Quinuclidine carbamate derivatives and their use as M3 antagonists

1. A compound of formula (I):

wherein

R1 represents

R3 represents a hydrogen or halogen atom, or a straight or branched lower alkyl group or a cyano group;

R2 represents a benzyl, phenethyl, furan-2-ylmethyl, furan-3-ylmethyl, thiophen-2-ylmethyl or thiophen-3-ylmethyl group or a straight or branched alkyl group having 3 to 8 carbon atoms, an alkenyl group having 3 to 8 carbon atoms, or a cycloalkyl group of 3 to 6 carbon atoms;

p is 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;

or a mixture thereof;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 ,

wherein said compound is a quaternary ammonium salt of a carbamate of formula (I),

wherein said compound is represented by formula (II):

wherein m is an integer from 0 to 8;

A represents a —CH 2 —, —CH═CR4-, —CR4=CH—, —CO—, —O—, —S—, —S(O), —SO 2 —, —NR4-, or —CR4R5- group, wherein R4 and R5 each independently represent a hydrogen atom, a straight or branched lower alkyl group, or R4 and R5 together form an alicyclic ring;

n is an integer from 0 to 4;

B represents a hydrogen atom, an alkoxy group, a cycloalkyl group, —COOR4 or —OOCR4, or a cyano group, a naphthalenyl group, a 5,6,7,8-tetrahydronaphthalenyl group, a biphenyl group, or a group of formula (I) or (ii)

wherein Z represents O, N or S; and

R6, R7 and R8 each independently represent a hydrogen or halogen atom, or a hydroxyl, phenyl, —OR4, —SR4, —NR4R5, —NHCOR4, —CONR4R5, —CN, —NO 2 , —COOR4 or —CF 3 group or a straight or branched, substituted or unsubstituted lower alkyl group;

wherein R4 and R5 each independently represent a hydrogen atom, a straight or branched lower alkyl group, or R4 and R5 together form an alicyclic ring; or R6 and R7 together form an aromatic, alicyclic or heterocyclic ring; and

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

or a mixture thereof of compounds of formula (II).

3. A compound according to claim 1 , wherein R1 represents a thiophen-2-ylmethyl, thienyl or furan-2-ylmethyl group.

4. A compound according to claim 1 , wherein R2 represents a benzyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl, furan-2-ylmethyl, phenethyl, pent-4-enyl, pentyl, butyl, allyl or cyclopentyl group.

5. A compound according to claim 2 , wherein B represents a hydrogen atom or a substituted or unsubstituted phenyl, pyrrolyl, thienyl or furyl group, or a biphenyl, naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl or benzo[1,3]dioxolyl group.

6. A compound according to claim 5 , wherein B represents a substituted or unsubstituted phenyl group and R6, R7 and R8 each independently represent a hydrogen or halogen atom, or a hydroxyl, methyl, —CH 2 OH, —OMe, —NMe 2 , —NHCOMe, —CONH 2 , —CN, —NO2, —COOMe, or —CF 3 group.

7. A compound according to claim 6 , wherein B represents a phenyl, 4-fluorophenyl or 3-hydroxyphenyl group.

8. A compound according to claim 2 , 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.

9. A compound according to claim 8 , wherein m is 1, 2 or 3 and A represents a —CH2-, —CH═CH—, or —O— group.

10. A compound according to claim 2 , wherein B—(CH 2 ) n -A-(CH 2 ) m — represents a group selected from 3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, phenethyl, 3-phenylpropyl, 3-(3-hydroxyphenoxy)propyl, 3-(4-fluorophenoxy)propyl, 3-thiophen-2-ylpropyl, 1-allyl and 1-heptyl.

11. A compound according to claim 2 , wherein X − represents a chloride, bromide, or trifluoroacetate anion.

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

13. A compound according to claim 1 , wherein the azoniabicyclo group is substituted in the 3′-position and the substituent at the 3-position has the (R) configuration.

14. A compound according to claim 1 , which is a single isomer.

15. A compound according to claim 1 which is:

Butylthiophen-2-ylmethylcarbamic acid 1-azabicyclo[2.2.2]oct-3-(R)yl ester

Bis-thiophen-2-ylmethylcarbamic acid 1-azabicyclo[2.2.2]oct-3-(R)-yl ester

Furan-2-ylmethyl-2-ylmethylcarbamic acid 1-azabicyclo[2.2.2]oct-3-(R)yl ester

Allylthiophen-2-ylmethylcarbamic acid 1-azabicyclo[2.2.2]oct-3-(R)yl ester

Cyclopentylthiophen-2-ylmethylcarbamic acid 1-azabicyclo[2.2.2]oct-3-(R)yl ester

Bis-furan-2-ylmethylcarbamic acid 1-azabicyclo[2.2.2]oct-3-(R)yl ester

or a pharmaceutically acceptably salt thereof.

16. A compound according to claim 2 which is:

3-(R)(Bis-thiophen-2-ylmethylcarbamoyloxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane; bromide

3-(R)(Bis-thiophen-2-ylmethylcarbamoyloxy)-1-(3-thiophen-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane; bromide

1-Allyl-3-(R)(allylthiophen-2-ylmethylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane; trifluoroacetate

3-(R)(Cyclopentylthiophen-2-ylmethylcarbamoyloxy)-1-(3-phenylpropyl)-1-azoniabicycle[2.2.2]octane; trifluoroacetateor

1-Allyl-3-(R)(bis-furan-2-ylmethylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane; trifluoroacetate.

17. A compound according to claim 1 characterised in that it has an IC 50 value (nM) for muscarinic M3 receptors of less than 35.

18. A process for the preparation of a compound of formula (I) as claimed in claim 1 ,

which process comprises reacting a compound of formula (III):

with a compound of formula (IV):

and optionally preparing a pharmaceutically acceptable salt of a compound of formula (I).

19. A process for producing a salt of formula (II) as claimed in claim 2 :

which process comprises quaternising the nitrogen atom of the azoniabicyclic ring of a compound of formula (I):

with an alkylating agent of formula (VI):

B—CH 2 ) n -A-(CH 2 ) m —W  (VI)

wherein W represents a leaving group.

20. A process according to claim 19 , wherein W represents a group X.

21. A process according to claim 19 , wherein the resulting reaction mixture is purified by solid phase extraction.

22. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.

23. A compound according to claim 2 , wherein R1 represents a thiophen-2-ylmethyl, thienyl or furan-2-ylmethyl group.

24. A compound according to claim 2 , wherein R2 represents a benzyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl, furan-2-ylmethyl, phenethyl, pent-4-enyl, pentyl, butyl, allyl or cyclopentyl group.

25. A compound according to claim 2 , wherein the azoniabicyclo group is substituted in the 3-position.

26. A compound according to claim 25 , wherein the substituent at the 3-position has the (R) configuration.

27. A compound according to claim 2 , which is a single isomer.

28. A compound according to claim 2 characterised in that it has an IC 50 value (nM) for muscarinic M3 receptors of less than 35.

29. A pharmaceutical composition comprising a compound according to claim 2 and a pharmaceutically acceptable carrier or diluent.