US 7,030,128 B2 · Imidazo-pyrimidine derivatives as ligands for GABA receptors

Abstract

A class of imidazo[1,2-α]pyrimidine derivatives, substituted at the 3-position by an optionally substituted five-membered or six-membered heteroaromatic ring, are selective ligands for GABAA receptors, in particular having good affinity for the α2 and/or α3 and/or α5 subunit thereof, and are accordingly of benefit in the treatment and/or prevention of adverse conditions of the central nervous system, including anxiety, convulsions and cognitive disorders.

A compound of formula I, or a pharmaceutically acceptable salt thereof:

wherein:
Z represents a five-membered heteroaromatic ring selected from furan, thiophene, pyrrole, oxazole, thiazole, isoxazole, isothiazole, imidazole, pyrazole, oxadiazole, thiadiazole, triazole and tetrazole, wherein the ring is unsubstituted or substituted with a substituent selected from the group consisting of:
halogen, cyano, trifluoromethyl, C1-6 alkyl, halo(C1-6)alkyl, dihalo(C1-6)alkyl, hydroxy(C1-6)alkyl, C1-6 alkoxy(C1-6)alkyl, C3-7 cycloalkyl, C3-7 heterocycloalkyl, benzyl-tetrahydropyridinyl, C1-6 alkoxy, methyltriazolyl(C1-6)alkoxy, C1-6 alkylthio, C1-6 alkylsulphonyl, C2-6 alkylcarbonyl, amino, C1-6 alkylamino, di(C1-6)alkylamino, C2-6 alkylcarbonylamino, phenyl, (C1-6)alkyl-phenyl, halophenyl, dihalophenyl, trihalophenyl, (fluoro)(methyl)phenyl, cyanophenyl, (cyano)(fluoro)phenyl, (cyano)(difluoro)phenyl, difluoromethyl-phenyl, trifluoromethyl-phenyl, (methyl)(trifluoromethyl)phenyl, (halo)(trifluoromethyl)phenyl, nitrophenyl, methoxyphenyl, (halo)(methoxy)phenyl, trifluoromethoxy-phenyl, (halo)(trifluoromethoxy)phenyl, methylenedioxy-phenyl, (C2-6)alkylcarbonyl-phenyl, trifluorothio-phenyl, (C1-6)alkylsulphonyl-phenyl, di(C1-6)alklaminocarbonyl-phenyl, di(C1-6)alkylaminosulphonyl-phenyl, (halo)(morpholinylmethyl)phenyl, (halo)(pyridinyl)phenyl, imidazolyl-phenyl, thiadiazolyl-phenyl, methylthiadiazolyl-phenyl, (halo)(triazolyl)phenyl, and methyltetrazolyl-phenyl;
or
Z represents a six-membered heteroaromatic ring selected from pyridine, pyrazine, pyrimidine and pyridazine, wherein the ring is unsubstituted or substituted with a substituent selected from the group consisting of:
halogen, cyano, trifluoromethyl, C1-6 alkyl, halo(C1-6)alkyl, dihalo(C1-6)alkyl, hydroxy(C1-6)alkyl, C1-6 alkoxy(C1-6)alkyl, C3-7 cycloalkyl, C3-7 heterocycloalkyl, benzyl-tetrahydropyridinyl, C1-6 alkoxy, methyltriazolyl(C1-6)alkoxy, C1-6 alkylthio, C1-6 alkylsulphonyl, C2-6 alkylcarbonyl, amino, C1-6 alkylamino, di(C1-6)alkylamino, C2-6 alkylcarbonylamino, phenyl, (C1-6)alkyl-phenyl, halophenyl, dihalophenyl, trihalophenyl, (fluoro)(methyl)phenyl, cyanophenyl, (cyano)(fluoro)phenyl, (cyano)(difluoro)phenyl, difluoromethyl-phenyl, trifluoromethyl-phenyl, (methyl)(trifluoromethyl)phenyl, (halo)(trifluoromethyl)phenyl, nitrophenyl, methoxyphenyl, (halo)(methoxy)phenyl, trifluoromethoxy-phenyl, (halo)(trifluoromethoxy)phenyl, methylenedioxy-phenyl, (C2-6)alkylcarbonyl-phenyl, trifluorothio-phenyl, (C1-6)alkylsulphonyl-phenyl, di(C1-6)alkylaminocarbonyl-phenyl, di(C1-6)alkylaminosulphonyl-phenyl, (halo)(morpholinylmethyl)phenyl, (halo)(pyridinyl)phenyl, imidazolyl-phenyl, thiadiazolyl-phenyl, methylthiadiazolyl-phenyl, (halo)(triazolyl)phenyl, and methyltetrazolyl-phenyl;
R1 represents hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-6)alkyl, indanyl, phenyl, phenyl(C1-6)alkyl, halogen, cyano, trifluoromethyl, nitro, —ORa, —SRa, —SORa, —SO2Ra, —SO2NRaRb, —NRaRb, —NRaCORb, —NRaCO2Rb, —CORa, —CO2Ra, —CONRaRb or —CRa═NORb;
and
Ra and Rb independently represent hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-6)alkyl, indanyl, phenyl, or phenyl(C1-6)alkyl.

6 more elements

Imidazo-pyrimidine derivatives as ligands for GABA receptors

Life of this patent

Imidazo-pyrimidine derivatives as ligands for GABA receptors

Life of this patent

Abstract

Claims10