Quinuclidine derivatives and medicinal compositions containing the same

1. A compound of formula (I):

wherein either (a) B is a phenyl, thienyl or furyl ring and p represents 2, or (b) B is a phenyl ring and p represents 1;

R 1 , R 2 and R 3 each independently represent a hydrogen or halogen atom, or a phenyl group, —OR 7 , —SR 7 , —NR 7 R 8 , —NHCOR 7 , —CONR 7 R 8 , —CN, —NO 2 , —COOR 7 or —CF 3 group, or a straight or branched, substituted or unsubstituted lower alkyl group, wherein R 7 and R 8 each independently represent a hydrogen atom, a straight or branched lower alkyl group;

n is an integer from 0 to 4;

A represents a group selected from —CH 2 —, —CH═R 9 —, —CR 9 ═CH—, —CO—, —O—, —S—, —S(O)—, —S(O) 2 — and —NR 9 —, wherein R 9 and R 10 each independently represent a hydrogen atom, a straight or branched lower alkyl group;

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

the substitution in the azoniabicyclic ring may be in the 2, 3 or 4 position including all possible configurations of the asymmetric carbons;

R 4 represents the structure:

wherein R 11 represents a hydrogen or halogen atom, a hydroxy group, an alkoxy group, a nitro group, a cyano group, —CO 2 R 12 or —NR 12 R 13 , wherein R 12 and R 13 are identical or different and are selected from hydrogen and straight or branched lower alkyl groups, or a straight or branched, substituted or unsubstituted lower alkyl group;

R 5 represents an alkyl group of 1 to 7 carbon atoms, an alkenyl group containing 2 to 7 carbon atoms, an alkynyl group containing 2 to 7 carbon atoms, a cycloalkyl group of 3 to 7 carbon atoms, or a group of formula

wherein q=1 or 2 and R 14 represents a hydrogen or halogen atom, a hydroxy group, an alkoxy group, a nitro group, a cyano group, —CO 2 R 12 or —NR 12 R 13 , wherein R 12 and R 13 are identical or different and are selected from hydrogen and straight or branched lower alkyl groups, or a straight or branched, substituted or unsubstituted lower alkyl group;

R 6 represents a hydrogen atom, a hydroxy group, a methyl group or a —CH 2 OH group; and

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

2. A compound according to claim 1 wherein R 4 represents an unsubstituted phenyl group.

3. A compound according to claim 1 , wherein R 5 represents a cyclopentyl, cyclohexyl, pentyl, allyl, vinyl, propynyl, benzyl or phenethyl group.

4. A compound according to claim 1 wherein the group —O—CO—C(R 4 )(R 5 )(R 6 ) represents a group selected from 2,3-diphenylpropionyloxy; 2-hydroxymethyl-2,3-diphenylpropionyloxy; 2-hydroxy-2,3-diphenylpropionyloxy; 2-cyclohexyl-2-hydroxy-2-phenylacetoxy and 2-cyclopentyl-2-hydroxy-2-phenylacetoxy.

5. 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, —NO 2 , —COOMe or —CF 3 group.

6. A compound according to claim 5 wherein R 1 , R 2 and R 3 each independently represent a hydrogen or halogen atom or a hydroxy group.

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

8. A compound according to claim 7 , wherein m is 1, 2 or 3 and A represents a —CH 2 —, —CH═CH—, —O— or —S— group.

9. A compound according to claim 1 , wherein the azoniabicyclo group is substituted on the nitrogen atom with a group selected from 3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, phenethyl, 3-phenylpropyl, 3-(3-hydroxyphenoxy)propyl, 3-(4-fluorophenoxy)propyl, 3-thien-2-ylpropyl, 4-oxo-4-thien-2-ylbutyl, 2-benzyloxyethyl, 3-o-tolyloxypropyl, 3-(3-cyanophenoxy)propyl, 3-(methylphenylamino)propyl, 3-phenylsulfanylpropyl, 4-oxo-4-phenylbutyl, 3-(2-chlorophenoxy)propyl, 3-(2,4-difluorophenoxy)propyl, and 3-(4-methoxyphenoxy)propyl.

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

11. A compound according to claim 1 , wherein the azoniabicyclic group is substituted in the 3-position.

12. A compound according to claim 11 , wherein the substituent at the 3-position of the azoniabicyclic group has R configuration.

13. A compound according to claim 11 , wherein the substituent at the 3-position of the azoniabicyclic group has S configuration.

14. A compound according to claim 1 , wherein the carbon substituted by R 4 , R 5 and R 6 has R configuration.

15. A compound according to claim 1 wherein the carbon substituted by R 4 , R 5 and R 6 has S configuration.

16. A compound according to claim 1 , which is present substantially as a single isomer.

17. A compound according to claim 1 which is:

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

(3R)-3-(2,3-Diphenylpropionyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane trifluoroacetate

(3R)-3-(2-Hydroxymethyl-2,3-diphenylpropionyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane trifluoroacetate

(3R)-3-(2-Hydroxymethyl-2,3-diphenylpropionyloxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane trifluoroacetate

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

(3R)-3-(2-Hydroxy-2,3-diphenylpropionyloxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane bromide

(3R)-3-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane trifluoroacetate

(3R)-3-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane trifluoroacetate

(3R)-3-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octane trifluoroacetate

(3R)-3-[(2S)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane trifluoroacetate

(3R)-3-[(2S)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane trifluoroacetate

(3R)-3-[(2S)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octane trifluoroacetate

(3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane trifluoroacetate

(3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octane trifluoroacetate

(3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenylsulfanylpropyl)-1-azoniabicyclo[2.2.2]octane trifluoroacetate

(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane trifluoroacetate

(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octane trifluoroacetate

(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenylsulfanylpropyl)-1-azoniabicyclo[2.2.2]octane trifluoroacetate

4-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane trifluoroacetate

4-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane trifluoroacetate.

18. A process for producing a compound of formula (I):

as defined in claim 1 , which process comprises quaternising the nitrogen atom of the azabicyclic ring of a compound of formula (III):

wherein R 4 , R 5 , R 6 and p are as defined in claim 1 , with an alkylating agent of formula

wherein R 1 , R 2 , R 3 , m, n, A and B are as defined in claim 1 , and W represents a leaving group.

19. A process according to claim 18 , wherein W represents a group X, wherein X represents a pharmaceutically acceptable anion of a mono or polyvalent acid.

20. A process according to claim 18 further comprising the step of purifying the reaction mixture by solid phase extraction.

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

22. A compound according to claim 1 , wherein each lower alkyl group is a C 1 -C 8 group.

23. A compound according to claim 1 , wherein said substituted lower alkyl group is a C 1 -C 8 alkyl group substituted by 1, 2 or 3 substituents selected from halogen atoms and hydroxyl and C 1 -C 6 alkoxy groups.