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Claims for Patent: 6,750,226

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Claims for Patent: 6,750,226

Title: Quinuclidine derivatives and their use as muscarinic M3 receptor ligands
Abstract:A compound according to formula (I) ##STR1## wherein: {character pullout} 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): Forner; Dolors Fernandez (Barcelona, ES), Quinones; Maria Prat (Barcelona, ES), Buil Albero; Maria Antonia (Barcelona, ES)
Assignee: Almirall-Prodesfarma, S.A. (Barcelona, ES)
Application Number:10/047,464
Patent Claims: 1. A compound according to formula (I) ##STR15##

wherein: {character pullout} 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.4 R.sup.5, --NHCOR.sup.4, --CONR.sup.4 R.sup.5, --CN, --NO.sub.2, --COOR.sup.4 or --CF.sub.3 group, or a straight or branched lower 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 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.6 R.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 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): ##STR16## wherein R.sup.10 represents a hydrogen atom, a hydroxy or methyl group; and R.sup.8 and R.sup.9 each independently represent ##STR17## wherein R.sup.11 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 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 {character pullout} 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 {character pullout} 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.2 OH, 3-hydroxypropyl, --OMe, --NMe.sub.2, --NHCOMe, --CONH.sub.2, --CN, --NO2, --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 --, --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 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)-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-azoniabic yclo [2.2.2]octane; bromide 3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(2-phenoxyethyl)-1-azoniabi cyclo [2.2.2]octane; bromide 3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(3-phenoxypropyl)-1-azoniab icyclo [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-bicyc lo[2.2.2]octane; bromide 1-[3-(4-Fluorophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-az oniabicyclo [2.2.2]octane; chloride 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(2-hydroxyphenoxy)propyl]-1-a zoniabicyclo [2.2.2]octane; trifluoroacetate 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-pyrrol-1-ylpropyl)-1-azonia-b icyclo[2.2.2]octane; trifluoroacetate 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(2-thien-2-ylethyl)-1-azoniabicy clo[2.2.2]octane; bromide 3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-thien-2-ylpropyl)-1-azoniabic yclo[2.2.2]octane; bromide 1-(2-Benzyloxyethyl)-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyc lo[2.2.2]octane; trifluoroacetate 3(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicycl o[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) ##STR18##

which comprises reacting an alkylating agent of formula (II) ##STR19##

with a compound of formula (III) ##STR20##

wherein, in each of formulae I, II and III, R.sup.1, R.sup.2 R.sup.3, {character pullout}, 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.
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