CA2393699A1 - Quaternary ammonium compounds and their use as anti-tussive agents - Google Patents

Abstract

In one aspect, the present invention concerns the use of certain quaternary ammonium compounds as active ingredient in the manufacture of a medicament f or use in the treatment and/or prevention of cough in warm-blooded animals, including humans, such as compounds of formula Y-J-E An- (I), wherein J is independently selected from a group represented by one of formulae (II), (II I) and (IV).

Description

QUATERNARY AMMONIUM AND THEIR USE AS ANTI-TUSSIVE AGENT
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 1 o 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 quaternary ammonium compounds that have been found to be useful in the treatment and/or prevention of cough.
2o In one aspect, the present invention concerns the use of certain 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 quaternary ammonium compounds.
Another aspect of the present invention is directed to certain novel quaternary 3o ammonium compounds that are useful for the treatment and/or prevention of cough in warm-blooded animals, including humans.
SUBSTITUTE SHEET (RULE 26) In another aspect. the present invention provides a pharmaceutical composition for the treatment and/or prevention of couch, comprising an effective amount of certain novel 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 cough determination; and 1 o 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 C3 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 (CH30CH~CH2-) and ethoxymethyl (CH3CH~OCH~-) are both 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 (-CH2CH2CH2-), a C3 alkylene.
"Aralkyl" refers to an alkylene group wherein one of the points of attachment is to an aryl group. An example is the benzyl group (C6HSCH2-), a C~ aralkyl group.

SUBSTITUTE SHEET (RULE 26) "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 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 (CH3CHzOC=O), a 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 aryl 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 (CSH~-), 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.
"Hydroxyalkyl" refers to a branched or unbranched hydrocarbon fragment bearing an hydroxy (-OH) group. Examples include hydroxymethyl (-CH20H, a Clhydroxyalkyl) and 1-hydroxyethyl (-CHOHCH3, a CZhydroxyalkyl).
"Pharmaceutically acceptable carriers" for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remin ons Pharmaceutical Sciences, Mack Publishing Co. (A.R. Gennaro edit. 1985). For example, sterile saline and SUBSTITUTE SHEET (RULE 26) phosphate-buffered saline at physiological pH may be used. Preservatives, stabilizers, dyes alnd even flavoring agents may be provided in the pharmaceutical composition. For example, sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid may be added as preservatives. Id. at 1449. In addition, antioxidants and suspending agents may be used. Id.
"Pharmaceutically acceptable salt" refers to salts of the compounds of the present invention derived from the combination of such compounds and an organic or inorganic acid (acid addition salts) or an organic or inorganic base (base addition salts).
The compounds of the present invention may be used in either the free base or salt forms, with both forms being 1 o considered as being within the scope of the present invention.
The "therapeutically effective amount" of a compound of the present invention will depend on the route of administration, the type of warm-blooded animal being treated, and the physical characteristics of the specific warm-blooded animal under consideration. These factors and their relationship to determining this amount are well known to skilled practitioners in the medical arts. This amount and the method of administration can be tailored to achieve optimal efficacy but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.
2o Compositions described herein as "containing a compound of formula (I)"
encompass compositions that contain more than one compound of formula (I).
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 pulmonary disease, tuberculosis, bronchitis, respiratory malignancies, asthma, allergy, pulmonary fibrosis, 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 3 o known cause.
This invention describes certain quaternary ammonium compounds and their utility as anti-tussive agents. The invention relates to the discovery that quaternary ammonium SUBSTITUTE SHEET (RULE 26) compounds of the following formula (I), and pharmaceutically acceptable salts.
esters, amiss, complexes, chelates, solvates, stereoisomers. stereoisomeric mixtures, geometric isomers, 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, to chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof:
Y-J-E Ari (I) wherein J is independently selected from a group represented by one of the following formulae (II), (III) and (IV):
R

NO~ ~N~~n ~NO ~n RI _ t s (II) (III) (IV) such that when J is represented by formulae (II), (III) or (IV), compounds of the present invention are represented by the following formulae (V), (VI) or (VII) respectively:
R Y N-E E-NO
Y-NO E
)n (V) (VI) (VII) wherein n is an integer of from 0 to 4; R, Rl and E are independently selected from 20 -CHZ-RI6 and a group represented by the following formula (VIII):
R2 R4 ~ i 7 C C C X-A
R3 ~R~ Ri 8 p r (VIII) SUBSTITUTE SHEET (RULE 26) wherein X is O (oxygen) or S (sulfur); R2, R;, R.~, R;, R16, R, ~ and R18 are independently selected from hydrogen, hydroxy, Cl-Cg alkoxv, C1-Cg alkyl, C~-Cg alkoxyalkyl, C~-Cg hydroxyalkyl and C~-C12 aralkyl; p is an integer of from 0 to 8, q is an integer of from 0 to 8 and r is an integer of from 0 to 8; A is selected from C,-C,~ alkyl, a C3-C,3 carbocyclic ring, and ring systems selected from formulae (IX), (X), (XI), (XII), (XIII), (XIV), (XV) and (XVI):
R~
\ ~ / \
/ \ H
R9 Rio Rl i Rio R~ t Rg \ / \ /
(IX) (X) (XI) \ ~ i \ Z \ / \
(XII) (XIII) (XIV) / /
Rl~ \ Z>
N
(XV) (XVI) where R6, R~, Rg, R9, Rlo, R> > and RI2 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7 alkanoyloxy, Cl-C6 alkyl, C1-C6 alkoxy, C2-C7 alkoxycarbonyl, CI-C6 thioalkyl, aryl and N(R13,R~4) where R13 and RI4 are independently selected from hydrogen, acetyl, methanesulfonyl and C1-C6 allcyl, and Z is selected from CH, CH2, O.
S, NH and N-Rl;
2o where Z may be directly bonded to X when Z is CH; and R1; is selected from hydrogen, C1-C6 alkyl, C3-Cg cyclocalkyl, aryl and benzyl;
Y is independently selected from hydrogen, -CHZ-Rlb and a group represented by the following formula (VIII):

SUBSTITUTE SHEET (RULE 26) R~ R4 I 17 C C C X-A
R3 IRs Ri s p q r (VIII) wherein X is O (oxygen) or S (sulfur); R2, R3, R4, R5, R~6, Rl~ and Rlg are independently selected from hydrogen, hydroxy, C,-Cgalkoxy, Ci-Cg alkyl, CZ-Cg allcoxyalkyl, Cl-C8 hydroxyalkyl and C~-C~Z aralkyl; p is an integer of from 0 to 8, q is an integer of from 0 to 8 and r is an integer of from 0 to 8; A is selected from C;-C i2 alkyl, a C3-C 13 carbocyclic ring, and ring systems selected from formulae (IX), (X), (XI), (XII), (XIII), (XIV), (XV) and (XVI):

\ H
\ ~ / \
R9 Rio Ru Rlo Rn Rg \ / \ /
(IX) (X) (XI) / / \ ~ i Ri2 \ Z \ / \
~ s (XII) (XIII) (XIV) /
Riz \ _ ~ wN
Z
(XV) (XVI) where R6, R7, R8, R9, Rlo, R1~ and R12 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, vitro, sulfamyl, ?o trifluoromethyl, C~-C~ alkanoyloxy, C,-C6 alkyl, C1-C6 alkoxy, C2-C~
allcoxycarbonyl, CI-C6 SUBSTITUTE SHEET (RULE 26) thioalkyl, aryl and N(R13,R,4) where R13 and R14 are independently selected from hydrogen, acetyl, methanesulfonyl and C~-C6 allyl, and Z is selected from CH, CHI, O, S, NH and N-R,5 where Z may be directly bonded to X when Z is CH, and R1; is selected from hydrogen, C~-C6 alkyl, C;-Cg cyclocalkyl, aryl and benzyl; when J is represented by formula (VII), Y is a group on any one of the carbon atoms of the nitrogen heterocyclic ring of formula (VII); 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 J is represented by formula (II) then Y is represented by formula (VIII); (b) when J is represented by formula (III) then Y is represented by formula (VIII); (c) t 0 when J is represented by formula (IV) and Y is not represented by formula (VIII), Ri and E
cannot both be -CHI-R~6 and (d) p, q and r cannot all be 0.
In one preferred aspect, the present invention concerns a method as described above in the first aspect, wherein J is represented by formula (II).
In another preferred aspect, the present invention concerns a method as described above in the first aspect, wherein J is represented by formula (III).
In another preferred aspect, the present invention concerns a method as described above 2o in the first aspect, wherein J is represented by formula (IV).
In 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 from formulae (IX), (X), (XI), (XII), (XIII), (XIV), (XV) and (XVI).
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 from formulae (IX), (X), (XI) and (XII).
3o In 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 X
is O (oxygen).
-g_ SUBSTITUTE SHEET (RULE 26) The present invention also provides a method for the treatmen'~and/or preven~on 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, solvate, stereoisomer, stereoisomeric mixture, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof:
Rz R4 ~ i 7 ~1 C C C X-A
An Rl IR3 IRs R~ s P q r 2 wherein R and Rl are each -CHZ-R,6; R2, R;, Ra, R;, R~6, Rl~ and R18 are independently selected from hydrogen, hydroxy, CI-C8 alkyl. C,-C8 hydroxyalkyl and C~-C12 aralkyl; p is an integer of 1o from 0 to 3, q is an integer of from 0 to 3 and r is an integer of from 0 to 3; X is O (oxygen); A is selected from formulae (IX), (X), (XI), (XII), (XIII), (XIV), (XV) and (XVI) as described above;
and An- is the anion from a pharmaceutically acceptable salt; with the proviso that p, q and r cannot all be 0.
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 having the following formula, or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, crystalline or amorphous form, metabolite, 2o metabolic precursor or prodrug thereof:
Rz R4 I i ~
E~1 C C C X-A
I I ( I
Rt R3 Rs R18 p q r An wherein R, R1 and E are each -CHZ-R16; R2, R3, R4, R5, R,6, Rl~ and RIg are independently selected from hydrogen, hydroxy, C,-C8 alkyl, CI-C8 hydroxyalkyl and C~-C12 aralkyl; p is an integer of from 0 to 3, q is an integer of from 0 to 3 and r is an integer of from 0 to 3; X is z5 O (oxygen); A is selected from formulae (IX), (X), (XI), (XII), (XIII), (XIV), (XV) and (XVI) as SUBSTITUTE SHEET (RULE 26) described above: and An- is the anion from a pharmaceutically acceptable salt:
with the prov~o that p, q and r cannot all be 0.
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,N,N-trimethyl-mexiletine 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:

D~N CH3 Cr to 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,N-dimethyl-propranolol 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:
~~, cry cr ,.
cue, crf; cue;
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 2o animal in need thereof, a therapeutically effective amount of a compound of formula (I) which is N,N-dimethyl-pindolol 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:

SUBSTITUTE SHEET (RULE 26) - p~ CH3 Cf O~N~CH3 OH

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 formula, or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, crystalline or amorphous form, metabolite, metabolic 1 o precursor or prodrug thereof:
+R R2 R4 I 17 ~N C C C X-A
-I
~ R1 R3 R5 Ri s P q r 2 wherein R and Rl are each -CHI-R16; RZ, R3, R~, R5, R16, R17 and R~8 are independently selected from hydrogen, hydroxy, Ci-C8 alkyl, C1-Cg hydroxyalkyl and C~-ClZ aralkyl; p is an integer of from 0 to 3, q is an integer of from 0 to 3 and r is an integer of from 0 to 3; X is O (oxygen); A is selected from formulae (IX), (X), (XI), (XII), (XIII), (XIV), (XV) and (XVI) as described above;
and An- is the anion from a pharmaceutically acceptable salt; with the proviso that p, q and r cannot all be 0, as active ingredient in the manufacture of a medicament for use in the treatment and/or prevention of cough in a warm-blooded animal.
2o The present invention further provides for the use of a compound having the following formula, or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture. crystalline or amorphous form, metabolite, metabolic SUBSTITUTE SHEET (RULE 26) precursor or prodrug thereof:
+R R2 Ra I i 7 E~l C C C X-A
I I II I
R1 R3 R5 R1 g r Ari p q wherein R, RI and E are each -CHI-R,6; RZ, R3, R4, R5, R~6, Rig and R1g are independently selected from hydrogen, hydroxy, C,-Cg alkyl, C1-Cg hydroxyalkyl and C~-CI~
aralkyl; p is an integer of from 0 to 3, q is an integer of from 0 to 3 and r is an integer of from 0 to 3; X is O
(oxygen); A is selected from formulae (IX), (X), (XI), (XII), (XIII), (XIV), (XV) and (XVI) as described above, and An- is the anion from a pharmaceutically acceptable salt;
with the proviso that p, q and r cannot all be 0, 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 selected from N,N,N-trimethyl-mexiletine chloride, N,N-dimethyl-propranolol chloride and N,N-dimethyl-pindolol 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 quaternary ammonium compounds of the following formula (I), and pharmaceutically acceptable salts, esters, amides, 2o complexes, chelates, solvates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof:
Y- J-E Ari (I) wherein J is independently selected from a group represented by one of the following formulae (II), (III) and (IV):
R
RI
NO~ ~N~ ~n ~NO )n R _ (II) (III) (IV) SUBSTITUTE SHEET (RULE 26) such that when J is represented by formulae (II), (III) or (IV), compounds of the present invention are represented by the following formulae (V), (VI) or (VII) respectively:
Y-ON-E E-NO
Y-N+ E
)n )n (V) (VI) (VII) wherein n is an integer of from 0 to 4; R, R1 and E are independently selected from -CHZ-Ri6 and a group represented by the following formula (VIII):
R4 ~ t 7 C C C X-A
R3 IRs Ri s p q r (VIII) wherein X is O (oxygen) or S (sulfur); R2, R3, R4, R;, Rib, R17 and R18 are independently selected from hydrogen, hydroxy, C,-Cg alkoxy, C,-Cg alkyl, CZ-Cg alkoxyalkyl, Cl-Cg hydroxyalkyl and C7-C12 aralkyl; p is an integer of from 0 to 8, q is an integer of from 0 to 8 and r is an integer of from 0 to 8; A is selected from C5-C~Z alkyl, a C3-C,3 carbocyclic ring, and ring systems selected from formulae (IX), (X), (XI), (XII), (XIII), (XIV), (XV) and (XVI):

\ ~ / \
/ \ "
/ ~ Rio \ / Rll Rio Rn R8 \/ \ /
(IX) (X) (XI) SUBSTITUTE SHEET (RULE 26) \ ~ i Rl2 Z \ /
(XII) (XIII) (XIV) / /
R12 \ Z~ ~ w N
(XV) (XVI) where R6, R~, R8, R9, Rlo, R1 ~ and R,Z are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C~ alkanoyloxy, Cl-C6 alkyl, C1-C6 allcoxy, C2-C7 allcoxycarbonyl, C1-C6 thioalkyl, aryl and N(Rl3,Ri4) where Rl3 and R14 are independently selected from hydrogen, acetyl, methanesulfonyl and C1-C6 alkyl, and Z is selected from CH, CH2, O, S, NH and N-Rls to where Z may be directly bonded to X when Z is CH; and RIS is selected from hydrogen, C1-C6 alkyl, C3-Cg cyclocalkyl, aryl and benzyl;
Y is independently selected from hydrogen, -CH2-R,6 and a group represented by the following formula (VIII):

C C C X-A
I I I
R3 Rs Ri s p q r (VIII) wherein X is O (oxygen) or S (sulfur); RZ, R3, R4, RS, R16, RI ~ and Rl8 are independently selected from hydrogen, hydroxy, C~-C8 alkoxy, C1-C8 alkyl, C2-Cg alkoxyalkyl, C~-C8 hydroxyalkyl and 2o C7-C12 aralkyl; p is an integer of from 0 to 8, q is an integer of from 0 to 8 and r is an integer of from 0 to 8; A is selected from C;-C 12 alkyl, a C3-C 13 carbocyclic ring, and ring systems selected from formulae (IX), (X), (XI), (XII), (XIII), (XIV), (XV) and (XVI):

SUBSTITUTE SHEET (RULE 26) R~
\ ~ / \ / \
R / ~ Rto \ / Rt t Rto \ / Rt t s (IX) (X) (XI) / / \ ~ i Rt2 \ Z \ /
(XIV) (XII) (XIII) Rt2 \ Z~ ~N
(XV) (XVI) where R6, R7, Rg, R9, Rlo, RI, and Rlz are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, vitro, sulfamyl, to trifluoromethyl, CZ-C~ alkanoyloxy, C,-C6 alkyl, C,-C6 allcoxy, CZ-C~
alkoxycarbonyl, Ci-C6 thioalkyl, aryl and N(Rt3,R,4) where R,3 and R14 are independently selected from hydrogen, acetyl, methanesulfonyl and C1-C6 alkyl, and Z is selected from CH, CHI, O, S, NH and N-Rts where Z may be directly bonded to X when Z is CH, and Ri; is selected from hydrogen, C,-C6 alkyl, C3-Cg cyclocalkyl, aryl and benzyl; when J is represented by formula (VII), Y is a group on any one of the carbon atoms of the nitrogen heterocyclic ring of formula (VII); 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 J is represented by formula (II) then Y and E
are both represented by formula (VIII); (b) when J is represented by formula (III) then Y is represented 2o by formula (VIII); (c) when J is represented by formula (IV) and Y is not represented by formula (VIII), R1 and E cannot both be -CHZ-R16 and (d) p, q and r cannot all be 0.
In another aspect, the present invention is directed to novel quaternary ammonium compounds of formula (I) as defined in the preceding paragraph wherein J is represented by SUBSTITUTE SHEET (RULE 26) formula (II), and pharmaceutically acceptable salts, esters, amides, complexes, chelates;
solvates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof.
In another aspect, the present invention is directed to novel quaternary ammonium compounds of formula (I) as defined in the preceding paragraph wherein J is represented by formula (III), and pharmaceutically acceptable salts, esters, amides, complexes, chelates, solvates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof.
to In yet another aspect, the present invention is directed to novel quaternary ammonium compounds of formula (I) as defined in the preceding paragraph wherein J is represented by formula (IV), and pharmaceutically acceptable salts, esters, amides, complexes, chelates, solvates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous 15 forms, metabolites, metabolic precursors or prodrugs thereof.
The present invention also provides for a pharmaceutical composition for the treatment and/or prevention of cough, comprising an effective amount of a novel quaternary ammonium compound of formula (I) as defined in any one of the preceding paragraphs, or a 2o 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.
25 The compounds of the present invention may be prepared by direct quaternisation of the corresponding amino precursors with an appropriate alkyl halide. For example, N,N,N-trimethyl-mexiletine chloride is synthesized by treatment of mexiletine (commercially available from e.g. Sigma-Aldrich) with methyl chloride. Similarly N,N,N-trimethyl-mexiletine iodide is synthesized by treatment of mexiletine (commercially available from e.g. Sigma-Aldrich) with 3o methyl iodide. Quaternary propranolol such as N,N-dimethyl-propranolol chloride and N,N-dimethyl-propranolol iodide can be similarly prepared from propranolol (commercially available from e.g. Sigma-Aldrich) and methyl chloride or methyl iodide respectively.
Conditions for these preparations and other closely related analogs were described in e.g.
U.S. 4,048,335. In an SUBSTITUTE SHEET (RULE 26) analogous approach, quaternary pindolol can be synthesized by treatment of pindolol (commercially available from e.g. Sigma-Aldrich) with the appropriate alkyl halide. N,N-dimethyl-pindolol chloride can thus be synthesized by reaction of pindolol with methyl chloride.
Alternatively, the compounds of the present invention may be prepared by analogy with other known synthetic methodology such as reaction of a halide (e.g. chlorine) derivative of formula (VIII) with an appropriate tertiary amine in a solvent such as methanol in the presence of a catalyst (e.g., potassium iodide) to form the corresponding quaternary ammonium product.
The chlorinated substrate can react as well with a secondary or primary amine to provide the 1 o respective tertiary or secondary amine, which is then further reacted with a halide derivative to form eventually a quaternary ammonium product.
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 forms. Applicants intend to include all the various stereoisomers within the scope of the 2o 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 of the anion of the initial salt.
3o 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 SUBSTITUTE SHEET (RULE 26) 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 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 1o 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 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.
2o Inert Garners 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 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 carrier, 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 Garner.
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 3o 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 injection or infusion techniques. Pharmaceutical composition of the invention are SUBSTITUTE SHEET (RULE 26) formulated so as to allow the active ingredients contained therein to 1~-bioavailable upyln 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.
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 1 o 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 Garners. The carriers) may be particulate, so 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 Garner(s) may be gaseous, so as to provide an aerosol composition useful in, e.g., 2o 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 Garners. In addition, one or more of the following adjuvants may be present:
binders such as 3o 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 SUBSTITUTE SHEET (RULE 26) lactose, mannitols, starch, calcium phosphate, sorbitol, methylcellulose; and mixtures tlfereof;
lubricants 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 t o 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 delivery by injection, 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 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;
3o buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as 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.

SUBSTITUTE SHEET (RULE 26) 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 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.
Low-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 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.

SUBSTITUTE SHEET (RULE 26) 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.
1o 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.
2o Suitable pharmaceutically acceptable salts include acid addition salts of acids such as hydrochloric, hydrobromic, benzenesulfonic (besylate), benzoic, camphorsulfonic, 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 3o 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 invention for the treatment or prevention of cough is from about 0.1 to about 800 mg in single or repeated doses.

SUBSTITUTE SHEET (RULE 26) 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.
1 o The compounds of the present invention can include pharmaceutically acceptable carriers and other conventional additives, including aqueous based Garners, 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, Garners, and/or propellants may be included in the formulations for use in appropriate devices. These are prepared by procedures well known to those skilled in the art (see e.g.
Medication Teaching Manual, 5th Ed., Bethesda, MD, American Society of Hospital Pharmacists, 1991 ).
2o 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.
The following examples are offered by way of illustration and not by way of limitation.

SUBSTITUTE SHEET (RULE 26) L V A l~ilDT L' 1 Synthesis of 1-(2.6-Dimethyl phenoxv)-N.N,N-trimethylpropan-2-aminium iodide (N,N.N-trimethyl-mexiletine iodide) Mexiletine hydrochloride (1.03 g, 4.76 mmol) was pardoned between dichloromethane (20 mL) and saturated aqueous NaHC03 (5 mL). The aqueous layer was collected and extracted with dichloromethane (2 x 5 mL). The organic layers were combined and dried over anhydrous Na2S04. To the filtrate was added methyl iodide (2.1 mL, 34.3 mmol) and Na2C03 (1.61 g, 15.2 mmol). The reaction mixture was stirred at room temperature for 162 hours, filtered, and the filtrate was concentrated in vacuo to give a brown solid. Recrystallization from a mixture of ethanol and ether ( 1:4, v/v, 25 mL) gave the product as yellow crystals ( 1.28 g, 77% yield). 13C
NMR (75 MHz, DMSO-db) b 12.1 (CH3), 16.4 (CH;), 51.4 (CH3), 68.9 (CH), 69.3 (CHZ), 124.4 (CH), 129.0 (CH), 130.3 (C), 154.6 (C).

Synthesis of 2-Hvdroxy-N isopropyl-N.N dimethvl-3-(1-naphthyloxy)propan-1-aminium iodide ~N,N-dimethvl-propranolol iodide) Propanolol hydrochloride (2.81 g, 9.49 mmol) was dissolved in H20 ( 15 mL), saturated 2o aqueous NaHC03 (45 mL), and extracted with dichloromethane (3 x 60 mL). The organic layers were combined, dried over anhydrous Na2S04, and concentrated in vacuo to 50 mL. To the residual solution was added methyl iodide (2.8 mL, 45.1 mmol) and KZC03 (4.1 g, 29.7 mmol). The reaction mixture was stirred for 63 hours at room temperature and then refluxed for 67 hours. The solvent was then concentrated in vacuo to give a white solid which was dissolved in H20 (220 mL). The solution was extracted with ether (3 x 220 mL) and again with dichloromethane (3 x 220 mL). The combined dichloromethane extracts were dried over anhydrous Na2S04 and the solvent removed in vacuo to give the crude product.
Recrystallization from a mixture of ethanol and ether (3:2, v/v, 25mL) provided the product as yellow crystals (1.2 g, 30% yield). 13C NMR (75MHz, CDC13 ) 8 16.8 (CH3), 16.9 (CH3), 49.3 (CH3), 49.8 (CH3), 65.7 (CH), 65.8 (CH2), 68.2 (CH), 71.6 (CHZ), 106.3 (CH), 121.9 (CH), 122.8 (CH), 126.4 (CH), 126.6 (CH), 126.9 (CH), 127.5 (CH), 128.5(CH), 135.9 (C), 155.2 (C).

SUBSTITUTE SHEET (RULE 26) Synthesis of 2-Hydroxv-3-(1H-indol-4=yloxy)-N-isoprowl-N.N-dimeth~propan-1-aminium iodide (N,N-dimethvl-pindolol iodide) To a solution of pindolol (0.280 g, 1.13 mmol) in THF (60 mL) was added methyl iodide (0.71 mL, 11.32 mmol). The resultant solution was stirred for 6 hours then refluxed for 40 hours. The precipitate was collected and washed with THF (5 x 5 mL) to give the title compound (0.10 g). The filtrate was then concentrated in vacuo to 30 ml, methyl iodide (0.50 1 o mL, 8.03 mmol) was added, and the mixture was refluxed for 16 hours. The resultant precipitate was collected and washed with THF (3 x 5 ml) to yield a second crop (0.02 g) (29% overall yield). 13C NMR (75MHz, DMSO ) 8 15.9 (CH3), 16.1 (CH3), 48.0 (CH3), 48.3 (CH3), 63.8 (CH), 64.2 (CH2), 65.5 (CH), 69.8 (CHI), 98.4 (CH), 100.0 (CH), 105.3 (CH), 118.2 (C), 121.6 (CH), 123.6 (CH), 137.2 (C), 151.3 (C).

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 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.
3o 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 SUBSTITUTE SHEET (RULE 26) differential pressure transducer (Grass model PTS) is attached to the outflow from the exposure 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 (PolyNe-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 (1M) for 1 o minutes. Animals are continuously monitored by trained observer, and the number of coughs are counted during a 1 ~ minute period from commencement of the citric acid aerosol administration. 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 irntant 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.
2o Each cough 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 3o 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 SUBSTITUTE SHEET (RULE 26) water, 0.9% sterile saline, Tween or 1 to 25% ethanol depending on the solubility of the compound), reference compound (e.g. mexiletine, propranolol or pindolol) 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.
In one set of experiments using the general protocol described above, the antitussive activity of N,N-dimethyl-propranolol iodide was tested. Results showed that pre-treatment of guinea pigs with aerosols of N,N-dimethyl-propranolol iodide at 10.0 mg/ml immediately before exposure to citric acid (1M) inhibited cough responses by 50-70%
compared with vehicle (saline) pre-treated guinea pigs over the 15 minute observation period.
Similarly, other quaternary ammonium compounds of the present invention can be evaluated by this method.

In another experiment similar to that described above in Example 4, the duration of the antitussive effects of the compounds of the present invention against citric acid-induced cough responses can be investigated in conscious guinea pigs. 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 4.
3 o EXAMPLE 6 The antitussive effects of a 5 minute pre-treatment with aerosolized compounds of the present invention and reference compound (e.g. mexiletine, propranolol or pindolol) on SUBSTITUTE SHEET (RULE 26) capsaicin aerosol-induced cough can be investigated in conscious guinea-pigs using a m,~thod similar to that described in Example 4. Data and results are analyzed as described in Example 4.
Ti'Y A MpT ~' '7 Therapeutic treatment with the compounds of the present invention can also be determined by a similar method as described in Example 4. The antitussive effects of compounds of the present invention and reference compound (e.g. mexiletine, propranolol or pindolol) 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 1 o 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 4.

Investigation of antitussive activity of aerosolized test compound on citric acid-induced cough responses in conscious rabbits Protocol 2o 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.

SUBSTITUTE SHEET (RULE 26) All rabbits are exposed to ozone before vehicle or test drug pre-treatment.
Data and results are analyzed as described in Example 4.
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.
1o 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 an admission that such references are prior art to the present invention.

SUBSTITUTE SHEET (RULE 26)

Claims

What is claimed is:

1. A method for the treatment and/or prevention of cough in a warm-blooded animal comprising 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:
Y~J~E An- (I) wherein J is independently selected from a group represented by one of the following formulae (II), (III) and (IV):
such that when J is represented by formulae (II), (III) or (IV), compounds of the present invention are represented by the following formulae (V), (VI) or (VII) respectively:
wherein n is an integer of from 0 to 4; R, R1 and E are independently selected from -CH2-R16 and a group represented by the following formula (VIII):
wherein X is O (oxygen) or S (sulfur); R2, R3, R4, R5, R16, R17 and R18 are independently selected from hydrogen. hydroxy, C1-C8 alkoxy, C1-C8 alkyl. C2-C8 alkoxyalkyl, C1-C8 hydroxyalkyl and C7-C12 aralkyl; p is an integer of from 0 to 8, q is an integer of from 0 to 8 and r is an integer of from 0 to 8; A is selected from C5-C12 alkyl, a C3-C13 carbocyclic ring, and ring systems selected from formulae (IX), (X), (XI), (XII), (XIII), (XIV), (XV) and (XVI):
where R6, R7, R8, R9, R10, R11, and R12 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7 alkanoyloxy, C1-C6 alkyl, C1-C6 alkoxy, C2-C7 alkoxycarbonyl, C1-C6 thioalkyl, aryl and N(R13,R14) where R13 and R14 are independently selected from hydrogen, acetyl, methanesulfonyl and C1-C6 alkyl, and Z is selected from CH, CH2, O, S, NH and N-R15 where Z may be directly bonded to X when Z is CH; and R15 is selected from hydrogen, C1-C6 alkyl, C3-C8 cyclocalkyl, aryl and benzyl;
Y is independently selected from hydrogen, -CH2-R16 and a group represented by the following formula (VIII):

wherein X is O (oxygen) or S (sulfur); R2, R3, R4, R5, R16, R17 and R18 are independently selected from hydrogen, hydroxy, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkoxyalkyl, C1-C8 hydroxyalkyl and C7-C12 aralkyl;
p is an integer of from 0 to 8, q is an integer of from 0 to 8 and r is an integer of from 0 to 8; A is selected from C5-C12 alkyl, a C3-C13 carbocyclic ring, and ring systems selected from formulae (IX), (X), (XI), (XII), (XIII), (XIV), (XV) and (XVI):
where R6, R7, R8, R9, R10, R11 and R12 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7 alkanoyloxy, C1-C6 alkyl, C1-C6 alkoxy, C2-C7 alkoxycarbonyl, C1-C6 thioalkyl, aryl and N(R13,R14) where R13 and R14 are independently selected from hydrogen, acetyl, methanesulfonyl and C1-C6 alkyl, and Z is selected from CH, CH2, O, S.
NH and N-R15 where Z may be directly bonded to X when Z is CH, and R15 is selected from hydrogen, C1-C6 alkyl, C3-C8 cyclocalkyl, aryl and benzyl; when J is represented by formula (VII), Y is a group on any one of the carbon atoms of the nitrogen heterocyclic ring of formula (VII); 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 J is represented by formula (II) then Y is represented by formula (VIII); (b) when J is represented by formula (III) then Y is represented by formula (VIII); (c) when J is represented by formula (IV) and Y is not represented by formula (VIII), R1 and E
cannot both be -CH2-R16 and (d) p, q and r cannot all be 0.
2. The method of claim 1 wherein J is represented by formula (II).
3. The method of claim 1 wherein J is represented by formula (III).
4. The method of claim 1 wherein J is represented by formula (IV).
5. A method according to any one of claims 1-4 wherein A is selected from formulae (IX), (X), (XI), (XII), (XIII), (XIV), (XV) and (XVI).
6. The method of claim 5 wherein A is selected from formulae (IX), (X), (XI) and (XII).
7. A method according to any one of claims 1-6 wherein X is O (oxygen).
8. A method for the treatment and/or prevention of cough in a warm-blooded animal comprising 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, solvate, stereoisomer, stereoisomeric mixture, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof:
wherein R and R1 are each -CH2-R16; R2, R3, R4, R5, R16, R17 and R18 are independently selected from hydrogen, hydroxy, C1-C8 alkyl, C1-C8 hydroxyalkyl and C7-C12 aralkyl; p is an integer of from 0 to 3, q is an integer of from 0 to 3 and r is an integer of from 0 to 3; X is O (oxygen); A is selected from formulae (IX), (X), (XI), (XII), (XIII), (XIV), (XV) and (XVI) as described in claim 1; and An- is the anion from a pharmaceutically acceptable salt; with the proviso that p, q and r cannot all be 0.
9. A method for the treatment and/or prevention of cough in a warm-blooded animal comprising 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, solvate, stereoisomer, stereoisomeric mixture, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof:
wherein R, R1 and E are each -CH2-R16; R2, R3, R4, R5, R16, R17 and R18 are independently selected from hydrogen, hydroxy, C1-C8 alkyl, C1-C8 hydroxyalkyl and C7-C12 aralkyl; p is an integer of from 0 to 3, q is an integer of from 0 to 3 and r is an integer of from 0 to 3; X is O
(oxygen); A is selected from formulae (IX), (X), (XI), (XII), (XIII), (XIV), (XV) and (XVI) as described in claim 1; and An- is the anion from a pharmaceutically acceptable salt; with the proviso that p, q and r cannot all be 0.
10. A method according to any one of claims 1-9 wherein An- is a chloride anion.

11. A method for the treatment and/or prevention of cough in a warm-blooded animal comprising administering to a warm-blooded animal in need thereof, a therapeutically effective amount of a compound which is N,N,N-trimethyl-mexiletine chloride or a pharmaceutically acceptable complex, chelate, solvate, stereoisomer, stereoisomeric mixture, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof.

12. A method for the treatment and/or prevention of cough in a warm-blooded animal comprising administering to a warm-blooded animal in need thereof, a therapeutically effective amount of a compound which is N,N-dimethyl-propranolol chloride or a pharmaceutically acceptable complex, chelate, solvate, stereoisomer, stereoisomeric mixture, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof.

13. A method for the treatment and/or prevention of cough in a warm-blooded animal comprising administering to a warm-blooded animal in need thereof, a therapeutically effective amount of a compound which is N,N-dimethyl-pindolol chloride or a pharmaceutically acceptable complex, chelate, solvate, stereoisomer, stereoisomeric mixture, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof.

14. The use of a compound of formula (I) as defined in claim 1 as active ingredient in the manufacture of a medicament for use in the treatment and/or prevention of cough in a warm-blooded animal.

15. The use of a compound of formula (I) wherein J is represented by formula (II) as defined in claim 2, as active ingredient in the manufacture of a medicament for use in the treatment and/or prevention of cough in a warm-blooded animal.

16. The use of a compound of formula (I) wherein J is represented by formula (III) as defined in claim 3, as active ingredient in the manufacture of a medicament for use in the treatment and/or prevention of cough in a warm-blooded animal.

17. The use of a compound of formula (I) wherein J is represented by formula (IV) as defined in claim 4, as active ingredient in the manufacture of a medicament for use in the treatment and/or prevention of cough in a warm-blooded animal.

18. The use of a compound having the following formula, or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, crystalline or amorphous form, metabolite. metabolic precursor or prodrug thereof:
wherein R and R1 are each -CH2-R16; R2, R3, R4, R5, R16, R17 and R18 are independently selected from hydrogen, hydroxy, C1-C8 alkyl, C1-C8 hydroxyalkyl and C7-C12 aralkyl; p is an integer of from 0 to 3, q is an integer of from 0 to 3 and r is an integer of from 0 to 3; X is O (oxygen); A is selected from formulae (IX), (X), (XI), (XII), (XIII), (XIV), (XV) and (XVI) as described in claim 1; and An- is the anion from a pharmaceutically acceptable salt; with the proviso that p, q and r cannot all be 0, as active ingredient in the manufacture of a medicament for use in the treatment and/or prevention of cough in a warm-blooded animal.
19. The use of a compound having the following formula, or a pharmaceutically acceptable salt, ester, amide, 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:
wherein R, R1 and E are each -CH2-R16; R2, R3, R4, R5, R16, R17 and R18 are independently selected from hydrogen, hydroxy, C1-C8 alkyl, C1-C8 hydroxyalkyl and C7-C12 aralkyl; p is an integer of from 0 to 3, q is an integer of from 0 to 3 and r is an integer of from 0 to 3; X is O
(oxygen); A is selected from formulae (IX), (X), (XI), (XII), (XIII), (XIV), (XV) and (XVI) as described in claim 1; and An- is the anion from a pharmaceutically acceptable salt; with the proviso that p, q and r cannot all be 0.
20. The use of a compound which is N,N,N-trimethyl-mexiletine 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.
21. The use of a compound which is N,N-dimethyl-propranolol 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.
22. The use of a compound which is N,N-dimethyl-pindolol 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.
23. A compound of the following 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:
Y~J~E An- (I) wherein J is independently selected from a group represented by one of the following formulae (II), (III) and (IV):
such that when J is represented by formulae (II), (III) or (IV), compounds of the present invention are represented by the following formulae (V), (VI) or (VII) respectively:
wherein n is an integer of from 0 to 4; R, R1 and E are independently selected from-CH2-R16 and a group represented by the following formula (VIII):
wherein X is O (oxygen) or S (sulfur); R2, R3, R4, R5, R16, R17 and R18 are independently selected from hydrogen, hydroxy, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkoxyalkyl, C1-C8 hydroxyalkyl and C7-C12 aralkyl; p is an integer of from 0 to 8, q is an integer of from 0 to 8 and r is an integer of from 0 to 8; A is selected from C5-C12 alkyl, a C3-C13 carbocyclic ring, and ring systems selected from formulae (IX), (X), (XI), (XII), (XIII), (XIV), (XV) and (XVI):
where R6, R7, R8, R9, R10, R11 and R12 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7 alkanoyloxy, C1-C6 alkyl, C1-C6 alkoxy, C2-C7 alkoxycarbonyl, C1-C6 thioalkyl, aryl and N(R13,R14) where R13 and R14 are independently selected from hydrogen, acetyl, methanesulfonyl and C1-C6 alkyl, and Z is selected from CH, CH2, O, S, NH and N-R15 where Z may be directly bonded to X when Z is CH; and R15 is selected from hydrogen, C1-C6 alkyl, C3-C8 cyclocalkyl, aryl and benzyl;
Y is independently selected from hydrogen, -CH2-R16 and a group represented by the following formula (VIII):
wherein X is O (oxygen) or S (sulfur); R2, R3, R4, R5, R16, R17 and R18 are independently selected from hydrogen, hydroxy, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkoxyalkyl, C1-C8 hydroxyalkyl and C7-C12 aralkyl; p is an integer of from 0 to 8, q is an integer of from 0 to 8 and r is an integer of from 0 to 8; A is selected from C5-C12 alkyl, a C3-C13 carbocyclic ring, and ring systems selected from formulae (IX), (X), (XI), (XII), (XIII), (XIV), (XV) and (XVI):

where R6, R7, R8, R9, R10, R11 and R12 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7 alkanoyloxy, C1-C6 alkyl, C1-C6 alkoxy, C2-C7 alkoxycarbonyl, C1-C6 thioalkyl, aryl and N(R13,R14) where R13 and R14 are independently selected from hydrogen, acetyl, methanesulfonyl and C1-C6 alkyl, and Z is selected from CH, CH2, O, S, NH and N-R15 where Z may be directly bonded to X when Z is CH, and R15 is selected from hydrogen, C1-C6 alkyl, C3-C8 cyclocalkyl, aryl and benzyl; when J is represented by formula (VII), Y is a group on any one of the carbon atoms of the nitrogen heterocyclic ring of formula (VII); 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 J is represented by formula (II) then Y and E
are both represented by formula (VIII); (b) when J is represented by formula (III) then Y is represented by formula (VIII); (c) when J is represented by formula (IV) and Y is not represented by formula (VIII), R1 and E cannot both be -CH2-R16 and (d) p, q and r cannot all be 0.
24. The compound of claim 23 wherein J is represented by formula (II).

25. The compound of claim 23 wherein J is represented by formula (III).
26. The compound of claim 23 wherein J is represented by formula (IV).
27. The compound of claims 25 and 26 wherein n is 1 or 2.
28. A compound according to any one of claims 23-27 wherein A is selected from formulae (IX), (X), (XI), (XII), (XIII), (XIV), (XV) and (XVI).
29. The compound of claim 28 wherein A is selected from formulae (IX), (X), (XI) and (XII).
30. A compound according to any one of claims 23-29 wherein X is O (oxygen).
31. A pharmaceutical composition for the treatment and/or prevention of cough, comprising an effective amount of a compound of claim 23 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.
32. A pharmaceutical composition for the treatment and/or prevention of cough, comprising an effective amount of a compound of claim 24 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.
33. A pharmaceutical composition for the treatment and/or prevention of cough, comprising an effective amount of a compound of claim 25 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.

34. A pharmaceutical composition for the treatment and/or prevention of cough, comprising an effective amount of a compound of claim 26 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.
35. A pharmaceutical composition for the treatment and/or prevention of cough, comprising an effective amount of a compound of claim 30 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.
36. The use of a compound of the following 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, as active ingredient in the manufacture of a medicament:
Y-J-E An (I) wherein J is independently selected from a group represented by one of the following formulae (II), (III) and (IV):
such that when J is represented by formulae (II), (III) or (IV), compounds of the present invention are represented by the following formulae (V), (VI) or (VII) respectively:

wherein n is an integer of from 0 to 4; R, R, R1 and E are independently selected from -CH2-R16 and a group represented by the following formula (VIII):

wherein X is O (oxygen) or S (sulfur); R2, R3, R4, R5, R16, R17 and R18 are independently selected from hydrogen, hydroxy, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkoxyalkyl, C1-C8 hydroxyalkyl and C7-C12 aralkyl; p is an integer of from 0 to 8, q is an integer of from 0 to 8 and r is an integer of from 0 to 8; A is selected from C5-C12 alkyl, a C3-C13 carbocyclic ring, and ring systems selected from formulae (IX), (X), (XI), (XII), (XIII), (XIV), (XV) and (XVI):

where R6, R7, R8, R9, R10, R11, and R12 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7 alkanoyloxy, C1-C6 alkyl, C1-C6 alkoxy, C2-C7 alkoxycarbonyl, C1-C6 thioalkyl, aryl and N(R13,R14) where R13 and R14 are independently selected from hydrogen, acetyl, methanesulfonyl and C1-C6 alkyl, and Z is selected from CH, CH2, O, S, NH and N-R15 where Z may be directly bonded to X when Z is CH; and R15 is selected from hydrogen, C1-C6 alkyl, C3-C8 cyclocalkyl, aryl and benzyl;

Y is independently selected from hydrogen, -CH2-R16 and a group represented by the following formula (VIII):

wherein X is O (oxygen) or S (sulfur); R2, R3, R4, R5, R16, R17 and R18 are independently selected from hydrogen, hydroxy, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkoxyalkyl, C1-C8 hydroxyalkyl and C7-C12 aralkyl; p is an integer of from 0 to 8, q is an integer of from 0 to 8 and r is an integer of from 0 to 8; A is selected from C5-C12 alkyl, a C3-C13 carbocyclic ring, and ring systems selected from formulae (IX), (X), (XI), (XII), (XIII), (XIV), (XV) and (XVI):

where R6, R7, R8, R9, R10, R11 and R12 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7 alkanoyloxy, C1-C6 alkyl, C1-C6 alkoxy, C2-C7 alkoxycarbonyl, C1-C6 thioalkyl, aryl and N(R13,R14) where R13 and R14 are independently selected from hydrogen, acetyl, methanesulfonyl and C1-C6 alkyl, and Z is selected from CH, CH2, O, S, NH and N-R15 where Z may be directly bonded to X when Z is CH, and R15 is selected from hydrogen, C1-C6 alkyl, C3-C8 cyclocalkyl, aryl and benzyl; when J is represented by formula (VII), Y is a group on any one of the carbon atoms of the nitrogen heterocyclic ring of formula (VII);
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 J is represented by formula (II) then Y and E are both represented by formula (VIII); (b) when J is represented by formula (III) then Y is represented by formula (VIII); (c) when J is represented by formula (IV) and Y is not represented by formula (VIII), R1 and E cannot both be -CH2-R16 and (d) p, q and r cannot all be 0.

37. The use of the compound according to claim 36, wherein J is represented by formula (II).

38. The use of the compound according to claim 36 wherein J is represented by formula (III).

39. The use of the compound according to claim 36 wherein J is represented by formula (IV).

40. The use of the compound according to claim 38 or 39 wherein n is 1 or 2.

41. The use of the compound according to any one of claims 36 through 40 wherein A is selected from formulae (IX), (X), (XI), (XII), (XIII), (XIV), (XV) and (XVI).

41. The use of the compound according to claim 41 wherein A is selected from formulae (IX), (X), (XI) and (XII).

42. The use of the compound according to any one of claims 36 through 42 wherein X is O (oxygen).

43. A pharmaceutical composition, comprising an effective amount of a compound of claim 36 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.

44. A pharmaceutical composition, comprising an effective amount of a compound of claim 37 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.

45. A pharmaceutical composition, comprising an effective amount of a compound of claim 38 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.

46. A pharmaceutical composition, comprising an effective amount of a compound of claim 39 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.

47. A pharmaceutical composition, comprising an effective amount of a compound of claim 43 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.

48. The use of a compound of formula (I) as defined in claim 1 to treat and/or prevent a cough in a warm-blooded animal.

49. The use of a compound of formula (I) wherein J is represented by formula (II) as defined in claim 2, to treat and/or prevent a cough in a warm-blooded animal.

50. The use of a compound of formula (I) wherein J is represented by formula (III) as defined in claim 3, to treat and/or prevent a cough in a warm-blooded animal.

51. The use of a compound of formula (I) wherein J is represented by formula (IV) as defined in claim 4, to treat and/or prevent a cough in a warm-blooded animal.

53. The use of a compound having the following formula, or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof:

wherein R and R1 are each -CH2-R16; R2, R3, R4, R5, R16, R17 and R18 are independently selected from hydrogen, hydroxy, C1-C8 alkyl, C1-C8 hydroxyalkyl and C7-C12 aralkyl; p is an integer of from 0 to 3, q is an integer of from 0 to 3 and r is an integer of from 0 to 3; X is O (oxygen); A is selected from formulae (IX), (X), (XI), (XII), (XIII), (XIV), (XV) and (XVI) as described in claim 1; and An- is the anion from a pharmaceutically acceptable salt; with the proviso that p, q and r cannot all be 0, to treat and/or prevent a cough in a warm-blooded animal.

54. The use of a compound having the following formula, or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, to treat and/or prevent a cough in a warm-blooded animal:

wherein R, R1 and E are each -CH2-R1b; R2, R3, R4, R5, R16, R17 and R18 are independently selected from hydrogen, hydroxy, C1-C8 alkyl, C1-C8 hydroxyalkyl and C7-C12 aralkyl; p is an integer of from 0 to 3, q is an integer of from 0 to 3 and r is an integer of from 0 to 3; X is O
(oxygen); A is selected from formulae (IX), (X), (XI), (XII), (XIII), (XIV), (XV) and (XVI) as described in claim 1; and An- is the anion from a pharmaceutically acceptable salt; with the proviso that p, q and r cannot all be 0.

55. The use of a compound which is N,N,N-trimethyl-mexiletine chloride or a pharmaceutically acceptable complex, chelate, solvate, stereoisomer, stereoisomeric mixture, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, to treat and/or prevent a cough in a warm-blooded animal.

56. The use of a compound which is N,N-dimethyl-propranolol chloride or a pharmaceutically acceptable complex, chelate, solvate, stereoisomer, stereoisomeric mixture, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, to treat and/or prevent a cough in a warm-blooded animal.

57. The use of a compound which is N,N-dimethyl-pindolol chloride or a pharmaceutically acceptable complex, chelate, solvate, stereoisomer, stereoisomeric mixture, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, to treat and/or prevent a cough in a warm-blooded animal.