Claims for Patent: 6,750,226

Summary for Patent: 6,750,226

Title:	Quinuclidine derivatives and their use as muscarinic M3 receptor ligands
Abstract:	A compound according to formula (I) wherein: is a phenyl ring, a C4 to C9 heteroaromatic compound containing one or more heteroatoms, or a naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl or biphenyl group; which shows high affinity for muscarinic M3 receptors (Hm3).
Inventor(s):	Dolors Fernandez Forner, Maria Prat Quiñones, Maria Antonia Buil Albero
Assignee:	Almirall SA
Application Number:	US10/047,464
Patent Claims:	1. A compound according to formula (I) wherein: is a phenyl ring, a C4 to C9 heteroaromatic group containing one or more heteroatoms or a naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl or biphenyl group; R1, R2 and R3 each independently represent a hydrogen atom or halogen atom, or a hydroxy group, or a phenyl, —OR4, —SR4, —NR4R5, —NHCOR4, —CONR4R5, —CN, —NO2, —COOR4 or —CF3 group, or a straight or branched lower alkyl group which may optionally be substituted, for example, with a hydroxy or alkoxy group, wherein R4 and R5 each independently represent a hydrogen atom, straight or branched lower alkyl group or together form an alicyclic ring; or R1 and R2 together form an aromatic, alicyclic or heterocyclic ring, n is an integer from 0 to 4; A represents a —CH2—, —CH═CR6—, —CR6═CH—, —CR6R7—, —CO—, —O—, —S—, —S(O)—, SO2 or —NR6— group, wherein R6 and R7 each independently represent a hydrogen atom, straight or branched lower alkyl group or R6 and R7 together form an alicyclic ring; m is an integer from 0 to 8; provided that when m=0, A is not —CH2—; 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 R10 represents a hydrogen atom, a hydroxy or methyl group; and R8 and R9 each independently represent wherein R11 represents a hydrogen or halogen atom or a straight or branched lower alkyl group; and 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 R1 to R7 or R11 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 R1, R2 and R3 each independently represent a hydrogen or halogen atom or a hydroxy, methyl, tert-butyl, —CH2OH, 3-hydroxypropyl, —OMe, —NMe2, —NHCOMe, —CONH2, —CN, —NO2, —COOMe or —CF3 group. 7. A compound according to claim 6 wherein R1, R2 and R3 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 —CH2—, —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 —CH2—, —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 R8 and R9 each independently represent a phenyl, 2-thienyl, 3-thienyl, 2-furyl, or 3-furyl group and R11 represents a hydrogen atom. 13. A compound according to claim 1 wherein 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 R8 is different from R9 in group i), and the asymmetric carbon to which R8 and R9 are bonded has the (R) configuration. 17. A compound according to claim 15, wherein R8 is different from R9 in group i), and the asymmetric carbon to which R8 and R9 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)-1-azoniabicyclo[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-di-thien-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 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 IC50 value for muscarinic M3 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, R1, R2 R3, , 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 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 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 1 to 12, 13 to 20 or of a pharmaceutical composition according to claim 23.