U.S. patent application number 16/380116 was filed with the patent office on 2020-05-07 for compounds for the treatment of tuberculosis.
The applicant listed for this patent is THE BROAD INSTITUE, INC. MASSACHUSETTS GENERAL HOSPITAL BRIGHAM AND WOMEN'S HOSPITAL. Invention is credited to Sivaraman Dandapani, Sarah Grant, Deborah Hung, Tomohiko Kawate, Timothy A. Lewis, Benito Munoz, Partha Nag.
Application Number | 20200140425 16/380116 |
Document ID | / |
Family ID | 51659060 |
Filed Date | 2020-05-07 |
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United States Patent
Application |
20200140425 |
Kind Code |
A1 |
Lewis; Timothy A. ; et
al. |
May 7, 2020 |
COMPOUNDS FOR THE TREATMENT OF TUBERCULOSIS
Abstract
Disclosed are compounds that can be used for treating
tuberculosis.
Inventors: |
Lewis; Timothy A.;
(Marlborough, MA) ; Dandapani; Sivaraman; (Malden,
MA) ; Hung; Deborah; (Cambridge, MA) ; Munoz;
Benito; (Newtonville, MA) ; Nag; Partha;
(Somerville, MA) ; Grant; Sarah; (Boston, MA)
; Kawate; Tomohiko; (Cambridge, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
THE BROAD INSTITUE, INC.
MASSACHUSETTS GENERAL HOSPITAL
BRIGHAM AND WOMEN'S HOSPITAL |
Cambridge
Boston
Boston |
MA
MA
MA |
US
US
US |
|
|
Family ID: |
51659060 |
Appl. No.: |
16/380116 |
Filed: |
April 10, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14776477 |
Sep 14, 2015 |
10301294 |
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PCT/US2014/024344 |
Mar 12, 2014 |
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16380116 |
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61779051 |
Mar 13, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 271/10 20130101;
C07D 263/46 20130101; C07D 413/12 20130101; C07D 413/04 20130101;
C07D 271/113 20130101; C07D 417/12 20130101; C07D 417/04 20130101;
C07D 285/125 20130101; C07D 413/14 20130101; A61P 31/06
20180101 |
International
Class: |
C07D 413/12 20060101
C07D413/12; C07D 271/10 20060101 C07D271/10; C07D 271/113 20060101
C07D271/113; C07D 413/14 20060101 C07D413/14; C07D 413/04 20060101
C07D413/04; C07D 417/12 20060101 C07D417/12; C07D 263/46 20060101
C07D263/46; C07D 285/125 20060101 C07D285/125; C07D 417/04 20060101
C07D417/04 |
Goverment Interests
REFERENCE TO GOVERNMENT GRANTS
[0002] This invention was made with government support under Grant
No. 1R03MH087444, awarded by the National Institutes of Health, and
under Grant No. 1K08AI085033, awarded by the National Institutes of
Health. The U.S. Government may therefore have certain rights in
the invention.
Claims
1-24. (canceled)
25. A compound of Formula I or a pharmaceutically acceptable salt
thereof: ##STR00294## wherein: A.sub.1, is O; A.sub.2 is N; R.sub.1
is S, N, O, optionally substituted C.sub.1-C.sub.6 linear or
branched alkyl, or sulfonyl, as valence and stability permit;
R.sub.2 is null or optionally substituted linear or branched
C.sub.1-C.sub.12 alkyl; R.sub.3 is null, O, H, optionally
substituted C.sub.1-C.sub.6 linear or branched alkyl, or
##STR00295## as valence and stability permit; R.sub.4 is H, an
optionally substituted aryl, an optionally substituted heteroaryl,
an optionally substituted heterocycle, optionally substituted
C.sub.1-C.sub.6 alkoxy, or an optionally substituted amide; R.sub.5
is an optionally substituted heteroaryl, optionally substituted
C.sub.4-C.sub.6 carbocycle, or optionally substituted
C.sub.1-C.sub.6 linear or branched alkyl.
26. The compound of claim 25 or a pharmaceutically acceptable salt
thereof, wherein R.sub.4 is H, ##STR00296## optionally substituted
C.sub.1-C.sub.6 alkoxy, or optionally substituted alkylamino,
wherein R.sub.7 is H, ##STR00297## halo, cyano, C.sub.1-C.sub.6
alkoxy, linear or branched alkyl, haloalkyl, optionally substituted
aryl; optionally substituted arylalkyl, halogen substituted
C.sub.1-C.sub.6 alkoxy; and R.sub.8 and R.sub.9 are independently
H, OH, halo, or C.sub.1-C.sub.6 alkyl.
27. The compound of claim 25 or or a pharmaceutically acceptable
salt thereof, wherein R.sub.5 is C.sub.1-C.sub.6 linear or branched
alkyl, ##STR00298## wherein R.sub.6 is H, halo, optionally
substituted aryl, C.sub.1-C.sub.6 linear or branched alkyl,
C.sub.1-C.sub.6 alkoxy, haloalkyl, halogen substituted
C.sub.1-C.sub.6 alkoxy, cyano, or ##STR00299##
28-30. (canceled)
31. The compound of claim 25 or a pharmaceutically acceptable salt
thereof, wherein R.sub.3 is null.
32. The compound of claim 25 or a pharmaceutically acceptable salt
thereof, wherein R.sub.2 is null or C.sub.1-C.sub.12 alkyl.
33. The compound of claim 25 or a pharmaceutically acceptable salt
thereof, wherein R.sub.1 is S; and R.sub.3 is null.
34. (canceled)
35. The compound of claim 25, or a pharmaceutically acceptable salt
thereof wherein R.sub.5 is C.sub.1-C.sub.6 linear or branched
alkyl, ##STR00300## wherein R.sub.6 is H, halo, optionally
substituted aryl, C.sub.1-C.sub.6 linear or branched alkyl,
C.sub.1-C.sub.6 alkoxy, haloalkyl, halogen substituted
C.sub.1-C.sub.6 alkoxy, cyano, or ##STR00301##
36. The compound of claim 35, or a pharmaceutically acceptable salt
thereof wherein R.sub.5 is: ##STR00302## wherein R.sub.6 is H,
halo, C.sub.1-C.sub.6 linear or branched alkyl, C.sub.1-C.sub.6
haloalkyl, cyano, C.sub.1-C.sub.6 alkoxy, halogen substituted
C.sub.1-C.sub.6 alkoxy, OH,
--O(CH.sub.2).sub.qC(.dbd.O)O(CH.sub.2).sub.pCH.sub.3,
--O(CH.sub.2).sub.qC(.dbd.O)N(H)(CH.sub.2).sub.pO(CH.sub.2).sub.mN.sub.3,
--O(CH.sub.2).sub.qC.ident.CH, or ##STR00303## wherein m, p and q
are independently 1-4.
37. (canceled)
38. The compound of claim 36, or a pharmaceutically acceptable salt
thereof wherein R.sub.6 is H, halo, methyl, ethyl, or propyl,
CF.sub.3, cyano, OH,
--O(CH.sub.2).sub.qC(.dbd.O)O(CH.sub.2).sub.pCH.sub.3,
--O(CH.sub.2).sub.qC(.dbd.O)N(H)(CH.sub.2).sub.pO(CH.sub.2).sub.mN.sub.3,
or --O(CH.sub.2).sub.qC.ident.CH.
39. The compound of claim 36, or a pharmaceutically acceptable salt
thereof wherein R.sub.6 is H, methyl, ethyl, or propyl, CF.sub.3,
halo, C.sub.1-C.sub.6 alkoxy, OH,
--O(CH.sub.2).sub.qC(.dbd.O)O(CH.sub.2).sub.pCH.sub.3,
--O(CH.sub.2).sub.qC(.dbd.O)N(H)(CH.sub.2).sub.pO(CH.sub.2).sub.mN.sub.3,
or --O(CH.sub.2).sub.qC.ident.CH.
40. The compound of claim 36, or a pharmaceutically acceptable salt
thereof wherein R.sub.6 is halo.
41. The compound of claim 25, or a pharmaceutically acceptable salt
thereof wherein R.sub.1 is S or sulfonyl.
42. The compound of claim 25, or a pharmaceutically acceptable salt
thereof wherein R.sub.1 is N.
43. The compound of claim 1, or a pharmaceutically acceptable salt
thereof wherein R.sub.1 is optionally substituted C.sub.1-C.sub.6
linear or branched alkyl.
44. The compound of claim 25, or a pharmaceutically acceptable salt
thereof wherein: R.sub.1 is S; R.sub.2 null or optionally
substituted linear or branched C.sub.1-C.sub.12 alkyl; R.sub.3 is
null or O; and R.sub.4 is H, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
heterocycle, optionally substituted C.sub.1-C.sub.6 alkoxy, or an
optionally substituted amide.
45. The compound of claim 44, or a pharmaceutically acceptable salt
thereof wherein: R.sub.4 is H, --C.ident.CH,
--C.ident.C(CH.sub.2).sub.tOH,
--C(.dbd.O)O(CH.sub.2).sub.tCH.sub.3, --O(CH.sub.2).sub.uCH.sub.3,
--O(CH.sub.2).sub.qC(.dbd.O)O(CH.sub.2).sub.pCH.sub.3 ##STR00304##
optionally substituted C.sub.1-C.sub.6 alkoxy, optionally
substituted alkylamino, or C.sub.1-C.sub.6 carbocycle, wherein
R.sub.7 is H, O, ##STR00305## halo, cyano,
--C(.dbd.O)N(H)(CH.sub.2).sub.pO(CH.sub.2).sub.mN.sub.3,
--O(CH.sub.2).sub.qC(.dbd.O)N(H)(CH.sub.2).sub.pO(CH.sub.2).sub.mN.sub.3,
--O(CH.sub.2).sub.mN.sub.3, --O(CH.sub.2).sub.mC.ident.CH,
C.sub.1-C.sub.6 alkoxy, optionally substituted C.sub.1-C.sub.6
linear or branched alkyl, haloalkyl, optionally substituted aryl;
optionally substituted arylalkyl, or halogen substituted
C.sub.1-C.sub.6 alkoxy; and R.sub.8 and R.sub.9 are independently
H, OH, .dbd.O, halo, or C.sub.1-C.sub.6 alkyl. m, p and q are
independently 1-6; and t and u are independently 0-6.
46. The compound of claim 25 or a pharmaceutically acceptable salt
thereof, wherein the compound has the Formula I-b, I-c, I-d, or
I-e: ##STR00306## wherein R.sub.4 is H, --C.ident.CH,
--C.ident.C(CH.sub.2).sub.tOH,
--C(.dbd.O)O(CH.sub.2).sub.tCH.sub.3, --O(CH.sub.2).sub.uCH.sub.3,
--O(CH.sub.2).sub.qC(.dbd.O)(O)CH.sub.2).sub.pCH.sub.3,
##STR00307## optionally substituted C.sub.1-C.sub.6 alkoxy,
optionally substituted alkylamino, or C.sub.1-C.sub.6 carbocycle,
R.sub.7 is H, O, ##STR00308## halo, cyano,
--C(.dbd.O)N(H)(CH.sub.2).sub.pO(CH.sub.2).sub.mN.sub.3,
--O(CH.sub.2).sub.qC(.dbd.O)N(H)(CH.sub.2).sub.pO(CH.sub.2).sub.mN.sub.3,
--O(CH.sub.2).sub.mN.sub.3, --O(CH.sub.2).sub.mC.ident.CH,
C.sub.1-C.sub.6 alkoxy, optionally substituted C.sub.1-C.sub.6
linear or branched alkyl, haloalkyl, optionally substituted aryl;
optionally substituted arylalkyl, or halogen substituted
C.sub.1-C.sub.6 alkoxy; and R.sub.8 and R.sub.9 are independently
H, OH, .dbd.O, halo, or C.sub.1-C.sub.6 alkyl; R.sub.5 is
##STR00309## R.sub.6 is H, halo, C.sub.1-C.sub.6 linear or branched
alkyl, C.sub.1-C.sub.6 haloalkyl, cyano, C.sub.1-C.sub.6 alkoxy,
halogen substituted C.sub.1-C.sub.6 alkoxy, OH,
--O(CH.sub.2).sub.qC(.dbd.O)O(CH.sub.2).sub.pCH.sub.3,
--O(CH.sub.2).sub.qC(.dbd.O)N(H)(CH.sub.2).sub.pO(CH.sub.2).sub.mN.sub.3,
--O(CH.sub.2).sub.qC.ident.CH, or ##STR00310## wherein m, p, q, and
z are independently 1-6; t and u are independently 0-6.
47. The compound of claim 25, or a pharmaceutically acceptable salt
thereof, wherein the compound is selected from ##STR00311##
##STR00312## ##STR00313##
48. The compound of claim 25, or a pharmaceutically acceptable salt
thereof, provided that the compound is not selected from:
49-55. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Continuation Application of U.S. Ser.
No. 14/776,477 filed Sep. 14, 2015, now U.S. Pat. No. 10,301,294,
which is a 371 National Stage of PCT/US2014/024344 filed Mar. 12,
2014, which claims priority to U.S. Provisional Application No.
61/779,051 filed Mar. 13, 2013, which is hereby incorporated by
reference in its entirety.
FIELD OF THE INVENTION
[0003] The present invention is directed, in part, to compounds or
pharmaceutically acceptable salts thereof, for treating
tuberculosis.
BACKGROUND OF THE INVENTION
[0004] The problem of tuberculosis continues to take a tremendous
toll on global health, accounting for almost 2 million deaths per
year, despite the discovery of antitubercular chemotherapy more
than half a century ago. In fact, the crisis is growing due to the
alarming increase in multi-drug resistant, and even totally-drug
resistant strains, coupled with the extremely little progress made
in discovering new TB drugs. One of the major barriers to
discovering new, potentially more effective agents has been the
lack of a fundamental understanding of the physiology of the M.
tuberculosis bacilli as they exist within the infected human host.
This physiology contributes to their ability to survive for decades
within an infected individual despite host immunity, and to persist
even in the face of what should otherwise be effective chemotherapy
thus dictating the extremely long treatment courses that are
required for cure. Accordingly, there is a need for new compounds
and therapeutics for treating tuberculosis. The present disclosure
fulfills these needs as well as others.
SUMMARY OF THE INVENTION
[0005] In some embodiments, pharmaceutical compositions are
provided. In some embodiments, the pharmaceutical composition
comprises a compound of Formula I or a pharmaceutically acceptable
salt, ester or prodrug thereof:
##STR00001##
[0006] wherein:
[0007] A.sub.1, is S or O;
[0008] A.sub.2 is C or N;
[0009] R.sub.1 is S, N, O, optionally substituted C.sub.1-C.sub.6
linear or branched alkyl, or sulfonyl,
[0010] R.sub.2 is null or optionally substituted linear or branched
C.sub.1-C.sub.12 alkyl;
[0011] R.sub.3 is null, O, H, optionally substituted
C.sub.1-C.sub.6 linear or branched alkyl,
##STR00002##
[0012] R.sub.4 is H, an optionally substituted aryl, an optionally
substituted heteroaryl, an optionally substituted heterocycle,
optionally substituted C.sub.1-C.sub.6 alkoxy, or an optionally
substituted amide;
[0013] R.sub.5 is an optionally substituted aryl, optionally
substituted arylalkyl, optionally substituted heteroaryl,
optionally substituted C.sub.4-C.sub.6 carbocycle, or optionally
substituted C.sub.1-C.sub.6 linear or branched alkyl.
[0014] In some embodiments, the pharmaceutical composition
comprises a compound described herein.
[0015] In some embodiments, a compound of Formula I or a
pharmaceutically acceptable salt, ester or prodrug thereof:
##STR00003##
[0016] wherein:
[0017] A.sub.1, is S or O;
[0018] A.sub.2 is C or N;
[0019] R.sub.1 is S, N, O, optionally substituted C.sub.1-C.sub.6
linear or branched alkyl, or sulfonyl,
[0020] R.sub.2 is null or optionally substituted linear or branched
C.sub.1-C.sub.12 alkyl;
[0021] R.sub.3 is null, O, H, optionally substituted
C.sub.1-C.sub.6 linear or branched alkyl,
##STR00004##
[0022] R.sub.4 is H, an optionally substituted aryl, an optionally
substituted heteroaryl, an optionally substituted heterocycle,
optionally substituted C.sub.1-C.sub.6 alkoxy, or an optionally
substituted amide;
[0023] R.sub.5 is an optionally substituted aryl, optionally
substituted arylalkyl, optionally substituted heteroaryl,
optionally substituted C.sub.4-C.sub.6 carbocycle, or optionally
substituted C.sub.1-C.sub.6 linear or branched alkyl is
provided.
[0024] In some embodiments, a method of treating tuberculosis
comprising administering to a subject a pharmaceutical composition
described herein or a compound described herein is provided. In
some embodiments, the tuberculosis is replicating. In some
embodiments, the tuberculosis is non-replicating. In some
embodiments, the compound or pharmaceutical composition selectively
inhibits replicating or non-replicating tuberculosis.
BRIEF DESCRIPTION OF FIGURES
[0025] FIGS. 1A-1D describe the characteristics of
2-(4-chlorophenyl)-5-(((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)thio)-1,3,4-
-oxadiazole;
[0026] FIG. 1A is a close response curve against replicating,
logarithmically growing bacteria measured by OD600;
[0027] FIG. 1B is a close response against replicating,
logarithmically growing bacteria measured by CFU/mL;
[0028] FIG. 1C is a close response curve for non-replicating
starved cells by luciferase assay; and
[0029] FIG. 1D is a close response against non-replicating, starved
cells by CFU/mL.
DESCRIPTION OF EMBODIMENTS
[0030] Unless defined otherwise, all technical and scientific terms
have the same meaning as is commonly understood by one of ordinary
skill in the art to which the embodiments disclosed belongs.
[0031] As used herein, the terms "a" or "an" means that "at least
one" or "one or more" unless the context clearly indicates
otherwise.
[0032] As used herein, the term "about" means that the numerical
value is approximate and small variations would not significantly
affect the practice of the disclosed embodiments. Where a numerical
limitation is used, unless indicated otherwise by the context,
"about" means the numerical value can vary by .+-.10% and remain
within the scope of the disclosed embodiments.
[0033] As used herein, the terms "IC90" or "IC99" when used as
reference to a non-replicating population of M. tuberculosis is the
inhibitory concentration of a compound or compositions that results
in 90% or 99% killing of the non-replicating population of M.
tuberculosis, respectively. As used herein, the terms "IC90" or
"IC99" when used as reference to a replicating population of M.
tuberculosis is the "inhibitory concentration" that results in 90%
or 99% growth inhibition of a replicating population of M.
tuberculosis.
[0034] As used herein, the term "alkenyl" means a straight or
branched alkyl group having one or more double carbon-carbon bonds
and 2-20 carbon atoms, including, but not limited to, ethenyl,
1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl,
and the like. In some embodiments, the alkenyl chain is from 2 to
10 carbon atoms in length, from 2 to 8 carbon atoms in length, from
2 to 6 carbon atoms in length, or from 2 to 4 carbon atoms in
length.
[0035] The terms "alkoxy", "phenyloxy", "benzoxy" and
"pyrimidinyloxy" refer to an alkyl group, phenyl group, benzyl
group, or pyrimidinyl group, respectively, each optionally
substituted, that is bonded through an oxygen atom. For example,
the term "alkoxy" means a straight or branched --O-alkyl group of 1
to 20 carbon atoms, including, but not limited to, methoxy, ethoxy,
n-propoxy, isopropoxy, t-butoxy, and the like. In some embodiments,
the alkoxy chain is from 1 to 10 carbon atoms in length, from 1 to
8 carbon atoms in length, from 1 to 6 carbon atoms in length, from
1 to 4 carbon atoms in length, from 2 to 10 carbon atoms in length,
from 2 to 8 carbon atoms in length, from 2 to 6 carbon atoms in
length, or from 2 to 4 carbon atoms in length.
[0036] As used herein, the term "alkyl" means a saturated
hydrocarbon group which is straight-chained or branched. An alkyl
group can contain from 1 to 20, from 2 to 20, from 1 to 10, from 2
to 10, from 1 to 8, from 2 to 8, from 1 to 6, from 2 to 6, from 1
to 4, from 2 to 4, from 1 to 3, or 2 or 3 carbon atoms. Examples of
alkyl groups include, but are not limited to, methyl (Me), ethyl
(Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl,
t-butyl, isobutyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl),
hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,
2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl,
2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,
3-methyl-1-butyl, 2-methyl-3-butyl, 2-methyl-1-pentyl,
2,2-dimethyl-1-propyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,
2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,
2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, and
the like.
[0037] As used herein, the term "alkylamino" means an amino group
substituted by an alkyl group having from 1 to 6 carbon atoms. An
example of an alkylamino is --NHCH.sub.2CH.sub.3.
[0038] As used herein, the term "alkylene" or "alkylenyl" means a
divalent alkyl linking group. An example of an alkylene (or
alkylenyl) is methylene or methylenyl (--CH.sub.2--).
[0039] As used herein, the term "alkylthio" means an --S-alkyl
group having from 1 to 6 carbon atoms. An example of an alkylthio
group is --SCH.sub.2CH.sub.3.
[0040] As used herein, the term "alkynyl" means a straight or
branched alkyl group having one or more triple carbon-carbon bonds
and 2-20 carbon atoms, including, but not limited to, acetylene,
1-propylene, 2-propylene, and the like. In some embodiments, the
alkynyl chain is 2 to 10 carbon atoms in length, from 2 to 8 carbon
atoms in length, from 2 to 6 carbon atoms in length, or from 2 to 4
carbon atoms in length.
[0041] As used herein, the term "amidino" means
--C(.dbd.NH)NH.sub.2.
[0042] As used herein, the term "amino" means --NH.sub.2.
[0043] As used herein, the term "aminoalkoxy" means an alkoxy group
substituted by an amino group. An example of an aminoalkoxy is
--OCH.sub.2CH.sub.2NH.sub.2.
[0044] As used herein, the term "aminoalkyl" means an alkyl group
substituted by an amino group. An example of an aminoalkyl is
--CH.sub.2CH.sub.2NH.sub.2.
[0045] As used herein, the term "aminosulfonyl" means
--S(.dbd.O).sub.2NH.sub.2.
[0046] As used herein, the term "aminoalkylthio" means an alkylthio
group substituted by an amino group. An example of an
aminoalkylthio is --SCH.sub.2CH.sub.2NH.sub.2.
[0047] As used herein, the term "animal" includes, but is not
limited to, humans and non-human vertebrates such as wild,
domestic, and farm animals.
[0048] As used herein, the term "aryl" means a monocyclic,
bicyclic, or polycyclic (e.g., having 2, 3 or 4 fused rings)
aromatic hydrocarbons. In some embodiments, aryl groups have from 6
to 20 carbon atoms or from 6 to 10 carbon atoms. Examples of aryl
groups include, but are not limited to, phenyl, naphthyl,
anthracenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthyl,
and the like. Examples of aryl groups include, but are not limited
to:
##STR00005## ##STR00006## ##STR00007## ##STR00008##
##STR00009##
[0049] As used herein, the term "arylalkyl" means a C.sub.1-6alkyl
substituted by aryl.
[0050] As used herein, the term "arylamino" means an amino group
substituted by an aryl group. An example of an arylamino is
--NH(phenyl).
[0051] As used herein, the term "arylene" means an aryl linking
group, i.e., an aryl group that links one group to another group in
a molecule.
[0052] As used herein, the term "carbamoyl" means
--C(.dbd.O)--NH.sub.2.
[0053] As used herein, the term "carbocycle" means a 5- or
6-membered, saturated or unsaturated cyclic ring, optionally
containing O, S, or N atoms as part of the ring. Examples of
carbocycles include, but are not limited to, cyclopentyl,
cyclohexyl, cyclopenta-1,3-diene, phenyl, and any of the
heterocycles recited above.
[0054] As used herein, the term "carrier" means a diluent,
adjuvant, or excipient with which a compound is administered.
Pharmaceutical carriers can be liquids, such as water and oils,
including those of petroleum, animal, vegetable or synthetic
origin, such as peanut oil, soybean oil, mineral oil, sesame oil
and the like. The pharmaceutical carriers can also be saline, gum
acacia, gelatin, starch paste, talc, keratin, colloidal silica,
urea, and the like. In addition, auxiliary, stabilizing,
thickening, lubricating and coloring agents can be used.
[0055] As used herein, the term, "compound" means all
stereoisomers, tautomers, and isotopes of the compounds described
herein.
[0056] As used herein, the terms "comprising" (and any form of
comprising, such as "comprise", "comprises", and "comprised"),
"having" (and any form of having, such as "have" and "has"),
"including" (and any form of including, such as "includes" and
"include"), or "containing" (and any form of containing, such as
"contains" and "contain"), are inclusive or open-ended and do not
exclude additional, unrecited elements or method steps.
[0057] As used herein, the term "contacting" means bringing
together of two elements in an in vitro system or an in vivo
system.
[0058] As used herein, the term "cyano" means --CN.
[0059] As used herein, the term "cycloalkyl" means non-aromatic
cyclic hydrocarbons including cyclized alkyl, alkenyl, and alkynyl
groups that contain up to 20 ring-forming carbon atoms. Cycloalkyl
groups can include mono- or polycyclic ring systems such as fused
ring systems, bridged ring systems, and spiro ring systems. In some
embodiments, polycyclic ring systems include 2, 3, or 4 fused
rings. A cycloalkyl group can contain from 3 to 15, from 3 to 10,
from 3 to 8, from 3 to 6, from 4 to 6, from 3 to 5, or 5 or 6
ring-forming carbon atoms. Ring-forming carbon atoms of a
cycloalkyl group can be optionally substituted by oxo or sulfido.
Examples of cycloalkyl groups include, but are not limited to,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl,
cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl,
adamantyl, and the like. Also included in the definition of
cycloalkyl are moieties that have one or more aromatic rings fused
(having a bond in common with) to the cycloalkyl ring, for example,
benzo or thienyl derivatives of pentane, pentene, hexane, and the
like (e.g., 2,3-dihydro-1H-indene-1-yl, or
1H-inden-2(3H)-one-1-yl).
[0060] As used herein, the term "cycloalkylalkyl" means a
C.sub.1-6alkyl substituted by cycloalkyl.
[0061] As used herein, the term "dialkylamino" means an amino group
substituted by two alkyl groups, each having from 1 to 6 carbon
atoms.
[0062] As used herein, the term "diazamino" means
--N(NH.sub.2).sub.2.
[0063] As used herein, the term "guanidino" means
--NH(.dbd.NH)NH.sub.2.
[0064] As used herein, the term "halo" means halogen groups
including, but not limited to fluoro, chloro, bromo, and iodo.
[0065] As used herein, the term "haloalkoxy" means an --O-haloalkyl
group. An example of an haloalkoxy group is OCF.sub.3.
[0066] As used herein, the term "haloalkyl" means a C.sub.1-6alkyl
group having one or more halogen substituents. Examples of
haloalkyl groups include, but are not limited to, CF.sub.3,
C.sub.2F.sub.5, CHF.sub.2, CCl.sub.3, CHCl.sub.2, C.sub.2Cl.sub.5,
CH.sub.2CF.sub.3, and the like.
[0067] As used herein, the term "heteroaryl" means an aromatic
heterocycle having up to 20 ring-forming atoms (e.g., C) and having
at least one heteroatom ring member (ring-forming atom) such as
sulfur, oxygen, or nitrogen. In some embodiments, the heteroaryl
group has at least one or more heteroatom ring-forming atoms, each
of which are, independently, sulfur, oxygen, or nitrogen. In some
embodiments, the heteroaryl group has from 3 to 20 ring-forming
atoms, from 3 to 10 ring-forming atoms, from 3 to 6 ring-forming
atoms, or from 3 to 5 ring-forming atoms. In some embodiments, the
heteroaryl group contains 2 to 14 carbon atoms, from 2 to 7 carbon
atoms, or 5 or 6 carbon atoms. In some embodiments, the heteroaryl
group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 or 2
heteroatoms. Heteroaryl groups include monocyclic and polycyclic
(e.g., having 2, 3 or 4 fused rings) systems. Examples of
heteroaryl groups include, but are not limited to, pyridyl,
pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl,
isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl (such as
indol-3-yl), pyrryl, oxazolyl, benzofuryl, benzothienyl,
benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl,
indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl,
carbazolyl, benzimidazolyl, indolinyl, pyranyl, oxadiazolyl,
isoxazolyl, triazolyl, thianthrenyl, pyrazolyl, indolizinyl,
isoindolyl, isobenzofuranyl, benzoxazolyl, xanthenyl, 2H-pyrrolyl,
pyrrolyl, 3H-indolyl,
[0068] 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinazolinyl,
phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl,
phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl,
phenoxazinyl groups, and the like. Suitable heteroaryl groups
include 1,2,3-triazole,
[0069] 1,2,4-triazole, 5-amino-1,2,4-triazole, imidazole, oxazole,
isoxazole, 1,2,3-oxadiazole,
[0070] 1,2,4-oxadiazole, 3-amino-1,2,4-oxadiazole,
1,2,5-oxadiazole, 1,3,4-oxadiazole, pyridine, and
2-aminopyridine.
[0071] As used herein, the term "heteroarylalkyl" means a
C.sub.1-6alkyl group substituted by a heteroaryl group.
[0072] As used herein, the term "heteroarylamino" means an amino
group substituted by a heteroaryl group. An example of a
heteroarylamino is --NH-(2-pyridyl).
[0073] As used herein, the term "heteroarylene" means a heteroaryl
linking group, i.e., a heteroaryl group that links one group to
another group in a molecule.
[0074] As used herein, the term "heterocycle" or "heterocyclic
ring" means a 5- to 7-membered mono- or bicyclic or 7- to
10-membered bicyclic heterocyclic ring system any ring of which may
be saturated or unsaturated, and which consists of carbon atoms and
from one to three heteroatoms chosen from N, O and S, and wherein
the N and S heteroatoms may optionally be oxidized, and the N
heteroatom may optionally be quaternized, and including any
bicyclic group in which any of the above-defined heterocyclic rings
is fused to a benzene ring. Particularly useful are rings
containing one oxygen or sulfur, one to three nitrogen atoms, or
one oxygen or sulfur combined with one or two nitrogen atoms. The
heterocyclic ring may be attached at any heteroatom or carbon atom
which results in the creation of a stable structure. Examples of
heterocyclic groups include, but are not limited to, piperidinyl,
piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl,
2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl,
pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl,
pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl,
oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl,
thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl,
indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl,
benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl,
tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl,
thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and
oxadiazolyl. Morpholino is the same as morpholinyl.
[0075] As used herein, the term "heterocycloalkyl" means
non-aromatic heterocycles having up to 20 ring-forming atoms
including cyclized alkyl, alkenyl, and alkynyl groups, where one or
more of the ring-forming carbon atoms is replaced by a heteroatom
such as an O, N, or S atom. Hetercycloalkyl groups can be mono or
polycyclic (e.g., fused, bridged, or spiro systems). In some
embodiments, the heterocycloalkyl group has from 1 to 20 carbon
atoms, or from 3 to 20 carbon atoms. In some embodiments, the
heterocycloalkyl group contains 3 to 14 ring-forming atoms, 3 to 7
ring-forming atoms, or 5 or 6 ring-forming atoms. In some
embodiments, the heterocycloalkyl group has 1 to 4 heteroatoms, 1
to 3 heteroatoms, or 1 or 2 heteroatoms. In some embodiments, the
heterocycloalkyl group contains 0 to 3 double bonds. In some
embodiments, the heterocycloalkyl group contains 0 to 2 triple
bonds. Examples of heterocycloalkyl groups include, but are not
limited to, morpholino, thiomorpholino, piperazinyl,
tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl,
1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl, pyrrolidinyl,
isoxazolidinyl, oxazolidinyl, isothiazolidinyl, pyrazolidinyl,
thiazolidinyl, imidazolidinyl, pyrrolidin-2-one-3-yl, and the like.
In addition, ring-forming carbon atoms and heteroatoms of a
heterocycloalkyl group can be optionally substituted by oxo or
sulfido. For example, a ring-forming S atom can be substituted by 1
or 2 oxo (form a S(O) or S(O).sub.2). For another example, a
ring-forming C atom can be substituted by oxo (form carbonyl). Also
included in the definition of heterocycloalkyl are moieties that
have one or more aromatic rings fused (having a bond in common
with) to the nonaromatic heterocyclic ring including, but not
limited to, pyridinyl, thiophenyl, phthalimidyl, naphthalimidyl,
and benzo derivatives of heterocycles such as indolene,
isoindolene, 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-yl,
5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one-5-yl,
isoindolin-1-one-3-yl, and 3,4-dihydroisoquinolin-1(2H)-one-3yl
groups. Ring-forming carbon atoms and heteroatoms of the
heterocycloalkyl group can be optionally substituted by oxo or
sulfido.
[0076] As used herein, the term "heterocycloalkylalkyl" refers to a
C.sub.1-6alkyl substituted by heterocycloalkyl.
[0077] As used herein, the term "hydoxy" or "hydroxyl" means an
--OH group.
[0078] As used herein, the term "hydroxyalkyl" or "hydroxylalkyl"
means an alkyl group substituted by a hydroxyl group. Examples of a
hydroxylalkyl include, but are not limited to, --CH.sub.2OH and
--CH.sub.2CH.sub.2OH.
[0079] As used herein, the term "individual" or "patient," used
interchangeably, means any animal, including mammals, such as mice,
rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,
horses, or primates, such as humans. The individual can also be
referred to as a subject.
[0080] As used herein, the phrase "in need thereof" means that the
animal or mammal has been identified as having a need for the
particular method or treatment. In some embodiments, the
identification can be by any means of diagnosis. In any of the
methods and treatments described herein, the animal or mammal can
be in need thereof. In some embodiments, the animal or mammal is in
an environment or will be traveling to an environment in which a
particular disease, disorder, or condition is prevalent.
[0081] As used herein, the phrase "integer from X to Y" means any
integer that includes the endpoints. For example, the phrase
"integer from X to Y" means 1, 2, 3, 4, or 5.
[0082] As used herein, the term "isolated" means that the compounds
described herein are separated from other components of either (a)
a natural source, such as a plant or cell, or (b) a synthetic
organic chemical reaction mixture, such as by conventional
techniques.
[0083] As used herein, the term "mammal" means a rodent (i.e., a
mouse, a rat, or a guinea pig), a monkey, a cat, a dog, a cow, a
horse, a pig, or a human. In some embodiments, the mammal is a
human.
[0084] As used herein, the term "nitro" means --NO.sub.2.
[0085] As used herein, the term "n-membered", where n is an
integer, typically describes the number of ring-forming atoms in a
moiety, where the number of ring-forming atoms is n. For example,
pyridine is an example of a 6-membered heteroaryl ring and
thiophene is an example of a 5-membered heteroaryl ring.
[0086] As used herein, the phrase "optionally substituted" means
that substitution is optional and therefore includes both
unsubstituted and substituted atoms and moieties. A "substituted"
atom or moiety indicates that any hydrogen on the designated atom
or moiety can be replaced with a selection from the indicated
substituent groups, provided that the normal valency of the
designated atom or moiety is not exceeded, and that the
substitution results in a stable compound. For example, if a methyl
group is optionally substituted, then 3 hydrogen atoms on the
carbon atom can be replaced with substituent groups.
[0087] As used herein, the phrase "pharmaceutically acceptable"
means those compounds, materials, compositions, and/or dosage forms
which are, within the scope of sound medical judgment, suitable for
use in contact with tissues of humans and animals. In some
embodiments, "pharmaceutically acceptable" means approved by a
regulatory agency of the Federal or a state government or listed in
the U.S. Pharmacopeia or other generally recognized pharmacopeia
for use in animals, and more particularly in humans.
[0088] As used herein, the phrase "pharmaceutically acceptable
salt(s)," includes, but is not limited to, salts of acidic or basic
groups. Compounds that are basic in nature are capable of forming a
wide variety of salts with various inorganic and organic acids.
Acids that may be used to prepare pharmaceutically acceptable acid
addition salts of such basic compounds are those that form
non-toxic acid addition salts, i.e., salts containing
pharmacologically acceptable anions including, but not limited to,
sulfuric, thiosulfuric, citric, maleic, acetic, oxalic,
hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate,
bisulfate, bisulfite, phosphate, acid phosphate, isonicotinate,
borate, acetate, lactate, salicylate, citrate, acid citrate,
tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate,
succinate, maleate, gentisinate, fumarate, gluconate, glucaronate,
saccharate, formate, benzoate, glutamate, methanesulfonate,
ethanesulfonate, benzenesulfonate, p-toluenesulfonate, bicarbonate,
malonate, mesylate, esylate, napsydisylate, tosylate, besylate,
orthophoshate, trifluoroacetate, and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds that
include an amino moiety may form pharmaceutically acceptable salts
with various amino acids, in addition to the acids mentioned above.
Compounds that are acidic in nature are capable of forming base
salts with various pharmacologically acceptable cations. Examples
of such salts include, but are not limited to, alkali metal or
alkaline earth metal salts and, particularly, calcium, magnesium,
ammonium, sodium, lithium, zinc, potassium, and iron salts. The
present invention also includes quaternary ammonium salts of the
compounds described herein, where the compounds have one or more
tertiary amine moiety.
[0089] As used herein, the term "phenyl" means --C.sub.6H.sub.5. A
phenyl group can be unsubstituted or substituted with one, two, or
three suitable substituents.
[0090] As used herein, the terms "prevention" or "preventing" mean
a reduction of the risk of acquiring a particular disease,
condition, or disorder.
[0091] As used herein, the term "prodrug" means a derivative of a
known direct acting drug, which derivative has enhanced delivery
characteristics and therapeutic value as compared to the drug, and
is transformed into the active drug by an enzymatic or chemical
process.
[0092] As used herein, the term "purified" means that when
isolated, the isolate contains at least 90%, at least 95%, at least
98%, or at least 99% of a compound described herein by weight of
the isolate.
[0093] As used herein, the phrase "substantially isolated" means a
compound that is at least partially or substantially separated from
the environment in which it is formed or detected.
[0094] As used herein, the phrase "suitable substituent" or
"substituent" means a group that does not nullify the synthetic or
pharmaceutical utility of the compounds described herein or the
intermediates useful for preparing them. Examples of suitable
substituents include, but are not limited to: C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkenyl, C.sub.1-C.sub.6alkynyl,
C.sub.5-C.sub.6aryl, C.sub.1-C.sub.6alkoxy,
C.sub.3-C.sub.5heteroaryl, C.sub.3-C.sub.6cycloalkyl,
C.sub.5-C.sub.6aryloxy, --CN, --OH, oxo, halo, haloalkyl,
--NO.sub.2, --CO.sub.2H, --NH.sub.2, --NH(C.sub.1-C.sub.5alkyl),
--N(C.sub.1-C.sub.5alkyl).sub.2, --NH(C.sub.6aryl),
--N(C.sub.5-C.sub.6aryl).sub.2, --CHO, --CO(C.sub.1-C.sub.6alkyl),
--CO((C.sub.5-C.sub.6)aryl), --CO.sub.2((C.sub.1-C.sub.6)alkyl),
and --CO.sub.2((C.sub.5-C.sub.6)aryl). One of skill in art can
readily choose a suitable substituent based on the stability and
pharmacological and synthetic activity of the compounds described
herein.
[0095] As used herein, the phrase "therapeutically effective
amount" means the amount of active compound or pharmaceutical agent
that elicits the biological or medicinal response that is being
sought in a tissue, system, animal, individual or human by a
researcher, veterinarian, medical doctor or other clinician. The
therapeutic effect is dependent upon the disorder being treated or
the biological effect desired. As such, the therapeutic effect can
be a decrease in the severity of symptoms associated with the
disorder and/or inhibition (partial or complete) of progression of
the disorder, or improved treatment, healing, prevention or
elimination of a disorder, or side-effects. The amount needed to
elicit the therapeutic response can be determined based on the age,
health, size and sex of the subject. Optimal amounts can also be
determined based on monitoring of the subject's response to
treatment.
[0096] As used herein, the terms "treat," "treated," or "treating"
mean both therapeutic treatment and prophylactic or preventative
measures wherein the object is to prevent or slow down (lessen) an
undesired physiological condition, disorder or disease, or obtain
beneficial or desired clinical results. Beneficial or desired
clinical results include, but are not limited to, alleviation of
symptoms; diminishment of extent of condition, disorder or disease;
stabilized (i.e., not worsening) state of condition, disorder or
disease; delay in onset or slowing of condition, disorder or
disease progression; amelioration of the condition, disorder or
disease state or remission (whether partial or total), whether
detectable or undetectable; an amelioration of at least one
measurable physical parameter, not necessarily discernible by the
patient; or enhancement or improvement of condition, disorder or
disease. Treatment includes eliciting a clinically significant
response without excessive levels of side effects. Treatment also
includes prolonging survival as compared to expected survival if
not receiving treatment. Thus, "treatment of tuberculosis" or
"treating tuberculosis" means an activity that prevents, alleviates
or ameliorates any of the primary phenomena (initiation,
progression, metastasis) or secondary symptoms associated with the
tuberculosis. As used herein, the phrase "treating tuberculosis" or
"treatment of tuberculosis" also refers to the treatment of a
subject infected with M. tuberculosis bacilli. The treatment can
target replicating M. tuberculosis bacilli and/or non-replicating
M. tuberculosis bacilli. In some embodiments, the compounds can
selectively target one form (e.g. non-replicating or replicating)
of M. tuberculosis bacilli.
[0097] At various places in the present specification, substituents
of compounds may be disclosed in groups or in ranges. It is
specifically intended that embodiments include each and every
individual subcombination of the members of such groups and ranges.
For example, the term "C.sub.1-6alkyl" is specifically intended to
individually disclose methyl, ethyl, propyl, C.sub.4alkyl,
C.sub.5alkyl, and C.sub.6alkyl.
[0098] For compounds in which a variable appears more than once,
each variable can be a different moiety selected from the Markush
group defining the variable. For example, where a structure is
described having two R groups that are simultaneously present on
the same compound, the two R groups can represent different
moieties selected from the Markush groups defined for R. In another
example, when an optionally multiple substituent is designated in
the form, for example,
##STR00010##
then it is understood that substituent R can occur s number of
times on the ring, and R can be a different moiety at each
occurrence. Further, in the above example, where the variable
T.sup.1 is defined to include hydrogens, such as when T.sup.1 is
CH.sub.2, NH, etc., any H can be replaced with a substituent.
[0099] It is further appreciated that certain features described
herein, which are, for clarity, described in the context of
separate embodiments, can also be provided in combination in a
single embodiment. Conversely, various features which are, for
brevity, described in the context of a single embodiment, can also
be provided separately or in any suitable subcombination.
[0100] It is understood that the present invention encompasses the
use, where applicable, of stereoisomers, diastereomers and optical
stereoisomers of the compounds of the invention, as well as
mixtures thereof. Additionally, it is understood that
stereoisomers, diastereomers, and optical stereoisomers of the
compounds of the invention, and mixtures thereof, are within the
scope of the invention. By way of non-limiting example, the mixture
may be a racemate or the mixture may comprise unequal proportions
of one particular stereoisomer over the other. Additionally, the
compounds can be provided as a substantially pure stereoisomers,
diastereomers and optical stereoisomers (such as epimers).
[0101] The compounds described herein can be asymmetric (e.g.,
having one or more stereocenters). All stereoisomers, such as
enantiomers and diastereomers, are intended to be included within
the scope of the invention unless otherwise indicated. Compounds
that contain asymmetrically substituted carbon atoms can be
isolated in optically active or racemic forms. Methods of
preparation of optically active forms from optically active
starting materials are known in the art, such as by resolution of
racemic mixtures or by stereoselective synthesis. Many geometric
isomers of olefins, C.dbd.N double bonds, and the like can also be
present in the compounds described herein, and all such stable
isomers are contemplated in the present invention. Cis and trans
geometric isomers of the compounds are also included within the
scope of the invention and can be isolated as a mixture of isomers
or as separated isomeric forms. Where a compound capable of
stereoisomerism or geometric isomerism is designated in its
structure or name without reference to specific R/S or cis/trans
configurations, it is intended that all such isomers are
contemplated.
[0102] Resolution of racemic mixtures of compounds can be carried
out by any of numerous methods known in the art, including, for
example, fractional recrystallization using a chiral resolving acid
which is an optically active, salt-forming organic acid. Suitable
resolving agents for fractional recrystallization methods include,
but are not limited to, optically active acids, such as the D and L
forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric
acid, mandelic acid, malic acid, lactic acid, and the various
optically active camphorsulfonic acids such as
.beta.-camphorsulfonic acid. Other resolving agents suitable for
fractional crystallization methods include, but are not limited to,
stereoisomerically pure forms of .alpha.-methylbenzylamine (e.g., S
and R forms, or diastereomerically pure forms), 2-phenylglycinol,
norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine,
1,2-diaminocyclohexane, and the like. Resolution of racemic
mixtures can also be carried out by elution on a column packed with
an optically active resolving agent (e.g.,
dinitrobenzoylphenylglycine). Suitable elution solvent compositions
can be determined by one skilled in the art.
[0103] Compounds may also include tautomeric forms. Tautomeric
forms result from the swapping of a single bond with an adjacent
double bond together with the concomitant migration of a proton.
Tautomeric forms include prototropic tautomers which are isomeric
protonation states having the same empirical formula and total
charge. Examples of prototropic tautomers include, but are not
limited to, ketone-enol pairs, amide-imidic acid pairs,
lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs,
and annular forms where a proton can occupy two or more positions
of a heterocyclic system including, but not limited to, 1H- and
3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole,
and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or
sterically locked into one form by appropriate substitution.
[0104] Compounds also include hydrates and solvates, as well as
anhydrous and non-solvated forms.
[0105] Compounds can also include all isotopes of atoms occurring
in the intermediates or final compounds. Isotopes include those
atoms having the same atomic number but different mass numbers. For
example, isotopes of hydrogen include tritium and deuterium.
[0106] In some embodiments, the compounds, or salts thereof, are
substantially isolated. Partial separation can include, for
example, a composition enriched in the compound of the invention.
Substantial separation can include compositions containing at least
about 50%, at least about 60%, at least about 70%, at least about
80%, at least about 90%, at least about 95%, at least about 97%, or
at least about 99% by weight of the compound of the invention, or
salt thereof. Methods for isolating compounds and their salts are
routine in the art.
[0107] Although the disclosed compounds are suitable, other
functional groups can be incorporated into the compound with an
expectation of similar results. In particular, thioamides and
thioesters are anticipated to have very similar properties. The
distance between aromatic rings can impact the geometrical pattern
of the compound and this distance can be altered by incorporating
aliphatic chains of varying length, which can be optionally
substituted or can comprise an amino acid, a dicarboxylic acid or a
diamine. The distance between and the relative orientation of
monomers within the compounds can also be altered by replacing the
amide bond with a surrogate having additional atoms. Thus,
replacing a carbonyl group with a dicarbonyl alters the distance
between the monomers and the propensity of dicarbonyl unit to adopt
an anti-arrangement of the two carbonyl moiety and alter the
periodicity of the compound. Pyromellitic anhydride represents
still another alternative to simple amide linkages which can alter
the conformation and physical properties of the compound. Modern
methods of solid phase organic chemistry (E. Atherton and R. C.
Sheppard, Solid Phase Peptide Synthesis A Practical Approach IRL
Press Oxford 1989) now allow the synthesis of homodisperse
compounds with molecular weights approaching 5,000 Daltons. Other
substitution patterns are equally effective.
[0108] The compounds also include derivatives referred to as
prodrugs.
[0109] Compounds containing an amine function can also form
N-oxides. A reference herein to a compound that contains an amine
function also includes the N-oxide. Where a compound contains
several amine functions, one or more than one nitrogen atom can be
oxidized to form an N-oxide. Examples of N-oxides include N-oxides
of a tertiary amine or a nitrogen atom of a nitrogen-containing
heterocycle. N-Oxides can be formed by treatment of the
corresponding amine with an oxidizing agent such as hydrogen
peroxide or a per-acid (e.g., a peroxycarboxylic acid) (see,
Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley
Interscience).
[0110] Embodiments of various compounds and salts thereof are
provided. Where a variable is not specifically recited, the
variable can be any option described herein, except as otherwise
noted or dictated by context.
[0111] In some embodiments, a compound of Formula I or a
pharmaceutically acceptable salt, ester or prodrug thereof is
provided:
##STR00011##
[0112] wherein:
[0113] A.sub.1, is S or O;
[0114] A.sub.2 is C or N;
[0115] R.sub.1 is S, N, O, optionally substituted C.sub.1-C.sub.6
linear or branched alkyl, or sulfonyl,
[0116] R.sub.2 is null or optionally substituted linear or branched
C.sub.1-C.sub.12 alkyl;
[0117] R.sub.3 is null, O, H, optionally substituted
C.sub.1-C.sub.6 linear or branched alkyl,
##STR00012##
[0118] R.sub.4 is H, an optionally substituted aryl, an optionally
substituted heteroaryl, an optionally substituted heterocycle,
optionally substituted C.sub.1-C.sub.6 alkoxy, or an optionally
substituted amide;
[0119] R.sub.5 is an optionally substituted aryl, optionally
substituted arylalkyl, optionally substituted heteroaryl,
optionally substituted C.sub.4-C.sub.6 carbocycle, or optionally
substituted C.sub.1-C.sub.6 linear or branched alkyl.
[0120] In some embodiments, embodiments, R.sub.4 is H,
##STR00013##
optionally substituted C.sub.1-C.sub.6 alkoxy, or optionally
substituted alkylamino, wherein
[0121] R.sub.7 is H,
##STR00014##
halo, cyano, C.sub.1-C.sub.6 alkoxy, linear or branched alkyl,
haloalkyl, optionally substituted aryl; optionally substituted
arylalkyl, halogen substituted C.sub.1-C.sub.6 alkoxy; and
[0122] R.sub.8 and R.sub.9 are independently H, OH, halo, or
C.sub.1-C.sub.6 alkyl.
[0123] In some embodiments, R.sub.5 is C.sub.1-C.sub.6 linear or
branched alkyl,
##STR00015##
wherein R.sub.6 and R.sub.10 are each independently H, halo,
optionally substituted aryl, C.sub.1-C.sub.6 linear or branched
alkyl, C.sub.1-C.sub.6 alkoxy, haloalkyl, halogen substituted
C.sub.1-C.sub.6 alkoxy, cyano, or
##STR00016##
[0124] In some embodiments, A.sub.1, is O. In some embodiments,
wherein A.sub.2 is N. In some embodiments, R.sub.1 is S. In some
embodiments, R.sub.3 is null. In some embodiments, R.sub.2 is null
or C.sub.1-C.sub.12 alkyl.
[0125] In some embodiments, A.sub.1, is O; A.sub.2 is N; R.sub.1 is
S; and R.sub.3 is null.
[0126] In some embodiments, the compound has the Formula I-a, or a
pharmaceutically acceptable salt, ester or prodrug thereof:
##STR00017##
wherein:
[0127] R.sub.1 is S, N, O, optionally substituted C.sub.1-C.sub.6
linear or branched alkyl, or sulfonyl,
[0128] R.sub.2 is null or optionally substituted linear or branched
C.sub.1-C.sub.12 alkyl;
[0129] R.sub.3 is null, O, H, optionally substituted
C.sub.1-C.sub.6 linear or branched alkyl,
##STR00018##
[0130] R.sub.4 is H, an optionally substituted aryl, an optionally
substituted heteroaryl, an optionally substituted heterocycle,
optionally substituted C.sub.1-C.sub.6 alkoxy, or an optionally
substituted amide;
[0131] R.sub.5 is an optionally substituted aryl, optionally
substituted arylalkyl, optionally substituted heteroaryl,
optionally substituted C.sub.4-C.sub.6 carbocycle, or optionally
substituted C.sub.1-C.sub.6 linear or branched alkyl.
[0132] In some embodiments, R.sub.5 is C.sub.1-C.sub.6 linear or
branched alkyl,
##STR00019##
[0133] wherein
[0134] R.sub.6 and R.sub.10 are each independently H, halo,
optionally substituted aryl, C.sub.1-C.sub.6 linear or branched
alkyl, C.sub.1-C.sub.6 alkoxy, haloalkyl, halogen substituted
C.sub.1-C.sub.6 alkoxy, cyano, or
##STR00020##
[0135] In some embodiments, R.sub.5 is:
##STR00021##
wherein R.sub.6 and R.sub.10 are each independently H, halo,
C.sub.1-C.sub.6 linear or branched alkyl, C.sub.1-C.sub.6
haloalkyl, cyano, C.sub.1-C.sub.6 alkoxy, halogen substituted
C.sub.1-C.sub.6 alkoxy, OH,
--O(CH.sub.2).sub.qC(.dbd.O)O(CH.sub.2).sub.pCH.sub.3,
--O(CH.sub.2).sub.qC(.dbd.O)N(H)(CH.sub.2).sub.pO(CH.sub.2).sub.mN.sub.3,
--O(CH.sub.2).sub.qC.ident.CH, or
##STR00022##
wherein m, p and q are independently 1-4. In some embodiments,
R.sub.5 is
##STR00023##
[0136] In some embodiments, R.sub.6 is H, halo, methyl, ethyl, or
propyl, CF.sub.3, cyano, OH,
--O(CH.sub.2).sub.qC(.dbd.O)O(CH.sub.2).sub.pCH.sub.3,
--O(CH.sub.2).sub.qC(.dbd.O)N(H)(CH.sub.2).sub.pO(CH.sub.2).sub.mN.sub.3,
or --O(CH.sub.2).sub.qC.ident.CH and R.sub.10 is H. In some
embodiments, R.sub.6 and R.sub.10 are both H, methyl, ethyl, or
propyl, CF.sub.3, halo, C.sub.1-C.sub.6 alkoxy, OH,
--O(CH.sub.2).sub.qC(.dbd.O)O(CH.sub.2).sub.pCH.sub.3,
--O(CH.sub.2).sub.qC(.dbd.O)N(H)(CH.sub.2).sub.pO(CH.sub.2).sub.mN.sub.3,
or --O(CH.sub.2).sub.qC.ident.CH. In some embodiments, R.sub.6 is
halo and R.sub.10 is H, methyl, ethyl, or propyl, CF.sub.3,
C.sub.1-C.sub.6 alkoxy, OH,
--O(CH.sub.2).sub.qC(.dbd.O)O(CH.sub.2).sub.pCH.sub.3,
--O(CH.sub.2).sub.qC(.dbd.O)N(H)(CH.sub.2).sub.pO(CH.sub.2).sub.mN.sub.3,
or --O(CH.sub.2).sub.qC.ident.CH.
[0137] In some embodiments, R.sub.1 is S or sulfonyl. In some
embodiments, R.sub.1 is N. In some embodiments, R.sub.1 is O.
[0138] In some embodiments, R.sub.1 is optionally substituted
C.sub.1-C.sub.6 linear or branched alkyl.
[0139] In some embodiments, R.sub.1 is S; R.sub.2 null or
optionally substituted linear or branched C.sub.1-C.sub.12 alkyl;
R.sub.3 is null or O; and R.sub.4 is H, an optionally substituted
aryl, an optionally substituted heteroaryl, an optionally
substituted heterocycle, optionally substituted C.sub.1-C.sub.6
alkoxy, or an optionally substituted amide. In some embodiments,
R.sub.4 is H, --C.ident.CH, --C.ident.C(CH.sub.2).sub.tOH,
--C(.dbd.O)O(CH.sub.2).sub.tCH.sub.3, --O(CH.sub.2).sub.uCH.sub.3,
--O(CH.sub.2).sub.qC(.dbd.O)O(CH.sub.2).sub.pCH.sub.3,
##STR00024##
optionally substituted C.sub.1-C.sub.6 alkoxy, or optionally
substituted alkylamino, or C.sub.1-C.sub.6 carbocycle,
Wherein R.sub.7 is H, O,
##STR00025##
[0140] halo, cyano,
--C(.dbd.O)N(H)(CH.sub.2).sub.pO(CH.sub.2).sub.mN.sub.3,
--O(CH.sub.2).sub.qC(.dbd.O)N(H)(CH.sub.2).sub.pO(CH.sub.2).sub.mN.sub.3,
--O(CH.sub.2).sub.mN.sub.3, --O(CH.sub.2).sub.mC.ident.CH,
C.sub.1-C.sub.6 alkoxy, optionally substituted C.sub.1-C.sub.6
linear or branched alkyl, haloalkyl, optionally substituted aryl;
optionally substituted arylalkyl, halogen substituted
C.sub.1-C.sub.6 alkoxy; R.sub.8 and R.sub.9 are independently H,
OH, .dbd.O, halo, or C.sub.1-C.sub.6 alkyl; m, p and q are
independently 1-6; and t and u are independently 0-6.
[0141] In some embodiments, a compound, or a pharmaceutically
acceptable salt, ester or prodrug thereof, of Formula I has the
Formula I-b, I-c, I-d, or I-e:
##STR00026##
[0142] R.sub.4 is H, --C.ident.CH, --C.ident.C(CH.sub.2).sub.tOH,
--C(.dbd.O)O(CH.sub.2).sub.tCH.sub.3, --O(CH.sub.2).sub.uCH.sub.3,
--O(CH.sub.2).sub.qC(.dbd.)O(CH.sub.2).sub.pCH.sub.3,
##STR00027##
optionally substituted C.sub.1-C.sub.6 alkoxy, or optionally
substituted alkylamino, or C.sub.1-C.sub.6 carbocycle,
[0143] R.sub.7 is H, O,
##STR00028##
halo, cyano,
--C(.dbd.O)N(H)(CH.sub.2).sub.pO(CH.sub.2).sub.mN.sub.3,
--O(CH.sub.2).sub.qC(.dbd.O)N(H)(CH.sub.2).sub.pO(CH.sub.2).sub.mN.sub.3,
--O(CH.sub.2).sub.mN.sub.3, --O(CH.sub.2).sub.mC.ident.CH,
C.sub.1-C.sub.6 alkoxy, optionally substituted C.sub.1-C.sub.6
linear or branched alkyl, haloalkyl, optionally substituted aryl;
optionally substituted arylalkyl, halogen substituted
C.sub.1-C.sub.6 alkoxy; and
[0144] R.sub.8 and R.sub.9 are independently H, OH, .dbd.O, halo,
or C.sub.1-C.sub.6 alkyl;
[0145] R.sub.5 is
##STR00029##
[0146] R.sub.6 and R.sub.10 are each independently H, halo,
C.sub.1-C.sub.6 linear or branched alkyl, C.sub.1-C.sub.6
haloalkyl, cyano, C.sub.1-C.sub.6 alkoxy, halogen substituted
C.sub.1-C.sub.6 alkoxy, OH,
--O(CH.sub.2).sub.qC(.dbd.O)O(CH.sub.2).sub.pCH.sub.3,
--O(CH.sub.2).sub.qC(.dbd.O)N(H)(CH.sub.2).sub.pO(CH.sub.2).sub.mN.sub.3,
--O(CH.sub.2).sub.qC.ident.CH, or
##STR00030##
[0147] wherein m, p, q, and z are independently 1-6; and
[0148] t and u are independently 0-6.
[0149] In some embodiments, the compound, or a pharmaceutically
acceptable salt, ester or prodrug thereof, is selected from the
group consisting of:
##STR00031## ##STR00032## ##STR00033## ##STR00034## ##STR00035##
##STR00036## ##STR00037## ##STR00038## ##STR00039##
##STR00040##
##STR00041## ##STR00042## ##STR00043## ##STR00044## ##STR00045##
##STR00046## ##STR00047## ##STR00048## ##STR00049##
##STR00050##
[0150] In some embodiments, a compound of Formula I, or a
pharmaceutically acceptable salt, ester or prodrug thereof, is not
one or more of a compound selected from the group consisting
of:
##STR00051## ##STR00052## ##STR00053## ##STR00054## ##STR00055##
##STR00056## ##STR00057## ##STR00058## ##STR00059##
##STR00060## ##STR00061## ##STR00062## ##STR00063## ##STR00064##
##STR00065## ##STR00066## ##STR00067## ##STR00068## ##STR00069##
##STR00070## ##STR00071##
[0151] In some embodiments, the present invention provides
pharmaceutical compositions comprising a compound, prodrug, or
pharmaceutically salt thereof of any compound described herein.
[0152] The compounds described herein can be made by can be made
according to the methods described herein and in the examples. The
methods described herein can be adapted based upon the compounds
desired and described herein. In some embodiments, the method is
made according to the following schemes. In some embodiments, this
method can be used to make one or more compounds as described
herein and will be apparent to one of skill in the art which
compounds can be made according to the methods described
herein.
[0153] The following representative schemes illustrate how
compounds described herein can be prepared. The specific solvents
and reaction conditions referred to are also illustrative and are
not intended to be limited. Compounds not described are either
commercially available or are readily prepared by one skilled in
the art using available starting materials.
[0154] The conditions and temperatures can be varied, such as shown
in the examples described herein. These schemes are non-limiting
synthetic schemes and the synthetic routes can be modified as would
be apparent to one of skill in the art reading the present
specification.
[0155] The compounds can be prepared according to any suitable
method. Examples of the schemes that can be used to synthesize the
compounds can be found in the Example sections. One of skill in the
art would be able to modify these schemes to synthesize additional
embodiments of the compounds. In some embodiments, the following
scheme is used to prepare one or more compounds:
##STR00072##
[0156] In some embodiments, the following scheme is used to prepare
one or more compounds:
##STR00073##
[0157] The compounds can also be prepared according to the
embodiments described in the Examples. The examples and schemes
described herein can also be readily modified to yield other
compounds described herein by modifying the substituents to produce
the desired compound.
[0158] The compounds described herein can be administered in any
conventional manner by any route where they are active.
Administration can be systemic, topical, or oral. For example,
administration can be, but is not limited to, parenteral,
subcutaneous, intravenous, intramuscular, intraperitoneal,
transdermal, oral, buccal, sublingual, or ocular routes, or
intravaginally, by inhalation, by depot injections, or by implants.
The mode of administration can depend on the conditions or disease
to be targeted or treated. The selection of the specific route of
administration can be selected or adjusted by the clinician
according to methods known to the clinician to obtain the desired
clinical response.
[0159] In some embodiments, it may be desirable to administer one
or more compounds, or a pharmaceutically acceptable salt thereof,
locally to an area in need of treatment. This may be achieved, for
example, and not by way of limitation, by local infusion during
surgery, topical application, e.g., in conjunction with a wound
dressing after surgery, by injection, by means of a catheter, by
means of a suppository, or by means of an implant, wherein the
implant is of a porous, non-porous, or gelatinous material,
including membranes, such as sialastic membranes, or fibers.
[0160] The compounds described herein can be administered either
alone or in combination (concurrently or serially) with other
pharmaceuticals. For example, the compounds can be administered in
combination with other analgesics, antidepressants, anti-anxiety
compounds, anti-overactive bladder compounds, compounds for the
treatment of Parkinsons, and the like. Examples of other
pharmaceuticals or medicaments are known to one of skill in the art
and include, but are not limited to those described herein.
[0161] The means and methods for administration are known in the
art and an artisan can refer to various pharmacologic references
for guidance (see, for example, Modern Pharmaceutics, Banker &
Rhodes, Marcel Dekker, Inc. (1979); and Goodman & Gilman's The
Pharmaceutical Basis of Therapeutics, 6th Edition, MacMillan
Publishing Co., New York (1980)).
[0162] The amount of compound to be administered is that amount
which is therapeutically effective. The dosage to be administered
will depend on the characteristics of the subject being treated,
e.g., the particular animal treated, age, weight, health, types of
concurrent treatment, if any, and frequency of treatments, and can
be easily determined by one of skill in the art (e.g., by the
clinician). The standard dosing for protamine can be used and
adjusted (i.e., increased or decreased) depending upon the factors
described above. The selection of the specific dose regimen can be
selected or adjusted or titrated by the clinician according to
methods known to the clinician to obtain the desired clinical
response.
[0163] The amount of a compound described herein that will be
effective in the treatment and/or prevention of a particular
disease, condition, or disorder will depend on the nature and
extent of the disease, condition, or disorder, and can be
determined by standard clinical techniques. In addition, in vitro
or in vivo assays may optionally be employed to help identify
optimal dosage ranges. The precise dose to be employed in the
compositions will also depend on the route of administration, and
the seriousness of the disorder, and should be decided according to
the judgment of the practitioner and each patient's circumstances.
However, a suitable dosage range for oral administration is,
generally, from about 0.001 milligram to about 200 milligrams per
kilogram body weight, from about 0.01 milligram to about 100
milligrams per kilogram body weight, from about 0.01 milligram to
about 70 milligrams per kilogram body weight, from about 0.1
milligram to about 50 milligrams per kilogram body weight, from 0.5
milligram to about 20 milligrams per kilogram body weight, or from
about 1 milligram to about 10 milligrams per kilogram body weight.
In some embodiments, the oral dose is about 5 milligrams per
kilogram body weight.
[0164] In some embodiments, suitable dosage ranges for intravenous
(i.v.) administration are from about 0.01 mg to about 500 mg per kg
body weight, from about 0.1 mg to about 100 mg per kg body weight,
from about 1 mg to about 50 mg per kg body weight, or from about 10
mg to about 35 mg per kg body weight. Suitable dosage ranges for
other modes of administration can be calculated based on the
forgoing dosages as known by those skilled in the art. For example,
recommended dosages for intranasal, transmucosal, intradermal,
intramuscular, intraperitoneal, subcutaneous, epidural, sublingual,
intracerebral, intravaginal, transdermal administration or
administration by inhalation are in the range of from about 0.001
mg to about 200 mg per kg of body weight, from about 0.01 mg to
about 100 mg per kg of body weight, from about 0.1 mg to about 50
mg per kg of body weight, or from about 1 mg to about 20 mg per kg
of body weight. Effective doses may be extrapolated from
close-response curves derived from in vitro or animal model test
systems. Such animal models and systems are well known in the
art.
[0165] The compounds described herein can be formulated for
parenteral administration by injection, such as by bolus injection
or continuous infusion. The compounds can be administered by
continuous infusion subcutaneously over a period of about 15
minutes to about 24 hours. Formulations for injection can be
presented in unit dosage form, such as in ampoules or in multi-dose
containers, with an optionally added preservative. The compositions
can take such forms as suspensions, solutions or emulsions in oily
or aqueous vehicles, and can contain formulatory agents such as
suspending, stabilizing and/or dispersing agents. In some
embodiments, the injectable is in the form of short-acting, depot,
or implant and pellet forms injected subcutaneously or
intramuscularly. In some embodiments, the parenteral dosage form is
the form of a solution, suspension, emulsion, or dry powder.
[0166] For oral administration, the compounds described herein can
be formulated by combining the compounds with pharmaceutically
acceptable carriers well known in the art. Such carriers enable the
compounds to be formulated as tablets, pills, dragees, capsules,
emulsions, liquids, gels, syrups, caches, pellets, powders,
granules, slurries, lozenges, aqueous or oily suspensions, and the
like, for oral ingestion by a patient to be treated. Pharmaceutical
preparations for oral use can be obtained by, for example, adding a
solid excipient, optionally grinding the resulting mixture, and
processing the mixture of granules, after adding suitable
auxiliaries, if desired, to obtain tablets or dragee cores.
Suitable excipients include, but are not limited to, fillers such
as sugars, including, but not limited to, lactose, sucrose,
mannitol, and sorbitol; cellulose preparations such as, but not
limited to, maize starch, wheat starch, rice starch, potato starch,
gelatin, gum tragacanth, methyl cellulose,
hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and
polyvinylpyrrolidone (PVP). If desired, disintegrating agents can
be added, such as, but not limited to, the cross-linked polyvinyl
pyrrolidone, agar, or alginic acid or a salt thereof such as sodium
alginate.
[0167] Orally administered compositions can contain one or more
optional agents, for example, sweetening agents such as fructose,
aspartame or saccharin; flavoring agents such as peppermint, oil of
wintergreen, or cherry; coloring agents; and preserving agents, to
provide a pharmaceutically palatable preparation. Moreover, where
in tablet or pill form, the compositions may be coated to delay
disintegration and absorption in the gastrointestinal tract thereby
providing a sustained action over an extended period of time.
Selectively permeable membranes surrounding an osmotically active
driving compound are also suitable for orally administered
compounds. Oral compositions can include standard vehicles such as
mannitol, lactose, starch, magnesium stearate, sodium saccharine,
cellulose, magnesium carbonate, etc. Such vehicles are suitably of
pharmaceutical grade.
[0168] Dragee cores can be provided with suitable coatings. For
this purpose, concentrated sugar solutions can be used, which can
optionally contain gum arabic, talc, polyvinyl pyrrolidone,
carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer
solutions, and suitable organic solvents or solvent mixtures.
Dyestuffs or pigments can be added to the tablets or dragee
coatings for identification or to characterize different
combinations of active compound doses.
[0169] Pharmaceutical preparations which can be used orally
include, but are not limited to, push-fit capsules made of gelatin,
as well as soft, sealed capsules made of gelatin and a plasticizer,
such as glycerol or sorbitol. The push-fit capsules can contain the
active ingredients in admixture with filler such as lactose,
binders such as starches, and/or lubricants such as talc or
magnesium stearate and, optionally, stabilizers. In soft capsules,
the active compounds can be dissolved or suspended in suitable
liquids, such as fatty oils, liquid paraffin, or liquid
polyethylene glycols. In addition, stabilizers can be added.
[0170] For buccal administration, the compositions can take the
form of, such as, tablets or lozenges formulated in a conventional
manner.
[0171] For administration by inhalation, the compounds described
herein can be delivered in the form of an aerosol spray
presentation from pressurized packs or a nebulizer, with the use of
a suitable propellant, such as dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide
or other suitable gas. In the case of a pressurized aerosol the
dosage unit can be determined by providing a valve to deliver a
metered amount. Capsules and cartridges of, such as gelatin for use
in an inhaler or insufflator can be formulated containing a powder
mix of the compound and a suitable powder base such as lactose or
starch.
[0172] The compounds described herein can also be formulated in
rectal compositions such as suppositories or retention enemas, such
as containing conventional suppository bases such as cocoa butter
or other glycerides. The compounds described herein can also be
formulated in vaginal compositions such as vaginal creams,
suppositories, pessaries, vaginal rings, and intrauterine
devices.
[0173] In transdermal administration, the compounds can be applied
to a plaster, or can be applied by transdermal, therapeutic systems
that are consequently supplied to the organism. In some
embodiments, the compounds are present in creams, solutions,
powders, fluid emulsions, fluid suspensions, semi-solids,
ointments, pastes, gels, jellies, and foams, or in patches
containing any of the same.
[0174] The compounds described herein can also be formulated as a
depot preparation. Such long acting formulations can be
administered by implantation (for example subcutaneously or
intramuscularly) or by intramuscular injection. Depot injections
can be administered at about 1 to about 6 months or longer
intervals. Thus, for example, the compounds can be formulated with
suitable polymeric or hydrophobic materials (for example as an
emulsion in an acceptable oil) or ion exchange resins, or as
sparingly soluble derivatives, for example, as a sparingly soluble
salt.
[0175] In some embodiments, the compounds can be delivered in a
controlled release system. In one embodiment, a pump may be used
(see Langer, supra; Sefton, CRC Crit. Ref Biomed. Eng., 1987, 14,
201; Buchwald et al., Surgery, 1980, 88, 507 Saudek et al., N.
Engl. J. Med., 1989, 321, 574). In some embodiments, polymeric
materials can be used (see Medical Applications of Controlled
Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla.
(1974); Controlled Drug Bioavailability, Drug Product Design and
Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger
et al., J. Macromol. Sci. Rev. Macromol. Chem., 1983, 23, 61; see,
also Levy et al., Science, 1985, 228, 190; During et al., Ann.
Neurol., 1989, 25, 351; Howard et al., J. Neurosurg., 1989, 71,
105). In yet another embodiment, a controlled-release system can be
placed in proximity of the target of the compounds described
herein, such as the liver, thus requiring only a fraction of the
systemic close (see, e.g., Goodson, in Medical Applications of
Controlled Release, supra, vol. 2, pp. 115-138 (1984)). Other
controlled-release systems discussed in the review by Langer,
Science, 1990, 249, 1527-1533) may be used.
[0176] It is also known in the art that the compounds can be
contained in such formulations with pharmaceutically acceptable
diluents, fillers, disintegrants, binders, lubricants, surfactants,
hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers,
humectants, moisturizers, solubilizers, preservatives and the like.
The pharmaceutical compositions can also comprise suitable solid or
gel phase carriers or excipients. Examples of such carriers or
excipients include, but are not limited to, calcium carbonate,
calcium phosphate, various sugars, starches, cellulose derivatives,
gelatin, and polymers such as polyethylene glycols. In some
embodiments, the compounds described herein can be used with agents
including, but not limited to, topical analgesics (e.g.,
lidocaine), barrier devices (e.g., GelClair), or rinses (e.g.,
Caphosol).
[0177] In some embodiments, the compounds described herein can be
delivered in a vesicle, in particular a liposome (see, Langer,
Science, 1990, 249, 1527-1533; Treat et al., in Liposomes in the
Therapy of Infectious Disease and Cancer, Lopez-Berestein and
Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein,
ibid., pp. 317-327; see generally ibid.).
[0178] Suitable compositions include, but are not limited to, oral
non-absorbed compositions. Suitable compositions also include, but
are not limited to saline, water, cyclodextrin solutions, and
buffered solutions of pH 3-9.
[0179] The compounds described herein, or pharmaceutically
acceptable salts thereof, can be formulated with numerous
excipients including, but not limited to, purified water, propylene
glycol, PEG 400, glycerin, DMA, ethanol, benzyl alcohol, citric
acid/sodium citrate (pH3), citric acid/sodium citrate (pH5),
tris(hydroxymethyl)amino methane HCl (pH7.0), 0.9% saline, and 1.2%
saline, and any combination thereof. In some embodiments, excipient
is chosen from propylene glycol, purified water, and glycerin.
[0180] In some embodiments, the formulation can be lyophilized to a
solid and reconstituted with, for example, water prior to use.
[0181] When administered to a mammal (e.g., to an animal for
veterinary use or to a human for clinical use) the compounds can be
administered in isolated form.
[0182] When administered to a human, the compounds can be sterile.
Water is a suitable carrier when the compound of Formula I is
administered intravenously. Saline solutions and aqueous dextrose
and glycerol solutions can also be employed as liquid carriers,
particularly for injectable solutions. Suitable pharmaceutical
carriers also include excipients such as starch, glucose, lactose,
sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium
stearate, glycerol monostearate, talc, sodium chloride, dried skim
milk, glycerol, propylene, glycol, water, ethanol and the like. The
present compositions, if desired, can also contain minor amounts of
wetting or emulsifying agents, or pH buffering agents.
[0183] The compositions described herein can take the form of a
solution, suspension, emulsion, tablet, pill, pellet, capsule,
capsule containing a liquid, powder, sustained-release formulation,
suppository, aerosol, spray, or any other form suitable for use.
Examples of suitable pharmaceutical carriers are described in
Remington's Pharmaceutical Sciences, A. R. Gennaro (Editor) Mack
Publishing Co.
[0184] In some embodiments, the compounds are formulated in
accordance with routine procedures as a pharmaceutical composition
adapted for administration to humans. Typically, compounds are
solutions in sterile isotonic aqueous buffer. Where necessary, the
compositions can also include a solubilizing agent. Compositions
for intravenous administration may optionally include a local
anesthetic such as lidocaine to ease pain at the site of the
injection. Generally, the ingredients are supplied either
separately or mixed together in unit dosage form, for example, as a
dry lyophilized powder or water free concentrate in a hermetically
sealed container such as an ampoule or sachette indicating the
quantity of active agent. Where the compound is to be administered
by infusion, it can be dispensed, for example, with an infusion
bottle containing sterile pharmaceutical grade water or saline.
Where the compound is administered by injection, an ampoule of
sterile water for injection or saline can be provided so that the
ingredients may be mixed prior to administration.
[0185] The pharmaceutical compositions can be in unit dosage form.
In such form, the composition can be divided into unit doses
containing appropriate quantities of the active component. The unit
dosage form can be a packaged preparation, the package containing
discrete quantities of the preparations, for example, packeted
tablets, capsules, and powders in vials or ampules. The unit dosage
form can also be a capsule, cachet, or tablet itself, or it can be
the appropriate number of any of these packaged forms.
[0186] In some embodiments, a composition of the present invention
is in the form of a liquid wherein the active agent (i.e., one of
the facially amphiphilic polymers or oligomers disclosed herein) is
present in solution, in suspension, as an emulsion, or as a
solution/suspension. In some embodiments, the liquid composition is
in the form of a gel. In other embodiments, the liquid composition
is aqueous. In other embodiments, the composition is in the form of
an ointment.
[0187] In some embodiments, the composition is in the form of a
solid article. For example, in some embodiments, the ophthalmic
composition is a solid article that can be inserted in a suitable
location in the eye, such as between the eye and eyelid or in the
conjunctival sac, where it releases the active agent as described,
for example, U.S. Pat. Nos. 3,863,633; 3,867,519; 3,868,445;
3,960,150; 3,963,025; 4,186,184; 4,303,637; 5,443,505; and
5,869,079. Release from such an article is usually to the cornea,
either via the lacrimal fluid that bathes the surface of the
cornea, or directly to the cornea itself, with which the solid
article is generally in intimate contact. Solid articles suitable
for implantation in the eye in such fashion are generally composed
primarily of polymers and can be bioerodible or non-bioerodible.
Bioerodible polymers that can be used in the preparation of ocular
implants carrying one or more of the anti-microbial, facially
amphiphilic polymer or oligomer active agents in accordance with
the present invention include, but are not limited to, aliphatic
polyesters such as polymers and copolymers of poly(glycolide),
poly(lactide), poly(epsilon-caprolactone), poly-(hydroxybutyrate)
and poly(hydroxyvalerate), polyamino acids, polyorthoesters,
polyanhydrides, aliphatic polycarbonates and polyether lactones.
Suitable non-bioerodible polymers include silicone elastomers.
[0188] The compositions described herein can contain preservatives.
Suitable preservatives include, but are not limited to,
mercury-containing substances such as phenylmercuric salts (e.g.,
phenylmercuric acetate, borate and nitrate) and thimerosal;
stabilized chlorine dioxide; quaternary ammonium compounds such as
benzalkonium chloride, cetyltrimethylammonium bromide and
cetylpyridinium chloride; imidazolidinyl urea; parabens such as
methylparaben, ethylparaben, propylparaben and butylparaben, and
salts thereof; phenoxyethanol; chlorophenoxyethanol;
phenoxypropanol; chlorobutanol; chlorocresol; phenylethyl alcohol;
disodium EDTA; and sorbic acid and salts thereof.
[0189] Optionally one or more stabilizers can be included in the
compositions to enhance chemical stability where required. Suitable
stabilizers include, but are not limited to, chelating agents or
complexing agents, such as, for example, the calcium complexing
agent ethylene diamine tetraacetic acid (EDTA). For example, an
appropriate amount of EDTA or a salt thereof, e.g., the disodium
salt, can be included in the composition to complex excess calcium
ions and prevent gel formation during storage. EDTA or a salt
thereof can suitably be included in an amount of about 0.01% to
about 0.5%. In those embodiments containing a preservative other
than EDTA, the EDTA or a salt thereof, more particularly disodium
EDTA, can be present in an amount of about 0.025% to about 0.1% by
weight.
[0190] One or more antioxidants can also be included in the
compositions. Suitable antioxidants include, but are not limited
to, ascorbic acid, sodium metabisulfite, sodium bisulfite,
acetylcysteine, polyquatemium-1, benzalkonium chloride, thimerosal,
chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol,
edetate disodium, sorbic acid, or other agents know to those of
skill in the art. Such preservatives are typically employed at a
level of from about 0.001% to about 1.0% by weight.
[0191] One or more acceptable pH adjusting agents and/or buffering
agents can be included in the compositions, including acids such as
acetic, boric, citric, lactic, phosphoric and hydrochloric acids;
bases such as sodium hydroxide, sodium phosphate, sodium borate,
sodium citrate, sodium acetate, sodium lactate and
tris-hydroxymethylaminomethane; and buffers such as
citrate/dextrose, sodium bicarbonate and ammonium chloride. Such
acids, bases and buffers are included in an amount required to
maintain pH of the composition in an acceptable range.
[0192] One or more acceptable salts can be included in the
compositions of the invention in an amount required to bring
osmolality of the composition into an acceptable range. Such salts
include, but are not limited to, those having sodium, potassium or
ammonium cations and chloride, citrate, ascorbate, borate,
phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions.
In some embodiments, salts include sodium chloride, potassium
chloride, sodium thiosulfate, sodium bisulfite and ammonium
sulfate. In some embodiments, the salt is sodium chloride.
[0193] Optionally one or more acceptable surfactants, preferably
nonionic surfactants, or co-solvents can be included in the
compositions to enhance solubility of the components of the
compositions or to impart physical stability, or for other
purposes. Suitable nonionic surfactants include, but are not
limited to, polyoxyethylene fatty acid glycerides and vegetable
oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and
polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol
10, octoxynol 40; polysorbate 20, 60 and 80;
polyoxyethylene/polyoxypropylene surfactants (e.g., Pluronic.RTM.
F-68, F84 and P-103); cyclodextrin; or other agents known to those
of skill in the art. Typically, such co-solvents or surfactants are
employed in the compositions at a level of from about 0.01% to
about 2% by weight.
[0194] The present invention also provides pharmaceutical packs or
kits comprising one or more containers filled with one or more
compounds described herein. Optionally 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 for treating a condition, disease, or disorder
described herein. In some embodiments, the kit contains more than
one compound described herein. In some embodiments, the kit
comprises a compound described herein in a single injectable dosage
form, such as a single dose within an injectable device such as a
syringe with a needle.
[0195] The present invention also provides methods of treating
tuberculosis. In some embodiments, the method comprises
administering to a subject with tuberculosis or suspected of having
tuberculosis a compound, or a pharmaceutically acceptable salt,
ester or prodrug thereof, or pharmaceutical composition described
herein. In some embodiments, the compounds are for the treatment of
tuberculosis in a subject in need thereof. The treatment of
tuberculosis can be targeted against replicating or non-replicating
tuberculosis. In some embodiments, the compounds selectively target
either replicating or non-replicating tuberculosis. Selective
targeting of one form of tuberculosis over another means that the
compound, or a pharmaceutically acceptable salt, ester or prodrug
thereof, has at least a 2, 3, 4, 5, 6, 7, 8, 9, 10 fold preference
for one form or other. Preference can be determined by comparing
the IC.sub.90 of the compound against replicating tuberculosis and
the IC.sub.99 of the compound against non-replicating tuberculosis.
For example, if the compound has a 10 .mu.m IC.sub.99 against
non-replicating tuberculosis and a 10 .mu.m IC.sub.90 against
replicating tuberculosis the compound is said to have a 10 fold
preference for non-replicating tuberculosis. The IC.sub.90 of the
compound against replicating tuberculosis and the IC.sub.99 of the
compound against non-replicating tuberculosis can be determined by
any method.
[0196] For example, but not limited to, to determine the IC.sub.99
of the compound against non-replicating tuberculosis a
non-replicating, carbon-starvation assay can be used. Carbon
starvation conditions can be used as a means of nutrient depriving
bacilli in order to induce a non-replicating, drug tolerant state.
The bacilli can be starved for 6 weeks in phosphate-buffered saline
(PBS), resulting in bacteria that were refractory to standard
antibiotics at closes up to 10 times the minimum inhibitory
concentration (MIC). This assay is then adapted to a high
throughput screen (HTS) against carbon starved TB in appropriate
growth medium. An example of growth medium is, but not limited to,
7H9/tyloxapol (0.05%), which includes several cofactors (biotin,
pyridoxine, iron), trace metals, and some nitrogen source (ammonium
sulfate). This buffer can be used to replicate carbon starvation
while still providing some minimal essential nutrients. Under these
conditions are instituted, no killing will be observed with control
anti-tuberculosis antibiotics, such as rifampin and isoniazid at
10.times. MIC (MIC: rifampin 0.01 ug/mL and INH 0.1 ug/mL). The TB
can be a TB strain that has been modified to express a fluorescent
protein, such as GFP. An example of such a strain is M.
tuberculosis H37Rv strain, which expresses constitutive, episomal
GFP. Fluorescence can then be used to measure cell survival. The
bacteria can also be transitioned back to replicating state by the
addition of 5.times. rich media, followed by a 4 day period of
outgrowth of replicating cells. Other examples of the assay are
described in the examples section herein.
[0197] The present invention also provides one or more compounds
described above, or a pharmaceutically acceptable salt thereof, or
a pharmaceutical composition comprising one or more compounds
described above, for use in the manufacture of a medicament for the
treatment of tuberculosis.
[0198] Any other known medicament, compound, or composition use for
the treatment of tuberculosis can be used in co-therapy,
co-administration or co-formulation with a composition or compound
as described herein.
[0199] Frequency of administration is typically such that the
dosing interval, for example, the period of time between one dose
and the next, during waking hours is from about 2 to about 12
hours, from about 3 to about 8 hours, or from about 4 to about 6
hours. It will be understood by those of skill in the art that an
appropriate dosing interval is dependent to some degree on the
length of time for which the selected composition is capable of
maintaining a concentration of the compound(s) in the subject
and/or in the target tissue (e.g., above the EC.sub.50 (the minimum
concentration of the compound which modulates the receptor's
activity by 90%). Ideally the concentration remains above the
EC.sub.50 for at least 100% of the dosing interval. Where this is
not achievable it is desired that the concentration should remain
above the EC.sub.50 for at least about 60% of the dosing interval,
or should remain above the EC.sub.50 for at least about 40% of the
dosing interval.
[0200] In order that the embodiments disclosed herein may be more
efficiently understood, examples are provided below. It should be
understood that these examples are for illustrative purposes only
and are not to be construed as limiting in any manner.
EXAMPLES
[0201] Assays used to measure growth or inhibition of TB.
[0202] Bacterial strains and growth conditions. The strain M.
tuberculosis H37Rv was used for all experiments. GFP was expressed
using a constitutive episomal plasmid driven by the Rv3583c
promoter. An inducible firefly luciferase expression plasmid was
constructed using an anhydrotetracycline inducible system, as
described previously (30). Mtb H37Rv was grown at 37.degree. C. in
Middlebrook 7H9 broth supplemented with 10% OADC (oleic
acid-albumin-dextrose complex), 0.2% glycerol and 0.05% Tween-80 or
on Middlebrook 7H10 plates supplemented with 10% OADC
enrichment.
[0203] Carbon Starvation. Freezer stocks of H37Rv were diluted 1:50
in fresh 7H9 OADC media and cultured until late log phase,
OD.sub.600 between 0.6 and 1.0. The bacteria were centrifuged at
2800.times.g for five minutes and resuspended in 50 mL of
starvation media (7H9 and 0.05% Tyloxapol without any
supplementation). The cells were then washed an additional two
times with starvation media. After the final wash the cells were
resuspended in starvation media to an OD.sub.600 of 0.2 and 50 mL
of culture aliquoted into a sterile roller bottle. The starvation
culture was incubated standing at 37.degree. C. for 5 weeks.
[0204] Compound Testing: An initial assay was developed and
utilized using a GFP-expressing M. tuberculosis reporter strain
that measured fluorescence as a marker for growth and survival
after an outgrowth period in rich 7H9 media. This assay was
modified to accommodate the scale of the screen involving the MLPCN
library. These modifications include using Alamar blue to measure
surviving bacteria rather than the fluorescence, and outgrowth in
7H12 media.
[0205] Carbon starvation assays. For M. tuberculosis starvation
screening assays, carbon-starved bacteria expressing GFP were
diluted and plated into 384 well plates into which compounds had
previously been pinned for a final OD600 of 0.05, a final volumes
of 40 .mu.L and a final compound concentration of 30 .mu.M. Plates
were incubated for a period of 120 h, at which time 10 .mu.L
5.times. concentrated media was added to each well of the plate
(7H9 media with 50% OADC, 1% glycerol, 0.05% tyloxapol). Plates
were then incubated for an additional 96 hours, at which time
fluorescence was read using an M5 Spectramax. Each compound was
screened in duplicate, and composite z-scores were calculated using
DMSO controls as reference. Compounds were compounds that could
inhibit growth or kill M. tuberculosis were defined as compounds
with a composite z-score of less than -6. This z-score cutoff was
selected as the z-score of the concentration of the control
antibiotic rifampicin that gave a Z'-factor of 0.
[0206] Alternative Carbon starvation assay. Carbon starved bacteria
were diluted and plated into 384 well plates into which compounds
had already been pinned for a final OD600 of 0.005 and final volume
of 50 uL. The plates were incubated for 96 hours, at which time 12
uL of concentrated media was added. Plates were incubated for an
additional 72 hours. For Alamar blue detection, a solution of 3
parts 18.2% Tween-80 to 4 parts Alamar Blue ( 3/7th Tween-80 to
4/7th Alamar Blue) is made and 9 ul added to each well in the
plate. The plates are incubated (stacked 2-3 high) overnight at
37.degree. C. in humidified incubator. The plates are removed from
the incubator and sealed with aluminum seals. The fluorescence is
read using the Envision plate reader (bottom read) with an
excitation wavelength of 531 nm and an emission wavelength of 595
nm (Excitation filter=BODIPY TMR FP 531, barcode 105; Emission
filter=Photometric 595, barcode 315; Mirror=BODIPY TMR, barcode
405).
[0207] Replicating, logarithmic assay. For M. tuberculosis
screening assays for logarithmically growing, actively replicating
activity, bacteria expressing GFP was grown to mid-log phase
(OD600=0.6-0.8), diluted, and plated into 384 well plates into
which compounds had previously been pinned for a final OD600 of
0.025. Plates were incubated for a period of 72 h, at which time
GFP fluorescence is read. Each compound is screened in duplicate,
and composite z-scores were calculated using DMSO controls as
reference. Compounds that inhibit replicating M. tuberculosis were
defined as compounds with a composite z-score of less than -4. This
z-score cutoff was selected using average of the z-scores of the
concentrations of the control antibiotics clofazimine and
rifampicin that gave a Z'-factor of 0.
[0208] Replicating IC90 determination by OD600. For close response
curves and IC90 determinations by OD600, bacteria were grown to
mid-log phase and plated in 96 well plates at OD600=0.05 in the
presence of small molecule inhibitors for 7 days unless otherwise
indicated, and growth was assessed by reading OD600. The IC90 was
defined as the minimum concentration that inhibited growth by 90%
relative to the DMSO control (31).
[0209] Non-replicating IC90 determination by luciferase. For the
luciferase secondary screen that tests for activity of small
molecules directly on non-replicating cells without an outgrowth
phase, carbon-starved M. tuberculosis H37Rv containing an inducible
firefly luciferase plasmid was dispersed into 96-well plates
containing the small molecules and anhydotetracycline 50 nM (to
induce luciferase expression). After 5 days the cells were lysed,
luciferase reagent added and luminescence measured (Promega
Corporation, Madison Wis.) in a Spectramax M5 (Molecular Devices).
The antibiotic rifampicin (at 80.times. the MIC) was used as a
positive control for the assay. Hits were defined as small
molecules that resulted in >95% inhibition of luciferase
signal.
[0210] Replicating IC90 determinations by CFU. To confirm the
replicating IC90 values determined using OD600, the activity of
selected small molecules were tested by plating for colony forming
units (CFU). M. tuberculosis H37Rv was grown to mid-log phase and
plated in 96 well plates at OD600=0.025 in the presence of small
molecule inhibitors for specified time periods. The number of
surviving bacteria was then determined by plating a dilution series
of the culture for colony forming units (CFU). The IC90 was defined
the concentration tested that inhibited growth by at least 90%
relative to the DMSO control.
[0211] Non-replicating IC90 determinations by CFU. To confirm the
non-replicating IC90 values determined using the luciferase
reporter, the activity of selected small molecules was tested by
plating for CFU. Carbon-starved bacteria were diluted to OD600=0.05
in starvation media and plated in 96 well plates in the presence of
small molecule inhibitors for indicated time periods. The number of
surviving bacteria was then determined by plating a dilution series
of the culture for colony forming units (CFU). The IC90 was defined
as the concentration tested that inhibited survival by at least 90%
relative to the DMSO control.
[0212] Generating resistant mutants. The MIC of each compound on
solid media was identified by plating 10.sup.7 bacteria on agar
containing a close response in 96 well plate format. The MIC was
defined as the lowest concentration resulting in inhibition of
bacterial growth. Resistant mutants were generated by plating M.
tuberculosis cells onto agar pads containing 2.times. and 10.times.
the agar MIC of each compound using four independently derived
wild-type clones. Colonies that arose on inhibitor containing
plates were inoculated into liquid media containing 1.times. the
liquid MIC of the inhibitor. These cultures were grown to mid-log
and samples were retested in a liquid MIC assay to confirm that a
shift relative to the wild-type MIC was observed.
[0213] Macrophage toxicity assay. To determine macrophage toxicity,
J774 macrophages were plated in 96 well plates at a concentration
of 6.25.times.10.sup.4 cells/well and rested overnight. A dilution
series of the small molecule being tested was then added to the
plates in quadruplicate. The top concentration tested was 50 uM.
The plates were incubated for 48 hours, upon which time
CellTiter-Glo (Promega Corporation) was used as a readout for
macrophage viability.
Example 2: Synthesis of Compounds
Synthesis of
2-(4-chlorophenyl)-5-(((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)thio)-1,3,4-
-oxadiazole
[0214] The compound below was synthesized by the two-step protocol
scheme outlined below. Alkylation of
5-(4-chlorophenyl)-1,3,4-oxadiazole-2-thiol (1) with propagyl
bromide yielded
2-(4-chlorophenyl)-5-(prop-2-yn-1-ylthio)-1,3,4-oxadiazole (2). The
resulting adduct 2 was then reacted with phenylazide to undergo
cycloaddition reaction under microwave irradiation condition to
provide the
2-(4-chlorophenyl)-5-(((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)thio)-1-
,3,4-oxadiazole.
##STR00074##
[0215] All reagents and solvents were purchased from commercial
vendors and used as received. NMR spectra were recorded on a Bruker
300 MHz or Varian UNITY INOVA 500 MHz spectrometer as indicated.
Proton, fluorine, and carbon chemical shifts are reported in parts
per million (ppm; 6) relative to tetramethylsilane or CDCl.sub.3
solvent (.sup.1H .delta. 0, .sup.19F .delta. 0, .sup.13C .delta.
77.16, respectively). NMR data are reported as follows: chemical
shifts, multiplicity (obs=obscured, app=apparent, br=broad,
s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet); coupling
constant(s) in Hz; integration. Unless otherwise indicated, NMR
data were collected at 25.degree. C. Flash chromatography was
performed using 40-60 um Silica Gel (60 .ANG. mesh) on a Teledyne
Isco Combiflash Rf system. Tandem liquid chromatography/mass
spectrometry (LCMS) was performed on a Waters 2795 separations
module and Waters 3100 mass detector. Analytical thin layer
chromatography (TLC) was performed on EM Reagent 0.25 mm silica gel
60-F plates. Visualization was accomplished with UV light and
aqueous potassium permanganate (KMnO.sub.4) stain followed by
heating. Liquid chromatography/mass spectrometry (LCMS) was
performed on an Agilent 1290 Infinity separations module and 6230
time-of-flight (TOF) mass detector operating in ESI+ mode. Compound
purity and identity were determined by UPLC-MS (Waters, Milford,
Mass.). Purity was measured by UV absorbance at 210 nm. Identity
was determined on a SQ mass spectrometer by positive electrospray
ionization. Mobile Phase A consisted of either 0.1% ammonium
hydroxide or 0.1% trifluoroacetic acid in water, while mobile Phase
B consisted of the same additives in acetonitrile. The gradient ran
from 5% to 95% mobile Phase B over 0.8 minutes at 0.45 mL/min. An
Acquity BEH C18, 1.7 um, 1.0.times.50 mm column was used with
column temperature maintained at 65.degree. C. Compounds were
dissolved in DMSO at a nominal concentration of 1 mg/mL, and 0.25
uL of this solution was injected.
[0216] Synthetic Procedure for TB Compound
##STR00075##
[0217] To a solution of 2.50 g (11.8 mmol) of
5-(4-chlorophenyl)-1,3,4-oxadiazole-2-thiol in 50 mL of EtOH and 2
mL of Et.sub.3N was added 1.54 g (12.9 mmol) of propargyl bromide
and the solution was stirred overnight. White crystals appeared
after cooling with an ice bath, the crystals were filtered and
rinsed with cold EtOH. The mother liquors were concentrated and
cooled to obtain more pure material, 1.82 g of white crystals (63%)
was obtained. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.96 (d,
J=8.47 Hz, 2H), 7.49 (d, J=8.49 Hz, 2H), 4.07 (s, 2H), 2.35 (s,
1H); .sup.13C NMR (CDCl.sub.3, 75 MHz) .delta. 165.38, 162.84,
138.08, 129.45, 127.98, 121.92, 77.19, 73.05, 21.14.
##STR00076##
[0218] To a mixture of 200 mg of this alkyne (0.80 mmol) in 3.5 mL
of t-BuOH in a small microwave vial was added 1.6 mL of a 0.5 M
solution of phenyl azide (0.80 mmol) in 2-methyl tetrahydrofuran
and 50 mg of copper metal. The mixture was heated at 100.degree. C.
with microwave irradiation for 1 h. Water and EtOAc were added to
the reaction mixture, the separated EtOAc layer was dried,
filtered, and concentrated. The crude material was purified by
chromatography with a gradient of 20-50% EtOAc in hexane to isolate
129 mg of product as a white solid (44%) which could be
recrystallized from EtOH. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.
8.23 (s, 1H), 7.93 (d, J=8.55 Hz, 2H), 7.71 (d, J=7.67 Hz, 2H),
7.43-7.54 (m, 5H), 4.69 (s, 1H); .sup.13C NMR (CDCl.sub.3, 75 MHz)
.delta. 165.39, 164.16, 143.59, 138.09, 136.86, 129.74, 129.50,
128.91, 127.93, 121.92, 121.57, 120.61, 26.89. HRMS (ESI+):
calculated for C.sub.17H.sub.12C.sub.1N.sub.5OS [M+H] 370.0524,
found 370.0527.
[0219] Additional analogues suitable for this protocol were
synthesized utilizing this Protocol
[0220] Protocol B: Thio-oxadiazole formation
##STR00077##
[0221] To 10 mL of DMF was added 1.0 g of
4-(methylsulfonyl)benzohydrazide (4.7 mmol), and 1.4 g of
tetramethylthiuram disulfide (5.6 mmol) and the mixture was heated
at 100.degree. C. for 30 min before cooling and concentration. The
residual DMF was removed by addition of toluene and evaporating
(3.times.), the resulting solid was stirred in toluene, filtered,
and rinsed with toluene to yield 1.2 g of pale yellow solid as the
dimethyl-ammonium salt (100%). .sup.1H NMR (DMSO-d.sub.6, 300 MHz)
.delta. 8.03 (s, 4H), 3.28 (s, 3H), 2.59 (s, 6H); .sup.13C NMR (75
MHz, DMSO-d6) .delta. 181.16, 159.77, 140.81, 129.41, 127.88,
125.32, 43.41, 34.40.
[0222] Benzylation of Thio-Oxadiazole Ammonium Salt
##STR00078##
[0223] To 200 mg of the dimethylammonium salt (0.66 mmol) in 5 mL
EtOH was added 1.43 g (0.093 mL, 0.78 mmol) of benzyl bromide.
White solids were seen within minutes and the mixture was stirred
overnight before filtration and rinsing with EtOH to yield 195 mg
of product (85%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.19
(d, J=8.1, 2H), 8.08 (d, J=8.5, 2H), 7.47 (d, J=7.2, 2H), 7.42-7.28
(m, 3H), 4.56 (s, 2H), 3.11 (s, 3H). .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. 163.83, 162.71, 141.50, 133.74, 127.60, 127.31,
126.82, 126.69, 125.87, 42.82, 35.32.
[0224] Protocol C: Benzylation of Thio-Oxadiazoles
##STR00079##
[0225] To a solution of 1.07 g of 5-phenyl-1,3,4-oxadiazole-2-thiol
(6.00 mmol) in 40 mL of 95% EtOH and 0.84 mL of Et.sub.3N (6.0
mmol) was added 1.03 g of benzyl bromide (0.72 mL, 6.0 mmol). White
precipitate was seen after ca. 1 h, after 2 h the precipitate was
filtered off and rinsed with EtOH to yield 1.20 g product (75%)
which could be recrystallized from EtOH. .sup.1H NMR (CDCl.sub.3,
300 MHz) .delta. 7.97-8.01 (m, 2H), 7.46-7.53 (m, 5H), 7.30-7.38
(m, 3H), 4.53 (s, 2H); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.
165.73, 163.76, 135.54, 131.54, 129.05, 128.93, 128.71,128.00,
126.56, 123.54, 36.76.
[0226] Additional analogues were synthesized utilizing these
protocol.
[0227] Protocol D:
##STR00080##
[0228] To a solution of 4.0 g of 5-phenyl-1,3,4-oxadiazole-2-thiol
(22.5 mmol) in 125 mL of DCM and 5 mL of Et.sub.3N was added 42 g
of 1,2-dibromoethane (19 mL, 220 mmol) via an addition funnel and
the reaction was stirred overnight. The solution was rinsed with
water, dried, filtered and concentrated before two
recrystallizations from ethanol to yield 3.8 g (60%) of product as
a white solid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.01 (dd,
J=7.68, 1.63, 2H), 7.47-7.57 (m, 3H), 3.68-3.83 (m, 4H); .sup.13C
NMR (75 MHz, CDCl.sub.3) .delta. 166.03, 162.98, 131.77, 129.02,
126.62, 123.29, 34.03, 29.24.
##STR00081##
[0229] To a solution of 250 mg (0.88 mmol) of the bromide in 1 mL
of DMF was added 1.0 mL of 2,2,2-trifluoroethylamine (13 mmol) and
the reaction was stirred several days. EtOAc and water were added,
the water was rinsed several times with EtOAc and the combined
EtOAc layers were rinsed with brine, dried, filtered and
concentrated to an oil. The crude product was dissolved in MeOH and
placed onto a column of acidic resin (5 g SCX resin, Isolute
brand), flushed with MeOH and the basic product was then eluted
with a solution of NH.sub.3 in MeOH. The impure material obtained
was then chromatographed with 20-50% EtOAc to isolate 64 mg of
product (24%). .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 10.24 (s,
1H), 7.87 (d, J=7.31, 2H), 7.40-7.48 (m, 3H), 4.23 (q, J=6.92 Hz,
2H), 3.80 (t, J=6.78, 2H), 3.24 (t, J=6.75 Hz, 2H); .sup.19F NMR
(CDCl.sub.3, 282 MHz) .delta.-64.75 (t, J=9.22 Hz).
[0230] Additional analogues were synthesized utilizing this
protocol.
[0231] Protocol E:
##STR00082##
[0232] To a solution of 166 mg of
2-(methylthio)-5-phenyl-1,3,4-oxadiazole (0.864 mmol) in 5 mL DCM
cooled in an ice bath was added 298 mg of mCPBA (70% max., ca. 2
eq.) and the solution was stirred overnight, warming to room
temperature. The mixture was added directly to a silica gel column
and eluted with 0-20% EtOAc in hexane to isolate 119 mg of product
as a white solid (62%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
8.19-8.03 (m, 2H), 7.65 (t, J=7.3, 1H), 7.56 (t, J=7.3, 2H), 3.54
(s, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 166.61, 162.10,
133.28, 129.36, 127.73, 122.03, 42.96.
[0233] To 35 mg of benzyl alcohol (0.32 mmol) dissolved in 1 mL of
THF was added NaH (60% oil dispersion, 13 mg, ca. 0.32 mmol) and
the mixture was stirred 1 h before addition of a solution of 60 mg
of the sulfoxide (0.27 mmol) in 1 mL THF. After stirring overnight,
EtOAc and water were added, the EtOAc was separated, dried,
concentrated and chromatographed with 0-20% EtOAc in hexane to
isolate 37 mg of product as a white solid (55%). .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.01-7.84 (m, 2H), 7.58-7.33 (m, 8H), 5.54
(s, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 165.66, 160.73,
133.87, 131.24, 129.27, 128.95, 128.83, 128.79, 126.09, 124.08,
74.49.
[0234] Additional analogues were synthesized utilizing this
protocol.
[0235] Protocol F:
##STR00083##
[0236] To a solution of 34 mg (0.092 mmol) of sulfide in 1 mL of
DCM was added 20.6 mg of mCPBA (70% max., ca. 1 eq.) and the
solution was stirred overnight before direct addition to a silica
gel column and elution with 20-50% EtOAc in hexane to isolate 27 mg
of product as a white solid (76%). .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta. 8.21 (s, 1H), 8.02 (d, J=8.53 Hz, 2H), 7.72 (d, J=7.46
Hz, 2H), 7.44-7.56 (m, 5H), 5.01 (d, J=13.92 Hz, 1H), 4.84 (d,
J=13.93, 1H); .sup.13C NMR (CDCl.sub.3, 75 MHz) .delta. 166.63,
165.33, 139.39, 136.62, 135.65, 129.87, 129.71, 129.22, 128.79,
123.09, 121.03, 120.57, 50.58.
[0237] Additional analogues were synthesized utilizing this
protocol.
##STR00084##
was synthesized by following procedure reported in literature
Zarudnitskii, E. V.; Pervak, I. I.; Merkulov, A. S.; Yurchenko, A.
A.; Tolmachev, A. A. Tetrahedron 2008, 64, 10431-10442.
##STR00085##
was synthesized by following procedure reported in literature:
Wang, Y.; Sauer, D. R.; Djuric, S. W. Tetrahedron Lett. 2006, 47,
105-108.
[0238] Example 3: Characteristics of
2-(4-chlorophenyl)-5-(((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)thio)-1,3,4-
-oxadiazole. The compound was tested against TB according to the
assays described in Example 1. Dose response curves for the
compound were determined. FIG. 1A is a close response curve against
replicating, logarithmically growing bacteria measured by OD600.
(AID xx), IC.sub.90>62 uM FIG. 1B is a close response against
replicating, logarithmically growing bacteria measured by CFU/mL.
(AID xx), IC.sub.90>62 uM FIG. 1C is a close response curve for
non-replicating, starved cells by luciferase assay. (AID xx),
IC.sub.90=4 uM FIG. 1D is a close response against non-replicating,
starved cells by CFU/mL. (AID xx), IC.sub.90=1 uM. The results are
shown below. The values are in .mu.M.
[0239] Example 4: Testing of Additional Compounds. The following
compounds were tested against replicating and non-replicating TB
according to the assays described in Example 1. As can be seen some
compounds can inhibit the growth of both replicating and
non-replicating TB, whereas others are more selective or completely
selective. The results are shown in the following table.
TABLE-US-00001 TB Growth Inhibition Activity, IC.sub.90
(uM).sup..dagger. Cytotoxicity Non- IC.sub.50 (uM)* replicat-
Replicat- Hek 293/ Compound ing_luciferase ing_logarithmic
HepG2/HeLa ##STR00086## 8 62 >26.0 ##STR00087## 8 62 >26.0
##STR00088## 62 N.A >26.0 ##STR00089## 8 N.A >26.0
##STR00090## 4 N.A >26.0 ##STR00091## 0.5 250 >26.0
##STR00092## 0.5 250 >26.0 ##STR00093## 16 N.A >26.0
##STR00094## 8 125 >26.0 ##STR00095## 8 125 >26.0
##STR00096## 1 125 >26.0 ##STR00097## 0.5 125 >26.0
##STR00098## 2 125 >26.0 ##STR00099## 31 N.A >26.0
##STR00100## 4 500 >26.0 ##STR00101## 32 250 >26.0
##STR00102## N.A N.A >26.0 ##STR00103## 16 N.A >26.0
##STR00104## 125 250 >26.0 ##STR00105## 2 125 >26.0
##STR00106## 32 250 >26.0 ##STR00107## 62 N.A >26.0
##STR00108## 62 500 >26.0 ##STR00109## 62 500 >26.0
##STR00110## 8 N.A >26.0 ##STR00111## 8 250 >26.0
##STR00112## 1 125 >26.0 ##STR00113## 8 N.A >26.0
##STR00114## 31 250 >26.0 ##STR00115## 31 N.A >26.0
##STR00116## 125 N.A >26.0 ##STR00117## 8 N.A >26.0
##STR00118## 4 125 >26.0 ##STR00119## 31 N.A >26.0
##STR00120## 2 125 >26.0 ##STR00121## 4 500 >26.0
##STR00122## 2 N.A >26.0 ##STR00123## 1 N.A >26.0
##STR00124## 8 N.A >26.0 ##STR00125## N.A N.A >26.0
##STR00126## 4 125 >26.0 ##STR00127## 2 125 >26.0
##STR00128## 31 N.A >26.0 ##STR00129## 8 N.A >26.0
##STR00130## 4 125 >26.0 ##STR00131## 2 N.A >26.0
##STR00132## 8 250 >26.0 ##STR00133## 2 N.A >26.0
##STR00134## 1 250 >26.0 ##STR00135## 2 250 >26.0
##STR00136## 1 N.A >26.0 ##STR00137## 4 500 >26.0
##STR00138## 4 N.A >26.0 ##STR00139## N.A N.A >26.0
##STR00140## 1 125 >26.0 ##STR00141## 1 N.A >26.0
##STR00142## 4 N.A >26.0 ##STR00143## 2 250 >26.0
##STR00144## 4 250 >26.0 ##STR00145## 2 N.A >26.0
##STR00146## 8 N.A >26.0 ##STR00147## 250 250 >26.0
##STR00148## 1 N.A >26.0 ##STR00149## 0.25 N.A >26.0
##STR00150## 1 N.A >26.0 ##STR00151## 1 N.A >26.0
##STR00152## 1 N.A >26.0 ##STR00153## 1 N.A >26.0
##STR00154## 2 N.A >26.0 ##STR00155## 31 N.A >26.0
##STR00156## 8 N.A >26.0 ##STR00157## 3 100 >26.0
##STR00158## 8 125 >26.0 ##STR00159## 31 250 >26.0
##STR00160## 16 31 >26.0 ##STR00161## 4 62 >26.0 ##STR00162##
16 >125 >26.0 ##STR00163## 3 125 >26.0 ##STR00164## 16 500
>26.0 ##STR00165## 250 N.A >26.0 ##STR00166## 250 N.A
>26.0 ##STR00167## 125 N.A >26.0 ##STR00168## 1 250 >26.0
##STR00169## 16 N.A >26.0 ##STR00170## 4 >62 >26.0
##STR00171## 2 >62 >26.0 ##STR00172## 2 >62 >26.0
##STR00173## 31 62 >26.0 ##STR00174## 8 >62 >26.0
##STR00175## 31 >62 >26.0 ##STR00176## 8 >62 >26.0
##STR00177## 4 >62 >26.0 ##STR00178## 2 >62 >26.0
##STR00179## 1 >62 >26.0 ##STR00180## 2 >62 >26.0
##STR00181## 2 62 >26.0 ##STR00182## 4 62 >26.0
.sup..dagger.Data is from three independent experiment, performed
in triplicats. *For each analogue, cytotoxicity was measured
against Hek 293, HepG2 and HeLa cell lines and IC50 was determined
to be >26.0 uM (highest concentration measured) for each cell
line
[0240] Example 5: Further testing of Compounds. Compounds were
further analyzed according to the assays described in Example 1.
The data demonstrates that the compounds can be used to treat
tuberculosis.
TABLE-US-00002 TABLE Antimycobacterial activity of the compounds
was determined using the fluorescent assay, either using GFP or
luciferase. These assasys are described in Example 1. Against
carbon Against starved non- Replicating Mtb replicating Mtb IC90
IC99 Compound (uM, GFP) (uM, luciferase) ##STR00183## 125 62
##STR00184## >250 None ##STR00185## 200 250 ##STR00186## 125 62
##STR00187## 125 None ##STR00188## 250 250 ##STR00189## 500 250
##STR00190## 125 16 ##STR00191## 125 31 ##STR00192## 100 31
##STR00193## 125 250 ##STR00194## 250 500 ##STR00195## >500 None
##STR00196## >500 62 ##STR00197## >500 None ##STR00198## 62 8
##STR00199## >500 62 ##STR00200## >500 None ##STR00201##
>500 None ##STR00202## >500 None ##STR00203## 62 16
##STR00204## 50 16 ##STR00205## >500 250 ##STR00206## >500
None ##STR00207## >500 500 ##STR00208## >500 500 ##STR00209##
62 125 ##STR00210## 31 4 ##STR00211## 31 31 ##STR00212## 250 62
##STR00213## >500 250 ##STR00214## >500 None ##STR00215##
>500 None ##STR00216## 125 8 ##STR00217## 500 125 ##STR00218##
>500 None ##STR00219## 250 250 ##STR00220## >500 500
##STR00221## >500 250 ##STR00222## 31 31 ##STR00223## 31 16
##STR00224## 125 62 ##STR00225## 31 8 ##STR00226## 62 31
##STR00227## 31 8 ##STR00228## 125 4 ##STR00229## 125 16
##STR00230## 31 62 ##STR00231## 31 16 ##STR00232## 62 31
##STR00233## 62 16 ##STR00234## 31 16 ##STR00235## 125 62
##STR00236## 62 8 ##STR00237## None 31 ##STR00238## 62 8
##STR00239## None 16 ##STR00240## None 16 ##STR00241## None 125
##STR00242## 62 16 ##STR00243## 31 8 ##STR00244## 125 62
##STR00245## 500 250 ##STR00246## 250 62 ##STR00247## 125 4
##STR00248## 31 16 ##STR00249## 125 31 ##STR00250## 125 62
##STR00251## 125 None ##STR00252## 62 62 ##STR00253## 250 62
##STR00254## 125 31 ##STR00255## 250 16 ##STR00256## 250 None (IC90
= 4) ##STR00257## None None (IC90 = 1) ##STR00258## 250 250 (IC90 =
1) ##STR00259## 500 500 (IC90 = 25) ##STR00260## 31 16 ##STR00261##
31 16 ##STR00262## 31 4 ##STR00263## 31 31 ##STR00264## 31 31
##STR00265## None 16 ##STR00266## None 16 ##STR00267## None 16
##STR00268## None 64 (IC90 = 4) ##STR00269## 62 31 ##STR00270##
16.sup.~31 ##STR00271## 31 ##STR00272## 31
None means inhibition did not reach to 90% in assay against
replicating Mtb or 99% in assay against non-replicating Mtb.
TABLE-US-00003 TABLE Antimy cobacterial activity of the compounds
was determined using the fluorescent assay, either using the CFU
assay described in Example 1. Against carbon Against starved non-
Relicating Mtb relicating Mtb Compound IC90 (uM) IC90 (uM)
##STR00273## 10 ##STR00274## 62 ##STR00275## 4 ##STR00276## 99% @
125 4 ##STR00277## 31 ##STR00278## None ##STR00279## 10
##STR00280## 10 ##STR00281## <8 ##STR00282## 100% @ 31 4
##STR00283## 62 ##STR00284## 98.5% @ 16 99% @ 4 ##STR00285## 31
<8 ##STR00286## 96% @ 62 <8 ##STR00287## 100% @ 62 100% @ 31
##STR00288## 98% @ 125 99% @ 4 ##STR00289## 99% @ 62 99% @ 16
##STR00290## 99.5% @ 16(7d) 99% @ 4 ##STR00291## 31 99% @ 8
##STR00292## 98% @ 8 ##STR00293## 97% @ 8
* * * * *