Patent CA-2314798-A1 (CA)
Title: 1,2,4,5-tetrahydro-benzo[d]azepin derivatives
Inventor: MUTEL VINCENT
IPC: C07D471/04
Filed: 2000-08-01
Abstract: The present invention is concerned with 1,2,4,5-tetrahydro-benzo[d]azepin derivatives of the general formula   wherein R1 signifies hydrogen, lower alkyl, oxygen, halogen, or -OR, -O(C3-C6)cycloalkyl, -O(CHR)n-(C3-C6)cycloalkyl, -O(CHR)n CN, -O(CHR)n CF3, -O(CHR)(CHR)n NR2, -O(CHR)(CHR)n OR, -O(CHR)n-lower alkenyl, -OCF3, -OCF2-R, -OCF2-lower alkenyl, -OCHRF, -OCHF-lower alkenyl, -OCF2CRF2, -OCF2Br, -O(CHR)n CF2Br, -O(CHR)n-phenyl, wherein the phenyl group may be optionally substituted independently from each other by one to three lower alkyl, lower alkoxy, halogen, nitro or cyano groups, -O(CHR)(CHR)n-morpholino, -O(CHR)(CHR)n-pyrrolidino, -O(CHR)(CHR)n-piperidino, -O(CHR)(CHR)n-imidazolo, -O(CHR)(CHR)n-triazolo, -O(CHR)n-pyridino, -O(CHR)(CHR)n-OSi-lower alkyl, -O(CHR)(CHR)nOS(O)2-lower alkyl, -O(CH2)n CH=CF2, -O(CHR)n-2,2-dimethyl-[1.3]dioxolane, -O(CHR)n-CHOR-CH2OR, -O(CHR)n-CHOR-(CHR)n-CH2OR or -SR or -S(CHR)n COOR, or -NR2, -N(R)(CHR)(CHR)n OR, -N(R)(CHR)n CF3, -N(R)(CHR)(CHR)n-morpholino, -N(R)(CHR)(CHR)n-imidazolo, -N(R)(CHR)(CHR)n-pyrrolidino, -N(R)(CHR)(CHR)n-pyrrolidin-2-one, -N(R)(CHR)(CHR)n-piperidino, -N(R)(CHR)(CHR)n-triazolo, -N(R)(CHR)n-pyridino, or n is 1 - 6;    R signifies hydrogen, lower alkyl or lower alkenyl, independently from each other, if more than one R is present;      R2 signifies nitro or cyano;      R3 signifies hydrogen, lower alkyl, =O, =S, -SR, -S(O)S-lower alkyl, -(C3-C6)cycloalky or piperazino, optionally substituted by lower alkyl, or -CONR2, -(CHR)n CONR2, -(CHR)n OR, -(CH2)n-CF3, -CF3, -(CHR)n OC(O)CF3, -(CHR)n COOR, -(CHR)n SC6H5, wherein the phenyl group may be optionally substituted independently from each other by one to three lower alkyl, lower alkoxy, halogen, nitro or cyano groups, -(CHR)n-1,3-dioxo-1,3-dihydro-isoindol, -(CHR)n-tetrahydro-pyran-2-yloxy or -(CHR)n-S-lower alkyl, or -NR2, -NRCO-lower alkyl, -NRCHO, -N(R)(CHR)n CN, -N(R)(CHR)n CF3, -N(R)(CHR)(CHR)n-OR, -N(R)C(O)(CHR)n O-lower alkyl, -NR(CHR)n-lower alkyl, -NR(CHR)(CHR)n-OR, -N(R)(CHR)(CHR)n-O-phenyl, wherein the phenyl group may be optionally substituted independently from each other by one to three lower alkyl, lower alkoxy, halogen, nitro or cyano groups, -N(R)(CHR)n-lower alkenyl, -N(R)(CHR)(CHR)n-O-(CHR)n OR, -N(R)(CHR)n C(O)O-lower alkyl, -N(R)(CHR)n C(O)NR-lower alkyl, -N(R)(CH2)n-2,2-dimethyl-[1.3]dioxolane, -N(R)(CHR)(CHR)n morpholino,-N(R)(CHR)n-pyridino, -N(R)(CHR)(CHR)n-piperidino, -N(R)(CHR)(CHR)n-pyrrolidino, -N(R)(CHR)(CHR)n-O-pyridino, -N(R)(CHR)(CHR)n imidazolo, -N(R)(CHR)n-CR2-(CHR)n-OR, -N(R)(CHR)n-CR2-OR, -N(R)(CHR)n-CHOR-CH2OR, -N(R)(CHR)n-CHOR-(CHR)n-CH2OR, or -OR, -O(CHR)n CF3, -OCF3, -O(CHR)(CHR)n-O-phenyl, wherein the phenyl group may be optionally substituted independently from each other by one to three lower alkyl, lower alkoxy, halogen, nitro or cyano groups, -O(CHR)(CHR)n-O-lower alkyl, -O(CHR)n-pyridino or -O(CHR)(CHR)n-morpholino; and R4 signifies hydrogen, lower alkyl, lower alkenyl or nitro, or -OR, -OCF3, -OCF2-R, -OCF2-lower alkenyl, -OCHRF, -OCHF-lower alkenyl, -O(CHR)n CF3, or -(CHR)n CHRF, -(CHR)n CF2R, -(CHR)n CF3, -(C3-C6)cycloalkyl, -(CHR)n(C3-C6)cycloalkyl, -(CHR)n CN, -(CHR)n-phenyl, wherein the phenyl group may be optionally substituted independently from each other by one to three lower alkyl, lower alkoxy, halogen, nitro or cyano groups, -(CHR)(CHR)n OR, -(CHR)n CHORCH2OR, -(CHR)(CHR)n NR2, -(CHR)n COOR, -(CHR)(CHR)n OSi-lower alkyl, -(CHR)(CHR)n-OS(O)2-lower alkyl, -(CH2)n-CH=CF2, -CF3, -CF2-R, -CF2-lower alkenyl, -CHRF, -CHF-lower alkenyl, -(CHR)n-2,2-dimethyl-[1.3] dioxolane, -(CH2)n-2-oxo-azepan-1-yl, -(CHR)(CHR)n-morpholino, -(CHR)n-pyridino, -(CHR)(CHR)n-imidazolo, -(CHR)(CHR)n-triazolo, -(CHR)(CHR)n-pyrrolidino, optionally substituted by -(CH2)n OH, -(CHR)(CHR)n-3-hydroxy-pyrrolidino or -(CHR)(CHR)n-piperidino, or -NR2, -N(R)(CHR)n-pyridino, -N(R)C(O)O-lower alkyl, -N(CH2CF3)C(O)O-lower alkyl, -N(C(O)O-lower alkyl]2, -NR-NR-C(O)O-lower alkyl or -N(R)(CHR)n CF3, -NRCF3, -NRCF,-R, -NRCF2-lower alkenyl, -NRCHRF, -NRCHF-lower alkenyl; or is absent, if X is -N= or =N-; or R4 and R1 or R3 and R4 are interconnected to the groups -(CH2)3-5, -(CH2)2-N=, -CH=N-N=-, -CH=CH-N=, -NH-CH=CH- or -NR-CH2-CH2- and form together with the N and C atoms to which they are attached an additional ring;   R5, R6 signify hydrogen, lower alkyl, lower alkoxy, amino, nitro, -SO2NH2 or halogen; or R5 and R6 are interconnected to the group -O-CH2-O- and form together with the C atoms to which they are attached an additional 5-membered ring;   R7, R8 signify hydrogen, lower alkyl, lower alkoxy, amino, nitro or halogen;      R9, R10 signify hydrogen or lower alkyl;     R11, R12 signifies hydrogen, lower alkyl, hydroxy, lower alkoxy, lower alkoxycarbonyloxy or lower alkanoyloxy;      R13 R14 signify hydrogen, tritium or lower alkyl; R15, R16 signifies hydrogen, tritium, lower alkyl, hydroxy, lower alkoxy, lower alkoxycarbonyloxy or lower alkanovloxy or are together an oxo group; or X signifies -N=, =N-, -N <, > C= or =C <;      Y signifies -N=, =N-, -NH-, -CH= or =CH-; and the dotted line may be a bond, as well as with their pharmaceutically acceptable salts in their racemic and optically active form.     It has surprisingly been found that the compounds of general formula I are antagonists at metabotropic glutamate receptors and therefore useful for the treatment of diseases related to these receptors.