| 主权项 |
1. A method of treatment of a disease selected from the group consisting:
inflammatory host responses, impaired humoral and cell-mediated immune responses, leukocyte adhesion and migration processes in the endothelium, multiple sclerosis, Guillain-Barré syndrome, chronic inflammatory demyelinizing polyradiculoneuropathy, mild cognitive impairment, Alzheimer's disease, Familial British Dementia, Familial Danish Dementia, neurodegeneration in Down Syndrome, Huntington's disease, rheumatoid arthritis, atherosclerosis, pancreatitis and restenosis, which comprises administering to a subject an effective amount of a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I), wherein said compound of formula (I) is the compound: or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof, wherein: (a) R1 represents heteroaryl, -carbocyclyl-heteroaryl, -C2-6alkenylheteroaryl, —C1-6alkylheteroaryl, or (CH2)aCR5R6(CH2)bheteroaryl wherein a and b independently represent integers 0-5 provided that a+b =0-5 and R5 and R6 are alkylene which together with the carbon to which they are attached form a C3-C5 cycloalkyl group; in which any of aforesaid heteroaryl groups may optionally be substituted by one or more groups selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, —C1-6thioalkyl, —SOC1-4alkyl, —SO2C1-4alkyl, C1-6alkoxy-, —O—C3-8cycloalkyl, C3-8cycloalkyl, —SO2C3-8cycloalkyl, —SOC3-6cycloalkyl, C3-6alkenyloxy-, C3-6alkynyloxy-, —C(O)C1-6alkyl, —C(O)OC1-6alkyl, C1-6alkoxy-C1-6alkyl-, nitro, halogen, cyano, hydroxyl, —C(O)OH, —NH2, —NHC1-4alkyl, —N(C1-4alkyl)(C1-4alkyl), —C(O)N(C1-4alkyl)(C1-4alkyl), —C(O)NH2, —C(O)NH(C1-4alkyl) and —C(O)NH(C3-10cycloalkyl); and in which any of aforesaid carbocyclyl groups may optionally be substituted by one or more groups selected from C1-4alkyl, oxo, halogen and C1-4alkoxy; (b) R2 and R3 are independently selected as follows,
(i) R2 represents
(1) H, C1-8alkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, —C1-4alkylaryl, —C1-4alkylheteroaryl, —C1-4alkylcarbocyclyl or —C1-4alkylheterocyclyl;in which any of aforesaid aryl and heteroaryl groups may optionally be substituted by one or more groups selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, —C1-6thioalkyl, —SOC1-4alkyl, —SO2C1-4alkyl, C1-6alkoxy-, —O—C3-8cycloalkyl, C3-8cycloalkyl, —SO2C3-8cycloalkyl, —SOC3-6cycloalkyl, C3-6alkenyloxy-, C3-6alkynyloxy-, —C(O)C1-6alkyl, —C(O)OC1-6alkyl, C1-6alkoxy-C1-6alkyl-, C1-6alkoxy-C1-6alkoxy-, nitro, halogen, haloC1-6alkyl, haloC1-6alkoxy, cyano, hydroxyl, —C(O)OH, —NH2, —NHC1-4alkyl, —N(C1-4alkyl)(C1-4alkyl), —N(C1-4alkyl)(C1-4alkyl)-N(C1-4alkyl)(C1-4alkyl), —C1-4alkyl-N(C1-4alkyl)(C1-4alkyl), —C1-4alkoxy-N(C1-4alkyl)(C1-4alkyl), —N(C3-8cycloalkyll)(C3-8cycloalkyl), —N(—C1-6alkyl-C1-6alkoxy)(-C1-6alkyl-C1-6alkoxy), —C(O)N(C1-4alkyl)(C1-4alkyl), —C(O)NH2, —C(O)NH(C1-4alkyl) and —C(O)NH(C3-10cycloalkyl); andin which any of aforesaid carbocyclyl and heterocyclyl groups may optionally be substituted by one or more groups selected from C1-4alkyl, oxo, halogen, —C(O)C1-6alkyl and C1-4alkoxy; or(2) phenyl substituted by phenyl, phenyl substituted by a monocyclic heteroaryl group, phenyl substituted by phenoxy, phenyl substituted by heterocyclyl, phenyl substituted by heterocyclyl wherein said heterocyclyl is substituted by phenyl, phenyl substituted by —O—C1-4alkyl-heterocyclyl, phenyl substituted by benzyloxy, phenyl substituted by carbocyclyl, phenyl substituted by carbocyclyl wherein said carbocyclyl is substituted by heterocyclyl, phenyl substituted by —O-carbocyclyl, heterocyclyl substituted by phenyl, carbocyclyl substituted by phenyl, phenyl fused to carbocyclyl, phenyl fused to heterocyclyl, —C1-4alkyl(phenyl substituted by phenyl), —C1-4alkyl(phenyl substituted by a monocyclic heteroaryl group), —C1-4alkyl(phenyl substituted by a monocyclic heterocyclyl group), —C1-4alkyl(phenyl substituted by an —O-carbocyclyl group), —C1-4alkyl(phenyl substituted by benzyloxy), —C1-4alkyl(optionally substituted phenyl fused to optionally substituted carbocyclyl or —C1-4alkyl(optionally substituted phenyl fused to optionally substituted heterocyclyl);in which any of aforesaid phenyl, benzyloxy and heteroaryl groups may optionally be substituted by one or more groups selected from C1-4alkyl, halogen and C1-4alkoxy, andin which any of aforesaid carbocyclyl and heterocyclyl groups may optionally be substituted by one or more groups selected from methyl, phenyl, oxo, halogen, hydroxyl and C1-4alkoxy; and(ii) R3 represents H, —C1-4alkyl or aryl;
in which aforesaid aryl may optionally be substituted by one or more groups selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, —C1-6thioalkyl, —SOC1-4alkyl, —SO2C1-4alkyl, C1-6alkoxy-, —O—C3-8cycloalkyl, C3-8cycloalkyl, —SO2C3-8cycloalkyl, —SOC3-6cycloalkyl, C3-6alkenyloxy-, C3-6alkynyloxy-, —C(O)C1-6alkyl, —C(O)OC1-6alkyl, C1-6alkoxy-C1-6alkyl-, nitro, halogen, cyano, hydroxyl, —C(O)OH, —NH2, —NHC1-4alkyl, —N(C1-4alkyl)(C1-4alkyl), —C(O)N(C1-4alkyl)(C1-4alkyl), —C(O)NH2, —C(O)NH(C1-4alkyl) and, —C(O)NH(C3-10cycloalkyl); or (c) R2 and R3 are jointly selected as follows,
(1) R2 and R3 are joined to form a carbocyclyl ring which is optionally substituted by one or more C1-2alkyl groups;(2) R2 and R3 are joined to form a carbocyclyl ring which is fused to phenyl, wherein aforesaid carbocyclyl and/or phenyl may optionally be substituted by one or more groups selected from C1-4alkyl, halogen and C1-4alkoxy; or(3) R2 and R3 are joined to form a carbocyclyl ring which is fused to monocyclic heteroaryl, wherein aforesaid carbocyclyl and/or heteroaryl may optionally be substituted by one or more groups selected from C1-4alkyl, halogen and C1-4alkoxy; (d) X and Z are independently selected as follows,
(i) X represents C═O, O, CR7R8, —O—CH2— or —CH2—CH2—; and(ii) Z represents —N—R4, O or CHR10, such that when X represents O, Z must represent CHR10; or (e) X and Z are jointly selected to represent two adjacent carbon atoms of a phenyl ring which is fused in that position and which is optionally substituted by one or more halogen or C1-2alkyl groups; and (f) Y represents CHR9, C═O or C═S; wherein,
R4 represents H, —C1-8alkyl, —C(O)C1-6alkyl or —NH2;R7 and R8 independently represent H, —C1-4alkyl or aryl;in which said aforesaid aryl may be optionally substituted by C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, —C1-6thioalkyl, —SOC1-4alkyl, —SO2C1-4alkyl, C1-6alkoxy-, —O—C3-8cycloalkyl, C3-8cycloalkyl, —SO2C3-8cycloalkyl, —SOC3-6cycloalkyl, C3-6alkenyloxy-, C3-6alkynyloxy-, —C(O)C1-6alkyl, —C(O)OC1-6alkyl,C1-6alkoxy-C1-6alkyl-, nitro, halogen, cyano, hydroxyl, —C(O)OH, —NH2, —NHC1-4alkyl, —N(C1-4alkyl)(C1-4alkyl), —C(O)N(C1-4alkyl)(C1-4alkyl), —C(O)NH2, —C(O)NH(C1-4alkyl) and, —C(O)NH(C3-10cycloalkyl); andR9 and R10 independently represent H or methyl;provided that the moiety —Y—Z—X— represents a moiety other than —C(═O)—N(—R4)—C(═O)— or —C(═S)—N(—R4)—C(═O)—. |
