Spiro-lactam NMDA receptor modulators and uses thereof
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:
or a pharmaceutically acceptable salt and/or stereoisomer thereof, wherein:
X is O or NR 2 ;
R 1 is selected from the group consisting of H, C 1 -C 6 alkyl, phenyl, —C(O)—C 1 -C 6 alkyl, and —C(O)—O—C 1 -C 6 alkyl;
R 2 is selected from the group consisting of H, C 1 -C 6 alkyl, phenyl, —C(O)—C 1 -C 6 alkyl, and —C(O)—O—C 1 -C 6 alkyl;
p is 1;
R 5 is independently selected for each occurrence from the group consisting of H, C 1 -C 6 alkyl, —S(O) w —C 1 -C 3 alkyl, —NR a R b , C 1 -C 3 alkoxy, cyano and halogen;
w is 0, 1, or 2;
R 3 is selected from the group consisting of H, C 1 -C 6 alkyl, phenyl, —C(O)R 31 and —C(O)OR 32 ;
R 31 and R 32 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, —C 3 -C 6 cycloalkyl, and phenyl; and
R 7 is independently selected for each occurrence from the group consisting of H, halogen, phenyl, and C 1 -C 6 alkyl; and
R a and R b are each independently for each occurrence selected from the group consisting of H, C 1 -C 3 alkyl, and phenyl, or R a and R b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring;
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, S(O) w —C 1 -C 3 alkyl, SH, phenyl and halogen, and any aforementioned phenyl, independently for each occurrence, is optionally substituted by one, two or three substituents each independently selected from hydroxyl, halogen, —C(O)—O—C 1 -C 3 alkyl, —C(O)—C 1 -C 3 alkyl, methyl, and CF 3 .
2. The compound of claim 1 , wherein R 1 is C 1 -C 6 alkyl, optionally substituted by phenyl, or one, two or three fluorines.
3. The compound of claim 1 , wherein R 1 is H.
4. The compound of claim 1 , wherein R 1 is a substituent 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 3 alkyl.
5. The compound of claim 1 , wherein R 1 is tert-butyloxycarbonyl, benzyl, methyl, or
6. The compound of claim 1 , wherein X is O.
7. The compound of claim 1 , wherein X is NR 2 .
8. The compound of claim 1 , wherein R 2 is H.
9. The compound of claim 1 , wherein R 2 is C 1 -C 6 alkyl, optionally substituted by phenyl, or one, two or three fluorines.
10. The compound of claim 1 , wherein R 2 is methyl, benzyl,
or tert-butyloxycarbonyl.
11. The compound of claim 1 , wherein R 2 is a substituent 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 3 alkyl.
12. The compound of claim 1 , wherein R 3 is H.
13. 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 6 alkyl.
14. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt and/or a stereoisomer thereof.
15. A compound selected from the group consisting of
or a pharmaceutically acceptable salt and/or a stereoisomer thereof.
16. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable excipient.
17. A method of treating depression, Alzheimer's disease, attention deficit disorder, schizophrenia, anxiety, acute neuropathic pain, chronic neuropathic pain, or a neurodevelopmental disorder related to synaptic dysfunction, in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the compound of claim 1 .
18. The method of claim 17 , wherein the acute neuropathic pain or the chronic neuropathic pain is selected from the group consisting of herpes-induced, HIV-induced, traumatic nerve injury-induced, stroke-induced, post-ischemia-induced, chronic back pain-induced, post-herpetic neuralgia-induced, fibromyalgia-induced, reflex sympathetic dystrophy-induced, complex regional pain syndrome-induced, spinal cord injury-induced, sciatica-induced, phantom limb pain-induced, diabetic neuropathy-induced, and cancer chemotherapeutic-induced neuropathic pain.