Oxime derivatives and their use as allosteric modulators of metabotropic glutamate receptors

摘要

The present invention provides new oxime derivatives of the general formula (I), pharmaceutical compositions containing them and their use for the treatment and/or prophylaxis of conditions associated with altered glutamatergic signalling and/or functions, and/or conditions which can be affected by alteration of glutamate level or signalling in mammals. This invention further provides new oxime derivatives of the general formula (I) consisting of modulators of nervous system receptors sensitive to glutamate, which makes them particularly suitable for the treatment and/or prophylaxis of acute and chronic neurological and/or psychiatric disorders. In particular embodiments, the new oxime derivatives of the invention are modulators of metabotropic glutamate receptors (mGluRs). The invention further provides positive allosteric modulators of mGluRs and more specifically positive alSosteric modulators of mGluR4.

主权项

1. A compound of the general formula (I)wherein:
R1, R2, R3, and R4 each independently represent a -L-R group, wherein: L is selected from a bond, C1-C10 alkylene, C2-C10 alkenylene, or C2-C10 alkynylene, wherein said alkylene, said alkenylene or said alkynylene is optionally substituted with one or more groups independently selected from halogen, —CF3, —CN, —OH, or —NH2, and further wherein one or more —CH2— units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from: —O—, —NR11—, —CO—, —S—, —SO—, or —SO2—; R is selected from hydrogen, C1-C10 alkyl, halogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, —NR11R12, —OR11, —SR11, —SOR11, —SO2R11, —CF3, or —CN, wherein said optionally substituted aryl, said optionally substituted heteroaryl, said optionally substituted cycloalkyl, or said optionally substituted heterocycloalkyl may be substituted with one or more groups independently selected from C1-C4 alkyl, halogen, —CF3, —CN, —OH, —O(C1-C4 alkyl), —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)(C1-C4 alkyl) wherein the two C1-C4 alkyl moieties of said —N(C1-C4 alkyl)(C1-C4 alkyl) are optionally mutually linked to form a ring together with the nitrogen atom which they are attached to, or -L1-R13; R11 and R12 are each independently selected from hydrogen, optionally substituted C1-C10 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or —CF3, wherein said optionally substituted alkyl, said optionally substituted aryl, said optionally substituted heteroaryl, said optionally substituted cycloalkyl, or said optionally substituted heterocycloalkyl may be substituted with one or more groups independently selected from C1-C4 alkyl, halogen, —CF3, —CN, —OH, —O(C1-C4 alkyl), —NH2, —NH(C1-C4 alkyl), or —N(C1-C4 alkyl)(C1-C4 alkyl) wherein the two C1-C4 alkyl moieties of said —N(C1-C4 alkyl)(C1-C4 alkyl) are optionally mutually linked to form a ring together with the nitrogen atom which they are attached to; L1 is selected from a bond, C1-C10 alkylene, C2-C10 alkenylene, or C2-C10 alkynylene, wherein one or two —CH2— units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from —O—, —NH—, —N(C1-C4 alkyl)-, —CO—, —S—, —SO—, or —SO2—; R13 is selected from hydrogen, C1-C4 alkyl, halogen, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)(C1-C4 alkyl), —OH, —O(C1-C4 alkyl), —SH, —S(C1-C4 alkyl), —CF3, or —CN, wherein said optionally substituted phenyl, said optionally substituted heteroaryl, said optionally substituted cycloalkyl, or said optionally substituted heterocycloalkyl may be substituted with one or more groups independently selected from C1-C4 alkyl, halogen, —CF3, —CN, —OH, —O(C1-C4 alkyl), —NH2, —NH(C1-C4 alkyl), or —N(C1-C4 alkyl)(C1-C4 alkyl) wherein the two C1-C4 alkyl moieties of said —N(C1-C4 alkyl)(C1-C4 alkyl) are optionally mutually linked to form a ring together with the nitrogen atom which they are attached to; R5 is selected from hydrogen, C1-C4 alkyl, halogen, —CF3, —CN, —OH, —O(C1-C4 alkyl), —COOH, —COO(C1-C4 alkyl), —CONH2, —CONH(C1-C4 alkyl), —CON(C1-C4 alkyl)(C1-C4 alkyl), wherein the two C1-C4 alkyl moieties of said —CON(C1-C4 alkyl)(C1-C4 alkyl) are optionally mutually linked to form a ring together with the nitrogen atom which they are attached to, —NH2, —NH(C1-C4 alkyl), or —N(C1-C4 alkyl)(C1-C4 alkyl), wherein the two C1-C4 alkyl moieties of said —N(C1-C4 alkyl)(C1-C4 alkyl) are optionally mutually linked to form a ring together with the nitrogen atom which they are attached to; A is a bicyclic moiety corresponding to formula (II): which may be saturated or unsaturated, and wherein: n is 0 or 1; X1 to X6 are each independently selected from N, N(Rx1), C(Rx2), C(Rx2)(Rx3), O, S, S(O), S(O)2, or C(O); X7 is N or N(Rx1); any of groups X1 to X7 containing a nitrogen atom may form an N-oxide group; X8 and X9 are each independently selected from N, C, or C(Rx2); each Rx1 is independently selected from hydrogen, C1-C4 alkyl, —OH, —O(C1-C4 alkyl), or —(C1-C4 alkylene)-phenyl; and each Rx2 and each Rx3 is independently selected from hydrogen, C1-C4 alkyl, halogen, —CF3, —CN, —OH, —O(C1-C4 alkyl), —COOH, —COO(C1-C4 alkyl), —CONH2, —CONH(C1-C4 alkyl), —CON(C1-C4 alkyl)(C1-C4 alkyl), —NH2, —NH(C1-C4 alkyl), or —N(C1-C4 alkyl)(C1-C4 alkyl), wherein the two C1-C4 alkyl moieties of said —N(C1-C4 alkyl)(C1-C4 alkyl) or of said —CON(C1-C4 alkyl)(C1-C4 alkyl) are optionally mutually linked to form a ring together with the nitrogen atom which they are attached to; or a pharmaceutically acceptable salt or solvate thereof.