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Details for Patent: 7,109,210

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Details for Patent: 7,109,210

Title:Quinuclidine derivatives and medicinal compositions containing the same
Abstract: Compounds of the formula ##STR00001## wherein: {circle around (C)} is phenyl, C.sub.4 to C.sub.9 heteroaromatic, naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl or biphenyl; R.sup.1, R.sup.2 and R.sup.3 are hydrogen or a substituent; n is 0 to 4; A represents --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--, wherein R.sup.6 and R.sup.7 are hydrogen or lower alkyl, or R.sup.6 and R.sup.7 together form an alicyclic ring; m is 0 to 8; (when m=0, A is not --CH.sub.2--); p is 1 or 2; B represents a group of the formula ii): ##STR00002## wherein R.sup.10 is hydrogen, hydroxy or methyl; and Q represents a single bond, --CH.sub.2--, --CH.sub.2--CH.sub.2--, --O--, --O--CH.sub.2--, --S--, --S--CH.sub.2-- or --CH.dbd.CH--, and x represents an anion and wherein the compounds show high affinity for muscarinic M.sub.3 receptors (Hm3).
Inventor(s): Fernandez Forner; Maria Dolors (Barcelona, ES), Prat Quinones; Maria (Barcelona, ES), Buil Albero; Maria Antonia (Barcelona, ES)
Assignee: Almirall Prodesfarma AG (Baar, CH)
Filing Date:Dec 17, 2003
Application Number:10/740,264
Claims:1. A compound according to formula (I) ##STR00016## wherein: {circle around (C)} 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 alkyl group which may optionally be substituted 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.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 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 ii): ##STR00017## wherein R.sup.10 represents a hydrogen atom, a hydroxy or methyl group; and Q represents a single bond, --CH.sub.2--, --CH.sub.2--CH.sub.2--, --O--, --O--CH.sub.2--, --S--, --S--CH.sub.2-- or --CH.dbd.CH--; 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 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 {circle around (C)} 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 {circle around (C)} 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, --NO.sub.2, --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 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 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 claim 1, wherein Q represents a single bond, a --CH.sub.2--, --CH.sub.2--CH.sub.2-- group or an oxygen atom.

13. A compound according 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 1 which is a single stereoisomer.

17. A compound according to claim 1 which is 1-(3-phenylallyl)-3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-azoniabi- cyclo[2.2.2]octane; bromide 3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-(3-phenoxypropyl)-1-azonia- bicyclo[2.2.2]octane; bromide 3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-phenethyl-1-azoniabicyclo[- 2.2.2]octane; bromide 3(R)-(9-Hydroxy-9H-fluorene-9-carbonyloxy)-1-(3-thien-2-ylpropyl)-1-azoni- abicyclo[2.2.2]octane; bromide 3(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-(3-phenylallyl)-1-azoniabic- yclo[2.2.2]octane; bromide 3(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-(3-phenoxypropyl)-1-azoniab- icyclo[2.2.2]octane; bromide 1-(4-Phenylbutyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.- 2]octane; bromide 1-(2-Phenoxyethyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2- .2]octane; bromide 1-(3-Phenoxypropyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.- 2.2]octane; bromide 1-Phenethyl-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octa- ne; bromide 3(R)-(9-Hydroxy-9[H]-xanthene-9-carbonyloxy)-1-(3-phenoxypropyl)-1-azonia- bicyclo[2.2.2]octane; bromide 3(R)-(9-Hydroxy-9[H]-xanthene-9-carbonyloxy)-1-phenethyl-1-azoniabicyclo[- 2.2.2]octane; bromide 3(R)-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(3-thien-2-ylpropyl)-1-azoni- abicyclo[2.2.2]octane; bromide or 3(R)-(9-Methyl-9[H]-xanthene-9-carbonyloxy)-1-(3-phenoxy-propyl)-1-azonia- -bicyclo[2.2.2]octane; bromide.

18. A compound according to claim 1 wherein it has an IC.sub.50 value for muscarinic M.sub.3 receptors (Hm3) of less than 35 nM.

19. 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## to obtain a reaction mixture comprising the compound of formula (I), wherein, in each of formulae I, II and III, R.sup.1, R.sup.2, R.sup.3, {circle around (C)}, A, X, B, n, m and p are as defined in claim 1.

20. A process according to claim 19 wherein the reaction mixture is purified 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 method for treating COPD, chronic bronchitis, bronchial hyperreactivity, asthma and/or rhinitis 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 1-18 or of a pharmaceutical composition according to claim 21.
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