Pyrimidine derivatives for treatment of alzheimer's disease
View Patent ↗The invention encompasses pyrimidine derivatives as gamma secretase modulators, useful for treating diseases associated with the deposition of beta-amyloid peptide in the brain, such as Alzheimer's disease, or of preventing or delaying the onset of dementia associated with such diseases. Pharmaceutical compositions and methods of use are included.
1. A compound of formula I:
or a pharmaceutically acceptable salt or hydrate thereof, wherein:
W represents CH;
Z represents N;
R 1 and R 2 independently represent H, C 1-4 alkyl, C 1-4 alkoxy, halogen or CF 3 ;
R 4 and R 5 independently represent H or (CH 2 ) m —X, where m is 0 or 1 and X represents halogen, 5- or 6-membered heteroaryl which is optionally substituted with up to 2 C 1-4 alkyl groups, CN, CF 3 , R 6 , OR 6 , N(R 6 ) 2 , SO 2 R 6 , CO 2 R 6 or CON(R 6 ) 2 where each R 6 independently represents H, phenyl, C 1-4 alkyl or hydroxyC 1-4 alkyl or two R 6 groups attached to the same nitrogen optionally complete an N-heterocycle; and
Ar represents a phenyl or 5- or 6-membered heteroaryl ring bearing from 2 to 4 substituents selected from:
(a) C 1-6 alkyl;
(b) C 3-6 cycloalkyl;
(d) C 3-6 cycloalkyl C 1-6 alkyl;
(e) C 2-6 alkenyl;
(f) OR 7 ;
(g) CO 2 R 7 ;
(h) N(R 7 ) 2
(i) SR 7 ; and
(j) CF 3 ;
where each R 7 represents C 1-6 alkyl.
2. A compound according to claim 1 or a pharmaceutically acceptable salt or hydrate thereof, wherein Ar represents:
where R 8 represents C 1-6 alkyl; and R 9 , R 10 and R 11 independently represent:
H;
C 1-6 alkyl;
OR 7 where R 7 represents C 1-6 alkyl;
CO 2 R 7 where R 7 represents C 1-6 alkyl; or
N(R 7 ) 2 where R 7 represents C 1-6 alkyl;
with the proviso that at least one of R 9 and R 10 is other than H and that R 11 is other than H.
3. A compound according to claim 2 of formula II:
or a pharmaceutically acceptable salt or hydrate thereof.
4. A compound according to claim 3 or a pharmaceutically acceptable salt or hydrate thereof, wherein at least one of R 4 and R 5 is H.
5. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.
6. A method of treating Alzheimer's disease, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt or hydrate thereof.