N-[(1-dimethylaminocycloalkyl)methyl]benzamide derivatives
View Patent ↗The present invention relates to N-[(1-dimethylaminocycloalkyl)methyl]benzamide derivatives having the general formula I wherein n is 0, 1, 2 or 3; R 1 and R 2 are independently H, (C 1-4 )alkyl or (C 1-4 )alkyloxy; R 3 is (C 3-8 )alkyl, (C 4-7 )cycloalkyl, (C 4-7 )cycloalkyl (C 1-3 )alkyl, (C 6-12 )aryl(C 1-3 )alkyl (wherein the aryl moiety is optionally substituted with 1–3 substituents selected from (C 1-4 )alkyl, (C 1-4 )alkyloxy, halogen, trifluoromethyl and methoxycarbonyl), or (C 4-9 )heteroaryl(C 1-3 )alkyl; or a pharmaceutically acceptable salt thereof. The invention also relates to pharmaceutical compositions comprising said derivatives, and to the use of these N-[(1-dimethylaminocycloalkyl)methyl]benzamide derivatives in the treatment of disorders or conditions which are responsive to inhibition of the GlyT-2 transporter, such as muscle spasticity, epilepsy and, particularly, acute, chronic and neuropathic pain.
1. A N-[(1-dimethylaminocycloalkyl)methyl]benzamide derivative having the general formula I
wherein
n is 0, 1, 2 or 3;
R 1 and R 2 are independently H, (C 1-4 )alkyl or C( 1-4 ) alkoxy;
R 3 is (C 3-8 )alkyl, (C 4-7 ) cycloalkyl, (C 4-7 ) cycloalkyl (C 1-3 )alkyl, (C 6-12 )aryl(C 1-3 )alkyl (wherein the aryl moiety is optionally substituted with 1–3 substituents selected from (C 1-4 )alkyl, (C 1-4 )alkyloxy, halogen, trifluoromethyl and methoxycarbonyl), or
(C 4-9 )heteroaryl(C 1-3 )alkyl; or a pharmaceutically acceptable salt thereof.
2. The N-[(1-dimethylaminocycloalkyl)methyl]benzamide derivative according to claim 1 , wherein n is 0 or 1.
3. The N-[(1-dimethylaminocycloalkyl)methyl]benzamide derivative according to claim 1 , wherein R 1 and R 2 are independently methyl or methyloxy.
4. The N-[(1-dimethylaminocycloalkyl)methyl]benzamide derivative according to claim 1 , which is selected from the group consisting of:
-4-benzyloxy-3,5-dimethoxy-N-[(1-dimethylaminocyclopentyl)methyl]benzamide;
-4-benzyloxy-3,5-dimethyl-N-[(1-dimethylaminocyclobutyl)methyl]benzamide;
-4-benzyloxy-3,5-dimethyl-N-[(1-dimethylaminocyclopentyl)methyl]benzamide;
-3,5-dimethoxy-4-(4-methylbenzyloxy)-N-[(1-dimethylaminocyclopentyl)methyl]benzamide;
-3,5-dimethoxy-4-(1-phenylethoxy)-N-[(1-dimethylaminocyclopentyl)methyl]benzamide; and
-4-(4-chlorobenzyloxy)-3,5-dimethoxy-N-[(1-dimethylaminocyclopentyl)methyl]benzamide.
5. A pharmaceutical composition, comprising:
the N-[(1-dimethylaminocycloalkyl)methyl]benzamide derivative according to claim 1 , or a pharmaceutically acceptable salt thereof, and
pharmaceutically acceptable auxiliaries.
6. A method of treating a neurological disorder which is responsive to inhibition of the GlyT-2 transporter, comprising:
administering to a mammal an effective amount of a N-[(1-dimethylaminocycloalkyl)methyl]benzamide derivative according to formula I of claim 1 .
7. The method according to claim 6 , wherein the mammal is a human.
8. A method of selectively inhibiting a GlyT-2 transporter in a mammal, comprising:
administering an amount of the N-[(1-dimethylaminocycloalkyl)methyl]benzamide derivative according to claim 1 , to effect the inhibition of a GlyT-2 transporter in a mammal.
9. The method according to claim 8 , wherein the mammal is a human.