Piperidines and related compounds for treatment of alzheimer's disease
View Patent ↗Compounds of formula I: selectively inhibit production of Aβ(1-42) and hence are useful in treatment or prevention of disease associated with deposition of β-amyloid in the brain.
1. A compound of formula II or formula III:
or a pharmaceutically acceptable salt thereof wherein
p is 0 or 1;
X represents a bond or C(R 1 ) 2 or CH 2 C(R 1 ) 2 ;
Y represents a bond or CH 2 or CH 2 CH 2 ;
m is 0 or 1;
R 7 is H or a hydrocarbon group of up to 10 carbon atoms, and A′ represents a 3- to 12-membered carbocyclic ring system optionally having one or more acyclic hydrocarbon groups attached thereto, such that the total number of carbon atoms in the moiety A′—(CHR 7 )m- is in the range of 5 to 25; A′ and R 7 optionally and independently bearing one or more additional substituents, up to a maximum of 5 in combined total, selected from halogen, CN, N 3 , NO 2 , C 1-4 perfluoroalkyl, OR 6 , SR 6 , OH, CO 2 R 6 , OCOR 6 and COR 6 ;
each R 1 independently represents H or a non-aromatic hydrocarbon group of up to 6 carbon atoms; or the two R 1 groups complete a C 3-6 alicyclic group;
R 2 represents a non-aromatic hydrocarbon group of up to 6 carbon atoms;
each R 5 independently represents halogen, CN, NO 2 , R 6 , OR 6 , CO 2 R 6 , OCOR 6 or COR 6 ; and
R 6 represents a hydrocarbon group of up to 7 carbon atoms which is optionally substituted with up to 3 halogen atoms.
2. A compound according to claim 1 of Formula II:
or a pharmaceutically acceptable salt thereof.
3. A compound of claim 1 of formula III:
or a pharmaceutically acceptable salt thereof.
4. A compound according to claim 1 of formula IV:
or a pharmaceutically acceptable salt thereof wherein:
R a represents H, halogen or CF 3 ;
R b , R c and R d are independently selected from H, halogen, CN, N 3 , C 1-4 perfluoroalkyl, C 1-4 alkoxy, OCF 3 , SCF 3 , C 1-4 alkyl, C 2-4 alkenyl, and phenyl which is optionally substituted with halogen or C 1-2 perfluoroalkyl, provided that R b , R c and R d together contain not more than 8 carbon atoms; and
R 7a represents a hydrocarbon group of up to 10 carbon atoms optionally bearing a C 1-4 perfluoroalkyl substituent or up to 2 halogen substituents.
5. A compound according to claim 4 in which R b , R c and R d complete a group selected from phenyl, vinylphenyl, fluorophenyl, chlorophenyl, bromophenyl, iodophenyl, isopropylphenyl, tert-butylphenyl, trifluoromethylphenyl, pentafluoroethylphenyl, cyanophenyl, methoxyphenyl, trifluoromethoxyphenyl, difluoromethoxyphenyl, trifluoromethylthiophenyl, biphenyl, 4′-trifluoromethylbiphenyl, bis(trifluoromethyl)phenyl, dichlorophenyl, dimethylphenyl, 5-fluoro-2-(trifluoromethyl)phenyl, 5-chloro-2-(trifluoromethyl)phenyl, 2-chloro-5-(trifluoromethyl)phenyl, 5-propyl-2-(trifluoromethyl)phenyl and 2-propyl-5-(trifluoromethyl)phenyl.
6. A compound according to claim 4 in which R 7a represents a branched alkyl group of up to 6 carbon atoms, or a branched alkenyl group of up to 6 carbon atoms, or a branched alkynyl group of up to 6 carbon atoms.
7. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
8. A compound according to claim 1 wherein R 5 is selected from halogen, R 6 and OR 6 , and R 6 represents C 1-6 alkyl bearing 0-3 fluorine substituents or C 2-6 alkenyl.