Spiro-lactam NMDA receptor modulators and uses thereof
Disclosed are compounds having enhanced potency in the modulation of NMDA receptor activity. Such compounds are contemplated for use in the treatment of conditions such as depression and related disorders. Orally available formulations and other pharmaceutically acceptable delivery forms of the compounds, including intravenous formulations, are also disclosed.
1. A compound represented by formula I:
or a pharmaceutically acceptable salt, a stereoisomer, or an N-oxide thereof, wherein
R b is selected from the group consisting of H, halogen, hydroxyl, cyano and C 1 -C 6 alkyl;
R is H or C 1 -C 6 alkyl;
R 1 is H or C 1 -C 6 alkyl;
R 2 is H or C 1 -C 6 alkyl;
R 3 is selected from the group consisting of H, C 1 -C 6 alkyl, —OH, C 1 -C 6 alkoxy, —CO 2 H, and —CONR′R′, wherein R′ for each occurrence is independently selected from the group consisting of H, C 1 -C 6 alkyl and a nitrogen protecting group; and
X is H, X′, —C 1 -C 6 alkylene-X′, or —C 1 -C 6 alkylene-C(O)—X′, wherein X′ is selected from the group consisting of:
(i) C 3 -C 6 cycloalkyl;
(ii) heterocyclyl including from 3 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C 1 -C 3 alkyl), O, and S;
(iii) phenyl; and
(iv) heteroaryl including from 5 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C 1 -C 3 alkyl), O, and S;
wherein X′ is optionally substituted by one or more substituents independently selected from the group consisting of halogen, hydroxyl, C 1 -C 6 alkyl and C 1 -C 6 alkoxy.
2. The compound of claim 1 , wherein R is H.
3. The compound of claim 1 , wherein R is C 1 -C 6 alkyl.
4. The compound of claim 1 , wherein R is methyl.
5. The compound of claim 1 , wherein R 1 is H.
6. The compound of claim 1 , wherein R 2 is H.
7. The compound of claim 1 , wherein R 3 is —CONR′R′.
8. The compound of claim 7 , wherein R′ for each occurrence is independently selected from H and a nitrogen protecting group.
9. The compound of claim 7 , wherein R′ for each occurrence is H.
10. The compound of claim 7 , wherein one R′ is H, and the other is a nitrogen protecting group.
11. The compound of claim 7 , wherein the nitrogen protecting group is para-methoxyphenyl.
12. The compound of claim 1 , wherein X is H.
13. The compound of claim 1 , wherein X is X′ or —C 1 -C 6 alkylene-X′.
14. The compound of claim 13 , wherein X is X′ or —CH 2 —X′.
15. The compound of claim 13 , wherein X′ is phenyl optionally substituted by one or more substituents independently selected from the group consisting of halogen, hydroxyl, C 1 -C 6 alkyl and C 1 -C 6 alkoxy.
16. The compound of claim 15 , wherein X′ is para-methoxyphenyl.
17. The compound of claim 1 , wherein X is —C 1 -C 6 alkylene-C(O)—X′.
18. The compound of claim 17 , wherein X′ is heterocyclyl including from 3 to 6 ring atoms wherein 1, 2, or 3 of the ring atoms are independently selected from the group consisting of N, NH, N(C 1 -C 3 alkyl), O, and S.
19. The compound of claim 18 , wherein X is
20. The compound of claim 1 , wherein the compound is selected from the group consisting of
21. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable excipient.
22. The pharmaceutical composition of claim 21 , suitable for oral administration.
23. The pharmaceutical composition of claim 21 , suitable for intravenous administration.
24. A method of treating depression, Alzheimer's disease, attention deficit disorder, schizophrenia, or anxiety, in a patient in need thereof, comprising administering to said patient: a pharmaceutically effective amount of a compound of claim 1 .
25. A compound represented by formula I:
and pharmaceutically acceptable salts, stereoisomers, and N-oxides thereof, wherein
R b is selected from the group consisting of H, halogen, hydroxyl, cyano and C 1 -C 6 alkyl;
R is H or C 1 -C 6 alkyl;
R 1 is H or C 1 -C 6 alkyl;
R 2 is H or C 1 -C 6 alkyl;
R 3 is selected from the group consisting of H, C 1 -C 6 alkyl, —OH, C 1 -C 6 alkoxy, —CO 2 H, and —CONR′R′, wherein R′ for each occurrence is independently selected from the group consisting of H, C 1 -C 6 alkyl and a nitrogen protecting group; and
X is H or —C 1 -C 6 alkylene-C(O)—X′, wherein X′ is selected from the group consisting of C 3 -C 6 cycloalkyl, a 4- to 6-membered heterocycloalkyl ring having 1, 2, or 3 heteroatoms selected from O, S, and N, phenyl and 4- to 6-membered heteroaryl ring having 1, 2, or 3 heteroatoms selected from O, S, and N, wherein X′ is optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, C 1 -C 6 alkyl and C 1 -C 6 alkoxy.
26. The compound of claim 25 , wherein R is C 1 -C 2 alkyl.
27. The compound of claim 25 , wherein R is methyl.
28. The compound of claim 25 , wherein R 1 is H.
29. The compound of claim 25 , wherein R 2 is H.
30. The compound of claim 25 , wherein R 3 is —C(O)NH 2 .
31. The compound of claim 25 , wherein X is
32. A compound represented by
and pharmaceutically acceptable salts, stereoisomers, and N-oxides thereof, wherein
R b is selected from the group consisting of H, halogen, hydroxyl, cyano and C 1 -C 6 alkyl;
R is H or methyl;
R 1 is H or methyl;
R 2 is H or methyl;
R 3 is selected from the group consisting of H, C 1 -C 6 alkyl, —OH, C 1 -C 6 alkoxy, —CO 2 H, and —CONR′R′, wherein R′ for each occurrence is independently selected from the group consisting of H, C 1 -C 6 alkyl and a nitrogen protecting group; and
X is H or —C 1 -C 6 alkylene-C(O)—NR c R d ; wherein
R c and R d , together with the nitrogen to which they are attached, form a 4-6 membered heterocyclic ring, which may have an additional heteroatom selected from O, S, and N; wherein the 4-6 membered heterocyclic ring may optionally be substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, and C 1-6 alkyl.
33. The compound of claim 32 , wherein the compound is
34. A pharmaceutical composition comprising a compound of claim 25 , and a pharmaceutically acceptable excipient.
35. The pharmaceutical composition of claim 34 , suitable for oral administration.
36. The pharmaceutical composition of claim 34 , suitable for intravenous administration.
37. A method of treating depression, Alzheimer's disease, attention deficit disorder, schizophrenia, or anxiety, in a patient in need thereof, comprising administering to said patient:
a pharmaceutically effective amount of a compound of claim 25 .