Phosphodiesterase inhibitors and uses thereof
The invention provides for novel benzonaphthyridine derivatives and compositions comprising novel benzonaphthyridine derivatives. In some embodiments, the compounds are phosphodiesterase inhibitors. The invention further provides for methods for inhibition of phosphodiesterase comprising contacting phosphodiesterase with novel benzonaphthyridine derivatives or compositions comprising novel benzonaphthyridine derivatives. The invention further provides for methods for treatment of neurodegenerative diseases, increasing memory or long term potentiation with novel benzonaphthyridine derivatives or compositions comprising novel benzonaphthyridine derivatives. In some embodiments, the phosphodiesterase is PDE5.
1. A compound of formula (I),
or a pharmaceutically acceptable salt or tautomer thereof,
wherein
A is NH;
B is C 16 or N;
V is a bond;
W is a bond;
X is CH 2 or CD 2 ;
Y is N 5 ;
Z is CR 2 or N;
R 1 is F or Cl;
R 2 is F;
R 3 is CN;
R 5 is hydrogen or —(C 1 -C 3 )-alkyl;
R 14 is hydrogen or halogen;
R 15 is hydrogen, —OR 17 , —OH or halogen;
R 16 is hydrogen or —(C 1 -C 6 )-alkyl;
R 17 is —(C 1 -C 6 )-alkyl, —(C 1 -C 6 )-haloalkyl, or —(C 3 -C 8 )-cycloalkyl; and
m is 1; and
n is 2 4.
2. The compound of claim 1 , having formula (Ia):
3. The compound of claim 1 , having formula (Ib):
4. The compound of claim 1 , having formula (Ic):
5. The compound of claim 1 , wherein
R 16 is hydrogen.
6. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
7. A method of treating neurodegenerative disease in a subject in need thereof comprising administration of a therapeutically effective amount of a compound of claim 1 to said subject.
8. The method of claim 7 , wherein the neurodegenerative disease is Alzheimer's Disease.
9. A method of increasing long-term potentiation in a subject comprising administration of a therapeutically effective amount of a compound of claim 1 to said subject.
10. A method of improving memory in a subject comprising administration of a therapeutically effective amount of a compound of claim 1 to said subject.
11. The method of claim 10 , wherein the subject has a neurodegenerative disease.
12. The method of claim 11 , wherein the neurodegenerative disease is Alzheimer's Disease.
13. The compound of formula R, which is
or a pharmaceutically acceptable salt or tautomer thereof.
14. A method of treating neurodegenerative disease in a subject in need thereof comprising administration of a therapeutically effective amount of the compound of claim 13 to said subject.
15. The method of claim 14 , wherein the neurodegenerative disease is Alzheimer's Disease.
16. A method of improving memory in a subject comprising administration of a therapeutically effective amount of the compound of claim 13 to said subject.
17. The compound of formula AB, which is
or a pharmaceutically acceptable salt or tautomer thereof.
18. A method of treating neurodegenerative disease in a subject in need thereof comprising administration of a therapeutically effective amount of the compound of claim 17 to said subject.
19. The method of claim 18 , wherein the neurodegenerative disease is Alzheimer's Disease.
20. A method of improving memory in a subject comprising administration of a therapeutically effective amount of the compound of claim 17 to said subject.