Anticonvulsant and anxiolytic lactam and thiolactam derivatives

• US 6,066,666 A
• Filed: 03/20/1998
• Issued: 05/23/2000
• Est. Priority Date: 06/05/1995
• Status: Expired due to Fees

• Current Assignee: Washington University In St Louis
• Original Assignee: Washington University In St Louis
• Inventors: Ferrendelli, James A., Reddy, P. Amruta, Covey, Douglas F.
• Primary Examiner(s): Richter, Johann
• Assistant Examiner(s): KEATING, DOMINIC J
• Application Number:
  US09/045,211
• Time in Patent Office: 795 Days
• Field of Search: 548/543, 514/424
• US Class Current: 514/424
• CPC Class Codes: A61K 31/4015 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
• CPC Class Codes: A61K 31/45 having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
• CPC Class Codes: C07D 207/267 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 211/76 attached in position 2 or 6

Abstract

This invention relates to lactam and thiolactam derivatives having useful anticonvulsant and anxiolytic activity, pharmaceutical compositions containing these compounds and therapeutic applications using such compositions.

Claims

1. A compound having anticonvulsant or anxiolytic activity having the formula:

and pharmaceutically acceptable salts thereof wherein;

Z is an oxygen or a sulfur atom;

R₁ and R₂ are selected from the group consisting of an optionally substituted alkyl or alkenyl group, and an optionally substituted phenylmethyl group; and

R₃ is selected from the group consisting of a hydrogen, an optionally substituted alkyl or alkenyl group, and an optionally substituted phenylmethyl group,

with the exception that the compound is not 3,3-dimethyl-2-pyrrolidinone or 3-ethyl-3-methyl-2-pyrrolidinone and the exception that when R₁ or R₂ are optionally substituted phenylmethyl groups, the phenyl ring is not halogen substituted.

2. The compound of claim 1 wherein Z is O.

3. The compound of claim 1 wherein one of R₁ and R₂ is an ethyl group.

4. The compound of claim 1 wherein one of R₁ and R₂ is a phenylmethyl group.

5. The compound of claim 1 wherein one of R₁ and R₂ is a phenylmethyl group and the other of R₁ and R₂ is an optionally substituted alkyl group.

6. The compound of claim 1 wherein R₃ is a hydrogen or a methyl group.

7. The compound of claim 1 wherein Z is O and R₃ is a hydrogen.

8. The compound of claim 7 wherein of one of R₁ and R₂ is an ethyl group and the other of R₁ and R₂ is an alkyl group other than a methyl or an ethyl group.

9. The compound of claim 7 wherein one of R₁ and R₂ is a phenylmethyl group and the other of R₁ and R₂ is an optionally substituted alkyl group.

10. The compound of claim 1 wherein said anticonvulsant and/or anxiolytic compound is an enantiomerically enriched mixture or a pure (+) or (-) enantiomer.

11. The compound of claim 1 that is 3,3-diethyl-2-pyrrolidinone.

12. The compound of claim 1 that is 3-ethyl-3-phenylmethyl pyrrolidinone.

26. The compound of claim 1 wherein R₃ is a hydrogen.

27. The compound of claim 1 wherein Z is sulfur.

28. The compound of claim 1 which is a pharmaceutically acceptable salt.

29. The compound of claim 1 wherein R₁ and R₂ are alkyl or alkenyl groups having from 2 to about 4 carbon atoms.

13. A pharmaceutical composition having anticonvulsant or anxiolytic activity which comprises a pharmaceutical carrier and one or more of the anticonvulsant and/or anxiolytic compounds having the formula:

##STR9## and pharmaceutically acceptable salts thereof wherein Z is an oxygen or a sulfur atom;

R₁ and R₂ are selected from the group consisting of a hydrogen, an optionally substituted alkyl or alkenyl group and an optionally substituted phenyl-methyl group; and

R₃ is selected from the group consisting of a hydrogen, an optionally substituted alkyl or alkenyl group, and an optionally substituted phenylmethyl group,

with the exceptions that the compound is not 3,3-dimethyl-2-pyrrolidinone or 3-ethyl-3-methyl-2-pyrrolidinone;

that when R₁ or R₂ are optionally substituted phenylmethyl groups, the phenyl ring is not halogen substituted and that both of R₁ and R₂ cannot be hydrogen and one of R₁ and R₂ can be a hydrogen only when the other of R₁ and R₂ is an optionally substituted phenylmethyl group.

14. The pharmaceutical composition of claim 13 wherein said anticonvulsant and/or anxiolytic compound is 3,3-diethyl-2-pyrrolidinone.

15. The pharmaceutical composition of claim 13 wherein said anticonvulsant and/or anxiolytic compound is 3-ethyl-3-phenylmethyl pyrrolidinone.

16. The pharmaceutical composition of claim 13 wherein in said anticonvulsant and/or anxiolytic compound one of R₁ or R₂ is an ethyl group.

17. The pharmaceutical composition of claim 13 wherein in said anticonvulsant and/or anxiolytic compound one of R₁ or R₂ is a phenyl methyl group.

18. The pharmaceutical composition of claim 13 wherein the anticonvulsant and/or anxiolytic compound is 3-phenylmethyl-2-pyrrolidinone, 3-ethyl-3-phenylmethyl-2-pyrrolidinone or 3-methyl-3-phenylmethyl-2-pyrrolidinone.

19. A method for enhancing GABA-induced chloride currents at the GABA receptor/ionophore complex which comprises administering to a mammal a pharmaceutical composition of claim 13.

20. The method of claim 19 wherein the composition comprises 3,3-diethyl pyrrolidinone, 3-ethyl-3-phenylmethyl-2-pyrrolidinone, 3-methyl-3-phenylmethyl-2-pyrrolidinone, or 3-phenylmethyl-2-pyrrolidinone.

21. A method for treating convulsant seizures in a mammal which comprises the step of administering a pharmaceutical composition of claim 13 to a mammal.

22. The method of claim 21 wherein the composition comprises 3,3-diethyl pyrrolidinone, 3-ethyl-3-phenylmethyl-2-pyrrolidinone, 3-methyl-3-phenylmethyl-2-pyrrolidinone, or 3-phenylmethyl-2-pyrrolidinone.

23. A method for treating anxiety in a mammal which comprises the step of administering a pharmaceutical composition of claim 13 to a mammal.

24. The method of claim 23 wherein the composition comprises 3,3-diethyl pyrrolidinone, 3-ethyl-3-phenylmethyl-2-pyrrolidinone, 3-methyl-3-phenylmethyl-2-pyrrolidinone, or 3-phenylmethyl-2-pyrrolidinone.

25. The pharmaceutical composition of claim 13 wherein R₁ and R₂ are not hydrogens.