility as well as to the use of such a composition for the
manufacture of a medicament. The present disclosure also relates to
a combination of disclosed compound, a product of a disclosed
method of making, a pharmaceutically acceptable salt, a hydrate
thereof, a solvate thereof, a polymorph thereof, and an
anti-microbial agent. The present disclosure also relates to such a
combination for use as a medicine. The present disclosure also
relates to a product comprising (a) disclosed compound, a product
of a disclosed method of making, a pharmaceutically acceptable
salt, a hydrate thereof, a solvate thereof, a polymorph thereof,
and (b) an additional therapeutic agent that has anti-microbial
activity, as a combined preparation for simultaneous, separate or
sequential use in the treatment or prevention of a condition in a
mammal, including a human, the treatment or prevention of which is
affected or facilitated by the modulatory effect of the disclosed
compound and the additional therapeutic agent. The different drugs
of such a combination or product may be combined in a single
preparation together with pharmaceutically acceptable carriers or
diluents, or they may each be present in a separate preparation
together with pharmaceutically acceptable carriers or diluents.
D. Methods of Treating a Clinical Condition Associated with a
Salmonella enterica Infection
[0174] In various aspects, the present disclosure provides methods
of treating an a Salmonella enterica clinical condition comprising
administration of a therapeutically effective amount of a disclosed
compound, a product of a disclosed method of making a compound, or
a disclosed pharmaceutical composition to a subject in need
thereof. It is understood that reference to a disclosed compound is
inclusive of the disclosed compound, as well as pharmaceutically
acceptable salt, hydrate, solvate, or polymorph forms thereof;
reference to a product of a disclosed method of making a compound
is inclusive of the disclosed product, as well as pharmaceutically
acceptable salt, hydrate, solvate, or polymorph forms thereof; and
reference to a disclosed pharmaceutical composition is inclusive of
a pharmaceutical composition comprising a disclosed compound or a
disclosed product of a method of making a compound, as well as
pharmaceutically acceptable salt, hydrate, solvate, or polymorph
forms of a disclosed compound or a disclosed product of a method of
making compound. It is understood that treating a Salmonella
enterica clinical condition is inclusive of treating, preventing,
ameliorating, controlling or reducing the risk of a Salmonella
enterica clinical condition.
[0175] Also provided is a method for the treatment of one or more
Salmonella enterica clinical conditions in a subject comprising the
step of administering to the subject at least one disclosed
compound; at least one disclosed pharmaceutical composition; and/or
at least one disclosed product in a dosage and amount effective to
treat the disorder in the subject. In some aspects, the subject is
a human subject.
[0176] In a further aspect, the disclosure relates to a method for
the treatment of a Salmonella enterica clinical condition in a
human subject, further comprising the step of identifying a human
subject in need of treatment of the infectious disease.
[0177] In a further aspect, the disclosure relates to a method for
the treatment of a Salmonella enterica clinical condition in a
human subject comprising the step of administering to the human
subject a therapeutically effective amount of at least one
disclosed compound; or a pharmaceutically acceptable salt, hydrate,
solvate, or polymorph thereof; wherein the compound is formulated
as a lotion, a cream, an ointment, a spray, or a soap.
[0178] In a further aspect, the compound is formulated as a solid
dosage form. In a still further aspect, the solid dosage form is
selected from a capsule, a tablet, a pill, a powder, a granule, an
effervescing granule, a gel, a paste, a troche, and a pastille. In
yet a further aspect, the solid dosage form is formulated for oral
administration.
[0179] In a further aspect, the compound is formulated as a liquid
dosage form. In a still further aspect, the liquid dosage form is
selected from an emulsion, a solution, a suspension, a syrup, and
an elixir. In yet a further aspect, the liquid dosage form is
formulated for intravenous administration or parenteral
administration.
[0180] In a further aspect, the disclosure relates to a method for
the treatment of a Salmonella enterica clinical condition in
subject, further comprising administering to the vertebrate animal
a therapeutically effective amount of second active agent. In a
still further aspect, the second active agent is an antibacterial
agent. In yet a further aspect, the antibacterial agent is
pencillin, a cephalosporin, a sulfonamide, a tetracycline, a
lincosamide, an aminoglycoside, or a fluoroquinolone, or
combinations thereof. In an even further aspect, the antibacterial
agent comprises a compound selected from amoxicillin, ampicillin,
azithromycin, aztreonam, azlocillin, bacitracin, carbenicillin,
cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cefdinir,
cefditorin, cefepime, cefixime, cefoperazone, cefotaxime,
cefoxitin, cefpodoxime, cefprozil, ceftazidime, ceftibuten,
ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol, cilastin,
ciprofloxacin, clarithromycin, clavulanic acid, clinafloxacin,
clindamycin, clofazimine, cloxacillin, colistin, cycloserin,
dalbavancin, dalfopristin, demeclocycline, dicloxacillin,
dirithromycin, doxycycline, erythromycin, enrofloxacin, enoxacin,
enviomycin, ertepenem, ethambutol, ethionmide, flucloxacillin,
fosfomycin, furazolidone, gatifloxacin, gentamicin, imipenem,
isoniazid, kanamycin, levofloxacin, linezolid, lomefloxacin,
loracarbef, mafenide, moxifloxacin, meropenem, metronidazole,
mezlocillin, minocycline, mupirocin, nafcillin, nalidixic acid,
neomycin, netilmicin, nitrofurantoin, norfloxacin, ofloxacin,
oritavancin, oxytetracycline, penicillin, piperacillin,
platensimycin, polymixin B, pyrazinamide, quinupristin,
retapamulin, rifabutin, rifampin, rifapentine, roxithromycin,
sparfloxacin, spectinomycin, sulbactam, sulfacetamide,
sulfamethizole, sulfamethoxazole, teicoplanin, telithromycin,
telavancin, temafloxacin, tetracycline, thioacetazone,
thioridazine, ticarcillin, tinidazole, tobramycin, torezolid,
tosufloxacin, trimethoprim, troleandomycin, trovafloxacin, and
vancomycin, or combinations thereof.
[0181] In a further aspect, the second agent comprises a compound
selected from amikacin, amoxicillin-clavulanic acid, bedaquiline,
capreomycin, ciprofloxacin, clarithromycin, clofazimine,
cycloserine, ethambutol, ethionamide, gatifloxacin, imipenem,
isoniazid, kanamycin, levofloxacin, meropenem, moxifloxacin,
ofloxacin, OPC-7683, para-aminosalicylic acid, pretomanid,
pyrazinamide, rifampin, rifapentine, rifabutin, SQ109,
streptomycin, sudoterb, terizidone, thiacetazone, viomycin, and
combinations thereof. In a yet further aspect, the
anti-tuberculosis agent is an aminoglycoside antibiotic, such as
kanamycin A, amikacin, tobramycin, dibekacin, gentamicin,
sisomicin, netilmicin, neomycin B, neomycin C, paromomycin and
streptomycin. In an even further aspect, the anti-tuberculosis
agent is a fluroquinolone, such as moxifloxacin, levofloxacin,
sparfloxacin, nalidixic acid, ciprofloxacin, cinoxacin, oxolinic
acid, piromidic acid, pipemidic acid, rosoxacin, enoxacin,
fleroxacin, lomefloxacin, nadifloxacin, norfloxacin, ofloxacin,
perfloxacin, rufloxacin, balofloxacin, grepafloxacin, pazufloxacin,
temafloxacin, tosufloxacin, clinafloxacin, gatlifloxacin,
sitafloxacin, prulifloxacin, delafloxacin, JNJ-Q2, nemofloxacin,
danofloxacin, difloxacin, enrofloxacin, ibafloxacin, marbofloxacin,
orbifloxacin, sarafloxacin and trovafloxacin. In a still further
aspect, the anti-tuberculosis agent is a nitroimidazole antibiotic,
such as metronidazole, tinidazole, nimorazole, or combinations
thereof.
[0182] In a further aspect, the second agent comprises a compound
selected from
[0183] The compounds are further useful in a method for the
prevention, treatment, control, amelioration, or reduction of risk
of the Salmonella enterica clinical conditions noted herein. The
compounds are further useful in a method for the prevention,
treatment, control, amelioration, or reduction of risk of the
aforementioned Salmonella enterica clinical conditions in
combination with other agents.
[0184] In one aspect, the disclosed compounds can be used in
combination with one or more other drugs in the treatment,
prevention, control, amelioration, or reduction of risk of
Salmonella enterica clinical conditions for which disclosed
compounds or the other drugs can have utility, where the
combination of the drugs together are safer or more effective than
either drug alone. Such other drug(s) can be administered, by a
route and in an amount commonly used therefor, contemporaneously or
sequentially with a compound of the present disclosure. When a
compound of the present disclosure is used contemporaneously with
one or more other drugs, a pharmaceutical composition in unit
dosage form containing such other drugs and a disclosed compound is
preferred. However, the combination therapy can also include
therapies in which a disclosed compound and one or more other drugs
are administered on different overlapping schedules. It is also
contemplated that when used in combination with one or more other
active ingredients, the disclosed compounds and the other active
ingredients can be used in lower doses than when each is used
singly.
[0185] Accordingly, the pharmaceutical compositions include those
that contain one or more other active ingredients, in addition to a
compound of the present disclosure.
[0186] The above combinations include combinations of a disclosed
compound not only with one other active compound, but also with two
or more other active compounds. Likewise, disclosed compounds can
be used in combination with other drugs that are used in the
prevention, treatment, control, amelioration, or reduction of risk
of the Salmonella enterica clinical conditions for which disclosed
compounds are useful. Such other drugs can be administered, by a
route and in an amount commonly used therefor, contemporaneously or
sequentially with a compound of the present disclosure. When a
compound of the present disclosure is used contemporaneously with
one or more other drugs, a pharmaceutical composition containing
such other drugs in addition to a disclosed compound is preferred.
Accordingly, the pharmaceutical compositions include those that
also contain one or more other active ingredients, in addition to a
compound of the present disclosure.
[0187] The weight ratio of a disclosed compound to the second
active ingredient can be varied and will depend upon the effective
dose of each ingredient. Generally, an effective dose of each will
be used. Thus, for example, when a compound of the present
disclosure is combined with another agent, the weight ratio of a
disclosed compound to the other agent will generally range from
about 1000:1 to about 1:1000, preferably about 200:1 to about
1:200. Combinations of a compound of the present disclosure and
other active ingredients will generally also be within the
aforementioned range, but in each case, an effective dose of each
active ingredient should be used.
[0188] In such combinations a disclosed compound and other active
agents can be administered separately or in conjunction. In
addition, the administration of one element can be prior to,
concurrent to, or subsequent to the administration of other
agent(s).
[0189] Accordingly, the subject compounds can be used alone or in
combination with other agents which are known to be beneficial in
the subject indications or other drugs that affect receptors or
enzymes that either increase the efficacy, safety, convenience, or
reduce unwanted side effects or toxicity of the disclosed
compounds. The subject compound and the other agent can be
coadministered, either in concomitant therapy or in a fixed
combination.
[0190] In one aspect, the compound can be employed in combination
with antibacterial or antimicrobial agents, and combinations
thereof, and the like, or the subject compound can be administered
in conjunction with the use of physical methods such as with
debridement of a wound or infected tissue.
[0191] In the treatment of a Salmonella enterica clinical
condition, an appropriate dosage level will generally be about 0.01
to 500 mg per kg patient body weight per day which can be
administered in single or multiple doses. Preferably, the dosage
level will be about 0.1 to about 250 mg/kg per day; more preferably
about 0.5 to about 100 mg/kg per day. A suitable dosage level can
be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per
day, or about 0.1 to 50 mg/kg per day. Within this range the dosage
can be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral
administration, the compositions are preferably provided in the
form of tablets containing 1.0 to 1000 milligrams of the active
ingredient, particularly 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100,
150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000
milligrams of the active ingredient for the symptomatic adjustment
of the dosage to the patient to be treated. The compounds can be
administered on a regimen of 1 to 4 times per day, preferably once
or twice per day. This dosage regimen can be adjusted to provide
the optimal therapeutic response. It will be understood, however,
that the specific dose level and frequency of dosage for any
particular patient can be varied and will depend upon a variety of
factors including the activity of the specific compound employed,
the metabolic stability and length of action of that compound, the
age, body weight, general health, sex, diet, mode and time of
administration, rate of excretion, drug combination, the severity
of the particular condition, and the host undergoing therapy.
[0192] In a further aspect, the present disclosure provides methods
of treating a Salmonella enterica clinical condition in a subject
comprising administering a disclosed compound or a disclosed
pharmaceutical composition, and further comprising administering to
the subject a therapeutically effective amount of an
immunomodulatory agent. In a still further aspect, the
immunomodulatory agent is a cytokine, an interleukin, a chemokine,
or combinations thereof. In a yet further aspect, the
immunomodulatory agent is selected from IL-2, IL-7 and IL-12,
IFN-.alpha., IFN-.beta., IFN-.epsilon., IFN-.kappa., IFN-.omega.,
IFN-.gamma., IFN-.gamma. 1b, CCL3, CCL26, CXCL7, and combinations
thereof.
[0193] In a further aspect, the administering is co-administering
of the disclosed compound and the antibacterial agent. In a still
further aspect, the co-administration is administration in a
substantially simultaneous manner of the disclosed compound and the
antibacterial agent. In yet a further aspect, the co-administration
is administration in a substantially sequential manner of the
disclosed compound and the antibacterial agent.
[0194] In a further aspect, the administration in a substantially
simultaneous manner comprises a single dose form containing a fixed
ratio of the compound and the antibacterial agent. In a still
further aspect, the single dose form is a capsule or a tablet. In
yet a further aspect, the single dose form is an ampule for a
single intravenous administration.
E. Kits
[0195] In a further aspect, the present disclosure relates to kits
comprising at least one disclosed compound, or a pharmaceutically
acceptable salt, hydrate, solvate, or polymorph thereof; a
disclosed pharmaceutical composition; and one or more of: (a) at
least one agent known to treat an infectious disease; (b)
instructions for treating an infectious disease; or (c)
instructions for treating a biofilm.
[0196] The disclosed compounds and/or pharmaceutical compositions
comprising the disclosed compounds can conveniently be presented as
a kit, whereby two or more components, which may be active or
inactive ingredients, carriers, diluents, and the like, are
provided with instructions for preparation of the actual dosage
form by the patient or person administering the drug to the
patient. Such kits may be provided with all necessary materials and
ingredients contained therein, or they may contain instructions for
using or making materials or components that must be obtained
independently by the patient or person administering the drug to
the patient. In further aspects, a kit can include optional
components that aid in the administration of the unit dose to
patients, such as vials for reconstituting powder forms, syringes
for injection, customized IV delivery systems, inhalers, etc.
Additionally, a kit can contain instructions for preparation and
administration of the compositions. The kit can be manufactured as
a single use unit dose for one patient, multiple uses for a
particular patient (at a constant dose or in which the individual
compounds may vary in potency as therapy progresses); or the kit
may contain multiple doses suitable for administration to multiple
patients ("bulk packaging"). The kit components may be assembled in
cartons, blister packs, bottles, tubes, and the like.
[0197] In a further aspect, the disclosed kits can be packaged in a
daily dosing regimen (e.g., packaged on cards, packaged with dosing
cards, packaged on blisters or blow-molded plastics, etc.). Such
packaging promotes products and increases patient compliance with
drug regimens. Such packaging can also reduce patient confusion.
The present invention also features such kits further containing
instructions for use.
[0198] In a further aspect, the present disclosure also provides a
pharmaceutical pack or kit comprising one or more containers filled
with one or more of the ingredients of the pharmaceutical
compositions of the invention. Associated with such container(s)
can be a notice in the form prescribed by a governmental agency
regulating the manufacture, use or sale of pharmaceuticals or
biological products, which notice reflects approval by the agency
of manufacture, use or sale for human administration.
[0199] In various aspects, the disclosed kits can also comprise
compounds and/or products co-packaged, co-formulated, and/or
co-delivered with other components. For example, a drug
manufacturer, a drug reseller, a physician, a compounding shop, or
a pharmacist can provide a kit comprising a disclosed compound
and/or product and another component for delivery to a patient.
[0200] It is contemplated that the disclosed kits can be used in
connection with the disclosed methods of making, the disclosed
methods of using or treating, and/or the disclosed
compositions.
[0201] Now having described the aspects of the present disclosure,
in general, the following Examples describe some additional aspects
of the present disclosure. While aspects of the present disclosure
are described in connection with the following examples and the
corresponding text and figures, there is no intent to limit aspects
of the present disclosure to this description. On the contrary, the
intent is to cover all alternatives, modifications, and equivalents
included within the spirit and scope of the present disclosure.
[0202] From the foregoing, it will be seen that aspects herein are
well adapted to attain all the ends and objects hereinabove set
forth together with other advantages which are obvious and which
are inherent to the structure.
[0203] While specific elements and steps are discussed in
connection to one another, it is understood that any element and/or
steps provided herein is contemplated as being combinable with any
other elements and/or steps regardless of explicit provision of the
same while still being within the scope provided herein.
[0204] It will be understood that certain features and
subcombinations are of utility and may be employed without
reference to other features and subcombinations. This is
contemplated by and is within the scope of the claims.
[0205] Since many possible aspects may be made without departing
from the scope thereof, it is to be understood that all matter
herein set forth or shown in the accompanying drawings and detailed
description is to be interpreted as illustrative and not in a
limiting sense.
[0206] It is also to be understood that the terminology used herein
is for the purpose of describing particular aspects only, and is
not intended to be limiting. The skilled artisan will recognize
many variants and adaptations of the aspects described herein.
These variants and adaptations are intended to be included in the
teachings of this disclosure and to be encompassed by the claims
herein.
[0207] Now having described the aspects of the present disclosure,
in general, the following Examples describe some additional aspects
of the present disclosure. While aspects of the present disclosure
are described in connection with the following examples and the
corresponding text and figures, there is no intent to limit aspects
of the present disclosure to this description. On the contrary, the
intent is to cover all alternatives, modifications, and equivalents
included within the spirit and scope of the present disclosure.
F. Examples
[0208] The following examples are put forth so as to provide those
of ordinary skill in the art with a complete disclosure and
description of how the compounds, compositions, articles, devices
and/or methods claimed herein are made and evaluated, and are
intended to be purely exemplary of the disclosure and are not
intended to limit the scope of what the inventors regard as their
disclosure. Efforts have been made to ensure accuracy with respect
to numbers (e.g., amounts, temperature, etc.), but some errors and
deviations should be accounted for. Unless indicated otherwise,
parts are parts by weight, temperature is in .degree. C. or is at
ambient temperature, and pressure is at or near atmospheric.
Example 1
[0209] As illustrated in FIG. 1, a biofilm is a community of
bacteria encased in a self-produced exopolysaccharide (EPS) matrix
and adhered to an inert or living surface. The biofilm EPS matrix
serves to protect the bacteria from antibiotics, host immune
responses, and other environmental threats.
[0210] Data obtained in assays of representative disclosed
compounds M1-M4 showed inhibition of the formation of S.
typhimurium (JSG210) biofilms. Assays for inhibition of formation
of S. typhimurium (JSG210) biofilms were also carried out using
representative disclosed compounds M4-M8. S. typhimurium (JSG210)
biofilms are commonly used to study biofilms associated with S.
typhimurium biofilms. Briefly, the assays utilized were 96-well
microtiter plate biofilm assays (Rapid Attachment Assays) were used
to compare inhibition of biofilm formation and existing 24-hour
biofilm dispersal in the presence of the anti-biofilm compounds
M4-M8. S. typhimurium (JSG210) was grown overnight in TSB and
normalized to OD600 0.8. The structures for the compounds
designated M1-M8 are given in FIG. 2.
[0211] FIGS. 3A and 3B show results of an inhibition assay (FIG.
3A) and dispersal assay (FIG. 3B). JSG210+20 .mu.M compound was
plated and grown for 24 hours at 30.degree. C. nutating for the
inhibition assay. For the dispersal assay, JSG210 was grown for 24
hours at 30.degree. C. nutating, and the media was replaced on Day
2 and 20 .mu.M compound was added. After 24 hours of growth in the
presence of the compound, the 96-well plates were heat fixed and
stained with Crystal Violet, and biofilm formation quantified using
a microplate reader at 570 nm. Based on results and projected
pharmacodynamic properties of representative disclosed compound,
compound M4, was investigated in greater detail as a biofilm
inhibitor and dispersal agent.
[0212] S. typhimurium was used to determine EC.sub.50 values for
inhibition of the formation of biofilms and dispersion of existing
biofilms by representative disclosed compound, compound M4. The
assays were was performed with Rapid Attachment Assay protocol.
JSG210 was grown overnight in TSB and grown in 96-well microtiter
plate at desired concentration with M4 for 24 hours at 30.degree.
C. nutating. For dispersal assay, media was replaced at 24 hours
and compound M4 added. After 24 hours of growth in the presence of
the compound, the 96-well plates were heat fixed and stained with
Crystal Violet, and biofilm formation quantified using a microplate
reader at 570 nm. Results are shown in FIGS. 4A and 4B.
[0213] S. typhimurium grown in the presence of 10 .mu.M of a
representative disclosed compound, compound M4, for 24 hours showed
no significant cell death over a 24-hour period (FIG. 5A). Toxicity
was measured by drip plating and counting cfu/mL. Results of
toxicity tests in Galleria mellonella larvae at 400 mg/kg, assessed
over five days is shown in FIG. 5B.
[0214] Mutants of S. typhimurium were generated by repeated
exposure to representative disclosed compound, compound M4, to
identify putative M4 target(s). FIG. 6 shows results from a Rapid
Attachment Assay of JSG210 M4 mutants compared to WT JSG210. These
strains are sequenced to identify genomic alterations.
[0215] A representative disclosed compound, compound M4, displayed
significant biofilm dispersal and inhibition of biofilm formation
in S. typhimurium, and no apparent toxicity to S. typhimurium at 10
.mu.M or Galleria mellonella up to 400 mg/kg.
Example 2
[0216] Salmonella species are a frequent cause of food and water
borne illness worldwide. They can cause a variety of disease
syndromes, and are normally grouped into typhoidal and
non-typhoidal species. Salmonella enterica serovar Typhi is the
causative agent of enteric fever and Salmonella enterica serovar
Typhiumiurum is typically associated with intestinal distress, or
salmonellosis (Truusalu, K., et al. Microb. Ecol. Health Dis.,
2009, 16:180-187). Typhoidal and non-typhoidal strains of
Salmonella have shown a remarkable ability to persist in a variety
of environments, including harsh environments within the human
body. One of these survival strategies centers around the ability
of Salmonella to form biofilms on gallstones (Crawford, R W., et
al. Proc. Natl. Acad. Sci. U.S.A, 2010, 107:4353-4358).
Colonization of gallstones can then lead to chronic carriage of S.
Typhi, which allows for the dissemination of Salmonella through
fecal shedding. Biofilms can be up to 1000-fold more resistant to
antibiotic treatment than their planktonic counterparts, rendering
typical antibiotic treatment regimens ineffective at eradicating
chronic carriage of Salmonella (Stewart P S., et al. Lancet, 2001,
358:135-138; Donlan R M., et al. Clin. Microbiol. Rev., 2002:15,
167-193; Gonzalez, J F., et al. Sci. Rep., 2018, 8:222). Presently,
chronic carriage of Salmonella is treated by invasive methods,
which are not well suited to areas where Salmonella is prevalent
(Gunn, J S., et al. Trends Microbiol., 2014, 22: 648-655). New
treatment options for chronic carriage of Salmonella are needed,
and compounds that perturb Salmonella biofilms could be a viable
treatment option.
[0217] Recently, there have been reports of derivatized
2-aminoimidazoles (2-Als) that inhibit S. Typhimurium biofilm
formation (Ermolat'ev, D S., et al. Angew. Chem., Int. Ed., 2010,
49:9465-9468; Steenackers, H P., et al. J. Med. Chem., 2011,
54:472-484; Steenackers, H P., et al. Bioorg. Med. Chem., 2011,
19:3462-3473; Robijns, S C., et al. FEMS Immunol. Med. Microbiol.,
2012, 65:390-394; Steenackers, H., et al. Org. Biomol. Chem., 2014,
12:3671-3678; Trang, T T T., et al. Bioorg. Med. Chem., 2018,
26:1470-1480). As our group has been deeply involved in exploring
the antibiofilm potential of 2-Als, we were curious if there were
2-Al derivatives in our library, or derivatives of other
nitrogen-dense heterocycles that we have assembled and assayed for
their antibiofilm activities, that possessed activity against S.
Typhimurium. As S. Typhi is a human-specific pathogen, reliable
murine pathogenic serovars such as S. Typhimurium have been used to
model S. Typhi infections, allowing for future in vivo testing (Wu,
S., et al. J. Visualized Exp., 2010, (39):1947; Truusalu, K. et al.
BMC Microbiol., 2008, 8:132). An initial library screen was
performed for inhibitors of S. Typhimurium biofilm formation and
identified 2-aminobenzimidazole (2-ABI) compound 1 as one lead
compound that returned an IC.sub.50 value of 13.1.+-.0.6 .mu.M.
2-ABIs display a wide variety of biological activity including
antibiotic activity against MRSA and MDR A. baumannii (Huigens, R
W., 3rd, et al. Bioorg. Med. Chem., 2010, 18:663-674), antibiofilm
activity against Gram-positive bacteria (Rogers, S A., et al. J.
Am. Chem. Soc., 2009, 131:9868-9869), and the ability to potentiate
p-lactam antibiotic activity against Mycobacterium smegmatis and M.
tuberculosis (Nguyen, T V., et al. Angew. Chem., Int. Ed., 2017,
56:3940-3944). With this compound in hand, it was decided to probe
the structure-activity relationship (SAR) of the 2-ABIs against S.
Typhimurium biofilms. The results of this SAR study of the 2-ABI
scaffold are reported in this Example, focusing on three regions:
the head region, the linker and the tail region (FIG. 7).
[0218] The first region of the molecule modified was the head
region of the 2-ABI using a synthetic scheme (Scheme 1A) (Lindsey,
E A., et al. Med Chem Comm, 2012, 3:1462-1465). Briefly,
4-fluoro-3-nitroaniline 2 was acylated with 4-pentylbenzoyl
chloride in the presence of triethylamine and
4-dimethylaminopyrimidine (DMAP) in DCM for 16 hours at room
temperature to yield compound 3. SNAr substitution of compound 3
with commercially available amines in refluxing ethanol for 16
hours yielded compounds 4a-n. Subsequent reduction of the nitro
group with ammonium formate and 10% Pd/C in ethanol at reflux
followed by cyclization with cyanogen bromide in DCM at room
temperature yielded 2-ABIs 5a-n. The unsubstituted 2-ABI
derivative, compound 5o, was prepared using a previously published
method (Huigens, R W., 3rd, et al. Bioorg. Med. Chem., 2010,
18:663-674; Kikuchi, K., et al. Bioorg. Med. Chem., 2006,
14:6189-6196).
[0219] Three head group substitutions, n-octyl (5a), butyl phenyl
(5b), and n-hexyl (5c) displayed improved activity (Table 1) over
the parent compound. Isobutyl substitution (compound 5d) or
substitution with tryptamine (5e) returned an IC.sub.50 value
between 10-15 .mu.M, similar to that of parent compound 1
(IC.sub.50 values were only quantified for compounds that had
marked improvement over compound 1). Substitution with cyclopentyl
(5g) or cyclohexyl rings (5h) returned slightly higher IC.sub.50
values compared to the parent (15-20 .mu.M). Shortening the phenyl
chain to two methylenes also reduced activity, with compound 5i
returning an IC.sub.50 value of 20-40 .mu.M (ESI.dagger.).
Replacement of the phenyl ring on compound 5i with an imidazole
(5j) ring also returned an IC.sub.50 value of 20-40 .mu.M. Alkyl
chains with less than four carbon atoms (5k, 5l) or longer than
eight carbon atoms (5m, 5n) reduced or completely abolished
antibiofilm activity. Removal of the head group (compound 5o) from
the 2-ABI lowers the IC.sub.50 from 13.1.+-.0.6 .mu.M to 20-40
.mu.M, demonstrating the necessity of the head group for biofilm
inhibitory activity.
TABLE-US-00001 TABLE 1 IC.sub.50 values of para 2-ABI, compounds
5a-h, and meta 2-ABI, compounds 9a-b. Full inhibition data can be
found in the ESI Compound R = IC.sub.50 (.mu.M) 5a ##STR00029##
6.66 .+-. 0.32 5b ##STR00030## 9.59 .+-. 0.23 5c ##STR00031## 10.8
.+-. 0.56 1 ##STR00032## 13.1 .+-. 0.6 5d ##STR00033## 10-15 5e
##STR00034## 10-15 5f ##STR00035## 15-20 5g ##STR00036## 15-20 5h
##STR00037## 15-20 9a ##STR00038## 10-15 9b ##STR00039## 10-15
TABLE-US-00002 TABLE 2 IC.sub.50 values of 2-ABIs with different
tails, compounds 10a-n. Full inhibition data can be found in the
ESI Compound R = IC.sub.50 (.mu.M) 10a ##STR00040## 5.22 .+-. 0.11
10b ##STR00041## 5.38 .+-. 0.79 10c ##STR00042## 5.58 .+-. 0.21 10d
##STR00043## 6.30 .+-. 1.29 1 ##STR00044## 13.1 .+-. 0.6 10e
##STR00045## 10-15 10f ##STR00046## 10-15 10g ##STR00047## 10-15
10h ##STR00048## 10-15 10i ##STR00049## 10-15 10j ##STR00050##
15-20 10k ##STR00051## 15-20 10l ##STR00052## 15-20 10m
##STR00053## 15-20 10n ##STR00054## 15-20
[0220] After investigating different head group substitutions in
the para position relative to the amide, analogues with the head
group substitution meta to the amide were prepared. The synthetic
route to these compounds (Scheme 1B), is identical to that of the
para analogues (Scheme 1A) except the starting material is
3-fluoro-4-nitroaniline 6. Compared to their para substituted
counterparts, the meta analogues did not display a significant
increase inactivity (Table 1). Only the butyl analogue 9a
(IC.sub.50 10-15 .mu.M) displayed increased activity compared to
butyl para analogue 5f (IC.sub.50 15-20 .mu.M). n-Hexyl analogue 9b
displayed almost identical activity to the para n-hexyl analogue
5c, returning an IC.sub.50 of 10-15 .mu.M. Methyl (9c), ethyl (9d),
and isopropyl (9e) analogues all displayed IC.sub.50 values of
20-40 .mu.M (ESI.dagger.). After modifying the head region of the
molecule, substitutions to the tail of the molecule were made in an
effort to improve the antibiofilm ability of the parent compound.
Previously, various 2-ABI derivatives with an identical head group
to the parent compound 1 and various tails were prepared (FIG. 8)
(Nguyen, T V., et al. Angew. Chem., Int. Ed., 2017, 56:3940-3944).
As these compounds were readily available in our laboratory, their
anti-Salmonella biofilm activity was investigated. Halogenation
(10b, 10c and 10d) of the aromatic ring lowers the IC50 value when
compared to a 4-pentylbenzoyl group, all returning IC.sub.50 values
of less than 7 .mu.M (Table 2). The 3,5-dichloro analogue 10e
displays lower activity compared to the other halogenated tails,
but displays essentially equivalent activity to the parent compound
1. Addition of a pentoxybenzoyl group (10a) returns the lowest
IC.sub.50 observed, with an IC.sub.50 of 5.22.+-.0.11 .mu.M.
Although substituted benzoyl groups are favored in the most active
compounds, removal of the aromatic ring in favor of a straight
alkyl chain is tolerated as observed with nonanoyl (10h) and
decanoyl (10i) tails. 4-Butylbenzoyl (10f), and 4-propoxybenzoyl
(10g) tails all returned an IC50 value of 10-15 .mu.M, similar to
that of the parent compound (1) and the 3,5-dichlorobenzoyl
compound (10e). Additional analogues were investigated, but all
displayed lower activity in comparison to the parent compound.
4-Butoxybenzoyl (10j), 4-propylbenzoyl (10k), 4-hexylbenzoyl (10l),
4-heptylbenzoyl (10m), and octanoyl (10n) tails all returned IC50
values of 15-20 .mu.M. 4-Ethylbenzoyl (100) and hexanoyl (10p)
tails returned IC.sub.50 values between 20-40 .mu.M (ESI.dagger.).
Lastly, heptanoyl (10q), 4-octylbenzoyl (10r), undecanoyl (10s),
and tridecanoyl (10t) tails returned IC.sub.50 values of greater
than 40 .mu.M.
##STR00055## ##STR00056##
[0221] The last region of the 2-ABIs that was modified was the
linker region. The 2-ABIs previously synthesized (Huigens, R W.,
3rd, et al. Bioorg. Med. Chem., 2010, 18:663-674; Rogers, S A., et
al. J. Am. Chem. Soc., 2009, 131:9868-9869; Nguyen, T V., et al.
Angew. Chem., Int. Ed., 2017, 56:3940-3944; Lindsey, E A., et al.
Med Chem Comm, 2012, 3:1462-1465) that served as the basis for the
2-ABIs used in this study have featured an amide linkage, with the
nitrogen in the amide connected to the 2-ABI head of the molecule.
Previous studies on other 2-Al natural products have demonstrated
the effect that modification of the amide moiety can have on a
compound's ability to control bacterial behavior as well as its
toxicity in C. elegans (Richards, J J., et al. J. Med. Chem., 2009,
52:4582-4585). With this in mind, 2-ABI derivatives were
synthesized with a reverse amide moiety as well as a urea moiety
replacing the amide. Compound 10d was chosen as the compound for
further analog development due to its predicted reduced metabolic
liabilities.
[0222] The synthesis of the reverse amide analogue (Scheme 2A)
began by reacting 4-fluoro-3-nitrobenzoic acid with thionyl
chloride in methanol at 0.degree. C., warming to room temperature
overnight to yield the methyl ester 12. Compound 12 was then
reacted with 3-phenyl-1-propylamine in ethanol at reflux to yield
13. Reduction of the nitro group followed by cyclization with
cyanogen bromide in DCM at room temperature yielded the 2-ABI 14.
Lastly, saponification of the methyl ester with sodium hydroxide in
1:1 MeOH/H.sub.2O followed by EDC coupling of the carboxylic acid
with 3,4-dichloroaniline delivered the reverse amide 2-ABI 15.
[0223] Synthesis of the urea analogue (Scheme 2B) began with the
Boc protection of 4-fluoro-3-nitroaniline, yielding 16. Compound 16
was then reacted with 3-phenyl-1-propylamine to yield the
diaminobenzene 17. Reduction of the nitro group using ammonium
formate and 10% Pd/C in ethanol at reflux followed by cyclization
with cyanogen bromide in DCM at room temperature yielded
Boc-protected 2-ABI 18. Alloc protection of the 2-ABI head
proceeded smoothly utilizing scandium(III) triflate as a Lewis-acid
catalyst in DCM overnight at room temperature, yielding alloc
protected 2-ABI 19. Boc deprotection of compound 20 followed by
coupling with 3,4-dichloroaniline using triphosgene yielded the
Alloc protected 2-ABI urea. Finally, Alloc deprotection with
Pd(PPh.sub.3).sub.4 and NaBH.sub.4 yielded the target 2-ABI urea
20.
##STR00057## ##STR00058##
[0224] While the reverse amide analogue 15 displayed a twofold
greater IC.sub.50 (12.6.+-.1.8 .mu.M) than that of the parent
compound 10d, the urea analogue 20 displayed only a slight
reduction in IC.sub.50 value from 6.30.+-.1.29 to 7.69.+-.0.25
.mu.M, demonstrating that the linker group of the 2-ABIs can be
modified while retaining biofilm inhibitory activity against S.
Typhimurium. Additionally, compounds 10a and 20 showed no toxicity
to planktonic bacterial growth at their IC.sub.50 values,
indicating that they are nontoxic biofilm inhibitors
(ESI.dagger.).
EXPERIMENTAL
[0225] All reagents used for chemical synthesis were purchased from
commercially available sources and used without further
purification. Chromatography was performed using 60 .ANG. mesh
standard grade silica gel from Sorbtech. NMR solvents were obtained
from Cambridge Isotope Laboratories and used as is. All 1H NMR (300
or 400 MHz) and .sup.13C NMR (75, 100, or 175 MHz) spectra were
recorded at 25.degree. C. on Varian Mercury spectrometers. Chemical
shifts (6) are given in parts per million relative to
tetramethylsilane or the respective NMR solvent; coupling constants
(J) are in hertz (Hz). Abbreviations used are s, singlet; brs,
broad singlet; d, doublet; dd, doublet of doublets; t, triplet; dt,
doublet of triplets; m, multiplet. Mass spectra were obtained at
the NCSU Department of Chemistry Mass Spectrometry Facility.
Infrared spectra were obtained on an FT/IR-4100 spectrophotometer
(vmax in cm.sup.-1). UV absorbance was recorded on a Genesys 10
scanning UV/visible spectrophotometer (.lamda.max in nm). The
purities of the tested compounds were all verified to be >95% by
LC-MS analysis on a Shimadzu LC-MS 2020 with Kinetex, 2.6 mm, C18
50.times.2.10 mm.
[0226] Procedure to Determine the Inhibitory Effect of Test
Compounds on Salmonella Typhimurium ATCC 14028 Biofilms: Inhibition
assays were performed by taking an overnight culture of S.
Typhimurium ATCC 14028 in tryptic soy broth (TSB, BD.TM. Bacto.TM.)
and subculturing it at an OD600 of 0.08 into 1:20 TSB:Water. Stock
solutions of predetermined concentrations of the test compounds
were then made in 1 mL of bacterial culture. The resulting
bacterial suspension was aliquoted (100 .mu.L) into the wells of a
96-well PVC microtiter plate. Sample plates were then incubated for
24 h at 30.degree. C. After incubation, the medium was discarded
from the wells and the plates were washed thoroughly with water.
Plates were then stained with 110 .mu.L of 0.1% solution of crystal
violet (CV) and then incubated at ambient temperature for 30 min.
Plates were washed with water again and the remaining stain was
solubilized with 200 .mu.L of 95% ethanol. A sample of 125 .mu.L of
solubilized CV stain from each well was transferred to the
corresponding wells of a polystyrene microtiter dish. Biofilm
inhibition was quantitated by measuring the OD540 of each well in
which a negative control lane wherein no biofilm was formed served
as a background and was subtracted out.
[0227] Growth Curves: S. typhimurium was grown overnight in TSB,
and this culture was used to inoculate fresh 1:20 TSB
(OD.sub.600=0.08). Inoculated medium was aliquoted (3 mL) into
culture tubes, and compound was added, with untreated inoculated
medium serving as the control. Tubes were incubated at 30.degree.
C. with shaking. Samples were taken at 2, 4, 6, 8, and 24 h time
points, serially diluted in fresh 1:20 TSB, and plated on nutrient
agar. Plates were incubated at 37.degree. C. overnight in
stationary conditions, and the number of colonies was
enumerated.
[0228] Complete 2-ABI library Inhibition Data against S.
Typhimurium 14028
TABLE-US-00003 1, 5a-n ##STR00059## 9a-e ##STR00060## Compound R =
IC.sub.50 (.mu.M) 5a ##STR00061## 6.66 .+-. 0.32 5b ##STR00062##
9.59 .+-. 0.23 5c ##STR00063## 10.8 .+-. 0.56 1 ##STR00064## 13.1
.+-. 0.6 5d ##STR00065## 10-15 5e ##STR00066## 10-15 5f
##STR00067## 15-20 5g ##STR00068## 15-20 5h ##STR00069## 15-20 5i
##STR00070## 20-40 5j ##STR00071## 20-40 5o H 20-40 5k ##STR00072##
20-40 5l ##STR00073## >40 5m ##STR00074## >50 5n ##STR00075##
>50 9a ##STR00076## 10-15 9b ##STR00077## 10-15 9c ##STR00078##
20-40 9d ##STR00079## 20-40 9e ##STR00080## 20-40
TABLE-US-00004 10a-t ##STR00081## Compound R = IC.sub.50 (.mu.M)
10a ##STR00082## 5.22 .+-. 0.11 10b ##STR00083## 5.38 .+-. 0.79 l0c
##STR00084## 5.58 .+-. 0.21 10d ##STR00085## 6.30 .+-. 1.29 1
##STR00086## 13.1 .+-. 0.6 10e ##STR00087## 13.3 .+-. 0.49 10f
##STR00088## 10-15 10g ##STR00089## 10-15 10h ##STR00090## 10-15
10i ##STR00091## 10-15 10j ##STR00092## 15-20 10k ##STR00093##
15-20 10l ##STR00094## 15-20 10m ##STR00095## 15-20 10n
##STR00096## 15-20 10o ##STR00097## 20-40 10p ##STR00098## 20-40
10q ##STR00099## >40 10r ##STR00100## >50 10s ##STR00101##
>50 10t ##STR00102## >50
TABLE-US-00005 15 ##STR00103## 20 ##STR00104## Compound IC.sub.50
(.mu.M) 15 12.6 .+-. 1.8 20 7.69 .+-. 0.25
[0229] General Synthetic Procedures
[0230] General synthetic procedure for aniline acylation (Compounds
3, 7): To a solution of nitroaniline (1.0 g, 6.41 mmol) in
anhydrous Dichloromethane (35 mL), was added DMAP (0.782 g, 1.0
mmol), and 4-pentylbenzoyl chloride (1.69 mL, 8.32 mmol) dropwise.
The reaction was stirred under N2 for 16 hours, after which it was
washed with H2O (3.times.100 mL), saturated aqueous NaHCO3
(2.times.100 mL), and saturated aqueous NaCl (1.times.100 mL). It
was then dried with sodium sulfate and purified on silica gel,
using EtOAc/Hexanes (30%) as the eluting solvent.
[0231] General synthetic procedure for SNAr substitution (Compounds
4a-n, 8a-e, 13, 17): Compounds 3, 7, 12, or 16 were added to a
round bottom flask and dissolved in ethanol (1.0 g, 0.5 M). To this
mixture the corresponding amine (3-5 equivalents) was added
dropwise. The reaction mixture was then heated to reflux and
allowed to stir for 16 hours. The mixture was then cooled to room
temperature. Water was added to the reaction mixture, causing the
product to precipitate out of solution. This mixture was then
cooled to 0.degree. C. The product was then filtered and washed
with cold water. The solid was then dried under high vacuum
overnight.
[0232] General procedure for the 2-ABI nitro reduction and
cyclization (Compounds 5a-n, 9a-e, 14, 18): The appropriate
nitro-compound was dissolved in ethanol (1.0 g, 0.4 M), and 10%
Pd/C (0.1 g) was added to the mixture. The reaction mixture was
then heated to reflux. Ammonium formate was then dissolved in
ethanol and added dropwise to the reaction mixture which was
allowed to stir until completion, via TLC analysis. The mixture was
then cooled to room temperature, and quickly filtered through a pad
of celite which was washed with dichloromethane. The crude product
was then placed under nitrogen, and solid cyanogen bromide (10 eq)
was added to the crude product and allowed to stir overnight. The
reaction mixture was then concentrated and purified using column
chromatography (1-5% MeOH/NH3-DCM). Methanol supplemented with 12N
HCl was added to the product forming the HCl salt, which was then
dried under high vacuum overnight.
[0233] General synthetic procedure for methyl ester synthesis
(Compound 12): To a solution of 4-fluoro-3-nitrobenzoic acid (2.00
g, 10.8 mmol) in MeOH (20 mL) at 0.degree. C. was added thionyl
chloride (2.35 mL, 32.4 mmol) dropwise, and the reaction mixture
was allowed to stir overnight. After completion, the reaction was
extracted with diluted in water and extracted with ethyl acetate
(3.times.20 mL). The combined organic layers were then washed with
saturated sodium bicarbonate (2.times.30 mL). The organic layer was
then dried with sodium sulfate, and the product was concentrated to
yield the product with no further purification.
[0234] General synthetic procedure for saponification followed by
EDC coupling (Compound 15): 2-ABI methyl ester (compound 14, 0.200
g, 0.645 mmol) was dissolved in a 1:1 mixture of MeOH:H2O (20 mL)
to which a 5M solution of sodium hydroxide (10 mL) was added. The
mixture was then heated to reflux while stirring for 16 hours.
After completion, the methanol was removed under reduced pressure.
The remaining aqueous solution was then cooled to 0.degree. C., and
12N HCl was added until the pH reached .about.2. The resulting
precipitate was then isolated using vacuum filtration and allowed
to dry under high vacuum for 2 hours. A solution of carboxylic acid
(0.107 g, 0.362 mmol), EDC (0.073, 0.471 mmol), DMAP (0.044 g,
0.362 mmol), and 3,4-dichloroaniline (0.176 g, 1.09 mmol) was made
in a 5:1 mixture of DCM: DMF. The reaction was allowed to stir for
16 hours at room temperature. After completion, the DCM was removed
under reduced pressure. The remaining solution was then dissolved
in ethyl acetate (25 mL) washed with water (1.times.40 mL),
saturated sodium bicarbonate (2.times.15 mL), and brine (1.times.20
mL). The organic layer was then dried over sodium sulfate and
concentrated under reduced pressure to yield the crude product. The
crude product was then purified using flash chromatography (0.5-5%
MeOH--NH3/DCM). Methanol supplemented with 12N HCl was added to the
product forming the HCl salt, which was then dried under high
vacuum overnight.
[0235] General synthetic procedure for aniline boc protection
(Compound 16): To a solution of 4-fluoro-3-nitroaniline (5.0 g,
32.03 mmol) in anhydrous THF (150 mL) was added triethylamine (44.7
mL, 320.28 mmol) and DMAP (0.039 g, 0.32 mmol). Di-tert-butyl
dicarbonate (10.49 g, 48.4 mmol) was added, and solution was
stirred at room temperature overnight (16 h). The solvent was
removed under reduced pressure, and the crude product was dissolved
in ethyl acetate (100 mL), and washed with 1N HCl (3.times.100 mL),
saturated sodium bicarbonate (3.times.100 mL), and brine
(1.times.100 mL). The organic layer was dried over sodium sulfate.
The solvent was removed under reduced pressure, and the crude
product was purified via flash chromatography (5-20% ethyl
acetate/hexanes).
[0236] General synthetic procedure for 2-ABI alloc protection
(Compound 19): Compound 18 (1.15 g, 3.14 mmol) was placed under an
inert atmosphere and dissolved in DCM (25 mL). To the reaction
mixture was added 0.05 equivalents of Sc(OTf)3 and triethylamine
triethylamine (0.482 mL, 3.45 mmol). The reaction mixture was
cooled to 0.degree. C. Allyl chloroformate (0.365 mL, 3.45 mmol)
was slowly added dropwise to the reaction mixture. The reaction
mixture was stirred at 0.degree. C. for 20 min and allowed to warm
up to room temperature overnight. The solvent was removed under
reduced pressure, and the crude product was dissolved in DCM (100
mL). The organic layer was washed with saturated sodium bicarbonate
(3.times.100 mL), and brine (1.times.100 mL). The organic layer was
dried over sodium sulfate. The solvent was removed under reduced
pressure, and the crude product was purified via flash
chromatography (1-5% MeOH--NH3/DCM).
[0237] General synthetic procedure for Boc deprotection, urea
coupling followed by alloc deprotection (Compound 20): Compound 19
(0.123 g, 0.273 mmol) was dissolved in 30% TFA/DCM under an inert
atmosphere at 0.degree. C. The reaction was allowed to stir for 4
h, and upon completion via TLC analysis, the solvent was then
removed under reduced pressure. The crude product was dissolved in
DCM, and washed with saturated sodium bicarbonate (3.times.100 mL).
The organic layer was dried over sodium sulfate, and the solvent
was removed under reduced pressure. The crude product was then
dissolved in dichloromethane (10 mL) to which sodium carbonate
(0.046 g, 0.434 mmol) and water (5 mL) was added and the mixture
was allowed to stir for 10 minutes at room temperature. A solution
of triphosgene (0.027 g, 0.089 mmol) in DCM (5 mL) was added to the
reaction mixture. After allowing the mixture to stir for 1 hour,
3,4-dichloroaniline (0.088 g, 0.542 mmol) in DCM (1 mL) was added
dropwise to the reaction mixture. The reaction was then allowed to
stir for 16 hours at room temperature. Following the completion of
the reaction, the product was extracted with dichloromethane (15
mL) and washed with water (2.times.20 mL) and brine (1.times.20
mL). The crude mixture was then purified with flash chromatography
(0.5-1.5% MeOH--NH3/DCM) to yield the product. After allowing the
product to dry under high vacuum for 2 hours, the alloc protected
urea (0.023 g, 0.427 mmol) was then placed under nitrogen and
dissolved in ethanol (10 mL) at 0.degree. C. Next,
tetrakis(triphenylphosphine)palladium (0) (0.0001 g, 0.0001 mmol)
and sodium borohydride (0.003 g, 0.085 mmol) were added to the
reaction mixture and allowed to stir for 1 hour while warming to
room temperature. The reaction was then acidified to pH 2.5-3 using
12 N HCl, and the reaction was allowed to stir for 4 h. After
completion, the reaction was extracted with 1:1 EtOAC/Hex
(2.times.20 mL). The combined organic layers were washed with water
(20 mL), saturated NaHCO3 (20 mL), brine (20 mL), dried (MgSO4) and
concentrated under reduced pressure. The residue was then purified
using flash chromatography (1-5% MeOH--NH3/DCM) to yield the
desired product. Methanol supplemented with 12N HCl was added to
the product forming the HCl salt, which was then dried under high
vacuum overnight.
[0238]
N-(2-Amino-1-phenethyl-1H-benzo[d]imidazol-5-yl)-4-pentylbenzamide
hydrochloride (1): Compound was synthesized using previously
reported methods (Lindsey, E A, et al. Med Chem Comm, 2012,
3:1462-1465).
[0239]
N-(2-Amino-1-octyl-1H-benzo[d]imidazol-5-yl)-4-pentylbenzamide
hydrochloride (5a): Compound was synthesized using previously
reported methods (Lindsey, E A, et al. Med Chem Comm, 2012,
3:1462-1465).
[0240]
N-(2-Amino-1-(4-phenylbutyl)-1H-benzo[d]imidazol-5-yl)-4-pentylbenz-
amide hydrochloride (5b): Compound was synthesized using previously
reported methods (Lindsey, E A, et al. Med Chem Comm, 2012,
3:1462-1465).
[0241]
N-(2-Amino-1-hexyl-1H-benzo[d]imidazol-5-yl)-4-pentylbenzamide
hydrochloride (5c): Compound was synthesized using previously
reported methods (Lindsey, E A, et al. Med Chem Comm, 2012,
3:1462-1465).
[0242]
N-(1-(2-(1H-Indol-3-yl)ethyl)-2-amino-1H-benzo[d]imidazol-5-yl)-4-p-
entylbenzamide hydrochloride (5e): Compound was synthesized using
previously reported methods (Lindsey, E A, et al. Med Chem Comm,
2012, 3:1462-1465).
[0243]
N-(2-Amino-1-butyl-1H-benzo[d]imidazol-5-yl)-4-pentylbenzamide
hydrochloride (5f): Compound was synthesized using previously
reported methods (Lindsey, E A, et al. Med Chem Comm, 2012,
3:1462-1465).
[0244]
N-(2-Amino-1-cyclopentyl-1H-benzo[d]imidazol-5-yl)-4-pentylbenzamid-
e hydrochloride (5g): Compound was synthesized using previously
reported methods (Lindsey, E A, et al. Med Chem Comm, 2012,
3:1462-1465).
[0245]
N-(2-Amino-1-cyclohexyl-1H-benzo[d]imidazol-5-yl)-4-pentylbenzamide
hydrochloride (5h): Compound was synthesized using previously
reported methods (Lindsey, E A, et al. Med Chem Comm, 2012,
3:1462-1465).
[0246]
N-(2-Amino-1-isopropyl-1H-benzo[d]imidazol-5-yl)-4-pentylbenzamide
hydrochloride (5k): Compound was synthesized using previously
reported methods (Lindsey, E A, et al. Med Chem Comm, 2012,
3:1462-1465).
[0247]
N-(2-Amino-1-methyl-1H-benzo[d]imidazol-5-yl)-4-pentylbenzamide
hydrochloride (5l): Compound was synthesized using previously
reported methods (Lindsey, E A, et al. Med Chem Comm, 2012,
3:1462-1465).
[0248]
N-(2-Amino-1-dodecyl-1H-benzo[d]imidazol-5-yl)-4-pentylbenzamide
hydrochloride (5n): Compound was synthesized using previously
reported methods (Lindsey, E A, et al. Med Chem Comm, 2012,
3:1462-1465).
[0249] N-(2-Amino-1H-benzo[d]imidazol-5-yl)-4-pentylbenzamide
hydrochloride (5o): Compound was synthesized using previously
reported method (Huigens, 3rd, R W, et al. Bioorg. Med. Chem.,
2010, 18:663-674).
[0250]
N-(2-Amino-1-(3-phenylpropyl)-1H-benzo[d]imidazol-5-yl)-4-pentoxybe-
nzamide hydrochloride (10a): Compound was synthesized using
previously reported methods (Nguyen, T V, aa et al. Angew. Chem.
Int. Ed., 2017, 56:3940-3944).
[0251]
N-(2-Amino-1-(3-phenylpropyl)-1H-benzo[d]imidazol-5-yl)-3,4-dibromo-
benzamide hydrochloride (10b): Compound was synthesized using
previously reported methods (Nguyen, T V, aa et al. Angew. Chem.
Int. Ed., 2017, 56:3940-3944).
[0252]
N-(2-Amino-1-(3-phenylpropyl)-1H-benzo[d]imidazol-5-yl)-3,5-dibromo-
benzamide hydrochloride (10c): Compound was synthesized using
previously reported methods (Nguyen, T V, aa et al. Angew. Chem.
Int. Ed., 2017, 56:3940-3944).
[0253]
N-(2-Amino-1-(3-phenylpropyl)-1H-benzo[d]imidazol-5-yl)-3,4-dichlor-
obenzamide hydrochloride (10d): Compound was synthesized using
previously reported methods (Nguyen, T V, aa et al. Angew. Chem.
Int. Ed., 2017, 56:3940-3944).
[0254]
N-(2-Amino-1-(3-phenylpropyl)-1H-benzo[d]imidazol-5-yl)-3,5-dichlor-
obenzamide hydrochloride (10e): Compound was synthesized using
previously reported methods (Nguyen, T V, aa et al. Angew. Chem.
Int. Ed., 2017, 56:3940-3944).
[0255]
N-(2-Amino-1-(3-phenylpropyl)-1H-benzo[d]imidazol-5-yl)-4-butylbenz-
amide hydrochloride (10f): Compound was synthesized using
previously reported methods (Nguyen, T V, aa et al. Angew. Chem.
Int. Ed., 2017, 56:3940-3944).
[0256]
N-(2-Amino-1-(3-phenylpropyl)-1H-benzo[d]imidazol-5-yl)-4-propoxybe-
nzamide hydrochloride (10g): Compound was synthesized using
previously reported methods (Nguyen, T V, aa et al. Angew. Chem.
Int. Ed., 2017, 56:3940-3944).
[0257]
N-(2-Amino-1-(3-phenylpropyl)-1H-benzo[d]imidazol-5-yl)decanamide
hydrochloride (10h): Compound was synthesized using previously
reported methods (Nguyen, T V, aa et al. Angew. Chem. Int. Ed.,
2017, 56:3940-3944).
[0258]
N-(2-Amino-1-(3-phenylpropyl)-1H-benzo[d]imidazol-5-yl)undecanamide
hydrochloride (10i): Compound was synthesized using previously
reported methods (Nguyen, T V, aa et al. Angew. Chem. Int. Ed.,
2017, 56:3940-3944).
[0259]
N-(2-Amino-1-(3-phenylpropyl)-1H-benzo[d]imidazol-5-yl)-4-butoxyben-
zamide hydrochloride (10j): Compound was synthesized using
previously reported methods (Nguyen, T V, aa et al. Angew. Chem.
Int. Ed., 2017, 56:3940-3944).
[0260]
N-(2-Amino-1-(3-phenylpropyl)-1H-benzo[d]imidazol-5-yl)-4-propylben-
zamide hydrochloride (10k): Compound was synthesized using
previously reported methods (Nguyen, T V, aa et al. Angew. Chem.
Int. Ed., 2017, 56:3940-3944).
[0261]
N-(2-Amino-1-(3-phenylpropyl)-1H-benzo[d]imidazol-5-yl)-4-hexylbenz-
amide hydrochloride (10l): Compound was synthesized using
previously reported methods (Nguyen, T V, aa et al. Angew. Chem.
Int. Ed., 2017, 56:3940-3944).
[0262]
N-(2-Amino-1-(3-phenylpropyl)-1H-benzo[d]imidazol-5-yl)-4-heptylben-
zamide hydrochloride (10m): Compound was synthesized using
previously reported methods (Nguyen, T V, aa et al. Angew. Chem.
Int. Ed., 2017, 56:3940-3944).
[0263]
N-(2-Amino-1-(3-phenylpropyl)-1H-benzo[d]imidazol-5-yl)nonanamide
hydrochloride (10n): Compound was synthesized using previously
reported methods (Nguyen, T V, aa et al. Angew. Chem. Int. Ed.,
2017, 56:3940-3944).
[0264]
N-(2-Amino-1-(3-phenylpropyl)-1H-benzo[d]imidazol-5-yl)-4-ethylbenz-
amide hydrochloride (100): Compound was synthesized using
previously reported methods (Nguyen, T V, aa et al. Angew. Chem.
Int. Ed., 2017, 56:3940-3944).
[0265]
N-(2-Amino-1-(3-phenylpropyl)-1H-benzo[d]imidazol-5-yl)heptanamide
hydrochloride (10p): Compound was synthesized using previously
reported methods (Nguyen, T V, aa et al. Angew. Chem. Int. Ed.,
2017, 56:3940-3944).
[0266]
N-(2-Amino-1-(3-phenylpropyl)-1H-benzo[d]imidazol-5-yl)octanamide
hydrochloride (10q): Compound was synthesized using previously
reported methods (Nguyen, T V, aa et al. Angew. Chem. Int. Ed.,
2017, 56:3940-3944).
[0267]
N-(2-Amino-1-(3-phenylpropyl)-1H-benzo[d]imidazol-5-yl)-4-octylbenz-
amide hydrochloride (10r): Compound was synthesized using
previously reported methods (Nguyen, T V, aa et al. Angew. Chem.
Int. Ed., 2017, 56:3940-3944).
[0268]
N-(2-Amino-1-(3-phenylpropyl)-1H-benzo[d]imidazol-5-yl)dodecanamide
hydrochloride (10s): Compound was synthesized using previously
reported methods (Nguyen, T V, aa et al. Angew. Chem. Int. Ed.,
2017, 56:3940-3944).
[0269]
N-(2-Amino-1-(3-phenylpropyl)-1H-benzo[d]imidazol-5-yl)tetradecanam-
ide hydrochloride (10t): Compound was synthesized using previously
reported methods (Nguyen, T V, aa et al. Angew. Chem. Int. Ed.,
2017, 56:3940-3944).
[0270] Methyl 4-fluoro-3-nitrobenzoate (12): Compound was
synthesized using previously reported methods (Gaugaz, F Z, et al.
Chem Med Chem, 2014, 9:2227-2232).
[0271] Methyl 3-nitro-4-((3-phenylpropyl)amino)benzoate (13):
Compound was synthesized using previously reported methods (Nguyen,
T V, aa et al. Angew. Chem. Int. Ed., 2017, 56:3940-3944;
Selvaraju, M, et al. J. Org. Chem., 2016, 81:8867-8875).
[0272] Methyl
2-amino-1-(3-phenylpropyl)-1H-benzo[d]imidazole-5-carboxylate (14):
Compound was synthesized using previously reported methods (Nguyen,
T V, aa et al. Angew. Chem. Int. Ed., 2017, 56:3940-3944;
Selvaraju, M, et al. J. Org. Chem., 2016, 81:8867-8875).
[0273] tert-Butyl (4-fluoro-3-nitrophenyl)carbamate (16): Compound
was synthesized using previously reported methods (Nguyen, T V, aa
et al. Angew. Chem. Int. Ed., 2017, 56:3940-3944).
[0274] tert-Butyl
(3-nitro-4-((3-phenylpropyl)amino)phenyl)carbamate (17): Compound
was synthesized using previously reported methods (Nguyen, T V, aa
et al. Angew. Chem. Int. Ed., 2017, 56:3940-3944).
[0275] tert-Butyl
(2-amino-1-(3-phenylpropyl)-1H-benzo[d]imidazol-5-yl)carbamate
(18): Compound was synthesized using previously reported methods
(Nguyen, T V, aa et al. Angew. Chem. Int. Ed., 2017,
56:3940-3944).
[0276] Compound Characterization.
[0277] N-(4-(Isobutylamino)-3-nitrophenyl)-4-pentylbenzamide (4d):
The title compound was synthesized from 3 following the general
procedure to afford 4d as a red solid (35%). 1H NMR (300 MHz,
CDCl3) .delta. 8.70 (brs, 1H), 8.24 (d, J=2.4 Hz, 1H), 8.06 (t,
J=4.8 Hz, 1H), 7.79 (d, J=8.4 Hz, 3H), 7.16 (d, J=8.1 Hz, 2H), 6.70
(d, J=8.7 Hz, 1H), 3.04 (t, J=6.0 Hz, 2H), 2.58 (t, J=7.2 Hz, 2H),
1.94 (m, J=6.6 Hz, 1H), 1.56 (m, 2H), 1.30 (m, 4H), 1.02 (d, J=6.9
Hz, 6H), 0.81 (t, J=6.8 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3)
.delta. 166.5, 147.3, 143.4, 131.6, 131.5, 130.4, 128.6, 127.3,
126.5, 118.7, 114.1, 50.8, 35.8, 31.5, 30.8, 28.0, 22.5, 20.4, 14.0
ppm; UV (.lamda.max nm) 296; IR vmax (cm-1) 3257, 2970, 1666, 1514,
800; HRMS (ESI) calcd for C22H29N3O3 [M+H]+ 384.2282, found
384.2279.
[0278]
N-(4-((2-(1H-Imidazol-5-yl)ethyl)amino)-3-nitrophenyl)-4-pentylbenz-
amide (4j): The title compound was synthesized from 3 following the
general procedure to afford 4j as a red solid (53%). 1H NMR (400
MHz, DMSO-d6) .delta. 10.30 (s, 1H), 8.69 (s, 1H), 8.23 (brs, 1H),
7.94 (m, S42 3H), 7.60 (s, 1H), 7.32 (d, J=8.0 Hz, 2H), 7.12 (d,
J=9.2 Hz, 1H), 6.93 (brs, 1H), 3.59 (m, 2H), 3.48 (brs, 3H), 2.88
(m, 2H), 2.63 (m, 2H), 1.55 (m, 2H), 1.26 (m, 4H), 0.84 (t, J=6.8
Hz, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) .delta. 165.2, 146.2,
142.2, 135.1, 132.0, 130.7, 129.8, 128.3, 127.8, 127.7, 116.4,
114.7, 42.7, 35.0, 30.9, 30.5, 22.0, 14.0 ppm; UV (.lamda.max nm)
292; IR vmax (cm-1) 3344, 2954, 1637, 1312, 811; HRMS (ESI) calcd
for C23H27N5O3 [M+H]+ 422.2187, found 422.2188.
[0279] N-(4-(Decylamino)-3-nitrophenyl)-4-pentylbenzamide (4m): The
title compound was synthesized from 3 following the general
procedure to afford 4m as a red solid (80%). 1H NMR (300 MHz,
CDCl3) .delta. 8.35 (brs, 1H), 8.21 (s, 1H), 7.97 (m, 1H), 7.87 (d,
J=8.7 Hz, 1H), 7.80 (d, J=7.8 Hz, 2H), 7.23 (d, J=7.5, 2H), 6.79
(d, J=9.3 Hz, 1H), 3.24 (m, 2H), 2.63 (t, J=7.8 Hz, 2H), 1.68 (m,
5H), 1.27 (m, 17H), 0.88 (m, 6H) ppm; 13C NMR (100 MHz, CDCl3)
.delta. 166.2, 147.5, 143.3, 131.7, 131.4, 130.6, 128.8, 127.3,
126.5, 118.4, 114.3, 43.3, 35.9, 32.0, 31.5, 31.0, 29.8, 29.6, 29.4
(.times.2), 29.1, 27.2, 22.8, 22.6, 14.2, 14.1 ppm; UV (.lamda.max
nm) 296; IR vmax (cm-1) 3370, 2920, 1649, 1520, 884; HRMS (ESI)
calcd for C28H41N3O3 [M+H]+ 468.3221, found 468.3220.
[0280]
N-(2-Amino-1-isobutyl-1H-benzo[d]imidazol-5-yl)-4-pentylbenzamide
hydrochloride (5d): The title compound was synthesized from 4d
following the general procedure to afford 5d as a white (53%). 1H 5
(300 MHz, CD3OD) 7.86 (d, J=7.5 Hz, 2H), 7.59 (s, 1H), 7.30 (m,
3H), 7.15 (m, 1H), 3.82 (d, J=7.8 Hz, 2H), 2.68 (t, J=7.5 Hz, 2H),
2.23 (m, 1H), 1.67 (m, 2H), 1.36 (m, 4H), 0.95 (m, 9H) ppm; 13C NMR
(100 MHz, CDCl3) .delta. 168.8, 151.8, 148.7, 136.8, 133.2, 130.1,
129.7, 128.7 (.times.2), 118.0, 111.8, 105.7, 50.6, 36.7, 32.5,
32.1, 28.9, 23.5, 19.9, 14.4 ppm; UV (.lamda.max nm) 286; IR vmax
(cm-1) 3227, 2945, 1663, 1514, 767; HRMS (ESI) calcd for C23H30N4O
[M+H]+ 379.2492, found 379.2495.
[0281]
N-(1-(2-(1H-Imidazol-5-yl)ethyl)-2-amino-1H-benzo[d]imidazol-5-yl)--
4-pentylbenzamide dihydrochloride (5j): The title compound was
synthesized from 4j following the general procedure to afford 5j as
a brown solid (61%). 1H NMR (300 MHz, CD3OD) .delta. 7.86 (m, 3H),
7.65 (s, 1H), 7.33 (m, 2H), 7.16 (d, J=8.7 Hz, 2H) 6.83 (s, 1H),
4.29 (t, J=6.9 Hz, 2H), 3.04 (t, J=6.6 Hz, 2H), 2.68 (t, J=7.5 Hz,
2H), 1.65 (m, 2H), 1.28 (m, 4H), 0.91 (t, J=7.2 Hz, 3H) ppm; 13C
NMR (100 MHz, CD3OD) .delta. 168.6, 151.5, 148.6, 136.9, 134.9,
133.0, 130.6, 130.0, 129.6, 128.7, 127.8, 118.9, 118.2, 111.1,
105.8, 43.2, 36.6, 32.4, 31.9, 24.1, 23.4, 14.3 ppm; UV (.lamda.max
nm) 294; IR vmax (cm-1) 3231, 2925, 1669, 1504, 805; HRMS (ESI)
calcd for C24H28N6O [M+H]+ 417.2397, found 417.2398.
[0282]
N-(2-Amino-1-decyl-1H-benzo[d]imidazol-5-yl)-4-pentylbenzamide
hydrochloride (5m): The title compound was synthesized from 4m
following the general procedure to afford 5m as a white solid
(39%). 1H NMR (300 MHz, CD3OD) .delta. 7.85 (m, 2H), 7.60 (brs,
1H), 7.29 (m, 3H), 7.09 (m, 1H), 3.95 (m, 2H), 2.65 (t, J=6.6 Hz,
2H), 1.71 (m, 4H), 1.31 (m, 18H), 0.89 (m, 6H) ppm; 13C NMR (100
MHz, CD3OD) .delta. 168.8, 156.4, 148.3, 141.8, 134.0, 133.8,
132.3, 129.6, 128.6, 115.4, 109.7, 108.7, 43.3, 36.7, 33.0, 32.6,
32.1, 30.7, 30.6, 30.5, 30.4, 29.7, 27.7, 23.7, 23.6, 14.5, 14.4
ppm; UV (.lamda.max nm) 296; IR vmax (cm-1) 3231, 2921, 1661, 1452,
801; HRMS (ESI) calcd for C29H42N4O [M+H]+ 463.3431, found
463.3434.
[0283] N-(3-Fluoro-4-nitrophenyl)-4-pentylbenzamide (7): The title
compound was synthesized from 6 following the general procedure to
afford 7 as a yellow solid (m.p=105.degree. C., 98%). 1H NMR (300
MHz, CDCl.sub.3) .delta. 8.60 (s, 1H), 8.04 (t, J=8.7 Hz, 1H), 7.92
(m, 1H), 7.78 (d, J=7.5 Hz, 2H), 7.43 (d, J=8.4 Hz, 1H), 7.26 (d,
J=8.4 Hz, 2H), 2.64 (5, J=7.5 Hz, 2H), 1.63 (m, 2H), 1.32 (m, 4H),
0.88 (t, J=6.6 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) .delta. 166.4,
158.1, 155.5, 148.8, 145.3, 145.2, 130.9, 129.1, 127.4, 127.3,
127.3, 114.9, 114.9, 108.9, 35.9, 31.5, 30.9, 22.6, 14.1 ppm; IR
vmax (cm-1) 3337, 2863, 1649, 1567, 1270, 866; HRMS (ESI) calcd for
C11H15N3S [M+H]+ 331.1453, found 331.1451.
[0284] N-(4-Nitro-3-(butylamino)phenyl)-4-pentylbenzamide (8a): The
title compound was synthesized from 7 following the general
procedure to afford 8a as a yellow solid (85%). 1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.59 (s, 1H), 8.20 (s, 1H), 8.08 (d, J=9.2 Hz,
1H), 7.80 (d, J=8.0 Hz, 2H), 7.69 (s, 1H), 7.23 (d, J=8.0 Hz, 2H),
6.68 (d, J=9.6 Hz, 1H), 3.26 (m, 2H), 2.64 (m, 2H), 1.66 (m, 4H),
1.4 (m, 2H), 1.31 (m, 4H), 0.95 (m, 3H), 0.86 (m, 3H) ppm; 13C NMR
(100 MHz, CDCl3) .delta. 166.5, 148.1, 147.3, 145.5, 131.5, 128.9,
128.2, 127.6, 127.3, 107.9, 102.4, 42.9, 35.9, 21.5, 31.0, 30.9,
22.5, 20.3, 14.0, 13.8 ppm; UV (.lamda.max nm) 320; IR vmax (cm-1)
3293, 2952, 1676, 1391, 800; HRMS (ESI) calcd for C22H29N3O3 [M+H]+
384.2282, found 384.2285.
[0285] N-(3-(Hexylamino)-4-nitrophenyl)-4-pentylbenzamide (8b): The
title compound was synthesized from 7 following the general
procedure to afford 8b as an orange solid (90%). 1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.26 (s, 1H), 8.16 (d, J=9.2 Hz, 1H), 8.00 (s,
1H), 7.79 (d, J=7.2 Hz, 2H), 7.74 (s, 1H), 7.31 (d, J=8.0 Hz, 2H),
6.54 (d, 9.2 Hz, 1H), 3.34 (m, 2H), 2.67 (t, J=7.2 Hz, 1.8 Hz, m,
2H), 1.73 (m, 2H), 1.65 (m, 2H), 1.45 (m, 2H), 1.33 (m, 8H), 0.90
(m, 6H) ppm; 13C NMR (100 MHz, CDCl3) .delta. 166.6, 148.0, 147.2,
145.6, 131.4, 128.8, 128.0, 127.3, 108.0, 102.4, 43.1, 35.8, 31.5,
30.8, 28.2, 26.7, 22.5, 22.4, 14.0 ppm; UV (.lamda.max nm) 320; IR
vmax (cm-1) 3295, 2955, 1678, 1395, 804; HRMS (ESI) calcd for
C24H33N3O3 [M+H]+ 412.2595, found 412.2601.
[0286] N-(3-(Methylamino)-4-nitrophenyl)-4-pentylbenzamide (8c):
The title compound was synthesized from 7 following the general
procedure to afford 8c as a yellow solid (m.p=127.degree. C.,
100%). 1H NMR (300 MHz, CDCl3) .delta. 8.21 (m, 3H), 7.78 (m, 2H),
7.68 (s, 1H), 7.24 (m, 3H), 6.60 (m, 1H), 3.04 (d, J=4.5 Hz, 3H),
2.63 (t, J=4.5 Hz, 2H), 1.64 (m, 2H), 1.36 (m, 4H), 0.91 (m, 3H)
ppm; 13C NMR (100 MHz, CDCl3) .delta. 166.6, 148.0, 147.9, 145.6,
131.3, 128.7, 128.0, 127.5, 127.3, 108.1, 102.0, 35.8, 31.4, 30.8,
29.6, 22.5, 14.0 ppm; IR vmax (cm-1) 3376, 2951, 1654, 1567, 1469,
803; HRMS (ESI) calcd for C11H15N3S [M+H]+ 342.1812, found
342.1809.
[0287] N-(3-(Ethylamino)-4-nitrophenyl)-4-pentylbenzamide (8d): The
title compound was synthesized from 7 following the general
procedure to afford 8d as a yellow solid (m.p=125.degree. C., 89%).
1H NMR (300 MHz, CDCl3) .delta. 8.15 (m, 3H), 7.75 (m, 3H), 7.22
(m, 2H), 6.58 (m, 1H), 3.38 (m, 2H), 2.65 (m, 2H), 1.65 (m, 2H),
1.33 (m, 7H), 0.87 (m, 3H) ppm; 13C NMR (100 MHz, CDCl3) .delta.
166.6, 148.1, 147.0, 145.6, 131.4, 128.8, 128.1, 127.4, 127.3,
108.0, 102.4, 37.8, 35.8, 31.4, 30.8, 22.5, 14.2, 14.0 ppm; IR vmax
(cm-1) 3378, 2950, 1658, 1560, 1473, 798; HRMS (ESI) calcd for
C11H15N3S [M+H]+ 356.1969, found 356.1965.
[0288] N-(3-(Isopropylamino)-4-nitrophenyl)-4-pentylbenzamide (8e):
The title compound was synthesized from 7 following the general
procedure to afford 8e as a yellow solid (53%). 1H NMR (300 MHz,
CDCl3) .delta. 8.59 (s, 1H), 8.20 (d, J=6.9 Hz, 1H), 8.07 (dd,
J=9.3 Hz, 3.6 Hz, 1H), 7.78 (m, 3H), 7.21 (m, 2H), 6.64 (m, 1H),
3.80 (m, 1H), 2.63 (m, 2H), 1.57 (t, J=5.1 Hz, 2H), 1.27 (m, 10H),
0.85 (m, 3H) ppm; 13C NMR (100 MHz, CDCl3) .delta. 166.9, 147.9,
146.2, 145.7, 131.3, 128.6, 128.0, 127.3, 127.2, 108.1, 102.7,
44.0, 35.7, 31.3, 30.7, 22.4 (.times.2), 13.9 ppm; UV (.lamda.max
nm) 320; IR vmax (cm-1) 3295, 2955, 1678, 1395, 804; HRMS (ESI)
calcd for C11H16N4S [M+H]+ 370.2125, found 370.2124.
[0289]
N-(2-Amino-1-butyl-1H-benzo[d]imidazol-6-yl)-4-pentylbenzamide
hydrochloride (9a): The title compound was synthesized from 8a
following the general procedure to afford 9a as a brown solid
(74%). '1H NMR (300 MHz, CD3OD) .delta. 8.03 (s, 1H), 7.88 (d,
J=8.1 Hz, 2H), 7.54 (d, J=8.4 Hz, 1H), 7.33 (m, 3H), 4.11 (t, J=7.2
Hz, 2H), 2.67 (t, J=6.9 Hz, 2H), 1.78 (m, 2H), 1.65 (m, 2H), 1.44
(m, 2H), 1.32 (m, 4H), 1.00 (t, J=7.2 Hz, 3H), 0.91 (t, J=6.9 Hz,
3H) ppm; 13C NMR (100 MHz, CD3OD) .delta. 168.7, 141.6, 148.7,
136.4, 133.1, 131.7, 129.6, 128.7, 126.5, 118.6, 112.6, 104.4,
48.4, 43.8, 36.7, 32.5, 32.0, 31.0, 23.5, 20.9, 14.4, 14.1 ppm; UV
(.lamda.max nm) 298; IR vmax (cm-1) 3316, 2961, 1638, 1499, 1426,
763; HRMS (ESI) calcd for C23H30N4O [M+H]+ 379.2492, found
379.2497.
[0290]
N-(2-Amino-1-hexyl-1H-benzo[d]imidazol-6-yl)-4-pentylbenzamide
hydrochloride (9b): The title compound was synthesized from 8b
following the general procedure to afford 9b as a burgundy solid
(69%). 1H NMR (300 MHz, CD3OD) .delta. 8.01 (d, J=1.8 Hz, 1H), 7.89
(d, J=8.1 Hz, 2H), 7.58 (dd, J=8.4 Hz, 1.5 Hz, 1H), 7.33 (d, J=8.1
Hz, 1H), 7.27 (d, J=8.1 Hz, 2H), 4.05 (t, J=7.5 Hz, 2H), 2.61 (t,
J=7.5, 2H), 1.70 (m, 2H), 1.35 (m, 2H), 1.29 (m, 10H), 0.83 (m, 6H)
ppm; 13C NMR (100 MHz, CD3OD) .delta. 168.5, 151.4, 148.6, 136.4,
133.0, 131.6, 129.5, 128.7, 126.4, 118.5, 112.5, 104.2, 43.9, 36.7,
32.5 (.times.2), 32.0, 28.9, 27.2, 23.5 (.times.2), 14.4, 14.3 ppm;
UV (.lamda.max nm) 298; IR vmax (cm-1) 3312, 2960, 1643, 1497,
1432, 758; HRMS (ESI) calcd for C25H34N4O [M+H]+ 407.2805, found
407.2810.
[0291]
N-(2-Amino-1-methyl-1H-benzo[d]imidazol-6-yl)-4-pentylbenzamide
hydrochloride (9c): The title compound was synthesized from 8c
following the general procedure to afford 9c as a white solid
(m.p=232.degree. C., 15%). 1H NMR (300 MHz, CD3OD) .delta. 7.86 (d,
J=7.2 Hz, 2H), 7.66 (s, 1H), 7.32 (d, J=7.8 Hz, 2H), 7.17 (s, 2H),
3.53 (s, 3H), 2.67 (t, J=7.2 Hz, 2H), 1.65 (m, 2H), 1.34 (m, 4H),
0.90 (t, J=6.8 Hz, 3H) ppm; 13C NMR (100 MHz, CD3OD) .delta. 168.8,
157.0, 148.4, 139.5, 135.6, 133.8, 132.4, 129.6, 128.6, 116.8,
115.3, 103.2, 36.7, 32.6, 32.2, 28.8, 23.6, 14.4 ppm; IR vmax
(cm-1) 3295, 2955, 1678, 1510, 1454, 732; HRMS (ESI) calcd for
C11H15N3S [M+H]+ 337.2023, found 337.2023.
[0292]
N-(2-Amino-1-ethyl-1H-benzo[d]imidazol-6-yl)-4-pentylbenzamide
hydrochloride (9d): The title compound was synthesized from 8d
following the general procedure to afford 9d as a whitepink solid
(m.p=234.degree. C., 30%). 1H NMR (400 MHz, CD3OD) .delta. 7.98 (s,
1H), 7.87 (d, J=8.0 Hz, 2H), 7.55 (d, J=8.8 Hz, 1H), 7.29 (m, 3H),
4.13 (q, J=7.2 Hz, 2H), 2.61 (t, J=7.6 Hz, 2H), 1.59 (m, 2H), 1.36
(t, J=7.2 Hz, 3H), 1.30 (m, 4H), 0.89 (t, J=6.4 Hz, 3H) ppm; 13C
NMR (100 MHz, CD3OD) .delta. 168.4, 151.4, 148.5, 136.4, 133.0,
131.1, 129.5, 128.7, 126.5, 118.6, 112.5, 104.1, 38.9, 36.7, 32.5,
32.0, 23.5, 14.4, 13.4 ppm; IR vmax (cm-1) 3299, 2940, 1659, 1540,
1470, 750; HRMS (ESI) calcd for C11H15N3S [M+H]+ 351.2179, found
351.2181.
[0293]
N-(2-Amino-1-isopropyl-1H-benzo[d]imidazol-6-yl)-4-pentylbenzamide
hydrochloride (9e): The title compound was synthesized from 8e
following the general procedure to afford 9e as a red solid
(m.p=252.degree. C., 20%). 1H NMR (400 MHz, CD3OD) .delta. 8.29 (s,
1H), 7.89 (d, J=7.6 Hz, 2H), 7.56 (d, J=8.4 Hz, 1H), 7.36 (m, 3H),
4.77 (m, J=6.4 Hz, 1H), 2.68 (t, J=7.2 Hz, 2H), 1.67 (m, 8H), 1.33
(m, 4H), 0.90 (t, J=6.8 Hz, 3H) ppm; 13C NMR (100 MHz, CD3OD)
.delta. 168.9, 151.1, 148.7, 136.1, 133.3, 130.1, 129.7, 128.7,
127.1, 118.4, 112.7, 106.5, 36.7, 32.6, 32.1, 23.5, 20.2, 14.4 ppm;
IR vmax (cm-1) 3315, 2963, 1640, 1497, 1432, 763; HRMS (ESI) calcd
for C11H15N3S [M+H]+ 365.2336, found 365.2338.
[0294]
2-Amino-N-(3,4-dichlorophenyl)-1-(3-phenylpropyl)-1H-benzo[d]imidaz-
ole-5-carboxamide hydrochloride (15): The title compound was
synthesized from 14 following the general procedure to afford 15 as
a white solid (40%). 1H NMR (400 MHz, CD3OD) .delta. 8.01 (s, 1H),
7.92 (m, 2H), 7.60 (m, 1H), 7.43 (m, 2H), 7.25 (m, 2H), 7.17 (m,
3H), 4.23 (t, J=6.6 Hz, 2H), 2.75 (t, J=7.4 Hz, 2H), 2.15 (t, J=6.8
Hz, 2H) ppm; 13C NMR (175 MHz, CD3OD) .delta. 167.2, 152.3, 141.7,
139.8, 134.3, 133.0, 131.5, 131.3, 130.1, 129.5, 129.2, 127.8,
127.2, 124.6, 123.1, 121.4, 112.5, 111.0, 43.9, 33.5, 30.3 ppm; UV
(.lamda.max nm) 298; IR vmax (cm-1) 3303, 1567, 1472, 1214, 856,
700; HRMS (ESI) calcd for C23H20Cl2N4O [M+H]+ 439.1087, found
439.1096.
[0295] Allyl tert-Butyl
(1-(3-phenylpropyl)-1H-benzo[d]imidazole-2,5-diyl)dicarbamate (19):
The title compound was synthesized from 18 following the general
procedure to afford 19 as a brown oil (25%). 1H NMR (300 MHz,
CD3OD) .delta. 7.62 (brs, 1H), 7.19 (m, 2H), 7.11 (m, 3H), 6.97 (d,
J=8.8 Hz, 2H), 6.00 (m, 1H), 5.36 (m, 1H), 5.18 (m, 1H), 4.61 (m,
2H), 3.35 (t, J=7.6 Hz, 2H), 2.57 (t, J=7.6 Hz, 2H), 1.95 (t, J=7.2
Hz, 2H), 1.49 (s, 9H) ppm; 13C NMR (100 MHz, CD3OD) .delta. 163.6,
155.2, 154.3, 142.3, 136.3, 134.9, 129.9, 129.3 (.times.2), 126.9,
126.6, 117.4, 115.5, 110.2, 103.6, 80.7, 67.1, 42.5, 33.7, 30.9,
28.7 ppm; UV (.lamda.max nm) 312; IR vmax (cm-1) 2929, 1710, 1499,
1364, 1150, 1052, 700; HRMS (ESI) calcd for C25H30N4O4 [M+H]+
451.2340, found 451.2351.
[0296]
1-(2-Amino-1-(3-phenylpropyl)-1H-benzo[d]imidazol-5-yl)-3-(3,4-dich-
lorophenyl)urea hydrochloride (19): The title compound was
synthesized from 19 following the general procedure to afford 20 as
a brown solid (20%). 1H NMR (300 MHz, CD3OD) .delta. 7.72 (m, 2H),
7.31 (m, 4H), 7.17 (m, 5H), 4.08 (t, J=7.4 Hz, 2H), 2.71 (t, J=7.8
Hz, 2H), 2.08 (t, J=7.2 Hz, 2H) ppm; 13C NMR (175 MHz, CD3OD)
.delta. 154.5, 151.2, 141.8, 140.6, 137.3, 133.1, 131.3, 130.4,
129.5, 129.2, 127.2, 127.0, 125.9, 121.1, 119.3, 116.2, 111.2,
103.7, 43.5, 33.6, 30.4 ppm; UV (.lamda.max nm) 298; IR vmax (cm-1)
2918, 1638, 1583, 1301, 1023, 813; HRMS (ESI) calcd for
C23H21Cl2N50 [M+H]+ 454.1196, found 454.1203.
CONCLUSIONS
[0297] After the identification of 2-ABI compound 1 as a S.
Typhimurium biofilm inhibitor, probing of the SAR of the 2-ABIs
elucidated six new analogues with IC.sub.50 values of less than 10
.mu.M. Utilizing the same para-pentyl benzoyl tail as the parent
compound 1, structural modifications to the head of the 2-ABIs in
the para position to the amide yielded compounds 5a and 5b with
IC.sub.50 values of 6.66.+-.0.32 and 9.59.+-.0.23 .mu.M
respectively. Modification of the tail region yielded compounds 15a
(5.22.+-.0.11 .mu.M), 15b (5.38.+-.0.79 .mu.M), 15c (5.58.+-.0.21
.mu.M), and 15d (6.3.+-.1.29 .mu.M) that displayed improved
activity. Modification of the linker between the head and the tail
yielded the urea compound 20 with a comparable IC50 (7.69.+-.0.25
.mu.M) to that of the amide parent compound, 10d (6.30.+-.1.29
.mu.M). Substitution the 2-ABI head at the meta position to the
amide (9a-e) and reversal of the amide moiety (15) did not produce
an increase in activity. Compounds 10a and 20 were then shown to be
non-toxic to planktonic bacterial growth at their IC.sub.50 values,
demonstrating that they show specific anti-S. Typhimurium biofilm
inhibitory activity. Additionally, compounds 10d and 10e and other
related 2-ABIs17 displayed no toxicity to G. mellonella at 400 mg
kg.sup.-1 (ESI.dagger.), thus making them potential candidates for
future in vivo studies.
[0298] It will be apparent to those skilled in the art that various
modifications and variations can be made in the present disclosure
without departing from the scope or spirit of the disclosure. Other
embodiments of the disclosure will be apparent to those skilled in
the art from consideration of the specification and practice of the
disclosure disclosed herein. It is intended that the specification
and examples be considered as exemplary only, with a true scope and
spirit of the disclosure being indicated by the following
claims.
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