Cyclic quaternary ammonium compounds

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:

• 21
• wherein n is 2;
• R1 and E are each —CH2—R16, where R16 is independently selected from hydrogen, hydroxy, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkoxyalkyl, C1-C8 hydroxyalkyl and C7-C12 aralkyl;
• and An− is the acid addition salt of a pharmaceutically acceptable acid or the anion from a pharmaceutically acceptable salt.

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:

• 22
• wherein n is 2;
• R1 and E are each —CH2—R16, where R16 is independently selected from hydrogen, hydroxy, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkoxyalkyl, C1-C8 hydroxyalkyl and C7-C12 aralkyl;
• and An− is the acid addition salt of a pharmaceutically acceptable acid or the anion from a pharmaceutically acceptable salt.

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:

• 23
• wherein n is an integer of from 0 to 4;
• R1 and E are independently selected from —CH2—R16 and a group represented by the following formula (II):
• 24
• wherein R2, R3, R4, R5, R6 and R16 are independently selected from hydrogen, hydroxy, C1-C8 alkoxy, C1-C8 alkoxyalkyl, C1-C8 hydroxyalkyl and C7-C12 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-C12 alkyl, a C3-C13 carbocyclic ring, and ring systems selected from formulae (III), (IV), (V), (VI), (VII), (VIII), (IX) and (X):
• 25
• where 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, 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, R15 is selected from hydrogen, C1-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, —CH2—R16 and a group represented by the following formula (II):
• 26
• wherein R2, R3, R4, R5, R6 and R16 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 and q 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 (III), (IV), (V), (VI), (VII), (VIII), (IX) and (X):
• 27
• where 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, 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, R15 is selected from hydrogen, C1-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;
• 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 R1 and E cannot both be —CH2—R16;
• and (b) when n is 0, 1 or 2, and p is 0 or 1, and q is 0 or 1 then A is selected from formulae (VI), (VII), (VIII) and (IX).

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, for the treatment and/or prevention of cough in a warm-blooded animal:

• 28
• wherein n is 2;
• R1 and E are each —CH2—R16, where R16 is independently selected from hydrogen, hydroxy, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkoxyalkyl, C1-C8 hydroxyalkyl and C7-C12 aralkyl;
• and An− is the acid addition salt of a pharmaceutically acceptable acid or the anion from a pharmaceutically acceptable salt.