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 thereof, wherein
R b is selected from the group consisting of H, halogen, hydroxyl, cyano and 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, and C(O)OR 31 ;
R 31 is selected from the group consisting of: C 1 -C 6 alkyl; C 1 -C 6 haloalkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 3 -C 10 cycloalkyl, wherein the C 3 -C 10 cycloalkyl is optionally substituted with from 1-3 independently selected C 1 -C 3 alkyl; —CH 2 —C 3 -C 10 cycloalkyl wherein the C 3 -C 10 cycloalkyl is optionally substituted with from 1-3 independently selected C 1 -C 3 alkyl; —CH 2 — phenyl, wherein the phenyl is optionally substituted with from 1-2 substituents independently selected from C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, nitro, halo, SO 2 Me, cyano, and —OC(O)CH 3 ; and —CH 2 -pyridyl;
R 4 and R 5 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, X, and —C 1 -C 6 alkylene-X, wherein X is selected from the group consisting of:
(i) C 3 -C 6 cycloalkyl;
(ii) 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;
(iii) 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; and
(iv) phenyl;
wherein C 3 -C 6 cycloalkyl and heterocyclyl are each optionally substituted with from 1-3 substituents independently selected from the group consisting of halogen, cyano, oxo, C 1 -C 6 alkyl, hydroxyl, C 1 -C 6 alkoxy, and —N(R′)R′, wherein R′ is independently selected for each occurrence from H and C 1 -C 6 alkyl; and heteroaryl and phenyl are each optionally substituted with from 1-3 substituents independently selected from the group consisting of halogen, cyano, C 1 -C 6 alkyl, hydroxyl, C 1 -C 6 alkoxy, and —N(R′)R′;
or R 4 and R 5 together with the nitrogen to which they are attached form:
heterocyclyl including from 4 to 6 ring atoms; wherein the heterocyclyl includes not more than two ring heteroatoms (including the nitrogen atom attached to R 4 and R 5 ), and the second ring heteroatom, when present, is independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; and wherein the heterocyclyl is optionally substituted with from 1-3 substituents independently selected from the group consisting of halogen, cyano, oxo, C 1 -C 6 alkyl, hydroxyl, C 1 -C 6 alkoxy, and —N(R′)R′; or
heteroaryl including from 5 to 6 ring atoms; wherein the heteroaryl includes not more than four ring heteroatoms (including the nitrogen atom attached to R 4 and R 5 ), and each additional ring heteroatom, when present, is independently selected from the group consisting of N, NH, N(C1-C3 alkyl), O, and S; and wherein the heteroaryl is optionally substituted with from 1-3 substituents independently selected from the group consisting of halogen, cyano, C 1 -C 6 alkyl, hydroxyl, C 1 -C 6 alkoxy, and —N(R′)R′;
R 6 is selected from the group consisting of —OH, C 1 -C 6 alkoxy, —OC(O)—C 1 -C 6 alkyl, —OC(O)phenyl, and —N(R′)R′; and
R 7 is H or C 1 -C 6 alkyl.
2. The compound of claim 1 , wherein R 1 is H.
3. The compound of claim 1 , wherein R 2 is H.
4. The compound of claim 1 , wherein R 3 is H.
5. The compound of claim 1 , wherein R 31 is C 1 -C 6 alkyl.
6. The compound of claim 5 , wherein R 31 is tert-butyl.
7. The compound of claim 1 , wherein R 4 and R 5 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, and —C 1 -C 6 alkylene-X.
8. The compound of claim 7 , wherein R 4 and R 5 are each independently selected from the group consisting of H and —C 1 -C 6 alkylene-X.
9. The compound of claim 8 , wherein one of R 4 and R 5 is H, and the other is —C 1 -C 6 alkylene-X.
10. The compound of claim 1 , wherein —C 1 -C 6 alkylene-X is —CH 2 —X.
11. The compound of claim 1 , wherein X is phenyl or 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; each optionally substituted with from 1-3 substituents independently selected from the group consisting of halogen, cyano, C 1 -C 6 alkyl, hydroxyl, C 1 -C 6 alkoxy, and —N(R′)R′.
12. The compound of claim 1 , wherein R 4 and R 5 are H.
13. The compound of claim 1 , wherein R 4 and R 5 taken together with the nitrogen to which they are attached form a pyrrolidinyl ring.
14. The compound of claim 1 , wherein R 1 is H or CH 3 ; R 2 is H or CH 3 ; R 3 is H; and R 4 and R 5 taken together form a pyrrolidinyl ring.
15. The compound of claim 1 , wherein R 1 is H or CH 3 ; R 2 is H or CH 3 ; R 3 is H; and R 4 and R 5 are H.
16. The compound of claim 1 , wherein R 1 is H or CH 3 ; R 2 is H or CH 3 ; R 3 is H; and one of R 4 and R 5 is H, and the other is —CH 2 —X, wherein X is phenyl or 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; each optionally substituted with from 1-3 substituents independently selected from the group consisting of halogen, cyano, C 1 -C 6 alkyl, hydroxyl, C 1 -C 6 alkoxy, and —N(R′)R′.
17. The compound of claim 1 , wherein R 1 is H or CH 3 ; R 2 is H or CH 3 ; and R 4 and R 5 taken together form a pyrrolidinyl ring.
18. The compound of claim 1 , wherein R 1 is H or CH 3 ; R 2 is H or CH 3 ; and R 4 and R 5 are H.
19. The compound of claim 1 , wherein R 1 is H or CH 3 ; R 2 is H or CH 3 ; and one of R 4 and R 5 is H, and the other is —CH 2 —X, wherein X is phenyl or 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; each optionally substituted with from 1-3 substituents independently selected from the group consisting of halogen, cyano, C 1 -C 6 alkyl, hydroxyl, C 1 -C 6 alkoxy, and —N(R′)R′.
20. The compound claim 1 , wherein R 6 is selected from the group consisting of —OH, C 1 -C 6 alkoxy, —OC(O)—C 1 -C 6 alkyl, and —OC(O)phenyl.
21. The compound of claim 20 , wherein R 6 is —OH.
22. The compound of claim 1 , wherein R 7 is C 1 -C 6 alkyl.
23. The compound of claim 20 , wherein R 7 is —CH 3 .
24. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable excipient.
25. The pharmaceutical composition of claim 24 , suitable for oral administration.
26. The pharmaceutical composition of claim 24 , suitable for intravenous administration.
27. 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 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 and C(O)OR 31 ;
R 31 is selected from the group consisting of: C 1 -C 6 alkyl; C 1 -C 6 haloalkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 3 -C 10 cycloalkyl, wherein the C 3 -C 10 cycloalkyl is optionally substituted with from 1-3 independently selected C 1 -C 3 alkyl; —CH 2 —C 3 -C 10 cycloalkyl wherein the C 3 -C 10 cycloalkyl is optionally substituted with from 1-3 independently selected C 1 -C 3 alkyl; —CH 2 -phenyl, wherein the phenyl is optionally substituted with from 1-2 substituents independently selected from C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, nitro, halo, SO 2 Me, cyano, and —OC(O)CH 3 ; and —CH 2 -pyridyl;
R 4 and R 5 are independently H or C 1 -C 6 alkyl, or R 4 and R 5 taken together with the nitrogen to which they are attached form a 4-, 5- or 6-membered heterocyclic or heteroaryl ring optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, oxo, C 1 -C 6 alkyl, —OH, C 1 -C 6 alkoxy, and —N(R′)R′, wherein R′ is independently selected for each occurrence from H or C 1 -C 6 alkyl;
R 6 is selected from the group consisting of —OH, C 1 -C 6 alkoxy, —OC(O)—C 1 -C 6 alkyl, and —OC(O)phenyl; and
R 7 is H or C 1 -C 6 alkyl.
28. The compound of claim 27 , wherein R 1 and R 2 is H.
29. The compound of claim 27 , wherein R 4 and R 5 taken together form a heteroaromatic ring selected from the group consisting of imidazole, pyrazole, oxazole, isoxazole, thiazole, pyridine, diazine, oxazine, and thiazine.
30. The compound of claim 27 , wherein R 1 is H; R 2 is H; R 3 is H; and R 4 and R 5 are H.
31. The compound of claim 27 , wherein the compound is selected from the group consisting of:
32. A pharmaceutical composition comprising a compound of claim 27 , and a pharmaceutically acceptable excipient.
33. The pharmaceutical composition of claim 32 , suitable for oral administration.
34. The pharmaceutical composition of claim 32 , suitable for intravenous administration.