Substituted hexahydropyrrolo[1,2-a]pyrazines, octahydropyrido[1,2-a]-pyrazines and decahydropyrazino[1,2-a]azepines
View Patent ↗Novel substituted hexahydropyrrolo[1,2-a]pyrazines, octahydropyrido[1,2-a]-pyrazines and decahydropyrazino[1,2-a]azepines, use of these compounds as pharmaceutical compositions, pharmaceutical compositions comprising the compounds, and a method of treatment employing these compounds and compositions. The compounds show a high and selective binding affinity to the histamine H3 receptor indicating histamine H3 receptor antagonistic, inverse agonistic or agonistic activity. As a result, the compounds are useful for the treatment of diseases and disorders related to the histamine H3 receptor.
1. A compound of the general formula (I):
wherein
n is 1, 2 or 3,
R 1a and R 1b independently are hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkenyl or fluoro,
R 2 is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-8 -cycloalkyl or C 3-8 -cycloalkenyl,
X is
R 3a , R 3b , R 3c and R 3d independently are hydrogen, halogen, C 1-6 -alkyl or C 3-8 -cycloalkyl, or R 3a and R 3b , R 3a and R 3c , or R 3b and R 3d can be taken together to form a C 1-6 -alkylene bridge,
R 4 , R 5 , R 6 and R 7 independently are hydrogen, halogen, C 1-6 -alkyl or C 3-8 -cycloalkyl,
Z is
R 8 , R 9 , R 10 , R 11 and R 12 independently are
hydrogen, cyano, nitro, halogen, carboxy, guanidino, or amidino,
C 1-6 -alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, C 2-6 -alkynyl, C 1-6 -alkylsulfonyl, C 1-6 -alkylsulfinyl, C 1-6 -alkylthio, C 1-6 -alkylcarbonyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkylcarbonyl, C 3-8 -cycloalkenyl, aryl, arylsulfonyl, arylsulfinyl or arylthio,
each of which may optionally be substituted with one or more groups selected from cyano, nitro, halogen, carboxy, guanidino, amidino, trifluoromethyl, trifluoromethoxy, —NR 13 R 14 , —NHC(═O)R 15 or —C(═O)NR 13 R 14 ,
—NR 13 R 14 , —NHC(═O)R 15 , —OC(═O)NR 13 R 14 , —NHC(═O)OR 16 or —C(═O)NR 13 R 14 , or
R 8 and R 9 , R 9 and R 10 , R 10 and R 11 , or R 11 and R 12 can be taken together to form a bridge selected from C 1-6 -alkylene, —O—(CH 2 ) o —O— and —O—(CH 2 ) o —,
o is 1, 2, 3, 4 or 5,
R 13 , R 14 and R 15 independently are hydrogen or
aryl, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-8 -cycloalkyl or C 3-8 -cycloalkenyl,
each of which may optionally be substituted with one or more groups selected from cyano, nitro and halogen,
R 16 is
aryl, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-8 -cycloalkyl or C 3-8 -cycloalkenyl,
each of which may optionally be substituted with one or more groups selected from cyano, nitro and halogen,
as well as any diastereomer or enantiomer or tautomeric form thereof or mixtures of these or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 , wherein n is 1.
3. A compound according to claim 1 , wherein n is 2.
4. A compound according to claim 1 , wherein R 1a and R 1b are hydrogen.
5. A compound according to claim 1 , wherein R 2 is hydrogen.
6. A compound according to claim 1 , wherein X is
wherein R 3a , R 3b , R 3c , R 3d , R 4 , R 5 , R 6 and R 7 are as defined in claim 1 .
7. A compound according to claim 6 , wherein X is —C(═O)—CH 2 —CH 2 —C(═O)—, —C(═O)—O—CH 2 —CH 2 — or
8. A compound according to claim 1 , wherein Z is
wherein R 8 to R 12 are as defined in claim 1 .
9. A compound according to claim 8 , wherein R 8 to R 12 independently are
hydrogen, cyano, nitro, halogen, carboxy, guanidino, or amidino,
C 1-6 -alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, C 2-6 -alkynyl, C 1-6 -alkylsulfonyl, C 1-6 -alkylsulfinyl, C 1-6 -alkylthio, C 1-6 -alkylcarbonyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkylcarbonyl, C 3-8 -cycloalkenyl, aryl, arylsulfonyl, arylsulfinyl or arylthio,
each of which may optionally be substituted with one or more groups selected from cyano, nitro, halogen, carboxy, guanidino, amidino, trifluoromethyl, trifluoromethoxy, —NR 13 R 14 , —NHC(═O)R 15 , or —C(═O)NR 13 R 14 , and wherein aryl is selected from phenyl, biphenylyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, 1,2,3,4-tetrahydronaphthyl, or 1,4-dihydronaphthyl,
—NR 13 R 14 , —NHC(═O)R 15 , —OC(═O)NR 13 R 14 , —NHC(═O)OR 16 or —C(═O)NR 13 R 14 , or
R 8 and R 9 , R 9 and R 10 , R 10 and R 11 , or R 11 and R 12 can be taken together to form a bridge selected from C 1-6 -alkylene, —O—(CH 2 ) o —O— and —O—(CH 2 ) o —.
10. A compound according to claim 8 , wherein Z is
wherein R 10 to R 11 are as defined in claim 1 .
11. A compound according to claim 10 , wherein R 10 and R 11 independently are hydrogen, C 1-6 -alkoxy, halogen or trifluoromethyl.
12. A compound according to claim 11 , wherein at least one of R 10 and R 12 is different from hydrogen.
13. 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.
14. A pharmaceutical composition according to claim 13 in unit dosage form, comprising from about 0.05 mg to about 1000 mg of the compound.
15. A pharmaceutical composition according to claim 13 in unit dosage form, comprising from about 0.1 mg to about 500 mg of the compound.
16. A pharmaceutical composition according to claim 13 in unit dosage form, comprising from about 0.5 mg to about 200 mg of the compound.