Spiro-lactam and bis-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 Formula I or Formula II:
or a pharmaceutically acceptable salt, a stereoisomer, and/or an N-oxide thereof, wherein:
R 1 and R 2 are independently 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, and —O—CH 2 -phenyl;
R 3 is selected from the group consisting of hydrogen, —C 1 -C 6 alkyl, —C(O)—R 31 , and —C(O)—O—R 32 ;
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; 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 a and R b are each independently for each occurrence selected from the group consisting of hydrogen, —C(O)—O—CH 2 -phenyl, and —C 1 -C 3 alkyl; or R a and R b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring;
R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, phenyl, amido, amino, C 1-4 alkyl, C 2-4 alkenyl, —NH—C(O)—C 1-6 alkyl, —NH—C(O)—C 1-6 alkylene-phenyl, —NH—C(O)—O—C 1-6 alkyl, and —NH—C(O)—O—C 1-6 alkylene-phenyl; wherein C 1-4 alkyl, C 1-6 alkylene, C 2-4 alkenyl, and phenyl are optionally substituted by one or more substituents selected from R P ; or
two R 5 s taken together form an oxo moiety; or
wherein for the compound of Formula I, R 6 and R 7 taken together with the adjacent carbons to which they are attached form a 3-membered carbocyclic ring which is 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 ; and
R P is selected, independently for each occurrence, from the group consisting of carboxy, hydroxyl, halogen, amino, phenyl, C 1-6 alkoxy, and C 1-6 alkyl optionally substituted by one or more substituents independently selected from the group consisting of halogen, hydroxyl and amino.
2. The compound of claim 1 , wherein R 1 and R 2 are hydrogen.
3. The compound of claim 1 , wherein R 1 and R 2 are —C 1 -C 6 alkyl each independently and optionally substituted by one, two or three substituents independently selected from the group consisting of —C(O)NR a R b , hydroxyl, —SH, and halogen.
4. The compound of claim 1 , wherein R 3 is hydrogen.
5. The compound of claim 1 wherein R 3 is —C 1 -C 6 alkyl.
6. The compound of claim 1 , wherein R 3 is —C(O)—C 1 -C 6 alkyl.
7. The compound of claim 1 , wherein R 3 is —C(O)—O—C 1 -C 6 alkyl.
8. The compound of claim 1 , wherein R 4 , R 5 , R 6 , and R 7 are hydrogen.
9. The compound of claim 1 represented by Formula III or Formula IV:
or a pharmaceutically acceptable salt, a stereoisomer, and/or an N-oxide thereof, wherein:
R 1 and R 2 are independently 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, and —O—H 2 -phenyl;
R 3 is selected from the group consisting of hydrogen, —C 1 -C 6 alkyl, —C(O)—R 31 , and —C(O)—O—R 32 ;
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; 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 a and R b are each independently for each occurrence selected from the group consisting of hydrogen, —C(O)—O—CH 2 -phenyl, and —C 1 -C 3 alkyl; or R a and R b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring;
R 6 and R 7 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, phenyl, amido, amino, C 1-4 alkyl, C 2-4 alkenyl, —NH—C(O)—C 1-6 alkyl, —NH—C(O)—C 1-6 alkylene-phenyl, —NH—C(O)—O—C 1-6 alkyl, and —NH—C(O)—O—C 1-6 alkylene-phenyl; wherein C 1-4 alkyl, C 1-6 alkylene, C 2-4 alkenyl, and phenyl are optionally substituted by one or more substituents selected from R P ; or
wherein for the compound of Formula III, R 6 and R 7 taken together with the adjacent carbons to which they are attached form a 3-membered carbocyclic ring which is 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 ; and
R P is selected, independently for each occurrence, from the group consisting of carboxy, hydroxyl, halogen, amino, phenyl, C 1-6 alkoxy, and C 1-6 alkyl optionally substituted by one or more substituents independently selected from the group consisting of halogen, hydroxyl and amino.
10. The compound of claim 1 represented by Formula V or Formula VI:
or a pharmaceutically acceptable salt, a stereoisomer, and/or an N-oxide thereof, wherein:
R 3 is selected from the group consisting of hydrogen, —C 1 -C 6 alkyl, —C(O)—R 31 , and —C(O)—O—R 32 ;
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; 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; and
R a and R b are each independently for each occurrence selected from the group consisting of hydrogen, —C(O)—O—CH 2 -phenyl, and —C 1 -C 3 alkyl; or R a and R b taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring.
11. A compound represented by Formula VI or Formula VII:
or a pharmaceutically acceptable salt, a stereoisomer, and/or an N-oxide thereof, wherein:
R 3 is selected from the group consisting of hydrogen, —C 1 -C 6 alkyl, —C(O)—R 31 , and —C(O)—O—R 32 ;
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;
R 10 and R 11 for each occurrence are independently selected from the group consisting of hydrogen, halogen, —OH, —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, —CO 2 H, or —NR′R′, wherein R′ for each occurrence is independently selected from hydrogen and, —C 1 -C 6 alkyl; and
R 12 and R 13 for each occurrence are independently selected from the group consisting of hydrogen and —C 1 -C 6 alkyl; or R 13 and R 12 together with the nitrogen to which they are bound form a 4-6 membered heterocycle; and wherein C 1 -C 6 alkyl is optionally for each occurrence substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl, and amino.
12. A compound represented by Formula IX or Formula X:
or a pharmaceutically acceptable salt, a stereoisomer, and/or an N-oxide thereof, wherein:
R 1 and R 2 are independently selected from the group consisting of hydrogen, —C 1 -C 6 alkyl, —C(O)—C 1 -C 6 alkyl, and —C(O)—O—C 1 -C 6 alkyl; or R 1 and R 2 taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring;
R 3 is selected from the group consisting of hydrogen, —C 1 -C 6 alkyl, —C(O)—R 31 , and —C(O)—O—R 32 ;
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;
R 4 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, and —O—CH 2 -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; 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 a and R b are each independently for each occurrence selected from the group consisting of hydrogen, —C(O)—O—CH 2 -phenyl, and —C 1 -C 3 alkyl; 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 , R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, phenyl, amido, amino, C 1-4 alkyl, C 2-4 alkenyl, —NH—C(O)—C 1-6 alkyl, —NH—C(O)—C 1-6 alkylene-phenyl, —NH—C(O)—O—C 1-6 alkyl, and —NH—C(O)—O—C 1-6 alkylene-phenyl; wherein C 1-4 alkyl and phenyl are optionally substituted by one or more substituents selected from R P ; or
R 6 and R 7 taken together with the adjacent carbons to which they are attached form a 3-membered carbocyclic ring which is 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 P is selected, independently for each occurrence, from the group consisting of carboxy, hydroxyl, halogen, amino, phenyl, C 1-6 alkoxy, and C 1-3 alkyl optionally substituted by one or more substituents independently selected from the group consisting of halogen, hydroxyl and amino;
R 9 and R 10 are each independently selected from the group consisting of hydrogen and —C 1 -C 3 alkyl, or R 9 and R 10 taken together form an oxo moiety; and
m is 0 or 1.
13. The compound of claim 12 , wherein R 1 and R 2 are hydrogen.
14. The compound of claim 12 , wherein R 1 is hydrogen and R 2 is —C 1 -C 6 alkyl optionally substituted by one, two or three substituents independently selected from the group consisting of —C(O)NR a R b , hydroxyl, —SH, and halogen.
15. The compound of claim 12 , wherein R 3 is hydrogen.
16. The compound of claim 12 , wherein R 4 , R 5 , R 6 , and R 7 are hydrogen.
17. A compound selected from the group consisting of
and pharmaceutically acceptable salts, stereoisomers, and/or N-oxides thereof.
18. A pharmaceutical composition comprising the compound of claim 1 , and a pharmaceutically acceptable excipient.
19. A method of lessening or reducing one or more symptoms of depression, Alzheimer's disease, attention deficit disorder, schizophrenia, or anxiety, in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the compound of claim 1 .
20. A method of lessening or reducing one or more symptoms of a migraine, neuropathic pain, or traumatic brain injury in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the compound of claim 1 .