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1. WO2002017922 - BRIDGED NICOTINE COMPOUNDS FOR USE IN THE TREATMENT OF CNS PATHOLOGIES

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

We claim:
1. A compound of the following formula III or IN:



wherein
A is a 1, 2 or 3 atom bridging species selected from straight chain or branched chain alkylene moiety having up to 3 atoms in the backbone thereof, or a substituted alkenylene moiety having up to 3 atoms in the backbone thereof, or a C(O), O, C(S), S, S(O) or S(O)2 containing alkylene moiety, provided however, that any heteroatom contained in A is separated from Ν by at least one carbon atom;
B is a 1, 2 or 3 atom bridging species selected from straight chain or branched chain alkylene moiety having up to 3 atoms in the backbone thereof, or a substituted alkenylene moiety having up to 3 atoms in the backbone thereof, or a C(O), O, Ν(Y ), C(S), S, S(O) or S(O)2 containing alkene moiety, wherein Y1 is hydrogen or lower alkyl or aryl;
R1 is selected from hydrogen, lower alkyl or an aromatic group-containing species;
R2 is selected from hydrogen or lower alkyl;

R3, R4 and R5 are each independently selected from hydrogen; alkyl; substituted alkyl; cycloalkyl; substituted cycloalkyl, alkenyl; subtituted alkenyl; alkynyl; substituted alkynyl; aryl; substituted aryl; alkylaryl; substituted alkylaryl; arylalkyl; substituted arylalkyl; arylalkenyl; substituted arylalkenyl; arylalkynyl; substituted arylalkynyl; heterocyclic; substituted heterocyclic; trifluoromethyl; halogen; cyano; nitro; S(O)Y2, S(O)2Y2, S(O)2OY2 or S(O)2NHY2, wherein each Y2 is independently hydrogen, lower alkyl, alkenyl, alkynyl or aryl, provided that when R , R or R is S(O)Y , Y is not hydrogen, and further provided that when Y is alkenyl or alkynyl, the site of unsaturation is not conjugated with a heteroatom; C(O)Y , wherein Y is selected from hydrogen, alkyl, substituted alkyl, alkoxy, alkylamino, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, aryloxy, arylamino, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic or trifluoromethyl, provided, however, that the carbonyl functionality is not conjugated with an alkenyl or alkynyl functionality; OY4 or N(Y4)2 wherein each Y4 is independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, subtituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic, acyl, trifluoromethyl, alkylsulfonyl or arylsulfonyl, provided that the OY4 or N(Y4)2 functionality is not conjugated with an alkenyl or alkynyl functionality; SY5 wherein Y5 is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, subtituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic or trifluoromethyl, provided that the SY5 functionality is not conjugated with an alkenyl or alkynyl functionality;
R6 is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, subtituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic; and
X is selected from chlorine, bromine, iodine, HSO4, 1 SO , CH3SO3, p-TsO or CF3SO3.

2. The compound according to claim 1, wherein A is selected from CH2 or CH CH2.

3. The compound according to claim 1, wherein B is CH2, CH2CH2 or N(Y ).

4. The compound according to claim 3, wherein Y1 is selected from hydrogen or methyl.

5. The compound according to claim 1, wherein R1 is Cι-C10 alkyl.

6. The compound according to claim 1, wherein R1 is Ci-C6 alkyl.

7. The compound according to claim 1, wherein R1 is methyl.

8. The compound according to claim 1, wherein R1 is ethyl.

9. The compound according to claim 1, wherein R1 is isopropyl.

10. The compound according to claim 1, wherein R1 is isobutyl.

11. The compound according to claim 1 , wherein R2 is hydrogen.

12. The compound according to claim 1, wherein R3, R4 and R5 are individually selected from hydrogen, halogen, alkyl or alkanoyl.

13. The compound according to claim 1, wherein R6 is a C4-C19 unbranched alkyl.

14. The compoxind according to claim 1, wherein X is iodine.

15. The compound according to claim 1, wherein said compound is cis-l-methyl-8-octyl-2,3,3a,4,5,9b-hexahydro-lH-pyrrolo [3 ,2-A]isoquinolin-8-ium iodide (ACO).

16. The compound according to claim 1, wherein said compound is cis-l-methyl-8-nonyl-2,3,3a,4,5,9b-hexahydro-lH-pyrrolo [3,2- j]isoquinolin-8-ium iodide (ACN).

17. The compound according to claim 1, wherein said compound is cis-8-decyl-l-methyl-2,3,3a,4,5,9b-hexahydro-lH-pyrrolo[3,2-/7]isoquinolin-8-ium iodide (ACD).

18. The compound according to claim 1, wherein said compound is cis-l-methyl-8-ιmdecyl-2,3,3a,4,5,9b-hexahydro-lH-pyrrolo[3,2-Λ]isoquinolin-8-iιιm iodide (ACU).

19. The compound according to claim 1, wherein said compound is cis-8-dodecyl-l-methyl-2,3,3a,4,5,9b-hexahydro-lH-pyrrolo [3,2-A]isoquinolin-8-ium iodide (ACDD).

20. The compound according to claim 1, wherein said compound is cis-l-methyl-6-octyl-2,3,3a,4,5,9b-hexahydro-lH-pyrrolo [2,3- |isoquinolm-8-ium iodide (BCO).

21. The compound according to claim 1, wherein said compound is cis-l-methyl-6-nonyl-2,3,3a,4,5,9b-hexahydro-lH-pyrrolo [2,3-/jisoquinolm-6-ium iodide (BCN).

22. The compound according to claim 1, wherein said compound is cis-6-decyl-l-methyl-2,3,3a,4,5,9b-hexahydro-lH-pyrrolo [2,3- ]isoquinolin-6-ium iodide (BCD).

23. The compound according to claim 1, wherein said compound is cis-l-methyl-6-undecyl-2,3,3a,4,5,9b-hexahydro-lH-pyrrolo [2,3^isoquinolin-6-ium iodide (BCU).

24. The compound according to claim 1, wherein said compound is cis-6-dodecyl-l-methyl-2,3,3a,4,5,9b-hexahydro-lH-pyrrolo [2,3-/jisoquinolin-6-ium iodide (BCDD).

25. A compound according to claim 1, wherein the ring junction between a and b rings is cis or trans.

26. A compound according to claim 1, wherein said compound is substantially optically pure.

27. A compound according to claim 1, wherein said compound is a racemic mixture or a diastereometric mixture.

28. A compound according to claim 1, wherein said compound is a nicotinic receptor antagonist.

29. A compound according to claim 1, wherein said compound inhibits NIC-evoked [3H]-DA release.

30. A compound according to claim 1, wherein said compound inhibits [ H]-NIC binding.

31. A method of antagonizing the nicotinic receptor comprising administering of a pharmaceutically effective amount of a compound according to claim 1.

32. A method of treatment of a condition selected from the group consisting of: abuse of nicotinic receptor agonists, addiction to tobacco products, addiction to nicotine comprising administering an effective amount of a compound according to claim 1.

33. A method of treatment of Alzheimer's disease comprising administering of a pharmaceutically effective amount of a compound according to claim 1.

34. A method of treatment of Parkinson's disease comprising administering of a pharmaceutically effective amount of a compound according to claim 1.

35. A method of controlling pain, comprising administering of a pharmaceutically effective amount of a compound according to claim 1.

36. A compound according to claim 1, wherein said compound competitively inhibits central nervous system acting nicotinic receptor agonists.

37. A compound according to claim 1, wherein said compound acts at the putative α3β2 neuronal nicotinic receptor in the central nervous system.

38. A compound according to claim 1, wherein said compound is useful for treatment of irritable bowel syndrome.

39. A compound according to claim 1, wherein said compound is useful for treatment of colitis.