Substituted homopiperidine, piperidine or pyrrolidine derivatives
View Patent ↗A novel class of substituted homopiperidine, piperidine and pyrrolidine derivatives, methods for their preparation, pharmaceutical compositions comprising them and use thereof in the treatment of disorders related to the histamine H3 receptor. More particularly, the compounds possess histamine H3 receptor antagonistic activity and are thus useful in the treatment of disorders in which a histamine H3 receptor blockade is beneficial.
1. A compound of the general formula (I):
wherein
R 1 is
C 3-8 -cycloalkyl or C 5-8 -cycloalkenyl,
wherein the cyclic moieties may optionally be substituted with one or more substituents independently selected from R 12 , wherein R 12 is C 1-6 -alkyl, halogen, trifluoromethyl or 2,2,2-trifluoroethyl,
r is 1,
s is 0, 1, 2 or 3,
t is 0, 1, 2 or 3,
X is C═O, CHOH or CR 2 R 3 ; wherein R 2 and R 3 independently are hydrogen or C 1-6 -alkyl,
or X is a bond,
Y is is selected from the group consisting of oxadiazolyl, thiadiazolyl, or triazolyl, optionally substituted with one or more substituents independently selected from R 18 ,
R 18 is halogen, nitro, cyano, hydroxy, C 1-6 -alkyl, C 1-6 -alkylthio or C 1-6 -alkoxy;
R 4 is
(a) C 1-6 -alkyl, C 3-8 -cycloalkyl or C 3-8 -cycloalkenyl, which may optionally be substituted with one or more substituents independently selected from R 13 , wherein R 13 is C 3-8 -cycloalkyl, C 1-6 -alkoxy, C 1-6 -alkylthio, cyano, halo-C 1-6 -alkyl, halo-C 1-6 alkoxy, and halogen,
or
(b) aryl, aryl-C 1-6 -alkyl, aryl-C 2-4 -alkenyl, or heteroaryl
which may optionally be substituted with one or more substituents independently selected from R 14
R 14 is
halogen, nitro, cyano, acyl, hydroxy, C 1-6 -alkyl, C 1-6 -alkylthio, C 1-6 -alkylsulfonyl, C 1-6 -alkylsulfonyloxy, C 1-6 -alkoxy, C 3-8 -cycloalky, halo-C 1-6 -alkyl, halo-C 1-6 -alkoxy, —NR 5 R 6 , R 5 R 6 N—C 1-6 -alkyl-, R 5 R 6 N—C 1-6 -alkoxy-, or —O(C═)NR 5 R 6 , or wherein two substituents in adjacent positions together form a radical —O—(CH 2 ) 1-3 -O—, wherein R 5 and R 6 independently are hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-6 -alkanoyl or aryl, or R 5 and R 6 together with the nitrogen atom to which they are attached form a 3 to 7 membered, saturated or unsaturated ring, which may be fused to a benzene ring,
a group of the formula
—(W) k -A wherein
W is —C 1-6 -alkyl-, —(O) l —C 2-6 -alkenyl-, —(O) l —C 1-6 -alkyl-O—, —(CH 2 ) n —(C═O)—CH 2 ) m —, —O—
wherein
l is 0 or 1
k is 0 or 1
n and m are independently 0, 1, 2 or 3,
A is
aryl, aryl -C 1-6 -alkyl, heteroaryl, heteroaryl-C 1-6 -alkyl, C 1-6 -alkyl or C 3-8 -cycloalkyl wherein the ring moieties optionally may be substituted with one or more substituents independently selected from R 15
R 15 is
halogen, nitro, cyano, hydroxy, C 1-6 -alkylthio, C 1-6 -alkylsulfonyl, C 1-6 -alkylsulfonyloxy, C 1-6 -alkyl, C 1-6 -alkoxy, C 3-8 -cycloalkyl, halo-C 1-6 -alkyl, halo-C 1-6 -alkoxy, —NR 7 R 8 , R 7 R 8 N—C 1-6 -alkyl-, R 7 R 8 N—C 1-6 -alkoxy-, or —O(C═O)NR 7 R 8 , or wherein two substituents in adjacent positions together form a radical O—(CH 2 ) 1-3 -O—,
wherein R 7 and R 8 independently are hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-6 -alkanoyl or aryl, or R 7 and R 8 together with the nitrogen atom to which they are attached form a 3 to 7 membered, saturated or unsaturated ring, which may be fused to a benzene ring,
NR 9 R 10 wherein R 9 and R 10 independently are hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-6 -alkanoyl or aryl, or R 9 and R 10 together with the nitrogen atom to which they are attached form a 3 to 7 membered, saturated or unsaturated ring, which may be fused to a benzene ring, and the ring may contain further heteroatoms and it may optionally be substituted with one or more substituents independently selected from R 16 ,
wherein R 16 is C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-6 -alkanoyl or aryl optionally substituted with one or more substituents independently selected from R 17 , wherein R 17 is halogen, nitro, cyano, hydroxy, or C 1-6 -alkyl;
as well as any diastereomer or enantiomer or tautomeric form, mixtures of these, or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 , wherein R 1 is C 3-8 -cycloalkyl.
3. A compound according to claim 2 wherein R 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
4. A compound according to claim 3 wherein R 1 is cyclopropyl or cyclopentyl.
5. A compound according to claim 4 wherein R 1 is cylopropyl.
6. A compound according to claim 1 , wherein X is a bond.
7. A compound according to claim 1 , wherein s and t together are 0, 1, 2 or 3.
8. A compound according to claim 1 wherein s is 0 or 1.
9. A compound according to claim 8 wherein s is 0.
10. A compound according to claim 1 wherein t is 0.
11. A compound according to claim 1 , wherein Y is selected from
12. A compound according to claim 1 , wherein R 4 is aryl, aryl-C 1-6 -alkyl, either of which may optionally be substituted with one or more substituents independently selected from R 14 , or C 3-8 -cycloalkyl optionally substituted with one or more substituents independently selected from R 13 .
13. A compound according to claim 12 wherein R 4 is aryl optionally substituted with one or more substituents independently selected from R 14 .
14. A compound according to claim 12 wherein R 4 is phenyl, biphenylyl, or naphthyl optionally substituted with one or more substituents independently selected from R 14 .
15. A compound according to claim 14 , wherein R 4 is phenyl optionally substituted with one or more substituents independently selected from R 14 .
16. A compound according to claim 1 wherein R 13 is C 1-6 -alkyl.
17. A compound according to claim 1 wherein R 14 is
halogen, cyano, hydroxy, C 1-6 -alkyl, C 1-6 -alkylsulfonyl, C 1-6 -alkylsulfonyloxy, C 1-6 -alkoxy, C 3-8 -cycloalkyl, —CF 3 , —OCF 3 , —NR 5 R 6 , R 5 R 6 N—C 1-6 -alkyl-, or
a group of the formula —(W) k -A.
18. A compound according to claim 17 wherein R 14 is
F, Cl, cyano, methyl, ethyl, propyl, butyl, tert-butyl, methyl-sulfonyl, methyl-sulfonyloxy, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —CF 3 , —OCF 3 , —NR 5 R 6 , R 5 R 6 N-methyl-, or a group of the formula -(W) k -A.
19. A compound according to claim 18 wherein R 14 is
F, Cl, cyano, methyl, tert-butyl, methyl-sulfonyl, methoxy, cyclopentyl, cyclohexyl, —CF 3 , —OCF 3 , —NR 5 R 6 , R 5 R 6 N-methyl-, or
a group of the formula -(W) k -A.
20. A compound according to claim 19 wherein R 14 is a group of the formula -(W) k -A.
21. A compound according to claim 1 , wherein k is 1.
22. A compound according to claim 1 wherein k is 0.
23. A compound according to claim 1 wherein W is —C 1-6 -alkyl-, —(O) l —C 1-6 -alkyl-O—, —(CH 2 ) n —(C═O)—(CH 2 ) m —, or —O—.
24. A compound according to claim 23 wherein W is —C 1-6 -alkyl- or —(CH 2 ) n —(C═O)—(CH 2 ) m —.
25. A compound according to claim 24 wherein W is methylene, ethylene, propylene or —(CH 2 ) n —(C═O)—(CH 2 ) m —.
26. A compound according to claim 1 wherein n is 0 or 1.
27. A compound according to claim 26 wherein n is 0.
28. A compound according to claim 1 wherein m is 0 or 1.
29. A compound according to claim 28 wherein m is 0.
30. A compound according to claim 1 wherein l is 0.
31. A compound according to claim 1 wherein A is C 1-6 -alkyl, aryl or C 3-8 -cycloalkyl, wherein the ring moieties optionally may be substituted with one or more substituents independently selected from R 15 , or A is NR 9 R 10 .
32. A compound according to claim 31 wherein A is methyl, ethyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein the ring moieties optionally may be substituted with one or more substituents independently selected from R 15 , or A is NR 9 R 10 .
33. A compound according to claim 32 wherein A is phenyl optionally substituted with one or more substituents independently selected from R 15 .
34. A compound according to claim 33 wherein A is phenyl.
35. A compound according to claim 32 wherein A is NR 9 R 10 .
36. A compound according to claim 1 wherein R 15 is halogen, nitro, cyano, hydroxy, C 1-6 -alkylthio, C 1-6 -alkylsulfonyl, C 1-6 -alkylsulfonyloxy, C 1-6 -alkyl, C 1-6 -alkoxy, C 3-8 -cycloalkyl, halo-C 1-6 -alkyl, or halo-C 1-6 -alkoxy.
37. A compound according to claim 36 wherein R 15 is halogen, cyano, hydroxy, CH 3 —S—, CH 3 CH 2 —S—, methylsulfonyl, methylsulfonyloxy, methyl, ethyl, propyl, butyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, —CF 3 , or —OCF 3 .
38. A compound according to claim 37 wherein R 15 is halogen, methyl, ethyl, methoxy, ethoxy, —CF 3 , or —OCF 3 .
39. A compound according to claim 1 wherein R 9 and R 10 together with the nitrogen atom to which they are attached form a 3 to 7 membered, saturated or unsaturated ring, which may be fused to a benzene ring, and the ring may contain further heteroatoms and it may optionally be substituted with one or more substituents independently selected from R 16 .
40. A compound according to claim 39 wherein R 9 and R 10 together with the nitrogen atom to which they are attached form a structure selected from
41. A compound according to claim 1 wherein R 16 is methyl, ethyl, 1-ethyl-propyl or phenyl optionally substituted with one or more substituents independently selected from R 17 .
42. A compound according to claim 1 wherein R 17 is halogen.
43. A pharmaceutical composition comprising, as an active ingredient, at least one compound according to claim 1 together with one or more pharmaceutically acceptable carriers or excipients.
44. A pharmaceutical composition according to claim 43 in unit dosage form, comprising from about 0.05 mg to about 1000 mg, from about 0.1 mg to about 500 mg or from about 0.5 mg to about 200 mg of the compound.
45. A pharmaceutical composition according to claim 43 wherein the compound exhibits histamine H3 antagonistic activity or histamine H3 inverse agonistic activity.