EP1074549A2 — Tetrahydro-benzo(d)azepines and their use as antagonists at metabotropic glutamate receptors

USPTO 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(C 3 -C 6 )cycloalkyl, -O(CHR) n -(C 3 -C 6 )cycloalkyl, -O(CHR) n CN, -O(CHR) n CF 3 , -O(CHR)(CHR) n NR 2 , -O(CHR)(CHR) n OR, -O(CHR) n -lower alkenyl, -OCF 3 , -OCF 2 -R, -OCF 2 -lower alkenyl, -OCHRF, -OCHF-lower alkenyl, -OCF 2 CRF 2 , -OCF 2 Br, -O(CHR) n CF 2 Br, -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) n OS(O) 2 -lower alkyl, -O(CH 2 ) n CH=CF 2 , -O(CHR) n -2,2-dimethyl-[1.3]dioxolane, -O(CHR) n -CHOR-CH 2 OR, -O(CHR) n -CHOR-(CHR) n -CH 2 OR or -SR or -S(CHR) n COOR, or -NR 2 , -N(R)(CHR)(CHR) n OR, -N(R)(CHR) n CF 3 , -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) 2 -lower alkyl, -(C 3 -C 6 )cycloalky or piperazino, optionally substituted by lower alkyl, or -CONR 2 , -(CHR) n CONR 2 , -(CHR) n OR, -(CH 2 ) n -CF 3 , -CF 3 , -(CHR) n OC(O)CF 3 , -(CHR) n COOR, -(CHR) n SC 6 H 5 , 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 -NR 2 , -NRCO-lower alkyl, -NRCHO, -N(R)(CHR) n CN, -N(R)(CHR) n CF 3 , -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)(CH 2 ) 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 -CR 2 -(CHR) n -OR, -N(R)(CHR) n -CR 2 -OR, -N(R)(CHR) n -CHOR-CH 2 OR, -N(R)(CHR) n -CHOR-(CHR) n -CH 2 OR, or -OR, -O(CHR) n CF 3 , -OCF 3 , -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, -OCF 3 , -OCF 2 -R, -OCF 2 -lower alkenyl, -OCHRF, -OCHF-lower alkenyl, -O(CHR) n CF 3 , or -(CHR) n CHRF, -(CHR) n CF 2 R, -(CHR) n CF 3 , -(C 3 -C 6 )cycloalkyl, -(CHR) n (C 3 -C 6 )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 CHORCH 2 OR, -(CHR)(CHR) n NR 2 , -(CHR) n COOR, -(CHR)(CHR) n OSi-lower alkyl, -(CHR)(CHR) n -OS(O) 2 -lower alkyl, -(CH 2 ) n -CH=CF 2 , -CF 3 , -CF 2 -R, -CF 2 -lower alkenyl, -CHRF, -CHF-lower alkenyl, -(CHR) n -2,2-dimethyl-[1.3]dioxolane, -(CH 2 ) 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 -(CH 2 ) n OH, -(CHR)(CHR) n -3-hydroxy-pyrrolidino or -(CHR)(CHR) n -piperidino, or -NR 2 , -N(R)(CHR) n -pyridino, -N(R)C(O)O-lower alkyl, -N(CH 2 CF 3 )C(O)O-lower alkyl, -N[C(O)O-lower alkyl] 2 , -NR-NR-C(O)O-lower alkyl or -N(R)(CHR) n CF 3 , -NRCF 3 , -NRCF 2 -R, -NRCF 2 -lower alkenyl, -NRCHRF, -NRCHF-lower alkenyl; or is absent, if X is -N= or =N-; or R 4 and R 1 or R 3 and R 4 are interconnected to the groups -(CH 2 ) 3-5 -, -(CH 2 ) 2 -N=, -CH=N-N=-, -CH=CH-N=, -NH-CH=CH- or -NR-CH 2 -CH 2 - 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, -SO 2 NH 2 or halogen; or R5 and R6 are interconnected to the group -O-CH 2 -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 alkanoyloxy 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.