Spiro-lactam NMDA modulators and methods of using same
Disclosed are compounds having potency in the modulation of NMDA receptor activity. Such compounds can be used in the treatment of conditions such as depression and related disorders. Orally delivered 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, and/or an N-oxide thereof, wherein:
m is 2 and n is 1; or
m is 1 and n is 2;
X is O or S;
R 1 is selected from the group consisting of hydrogen, —C 1 -C 6 alkyl, —C(O)—C 1 -C 6 alkyl, —C(O)—O—C 1 -C 6 alkyl, —C 1 -C 6 alkylene—C 3 -C 6 cycloalkyl, and phenyl;
R 2 is independently selected for each occurrence from the group consisting of hydrogen, cyano, —C 1 -C 6 alkyl, and halogen;
R 3 is selected from the group consisting of hydrogen, —C 2 -C 6 alkyl, —C(O)—R 31 , —C(O)—O—R 32 , and phenyl;
R 31 is selected from the group consisting of hydrogen, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 3 -C 6 cycloalkyl, and phenyl;
R 32 is selected from the group consisting of hydrogen, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 3 -C 6 cycloalkyl, and phenyl;
wherein:
any aforementioned C 1 -C 6 alkyl, independently for each occurrence, is optionally substituted by one, two or three substituents each independently selected from —C(O)NR a R b , —NR a R b , hydroxyl, —SH, phenyl, —O—CH 2 -phenyl, and halogen;
any aforementioned C 2 -C 6 alkyl is optionally substituted by one, two or three substituents each independently selected from —C(O)NR a R b , —NR a R b , hydroxyl, —SH, and halogen; and
any aforementioned phenyl, independently for each occurrence, is optionally substituted by one, two or three substituents each independently selected from —C(O)NR a R b , —NR a R b , —C 1 -C 3 alkoxy, hydroxyl, and halogen;
R 4 is independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, cyano, phenyl, —C 1 -C 4 alkyl, —C 2-4 alkenyl, —C 1-4 alkoxy, —C(O)NR a R b , —NR a R b , —N(R a )-phenyl, —N(R a )—C 1 -C 6 alkylene-phenyl, —N(R a )—C(O)—C 1 -C 6 alkyl, —N(R a )—C(O)—C 1 -C 6 alkylene-phenyl, —N(R a )—C(O)—O—C 1 -C 6 alkyl, and —N(R a )—C(O)—O—C 1 -C 6 alkylene-phenyl; wherein C 1 -C 4 alkyl, C 1 -C 6 alkylene, C 2 -C 4 alkenyl, C 1 -C 4 alkoxy, and phenyl are optionally substituted by one or more substituents selected from R P ; or
two R 4 moieties, when present on adjacent carbons, form a 3-membered carbocyclic ring taken together with the adjacent carbons to which they are attached, optionally substituted by one or two substituents independently selected from the group consisting of halogen, hydroxyl, —C 1 -C 3 alkyl, —C 1 -C 3 alkoxy, —C(O)NR a R b , and —NR a R b ;
R a and R b are each independently for each occurrence selected from the group consisting of hydrogen, —C 1 -C 4 alkyl, and —CH 2 -phenyl; or R a and R b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring;
R 5 is independently selected for each occurrence from the group consisting of hydrogen, —C 1 -C 3 alkyl, phenyl, and halogen; wherein phenyl is optionally substituted by one or more substituents selected from R P ; or two R 5 moieties together with the carbon to which they are attached form a carbonyl or thiocarbonyl moiety;
R 6 is independently selected for each occurrence from the group consisting of hydrogen, —C 1 -C 3 alkyl, phenyl and halogen; wherein phenyl is optionally substituted by one or more substituents selected from R P ; or two R 6 moieties together with the carbon to which they are attached form a carbonyl or thiocarbonyl moiety; and
R P is independently selected for each occurrence from the group consisting of carboxy, hydroxyl, halogen, —NR a R b , phenyl, —C 1 -C 6 alkoxy, and —C 1 -C 6 alkyl; wherein each phenyl, C 1 -C 6 alkoxy and C 1 -C 6 alkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen and hydroxyl.
2. The compound of claim 1 , wherein m is 2 and n is 1.
3. The compound of claim 1 , wherein X is O, and two R 6 moieties together with the carbon to which they are attached form a carbonyl moiety.
4. The compound of claim 1 , represented by Formula Ia:
wherein Y is O or S.
5. The compound of claim 4 , wherein X and Y are both O.
6. The compound of claim 4 , wherein R 2 for each occurrence is hydrogen.
7. The compound of claim 1 , wherein R 4 is independently selected for each occurrence from the group consisting of hydrogen, fluoro, hydroxyl, methyl, —NH 2 ,
8. The compound of claim 1 , wherein R 5 is independently selected for each occurrence from the group consisting of hydrogen, C 1 -C 3 alkyl, and phenyl.
9. The compound of claim 1 , wherein R 1 is hydrogen.
10. The compound of claim 1 , wherein R 1 is —C 1 -C 6 alkyl optionally substituted by phenyl, wherein phenyl is optionally substituted by one, two or three substituents each independently selected from —C 1 -C 3 alkoxy and fluoro.
11. The compound of claim 1 , wherein R 1 is —C 1 -C 6 alkyl—C 3 -C 6 cycloalkyl.
12. The compound of claim 1 , wherein R 1 is phenyl, wherein phenyl is optionally substituted by one, two or three substituents each independently selected from —C 1 -C 3 alkoxy and fluoro.
13. The compound of claim 1 , wherein R 1 is —C(O)—O—C 1 -C 6 alkyl, wherein C 1 -C 6 alkyl is optionally substituted by one, two or three substituents each independently selected from —C(O)NR a R b , —NR a R b , hydroxyl, —SH, phenyl, —O—CH 2 -phenyl, and halogen; and
wherein each phenyl, independently for each occurrence, is optionally substituted by one, two or three substituents each independently selected from —C(O)NR a R b , —NR a R b , —C 1 -C 3 alkoxy, hydroxyl, and halogen.
14. The compound of claim 13 , wherein R 1 is selected from the group consisting of —C(O)—O—CH 2 -phenyl
methyl, isobutyl, and
15. The compound of claim 1 , wherein R 3 is hydrogen.
16. The compound of claim 1 , wherein R 3 is —C(O)—O—C 1 -C 6 alkyl.
17. The compound of claim 1 , wherein R 3 is —C(O)—O—tert-butyl.
18. The compound of claim 1 , wherein R 3 is selected from the group consisting of:
wherein:
R a and R b are each independently selected for each occurrence from the group consisting of hydrogen and —C 1 -C 4 alkyl.
19. The compound of claim 18 , wherein R a and R b are hydrogen.
20. A pharmaceutical composition comprising the compound of claim 1 ; and a pharmaceutically acceptable excipient.
21. A method of treating of treating depression, attention deficit disorder, schizophrenia, anxiety, a migraine, or neuropathic pain, in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the compound of claim 1 .