Isoindolona compounds as metabotropic glutamate receptor Enhancers. Processes of production and Pharmaceutical compositions.

摘要

These compounds belong to the class of isoperons used as enhancers of glutamate metabolite receptor. Their access procedure. The pharmaceutical ingredients that contain them 1. Compound with response formula (1): R1 is a ring composed of 3 to 7 members, which may contain one or more heteroatoms independent of N, O and s groups, in which one or more a can be substituted; R2 and R3 are selected independently of H, c1-6-tar, c2-6-aluminum, c2-6-tar, arilo, isopropyl, isopropyl and c3-8-cyclopropene groups,C1-6-alkyl-aryl, C1-6-alkyl-heteroaryl, C1-6-alkyl-heterocycloalkyl, and C1-6-alkyl-cycloalkyl, wherein R2 and R3 may be substituted with one or more A; R4 and R6 are independently selected from the group consisting of H, hydroxy, F, Cl, Br, I, nitro, cyano, C1-6-alkyl, C1-6-alkylhalo, OC1-6alkyl, OC1-6-alkylhalo, C2-6-alkenyl, OC2-6-alkenyl, C2-6-alkynyl, OC2-6-alkynyl, C3-8-cycloalkyl, C1-6-alkyl-C3-8-cycloalkyl, OC0-6-alkyl-C3- 8-cycloalkyl, aryl, C1-6-alkylaryl, OC0-6-alkylaryl, (CO) R10, O (CO) R10, O (CO) OR10, C (O) OR10, O (CNR10) OR11, C1-6 -alkylOR10, OC2-6alkylOR10, C1-6-alkyl (CO) R10, OC1-6- alkyl (CO) R10, C0-6-alkylCO2R10, OC1-6-alkylCO2R10,10-10, c0-6-6-10-6-10-10-10-10-10-10-10-10-10-10-10-10-oc2-6-asphalt (so) R10, c0-6-asphalt 2r10, oc2-6-asphalt 2r10, c0-6-asphalt (SO2) n10r11, A single group of atoms made up of one atom, a single group of atoms made up of five atoms.In the case where R4 and R6 can be replaced by one or more a's, any cyclopropyl or arilo may be selectively combined into a ring of 5 to 7 members, which may contain one or more heteroatoms independent of groups C, N, O and S; R5 is selected from groups h, F, Cl, br, I and nitro, 6-6-6-6-6-6, c16-6-6-6-6-from, c16-oarillo, c1-6-asphalt, oheterocyclohedilo,OC1-6-alquilheterocicloalquilo C (O) H (CO) R10 O (CO) R10 O (CO) OR10 C (O) OR10 O (CN) OR10 C1-6-alquilOR10 OC2-6-alquilOR10 C1-6-alquil ( NR10R11, C0-6-alkylNR10 (CO) OR11, OC2-6-alkylNR10 (CO) OR11, SO3R10 and a 5- to 7-membered ring that may contain one or more heteroatoms independently selected from the group consisting of N, O and S, wherein R5 may be substituted with one or more A, and where any cyclic portion may be optionally fused with a 5- to 7-membered ring that may contain one or more heteroatoms independently selected from the group consisting of C, N , O and S; R7 is selected from the group consisting of H, F, Cl, Br, I, nitro, cyano, OC1-4-alkyl, C1-6-alkyl, C1-6-alkylhalo, OC1-6-alkylhalo, C2-6-alkenyl , OC2-6-alkenyl, C2-6-alkynyl, OC2-6-alkynyl,and C3-8-cycloalkyl; R8 and R9 are independently selected from the group consisting of H, F, Cl, Br, I, nitro, cyano, C1-6-alkyl, C1-6-alkylhalo, OC1-6alkyl, OC1-6-alkylhalo, C2- 6-alkenyl, OC2-6-alkenyl, C2-6-alkynyl, and OC2-6-alkynyl, or when n is greater than | 1, two or more R8 and / or R9 in adjacent carbon atoms may be absent to form an alkenyl or alkynyl portion; R10 and r11 are independently selected from the group consisting of H, hydroxy, oxo, F, Cl, Br, I, nitro, cyano, C1-6-alkyl, C1-6-alkylhalo, OC1-6alkyl, OC1-6- alkylhalo, C2-6-alkenyl, OC2-6-alkenyl, C2-6-alkynyl, OC2-6-alkynyl, C3-8-cycloalkyl, C1-6-alkyl-C3-8-cycloalkyl,OC0-6-C3-8-alkylcycloalkyl, aryl, C1-6-alkylaryl, OC0-6-alkylaryl, C0-6-alkyl-heterocycloalkyl, OC1-6-alkyl-heterocycloalkyl, heteroaryl, and C1-6alkyl heteroaryl, in where any cyclic portion may be optionally fused with a 5- to 7-membered ring that may contain one or more heteroatoms independently selected from the group consisting of C, N, O and S and any cyclic portion is optionally substituted with a substituent selected from alkyl, halo, hydroxyl, Oalkyl, haloalkyl and Ohaloalkyl; A is selected from the group consisting of H, hydroxy, F, Cl, Br, I, nitro, cyano, oxo, C1-6-alkyl, C1-6-alkylhalo, OC1-6alkyl,OC1-6-alkylhalo, C2-6-alkenyl, OC2-6-alkenyl, C2-6-alkynyl, OC2-6-alkynyl, C3-8-cycloalkyl, C1-6-alkyl-C3-8-cycloalkyl, OC0- 6-alkyl-C3-8-cycloalkyl, aryl, C1-6-alkylaryl, OC0-6-alkylaryl, C1-6-alkyl-heterocyclyl, C1-6-alkyl-heterocycloalkyl, OC0-6-alkyl-heterocycloalkyl, (CO ) R10, O (CO) R10, O (CO) OR10, O (CNR10) OR11, C1-6-alkylOR10, OC2-6alkylOR10, C1-6-alkyl (CO) R10, OC1-6- alkyl (CO) R10 , C0-6- alkylCO2R10, OC1-6-alkylCO2R10, C1-6-alkylcyano, OC2-6-alkylcyano, C0-6-alkylNR10R11, OC2-6-alkylNR10R11, C0-6-alkyl (CO) NR10R11, OC1-6 -alkyl (CO) NR10R11, C0-6-alkylNR10 (CO) R11, OC2-6-alkylNR10 (CO) R11, C0-6-alkylNR10 (CO) NR10R11, C0-6- alkylSR10,- 10-10-10-11, c0-6-6-10-10-10-11, c0-6-6-6-10-10 (SO2) n10r11, (CO) n10r11, O (CO) n10r11, n10or11, c0-6-rent 10 (CO) R11, oc2-6-rent 10 (CO) or11, a. S3r10 and a ring of 5 to 7 members, which may contain one or more heteroatoms independent of the N, O and s groups, in which the rings of 5 to 7 members may be replaced by one or more R10 and R11; n is selected from groups 1, 2, 3, 4, 5, 6, 7 and 8;Or an acceptable salt, hydrate, solution, optical isomer or combination thereof for pharmaceutical use, provided that the compound shall not be: 1,1-dimethylacetic acid 4 - [(5-bromo-1,3-dihydro-1-oxo-2h-isoindia-2-il) methyl] - 1-dihydro-2 - (4-dimethyl) - 1-isohydrogen-chloro-1 1-dimethyldimethyldimethyl dimethyl ether, 1-dimethyl ether, 1-1 -- 1h-isooctyl-1-ona1,1- dimethyl ethyl ester of 4 - [(5-cyano-1,3-dihydro-1-oxo-2H-isoindol-2-yl) methyl] -1-piperidinecarboxylic acid, 2,3-dihydro-1-oxo- 2- (4-Piperidinylmethyl) -1H-isoindole-5- carbonitrile, 1,1-dimethyl ethyl ester of 4 - [(5-fluoro-1,3-dihydro-1-oxo-2H-isoindol-2-yl) methyl ] -1-piperidinecarboxylic, 5-fluoro-2,3-dihydro-2- (4-piperidinylmethyl) -1H-isoindol-1-one, 2,3-dihydro-5- (methoxymethyl) -2- (phenylmethyl) - 1H-isoindole-1-one, 2,3-dihydro-5-hydroxy-2- [2- (4-morpholinyl) ethyl] -1H-isoindol-1-one, 2 - [[((2R) -4.4 -diethoxy-1 - [(1S) -1-phenylethyl] -2-piperidinyl] methyl] -2,3-dihydro-7-methoxy-1H-isoindole-1-one, 2,3-dihydro-7-methoxy- 2 - [[(2R) -4-oxo - [(1S) -1-phenylethyl] -2-piperidinyl] methyl] -1H- isoindole-1-one,2-2 (2-2-2-2-2-2-2-2-2-2-2 (2-2) (2-2-2-2-2-2-2-2-2 acid R [[2, - 1-1-1-2-2-2-2-vinegar-2-2-2-2-2-2-2-2-acetic acid-2-2, 3-dihydro-1h-isoindol-1-il-acetic anhydride, 5, 6-dimethoxy-1-oxo-n-2 - (4 - (2-methoxy) - 1-pyridine-ethanol;5,6-dimethoxy-1- (3,4-dimethoxy) benzyl-3-oxo-2- (4- (2-methoxyphenyl) -1-piperazinyl) ethyl-isoindole, 2,3-dihydro-3-allyl- 3-hydroxy-2-benzyl-1H-isoindol-1-one, 2,3-dihydro-2-benzyl-3-methyl-1H-isoindol-1-one, 2,3-dihydro-2,3-dibenzyl- 1H-isoindol-1-one, 2-3-dihydro-3-allyl-2-benzyl-1H-isoindol-1-one, 2,3-dihydro-2-benzyl-3 - ((1- hydroxy) butyl- 3-methyl-1H-isoindole-1-one, 2,3-dihydro-2-benzyl-3 - ((1-hydroxy-1-methyl) ethyl) -3-methyl-1H-isoindol-1-one, methyl - (2,3-dihydro-3-methyl-3-oxo-2-benzyl-1H-isoindol-1-yl) -acetate, methyl- (2,3-dihydro-3-phenyl-3-oxo-2- Benzyl-1H-isoindol-1-yl) - acetate, methyl- (2,3-dihydro-3- (furan-2-yl) -3-oxo-2-benzyl-1H-isoindol-1-yl) -acetate ,- - (3-1 -----) (3-1 ------ TATO, 2, 3-dihydro-3-fenil-2, 3-dibencil-1h-isoindol-1-ona, 2, 3-dihydro-2, 3, 3-tribencil-1h-isoindol-1-ona, 2, 3-dihydro-2,3-dibenzo-diol-1h-isooctanol-1-ona or 2,3-dihydro-3,3-dimethyl-2-phenyl-1h-isooctanol-1-ona.