Patent EP-1074549-A2 (EP)
Inventor: ADAM GEO
IPC: A61P43/00
Filed: 2000-07-27
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.