Macrocyclic β-secretase inhibitors
View Patent ↗Disclosed are novel compounds of the formula or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 , R 2 , R 3 , n and X are as defined in the specification. Also disclosed are pharmaceutical compositions comprising the compounds of formula I. Also disclosed are methods of treating cognitive or neurodegenerative diseases such as Alzheimer's disease. Also disclosed are methods of treating a cognitive or neurodegenerative disease comprising administering to a patient I need of such treatment a combination of at least one compound of formula I and at least one compound selected from the group consisting of β-secretase inhibitors other than those of formula I, HMG-CoA reductase inhibitors, gamma-secretase inhibitors, non-steroidal anti-inflammatory agents, N-methyl-D-aspartate receptor antagonists, cholinesterase inhibitors and anti-amyloid antibodies.
1. A compound having the structural formula
or a pharmaceutically acceptable salt thereof, wherein
R 2 is a heterocyclylene ring or a heterocyclylene ring substituted with ═O;
R 3 is arylene;
R 5 is hydrogen, alkyl, aryl, heteroaryl, or cycloalkyl;
R 8 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, —C(O)R 9 , —C(O)OR 12 , —S(O)R 9 , —S(O 2 )R 9 or —CN; with the proviso that when Y is ═O, R 8 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl;
R 9 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl or —N(R 10 )(R 11 );
R 10 R 11 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, alkenyl and alkynyl;
or R 10 and R 11 together with the nitrogen to which they are attached, form a 3-7 membered heterocyclyl ring;
R 12 is alkyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, alkenyl or alkynyl;
X is O, S, —C(R 5 ), or —NH;
Y is ═O, or (H,H);
m is 1, 2, or 3;
n is 0, 1, 2, or 3; and
wherein each alkyl is optionally substituted with 1 to 3 moieties selected from the group consisting of halo, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, —NH(alkyl), —NH(cycloalkyl), —N(alkyl) 2 , carboxy and —C(O)O—alkyl; and
wherein each arylene, heterocyclyl, heterocyclylalkyl, heterocyclylene, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, or heteroaralkyl is optionally substituted with 1 to 4 moieties selected from the group consisting of —CF 3 , alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, —C(═N—CN)—NH 2 , —C(═NH)—NH 2 , —C(═NH)—NH(alkyl), Y 1 Y 2 N—, Y 1 Y 2 N—alkyl-, Y 1 Y 2 NC(O)—, Y 1 Y 2 NSO 2 — and —SO 2 NY 1 Y 2 , wherein Y 1 and Y 2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl, with the proviso that cycloalkylene and heterocyclylene can be substituted with ═O.
2. The compound of claim 1 wherein R 3 is phenylene or halo-substituted phenylene.
3. The compound of claim 1 wherein R 3 is
4. The compound of claim 1 wherein R 3 is
5. The compound of claim 1 wherein R 2 is heterocyclylene.
6. The compound of claim 5 wherein R 2 is heterocyclylene substituted with ═O.
7. The compound of claim 6 wherein R 2 is
8. The compound of claim 1 wherein m is 2 and n is 1.
9. The compound of claim 1 wherein X is O.
10. The compound of claim 1 wherein Y is O.
11. The compound of claim 1 wherein R 8 is aralkyl or —S(O 2 )R 9 .
12. The compound of claim 1 wherein R 8 is
13. The compound of claim 1 wherein
R 2 is heterocyclylene substituted with ═O;
R 3 is arylene
R 8 is aralkyl or —S(O 2 )R 9 ;
m is 2;
n is 1;
X is O; and
Y is O.
14. The compound of claim 13 wherein R 3 is phenylene or halo-substituted phenylene.
15. The compound of claim 14 wherein R 3 is
16. The compound of claim 15 wherein R 3 is
17. The compound of claim 13 wherein R 2 is
18. The compound of claim 13 wherein R 8 is
19. A compound of claim 1 having the stereochemical structure
20. A compound, or a pharmaceutically acceptable salt thereof, said compound having a structural formula:
21. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically effective carrier.
22. A compound, or a pharmaceutically acceptable salt thereof, said compound having a structural formula:
23. A pharmaceutical composition comprising a compound of claim 20 and a pharmaceutically effective carrier.
24. A pharmaceutical composition comprising a compound of claim 22 and a pharmaceutically effective carrier.