Quinuclidine derivatives and their use as muscarinic M3 receptor ligands

1. A compound according to formula (I)

wherein:

© is a phenyl ring, a C 4 to C 9 heteroaromatic group containing one or more heteroatoms or a naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl or biphenyl group;

R 1 , R 2 and R 3 each independently represent a hydrogen atom or halogen atom, or a hydroxy group, or a phenyl, —OR 4 , —SR 4 , —NR 4 R 5 , —NHCOR 4 , —CONR 4 R 5 , —CN, —NO 2 , —COOR 4 or —CF 3 group, or a straight or branched lower C 1 to C 4 alkyl group which may optionally be substituted, for example, with a hydroxy or alkoxy group, wherein R 4 and R 5 each independently represent a hydrogen atom, straight or branched lower C 1 to C 4 alkyl group or together form an alicyclic ring; or R 1 and R 2 together form an aromatic, alicyclic or heterocyclic ring,

n is an integer from 0 to 4;

A represents a —CH 2 —, —CH═CR 6 —, —CR 6 ═CH—, —CR 6 R 7 —, —CO—, —O—, —S—, —S(O)—, SO 2 or —NR 6 — group, wherein R 6 and R 7 each independently represent a hydrogen atom, straight or branched lower C 1 to C 4 alkyl group or R 6 and R 7 together form an alicyclic ring;

m is an integer from 0 to 8; provided that when m=0, A is not —CH 2 —;

p is an integer from 1 to 2 and the substitution in the azoniabicyclic ring may be in the 2, 3 or 4 position including all possible configurations of the asymmetric carbons;

B represents a group of formula i):

 wherein R 10 represents a hydrogen atom, a hydroxy or methyl group; and R 8 and R 9 each independently represent

 wherein R 11 represents a hydrogen or halogen atom or a straight or branched lower C 1 to C 4 alkyl group; and

X X − represents a pharmaceutically acceptable anion of a mono or polyvalent acid.

2. A compound according to claim 1 , wherein any alkyl group present as R 1 to R 7 or R 11 contains from 1 to 4 carbon atoms.

3. A compound according to claim 1 wherein p=2.

4. A compound according to claim 1 wherein © represents a phenyl, pyrrolyl, thienyl, furyl, biphenyl, naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl, benzo[1,3]dioxolyl, imidazolyl or benzothiazolyl group.

5. A compound according to claim 4 , wherein © represents a phenyl, pyrrolyl or thienyl group.

6. A compound according to claim 1 wherein R 1 , R 2 and R 3 each independently represent a hydrogen or halogen atom or a hydroxy, methyl, tert-butyl, —CH 2 OH, 3-hydroxypropyl, —OMe, —NMe 2 , —NHCOMe, —CONH 2 , —CN, —NO2 —NO 2 , —COOMe or —CF 3 group.

7. A compound according to claim 6 wherein R 1 , R 2 and R 3 each independently represent a hydrogen or halogen atom or a hydroxy group.

8. A compound according to claim 7 , wherein the halogen atom is fluorine.

9. A compound according to claim 1 wherein A represents a —CH 2 —, —CH═CH—, —CO—, —NH—, —NMe—, —O— or —S— group; n is 0 or 1; and m is an integer from 1 to 6.

10. A compound according to claim 9 , wherein A represents a —CH 2 —, 13 CH═CH— or —O— group and m is 1, 2 or 3.

11. A compound according to claim 1 wherein the azoniabicyclo group is substituted on the nitrogen atom with a 3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 3-(2-hydroxyphenoxy)propyl, 3-(4-fluorophenoxy)propyl, 2-benzyloxyethyl, 3-pyrrol-1-ylpropyl, 2-thien-2-ylethyl or 3-thien-2-ylpropyl group.

12. A compound according to claim 1 wherein B represents a group of formula (i) and R 8 and R 9 each independently represent a phenyl, 2-thienyl, 3-thienyl, 2-furyl, or 3-furyl group and R 11 represents a hydrogen atom.

13. A compound according to claim 1 wherein X X − represents a bromide, chloride or trifluoroacetate anion.

14. A compound according to claim 1 wherein the azoniabicyclo group is substituted in the 3-position.

15. A compound according to claim 14 , wherein the substituent in the 3 position has (R) configuration.

16. A compound according to claim 15 , wherein R 8 is different from R 9 in group i), and the asymmetric carbon to which R 8 and R 9 are bonded has the (R) configuration.

17. A compound according to claim 15 , wherein R 8 is different from R 9 in group i), and the asymmetric carbon to which R 8 and R 9 are bonded has the (S) configuration.

18. A compound according to claim 1 which is a single stereoisomer.

19. A compound according to claim 1 which is

3(R)-Diphenylacetoxy-1-(3-phenoxy-propyl)-1azoniabicyclo[2.2.2]octane; bromide,

3(R)-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; bromide,

3(R)-(2,2-Diphenylpropionyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; bromide,

3(R)-(2-Hydroxy-2-phenyl-2-thien-2-yl-acetoxy)-1-(3-phenoxypropyl)-1-azonia-bicyclo [2.2.2]octane; bromide,

3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(3-phenylallyl)-1-azoniabicyclo [2.2.2]octane; bromide,

3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(2-phenoxyethyl)-1-azoniabicyclo [2.2.2]octane; bromide,

3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo [2.2.2]octane; bromide,

3(R)-(2,2-Dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; bromide,

3(R)-(2-Hydroxy-2,2-di-thien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane; bromide 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane; bromide,

3(R)-(2-Hydroxy-2,2-di-thien-2-ylacetoxy)-1-(4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane; bromide 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane; bromide,

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azonia-bicyclo[2.2.2]octane; bromide,

1-[3-(4-Fluorophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo [2.2.2]octane; chloride,

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(2-hydroxyphenoxy)propyl]-1-azoniabicyclo [2.2.2]octane; Trifluoroacetate,

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-pyrrol-1-ylpropyl)-1-azonia-bicyclo[2.2.2]octane; trifluoroacetate,

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(2-thien-2-ylethyl)-1-azoniabicyclo[2.2.2]octane; bromide,

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane; bromide,

1-(2-Benzyloxyethyl)-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane; trifluoroacetate, or

3(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; bromide.

20. A compound according to claim 1 characterised in that it has an IC 50 value for muscarinic M 3 receptors (Hm3) of less than 35 nM.

21. A process for the preparation of a compound of formula (I)

which comprises reacting an alkylating agent of formula (II)

with a compound of formula (III)

wherein, in each of formulae I, II and III, R 1 , R 2 R 3 , ©, A, X, B, n, m and p are as defined in any one of claims 1 to 12 or 13 to 19 .

22. A process according to claim 21 characterised in that the resulting reaction mixture is purified by solid phase extraction.

23. A pharmaceutical composition comprising a compound according to claim 1 in admixture with a pharmaceutically acceptable carrier or diluent.

24. A method for treating respiratory, urinary and/or gastrointestinal disease which method comprises administering to a human or animal patient in need of such treatment an effective amount of a compound according to any one of claims claim 1 to 12 , 13 to 20 or of a pharmaceutical composition according to claim 23 .

25. A method for treating COPD, chronic bronchitis, asthma and/or ehinitis rhinitis which method comprises administering to a human or animal patient in need of such treatment an effective amount of a compound according to any one of claims claim 1 to 12 , 13 to 20 or of a pharmaceutical composition according to claim 23 .

26. A compound chosen from

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; X −

or

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane; X − ,

wherein X − represents a pharmaceutically acceptable anion of a mono or polyvalent acid.

27. A compound chosen from

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; X −

or

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane; X − ,

wherein X − represents chloride, bromide, iodide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, or p-toluenesulfonate.

28. A compound according to claim 27, wherein X − represents chloride, bromide, iodide, sulfate, nitrate, acetate, trifluoroacetate, maleate, oxalate, or succinate.

29. A compound according to claim 27, wherein X − represents chloride, bromide, or trifluoroacetate.

30. A compound chosen from

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; bromide

or

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane; bromide.