Note: Descriptions are shown in the official language in which they were submitted.
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CYCLIC QUATERNARY AMMONIUM COMPOUNDS
BACKGROUND OF THE INVENTION
Conventional cough preparations containing an effective anti-tussive agent
such as
codeine have long been used for the symptomatic relief of coughs. However,
codeine has
various side effects which are undesirable.
Accordingly, the present invention relates to compounds and pharmaceutical
compositions having anti-tussive activity, and a method of treating and/or
preventing coughs in
l0 warm-blooded animals in need thereof by administering an effective amount
of the compounds
or the pharmaceutical compositions of the invention.
SUMMARY OF THE INVENTION
The problems of the prior art have been overcome by the present invention,
which
provides compounds and pharmaceutical compositions possessing anti-tussive
activity, and a
method of administering the same to warm-blooded animals, including humans.
The present
invention is related to cyclic quaternary ammonium compounds that have been
found to be useful
in the treatment and/or prevention of cough.
In one aspect, the present invention concerns the use of certain cyclic
quaternary
ammonium compounds as active ingredient in the manufacture of a medicament for
use in the
treatment and/or prevention of cough in warm-blooded animals, including
humans.
Another aspect of the present invention provides a method for the treatment
and/or
prevention of cough in warm-blooded animals, including humans, which method
comprises
administering to a warm-blooded animal in need thereof certain cyclic
quaternary ammonium
compounds.
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Another aspect of the present invention is directed to certain novel cyclic
quaternary
ammonium compounds that are useful for the treatment and/or prevention of
cough in warm-
blooded animals, including humans.
In another aspect, the present invention provides a pharmaceutical composition
for the
treatment and/or prevention of cough, comprising an effective amount of
certain novel cyclic
quaternary ammonium compounds and a pharmaceutically acceptable carrier,
diluent or
excipient.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a flow diagram showing the layout of the experimental apparatus
used for
1 o cough determination; and
Figures 2A and 2B are expanded scale recordings of pressure changes derived
from the
differential pressure transducer during characteristic responses exhibited by
a guinea-pig during
exposure to an aerosol of citric acid.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the following terms have the following meaning:
"Alkyl" refers to a branched or unbranched hydrocarbon fragment containing the
specified number of carbon atoms and having one point of attachment. Examples
include n-
propyl (a C; alkyl), isopropyl (also a C3 alkyl) and t-butyl (a C4 alkyl).
"Alkoxyalkyl" refers to an alkylene group substituted with an alkoxy group.
For
example, methyoxyethyl (CH30CHZCH2-) and ethoxymethyl (CH3CHZOCH2-) are both
C3
alkoxyalkyl groups.
"Alkylene" refers to a divalent radical which is a branched or unbranched
hydrocarbon
fragment containing the specified number of carbon atoms and having two points
of attachment.
An example is propylene (-CHZCHZCHZ-), a C3 alkylene.
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"Aralkyl" refers to an alkylene group wherein one of the points of attachment
is to an aryl
group. An example is the benzyl group (C6H;CH2-), a C~ aralkyl group.
"Alkanoyloxy" refers to an ester substituent wherein the ether oxygen is the
point of
attachment to the molecule. Examples include propanoyloxy (CH3CHZC(O)-O-), a
C3
alkanoyloxy and ethanoyloxy (CH3C(O)-O), a CZ alkanoyloxy.
"Alkoxy" refers to an O-atom substituted by an alkyl group, for example
methoxy (-
OCH3), a C1 alkoxy.
"Alkoxycarbonyl" refers to an ester substituent wherein the carbonyl carbon is
the point
of attachment to the molecule. Examples include ethoxycarbonyl (CH3CH~OC=0), a
C3
1o alkoxycarbonyl, and methoxycarbonyl (CH30C(O)-), a CZ alkoxycarbonyl.
"Aryl" refers to aromatic groups which have at least one ring having a
conjugated pi
electron system and includes carbocyclic aryl, heterocyclic aryl (also known
as heteroaryl
groups) and biaryl groups, all of which may be optionally substituted.
Carbocyclic anal groups
are generally preferred in the compounds of the present invention, wherein
phenyl and naphthyl
groups are preferred carbocyclic aryl groups.
"Cycloalkyl" refers to a ring, which may be saturated or unsaturated and
monocyclic,
bicyclic or tricyclic formed entirely from carbon atoms. An example is the
cyclopentenyl group
(C;H~-), which is a five carbon unsaturated cycloalkyl group.
"Carbocyclic" refers to a ring which may be either an aryl ring or a
cycloalkyl ring, both
as defined above.
"Thioalkyl" refers to a sulfur atom substituted by an alkyl group, for example
thiomethyl
(CH3S-), a C1 thioalkyl.
The origin of the cough to be treated by the present invention is not
particularly limited,
and can include virtually any respiratory disorder, such as chronic
obstructive pulmonay disease,
tuberculosis; bronchitis, respiratory malignancies, asthma, allergy, pulmonary
fibrosis,
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respiratory tract inflammation, emphysema, pneumonia, lung cancer, presence of
foreign bodies,
soar throat, common cold, influenza, respiratory tract infection,
bronchoconstriction, inhalation
of irritants, smoker's cough, chronic non-productive cough, neoplastic cough,
cough due to
angiotension converting enzyme (ACE) inhibitor therapy, etc. Cough may also
occur without a
known cause.
This invention describes certain cyclic quaternary ammonium compounds and
their utility
as anti-tussive agents. The invention relates to the discovery that cyclic
quaternary ammonium
compounds of the following formula (I), and pharmaceutically acceptable salts,
esters, amides,
complexes, chelates, solvates, stereoisomers, stereoisomeric mixtures,
geometric isomers,
l0 crystalline or amorphous forms, metabolites, metabolic precursors or
prodrugs thereof, are useful
in the treatment and/or prevention of cough in warm-blooded animals, including
humans.
Thus in a first aspect, the present invention is directed to a method for the
treatment
and/or prevention of cough in a warm-blooded animal, which method comprises
administering
to a warm-blooded animal in need thereof, a therapeutically effective amount
of a compound
of formula (I), or a pharmaceutically acceptable salt, ester, amide, complex,
chelate, solvate,
stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or
amorphous form,
metabolite, metabolic precursor or prodrug thereof:
R
1N, E
Y ~ An
~n
(I)
wherein n is an integer of from 0 to 4; R1 and E are independently selected
from -CHZ-R16 and a
group represented by the following formula (II):
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R2 R4 O
C C C-X-A
I ~I
R3 Rs
p q
(II)
wherein R2, R3, R4, R;, R6 and R,6 are independently selected from hydrogen,
hydroxy, C,-Cg
alkoxy, C1-Cg alkyl, C2-C8 alkoxyalkyl, CI-Cg hydroxyalkyl and C~-C1~ aralkyl;
p is an integer of
from 0 to 8 and q is an integer of from 0 to 8; A is selected from CS-Cl~
alkyl, a C3-C13
carbocyclic ring, and ring systems selected from formulae (III), (IV), (V),
(VI], (VII), (VIII), (IX)
and (X):
R7
\ ~' / \ / \
R / ~ RIO \ / RII RIO \ / RII
s
to (III) (IV) (V)
/ / \ w
R12 \ Z \ / \
(VI) (VII) (VIII)
,~ /
RI Z \ Z, w
N
(IX) (X)
where R~, Rg, R9 Rlo, R> > and R12 are independently selected from bromine,
chlorine, fluorine,
carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro,
sulfamyl,
2o trifluoromethyl, CZ-C~ alkanoyloxy, C~-C6 alkyl, C1-C6 alkoxy, C~-C~
alkoxycarbonyl, Ci-C6
_s_
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thioalkyl, aryl and N(RI3,Ria) where R13 and R~4 are independently selected
from hydrogen,
acetyl, methanesulfonyl and C~-C6 alkyl, and Z is selected from CH, CH2, O, N
and S, where Z
may be directly bonded to X when Z is CH, or X may be a direct bond to Z when
Z is N, or Z
may be directly bonded to Rls when Z is N and X is not a direct bond to Z, R15
is selected from
hydrogen, C~-C6 alkyl, C3-C8 cycloalkyl, aryl and benzyl; and X is N-R6 except
when Z in A is
nitrogen and X is a direct bond to Z;
Y is a group on any one of the carbon atoms of the nitrogen heterocyclic ring
of formula (I) and
is independently selected from hydrogen, -CHZ-R~6 and a group represented by
the following
formula (II):
R2 R4 O
C C C-X-A
I ~I
R3 R5
p q
to (II)
wherein RZ, R3, R~, R5, R6 and Rlb are independently selected from hydrogen,
hydroxy, C1-C8
alkoxy, C~-C8 alkyl, CZ-Cg alkoxyalkyl, C~-C8 hydroxyalkyl and C~-Cl~ aralkyl;
p is an integer of
from 0 to 8 and q is an integer of from 0 to 8; A is selected from C5-CI~
alkyl, a C;-C1;
carbocyclic ring, and ring systems selected from formulae (III), (IV), (V),
(VI], (VII), (VIII), (IX)
and (X)
R7 \ / \ / \
R / ~ Ri o \ / Ro R~ o \ / Rn
s
(IV) (V)
(III)
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/ / \ w i
\ Z \ /
(VI) (VII) (VIII)
,~ /
Rt2 , Z~ , J
N
(IX) (X)
where R~, R8, R9, Rio, RI~ and Rl~ are independently selected from bromine,
chlorine. fluorine,
carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro,
sulfamyl,
trifluoromethyl, CZ-C~ alkanoyloxy, CI-C6 alkyl, C~-C6 alkoxy, CZ-C~
alkoxycarbonyl. CI-C6
thioalkyl, aryl and N(R~3,R14) where R13 and R14 are independently selected
from hydrogen,
to acetyl, methanesulfonyl and C~-C6 alkyl, and Z is selected from CH, CHI, O,
N and S, where Z
may be directly bonded to X when Z is CH, or X may be a direct bond to Z when
Z is N, or Z
may be directly bonded to R15 when Z is N and X is not a direct bond to Z, Rl;
is selected from
hydrogen, C,-C6 alkyl, C3-Cg cycloalkyl, aryl and benzyl; and X is N-R6 except
when Z in A is
nitrogen and X is a direct bond to Z; An- is the acid addition salt of a
pharmaceutically acceptable
acid or the anion from a pharmaceutically acceptable salt, with the proviso
that when Y is not
represented by formula (II) then RI and E cannot both be
-CHa-Ri 6.
In one preferred aspect, the present invention concerns a method as described
above in
the first aspect, wherein n is 1 or 2 in formula (I).
2o In another preferred aspect, the present invention concerns a method as
described above
in the first aspect, wherein Y is represented by formula (II).
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In another preferred aspect, the present invention concerns a method as
described above
in the first aspect, wherein p is 0 and q is 0.
In yet another preferred aspect, the present invention concerns a method as
described
above in the first aspect, wherein A is selected from formulae (III), (IV),
(V), (VI), (VII), (VIII),
s (IX) and (X).
In another preferred aspect, the present invention concerns a method as
described above
in the first aspect, wherein Rl and E both are -CHZ-Rlb.
In yet another preferred aspect, the present invention concerns a method as
described
above in the first aspect or any one of the preceding preferred aspects,
wherein A is selected
i0 from formulae (III), (IV) and (V).
The present invention also provides a method for the treatment and/or
prevention of
cough in a warm-blooded animal, which method comprises administering to a warm-
blooded
animal in need thereof, a therapeutically effective amount of a compound
having the
following formula, or a pharmaceutically acceptable salt, ester, amide,
complex, chelate,
15 solvate, stereoisomer, stereoisomeric mixture, crystalline or amorphous
form, metabolite,
metabolic precursor or prodrug thereof:
O Ry E
~ NH~ N
O An
n
wherein n is 2; RI and E are each -CHZ-R16, where R~6 is independently
selected from hydrogen,
hydroxy, Cl-C8 alkoxy, C1-C8 alkyl, CZ-C8 alkoxyalkyl, C1-Cg hydroxyalkyl and
C~-C1~ aralkyl;
2o and An- is the acid addition salt of a pharmaceutically acceptable acid or
the anion from a
pharmaceutically acceptable salt.
_g_
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The present invention further provides a method for the treatment and/or
prevention of
cough in a warm-blooded animal, which method comprises administering to a warm-
blooded
O R~
ll v ,E
NH~~ Ari
n
animal in need thereof, a therapeutically effective amount of a compound of
formula (I) which
is N-methyl-bupivacaine chloride having the following structure, or a
pharmaceutically
acceptable complex, chelate, solvate, stereoisomer, stereoisomeric mixture,
crystalline or
amorphous form, metabolite, metabolic precursor or prodrug thereof:
wherein n is 2; R~ is CH;; E is n-C4H9 and An- is chloride anion.
The present invention further provides a method for the treatment and/or
prevention of
to cough in a warm-blooded animal, which method comprises administering to a
warm-blooded
animal in need thereof, a therapeutically effective amount of a compound of
formula (I) which
is N-methyl-mepivacaine chloride having the following structure, or a
pharmaceutically
acceptable complex, chelate, solvate, stereoisomer, stereoisomeric mixture,
crystalline or
amorphous form, metabolite, metabolic precursor or prodrug thereof:
O RI
~E
/ ~ NH O+N An
n
wherein n is 2; R1 is CH3; E is CH3 and An- is chloride anion.
The present invention further provides a method for the treatment and/or
prevention of
cough in a warm-blooded animal, which method comprises administering to a warm-
blooded
animal in need thereof, a therapeutically effective amount of a compound of
formula (I) which
is N-methyl-vadocaine chloride having the following structure, or a
pharmaceutically
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acceptable complex, chelate, solvate, stereoisomer, stereoisomeric mixture,
crystalline or
amorphous form, metabolite, metabolic precursor or prodrug thereof:
CH3
3
CH; CH
CH3 NH ND An
OCH3
wherein Ari is chloride anion.
The present invention also provides for the use of a compound of formula (I)
as defined
in the first aspect as active ingredient in the manufacture of a medicament
for use in the
treatment and/or prevention of cough in a warm-blooded animal.
The present invention further provides for the use of a compound having the
following
to formula, or a pharmaceutically acceptable salt, ester, amide, complex,
chelate, solvate,
stereoisomer, stereoisomeric mixture, crystalline or amorphous form,
metabolite, metabolic
precursor or prodrug thereof:
O R~
~ ,E
~ NH ~ An
n
wherein n is 2; R, and E are each -CHZ-RI6, where R~6 is independently
selected from hydrogen,
hydroxy, C~-C8 alkoxy, C~-Cg alkyl, CZ-C8 alkoxyalkyl, Cl-C8 hydroxyalkyl and
C~-CIZ aralkyl;
and An- is the acid addition salt of a pharmaceutically acceptable acid or the
anion from a
pharmaceutically acceptable salt, as active ingredient in the manufacture of a
medicament for
use in the treatment and/or prevention of cough in a warm-blooded animal.
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The present invention further provides for the use of a compound selected from
N-
methyl-bupivacaine chloride, N-methyl-mepivacaine chloride and N-methyl-
vadocaine
chloride, or a pharmaceutically acceptable complex, chelate, solvate.
stereoisomer,
stereoisomeric mixture, crystalline or amorphous form, metabolite, metabolic
precursor or
prodrug thereof, as active ingredient in the manufacture of a medicament for
use in the
treatment and/or prevention of cough in a warm-blooded animal.
In another aspect, the present invention is directed to novel cyclic
quaternary ammonium
compounds of the following formula (I), and pharmaceutically acceptable salts.
esters. amides,
complexes, chelates, solvates, stereoisomers, stereoisomeric mixtures,
geometric isomers,
crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs
thereof:
R1N, E
Y ~ An-
~n
(I)
wherein n is an integer of from 0 to 4; Rl and E are independently selected
from -CHZ-R16 and a
group represented by the following formula (II):
R2 R4 O
I I II
C C C-X-A
R3 IRs
p q
(II)
wherein RZ, R3, R4, R;, R6 and R~6 are independently selected from hydrogen.
hydrox~-. C,-Cg
alkoxy, Ci-Cg alkyl, C2-C8 alkoxyalkyl, C1-Cg hydroxyalkyl and C~-C,~ aralkyl:
p is an integer of
from 0 to 8 and q is an integer of from 0 to 8; A is selected from CS-C1~
alkyl, a C;-C,;
carbocyclic ring, and ring systems selected from formulae (III), (IV), (V),
(VI), (VII), (VIII), (IX)
and (X):
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R~
\ ~ / \ / \
R / ~ Rio \ / Ri i Rio \ / R> >
a
(V)
(III) (IV)
/ / \ ~ i
Rl2 \ Z/ \ /
s
(VI) (VII) (VIII)
/ /
R12 \ Z w
N
(IX) (X)
where R~, R$, R9, Rl~, Rl~ and Rl, are independently selected from bromine,
chlorine, fluorine,
l0 carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro,
sulfamyl,
trifluoromethyl, C2-C~ alkanoyloxy, Cl-C6 alkyl, C,-C6 alkoxy, CZ-C~
alkoxycarbonyl, C1-C6
thioalkyl, aryl and N(RI3,Ri4) where R13 and R~4 are independently selected
from hydrogen,
acetyl, methanesulfonyl and Cl-C6 alkyl, and Z is selected from CH, CHI, O, N
and S, where Z
may be directly bonded to X when Z is CH, or X may be a direct bond to Z when
Z is N, or Z
15 may be directly bonded to Rl5 when Z is N and X is not a direct bond to Z,
R~; is selected from
hydrogen, Cl-C6 alkyl, C3-Cg cycloalkyl, aryl and benzyl; and X is N-R6 except
when Z in A is
nitrogen and X is a direct bond to Z;
Y is a group on any one of the carbon atoms of the nitrogen heterocyclic ring
of formula (I) and
is independently selected from hydrogen, -CH2-RI6 and a group represented by
the following
2o formula (II):
-12-
W~ X1/44192 CA 02393706 2002-06-07 PCT/CA00/015~6
R2 R4 O
C C C-X-A
R3 ~Rs
p q
(II)
wherein R2, R3, R4, R5, R6 and Rlb are independently selected from hydrogen,
hydroxy, C~-Cg
alkoxy, CI-Cg alkyl, CZ-C8 alkoxyalkyl, C~-Cg hydroxyalkyl and C~-C1z aralkyl;
p is an integer of
from 0 to 8 and q is an integer of from 0 to 8; A is selected from C5-CIZ
alkyl, a C3-C13
carbocyclic ring, and ring systems selected from formulae (III), (IV), (V),
(VI), (VII), (VIII), (IX)
and (X):
v ~ / \
R7 \ / \
R / ~ Rlo \ / R> > Rio \ / R> >
s
(III) (IV) (V)
/ / \ w
R12 ~ Z \ /
(VI) (VII) (VIII)
~ / _.
Rl~ ~ ~ z~ ~ J
N
(IX) (X)
where R~, R8, R9, Rlo, R~ ~ and Rlz are independently selected from bromine,
chlorine, fluorine,
carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro,
sulfamyl,
trifluoromethyl, C2-C~ alkanoyloxy, Cl-C6 alkyl, C1-C6 allcoxy, C~-C~
alkoxycarbonyl, C~-C6
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thioalkyl, aryl and N(Rl3,Ri4) where R13 and RI4 are independently selected
from hydrogen,
acetyl, methanesulfonyl and C1-C6 alkyl, and Z is selected from CH, CHI, O, N
and S, where Z
may be directly bonded to X when Z is CH, or X may be a direct bond to Z when
Z is N, or Z
may be directly bonded to R15 when Z is N and X is not a direct bond to Z, Rl;
is selected from
hydrogen, C~-C6 alkyl, C3-Cg cycloalkyl, aryl and benzyl; and X is N-Rb except
when Z in A is
nitrogen and X is a direct bond to Z; An- is the acid addition salt of a
pharmaceutically acceptable
acid or the anion from a pharmaceutically acceptable salt, with the provisos
that (a) when Y is not
represented by formula (II) then R, and E cannot both be
-CHZ-R,6; and (b) when n is 0, 1 or 2, and p is 0 or 1, and q is 0 or l then A
is selected from
to formulae (VI), (VII), (VIII) and (IX).
The present invention further provides for a pharmaceutical composition for
the
treatment and/or prevention of cough, comprising an effective amount of a
compound of
formula (I) as defined in the preceding paragraph, or a pharmaceutically
acceptable salt, ester,
amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture,
geometric isomer,
crystalline or amorphous form, metabolite, metabolic precursor or prodrug
thereof and a
pharmaceutically acceptable carrier, diluent or excipient.
The compounds of the present invention may be prepared by direct
quaternisation of the
2o corresponding amino precursors with an appropriate alkyl halide. For
example, N-methyl-
bupivacaine chloride can be synthesized by treatment of bupivacaine
(commercially available
from e.g. Sigma-Aldrich) with methyl chloride. Similarly N-methyl-bupivacaine
iodide can be
synthesized by treatment of bupivacaine (commercially available from e.g.
Sigma-Aldrich)
with methyl iodide. Quaternary mepivacaine such as N-methyl-mepivacaine
chloride and N-
methyl-mepivacaine iodide can be similarly prepared from mepivacaine and
methyl chloride
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or methyl iodide respectively. In an analogous approach, quaternary vadocaine
can be
synthesized by treatment of vadocaine (methods for the preparation of this
compound and
other closely related analogs are described in U.S. 4,353,914) with an
appropriate alkyl halide.
N-methyl-vadocaine chloride can thus be synthesized by reaction of vadocaine
with methyl
chloride.
Alternatively, the compounds of the present invention may be prepared by
analogy with
known synthetic methodology (see, e.g., Belgian Patent 614,154, which follows
from Swedish
Patent 1779/71, the disclosures of which are herein incorporated by
reference). A conventional
route of synthesis involves three steps and can be described (as in the
aforementioned patent, see
1 o also T. Takahashi, J. Okada, M. Hori, A. Kato, K. Kanematsu, and Y.
Yamamoto, J. Pharm. Soc.
Japan 76, 1180-6 (1956)) as follows.
In a first step an aromatic amine is reacted with chloracetyl chloride in a
suitable solvent
such as dichloromethane and in the presence of triethylamine. The reaction is
conducted at low
temperature (-15°C) and the desired product is recovered from the
reaction mixture by
conventional organic chemistry techniques, and if necessary, can be purified
by chromatography
techniques. In a second step, the above chlorinated derivative can be reacted
with an appropriate
cyclic tertiary amine in a solvent such as methanol with a catalyst (e.g.,
potassium iodide) to form
a quaternary ammonium salt. The chlorinated intermediate can react as well
with a secondary
amine to provide the corresponding tertiary amine, which is then further
reacted with a
2o chlorinated derivative to form a quaternary ammonium salt.
The synthetic procedures described herein, especially when taken with the
general
knowledge in the art, provide sufficient guidance to those of ordinary skill
in the art to perform
the synthesis, isolation, and purification of the compounds of the present
invention.
It is recognized that there is at least one chiral center in the compounds
used within the
scope of the present invention and thus such compounds will exist as various
stereoisomeric
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forms. Applicants intend to include all the various stereoisomers within the
scope of the
invention. Though the compounds may be prepared as racemates and can
conveniently be used
as such, individual enantiomers also can be isolated or preferentially
synthesized by known
techniques if desired. Such racemates and individual enantiomers and mixtures
thereof are
intended to be included within the scope of the present invention. Pure
enantiomeric forms if
produced may be isolated by preparative chiral HPLC. The free base may be
converted if
desired, to the monohydrochloride salt by known methodologies, and
subsequently, if desired, to
other acid addition salts by reaction with inorganic or organic salts. Acid
addition salts can also
be prepared metathetically by reacting one acid addition salt with an acid
that is stronger than that
to of the anion of the initial salt.
The present invention also encompasses the pharmaceutically acceptable salts,
esters,
amides, complexes, chelates, solvates, crystalline or amorphous forms,
metabolites, metabolic
precursors or prodrugs of the compounds of formulae (I). Pharmaceutically
acceptable esters and
amides can be prepared by reacting, respectively, a hydroxy or amino
functional group with a
pharmaceutically acceptable organic acid, such as identified below. A prodrug
is a drug which
has been chemically modified and may be biologically inactive at its site of
action, but which is
degraded or modified by one or more enzymatic or other in vivo processes to
the parent bioactive
form. Generally, a prodrug has a different pharmakokinetic profile than the
parent drug such that,
for example, it is more easily absorbed across the mucosal epithelium, it has
better salt formation
2o or solubility and/or it has better systemic stability (e. g., an increased
plasma half life).
Those skilled in the art recognize that chemical modifications of a parent
drug to yield a
prodrug include: (1) terminal ester or amide derivatives which are susceptible
to being cleaved by
esterases or lipases; (2) terminal peptides which may be recognized by
specific or nonspecific
proteases; or (3) a derivative that causes the prodrug to accumulate at a site
of action through
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membrane selection, and combinations of the above techniques. Conventional
procedures for the
selection and preparation of prodrug derivatives are described in H.
Bundgaard, Design of
Prodrugs, (1985). Those skilled in the art are well-versed in the preparation
of prodrugs and are
well-aware of its meaning.
In another embodiment, the present invention provides compositions which
include a
compound of the present invention as described above in admixture or otherwise
in association
with one or more inert carriers, excipients and diluents, as well as optional
ingredients if desired.
Inert carriers include any material which does not degrade or otherwise
covalently react with a
compound of the invention. Thus, the present invention provides a
pharmaceutical or veterinary
1 o composition (hereinafter, simply referred to as a pharmaceutical
composition) containing a
compound of the present invention as described above, in admixture with a
pharmaceutically
acceptable Garner, excipient or diluent. The invention further provides a
pharmaceutical
composition containing an effective amount of a compound of the present
invention as described
above, in association with a pharmaceutically acceptable carrier.
The pharmaceutical compositions of the present invention may be in any form
which
allows for the composition to be administered to a patient. For example, the
composition may be
in the form of a solid, liquid or gas (aerosol). Typical routes of
administration include, without
limitation, oral, topical, parenteral, sublingual, rectal, vaginal, and
intranasal. The term parenteral
as used herein includes subcutaneous injections, intravenous, intramuscular,
epidural, intrasternal
2o injection or infusion techniques. Pharmaceutical composition of the
invention are formulated so
as to allow the active ingredients contained therein to be bioavailable upon
administration of the
composition to a patient. Compositions that will be administered to a patient
take the form of
one or more dosage units, where for example, a tablet, capsule or cachet may
be a single dosage
unit, and a container of a compound of the present invention in aerosol form
may hold a plurality
of dosage units.
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W~ ~l/44192 CA 02393706 2002-06-07 PCT/CA00/0150f>
Materials used in preparing the pharmaceutical compositions should be
pharmaceutically
pure and non-toxic in the amounts used. The inventive compositions may include
one or more
compounds (active ingredients) known for a particularly desirable effect. It
will be evident to
those of ordinary skill in the art that the optimal dosage of the active
ingredients) in the
pharmaceutical composition will depend on a variety of factors. Relevant
factors include,
without limitation, the type of subject (e.g., human), the particular form of
the active ingredient,
the manner of administration and the composition employed.
In general, the pharmaceutical composition includes a compound of the present
invention
as described herein, in admixture with one or more carriers. The carriers) may
be particulate, so
IO that the compositions are, for example, in tablet or powder form. The
carriers) may be liquid,
with the compositions being, for example, an oral syrup or injectable liquid.
In addition, the
carriers) may be gaseous, so as to provide an aerosol composition useful in,
e.g., inhalatory
administration.
When intended for oral administration, the composition is preferably in either
solid or liquid
form, where semi-solid, semi-liquid, suspension and gel forms are included
within the forms
considered herein as either solid or liquid.
As a solid composition for oral administration, the composition may be
formulated into a
powder, granule, compressed tablet, pill, capsule, cachet, chewing gum, wafer,
lozenges, or the
like form. Such a solid composition will typically contain one or more inert
diluents or edible
2o carriers. In addition, one or more of the following adjuvants may be
present: binders such as
syrups, acacia, sorbitol, polyvinylpyrrolidone, carboxymethylcellulose, ethyl
cellulose,
microcrystalline cellulose, gum tragacanth or gelatin, and mixtures thereof;
excipients such as
starch, lactose or dextrins, disintegrating agents such as alginic acid,
sodium alginate, Primogel,
corn starch and the like; lubricants such as magnesium stearate or Sterotex;
fillers such as lactose,
mannitols, starch, calcium phosphate, sorbitol, methylcellulose, and mixtures
thereof; lubricants
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such as magnesium stearate, high molecular weight polymers such as
polyethylene glycol. high
molecular weight fatty acids such as stearic acid, silica, wetting agents such
as sodium lauryl
sulfate, glidants such as colloidal silicon dioxide; sweetening agents such as
sucrose or saccharin,
a flavoring agent such as peppermint, methyl salicylate or orange flavoring,
and a coloring agent.
When the composition is in the form of a capsule, e.g., a gelatin capsule, it
may contain,
in addition to materials of the above type, a liquid carrier such as
polyethylene glycol or a fatty
oil.
The composition may be in the form of a liquid, e.g., an elixir, syrup,
solution, aqueous or oily
emulsion or suspension, or even dry powders which may be reconstituted with
water and/or other
liquid media prior to use. The liquid may be for oral administration or for
delivey by inj ection,
as two examples. When intended for oral administration, preferred compositions
contain, in
addition to the present compounds, one or more of a sweetening agent,
thickening agent,
preservative (e.g., alkyl p-hydoxybenzoate), dye/colorant and flavor enhancer
(flavorant). In a
composition intended to be administered by injection, one or more of a
surfactant, preservative
(e.g., alkyl p-hydroxybenzoate), wetting agent, dispersing agent, suspending
agent (e.g., sorbitol,
glucose, or other sugar syrups), buffer, stabilizer and isotonic agent may be
included. The
emulsifying agent may be selected from lecithin or sorbitol monooleate.
The liquid pharmaceutical compositions of the invention, whether they be
solutions,
suspensions or other like form, may include one or more of the following
adjuvants: sterile
2o diluents such as water for injection, saline solution, preferably
physiological saline, Ringer's
solution, isotonic sodium chloride, fixed oils such as synthetic mono or
digylcerides which may
serve as the solvent or suspending medium, polyethylene glycols, glycerin,
propylene glycol or
other solvents; antibacterial agents such as benzyl alcohol or methyl paraben;
antioxidants such
as ascorbic acid or sodium bisulfate; chelating agents such as
ethylenediaminetetraacetic acid;
buffers such as acetates, citrates or phosphates and agents for the adjustment
of tonicity such as
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sodium chloride or dextrose. The parenteral preparation can be enclosed in
ampoules, disposable
syringes or multiple dose vials made of glass or plastic. Physiological saline
is a preferred
adjuvant. An injectable pharmaceutical composition is preferably sterile.
A liquid compositions intended for either parenteral or oral administration
should contain
an amount of the inventive compound such that a suitable dosage will be
obtained. Typically,
this amount is at least 0.01 % of a compound of the invention in the
composition. When intended
for oral administration, this amount may be varied to be between 0.1 and about
70% of the
weight of the composition. Preferred oral compositions contain between about
4% and about
50% of the active compound of the present invention. Preferred compositions
and preparations
to according to the present invention are prepared so that a parenteral dosage
unit contains between
0.01 to 10% by weight of active compound.
The pharmaceutical composition may be intended for topical ~ administration,
in which
case the carrier may suitably comprise a solution, emulsion, ointment, cream
or gel base. The
base, for example, may comprise one or more of the following: petrolatum,
lanolin, polyethylene
glycols, bee wax, mineral oil, diluents such as water and alcohol, and
emulsifiers and stabilizers.
Thickening agents may be present in a pharmaceutical composition for topical
administration. If
intended for transdermal administration, the composition may include a
transdermal patch or
iontophoresis device. Topical formulations may contain a concentration of the
inventive
compound of from about 0.1 to about 25% w/v (weight per unit volume).
2o The composition may be intended for rectal administration, in the form,
e.g., of a
suppository which will melt in the rectum and release the drug. The
composition for rectal
administration may contain an oleaginous base as a suitable nonirritating
excipient. Such bases
include, without limitation, lanolin, cocoa butter and polyethylene glycol.
Love-melting waxes
are preferred for the preparation of a suppository, where mixtures of fatty
acid glycerides and/or
cocoa butter are suitable waxes. The waxes may be melted, and the compound of
the present
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invention is dispersed homogeneously therein by stirring. The molten
homogeneous mixture is
then poured into convenient sized molds, allowed to cool and thereby solidify.
The composition may include various materials which modify the physical form
of a
solid or liquid dosage unit. For example, the composition may include
materials that form a
coating shell around the active ingredients. The materials which form the
coating shell are
typically inert, and may be selected from, for example, sugar, shellac, and
other enteric coating
agents. Alternatively, the active ingredients may be encased in a gelatin
capsule or cachet.
The composition in solid or liquid form may include an agent which binds to
the
compound of the present invention and thereby assists in the delivery of the
active components.
Suitable agents which may act in this capacity include a monoclonal or
polyclonal antibody, a
protein or a liposome.
The pharmaceutical composition of the present invention may consist of gaseous
dosage
units, e.g., it may be in the form of an aerosol. The term aerosol is used to
denote a variety of
systems ranging from those of colloidal nature to systems consisting of
pressurized packages.
Delivery may be by a liquefied or compressed gas or by a suitable pump system
which dispenses
the active ingredients. Aerosols of compounds of the invention may be
delivered in single phase,
bi-phasic, or tri-phasic systems in order to deliver the active ingredient(s).
Delivery of the
aerosol includes the necessary container, activators, valves, subcontainers,
and the like, which
together may form a kit. Preferred aerosols may be determined by one skilled
in the art, without
undue experimentation. The pharmaceutical compositions may be prepared by
methodology well
known in the pharmaceutical art. The compounds of the present invention may be
in the form of
a solvate in a pharmaceutically acceptable solvent such as water or
physiological saline.
Suitable pharmaceutically acceptable salts include acid addition salts of
acids such as
hydrochloric, hydrobromic, benzenesulfonic (besylate), benzoic,
camphorsulfonic,
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ethanesulfonic, fumaric, gluconic, glutamic, isethionic, malefic, malic,
mandelic,
methanesulfonic, mucic, nitric, pamoic, pantothenic, succinic, p-
toluenesulfonic, phosphoric,
sulphuric, citric, tartaric, lactic and acetic acid, although the preferred
acid addition salt is the
hydrochloride salt.
As indicated above the magnitude of the therapeutic or prophylactic dose of
the
compounds of the present invention in the treatment and/or prevention of cough
will depend
upon the severity and nature of the condition being treated and the route of
administration. The
dose and the frequency of the dosing will also vary according to age, body
weight and response
of the individual patient. In general, the total daily dose range for the
compounds of the present
I O invention for the treatment or prevention of cough is from about 0.1 to
about 800 mg in single or
repeated doses.
Any suitable route of administration as described above may be employed to
provide an
effective dosage of the compounds of the present invention, although
administration by
inhalation is preferred, most preferably in aerosol form. Suitable forms of
administration include,
but are not limited to, inhalation (delivered by, e.g., metered-dose inhaler,
jet nebulizer.
ultrasonic nebulizer, dry powder inhaler, etc.), nasal sprays, nebulization,
oral administration
such as via tablets, capsules, lozenges, syrups, sprays, suspensions, elixirs,
gargles, and other
liquid preparations, aerosol foams, parental administration, and sublingal
administration.
The compounds of the present invention can include pharmaceutically acceptable
carriers
and other conventional additives, including aqueous based carriers, co-
solvents such as ethyl
alcohol, propylene glycol and glycerin, fillers, lubricants, wetting agents,
flavoring agents.
coloring agents, emulsifying, suspending or dispersing agents, suspending
agents, etc. For
aerosol delivery of the compounds of the present invention, pharmaceutically
acceptable diluents.
earners, and/or propellants may be included in the
formulations for use in appropriate devices. These are prepared by procedures
well known to
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those skilled in the art (see e.g., Medication Teaching Manual, 5th Ed.,
Bethesda, MD, American
Society of Hospital Pharmacists, 1991).
The compositions of the present invention may optionally include other known
therapeutic agents, including decongestants such as pseudoephedrine HCI,
phenylephrine HCl
and ephedrine HCI, non-steroidal anti-inflammatory drugs such as
acetaminophen. aspirin,
phenacetin, ibuprofen and ketoprofen, expectorants such as glyceryl
guaiacolate, tenpin hydrate
and ammonium chloride, antihistamines such as chlorpheniramine maleate,
doxylamine
succinate, brompheniramine maleate and diphenhydramine hydrochloride, and
anesthetic
compounds such as phenol.
1o
The following examples are offered by way of illustration and not by way of
limitation.
L'V A I~iTDT L' 1
Synthesis of 2-fj(2 6-Dimeth~phen~)amino]carbonyl~-1-methyl-1-
pentylpiperidinium
...a:ao
(N-methyl-bupivacaine iodide)
Bupivacaine hydrochloride was dissolved in HBO ( 15 mL), saturated aqueous
NaHCO;
(30 mL), and extracted with dichloromethane (3 x 50 mL). The organic layers
were combined.
dried over anhydrous Na2S04, and concentrated in vacuo to 60 mL. Methyl iodide
( 1.0 mL,
16.12 mmol) was then added to the filtrate and the reaction mixture was
stirred at room
2o temperature for 48 hours. The solvent was evaporated and the resultant
solid dissolved in water
(50 mL). The resulting solution was extracted with ether (2 x 50 mL) and then
with CH~C12 (2 x
50 mL). The combined dichloromethane layers were dried over anhydrous Na~SO~,
and the
solvent was evaporated to give the product (2.62 g, 79% yield) as yellow
crystals. ''C IvvIR (75
MHz, CDC13 ) b 13.4 (CH;), 18.7 (CH;), 19.6 (CH2), 19.7 (CHZ), 19.8 (CHZ),
23.9 (CHI), 24.8
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WO ~l/44192 CA 02393706 2002-os-07 pCT/CA00/01506
(CH3), 43.9 (CH3), 61.1 (CHZ), 65.1 (CH3), 69.1 (CH), 127.6 (CH), 128.1 (CH),
132.3 (C), 134.9
(C), 165.1 (C).
FYAMPT P 7
Synthesis of 2-~~(2,6-Dimethylphenyl)amino]carbonyl-1.1-dimeth~piperidinium
iodide
(N-methyl-mepivacaine iodide)
Mepivacaine hydrochloride (2.92 g, 10.32 mmol) was dissolved in H20 (1~ mL),
saturated aqueous NaHC03 (30 mL), and extracted with dichloromethane (3 x 50
mL). The
organic layers were combined, dried over anhydrous Na2S04, and concentrated in
vacuo (50
1 o mL). Methyl iodide ( 1.3 mL, 20.64 mmol) was then added to the filtrate
and the reaction mixture
was stirred at room temperature for 48 hours. The solvent was evaporated, and
the resultant solid
dissolved in water (200 mL). The aqueous solution was extracted with ether (2
x 200 mL) and
then with CH2C12 (2 x 200 mL). The combined CHZC12 layers were dried over
anhydrous
NaZS04, and the solvent was evaporated to give the product (3.19 g, 80% yield)
as yellow
crystals. '3C NMR (75 MHz, CDCl3) 8 18.9 (CH3), 19.6 (CHZ), 20.2 (CHZ), 24.5
(CHI), 46.4
(CH3), 53.6 (CH3), 65.0 (CH2), 69.9 (CH), 127.8 (CH), 128.2 (CH), 132.4 (C).
134.9 (C), 164.7
]
EXAMPLE 3
The following method is one of the general methods available to determine the
antitussive activity of the compounds of the present invention.
Male albino Dunkin-Hartley strain guinea-pigs (weight 300-400g) can be
obtained from
various commercial suppliers.
The method is a modification of that described by Adcock J.J.., Schneider C.
and Smith
T.W., "Effects of Morphine and a Novel Opioid Pentapeptide BW443C, on Cough,
Nociception
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and Ventilation in the Unanaesthetized Guinea-pig", Br. J. Pharmacol., 93, 93-
100 (1988).
Individual conscious guinea-pigs are placed unrestrained into a sealed purpose
built perspex
exposure chamber (3,000 cm3 volume) and allowed to acclimatize prior to
aerosol administration.
The layout of the experimental apparatus used is shown in Figure 1.
Cylinder air is introduced into the exposure chamber at a flow rate of 1
liter/min,
maintained by a needle valve and monitored by a rotameter. From the rotameter
the air passes
through the cup of an ultrasonic nebulizer (DeVilbis UltraNeb 2000) which is
used to generate
aerosols of drug or citric acid at 0.15 ml/min. A Fleisch pneumotachograph,
connected to a
differential pressure transducer (Grass model PTS) is attached to the outflow
from the exposure
1 o chamber and provides a measurement of airflow from the chamber. The
differential pressure
transducer is connected to a Grass polygraph from which a hard copy record can
be produced.
The output from the polygraph is directed to a computerized data acquisition
system (Poh-Ne-
Mah) for real time recording of data. A tie-clip microphone is placed in the
exposure chamber
and connected via a pre-amplifier to a loudspeaker output to provide the
observer with an audio
monitor of responses.
Cough responses are induced by exposure to an aerosol of citric acid ( 1 M)
for 10
minutes. Animals are continuously monitored by trained observer, and the
number of coughs are
counted during a 15 minute period from commencement of the citric acid aerosol
adnunistration.
Three characteristic responses can be produced by exposure to citric acid:
cough, sneeze and
"wet dog" shake.
The three types of response are differentiated primarily by sound and visual
observation.
Confirmation of the numbers of multiple coughs is determined by reference to
the change in flow
rate displayed by the Poh-Ne-Mah system monitor. Printouts demonstrating the
pressure changes
characteristic of the different response to irritant are shown in Figures 2A
and 2B. Data records
for individual guinea-pigs on the Poh-Ne-Mah system are stored on an optical
disk. Each cough
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is marked on the Grass polygraph paper trace, and from these record numbers,
frequency and
time of onset of coughs are determined. The cough response is defined by a
characteristic
coughing sound and behavior, associated with a marked biphasic pressure
change. The biphasic
pressure changes associated with a sneeze are not of as great a magnitude as
those associated
with a cough, the secondary rise in pressure also being far less than during a
cough (Figure 2B).
The sound of a sneeze differed from that of a cough, and sneezing is
associated with nose
rubbing activity. The third response, a "wet dog" shake, produces a rise in
pressure only (Figure
2A) and lacked the definitive sound of a cough or sneeze.
Quantities of drugs are weighed out and dissolved in a vehicle. Equal volumes
are
1 o aliquotted into sample tubes before being passed, together with another
sample tube containing
the same volume of vehicle, to an independent observer for coding. Pre-
treatments are matched
by concentration together with a vehicle control group. Two to five guinea-
pigs are randomly
allocated to each treatment group. Animals are pre-treated with either vehicle
(e.g. distilled
water, 0.9% sterile saline, Tween or 1 to 25% ethanol depending on the
solubility of the
compound), reference compound (e.g. lidocaiiie, bupivacaine or mepivacaine) or
test drugs for 5
minutes immediately prior to citric acid aerosol exposure. Test drugs and
reference compound
are administered as aerosols at concentrations selected from 0.1, 1.0, 2.0,
5.0 and 10.0 mg/ml.
The sequence of pre-treatment administration is determined according to a 4x4
Latin Square
design.
Data can be presented as the mean ~SEM number of coughs produced by individual
guinea-pigs within each group during the 15 minute observation period or
mean~SEM latency of
cough and are analyzed using one way analysis of variance to compare mean
responses between
matched groups of animals (doses) and between unmatched groups (treatments)
followed by the
Tukey-Kramer multiple comparison test where appropriate.
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In one set of experiments using the general protocol described above, the
antitussive
activity of N-methyl-bupivacaine iodide was tested. Results showed that pre-
treatment of
guinea pigs with aerosols of N-methyl-bupivacaine iodide at 5.0 mg/ml
immediately before
exposure to citric acid ( 1 M) inhibited cough responses by >90% compared with
vehicle (25%
ethanol) pre-treated guinea pigs over the 15 minute observation period.
Similarly, other cyclic
quaternary ammonium compounds of the present invention can be evaluated by
this method.
EXAMPLE 4
In another experiment similar to that described above in Example 3, the
duration of the
to antitussive effects of the compounds of the present invention against
citric acid-induced cough
responses can be investigated in conscious guinea pigs. Cyclic quaternary
ammonium
compounds of the present invention, reference compounds or vehicle are tested
by administering
as aerosol pre-treatments (0.1, 1.0, 2.0, 5.0 or 10.0 mg/ml, 5 minute
duration) at 5 minutes, 30
minutes, 1 hour, 2 hours and 4 hours prior to induction of cough responses by
citric acid aerosol.
Data and results are analyzed as described in Example 3
EXAMPLE 5
The antitussive effects of a 5 minute pre-treatment with aerosolized compounds
of the
present invention and reference compound (e.g. lidocaine, bupivacaine or
mepivacaine) on
2o capsaicin aerosol-induced cough can be investigated in conscious guinea-
pigs using a method
similar to that described in Example 1. Data and results are analyzed as
described in Example 3
EXAMPLE 6
Therapeutic treatment with the compounds of the present invention can also be
determined by a similar method as described in Example 3. The antitussive
effects of
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compounds of the present invention and reference compound (e.g. lidocaine,
bupivacaine or
mepivacaine) that are administered after induction of cough responses by
exposure to citric
acid aerosol are investigated in conscious guinea pigs. Vehicle or test agents
are administered
as aerosols ( 10, 5, 2, 1.0 or 0.1 mg/ml; 5 minute duration) 2 minutes after
exposure to citric
acid aerosol began. Cough responses are recorded during a 15 minute
observation period (t=0
to t=15 minutes) from initiation of the citric acid exposure. Data and results
are analyzed as
described in Example 3.
EXAMPLE 7
Investi anon of antitussive activity of aerosolized test compound on citric
acid-induced cough
responses in conscious rabbits
Protocol
Twenty-two male New Zealand white rabbits are randomly allocated to either of
two
groups of 11 rabbits.
Pairs of rabbits (control versus test) are placed in individual exposure
chambers with an
airflow of 5 liter/min through the chambers.
Each rabbit is exposed to ozone (3 ppm) for 1 hour.
The rabbits are then immediately exposed to aerosols of either vehicle
(chamber 1 ) or test
compound ( 10 mg/ml, chamber 2) at a nebulization rate of 0.9 ml/min.
Cough responses are induced with citric acid aerosol (1.6 M).
Coughs are counted during the 10 minute exposure to citric acid.
All rabbits are exposed to ozone before vehicle or test drug pre-treatment.
Data and results are analyzed as described in Example 3
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WO 01/44192 PCT/CA00/01506
All publications and patent applications mentioned in this specification are
herein
incorporated by reference to the same extent as if each individual publication
or patent
application was specifically and individually incorporated by reference.
From the foregoing, it will be appreciated that, although specific embodiments
of the
invention have been described herein for purposes of illustration, various
modifications may be
made without deviating from the spirit and scope of the invention.
Accordingly, the invention is
not limited except as by the appended claims.
The invention includes all embodiments and variations substantially as
hereinbefore
described and with reference to the examples and drawings. From the foregoing,
it will be
appreciated that, although specific embodiments of the invention have been
described herein for
purposes of illustration, various modifications may be made without deviating
from the spirit and
scope of the invention. Accordingly, the invention is not limited by the
disclosed embodiments
or examples. Many adaptations and modifications may be made within the scope
of the invention
in accordance with the common general knowledge of those skilled in this art.
Such
modifications include the substitution of known equivalents for any aspect of
the invention in
order to achieve the same result in substantially the same way. Numeric ranges
are inclusive of
the numbers defining the range. In the specification, the word "comprising" is
used as an open-
ended term, substantially equivalent to the phrase "including, but not limited
to", and the word
"comprises" has a corresponding meaning. Citation of references herein shall
not be construed as
2o an admission that such references are prior art to the present invention.
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