NOVELTY - Bridged N-cyclic sulfonamido compounds (I) and their stereoisomers and/or tautomers or salts are new.
USE - For treating Alzheimer's disease (claimed), Down's syndrome, hereditary cerebral hemorrhage with Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy, other degenerative dementias (including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, age related macular degeneration or diffuse Lewy body type of Alzheimer's disease); preventing single and recurrent lobar hemorrhages.
ADVANTAGE - (I) Are potent inhibitors of gamma-secretase.
DETAILED DESCRIPTION - Bridged N-cyclic sulfonamido compounds of formula A-S(O2)-N(R1)(R2) (I) and their stereoisomers and/or tautomers or salts are new.
A=(hetero)aryl or (hetero)cycloalkyl (all optionally substituted with T, haloalkyl, aryloxy, S(O)0-2-(1-6C alkyl), NR10R11, 1-6C alkanoyl, 0-3C alkyl-CO2Ra, (hetero)aryl, heterocycloalkyl, arylalkyl or SO2NR10R11);
T=halogen, 1-6C alkyl, 2-6C alkenyl, 2-6C alkynyl, 1-6C alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl or CN;
NR1R2=(3.3.1) or a (3.2.1) ring system (where the nitrogen is attached to the two bridgehead carbons, where optionally 1 carbon in the ring system is optionally replaced with O, S(O)0-2, or NR15, and the (3.3.1) or (3.2.1) ring system is optionally mono - tetra-substituted with oxo, 1-6C haloalkyl, C(O)OR13, (1-4C alkyl)-C(O)OR13, CONR10R11, OC(O)NR10R11, NRaC(O)ORb, NRaS(O)2Rb, OS(O)2Rb, NRaC(O)Rb, =N-NR12 or =N-O-R13);
R10 and R11=H or 1-6C alkyl (optionally substituted with aryl (optionally mono- - penta-substituted with T1);
T1=halogen, hydroxyl, (halo)alkyl, (halo)alkoxy or CN or NO2;
R10R11=3-8 membered ring optionally including an additional heteroatom such as N, O or S;
R12=H, 1-6C alkyl or SO2-aryl (optionally mono- - penta-substituted with T1);
R13=H or 1-6C alkyl (optionally substituted with aryl (such as phenyl or naphthyl, preferably phenyl) (optionally mono -penta-substituted with T1), hydroxyl or halogen;
R15=H, (hetero)aryl, heterocycloalkyl, SO2Ra, C(O)Ra, C(O)ORa or 1-6C alkyl (optionally substituted with aryl (optionally mono- - penta-substituted with T1, amino, NH(1-6C alkyl), N(1-6C alkyl)(1-6C alkyl)), hydroxyl or halogen;
Ra and Rb=H, 1-6C alkyl, haloalkyl, 2-6C alkenyl or phenyl (optionally mono- - penta-substituted with halogen, 1-6C alkyl, C(O)ORa, 1-6C alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, aryloxy, SO2-(1-6C alkyl), NR10R11, 1-6C alkanoyl, pyridyl, phenyl, NO2 or SO2NR10R11).
The two adjacent carbons (not including the bridgehead carbons) in the (3.3.1) or (3.2.1) ring system of NR1R2 combines to form part of a fused heteroaryl or heterocycloalkyl ring (both optionally substituted with 1-6C alkyl, 3-8C cycloalkyl, 2-6C alkenyl, 2-6C alkynyl, 1-6C alkoxy, amino, 1-6C alkylamino, 1-6C dialkylamino, S(O)0-2Rb, hydroxy, hydroxyalkyl, halo, 1-2C haloalkyl, 1-2C haloalkoxy, NRaO(O)Rb, -NRaSO2Rb, C(O)Ra, C(O)ORa, C(O)alkyl-OC(O)Ra, C(O)NR10R11, oxo, CN or 0-1C alkylphenyl (where phenyl is optionally mono- - penta-substituted with halogen, 1-6C alkyl, CO2Ra, 1-6C alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, NO2, aryloxy, S(O)0-2-(1-6C alkyl), NR10R11, 1-6C alkanoyl, pyridyl, phenyl or SO2NR10R11)), and additionally, two adjacent carbons in the (3,3.1) or the (3.2.1) ring system (not including the bridgehead carbons) optionally combine with at least one C, CH and/or CH2 to form a cycloalkyl (optionally substituted with at least one of halogen, 1-6C alkyl or haloalkyl).
