Substituted pyrrolidine compounds with central nervous system activity
View Patent ↗Provided herein are substituted pyrrolidines that demonstrate binding at biogenic amine transporters and can be synthesized by a methodology based on a chiral dirhodium catalyst. Compositions comprising substituted pyrrolidines can be used to treat central nervous system disorders such as schizophrenia.
1. A compound having the following structure:
wherein R 1 and R 2 are selected from H, ORx, C(O)ORx or C(O)N(Rx)Rx and Rx is independently at each occurrence, a hydrogen, alkyl or alkenyl group comprising chains of 8 carbons or less, aryl group, or amino group, further if R 1 is ORx, C(O)ORx or C(O)N(Rx)Rx then R 2 is H or if R 2 is ORx, C(O)ORx or C(O)N(Rx)Rx then R 1 is H, and if R 1 is H, R 2 is not H;
wherein R 3 =CO 2 Ry, CH 2 ORy and Ry is a hydrogen, alkyl or alkenyl group comprising chains of 8 carbons or less, aryl group, or amino group;
wherein R 4 =alkyl, aryl, alkenyl, alkoxy, halo, nitro, cyano, keto, amino, or carboxylate; and,
wherein R 5 =alkyl, aryl, alkenyl, alkoxy, halo, nitro, cyano, keto, amino, or carboxylate;
wherein R 6 =hydrogen, alkyl, aryl, alkenyl, alkoxy, halo, nitro, cyano, keto, amino, or carboxylate; and,
wherein R 7 =hydrogen, alkyl, aryl, alkenyl, alkoxy, halo, nitro, cyano, keto, amino, or carboxylate;
a stereoisomer thereof, or a racemic mixture of the compound and the enantiomer of the compound or a pharmaceutically useful salt thereof.
2. The compound of claim 1 , wherein Z is a 2-naphthyl group.
3. The compound of claim 1 , wherein the stereoisomer is:
or its enantiomer.
4. The compound of claim 1 , wherein the stereoisomer is:
or its enantiomer.
5. The compound of claim 1 , wherein the structure of the compound is:
or its enantiomer.
6. The compound of claim 1 , wherein the structure of the compound is:
or its enantiomer.
7. The compound of claim 1 , wherein the structure of the compound is:
or its enantiomer.
8. The compound of claim 1 , wherein the structure of the compound is:
or its enantiomer.
9. The compound of claim 1 , wherein the structure of the compound is:
or its enantiomer.
10. The compound of claim 1 , wherein the compound is a pharmaceutically useful salt.
11. The compound of claim 1 , wherein the compound is the hydrochloride salt.
12. A composition comprising a compound having the following structure:
wherein R 1 and R 2 are selected from H, ORx, C(O)ORx or C(O)N(Rx)Rx and Rx is independently at each occurrence, a hydrogen, alkyl or alkenyl group comprising chains of 8 carbons or less, aryl group, or amino group, further if R 1 is ORx, C(O)ORx or C(O)N(Rx)Rx then R 2 is H or if R 2 is ORx, C(O)ORx or C(O)N(Rx)Rx then R 1 is H, and if R 1 is H, R 2 is not H;
wherein R 3 =CO 2 Ry, CH 2 ORy and Ry is a hydrogen, alkyl or alkenyl group comprising chains of 8 carbons or less, aryl group, or amino group;
wherein R 4 =alkyl, aryl, alkenyl, alkoxy, halo, nitro, cyano, keto, amino, or carboxylate; and,
wherein R 5 =alkyl, aryl, alkenyl, alkoxy, halo, nitro, cyano, keto, amino, or carboxylate;
wherein R 6 =hydrogen, alkyl, aryl, alkenyl, alkoxy, halo, nitro, cyano, keto, amino, or carboxylate; and,
wherein R 7 =hydrogen, alkyl, aryl, alkenyl, alkoxy, halo, nitro, cyano, keto, amino, or carboxylate;
a stereoisomer thereof, or a racemic mixture of the compound and the enantiomer of the compound or a pharmaceutically useful salt thereof.
13. A composition as in claim 12 wherein Z is a 2-naphthyl group.
14. A composition as in claim 12 wherein the stereoisomer is:
or its enantiomer.
15. A composition as in claim 12 wherein the stereoisomer is:
or its enantiomer.
16. A composition as in claim 12 wherein the structure of the compound is:
or its enantiomer.
17. A composition as in claim 12 wherein the structure of the compound is:
or its enantiomer.
18. A composition as in claim 12 wherein the structure of the compound is:
or its enantiomer.
19. A composition as in claim 12 wherein the structure of the compound is:
or its enantiomer.
20. A composition as in claim 12 wherein the structure of the compound is:
or its enantiomer.
21. A composition as in claim 12 wherein the compound is a pharmaceutically useful salt.
22. A composition as in claim 12 wherein the compound is the hydrochloride salt.
23. A method for alleviating one or more symptoms of a neuropsychiatric disorder in an individual comprising administering to the individual a composition of claim 12 in an amount effective to alleviate the symptoms of the neuropsychiatric disorder.
24. The method of claim 23 wherein the structure of the compound is:
or its enantiomer.
25. The method of claim 23 wherein the structure of the compound is:
or its enantiomer.
26. The method of claim 23 wherein the structure of the compound is:
or its enantiomer.
27. The method of claim 23 wherein the structure of the compound is:
or its enantiomer.
28. The method of claim 23 wherein the compound is a pharmaceutically useful salt.
29. The method of claim 28 wherein the compound is the hydrochloride salt.