US 2008/0293718 A1 · Novel 2-Amino-Imidazole-4-One Compounds and Their Use in the Manufacture of a Medicament to Be Used in the Treatment of Cognitive Impairment, Alzheimer's Disease, Neurodegeneration and Dementia

Abstract

This invention relates to novel compounds having the structural formula I below: and to their pharmaceutically acceptable salt, compositions and methods of use. These novel compounds provide a treatment or prophylaxis of cognitive impairment, Alzheimer Disease, neurodegeneration and dementia.

A compound of Formula I

wherein
R1 is selected from hydrogen, C1-6alkyl, C3-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, C5-7cycloalkenyl, aryl, heteroaryl, heterocyclyl, C1-6alkylC3-6cycloalkyl, C1-6alkylaryl, C1-6alkylheteroaryl and C1-6alkylheterocyclyl, wherein the C1-6alkyl, C3-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, C5-7cycloalkenyl, aryl, heteroaryl, heterocyclyl, C1-6alkylC3-6cycloalkyl, C1-6alkylaryl, C1-6alkylheteroaryl or C1-6alkylheterocyclyl is optionally substituted with one, two or three A;
R2 is selected from hydrogen, nitro, cyano, -Q-C1-6alkyl, -Q-C2-6alkenyl, -Q-C2-6alkynyl, -Q-C3-6cycloalkyl, -Q-C5-7cycloalkenyl, -Q-C1-6alkylC3-6cycloalkyl, -Q-aryl, -Q-heteroaryl, -Q-C1-6alkylaryl, -Q-C1-6alkylheteroaryl, -Q-heterocyclyl, and -Q-C1-6alkylheterocyclyl, wherein said -Q-C1-6alkyl, -Q-C2-6alkenyl, -Q-C2-6alkynyl, -Q-C3-6cycloalkyl, -Q-C5-7cycloalkenyl, -Q-C1-6alkylC3-6cycloalkyl, -Q-aryl, -Q-heteroaryl, -Q-C1-6alkylaryl, -Q-C1-6alkylheteroaryl, -Q-heterocyclyl, or -Q-C1-6alkylheterocyclyl is optionally substituted by one, two or three R7;
-Q- is a direct bond, —CONH—, —CO—, —CON(C1-6alkyl)-, —CON(C3-6cycloalkyl)-, —SO—, —SO2—, —SO2NH—, —SO2N(C1-6alkyl)-, —SO2N(C3-6cycloalkyl)-, —NHSO2—, —N(C1-6alkyl)SO2—, —NHCO—, —N(C1-6alkyl)CO—, —N(C3-6cycloalkyl)CO— or —N(C3-6cycloalkyl)SO2—;
R3 is (C(R4)(R5))nR6, C2-4alkenylR6, C2-4alkynylR6, C5-7cycloalkenylR6, nitro or cyano and if n>1 then each C(R4)(R5) is independent of the others;
R4 and R5 are independently selected from hydrogen, C1-6alkyl, cyano, halo and nitro;
or R4 and R5 together form oxo, C3-6cycloalkyl or heterocyclyl;
R6 is selected from methyl, C3-6cycloalkyl, heterocyclyl, aryl and heteroaryl wherein each of said methyl, C3-6cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with between one and four R7, and wherein any of the individual aryl or heteroaryl groups may be optionally fused with a 4, 5, 6 or 7 membered cycloalkyl, cycloalkenyl or heterocyclyl group to form a bicyclic ring system where the bicyclic ring system is optionally substituted with between one and four A with the proviso that the bicyclic ring is not an indane, benzo[1,3]dioxole or 2,3-dihydrobenzo[1,4]-dioxine ring system;
R7 is selected from halogen, nitro, CHO, C0-6alkylCN, OC1-6alkylCN, C0-6alkylOR8, OC2-6alkylOR8, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, C0-6alkylNR8R9, OC2-6alkylNR8R9, OC2-6alkylOC2-6alkylNR8R9, NR3OR9, C0-6alkylCO2R8, OC1-6alkylCO2R8, C0-6alkylCONR8R9, OC1-6alkylCONR8R9, OC2-6alkylNR8(CO)R9, C0-6alkylNR8 (CO)R9, O(CO)NR8R9, NR8(CO)OR9, NR8(CO)NR8R9, O(CO)OR8, O(CO)R8, C0-6alkylCOR8, OC1-6alkylCOR3, NR8(CO)(CO)R8, NR8(CO)(CO)NR8R9, C0-6alkylSR8, C0-6alkyl(SO2)NR3R9, OC1-6alkylNR3(SO2)R9, OC0-6alkyl(SO2)NR3R9, C0-6alkyl(SO)NR3R9, OC1-6alkyl(SO)NR3R9, OSO2R8, SO3R8, C0-6alkylNR8(SO2)NR8R9, C0-6alkylNR3(SO)R9, OC2-6alkylNR8(SO)R8, OC1-6alkylSO2R3, C1-6alkylSO2R8, C0-6alkylSOR8, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, C0-6alkylheteroaryl, C0-6alkylheterocyclyl, and OC2-6alkylheterocyclyl, wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, C0-6alkylheteroaryl, C0-6alkylheterocyclyl, and OC2-6alkylheterocyclyl may be optionally substituted by one or more R14, and wherein any of the individual aryl or heteroaryl groups may be optionally fused with a 4, 5, 6 or 7 membered cycloalkyl, cycloalkenyl or heterocyclyl group to form a bicyclic ring system where the bicyclic ring system is optionally substituted with between one and four A with the proviso that said bicyclic ring system is not an indane, benzo[1,3]dioxole or 2,3-dihydrobenzo[1,4]-dioxine ring system;
R14 is selected from halogen, nitro, CHO, C0-6alkylCN, OC1-6alkylCN, C0-6alkylOR8, OC1-6alkylOR8, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, C0-6alkylNR8R9, OC2-6alkylNR8R9, OC2-6alkylOC2-6alkylNR8R9, NR8OR9, C0-6alkylCO2R8, OC1-6alkylCO2R8, C0-6alkylCONR8R9, OC1-6alkylCONR8R9, OC2-6alkylNR8(CO)R9, C0-6alkylNR8 (CO)R9, O(CO)NR8R9, NR8(CO)OR9, NR8(CO)NR8R9, OR8, O(CO)OR8, O(CO)R8, C0-6alkylCOR8, OC1-6alkylCOR8, NR8(CO)(CO)R8, NR8(CO)(CO)NR8R9, C0-6alkylSR8, C0-6alkyl(SO2)NR8R9, OC2-6alkylNR3(SO2)R9, OC0-6alkyl(SO2)NR8R9, C0-6alkyl(SO)NR8R9, OC1-6alkyl(SO)NR8R9, OSO2R8, OSO2R8R9, SO3R8, C0-6alkylNR8(SO2)NR8R9, C0-6alkylNR8(SO)R9, OC2-6alkylNR8(SO)R8, OC1-6alkylSO2R8, C1-6alkylSO2R8, C0-6alkylSOR8, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, C0-6alkylheteroaryl, C0-6alkylheterocyclyl and OC2-6alkylheterocyclyl wherein any C1-16alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, C0-6alkylheteroaryl, C0-6alkylheterocyclyl and OC2-6alkylheterocyclyl may be optionally substituted by between one and four A;
R8 and R9 are independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, C0-6alkylheteroaryl, C0-6alkylheterocyclyl and C0-6alkylNR10R11, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, C0-6alkylheteroaryl or C0-6alkylheterocyclyl are optionally substituted by A;
or
R8 and R9 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O and S that is optionally substituted by A;
whenever two R8 groups occur in the structure then they may optionally together form a 5 or 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O and S, that is optionally substituted by A;
R10 and R11 are independently selected from hydrogen, C1-6alkyl, C3-6alkenyl, C3-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, C0-6alkylheterocyclyl and C0-6alkylheteroaryl, wherein the C1-6alkyl, C3-6alkenyl, C3-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, C0-6alkylheteroaryl, C0-6alkylheterocyclyl are optionally substituted by A;
or
R10 and R11 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O and S optionally substituted by A;
n is 0, 1, 2 or 3
A is selected from oxo, halogen, nitro, CN, OR12, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylaryl, C0-6alkylheteroaryl, C0-6alkylC3-6cycloalkyl, C0-6alkylheterocyclyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, OC2-6alkylNR12R13, NR12R13, CONR12R13, NR12(CO)R13, O(CO)C1-6alkyl, (CO)OC1-6alkyl, COR12, (SO2)NR12R13, NSO2R12, SO2R12, SOR12, (CO)C1-6alkylNR12R13, (SO2)C1-6alkylNR12R13, OSO2R12, and SO3R12 wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylaryl, C0-6alkylheteroaryl, C0-6alkylheterocyclyl and C0-6alkylC3-6cycloalkyl groups may be optionally substituted with halo, OSO2R12, SO3R12, nitro, cyano, OR12, C1-6alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy or trifluoromethoxy;
R12 and R13 are independently selected from hydrogen, C1-6alkyl, C3-6cycloalkyl, aryl, heteroaryl and heterocyclyl wherein said C1-6alkyl, C3-6cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted by one, two or three hydroxy, cyano, halo or C1-3alkyloxy;
or
R12 and R13 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O and S optionally substituted by hydroxy, C1-3alkyloxy, cyano or halo;
provided that either any of the aryl or heteroaryl groups in R1, R2 or R3 is substituted with a OSO2R8, SO3R8, OSO2R12 or SO3R12 group;
or
provided that any of the individual aryl or heteroaryl groups in R1, R2 or R3 are fused with a 4, 5, 6 or 7 membered cycloalkyl, cycloalkenyl or heterocyclyl group to form a bicyclic ring system where the bicyclic ring system is optionally substituted with between one and four A with the proviso that the bicyclic ring is not an indane, benzo[1,3]dioxole or 2,3-dihydrobenzo[1,4]-dioxine ring system;
or
provided that R1 is C3-6alkynyl or C5-7cycloalkenyl optionally substituted with one, two or three A;
or
provided that Q is selected from —NHSO2—, —N(C1-6alkyl)SO2—, —SO2NH—, —SO2N(C1-6alkyl)-SO2N(C3-6cycloalkyl)-, —SO—, —SO2— and —N(C3-6cycloalkyl)SO2—;
or
provided that R3 is selected from C2-4alkenylR6, C2-4alkynylR6, C5-7cycloalkenylR6, nitro and cyano;
or
provided that R2 is selected from nitro, cyano, C2-6alkynyl, C5-7cycloalkenyl and C2-6alkenyl group where the C2-6alkynyl, C5-7cycloalkenyl or C2-6alkenyl group is optionally substituted by one, two or three R7;
as a free base or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof.

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Novel 2-Amino-Imidazole-4-One Compounds and Their Use in the Manufacture of a Medicament to Be Used in the Treatment of Cognitive Impairment, Alzheimer's Disease, Neurodegeneration and Dementia

Life of this patent

Novel 2-Amino-Imidazole-4-One Compounds and Their Use in the Manufacture of a Medicament to Be Used in the Treatment of Cognitive Impairment, Alzheimer's Disease, Neurodegeneration and Dementia

Life of this patent

Abstract

Claims40