Compounds for the treatment of diseases associated with amyloid or amyloid-like proteins
The present invention relates to novel compounds that can be employed in the treatment of a group of disorders and abnormalities associated with amyloid protein, such as Alzheimer's disease, and of diseases or conditions associated with amyloid-like proteins. The compounds of the present invention can also be used in the treatment of ocular diseases associated with pathological abnormalities/changes in the tissues of the visual system. The present invention further relates to pharmaceutical compositions comprising these compounds and to the use of these compounds for the preparation of medicaments for treating or preventing diseases or conditions associated with amyloid and/or amyloid-like proteins. A method of treating or preventing diseases or conditions associated with amyloid and/or amyloid-like proteins is also disclosed.
1. A compound having the formula (I):
A-L 1 -B (I)
and all stereoisomers, racemic mixtures, and pharmaceutically acceptable salts thereof;
wherein A is:
L 1 is:
B is:
wherein
R 2 and R 3 are each independently selected from the group consisting of hydrogen, halogen, —CN, —CF 3 , —CONR 30 R 31 , —N(R 30 )—C(O)—R 31 , a —O—C 1 -C 6 alkyl, and C 5 -C 10 heterocycloalkyl, or wherein R 2 and R 3 taken together form a 5- or 6-membered ring containing carbon atoms and optionally one or two heteroatoms selected from O, S, or N;
R 1 is hydrogen or halogen;
R a is hydrogen or C 1 -C 6 alkyl;
for each occurrence, R b is independently selected from the group consisting of: hydrogen, halogen, CN, CONR 30 R 31 , or C 1 -C 6 alkyl;
for each occurrence, R 30 , R 31 , and R 20 are each independently selected from the group consisting of hydrogen, or C 1 -C 6 alkyl;
Y is CH or N; and
z is 1 or 2.
2. The compound of claim 1 , wherein Y is N.
3. The compound of claim 1 , wherein Y is CH.
4. The compound of claim 1 , wherein z is 1.
5. The compound of claim 1 , wherein z is 2.
6. The compound of claim 1 , wherein Y is N and z is 2.
7. The compound of claim 1
wherein
B is:
8. The compound of claim 7
wherein
B is:
9. The compound of claim 8
wherein A is:
L 1 is:
and
B is:
10. The compound of claim 9 , comprising:
11. The compound of claim 9 , comprising:
12. The compound of claim 1
wherein
B is:
13. The compound of claim 1 , wherein the compound is selected from:
14. A pharmaceutical composition comprising the compound of claim 1 .
15. The pharmaceutical composition of claim 14 , further comprising a pharmaceutically acceptable carrier or excipient.
16. The composition of claim 15 further comprising a cholinesterase inhibitor (ChEI).
17. The composition of claim 15 further comprising: pirenzepin, 3-amino-1-propanesulfonic acid (3APS), 1,3-propanedisulfonate (1,3PDS), α-secretase activator, βsecretase, γ-secretase inhibitor, tau protein, pyroglutamated amyloid beta 3-42, M1 agonists, neurotransmitters, β-sheet breakers, tacrine, rivastigmine, donepezil, galantamine, niacin and memantine.
18. The compound of claim 1 wherein the compound comprises a radionuclide.