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 as well as other disorders.
1. A compound represented by
or a pharmaceutically acceptable salt and/or stereoisomer thereof, wherein
when q is 2 or 3:
R 1 is independently selected from the group consisting of H, —C 1 -C 6 alkyl, —C(O)—C 1 -C 6 alkyl, and —S(O) w —C 1 -C 6 alkyl, wherein C 1 -C 6 alkyl is optionally substituted by one, two or three substituents each independently selected from R P ;
w is 0, 1 or 2;
R 6 , if present, is independently, for each occurrence, selected from the group consisting of H, —C 1 -C 6 alkyl, hydroxyl, and halogen, wherein C 1 -C 6 alkyl is optionally substituted by one, two or three substituents each independently selected from R P ;
m is 0, 1, 2, 3, or 4;
R 3 is selected from the group consisting of H, —C 1 -C 6 alkyl, —C(O)—R 31 , and —C(O)—O—R 32 , wherein C 1 -C 6 alkyl is optionally substituted by one, two or three substituents each independently selected from R P ;
R 31 is selected from the group consisting of H, —C 1 -C 6 alkyl, and —C 3 -C 6 cycloalkyl, wherein C 1 -C 6 alkyl is optionally substituted by one, two or three substituents each independently selected from R P , and C 3 -C 6 cycloalkyl is optionally substituted by one, two or three substituents each independently selected from R Q ;
R 32 is selected from the group consisting of —C 1 -C 6 alkyl, and —C 3 -C 6 cycloalkyl, wherein C 1 -C 6 alkyl is optionally substituted by one, two or three substituents each independently selected from R P , and C 3 -C 6 cycloalkyl is optionally substituted by one, two or three substituents each independently selected from R Q ;
R P is independently, for each occurrence, selected from the group consisting of —C(O)NR a R b , —NR a R b , hydroxyl, —SH, and halogen;
R Q is independently, for each occurrence, selected from the group consisting of —C(O)NR a R b , —NR a R b , —C 1 -C 3 alkyl, hydroxyl, and halogen; and
R a and R b are each independently, for each occurrence, selected from the group consisting of H, —C 1 -C 3 alkyl, phenyl, and benzyl, wherein each C 1 -C 3 alkyl, phenyl, and benzyl is optionally substituted by one, two or three substituents each independently selected from the group consisting of hydroxyl, C 1 -C 3 alkyl, and halogen; and
when q is 1:
R 1 is independently selected from the group consisting of —C(O)—C 1 -C 6 alkyl, and —S(O) W —C 1 -C 6 alkyl, wherein C 1 -C 6 alkyl is optionally substituted by one, two or three substituents each independently selected from R P ;
w is 0, 1, or 2;
R 6 , if present, is independently, for each occurrence, selected from the group consisting of H, —C 1 -C 6 alkyl, and hydroxyl, and halogen, wherein C 1 -C 6 alkyl is optionally substituted by one, two or three substituents each independently selected from R P ;
m is 0, 1, 2, 3, or 4;
R 3 is selected from the group consisting of H, —C 1 -C 6 alkyl, —C(O)—R 31 , and —C(O)—O—R 32 , wherein C 1 -C 6 alkyl is optionally substituted by one, two or three substituents each independently selected from R P ;
R 31 is selected from the group consisting of H, —C 1 -C 6 alkyl, and —C 3 -C 6 cycloalkyl, wherein C 1 -C 6 alkyl is optionally substituted by one, two or three substituents each independently selected from R P , and C 3 -C 6 cycloalkyl is optionally substituted by one, two or three substituents each independently selected from R Q ;
R 32 is selected from the group consisting of —C 1 -C 6 alkyl, and —C 3 -C 6 cycloalkyl, wherein C 1 -C 6 alkyl is optionally substituted by one, two or three substituents each independently selected from R P , and C 3 -C 6 cycloalkyl is optionally substituted by one, two or three substituents each independently selected from R Q ;
R P is independently, for each occurrence, selected from the group consisting of —C(O)NR a R b , —NR a R b , hydroxyl, —SH, and halogen;
R Q is independently, for each occurrence, selected from the group consisting of —C(O)NR a R b , —NR a R b , —C 1 -C 3 alkyl, hydroxyl, and halogen; and
R a and R b are each independently, for each occurrence, selected from the group consisting of H, —C 1 -C 3 alkyl, phenyl, and benzyl, wherein each C 1 -C 3 alkyl, phenyl, and benzyl is optionally substituted by one, two or three substituents each independently selected from the group consisting of hydroxyl, C 1 -C 3 alkyl, and halogen.
2. The compound of claim 1 , wherein the compound is represented by:
or a pharmaceutically acceptable salt and/or stereoisomer thereof, wherein
R 1 is —C(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 R P ;
R 3 is selected from the group consisting of H and —C 1 -C 6 alkyl, wherein C 1 -C 6 alkyl is optionally substituted by one, two or three substituents each independently selected from R P ;
R P is independently, for each occurrence, selected from the group consisting of —C(O)NR a R b , —NR a R b , hydroxyl, —SH, and halogen; and
R a and R b are each independently, for each occurrence, selected from the group consisting of H, —C 1 -C 3 alkyl, phenyl, and benzyl, wherein each C 1 -C 3 alkyl, phenyl, and benzyl is optionally substituted by one, two or three substituents each independently selected from the group consisting of hydroxyl, C 1 -C 3 alkyl, and halogen.
3. The compound of claim 1 , wherein R 1 is —C(O)—C 1 -C 4 alkyl.
4. The compound of claim 1 , wherein R 3 is H.
5. The compound of claim 1 , wherein R 3 is —C 1 -C 6 alkyl optionally substituted by one, two or three substituents independently selected from R P .
6. The compound of claim 5 , 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 H and —C 1 -C 3 alkyl.
7. The compound of claim 6 , wherein R a and R b are H.
8. The compound of claim 1 , wherein m is 0.
9. The compound of claim 1 , wherein m is 1, 2 or 3.
10. A compound selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
11. A compound represented by
or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising the compound of claim 1 , and a pharmaceutically acceptable excipient.
13. The pharmaceutical composition of claim 12 , suitable for oral administration, parenteral administration, topical administration, intravaginal administration, intrarectal administration, sublingual administration, ocular administration, transdermal administration, or nasal administration.
14. A method of treating of treating depression in a patient in need thereof, comprising administering to the patient an effective amount of the compound of claim 1 .
15. A method of treating neuropathic pain in a patient in need thereof, comprising administering to the patient an effective amount of the compound of claim 1 .