Macrocyclic beta-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 1 is
R 2 is —N(R 5 )C(O)R 4 —;
R 3 is arylene, heteroarylene, heterocyclylene or cycloalkylene;
R 4 is arylene, heteroarylene, heterocyclylene or cycloalkylene;
R 5 is hydrogen, alkyl, aryl, heteroaryl or cycloalkyl;
R 6 and R 7 (when present) are independently selected from hydrogen, —OH, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl, aralkoxy, heteroaralkoxy and alkoxy, with the proviso that when R 6 and R 7 are —OH, aralkoxy, heteroaralkoxy and alkoxy, R 6 and R 7 are not attached to a ring carbon adjacent to a ring nitrogen;
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 cannot be —C(O)R 9 , —C(O)OR 12 , —S(O)R 9 , —S(O 2 )R 9 or —CN;
R 9 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl or —N(R 10 )(R 11 );
R 10 and 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
o is 0, 1, 2, or 3;
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, heteroarylene, heterocyclyl, heterocyclylalkyl, heterocyclylene, cycloalkylene, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, aralkoxy or heteroaralkoxy 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 1 is
3. The compound of claim 1 wherein R 3 is arylene.
4. The compound of claim 3 wherein R 3 is phenylene or halo-substituted phenylene.
5. The compound of claim 3 wherein R 3 is
6. The compound of claim 3 wherein R 3 is
7. The compound of claim 1 wherein R 4 is arylene.
8. The compound of claim 1 wherein R 4 is phenylene.
9. The compound of claim 1 wherein R 4 is
10. The compound of claim 1 wherein R 5 is alkyl.
11. The compound of claim 10 wherein R 5 is propyl.
12. The compound of claim 1 wherein m is 2 and n is 1.
13. The compound of claim 1 wherein R 7 is hydrogen.
14. The compound of claim 1 wherein X is O.
15. The compound of claim 1 wherein Y is O.
16. The compound of claim 1 wherein R 8 is aralkyl or —S(O 2 )R 9 .
17. The compound of claim 1 wherein R 8 is
18. The compound of claim 1 wherein
R 1 is
R 2 is —N(R 5 )C(O)R 4 —;
R 3 is arylene
R 4 is arylene or heterocyclylene;
R 5 is alkyl;
R 7 is hydrogen;
R 8 is aralkyl or —S(O 2 )R 9 ;
m is 2;
n is 1;
X is O; and
Y is O.
19. The compound of claim 18 wherein R 3 is phenylene or halo-substituted phenylene.
20. The compound of claim 19 wherein R 3 is
21. The compound of claim 20 wherein R 3 is
22. The compound of claim 18 wherein R 4 is arylene.
23. The compound of claim 18 wherein R 4 is
24. The compound of claim 18 wherein R 2 is heterocyclylene or heterocyclylene substituted with ═O.
25. The compound of claim 18 wherein R 5 is propyl.
26. The compound of claim 18 wherein R 8 is
27. A compound of claim 1 having the stereochemical structure
28. A compound of claim 1 selected from the group consisting of
29. A pharmaceutical composition comprising an effective amount of a compound of claim 1 and a pharmaceutically effective carrier.
30. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , and an effective amount of a cholinesterase inhibitor in a pharmaceutically effective carrier.