Therapeutic agents
View Patent ↗The invention encompasses 2-[4-(imidazolyl)-phenyl]vinyl-heterocycle derivatives which selectively attenuate production of Abeta(1-42) and are useful in the treatment of Alzheimer's disease. Pharmaceutical compositions and methods of use are also encompassed.
1. A compound of formula I:
or a pharmaceutically acceptable salt thereof; wherein:
R 1 represents H, C 1-6 alkyl, C 3-6 cycloalkyl or C 2-6 alkenyl;
R 2 represents C 1-6 alkyl, C 3-6 cycloalkyl or C 2-6 alkenyl;
Het represents:
W represents C═O or SO 2 ;
each R 7 independently represents H or a substituent selected from:
alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkylalkyl groups, all of up to 10 carbon atoms, phenyl, naphthyl, 5- or 6-membered heterocyclyl, halogen, CN, NO 2 , CF 3 , OR 4 , COR 4 , CO 2 R 4 , OCOR 3 , N(R 4 ) 2 , CON(R 4 ) 2 , SR 3 , SO 2 R 3 , and SO 2 N(R 4 ) 2 ;
where said alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkylalkyl groups bear 0-1 substituents selected from halogen, CN, NO 2 , CF 3 , OR 6 , COR 6 , CO 2 R 6 , OCOR 5 , N(R 6 ) 2 , CON(R 6 ) 2 , SR 5 , S 2 R 5 , and SO 2 N(R 6 ) 2 ;
and said phenyl, naphthyl and 5- or 6-membered heterocyclyl bear 0-3 substituents selected from halogen, CN, NO 2 , R 5 , OR 6 , COR 6 , CO 2 R 6 OCOR 5 , N(R 6 ) 2 , CON(R 6 ) 2 , SR 5 , SO 2 R 5 , and SO 2 N(R 6 ) 2 ;
or two R 7 groups attached to adjacent ring atoms may together represent a fused ring system consisting of a phenyl or a 5- or 6-membered heteroaryl ring which is optionally fused to a further 5- or 6-membered carbocyclic or heterocyclic ring, said fused ring system bearing 0-3 substituents selected from halogen, CN, NO 2 , R 3 , OR 4 , COR 4 , CO 2 R 4 , OCOR 3 , N(R 4 ) 2 , CON(R 4 ) 2 , SR 3 , SO 2 R 3 , and SO 2 N(R 4 2 ; and
R 8 represents H, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl,C 1-4 alkyl, phenyl or benzyl wherein said phenyl and benzyl bear 0-2 substituents selected from halogen, CF 3 and C 1-4 alkyl;
R 3 represents C 1-6 alkyl, C 3-6 cycloalkyl, c 2-6 alkenyl, phenyl, benzyl or CF 3 ;
R 4 represents H or R 3 or two R 4 groups attached to the same nitrogen atom optionally complete a heterocyclic group of up to 7 ring atoms which bears 0-3 substituents selected from halogen, CF 3 , C 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkoxycarbonyl;
R 5 represents C 1-6 alkyl, phenyl or CF 3 ; and
R 6 represents H or R 5 or two R 6 groups attached to the same nitrogen atom optionally complete a heterocyclic group of up to 7 ring atoms which bears 0-3 substituents selected from halogen, CF 3 , C 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkoxycarbonyl.
2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein W represents C═O.
3. A compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein Het represents:
wherein R a , R b , R c and R d independently represent H, halogen, CN, NO 2 , R 3 , OR 4 , COR 4 , CO 2 R 4 , OCOR 3 , N(R 4 ) 2 , CON(R 4 ) 2 , SR 3 , SO 2 R 3 , and SO 2 N(R 4 ) 2 ; or R a together with R b , or R b together with R c or R c together with R d represents a fused 5- or 6-membered carbocyclic or heterocyclic ring; with the proviso that at least one of R a , R b , R c and R d is H.
4. A compound according to claim 3 or a pharmaceutically acceptable salt thereof wherein R a , R b , R c and R d independently represent H, halogen, CF 3 , C 0-1 alkyl, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, C 1-4 alkylsulfonyl or C 1-4 alkylcarbonyl, provided at least one of R a , R b , R c and R d is H.
5. A compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein Het represents:
where A represents O or S;
R a and R b independently represent H, halogen, CN, NO 2 , R 3 , OR 4 , COR 4 , CO 2 R 4 , OCOR 3 , N(R 4 ) 2 , CON(R 4 ) 2 , SR 3 , SO 2 R 3 , and SO 2 N(R 4 ) 2 ; or R a together with R b represents a fused 5- or 6-membered carbocyclic or heterocyclic ring.
6. A compound according to claim 5 or a pharmaceutically acceptable salt thereof wherein R a and R b independently represent H, halogen, CF 3 , C 1-4 alkyl, phenyl, C 1-4 alkylcarbonyl, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, C 1-4 alkoxylsulfonyl, or di(C 1-4 alkyl)aminocarbonyl, or together represent a fused 5- or 6-membered carbocyclic or heterocyclic ring.
7. A pharmaceutical composition comprising a compound of formula I as defined in claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.