U.S. patent application number 16/647821 was filed with the patent office on 2020-07-23 for selective p2x3 modulators.
The applicant listed for this patent is BELLUS HEALTH COUGH INC. NEOMED INSTITUTE. Invention is credited to Roberto BELLINI, Susan E. BROWNE, Nathalie CHAURET, Denis GARCEAU, Antonios MATZOURANIS, Kemal PAYZA.
Application Number | 20200230148 16/647821 |
Document ID | / |
Family ID | 71610467 |
Filed Date | 2020-07-23 |
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United States Patent
Application |
20200230148 |
Kind Code |
A1 |
GARCEAU; Denis ; et
al. |
July 23, 2020 |
SELECTIVE P2X3 MODULATORS
Abstract
The current application relates to the use of a selective P2X3
antagonist for avoiding loss of taste response while treating a
chronic cough in warm-blooded animals; wherein said selective P2X3
antagonist is selective for P2X3 homomeric receptor antagonism
versus P2X2/3 heteromeric receptor antagonism.
Inventors: |
GARCEAU; Denis; (Laval,
CA) ; MATZOURANIS; Antonios; (Laval, CA) ;
BELLINI; Roberto; (Laval, CA) ; PAYZA; Kemal;
(Montreal, CA) ; CHAURET; Nathalie; (Laval,
CA) ; BROWNE; Susan E.; (Christiana, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BELLUS HEALTH COUGH INC.
NEOMED INSTITUTE |
Laval
Montreal |
|
CA
CA |
|
|
Family ID: |
71610467 |
Appl. No.: |
16/647821 |
Filed: |
September 14, 2018 |
PCT Filed: |
September 14, 2018 |
PCT NO: |
PCT/IB2018/001513 |
371 Date: |
March 16, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15936316 |
Mar 26, 2018 |
10111883 |
|
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16647821 |
|
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|
62560077 |
Sep 18, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/5377 20130101;
A61K 31/4545 20130101; A61P 27/00 20180101; A61K 31/437
20130101 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61K 31/437 20060101 A61K031/437; A61K 31/4545
20060101 A61K031/4545; A61P 27/00 20060101 A61P027/00 |
Claims
1. A method of avoiding loss of taste response while treating a
chronic cough patient, the method comprising administering to the
patient a therapeutically effective amount of a selective P2X3
antagonist, wherein the selective P2X3 antagonist is at least
10-fold selective for P2X3 homomeric receptor antagonism versus
P2X2/3 heteromeric receptor antagonism.
2. The method of claim 1, wherein the selective P2X3 antagonist is
at least 20-fold selective for P2X3 homomeric receptor antagonism
versus P2X2/3 heteromeric receptor antagonism.
3. The method of claim 1, wherein the selective P2X3 antagonist is
at least 50-fold selective for P2X3 homomeric receptor antagonism
versus P2X2/3 heteromeric receptor antagonism.
4. The method of claim 1, wherein the selective P2X3 antagonist is
at least 100-fold selective for P2X3 homomeric receptor antagonism
versus P2X2/3 heteromeric receptor antagonism.
5. The method of claim 1, wherein the selective P2X3 antagonist is
at least 500-fold selective for P2X3 homomeric receptor antagonism
versus P2X2/3 heteromeric receptor antagonism.
6. The method of claim 1, wherein the selective P2X3 antagonist is
at least 1000-fold selective for P2X3 homomeric receptor antagonism
versus P2X2/3 heterotrimer receptor antagonism.
7. The method of claim 1, wherein the selective P2X3 antagonist is
at least 2000-fold selective for P2X3 homomeric receptor antagonism
versus P2X2/3 heterotrimer receptor antagonism.
8. The method of claim 1, wherein the selective P2X3 antagonist is
at least 2700-fold selective for P2X3 homomeric receptor antagonism
versus P2X2/3 heterotrimer receptor antagonism.
9. The method of any one of claims 1-8, wherein the selective P2X3
antagonist is a compound of Formula (I), or a pharmaceutically
acceptable salt thereof, having the structure: ##STR00040## Formula
(I); wherein: R.sup.1 is selected from the group consisting of
cyano, halogen, methyl, and ethyl; R.sup.2 is selected from the
group consisting of hydrogen, halogen, methyl, and ethyl; R.sup.3
is selected from the group consisting of halogen, methyl, and
ethyl; R.sup.4 is selected from the group consisting of hydrogen,
halogen, methyl, ethyl, and methoxy; R.sup.5 and R.sup.6 are
independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.6-alkyl, and hydroxy-C.sub.1-C.sub.6-alkyl; or
R.sup.5 and R.sup.6, together with the nitrogen to which they are
both attached, form a 5- or 6-member heterocycloalkyl, wherein the
heterocycloalkyl is optionally substituted with one or more
substituents independently selected from the group consisting of
halogen, hydroxyl, and C.sub.1-C.sub.4-alkyl; R.sup.7 and R.sup.8
are independently selected from the group consisting of hydrogen
and C.sub.1-C.sub.4-alkyl; R.sup.9 is selected from the group
consisting of C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.1-C.sub.6-alkyl-C.sub.3-C.sub.6-cycloalkyl,
halo-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy,
halo-C.sub.1-C.sub.6-alkoxy, and
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl; and X is selected
from a bond, CH.sub.2, and O.
10. The method of claim 9, wherein R.sup.1 is methyl.
11. The method of claim 9 or claim 10, wherein R.sup.2 is
hydrogen.
12. The method of any one of claims 9-11, wherein R.sup.3 is
fluoro.
13. The method of any one of claims 9-12, wherein R.sup.4 is
fluoro.
14. The method of any one of claims 9-13, wherein X is O.
15. The method of any one of claims 9-14, wherein: the compound
corresponds in structure to: ##STR00041## and R.sup.4 is selected
from the group consisting of halogen, methyl, and ethyl.
16. The method of any one of claims 9-15, wherein R.sup.5 is
hydrogen.
17. The method of any one of claims 9-16, wherein R.sup.6 is
C.sub.1-C.sub.6-alkyl.
18. The method of any one of claims 9-17, wherein R.sup.6 is
methyl.
19. The method of any one of claims 9-18, wherein R.sup.7 is
hydrogen.
20. The method of any one of claims 9-19, wherein R.sup.8 is
hydrogen.
21. The method of any one of claims 9-20, wherein R.sup.9 is
C.sub.1-C.sub.6-alkoxy.
22. The method of any one of claims 9-21, wherein R.sup.9 is
methoxy.
23. The method of any one of claims 9-22, wherein the compound
corresponds in structure to: ##STR00042##
24. The method of claim 9, wherein the compound corresponds in
structure to: ##STR00043## ##STR00044## ##STR00045## ##STR00046##
##STR00047## ##STR00048## ##STR00049## ##STR00050##
##STR00051##
25. The method of claim 9, wherein the compound corresponds in
structure to: ##STR00052##
26. The method of claim 9, wherein the compound corresponds in
structure to: ##STR00053##
27. The method of claim 9, wherein the compound corresponds in
structure to: ##STR00054##
28. The method of claim 9, wherein the compound corresponds in
structure to: ##STR00055##
29. The method of any one of claims 1-8, wherein the selective P2X3
antagonist corresponds in structure to: ##STR00056##
30. The method of any one of claims 1-8, wherein the selective P2X3
antagonist corresponds in structure to: ##STR00057##
31. The method of any one of claims 1-8, wherein the selective P2X3
antagonist corresponds in structure to: ##STR00058##
Description
CROSS-REFERENCE
[0001] This application claims benefit of U.S. Provisional
Application No. 62/560,077, filed on Sep. 18, 2017, and is a
continuation of U.S. Utility application Ser. No. 15/936,316, filed
on Mar. 26, 2018, each of which is herein incorporated by reference
in its entirety.
BACKGROUND
[0002] Chronic cough is a cough that lasts for more than eight
weeks and is associated with significant adverse social,
psychosocial and physical effects on quality of life. It is
estimated that, in the United States alone, more than 27 million
patients suffer from chronic cough. While an underlying etiology
such as gastro-oesophageal reflux, asthma, or allergic rhinitis may
contribute to cough in some of these patients, an underlying
condition cannot be identified in 10%-40% of chronic cough patients
(unexplained chronic cough). A portion of patients with an
underlying condition as well as the large majority of unexplained
chronic cough patients are not well controlled by current
therapies.
BRIEF SUMMARY OF THE INVENTION
[0003] This disclosure provides, for example, methods of avoiding
loss of taste response while treating a chronic cough patient with
a selective P2X3 modulator. The disclosure also provides for the
use of selective P2X3 modulators as medicaments and/or in the
manufacture of medicaments for avoiding loss of taste response
while treating a chronic cough patient in warm-blooded animals such
as humans.
[0004] In some embodiments is a method of avoiding loss of taste
response while treating a chronic cough patient, the method
comprising administering to the patient a therapeutically effective
amount of a selective P2X3 antagonist, wherein the selective P2X3
antagonist is at least 10-fold selective for P2X3 homomeric
receptor antagonism versus P2X2/3 heteromeric receptor antagonism.
In some embodiments is a method of avoiding loss of taste response
while treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 20-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 50-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 100-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 500-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 1000-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 2000-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 2700-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism.
[0005] In some embodiments is a method of avoiding loss of taste
response while treating a chronic cough patient, the method
comprising administering to the patient a therapeutically effective
amount of a selective P2X3 antagonist, wherein the selective P2X3
antagonist is at least 10-fold selective, at least 20-fold
selective, at least 50-fold selective, at least 100-fold selective,
at least 500-fold selective, at least 1000-fold selective, at least
2000-fold selective, or at least 2700-fold selective, for P2X3
homomeric receptor antagonism versus P2X2/3 heteromeric receptor
antagonism, wherein the selective P2X3 antagonist is a compound of
Formula (I), or a pharmaceutically acceptable salt thereof, having
the structure:
##STR00001##
wherein: R.sup.1 is selected from the group consisting of cyano,
halogen, methyl, and ethyl;
[0006] R.sup.2 is selected from the group consisting of hydrogen,
halogen, methyl, and ethyl;
[0007] R.sup.3 is selected from the group consisting of halogen,
methyl, and ethyl;
[0008] R.sup.4 is selected from the group consisting of hydrogen,
halogen, methyl, ethyl, and methoxy;
R.sup.5 and R.sup.6 are independently selected from the group
consisting of hydrogen, C.sub.1-C.sub.6-alkyl, and
hydroxy-C.sub.1-C.sub.6-alkyl; or R.sup.5 and R.sup.6, together
with the nitrogen to which they are both attached, form a 5- or
6-member heterocycloalkyl, wherein the heterocycloalkyl is
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, hydroxyl, and
C.sub.1-C.sub.4-alkyl;
[0009] R.sup.7 and R.sup.8 are independently selected from the
group consisting of hydrogen and C.sub.1-C.sub.4-alkyl;
R.sup.9 is selected from the group consisting of
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.1-C.sub.6-alkyl-C.sub.3-C.sub.6-cycloalkyl,
halo-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy,
halo-C.sub.1-C.sub.6-alkoxy, and
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl; and X is selected
from a bond, CH.sub.2, and O.
[0010] In some embodiments, R.sup.1 is methyl. In some embodiments,
R.sup.2 is hydrogen. In some embodiments, R.sup.3 is fluoro. In
some embodiments, X is O. In some embodiments, the compound of
Formula (I) corresponds in structure to
##STR00002##
and R.sup.4 is selected from the group consisting of halogen,
methyl, and ethyl. In some embodiments, R.sup.5 is hydrogen. In
some embodiments, R.sup.6 is C.sub.1-C.sub.6-alkyl. In some
embodiments, R.sup.6 is methyl. In some embodiments, R.sup.7 is
hydrogen. In some embodiments, R.sup.8 is hydrogen. In some
embodiments, R.sup.9 is C.sub.1-C.sub.6-alkoxy. In some
embodiments, R.sup.9 is methoxy. In some embodiments, X is O. In
some embodiments, the compound of Formula (I) corresponds in
structure to
##STR00003##
In some embodiments, the compound of Formula (I) corresponds in
structure to:
##STR00004## ##STR00005## ##STR00006## ##STR00007## ##STR00008##
##STR00009## ##STR00010## ##STR00011## ##STR00012##
[0011] In some embodiments, the compound of Formula (I) corresponds
in structure to
##STR00013##
[0012] In some embodiments, the compound of Formula (I) corresponds
in structure to
##STR00014##
[0013] In some embodiments, the compound of Formula (I) corresponds
in structure to
##STR00015##
[0014] In some embodiments, the compound of Formula (I) corresponds
in structure to
##STR00016##
[0015] In some embodiments, the compound of Formula (I) corresponds
in structure to
##STR00017##
[0016] In some embodiments, the compound of Formula (I) corresponds
in structure to
##STR00018##
[0017] In some embodiments, the compound of Formula (I) corresponds
in structure to
##STR00019##
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIG. 1 depicts the role of P2X3 receptors in chronic
cough.
[0019] FIG. 2 depicts the roles of P2X3 and P2X2/3 receptors in
chronic cough and taste function.
[0020] FIG. 3 shows the potency and selectivity of Compound 1 and
Gefapixant (also know as AF-219) for human P2X3 and P2X2/3
receptors.
[0021] FIG. 4 shows the anti-tussive effect of Compound 1 and
AF-219 at three doses in a guinea pig cough model.
[0022] FIG. 5 shows the the duration of the anti-tussive effect of
Compound 1 and AF-219 in a time course study of a guinea pig cough
model.
[0023] FIG. 6 shows the effect on taste function of Compound 1 and
AF-219 in a two bottle rat taste study.
DETAILED DESCRIPTION OF THE INVENTION
[0024] P2X2 receptors and P2X3 receptors are homotrimers containing
3 subunits of P2X2 and P2X3, respectively. P2X2/3 receptors are
heterotrimers, containing a mix of P2X3 and P2X2 subunits.
Compounds can have differential effects, in terms of potency and/or
maximal inhibition, with respect to their ability to inhibit P2X3
homomers vs. P2X2/3 heteromers. Thus, the effect of a compound on a
cell will depend on the mixture of receptors that cell expresses
(P2X3 homomers, P2X2 homomers, or P2X2/3 heteromers) and the drug's
selectivity for the various P2X subtypes.
[0025] In chronic cough, the majority of stimuli triggering cough
are affecting the upper airways (e.g. strong odor/smoke, cold air,
post-nasal drips, aspiration of gastroesophageal reflux, speaking).
Furthermore, the greatest concentration of cough receptors is in
the larynx, carina and bifurcation of the medium to large-sized
bronchi. These observations indicate that the upper airways play a
major role in cough. Therefore, given that upper airways are
innervated by jugular C-fibres that express primarily P2X3
channels, it suggests that P2X3 homotrimeric receptors are
responsible for the increase in cough reflex sensitivity (FIG. 1;
P2X2 vs. P2X3 expression adapted from Kwong et al 2008 AJP Lung
cell Mol Physiol 295 L858-65). Whereas P2X3 receptors have a
primary role in the cough reflex, P2X2/3 receptors have a major
role in taste function (FIG. 2). Immunohistochemical staining of
the nerve fibres innervating the taste buds of rats showed the
presence of both P2X2 and P2X3 subunits and studies of double
knock-out mice suggest that P2X2/3 heteromeric receptors are an
important component of taste signal transduction. As such, this
disclosure is directed, at least in part, to a method of avoiding
loss of taste response while treating a chronic cough patient, the
method comprising administering to the patient a therapeutically
effective amount of a P2X3 antagonist which is selective versus
P2X2/3.
Definitions
[0026] As used herein and in the appended claims, the singular
forms "a," "and," and "the" include plural referents unless the
context clearly dictates otherwise. Thus, for example, reference to
"an agent" includes a plurality of such agents, and reference to
"the cell" includes reference to one or more cells (or to a
plurality of cells) and equivalents thereof. When ranges are used
herein for physical properties, such as molecular weight, or
chemical properties, such as chemical formulae, all combinations
and subcombinations of ranges and specific embodiments therein are
intended to be included. The term "about" when referring to a
number or a numerical range means that the number or numerical
range referred to is an approximation within experimental
variability (or within statistical experimental error), and thus
the number or numerical range varies between 1% and 15% of the
stated number or numerical range. The term "comprising" (and
related terms such as "comprise" or "comprises" or "having" or
"including") is not intended to exclude that which in other certain
embodiments, for example, an embodiment of any composition of
matter, composition, method, or process, or the like, described
herein, may "consist of" or "consist essentially of" the described
features.
[0027] As used in the specification and appended claims, unless
specified to the contrary, the following terms have the meaning
indicated below.
[0028] As used herein, C.sub.1-C.sub.x includes C.sub.1-C.sub.2,
C.sub.1-C.sub.3 . . . C.sub.1-C.sub.x. C.sub.1-C.sub.x refers to
the number of carbon atoms that make up the moiety to which it
designates (excluding optional substituents).
[0029] "Amino" refers to the --NH.sub.2 radical.
[0030] "Cyano" refers to the --CN radical.
[0031] "Nitro" refers to the --NO.sub.2 radical.
[0032] "Oxa" refers to the --O-- radical.
[0033] "Oxo" refers to the .dbd.O radical.
[0034] "Thioxo" refers to the .dbd.S radical.
[0035] "Imino" refers to the .dbd.N--H radical.
[0036] "Oximo" refers to the .dbd.N--OH radical.
[0037] "Alkyl" or "alkylene" refers to a straight or branched
hydrocarbon chain radical consisting solely of carbon and hydrogen
atoms, containing no unsaturation, having from one to fifteen
carbon atoms (e.g., C.sub.1-C.sub.15 alkyl). In certain
embodiments, an alkyl comprises one to thirteen carbon atoms (e.g.,
C.sub.1-C.sub.13 alkyl). In certain embodiments, an alkyl comprises
one to eight carbon atoms (e.g., C.sub.1-C.sub.8 alkyl). In other
embodiments, an alkyl comprises one to six carbon atoms (e.g.,
C.sub.1-C.sub.6 alkyl). In other embodiments, an alkyl comprises
one to five carbon atoms (e.g., C.sub.1-C.sub.5 alkyl). In other
embodiments, an alkyl comprises one to four carbon atoms (e.g.,
C.sub.1-C.sub.4 alkyl). In other embodiments, an alkyl comprises
one to three carbon atoms (e.g., C.sub.1-C.sub.3 alkyl). In other
embodiments, an alkyl comprises one to two carbon atoms (e.g.,
C.sub.1-C.sub.2 alkyl). In other embodiments, an alkyl comprises
one carbon atom (e.g., C.sub.1 alkyl). In other embodiments, an
alkyl comprises five to fifteen carbon atoms (e.g.,
C.sub.5-C.sub.15 alkyl). In other embodiments, an alkyl comprises
five to eight carbon atoms (e.g., C.sub.5-C.sub.8 alkyl). In other
embodiments, an alkyl comprises two to five carbon atoms (e.g.,
C.sub.2-C.sub.5 alkyl). In other embodiments, an alkyl comprises
three to five carbon atoms (e.g., C.sub.3-C.sub.5 alkyl). In other
embodiments, the alkyl group is selected from methyl, ethyl,
1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl),
1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl),
1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). The alkyl
is attached to the rest of the molecule by a single bond. Unless
stated otherwise specifically in the specification, an alkyl group
is optionally substituted by one or more of the following
substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,
trimethylsilanyl, --OR.sup.a, --SR.sup.a, --OC(O)R.sup.a,
--N(R.sup.a).sub.2, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)N(R.sup.a).sub.2, --N(R.sup.a)C(O)OR,
--OC(O)--NR.sup.aR.sup.f, --N(R.sup.a)C(O)R.sup.f,
--N(R.sup.a)S(O).sub.tR.sup.f (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2), --S(O).sub.tR.sup.f
(where t is 1 or 2) and --S(O).sub.tN(R.sup.a).sub.2 (where t is 1
or 2) where each R.sup.a is independently hydrogen, alkyl,
fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl,
heteroaryl or heteroarylalkyl, and each R.sup.f is independently
alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl,
heteroaryl or heteroarylalkyl.
[0038] "Alkoxy" refers to a radical bonded through an oxygen atom
of the formula --O-alkyl, where alkyl is an alkyl chain as defined
above.
[0039] "Alkenyl" refers to a straight or branched hydrocarbon chain
radical group consisting solely of carbon and hydrogen atoms,
containing at least one carbon-carbon double bond, and having from
two to twelve carbon atoms. In certain embodiments, an alkenyl
comprises two to eight carbon atoms. In other embodiments, an
alkenyl comprises two to four carbon atoms. The alkenyl is attached
to the rest of the molecule by a single bond, for example, ethenyl
(i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl,
penta-1,4-dienyl, and the like. Unless stated otherwise
specifically in the specification, an alkenyl group is optionally
substituted by one or more of the following substituents: halo,
cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl,
--OR.sup.a, --SR.sup.a, --OC(O)--R.sup.f, --N(R.sup.a).sub.2,
--C(O)R.sup.a, --C(O)OR.sup.a, --C(O)N(R.sup.a).sub.2,
--N(R.sup.a)C(O)OR.sup.f, --OC(O)--NR.sup.aR.sup.f,
--N(R.sup.a)C(O)R.sup.f, --N(R.sup.a)S(O).sub.tR.sup.f (where t is
1 or 2), --S(O).sub.tOR.sup.a (where t is 1 or 2),
--S(O).sub.tR.sup.f (where t is 1 or 2) and
--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2) where each R.sup.a
is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl,
aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each
R.sup.f is independently alkyl, fluoroalkyl, cycloalkyl, aryl,
aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.
[0040] "Alkynyl" refers to a straight or branched hydrocarbon chain
radical group consisting solely of carbon and hydrogen atoms,
containing at least one carbon-carbon triple bond, having from two
to twelve carbon atoms. In certain embodiments, an alkynyl
comprises two to eight carbon atoms. In other embodiments, an
alkynyl has two to four carbon atoms. The alkynyl is attached to
the rest of the molecule by a single bond, for example, ethynyl,
propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated
otherwise specifically in the specification, an alkynyl group is
optionally substituted by one or more of the following
substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,
trimethylsilanyl, --OR.sup.a, --SR.sup.a, --OC(O)R.sup.a,
--N(R.sup.a).sub.2, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)N(R.sup.a).sub.2, --N(R.sup.a)C(O)OR.sup.f,
--OC(O)--NR.sup.aR.sup.f, --N(R.sup.a)C(O)R.sup.f,
--N(R.sup.a)S(O).sub.tR.sup.f (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2), --S(O).sub.tR.sup.f
(where t is 1 or 2) and --S(O).sub.tN(R.sup.a).sub.2 (where t is 1
or 2) where each R.sup.a is independently hydrogen, alkyl,
fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl,
heteroaryl or heteroarylalkyl, and each R.sup.f is independently
alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl,
heteroaryl or heteroarylalkyl.
[0041] "Aryl" refers to a radical derived from an aromatic
monocyclic or multicyclic hydrocarbon ring system by removing a
hydrogen atom from a ring carbon atom. The aromatic monocyclic or
multicyclic hydrocarbon ring system contains only hydrogen and
carbon from six to eighteen carbon atoms, where at least one of the
rings in the ring system is fully unsaturated, i.e., it contains a
cyclic, delocalized (4n+2) n-electron system in accordance with the
Huckel theory. The ring system from which aryl groups are derived
include, but are not limited to, groups such as benzene, fluorene,
indane, indene, tetralin and naphthalene. Unless stated otherwise
specifically in the specification, the term "aryl" or the prefix
"ar-" (such as in "aralkyl") is meant to include aryl radicals
optionally substituted by one or more substituents independently
selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano,
nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl,
heterocycloalkyl, heteroaryl, heteroarylalkyl, --R.sup.b--OR.sup.a,
--R.sup.b--OC(O)--R.sup.a, --R.sup.b--OC(O)--OR.sup.a,
--R.sup.b--OC(O)--N(R.sup.a).sub.2, --R.sup.b--N(R.sup.a).sub.2,
--R.sup.b--C(O)R.sup.a, --R.sup.b--C(O)OR.sup.a,
--R.sup.b--C(O)N(R.sup.a).sub.2,
--R.sup.b--O--R--C(O)N(R.sup.a).sub.2,
--R.sup.b--N(R.sup.a)C(O)OR.sup.a,
--R.sup.b--N(R.sup.a)C(O)R.sup.a,
--R.sup.b--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--R.sup.b--S(O).sub.tOR.sup.a (where t is 1 or 2),
--R.sup.b--S(O).sub.tR.sup.a (where t is 1 or 2) and
--R.sup.b--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), where
each R.sup.a is independently hydrogen, alkyl, fluoroalkyl,
cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one
or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or
heteroarylalkyl, each R.sup.b is independently a direct bond or a
straight or branched alkylene or alkenylene chain, and R.sup.c is a
straight or branched alkylene or alkenylene chain.
[0042] "Aryloxy" refers to a radical bonded through an oxygen atom
of the formula --O-aryl, where aryl is as defined above.
[0043] "Aralkyl" refers to a radical of the formula --R.sup.c-aryl
where R.sup.c is an alkylene chain as defined above, for example,
methylene, ethylene, and the like. The alkylene chain part of the
aralkyl radical is optionally substituted as described above for an
alkylene chain. The aryl part of the aralkyl radical is optionally
substituted as described above for an aryl group.
[0044] "Aralkyloxy" refers to a radical bonded through an oxygen
atom of the formula --O-- aralkyl, where aralkyl is as defined
above.
[0045] "Aralkenyl" refers to a radical of the formula
--R.sup.d-aryl where R.sup.d is an alkenylene chain as defined
above. The aryl part of the aralkenyl radical is optionally
substituted as described above for an aryl group. The alkenylene
chain part of the aralkenyl radical is optionally substituted as
defined above for an alkenylene group.
[0046] "Aralkynyl" refers to a radical of the formula
--R.sup.e-aryl, where R.sup.e is an alkynylene chain as defined
above. The aryl part of the aralkynyl radical is optionally
substituted as described above for an aryl group. The alkynylene
chain part of the aralkynyl radical is optionally substituted as
defined above for an alkynylene chain.
[0047] "Cycloalkyl" refers to a stable non-aromatic monocyclic or
polycyclic hydrocarbon radical consisting solely of carbon and
hydrogen atoms, which includes fused or bridged ring systems,
having from three to fifteen carbon atoms. In certain embodiments,
a cycloalkyl comprises three to ten carbon atoms. In other
embodiments, a cycloalkyl comprises five to seven carbon atoms. The
cycloalkyl is attached to the rest of the molecule by a single
bond.
[0048] Cycloalkyls are saturated, (i.e., containing single C--C
bonds only) or partially unsaturated (i.e., containing one or more
double bonds or triple bonds.) Examples of monocyclic cycloalkyls
include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, and cyclooctyl. In certain embodiments, a cycloalkyl
comprises three to eight carbon atoms (e.g., C.sub.3-C.sub.8
cycloalkyl). In other embodiments, a cycloalkyl comprises three to
seven carbon atoms (e.g., C.sub.3-C.sub.7 cycloalkyl). In other
embodiments, a cycloalkyl comprises three to six carbon atoms
(e.g., C.sub.3-C.sub.6 cycloalkyl). In other embodiments, a
cycloalkyl comprises three to five carbon atoms (e.g.,
C.sub.3-C.sub.5 cycloalkyl). In other embodiments, a cycloalkyl
comprises three to four carbon atoms (e.g., C.sub.3-C.sub.4
cycloalkyl). A partially unsaturated cycloalkyl is also referred to
as "cycloalkenyl." Examples of monocyclic cycloalkenyls include,
e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
Polycyclic cycloalkyl radicals include, for example, adamantyl,
norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl,
7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise
stated specifically in the specification, the term "cycloalkyl" is
meant to include cycloalkyl radicals optionally substituted by one
or more substituents independently selected from alkyl, alkenyl,
alkynyl, halo, fluoroalkyl, cyano, nitro, aryl, aralkyl, aralkenyl,
aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl,
heteroarylalkyl, --R.sup.b--OR.sup.a, --R.sup.b--OC(O)--R.sup.a,
--R.sup.b--OC(O)--OR.sup.a, --R.sup.b--OC(O)--N(R.sup.a).sub.2,
--R.sup.b--N(R.sup.a).sub.2, --R.sup.b--C(O)R.sup.a,
--R.sup.b--C(O)OR.sup.a, --R.sup.b--C(O)N(R.sup.a).sub.2,
--R.sup.b--O--R.sup.c--C(O)N(R.sup.a).sub.2,
--R.sup.b--N(R.sup.a)C(O)OR.sup.a,
--R.sup.b--N(R.sup.a)C(O)R.sup.a,
--R.sup.b--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--R.sup.b--S(O).sub.tOR.sup.a (where t is 1 or 2),
--R.sup.b--S(O).sub.tR.sup.a (where t is 1 or 2) and
--R.sup.b--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), where
each R.sup.a is independently hydrogen, alkyl, fluoroalkyl,
cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one
or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or
heteroarylalkyl, each R.sup.b is independently a direct bond or a
straight or branched alkylene or alkenylene chain, and R.sup.c is a
straight or branched alkylene or alkenylene chain.
[0049] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo
substituents.
[0050] "Haloalkyl" refers to an alkyl radical, as defined above,
that is substituted by one or more halo radicals, as defined
above.
[0051] "Fluoroalkyl" refers to an alkyl radical, as defined above,
that is substituted by one or more fluoro radicals, as defined
above, for example, trifluoromethyl, difluoromethyl, fluoromethyl,
2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
The alkyl part of the fluoroalkyl radical are optionally
substituted as defined above for an alkyl group.
[0052] "Haloalkoxy" refers to an alkoxy radical, as defined above,
that is substituted by one or more halo radicals, as defined
above.
[0053] "Heterocycloalkyl" refers to a stable 3- to 18-membered
non-aromatic ring radical that comprises two to twelve carbon atoms
and from one to six heteroatoms selected from nitrogen, oxygen and
sulfur. Unless stated otherwise specifically in the specification,
the heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic
or tetracyclic ring system, which include fused, spiro, or bridged
ring systems. The heteroatoms in the heterocycloalkyl radical are
optionally oxidized. One or more nitrogen atoms, if present, are
optionally quaternized. The heterocycloalkyl radical is partially
or fully saturated. In some embodiments, the heterocycloalkyl is
attached to the rest of the molecule through any atom of the
ring(s). Examples of such heterocycloalkyl radicals include, but
are not limited to, dioxolanyl, thienyl[1,3]dithianyl,
decahydroisoquinolyl, imidazolinyl, imidazolidinyl,
isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl,
octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl,
2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl,
4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,
thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,
thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and
1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in
the specification, the term "heterocycloalkyl" is meant to include
heterocycloalkyl radicals as defined above that are optionally
substituted by one or more substituents selected from alkyl,
alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro,
aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl,
heteroaryl, heteroarylalkyl, --R.sup.b--OR.sup.a,
--R.sup.b--OC(O)--R.sup.a, --R.sup.b--OC(O)--OR.sup.a,
--R.sup.b--OC(O)--N(R.sup.a).sub.2, --R.sup.b--N(R.sup.a).sub.2,
--R.sup.b--C(O)R.sup.a, --R.sup.b--C(O)OR.sup.a,
--R.sup.b--C(O)N(R.sup.a).sub.2,
--R.sup.b--O--R.sup.c--C(O)N(R.sup.a).sub.2,
--R.sup.b--N(R.sup.a)C(O)OR.sup.a,
--R.sup.b--N(R.sup.a)C(O)R.sup.a,
--R.sup.b--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--R.sup.b--S(O).sub.tOR.sup.a (where t is 1 or 2),
--R.sup.b--S(O).sub.tR.sup.a (where t is 1 or 2) and
--R.sup.b--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), where
each R.sup.a is independently hydrogen, alkyl, fluoroalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl,
heteroaryl or heteroarylalkyl, each R.sup.b is independently a
direct bond or a straight or branched alkylene or alkenylene chain,
and R is a straight or branched alkylene or alkenylene chain.
[0054] "Heteroaryl" refers to a radical derived from a 5- to
18-membered aromatic ring radical that comprises one to seventeen
carbon atoms and from one to six heteroatoms selected from
nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical
is a monocyclic, bicyclic, tricyclic or tetracyclic ring system,
wherein at least one of the rings in the ring system is fully
unsaturated, i.e., it contains a cyclic, delocalized (4n+2)
in-electron system in accordance with the Huckel theory. Heteroaryl
includes fused or bridged ring systems. The heteroatom(s) in the
heteroaryl radical is optionally oxidized. One or more nitrogen
atoms, if present, are optionally quaternized. The heteroaryl is
attached to the rest of the molecule through any atom of the
ring(s). Unless stated otherwise specifically in the specification,
the term "heteroaryl" is meant to include heteroaryl radicals as
defined above that are optionally substituted by one or more
substituents selected from alkyl, alkenyl, alkynyl, halo,
haloalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl,
aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl,
heteroarylalkyl, --R.sup.b--OR.sup.a, --R.sup.b--OC(O)--R.sup.a,
--R.sup.b--OC(O)--OR.sup.a, --R.sup.b--OC(O)--N(R.sup.a).sub.2,
--R.sup.b--N(R.sup.a).sub.2, --R.sup.b--C(O)R.sup.a,
--R.sup.b--C(O)OR.sup.a, --R.sup.b-C(O)N(R.sup.a).sub.2,
--R.sup.b--O--R.sup.c--C(O)N(R.sup.a).sub.2,
--R.sup.b--N(R.sup.a)C(O)OR.sup.a,
--R.sup.b--N(R.sup.a)C(O)R.sup.a,
--R.sup.b--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--R.sup.b--S(O).sub.tOR.sup.a (where t is 1 or 2),
--R.sup.b--S(O).sub.tR.sup.a (where t is 1 or 2) and
--R.sup.b--S(O)N(R.sup.a).sub.2 (where t is 1 or 2), where each
R.sup.a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl,
cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or
heteroarylalkyl, each R.sup.b is independently a direct bond or a
straight or branched alkylene or alkenylene chain, and R.sup.c is a
straight or branched alkylene or alkenylene chain.
[0055] "N-heteroaryl" refers to a heteroaryl radical as defined
above containing at least one nitrogen and where the point of
attachment of the heteroaryl radical to the rest of the molecule is
through a nitrogen atom in the heteroaryl radical. An N-heteroaryl
radical is optionally substituted as described above for heteroaryl
radicals.
[0056] "C-heteroaryl" refers to a heteroaryl radical as defined
above and where the point of attachment of the heteroaryl radical
to the rest of the molecule is through a carbon atom in the
heteroaryl radical. A C-heteroaryl radical is optionally
substituted as described above for heteroaryl radicals.
[0057] "Heteroaryloxy" refers to radical bonded through an oxygen
atom of the formula --O-- heteroaryl, where heteroaryl is as
defined above.
[0058] "Heteroarylalkyl" refers to a radical of the formula
--R.sup.c-heteroaryl, where R.sup.c is an alkylene chain as defined
above. If the heteroaryl is a nitrogen-containing heteroaryl, the
heteroaryl is optionally attached to the alkyl radical at the
nitrogen atom. The alkylene chain of the heteroarylalkyl radical is
optionally substituted as defined above for an alkylene chain. The
heteroaryl part of the heteroarylalkyl radical is optionally
substituted as defined above for a heteroaryl group.
[0059] "Heteroarylalkoxy" refers to a radical bonded through an
oxygen atom of the formula --O--R.sup.C-heteroaryl, where R.sup.c
is an alkylene chain as defined above. If the heteroaryl is a
nitrogen-containing heteroaryl, the heteroaryl is optionally
attached to the alkyl radical at the nitrogen atom. The alkylene
chain of the heteroarylalkoxy radical is optionally substituted as
defined above for an alkylene chain. The heteroaryl part of the
heteroarylalkoxy radical is optionally substituted as defined above
for a heteroaryl group.
[0060] In some embodiments, the compounds disclosed herein contain
one or more asymmetric centers and thus give rise to enantiomers,
diastereomers, and other stereoisomeric forms that are defined, in
terms of absolute stereochemistry, as (R)-- or (S)--. Unless stated
otherwise, it is intended that all stereoisomeric forms of the
compounds disclosed herein are contemplated by this disclosure.
When the compounds described herein contain alkene double bonds,
and unless specified otherwise, it is intended that this disclosure
includes both E and Z geometric isomers (e.g., cis or trans.)
Likewise, all possible isomers, as well as their racemic and
optically pure forms, and all tautomeric forms are also intended to
be included. The term "geometric isomer" refers to E or Z geometric
isomers (e.g., cis or trans) of an alkene double bond. The term
"positional isomer" refers to structural isomers around a central
ring, such as ortho-, meta-, and para-isomers around a benzene
ring.
[0061] A "tautomer" refers to a molecule wherein a proton shift
from one atom of a molecule to another atom of the same molecule is
possible. In certain embodiments, the compounds presented herein
exist as tautomers. In circumstances where tautomerization is
possible, a chemical equilibrium of the tautomers will exist. The
exact ratio of the tautomers depends on several factors, including
physical state, temperature, solvent, and pH. Some examples of
tautomeric equilibrium include:
##STR00020##
[0062] "Optional" or "optionally" means that a subsequently
described event or circumstance may or may not occur and that the
description includes instances when the event or circumstance
occurs and instances in which it does not. For example, "optionally
substituted aryl" means that the aryl radical may or may not be
substituted and that the description includes both substituted aryl
radicals and aryl radicals having no substitution.
[0063] "Pharmaceutically acceptable salt" includes both acid and
base addition salts. A pharmaceutically acceptable salt of any one
of the compounds described herein is intended to encompass any and
all pharmaceutically suitable salt forms. Preferred
pharmaceutically acceptable salts of the compounds described herein
are pharmaceutically acceptable acid addition salts and
pharmaceutically acceptable base addition salts.
[0064] "Pharmaceutically acceptable acid addition salt" refers to
those salts which retain the biological effectiveness and
properties of the free bases, which are not biologically or
otherwise undesirable, and which are formed with inorganic acids
such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, phosphoric acid, hydroiodic acid, hydrofluoric acid,
phosphorous acid, and the like. Also included are salts that are
formed with organic acids such as aliphatic mono- and dicarboxylic
acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids,
alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic
acids, etc. and include, for example, acetic acid, trifluoroacetic
acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,
maleic acid, malonic acid, succinic acid, fumaric acid, tartaric
acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,
salicylic acid, and the like. Exemplary salts thus include
sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates,
phosphates, monohydrogenphosphates, dihydrogenphosphates,
metaphosphates, pyrophosphates, chlorides, bromides, iodides,
acetates, trifluoroacetates, propionates, caprylates, isobutyrates,
oxalates, malonates, succinate suberates, sebacates, fumarates,
maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates,
dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates,
phenylacetates, citrates, lactates, malates, tartrates,
methanesulfonates, and the like. Also contemplated are salts of
amino acids, such as arginates, gluconates, and galacturonates
(see, for example, Berge S. M. et al., "Pharmaceutical Salts,"
Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition
salts of basic compounds are prepared by contacting the free base
forms with a sufficient amount of the desired acid to produce the
salt.
[0065] "Pharmaceutically acceptable base addition salt" refers to
those salts that retain the biological effectiveness and properties
of the free acids, which are not biologically or otherwise
undesirable. These salts are prepared from addition of an inorganic
base or an organic base to the free acid. In some embodiments,
pharmaceutically acceptable base addition salts are formed with
metals or amines, such as alkali and alkaline earth metals or
organic amines. Salts derived from inorganic bases include, but are
not limited to, sodium, potassium, lithium, ammonium, calcium,
magnesium, iron, zinc, copper, manganese, aluminum salts and the
like. Salts derived from organic bases include, but are not limited
to, salts of primary, secondary, and tertiary amines, substituted
amines including naturally occurring substituted amines, cyclic
amines and basic ion exchange resins, for example, isopropylamine,
trimethylamine, diethylamine, triethylamine, tripropylamine,
ethanolamine, diethanolamine, 2-dimethylaminoethanol,
2-diethylaminoethanol, dicyclohexylamine, lysine, arginine,
histidine, caffeine, procaine, N,N-dibenzylethylenediamine,
chloroprocaine, hydrabamine, choline, betaine, ethylenediamine,
ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine,
theobromine, purines, piperazine, piperidine, N-ethylpiperidine,
polyamine resins and the like. See Berge et al., supra.
[0066] As used herein, "treatment" or "treating" or "palliating" or
"ameliorating" are used interchangeably herein. These terms refers
to an approach for obtaining beneficial or desired results
including but not limited to therapeutic benefit and/or a
prophylactic benefit. By "therapeutic benefit" is meant eradication
or amelioration of the underlying disorder being treated. Also, a
therapeutic benefit is achieved with the eradication or
amelioration of one or more of the physiological symptoms
associated with the underlying disorder such that an improvement is
observed in the patient, notwithstanding that the patient is still
afflicted with the underlying disorder. For prophylactic benefit,
the compositions are administered to a patient at risk of
developing a particular disease, or to a patient reporting one or
more of the physiological symptoms of a disease, even though a
diagnosis of this disease has not been made.
[0067] As used herein, "loss of taste response while treating a
chronic cough patient" refers to any loss of a patient's taste
response while being treating for chronic cough. In some
embodiments, the patient's loss of taste response is a 10% loss. In
some embodiments, the patient's loss of taste response is a 20%
loss. In some embodiments, the patient's loss of taste response is
a 30% loss. In some embodiments, the patient's loss of taste
response is a 40% loss. In some embodiments, the patient's loss of
taste response is a 50% loss. In some embodiments, the patient's
loss of taste response is a 60% loss. In some embodiments, the
patient's loss of taste response is a 70% loss. In some
embodiments, the patient's loss of taste response is a 80% loss. In
some embodiments, the patient's loss of taste response is a 90%
loss. In some embodiments, the patient's loss of taste response is
a 100% loss. In some embodiments, the patient's loss of taste
response refers to an alteration of patient's taste response.
[0068] Methods
[0069] In some embodiments disclosed herein are methods of avoiding
loss of taste response while treating a chronic cough patient. In
some embodiments, is a method of avoiding loss of taste response
while treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is selective for P2X3 homomeric receptor antagonism versus P2X2/3
heteromeric receptor antagonism. In some embodiments, is a method
of avoiding loss of taste response while treating a chronic cough
patient, the method comprising administering to the patient a
therapeutically effective amount of a selective P2X3 antagonist,
wherein the selective P2X3 antagonist is at least 10-fold selective
for P2X3 homomeric receptor antagonism versus P2X2/3 heteromeric
receptor antagonism. In some embodiments is a method of avoiding
loss of taste response while treating a chronic cough patient, the
method comprising administering to the patient a therapeutically
effective amount of a selective P2X3 antagonist, wherein the
selective P2X3 antagonist is at least 20-fold selective for P2X3
homomeric receptor antagonism versus P2X2/3 heteromeric receptor
antagonism. In some embodiments is a method of avoiding loss of
taste response while treating a chronic cough patient, the method
comprising administering to the patient a therapeutically effective
amount of a selective P2X3 antagonist, wherein the selective P2X3
antagonist is at least 20-fold selective for P2X3 homomeric
receptor antagonism versus P2X2/3 heteromeric receptor antagonism.
In some embodiments is a method of avoiding loss of taste response
while treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 30-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 40-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 50-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 60-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 70-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 80-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 90-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 100-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 150-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 200-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 250-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 300-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 350-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 400-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 450-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 500-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 600-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 700-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 800-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 900-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 1000-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 1200-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 1400-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 1600-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 1800-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 2000-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 2200-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 2500-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 2700-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 3000-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism.
[0070] In some embodiments is a method of avoiding loss of taste
response while treating a chronic cough patient, the method
comprising administering to the patient a therapeutically effective
amount of a selective P2X3 antagonist, wherein the selective P2X3
antagonist is a compound of Formula (I), or a pharmaceutically
acceptable salt thereof, having the structure:
##STR00021##
wherein: R.sup.1 is selected from the group consisting of cyano,
halogen, methyl, and ethyl;
[0071] R.sup.2 is selected from the group consisting of hydrogen,
halogen, methyl, and ethyl;
[0072] R.sup.3 is selected from the group consisting of halogen,
methyl, and ethyl;
[0073] R.sup.4 is selected from the group consisting of hydrogen,
halogen, methyl, ethyl, and methoxy;
R.sup.5 and R.sup.6 are independently selected from the group
consisting of hydrogen, C.sub.1-C.sub.6-alkyl, and
hydroxy-C.sub.1-C.sub.6-alkyl; or R.sup.5 and R.sup.6, together
with the nitrogen to which they are both attached, form a 5- or
6-member heterocycloalkyl, wherein the heterocycloalkyl is
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, hydroxyl, and
C.sub.1-C.sub.4-alkyl;
[0074] R.sup.7 and R.sup.8 are independently selected from the
group consisting of hydrogen and C.sub.1-C.sub.4-alkyl;
R.sup.9 is selected from the group consisting of
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.1-C.sub.6-alkyl-C.sub.3-C.sub.6-cycloalkyl,
halo-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy,
halo-C.sub.1-C.sub.6-alkoxy, and
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl; and X is selected
from a bond, CH.sub.2, and O.
[0075] In some embodiments of the methods described herein, the
selective P2X3 antagonist is a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, wherein X is a bond. In
some embodiments of the methods described herein, the selective
P2X3 antagonist is a compound of Formula (I), or a pharmaceutically
acceptable salt thereof, wherein X is CH.sub.2. In some embodiments
of the methods described herein, the selective P2X3 antagonist is a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof, wherein X is O.
[0076] In some embodiments of the methods described herein, the
selective P2X3 antagonist is a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, wherein R.sup.1 is cyano.
In some embodiments of the methods described herein, the selective
P2X3 antagonist is a compound of Formula (I), or a pharmaceutically
acceptable salt thereof, wherein R.sup.1 is halogen. In some
embodiments of the methods described herein, the selective P2X3
antagonist is a compound of Formula (I), or a pharmaceutically
acceptable salt thereof, wherein R.sup.1 is methyl. In some
embodiments of the methods described herein, the selective P2X3
antagonist is a compound of Formula (I), or a pharmaceutically
acceptable salt thereof, wherein R.sup.1 is ethyl.
[0077] In some embodiments of the methods described herein, the
selective P2X3 antagonist is a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, wherein R.sup.2 is
hydrogen. In some embodiments of the methods described herein, the
selective P2X3 antagonist is a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, wherein R.sup.2 is
halogen. In some embodiments of the methods described herein, the
selective P2X3 antagonist is a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, wherein R.sup.2 is
methyl. In some embodiments of the methods described herein, the
selective P2X3 antagonist is a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, wherein R.sup.2 is
ethyl.
[0078] In some embodiments of the methods described herein, the
selective P2X3 antagonist is a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, wherein R.sup.3 is
halogen. In some embodiments of the methods described herein, the
selective P2X3 antagonist is a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, wherein R.sup.3 is
fluoro. In some embodiments of the methods described herein, the
selective P2X3 antagonist is a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, wherein R.sup.3 is
methyl. In some embodiments of the methods described herein, the
selective P2X3 antagonist is a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, wherein R.sup.3 is
ethyl.
[0079] In some embodiments of the methods described herein, the
selective P2X3 antagonist is a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, wherein R.sup.4 is
hydrogen. In some embodiments of the methods described herein, the
selective P2X3 antagonist is a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, wherein R.sup.4 is
halogen. In some embodiments of the methods described herein, the
selective P2X3 antagonist is a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, wherein R.sup.4 is
fluoro. In some embodiments of the methods described herein, the
selective P2X3 antagonist is a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, wherein R.sup.4 is
methyl. In some embodiments of the methods described herein, the
selective P2X3 antagonist is a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, wherein R.sup.4 is ethyl.
In some embodiments of the methods described herein, the selective
P2X3 antagonist is a compound of Formula (I), or a pharmaceutically
acceptable salt thereof, wherein R.sup.4 is methoxy.
[0080] In some embodiments of the methods described herein, the
selective P2X3 antagonist is a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, wherein R.sup.5 and
R.sup.6 are independently selected from the group consisting of
hydrogen and C.sub.1-C.sub.6-alkyl. In some embodiments of the
methods described herein, the selective P2X3 antagonist is a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof, wherein R.sup.5 and R.sup.6 are each hydrogen. In some
embodiments of the methods described herein, the selective P2X3
antagonist is a compound of Formula (I), or a pharmaceutically
acceptable salt thereof, wherein R.sup.5 and R.sup.6 are each
C.sub.1-C.sub.6-alkyl. In some embodiments of the methods described
herein, the selective P2X3 antagonist is a compound of Formula (I),
or a pharmaceutically acceptable salt thereof, wherein R.sup.5 is
hydrogen and R.sup.6 is C.sub.1-C.sub.6-alkyl. In some embodiments
of the methods described herein, the selective P2X3 antagonist is a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof, wherein R.sup.5 is hydrogen and R.sup.6 is methyl.
[0081] In some embodiments of the methods described herein, the
selective P2X3 antagonist is a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, wherein R.sup.7 and
R.sup.8 are independently selected from the group consisting of
hydrogen and methyl. In some embodiments of the methods described
herein, the selective P2X3 antagonist is a compound of Formula (I),
or a pharmaceutically acceptable salt thereof, wherein R.sup.7 and
R.sup.8 are each hydrogen. In some embodiments of the methods
described herein, the selective P2X3 antagonist is a compound of
Formula (I), or a pharmaceutically acceptable salt thereof, wherein
R.sup.7 is hydrogen and R.sup.8 is methyl.
[0082] In some embodiments of the methods described herein, the
selective P2X3 antagonist is a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, wherein R.sup.9 is
selected from the group consisting of C.sub.1-C.sub.6-alkyl and
C.sub.1-C.sub.6-alkoxy. In some embodiments of the methods
described herein, the selective P2X3 antagonist is a compound of
Formula (I), or a pharmaceutically acceptable salt thereof, wherein
R.sup.9 is C.sub.1-C.sub.6-alkyl. In some embodiments of the
methods described herein, the selective P2X3 antagonist is a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof, wherein R.sup.9 is methyl. In some embodiments of the
methods described herein, the selective P2X3 antagonist is a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof, wherein R.sup.9 is ethyl. In some embodiments of the
methods described herein, the selective P2X3 antagonist is a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof, wherein R.sup.9 is C.sub.1-C.sub.6-alkoxy. In some
embodiments of the methods described herein, the selective P2X3
antagonist is a compound of Formula (I), or a pharmaceutically
acceptable salt thereof, wherein R.sup.9 is methoxy.
[0083] In some embodiments of the methods described herein, the
selective P2X3 antagonist is a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, wherein the compound of
Formula (I) corresponds in structure to
##STR00022##
and R.sup.4 is selected from the group consisting of halogen,
methyl, and ethyl. In some embodiments of the methods described
herein, the selective P2X3 antagonist is a compound of Formula (I),
or a pharmaceutically acceptable salt thereof, wherein the compound
of Formula (I) corresponds in structure to
##STR00023##
[0084] In some embodiments of the methods described herein, the
selective P2X3 antagonist is a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, wherein X is O, R.sup.1
is methyl, R.sup.2 is hydrogen, R.sup.3 is halogen, R.sup.4 is
halogen, R.sup.5 is hydrogen, R.sup.6 is C.sub.1-C.sub.6-alkyl,
R.sup.7 is hydrogen, R.sup.8 is hydrogen, and R.sup.9 is
C.sub.1-C.sub.6-alkyl. In some embodiments of the methods described
herein, the selective P2X3 antagonist is a compound of Formula (I),
or a pharmaceutically acceptable salt thereof, wherein X is O,
R.sup.1 is methyl, R.sup.2 is hydrogen, R.sup.3 is fluoro, R.sup.4
is fluoro, R.sup.5 is hydrogen, R.sup.6 is methyl, R.sup.7 is
hydrogen, R.sup.8 is hydrogen, and R.sup.9 is methyl.
[0085] In some embodiments of the methods described herein, the
selective P2X3 antagonist is a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, wherein X is O, R.sup.1
is methyl, R.sup.2 is hydrogen, R.sup.3 is halogen, R.sup.4 is
halogen, R.sup.5 is hydrogen, R.sup.6 is C.sub.1-C.sub.6-alkyl,
R.sup.7 is hydrogen, R.sup.8 is hydrogen, and R.sup.9 is
C.sub.1-C.sub.6-alkoxy. In some embodiments of the methods
described herein, the selective P2X3 antagonist is a compound of
Formula (I), or a pharmaceutically acceptable salt thereof, wherein
X is O, R.sup.1 is methyl, R.sup.2 is hydrogen, R.sup.3 is fluoro,
R.sup.4 is fluoro, R.sup.5 is hydrogen, R.sup.6 is methyl, R.sup.7
is hydrogen, R.sup.8 is hydrogen, and R.sup.9 is methoxy.
[0086] In some embodiments of the methods described herein, the
selective P2X3 antagonist is a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, wherein X is O, R.sup.1
is methyl, R.sup.2 is hydrogen, R.sup.3 is methyl, R.sup.4 is
hydrogen, R.sup.5 is hydrogen, R.sup.6 is C.sub.1-C.sub.6-alkyl,
R.sup.7 is hydrogen, R.sup.8 is hydrogen, and R.sup.9 is
C.sub.1-C.sub.6-alkyl. In some embodiments of the methods described
herein, the selective P2X3 antagonist is a compound of Formula (I),
or a pharmaceutically acceptable salt thereof, wherein X is O,
R.sup.1 is methyl, R.sup.2 is hydrogen, R.sup.3 is methyl, R.sup.4
is hydrogen, R.sup.5 is hydrogen, R.sup.6 is methyl, R.sup.7 is
hydrogen, R.sup.8 is hydrogen, and R.sup.9 is methyl.
[0087] In some embodiments of the methods described herein, the
selective P2X3 antagonist is a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, wherein X is O, R.sup.1
is methyl, R.sup.2 is hydrogen, R.sup.3 is methyl, R.sup.4 is
hydrogen, R.sup.5 is hydrogen, R.sup.6 is C.sub.1-C.sub.6-alkyl,
R.sup.7 is hydrogen, R.sup.8 is hydrogen, and R.sup.9 is
C.sub.1-C.sub.6-alkoxy. In some embodiments of the methods
described herein, the selective P2X3 antagonist is a compound of
Formula (I), or a pharmaceutically acceptable salt thereof, wherein
X is O, R.sup.1 is methyl, R.sup.2 is hydrogen, R.sup.3 is methyl,
R.sup.4 is hydrogen, R.sup.5 is hydrogen, R.sup.6 is methyl,
R.sup.7 is hydrogen, R.sup.8 is hydrogen, and R.sup.9 is
methoxy.
[0088] In some embodiments of the methods described herein, the
selective P2X3 antagonist is a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, wherein the compound of
Formula (I) corresponds in structure to:
##STR00024## ##STR00025## ##STR00026## ##STR00027## ##STR00028##
##STR00029## ##STR00030## ##STR00031## ##STR00032##
[0089] In some embodiments of the methods described herein, the
selective P2X3 antagonist is a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, wherein the compound of
Formula (I) corresponds in structure to
##STR00033##
[0090] In some embodiments of the methods described herein, the
selective P2X3 antagonist is a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, wherein the compound of
Formula (I) corresponds in structure to
##STR00034##
[0091] In some embodiments of the methods described herein, the
selective P2X3 antagonist is a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, wherein the compound of
Formula (I) corresponds in structure to
##STR00035##
[0092] In some embodiments of the methods described herein, the
selective P2X3 antagonist is a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, wherein the compound of
Formula (I) corresponds in structure to
##STR00036##
[0093] In some embodiments of the methods described herein, the
selective P2X3 antagonist corresponds in structure to
##STR00037##
[0094] In some embodiments of the methods described herein, the
selective P2X3 antagonist corresponds in structure to
##STR00038##
[0095] In some embodiments of the methods described herein, the
selective P2X3 antagonist corresponds in structure to
##STR00039##
In some embodiments, is a method of avoiding loss of taste response
while treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is selective for P2X3 homomeric receptor antagonism versus P2X2/3
heteromeric receptor antagonism and is a compound of Formula (I)
described herein, or a pharmaceutically acceptable salt thereof. In
some embodiments, is a method of avoiding loss of taste response
while treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 10-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism and is a
compound of Formula (I) described herein, or a pharmaceutically
acceptable salt thereof. In some embodiments is a method of
avoiding loss of taste response while treating a chronic cough
patient, the method comprising administering to the patient a
therapeutically effective amount of a selective P2X3 antagonist,
wherein the selective P2X3 antagonist is at least 20-fold selective
for P2X3 homomeric receptor antagonism versus P2X2/3 heteromeric
receptor antagonism and is a compound of Formula (I) described
herein, or a pharmaceutically acceptable salt thereof. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 25-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism and is a
compound of Formula (I) described herein, or a pharmaceutically
acceptable salt thereof. In some embodiments is a method of
avoiding loss of taste response while treating a chronic cough
patient, the method comprising administering to the patient a
therapeutically effective amount of a selective P2X3 antagonist,
wherein the selective P2X3 antagonist is at least 30-fold selective
for P2X3 homomeric receptor antagonism versus P2X2/3 heteromeric
receptor antagonism and is a compound of Formula (I) described
herein, or a pharmaceutically acceptable salt thereof. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 40-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism and is a
compound of Formula (I) described herein, or a pharmaceutically
acceptable salt thereof. In some embodiments is a method of
avoiding loss of taste response while treating a chronic cough
patient, the method comprising administering to the patient a
therapeutically effective amount of a selective P2X3 antagonist,
wherein the selective P2X3 antagonist is at least 50-fold selective
for P2X3 homomeric receptor antagonism versus P2X2/3 heteromeric
receptor antagonism and is a compound of Formula (I) described
herein, or a pharmaceutically acceptable salt thereof. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 60-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism and is a
compound of Formula (I) described herein, or a pharmaceutically
acceptable salt thereof. In some embodiments is a method of
avoiding loss of taste response while treating a chronic cough
patient, the method comprising administering to the patient a
therapeutically effective amount of a selective P2X3 antagonist,
wherein the selective P2X3 antagonist is at least 70-fold selective
for P2X3 homomeric receptor antagonism versus P2X2/3 heteromeric
receptor antagonism and is a compound of Formula (I) described
herein, or a pharmaceutically acceptable salt thereof. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 80-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism and is a
compound of Formula (I) described herein, or a pharmaceutically
acceptable salt thereof. In some embodiments is a method of
avoiding loss of taste response while treating a chronic cough
patient, the method comprising administering to the patient a
therapeutically effective amount of a selective P2X3 antagonist,
wherein the selective P2X3 antagonist is at least 90-fold selective
for P2X3 homomeric receptor antagonism versus P2X2/3 heteromeric
receptor antagonism and is a compound of Formula (I) described
herein, or a pharmaceutically acceptable salt thereof. In some
embodiments is a method of avoiding loss of taste response while
treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 100-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism and is a
compound of Formula (I) described herein, or a pharmaceutically
acceptable salt thereof. In some embodiments is a method of
avoiding loss of taste response while treating a chronic cough
patient, the method comprising administering to the patient a
therapeutically effective amount of a selective P2X3 antagonist,
wherein the selective P2X3 antagonist is at least 150-fold
selective for P2X3 homomeric receptor antagonism versus P2X2/3
heteromeric receptor antagonism and is a compound of Formula (I)
described herein, or a pharmaceutically acceptable salt thereof. In
some embodiments is a method of avoiding loss of taste response
while treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 200-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism and is a
compound of Formula (I) described herein, or a pharmaceutically
acceptable salt thereof. In some embodiments is a method of
avoiding loss of taste response while treating a chronic cough
patient, the method comprising administering to the patient a
therapeutically effective amount of a selective P2X3 antagonist,
wherein the selective P2X3 antagonist is at least 250-fold
selective for P2X3 homomeric receptor antagonism versus P2X2/3
heteromeric receptor antagonism and is a compound of Formula (I)
described herein, or a pharmaceutically acceptable salt thereof. In
some embodiments is a method of avoiding loss of taste response
while treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 300-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism and is a
compound of Formula (I) described herein, or a pharmaceutically
acceptable salt thereof. In some embodiments is a method of
avoiding loss of taste response while treating a chronic cough
patient, the method comprising administering to the patient a
therapeutically effective amount of a selective P2X3 antagonist,
wherein the selective P2X3 antagonist is at least 350-fold
selective for P2X3 homomeric receptor antagonism versus P2X2/3
heteromeric receptor antagonism and is a compound of Formula (I)
described herein, or a pharmaceutically acceptable salt thereof. In
some embodiments is a method of avoiding loss of taste response
while treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 400-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism and is a
compound of Formula (I) described herein, or a pharmaceutically
acceptable salt thereof. In some embodiments is a method of
avoiding loss of taste response while treating a chronic cough
patient, the method comprising administering to the patient a
therapeutically effective amount of a selective P2X3 antagonist,
wherein the selective P2X3 antagonist is at least 450-fold
selective for P2X3 homomeric receptor antagonism versus P2X2/3
heteromeric receptor antagonism and is a compound of Formula (I)
described herein, or a pharmaceutically acceptable salt thereof. In
some embodiments is a method of avoiding loss of taste response
while treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 500-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism and is a
compound of Formula (I) described herein, or a pharmaceutically
acceptable salt thereof. In some embodiments is a method of
avoiding loss of taste response while treating a chronic cough
patient, the method comprising administering to the patient a
therapeutically effective amount of a selective P2X3 antagonist,
wherein the selective P2X3 antagonist is at least 600-fold
selective for P2X3 homomeric receptor antagonism versus P2X2/3
heteromeric receptor antagonism and is a compound of Formula (I)
described herein, or a pharmaceutically acceptable salt thereof. In
some embodiments is a method of avoiding loss of taste response
while treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 700-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism and is a
compound of Formula (I) described herein, or a pharmaceutically
acceptable salt thereof. In some embodiments is a method of
avoiding loss of taste response while treating a chronic cough
patient, the method comprising administering to the patient a
therapeutically effective amount of a selective P2X3 antagonist,
wherein the selective P2X3 antagonist is at least 800-fold
selective for P2X3 homomeric receptor antagonism versus P2X2/3
heteromeric receptor antagonism and is a compound of Formula (I)
described herein, or a pharmaceutically acceptable salt thereof. In
some embodiments is a method of avoiding loss of taste response
while treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 900-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism and is a
compound of Formula (I) described herein, or a pharmaceutically
acceptable salt thereof. In some embodiments is a method of
avoiding loss of taste response while treating a chronic cough
patient, the method comprising administering to the patient a
therapeutically effective amount of a selective P2X3 antagonist,
wherein the selective P2X3 antagonist is at least 1000-fold
selective for P2X3 homomeric receptor antagonism versus P2X2/3
heteromeric receptor antagonism and is a compound of Formula (I)
described herein, or a pharmaceutically acceptable salt thereof. In
some embodiments is a method of avoiding loss of taste response
while treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 1200-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism and is a
compound of Formula (I) described herein, or a pharmaceutically
acceptable salt thereof. In some embodiments is a method of
avoiding loss of taste response while treating a chronic cough
patient, the method comprising administering to the patient a
therapeutically effective amount of a selective P2X3 antagonist,
wherein the selective P2X3 antagonist is at least 1400-fold
selective for P2X3 homomeric receptor antagonism versus P2X2/3
heteromeric receptor antagonism and is a compound of Formula (I)
described herein, or a pharmaceutically acceptable salt thereof. In
some embodiments is a method of avoiding loss of taste response
while treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 1600-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism and is a
compound of Formula (I) described herein, or a pharmaceutically
acceptable salt thereof. In some embodiments is a method of
avoiding loss of taste response while treating a chronic cough
patient, the method comprising administering to the patient a
therapeutically effective amount of a selective P2X3 antagonist,
wherein the selective P2X3 antagonist is at least 1800-fold
selective for P2X3 homomeric receptor antagonism versus P2X2/3
heteromeric receptor antagonism and is a compound of Formula (I)
described herein, or a pharmaceutically acceptable salt thereof. In
some embodiments is a method of avoiding loss of taste response
while treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 2000-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism and is a
compound of Formula (I) described herein, or a pharmaceutically
acceptable salt thereof. In some embodiments is a method of
avoiding loss of taste response while treating a chronic cough
patient, the method comprising administering to the patient a
therapeutically effective amount of a selective P2X3 antagonist,
wherein the selective P2X3 antagonist is at least 2200-fold
selective for P2X3 homomeric receptor antagonism versus P2X2/3
heteromeric receptor antagonism and is a compound of Formula (I)
described herein, or a pharmaceutically acceptable salt thereof. In
some embodiments is a method of avoiding loss of taste response
while treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 2500-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism and is a
compound of Formula (I) described herein, or a pharmaceutically
acceptable salt thereof. In some embodiments is a method of
avoiding loss of taste response while treating a chronic cough
patient, the method comprising administering to the patient a
therapeutically effective amount of a selective P2X3 antagonist,
wherein the selective P2X3 antagonist is at least 2700-fold
selective for P2X3 homomeric receptor antagonism versus P2X2/3
heteromeric receptor antagonism and is a compound of Formula (I)
described herein, or a pharmaceutically acceptable salt thereof. In
some embodiments is a method of avoiding loss of taste response
while treating a chronic cough patient, the method comprising
administering to the patient a therapeutically effective amount of
a selective P2X3 antagonist, wherein the selective P2X3 antagonist
is at least 3000-fold selective for P2X3 homomeric receptor
antagonism versus P2X2/3 heteromeric receptor antagonism and is a
compound of Formula (I) described herein, or a pharmaceutically
acceptable salt thereof.
[0097] In some embodiments of the methods described herein, the
chronic cough is due or associated with asthma, chronic bronchitis,
chronic postnasal drip, eosinophilic bronchitis, or chronic
obstructive pulmonary disease.
[0098] In some embodiments of the methods described herein, the
chronic cough is due or associated with chronic infections such as
bronchiectasis, tuberculosis, or cystic fibrosis.
[0099] In some embodiments of the methods described herein, the
chronic cough is due or associated with lung tumors such as
bronchogenic carcinoma, alveolar cell carcinoma, benign airway
tumors, or mediastinal tumors.
[0100] In some embodiments of the methods described herein, the
chronic cough is due or associated with a cardiovascular disease
such as left ventricular failure, pulmonary infarction, or aortic
aneurysm.
[0101] In some embodiments of the methods described herein, the
chronic cough is due or associated with reflux oesophagitis,
recurrent aspiration, endobronchial sutures, postnasal drip
syndrome, or rhinosinusitis.
[0102] In certain embodiments, a disclosed compound utilized by one
or more of the foregoing methods is one of the generic, subgeneric,
or specific compounds described herein, such as a compound of
Formula (I) described herein.
Preparation of the Compounds
[0103] The compounds used in the methods described herein are made
according to procedures disclosed in U.S. Pat. No. 9,598,409, which
is herein incorporated by reference in its entirety, or by known
organic synthesis techniques, starting from commercially available
chemicals and/or from compounds described in the chemical
literature. Commercially available chemicals are obtained from
standard commercial sources including Acros Organics (Geel,
Belgium), Aldrich Chemical (Milwaukee, Wis., including Sigma
Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Ark
Pharm, Inc. (Libertyville, Ill.), Avocado Research (Lancashire,
U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.),
Chemservice Inc. (West Chester, Pa.), Combi-blocks (San Diego,
Calif.), Crescent Chemical Co. (Hauppauge, N.Y.), eMolecules (San
Diego, Calif.), Fisher Scientific Co. (Pittsburgh, Pa.), Fisons
Chemicals (Leicestershire, UK), Frontier Scientific (Logan, Utah),
ICN Biomedicals, Inc. (Costa Mesa, Calif.), Key Organics (Cornwall,
U.K.), Lancaster Synthesis (Windham, N.H.), Matrix Scientific,
(Columbia, S.C.), Maybridge Chemical Co. Ltd. (Cornwall, U.K.),
Parish Chemical Co. (Orem, Utah), Pfaltz & Bauer, Inc.
(Waterbury, Conn.), Polyorganix (Houston, Tex.), Pierce Chemical
Co. (Rockford, Ill.), Riedel de Haen AG (Hanover, Germany), Ryan
Scientific, Inc. (Mount Pleasant, S.C.), Spectrum Chemicals
(Gardena, Calif.), Sundia Meditech, (Shanghai, China), TCI America
(Portland, Oreg.), Trans World Chemicals, Inc. (Rockville, Md.),
and WuXi (Shanghai, China).
[0104] Suitable reference books and treatises that detail the
synthesis of reactants useful in the preparation of compounds
described herein, or provide references to articles that describe
the preparation, include for example, "Synthetic Organic
Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et
al., "Organic Functional Group Preparations," 2nd Ed., Academic
Press, New York, 1983; H. O. House, "Modern Synthetic Reactions",
2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L.
Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley &
Sons, New York, 1992; J. March, "Advanced Organic Chemistry:
Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience,
New York, 1992. Additional suitable reference books and treatises
that detail the synthesis of reactants useful in the preparation of
compounds described herein, or provide references to articles that
describe the preparation, include for example, Fuhrhop, J. and
Penzlin G. "Organic Synthesis: Concepts, Methods, Starting
Materials", Second, Revised and Enlarged Edition (1994) John Wiley
& Sons ISBN: 3-527-29074-5; Hoffman, R. V. "Organic Chemistry,
An Intermediate Text" (1996) Oxford University Press, ISBN
0-19-509618-5; Larock, R. C. "Comprehensive Organic
Transformations: A Guide to Functional Group Preparations" 2nd
Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced
Organic Chemistry: Reactions, Mechanisms, and Structure" 4th
Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera,
J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN:
3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of
Functional Groups" (1992) Interscience ISBN: 0-471-93022-9;
Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John
Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J. C.,
"Intermediate Organic Chemistry" 2nd Edition (1993)
Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic
Chemicals: Starting Materials and Intermediates: An Ullmann's
Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in
8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons,
in over 55 volumes; and "Chemistry of Functional Groups" John Wiley
& Sons, in 73 volumes.
[0105] Specific and analogous reactants are also identified through
the indices of known chemicals prepared by the Chemical Abstract
Service of the American Chemical Society, which are available in
most public and university libraries, as well as through on-line
databases (the American Chemical Society, Washington, D.C., may be
contacted for more details). Chemicals that are known but not
commercially available in catalogs are optionally prepared by
custom chemical synthesis houses, where many of the standard
chemical supply houses (e.g., those listed above) provide custom
synthesis services. A reference for the preparation and selection
of pharmaceutical salts of the compounds described herein is P. H.
Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts",
Verlag Helvetica Chimica Acta, Zurich, 2002.
Further Forms of Compounds Disclosed Herein
Isomers
[0106] Furthermore, in some embodiments, the compounds described
herein exist as geometric isomers. In some embodiments, the
compounds described herein possess one or more double bonds. The
compounds presented herein include all cis, trans, syn, anti,
entgegen (E), and zusammen (Z) isomers as well as the corresponding
mixtures thereof. In some situations, compounds exist as tautomers.
The compounds described herein include all possible tautomers
within the formulas described herein. In some situations, the
compounds described herein possess one or more chiral centers and
each center exists in the R configuration, or S configuration. The
compounds described herein include all diastereomeric,
enantiomeric, and epimeric forms as well as the corresponding
mixtures thereof. In additional embodiments of the compounds and
methods provided herein, mixtures of enantiomers and/or
diastereoisomers, resulting from a single preparative step,
combination, or interconversion are useful for the applications
described herein. In some embodiments, the compounds described
herein are prepared as their individual stereoisomers by reacting a
racemic mixture of the compound with an optically active resolving
agent to form a pair of diastereoisomeric compounds, separating the
diastereomers and recovering the optically pure enantiomers. In
some embodiments, dissociable complexes are preferred (e.g.,
crystalline diastereomeric salts). In some embodiments, the
diastereomers have distinct physical properties (e.g., melting
points, boiling points, solubilities, reactivity, etc.) and are
separated by taking advantage of these dissimilarities. In some
embodiments, the diastereomers are separated by chiral
chromatography, or preferably, by separation/resolution techniques
based upon differences in solubility. In some embodiments, the
optically pure enantiomer is then recovered, along with the
resolving agent, by any practical means that would not result in
racemization.
Labeled Compounds
[0107] In some embodiments, the compounds described herein exist in
their isotopically-labeled forms. In some embodiments, the methods
disclosed herein include methods of treating diseases by
administering such isotopically-labeled compounds. In some
embodiments, the methods disclosed herein include methods of
treating diseases by administering such isotopically-labeled
compounds as pharmaceutical compositions. Thus, in some
embodiments, the compounds disclosed herein include
isotopically-labeled compounds, which are identical to those
recited herein, but for the fact that one or more atoms are
replaced by an atom having an atomic mass or mass number different
from the atomic mass or mass number usually found in nature.
Examples of isotopes that are incorporated into compounds of the
invention include isotopes of hydrogen, carbon, nitrogen, oxygen,
phosphorous, sulfur, fluorine and chloride, such as .sup.2H,
.sup.3H, .sup.13C, .sup.14C, .sup.15N, .sup.18O, .sup.17O,
.sup.31P, .sup.32P, .sup.35S, .sup.18F, and .sup.36Cl,
respectively. Compounds described herein, and the pharmaceutically
acceptable salts, esters, solvate, hydrates or derivatives thereof
which contain the aforementioned isotopes and/or other isotopes of
other atoms are within the scope of this invention. Certain
isotopically-labeled compounds, for example those into which
radioactive isotopes such as .sup.3H and .sup.14C are incorporated,
are useful in drug and/or substrate tissue distribution assays.
Tritiated, i. e., .sup.3H and carbon-14, i. e., .sup.14C, isotopes
are particularly preferred for their ease of preparation and
detectability. Further, substitution with heavy isotopes such as
deuterium, i.e., .sup.2H, produces certain therapeutic advantages
resulting from greater metabolic stability, for example increased
in vivo half-life or reduced dosage requirements. In some
embodiments, the isotopically labeled compounds, pharmaceutically
acceptable salt, ester, solvate, hydrate or derivative thereof is
prepared by any suitable method.
[0108] In some embodiments, the compounds described herein are
labeled by other means, including, but not limited to, the use of
chromophores or fluorescent moieties, bioluminescent labels, or
chemiluminescent labels.
Pharmaceutically Acceptable Salts
[0109] In some embodiments, the compounds described herein exist as
their pharmaceutically acceptable salts. In some embodiments, the
methods disclosed herein include methods of treating diseases by
administering such pharmaceutically acceptable salts. In some
embodiments, the methods disclosed herein include methods of
treating diseases by administering such pharmaceutically acceptable
salts as pharmaceutical compositions.
[0110] In some embodiments, the compounds described herein possess
acidic or basic groups and therefore react with any of a number of
inorganic or organic bases, and inorganic and organic acids, to
form a pharmaceutically acceptable salt. In some embodiments, these
salts are prepared in situ during the final isolation and
purification of the compounds of the invention, or by separately
reacting a purified compound in its free form with a suitable acid
or base, and isolating the salt thus formed.
Solvates
[0111] In some embodiments, the compounds described herein exist as
solvates. The invention provides for methods of treating diseases
by administering such solvates. The invention further provides for
methods of treating diseases by administering such solvates as
pharmaceutical compositions.
[0112] Solvates contain either stoichiometric or non-stoichiometric
amounts of a solvent, and, in some embodiments, are formed during
the process of crystallization with pharmaceutically acceptable
solvents such as water, ethanol, and the like. Hydrates are formed
when the solvent is water, or alcoholates are formed when the
solvent is alcohol. Solvates of the compounds described herein are
conveniently prepared or formed during the processes described
herein. By way of example only, hydrates of the compounds described
herein are conveniently prepared by recrystallization from an
aqueous/organic solvent mixture, using organic solvents including,
but not limited to, dioxane, tetrahydrofuran or methanol. In
addition, the compounds provided herein exist in unsolvated as well
as solvated forms. In general, the solvated forms are considered
equivalent to the unsolvated forms for the purposes of the
compounds and methods provided herein.
Pharmaceutical Compositions
[0113] In certain embodiments, the compounds described herein are
administered as a pure chemical. In other embodiments, the
compounds described herein are combined with a pharmaceutically
suitable or acceptable carrier (also referred to herein as a
pharmaceutically suitable (or acceptable) excipient,
physiologically suitable (or acceptable) excipient, or
physiologically suitable (or acceptable) carrier) selected on the
basis of a chosen route of administration and standard
pharmaceutical practice as described, for example, in Remington:
The Science and Practice of Pharmacy (Gennaro, 21.sup.st Ed. Mack
Pub. Co., Easton, Pa. (2005)).
[0114] Accordingly, provided herein is a pharmaceutical composition
comprising at least one compound described herein, or a
pharmaceutically acceptable salt, together with one or more
pharmaceutically acceptable carriers. The carrier(s) (or
excipient(s)) is acceptable or suitable if the carrier is
compatible with the other ingredients of the composition and not
deleterious to the recipient (i.e., the subject) of the
composition.
[0115] One embodiment provides a pharmaceutical composition
comprising a pharmaceutically acceptable carrier and a compound of
Formula (I), or a pharmaceutically acceptable salt thereof.
[0116] Another embodiment provides a pharmaceutical composition
consisting essentially of a pharmaceutically acceptable carrier and
a compound of Formula (I), or a pharmaceutically acceptable salt
thereof.
[0117] In certain embodiments, the compound as described herein is
substantially pure, in that it contains less than about 5%, or less
than about 1%, or less than about 0.1%, of other organic small
molecules, such as contaminating intermediates or by-products that
are created, for example, in one or more of the steps of a
synthesis method.
[0118] These formulations include those suitable for oral, topical,
buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal,
or intravenous), or aerosol administration.
[0119] Exemplary pharmaceutical compositions are used in the form
of a pharmaceutical preparation, for example, in solid, semisolid
or liquid form, which includes one or more of a disclosed compound,
as an active ingredient, in a mixture with an organic or inorganic
carrier or excipient suitable for external, enteral or parenteral
applications. In some embodiments, the active ingredient is
compounded, for example, with the usual non-toxic, pharmaceutically
acceptable carriers for tablets, pellets, capsules, suppositories,
solutions, emulsions, suspensions, and any other form suitable for
use. The active object compound is included in the pharmaceutical
composition in an amount sufficient to produce the desired effect
upon the process or condition of the disease.
[0120] In some embodiments for preparing solid compositions such as
tablets, the principal active ingredient is mixed with a
pharmaceutical carrier, e.g., conventional tableting ingredients
such as corn starch, lactose, sucrose, sorbitol, talc, stearic
acid, magnesium stearate, dicalcium phosphate or gums, and other
pharmaceutical diluents, e.g., water, to form a solid
preformulation composition containing a homogeneous mixture of a
disclosed compound or a non-toxic pharmaceutically acceptable salt
thereof. When referring to these preformulation compositions as
homogeneous, it is meant that the active ingredient is dispersed
evenly throughout the composition so that the composition is
readily subdivided into equally effective unit dosage forms such as
tablets, pills and capsules.
[0121] In solid dosage forms for oral administration (capsules,
tablets, pills, dragees, powders, granules and the like), the
subject composition is mixed with one or more pharmaceutically
acceptable carriers, such as sodium citrate or dicalcium phosphate,
and/or any of the following: (1) fillers or extenders, such as
starches, cellulose, microcrystalline cellulose, silicified
microcrystalline cellulose, lactose, sucrose, glucose, mannitol,
and/or silicic acid; (2) binders, such as, for example,
carboxymethylcellulose, hypromellose, alginates, gelatin, polyvinyl
pyrrolidone, sucrose and/or acacia; (3) humectants, such as
glycerol; (4) disintegrating agents, such as crospovidone,
croscarmellose sodium, sodium starch glycolate, agar-agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate; (5) solution retarding agents,
such as paraffin; (6) absorption accelerators, such as quaternary
ammonium compounds; (7) wetting agents, such as, for example,
docusate sodium, cetyl alcohol and glycerol monostearate; (8)
absorbents, such as kaolin and bentonite clay; (9) lubricants, such
a talc, calcium stearate, magnesium stearate, solid polyethylene
glycols, sodium lauryl sulfate, and mixtures thereof; and (10)
coloring agents. In the case of capsules, tablets and pills, in
some embodiments, the compositions comprise buffering agents. In
some embodiments, solid compositions of a similar type are also
employed as fillers in soft and hard-filled gelatin capsules using
such excipients as lactose or milk sugars, as well as high
molecular weight polyethylene glycols and the like.
[0122] In some embodiments, a tablet is made by compression or
molding, optionally with one or more accessory ingredients. In some
embodiments, compressed tablets are prepared using binder (for
example, gelatin or hydroxypropylmethyl cellulose), lubricant,
inert diluent, preservative, disintegrant (for example, sodium
starch glycolate or cross-linked sodium carboxymethyl cellulose),
surface-active or dispersing agent. In some embodiments, molded
tablets are made by molding in a suitable machine a mixture of the
subject composition moistened with an inert liquid diluent. In some
embodiments, tablets, and other solid dosage forms, such as
dragees, capsules, pills and granules, are scored or prepared with
coatings and shells, such as enteric coatings and other
coatings.
[0123] Compositions for inhalation or insufflation include
solutions and suspensions in pharmaceutically acceptable, aqueous
or organic solvents, or mixtures thereof, and powders. Liquid
dosage forms for oral administration include pharmaceutically
acceptable emulsions, microemulsions, solutions, suspensions,
syrups and elixirs. In addition to the subject composition, in some
embodiments, the liquid dosage forms contain inert diluents, such
as, for example, water or other solvents, solubilizing agents and
emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, oils (in particular,
cottonseed, groundnut, corn, germ, olive, castor and sesame oils),
glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty
acid esters of sorbitan, cyclodextrins and mixtures thereof.
[0124] In some embodiments, suspensions, in addition to the subject
composition, contain suspending agents as, for example, ethoxylated
isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar and tragacanth, and mixtures thereof.
[0125] In some embodiments, powders and sprays contain, in addition
to a subject composition, excipients such as lactose, talc, silicic
acid, aluminum hydroxide, calcium silicates and polyamide powder,
or mixtures of these substances. In some embodiments, sprays
additionally contain customary propellants, such as
chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,
such as butane and propane.
[0126] Compositions and compounds disclosed herein alternatively
are administered by aerosol. This is accomplished by preparing an
aqueous aerosol, liposomal preparation or solid particles
containing the compound. In some embodiments, a non-aqueous (e.g.,
fluorocarbon propellant) suspension is used. In some embodiments,
sonic nebulizers are used because they minimize exposing the agent
to shear, which results in degradation of the compounds contained
in the subject compositions. Ordinarily, an aqueous aerosol is made
by formulating an aqueous solution or suspension of a subject
composition together with conventional pharmaceutically acceptable
carriers and stabilizers. The carriers and stabilizers vary with
the requirements of the particular subject composition, but
typically include non-ionic surfactants (Tweens, Pluronics, or
polyethylene glycol), innocuous proteins like serum albumin,
sorbitan esters, oleic acid, lecithin, amino acids such as glycine,
buffers, salts, sugars or sugar alcohols. Aerosols generally are
prepared from isotonic solutions.
[0127] Pharmaceutical compositions suitable for parenteral
administration comprise a subject composition in combination with
one or more pharmaceutically-acceptable sterile isotonic aqueous or
non-aqueous solutions, dispersions, suspensions or emulsions, or
sterile powders which are reconstituted into sterile injectable
solutions or dispersions just prior to use, which, in some
embodiments, contain antioxidants, buffers, bacteriostats, solutes
which render the formulation isotonic with the blood of the
intended recipient or suspending or thickening agents.
[0128] Examples of suitable aqueous and non-aqueous carriers which
are employed in the pharmaceutical compositions include water,
ethanol, polyols (such as glycerol, propylene glycol, polyethylene
glycol, and the like), and suitable mixtures thereof, vegetable
oils, such as olive oil, and injectable organic esters, such as
ethyl oleate and cyclodextrins. Proper fluidity is maintained, for
example, by the use of coating materials, such as lecithin, by the
maintenance of the required particle size in the case of
dispersions, and by the use of surfactants
[0129] The dose of the composition comprising at least one compound
described herein differs, depending upon the patient's (e.g.,
human) condition, that is, stage of the disease, general health
status, age, and other factors.
[0130] Pharmaceutical compositions are administered in a manner
appropriate to the disease to be treated (or prevented). An
appropriate dose and a suitable duration and frequency of
administration will be determined by such factors as the condition
of the patient, the type and severity of the patient's disease, the
particular form of the active ingredient, and the method of
administration. In general, an appropriate dose and treatment
regimen provides the composition(s) in an amount sufficient to
provide therapeutic and/or prophylactic benefit (e.g., an improved
clinical outcome, such as more frequent complete or partial
remissions, or longer disease-free and/or overall survival, or a
lessening of symptom severity). Optimal doses are generally
determined using experimental models and/or clinical trials. In
some embodiments, the optimal dose depends upon the body mass,
weight, or blood volume of the patient.
[0131] Oral doses typically range from about 1.0 mg to about 1000
mg, one to four times, or more, per day.
EXAMPLES
[0132] These examples are provided for illustrative purposes only
and not to limit the scope of the claims provided herein.
Example 1: Potency and Selectivity for Human P2X3 and P2X2/3
Receptors
[0133] The ability of the compounds described herein and Gefapixant
(also known as AF-219) to act as an antagonist of the P2X3 and
P2X2/P2X3 channel (encoded by the human P2RX2 and P2RX3 genes,
stably expressed in HEK293 cells) was evaluated with a Fluo-8
calcium kit. Compounds 1, 2, 9, 11, 15, and AF-219 were evaluated
at twelve concentrations.
[0134] For the antagonist effect assessment, the cells were
pre-incubated with Compounds 1, 2, 9, 11, 15, and AF-219 for 20
minutes, then stimulated with the P2X3 and P2X2/P2X3 agonist
.alpha.,.beta.-methyleneATP (meATP) at final concentrations of 3
.mu.M and 30 .mu.M. Four minutes fifty seconds after addition of
meATP, ionomycin was added at a final concentration of 5 .mu.M in
order to obtain the maximum calcium influx and fluorescence signal
possible from the cells. Fluorescence was recorded continuously for
10 minutes, starting 10 seconds prior to the addition of meATP.
IC.sub.50s obtained using the above methods are shown in FIG. 3.
These results indicate that compounds of Formula I (compounds 1, 2,
9, 11, and 15) are selective P2X3 antagonists, while AF-219 is
not.
Example 2: Guinea Pig Cough Response Model
[0135] The anti-tussive effect of Compound 1 was compared to that
of AF-219 in a guinea pig cough model. Guinea pigs are the most
commonly used animal in cough studies for both the investigation of
the cough reflex at a fundamental level and for use as an
antitussive screen (Mackensie et al., Drug Discovery Today, 2004,
1, 297-302). In the guinea pig, it was shown that exposure to ATP
and histamine aerosols increases cough responses to tussive stimuli
via P2X3 receptor-mediated mechanisms (Kamei et al., Eur J
Pharmacol (2005) 528: 158-161; Kamei et al., Eur J Pharmacol (2006)
547: 160-164).
[0136] Treatments (control, Compound 1 (0.3, 3 and 30 mg/kg) or
AF-219 (0.3, 3 or 30 mg/kg)) were administered orally in seven
groups of 6 animals 2 hours prior to tussive agent exposure (citric
acid and histamine) and the number of coughs were counted for a
period of 15 minutes. Both treatments showed comparable
dose-dependent reduction in cough frequency as compared to the
control. The reduction in cough was statistically significant at 3
mg/kg (39% vs. control) and 30 mg/kg (52% vs. control) with
Compound 1, and at 30 mg/kg (45% vs. control) with AF-219 (FIG.
4).
Example 3: Time Course Study in Guinea Pig Cough Response Model
[0137] Using the same guinea pig cough model as described in
Example 2, a time course study was conducted to assess the duration
of the anti-tussive effect of Compound 1 and AF-219 following the
administration of a single oral 30 mg/kg dose. In this study,
animals in groups of 6 were exposed to tussive agents (citric acid
and histamine) at various times after the administration of the
study drugs (2, 4, 6, 8 and 12 hours post-dose for Compound 1; and
2 and 8 hours post-dose for AF-219) and the number of coughs were
measured for 15 minutes. The reduction in cough frequency compared
to control was shown to be statistically significant at 2, 4 and 6
hours post-dose with Compound 1, and at 2 hours post-dose with
AF-219. The anti-tussive effect was no longer significant at 8
hours post-dose for both agents. These results indicate that
Compound 1 and AF-219 have comparable duration of effect (FIG.
5).
Example 4: Two Bottle Taste Study
[0138] A rat taste model was used to compare the effect of Compound
1 on taste function with that of AF-219. Animals were water-fasted
overnight and presented with one bottle of water and one bottle of
(bitter-tasting) quinine at the time corresponding to the maximum
plasma concentration of study drugs; and the volume of liquid
consumed from each bottle was measured for 15 minutes. Treatments
(control, Compound 1 (10 or 20 mg/kg) or AF-219 (10 or 20 mg/kg))
were administered intraperitoneally in two groups of 10 rats.
Animals treated with Compound 1 did not drink more quinine than the
control animals, while those treated with AF-219 drank
significantly (approximately 5 times) more quinine than the control
at the two doses tested. These results indicate that AF-219 altered
taste function, while Compound 1 did not (FIG. 6).
* * * * *