Claims for Patent: RE46417

Summary for Patent: RE46417

Title:	Quinuclidine derivatives and their use as muscarinic M3 receptor ligands
Abstract:	A compound according to formula (I) ##STR00001## wherein: .COPYRGT. is a phenyl ring, a C.sub.4 to C.sub.9 heteroaromatic compound containing one or more heteroatoms, or a naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl or biphenyl group; which shows high affinity for muscarinic M.sub.3 receptors (Hm3).
Inventor(s):	Fernandez Forner; Dolors (Barcelona, ES), Prat Quinones; Maria (Barcelona, ES), Buil Albero; Maria Antonia (Barcelona, ES)
Assignee:	Almirall, S.A. (Barcelona, ES)
Application Number:	15/019,009
Patent Claims:	1. A compound according to formula (I) ##STR00015## wherein: .COPYRGT. is a phenyl ring, a C.sub.4 to C.sub.9 heteroaromatic group containing one or more heteroatoms or a naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl or biphenyl group; R.sup.1, R.sup.2 and R.sup.3 each independently represent a hydrogen atom or halogen atom, or a hydroxy group, or a phenyl, --OR.sup.4, --SR.sup.4, --NR.sup.4R.sup.5, --NHCOR.sup.4, --CONR.sup.4R.sup.5, --CN, --NO.sub.2, --COOR.sup.4 or --CF.sub.3 group, or a straight or branched .[.lower.]. .Iadd.C.sub.1 to C.sub.4 .Iaddend.alkyl group which may optionally be substituted.[., for example,.]. with a hydroxy .[.or alkoxy.]. group, wherein R.sup.4 and R.sup.5 each independently represent a hydrogen atom, straight or branched .[.lower.]. .Iadd.C.sub.1 to C.sub.4 .Iaddend.alkyl group or together form an alicyclic ring; or R.sup.1 and R.sup.2 together form an aromatic, alicyclic or heterocyclic ring, n is an integer from 0 to 4; A represents a --CH.sub.2--, --CH.dbd.CR.sup.6--, --CR.sup.6.dbd.CH--, --CR.sup.6R.sup.7--, --CO--, --O--, --S--, --S(O)--, SO.sub.2 or --NR.sup.6-- group, wherein R.sup.6 and R.sup.7 each independently represent a hydrogen atom, straight or branched .[.lower.]. .Iadd.C.sub.1 to C.sub.4 .Iaddend.alkyl group or R.sup.6 and R.sup.7 together form an alicyclic ring; m is an integer from 0 to 8; provided that when m=0, A is not --CH.sub.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): ##STR00016## wherein R.sup.10 represents a hydrogen atom, a hydroxy or methyl group; and R.sup.8 and R.sup.9 each independently represent ##STR00017## wherein R.sup.11 represents a hydrogen or halogen atom or a straight or branched .[.lower.]. .Iadd.C.sub.1 to C.sub.4 .Iaddend.alkyl group; and .[.X.]. .Iadd.X.sup.- .Iaddend.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.sup.1 to R.sup.7 or R.sup.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 .COPYRGT. 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 .COPYRGT. represents a phenyl, pyrrolyl or thienyl group. 6. A compound according to claim 1 wherein R.sup.1, R.sup.2 and R.sup.3 each independently represent a hydrogen or halogen atom or a hydroxy, methyl, tert-butyl, --CH.sub.2OH, 3-hydroxypropyl, --OMe, --NMe.sub.2, --NHCOMe, --CONH.sub.2, --CN, .[.--NO2.]. .Iadd.--NO.sub.2.Iaddend., --COOMe or --CF.sub.3 group. 7. A compound according to claim 6 wherein R.sup.1, R.sup.2 and R.sup.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.sub.2--, --CH.dbd.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.sub.2--, 13 CH.dbd.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.sup.8 and R.sup.9 each independently represent a phenyl, 2-thienyl, 3-thienyl, 2-furyl, or 3-furyl group and R.sup.11 represents a hydrogen atom. 13. A compound according to claim 1 wherein .[.X.]. .Iadd.X.sup.- .Iaddend.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.sup.8 is different from R.sup.9 in group i), and the asymmetric carbon to which R.sup.8 and R.sup.9 are bonded has the (R) configuration. 17. A compound according to claim 15, wherein R.sup.8 is different from R.sup.9 in group i), and the asymmetric carbon to which R.sup.8 and R.sup.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.Iadd., .Iaddend. 3(R)-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo- [2.2.2]octane; bromide.Iadd., .Iaddend. 3(R)-(2,2-Diphenylpropionyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2- ]octane; bromide.Iadd., .Iaddend. 3(R)-(2-Hydroxy-2-phenyl-2-thien-2-yl-acetoxy)-1-(3-phenoxypropyl)-1-azon- ia-bicyclo [2.2.2]octane; bromide.Iadd., .Iaddend. 3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(3-phenylallyl)-1-azoniab- icyclo [2.2.2]octane; bromide.Iadd., .Iaddend. 3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(2-phenoxyethyl)-1-azonia- bicyclo [2.2.2]octane; bromide.Iadd., .Iaddend. 3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(3-phenoxypropyl)-1-azoni- abicyclo [2.2.2]octane; bromide.Iadd., .Iaddend. 3(R)-(2,2-Dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]- octane; bromide.Iadd., .Iaddend. .[.3(R)-(2-Hydroxy-2,2-di-thien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[- 2.2.2]octane; bromide.]. .Iadd.3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-phenethyl-1-azoniabicycl- o[2.2.2]octane; bromide, .Iaddend. .[.3(R)-(2-Hydroxy-2,2-di-thien-2-ylacetoxy)-1-(4-phenylbutyl)-1-azoniabi- cyclo[2.2.2]octane; bromide.]. .Iadd.3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(4-phenylbutyl)-1-azonia- bicyclo[2.2.2]octane; bromide, .Iaddend. 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azonia-bic- yclo[2.2.2]octane; bromide.Iadd., .Iaddend. 1-[3-(4-Fluorophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-- azoniabicyclo [2.2.2]octane; chloride.Iadd., .Iaddend. 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(2-hydroxyphenoxy)propyl]-1- -azoniabicyclo [2.2.2]octane; Trifluoroacetate.Iadd., .Iaddend. 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-pyrrol-1-ylpropyl)-1-azonia- -bicyclo[2.2.2]octane; trifluoroacetate.Iadd., .Iaddend. 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(2-thien-2-ylethyl)-1-azoniabi- cyclo[2.2.2]octane; bromide.Iadd., .Iaddend. 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-thien-2-ylpropyl)-1-azoniab- icyclo[2.2.2]octane; bromide.Iadd., .Iaddend. 1-(2-Benzyloxyethyl)-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabic- yclo[2.2.2]octane; trifluoroacetate.Iadd., or .Iaddend. 3(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicy- clo[2.2.2]octane; bromide. 20. A compound according to claim 1 characterised in that it has an IC.sub.50 value for muscarinic M.sub.3 receptors (Hm3) of less than 35 nM. .[.21. A process for the preparation of a compound of formula (I) ##STR00018## which comprises reacting an alkylating agent of formula (II) ##STR00019## with a compound of formula (III) ##STR00020## wherein, in each of formulae I, II and III, R.sup.1, R.sup.2 R.sup.3, .COPYRGT., 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.]. .Iadd.claim .Iaddend.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.]. .Iadd.rhinitis .Iaddend.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.]. .Iadd.claim .Iaddend.1 .[.to 12, 13 to 20.]. or of a pharmaceutical composition according to claim 23. .Iadd.26. A compound chosen from 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicy- clo[2.2.2]octane; X.sup.- or 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.- 2]octane; X.sup.-, wherein X.sup.- represents a pharmaceutically acceptable anion of a mono or polyvalent acid. .Iaddend. .Iadd.27. A compound chosen from 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicy- clo[2.2.2]octane; X.sup.- or 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.- 2]octane; X.sup.-, wherein X.sup.- represents chloride, bromide, iodide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, or p-toluenesulfonate. .Iaddend. .Iadd.28. A compound according to claim 27, wherein X.sup.- represents chloride, bromide, iodide, sulfate, nitrate, acetate, trifluoroacetate, maleate, oxalate, or succinate. .Iaddend. .Iadd.29. A compound according to claim 27, wherein X.sup.- represents chloride, bromide, or trifluoroacetate. .Iaddend. .Iadd.30. A compound chosen from 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicy- clo[2.2.2]octane; bromide or 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.- 2]octane; bromide. .Iaddend.