Melatonin ligands having antidepressant activity as well as sleep inducing properties

摘要

Novel melatonin ligands of Formula I:;
or pharmaceutically acceptable salts thereof wherein: n is 1 or 2; m is 0, 1 or 2; p is 0, 1, 2, 3, 4, 5, 6, 7 or 8; v is 2 or 3; A is aryl or heteroaryl; Z is O, S or NR8; Y is selected from the group consisting of hydrogen, aryl, heteroaryl, C1-C6 alkyl, C3-C6 cycloalkyl, and
;
R is selected from the group consisting of hydrogen, hydroxyl, —OCF3, CF3, C1-C8 alkyl, C1-C8 alkyloxy, C1-C8 alkylthio, halogen and —Z—(CH2)p-A; R1 is selected from the group consisting of C1-C4 alkyl, C3-C6 cycloalkyl, CF3, hydroxy-substituted C1-C4 alkyl, hydroxy-substituted C3-C8 cycloalkyl, and NHR5, wherein R5 is C1-C3 alkyl or C3-C6 cycloalkyl; R2 is selected from the group consisting of: hydrogen, C1-C4 alkyl, C1-C4 alkyloxy, OCF3, CF3, hydroxyl, and halogen; R3 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkyloxy, OCF3, CF3, hydroxyl, and halogen; R and R3 may be connected together to form an —O—(CH2)v bridge representing with the carbon atoms to which they are attached a 5- or 6-membered heterocyclic ring system; R4 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkyloxy, OCF3, CF3, hydroxyl, and halogen; R6 is selected from the group consisting of hydrogen and C1-C6 alkyl; R7 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkyloxy, OCF3, CF3, hydroxyl, and halogen; and R8 is selected from the group consisting of hydrogen and C1-C4 alkyl.

主权项

1. A composition comprising a compound of Formula I and a pharmaceutically acceptable excipient, wherein said composition is formulated for oral, transdermal, or parenteral administration, and wherein Formula I isor a pharmaceutically acceptable salt thereof, wherein:
a) n is 1 or 2; b) m is 0, 1 or 2; c) p is 0, 1, 2, 3, 4, 5, 6, 7 or 8; d) v is 2 or 3; e) A is aryl or heteroaryl; f) Z is O, S or NR8; g) Y is selected from the group consisting of hydrogen, aryl, heteroaryl, C2-C6 alkyl, C3-C6cycloalkyl, and h) R is selected from the group consisting of hydrogen, hydroxyl, —OCF3, CF3, C1-C8 alkyl, C1-C8 alkyloxy, C1-C8 alkylthio, halogen and —Z—(CH2)p-A; i) R1 is selected from the group consisting of C1-C3 alkyl, C3-C6 cycloalkyl, CF3, hydroxy-substituted C1-C4 alkyl, hydroxy-substituted C3-C6 cycloalkyl, and NHR5, wherein R5 is C1-C3 alkyl or C3-C6 cycloalkyl; j) R2 is selected from the group consisting of: hydrogen, C1-C4 alkyl, C1-C4 alkyloxy, OCF3, CF3, hydroxyl, and halogen; k) R3 is selected from the group consisting of C2-C4 alkyl, C1-C4 alkyloxy, OCF3, CF3, hydroxyl, F, Br, and I; l) R and R3 may be connected together to form an —O—(CH2)v bridge representing with the carbon atoms to which they are attached a 5- or 6-membered heterocyclic ring system; m) R4 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkyloxy, OCF3, CF3, hydroxyl, and halogen; n) R6 is selected from the group consisting of hydrogen and C1-C6 alkyl; o) R7 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkyloxy, OCF3, CF3, hydroxyl, and halogen; and p) R8 is selected from the group consisting of hydrogen and C1-C4 alkyl, with the proviso that when
a) Y is CH3, then R is OMe, OBu, OHex or O(CH2)4Ph, R1 is CH3, and R6 is H, with the further proviso that when R is OMe then n is 2;b) R3 is hydrogen, then R is hydrogen, OMe, Br, OBu, OHex or O(CH2)4Ph, with the further proviso that when:
i) R is hydrogen, then Y is Ph, n is 1, R6 is H and R1 is CH3;ii) R is OMe, then Y is Ph, n is 1, R6 is H and R1 is CH3;iii) R is OMe, then Y is 3-MeOPh, n is 1, R6 is H and R1 is CH3;iv) R is Br, then Y is Ph, n is 1, R6 is H and R1 is CH3;v) R is OMe, then Y is β-naphthyl; n is 1, R6 is H and R1 is CH3;vi) R is O(CH2)4Ph, then Y is Ph, n is 1, R6 is H and R1 is CH3;vii) R is OMe, then Y is CH2Ph; n is 1, R6 is H and R1 is CH3;ix) R is OMe, then Y is Ph; n is 1, R6 is H and R1 is Pr;x) R is OMe, then Y is Ph; n is 1, R6 is H and R1 is c-Bu; andxi) R is OMe, then Y is Ph; n is 1, R6 is Me and R1 is CH3; andc) Y is Et, then R cannot be H, CH3, OMe or Et,wherein the compound of Formula I does not have structures where:
R is OMe, R3 is H, Y is H, n is 1, R6 is H, and R1 is CH3; and R is H, R3 is OMe, Y is H, n is 1, R6 is H, and R1 is CH3, andwherein the compound has antidepressant activity or sleep inducing properties.