Compositions, Synthesis, and Methods of Using Quinolinone Based Atypical Antipsychotic Agents

• US 20080293736A1
• Filed: 05/21/2008
• Published: 11/27/2008
• Est. Priority Date: 05/21/2007
• Status: Active Grant

• Current Assignee: Reviva Pharmaceuticals, Inc.
• Original Assignee: Reviva Pharmaceuticals, Inc.
• Inventors: Bhat, Laxminarayan, Bhat, Seema Rani, Mohapatra, Prabhu P.
• Granted Patent: US 8,247,420 B2
• Time in Patent Office: Days
• US Class Current: 514/253.04
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: C07D 215/22 attached in position 2 or 4
• CPC Class Codes: C07D 215/48 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Abstract

The present invention provides novel quinolinone derivatives which can be advantageously used for treating schizophrenia and related psychoses such as acute manic, bipolar disorder, autistic disorder, and depression.

Claims

1. A compound comprising structural Formula (I):

2. The compound of claim 1, wherein the soft-moiety is an amide, an ester, a carbonate, a phosphate, a sulfate, or a carbamate.

3. The compound of claim 2, wherein the soft-moiety further comprises a spacer.

4. The compound of claim 3, wherein the spacer is O, S, alkyl, substituted alkyl, acyl, acylamino, alkoxy, alkylamino, alkylthio, amino, carboxy, or alkoxycarbonyl.

5. The compound of claim 4, wherein the spacer is alky or substituted alkyl.

28. A compound of the claim 2, wherein the compound is characterized by

(a) having an affinity for dopamine D₂ receptors;

(b) having an affinity for serotonin 5-HT_1A receptors;

(c) having an affinity for serotonin 5-HT_2A receptors;

(d) having at least one hydrolyzable bond that can be cleaved non-oxidatively by hydrolytic enzyme(s);

(e) having primary metabolites resulting from a non-oxidative metabolic pathway;

(f) having primary metabolite(s) with negligible inhibitory activity at the HERG (human ether-a-go-go related gene) potassium channel at the normal therapeutic concentration of the parent drug in plasma;

(g) lacking or having reduced incidence of metabolic drug-drug interaction (DDI) when co-administered with other drugs;

(h) not substantially elevating liver function test (LFT) values when administered alone;

or

(i) having oral bioavailability.

6. A compound comprising structural Formula (II):

7. The compound of claim 6, wherein the spacer is O, S, alkyl, substituted alkyl, acyl, acylamino, alkoxy, alkylamino, alkylthio, amino, carboxy, or alkoxycarbonyl.

8. The compound of claim 7, wherein the spacer is alky or substituted alkyl.

9. The compound of claim 6, wherein R⁴ and R⁵ form a 5- or 6-membered substituted or unsubstituted ring.

10. The compound of claim 9, wherein the ring comprises a heteroatom selected from the group consisting of O, N, or S.

11. The compound of claim 9, wherein the ring is substituted with a substituent.

12. The compound of claim 11, wherein the substituent is alkyl, substituted alkyl, halo, hydroxyl, or carbonyl.

13. The compound of claim 6, wherein R⁷ and R⁸ form a 5- or 6-membered substituted or unsubstituted ring.

14. The compound of claim 13, wherein the ring comprises a heteroatom selected from the group consisting of O, N, or S.

15. The compound of claim 13, wherein the ring is substituted with a substituent.

16. The compound of claim 15, wherein the substituent is alkyl, substituted alkyl, halo, hydroxyl, or carbonyl.

17. The compound of claim 6, wherein R⁷ and R⁸ form a 5- or 6-membered substituted or unsubstituted lactone or lactam.

18. The compound of claim 17, wherein the lactone or lactam is substituted with a substituent.

19. The compound of claim 18, wherein the substituent is alkyl, halo, hydroxyl, or carbonyl.

20. A compound comprising structural Formula (III):

21. A compound comprising structural Formula (IV):

22. A compound comprising structural Formula (V):

23. A compound comprising structural Formula (VI):

24. A compound comprising structural Formula (VII):

25. A compound comprising structural Formula (VIII):

26. A compound comprising structural Formula (IX):

27. A compound comprising structural Formula (X):

29. A method of treating a patient, the method comprising:

administering to the patient a pharmaceutical composition comprising a compound of Formula (II);

30. The method of claim 29, wherein the spacer is O, S, alkyl, substituted alkyl, acyl, acylamino, alkoxy, alkylamino, alkylthio, amino, carboxy, or alkoxycarbonyl.

31. The method of claim 29, wherein R⁴ and R⁵ form a 5- or 6-membered substituted or unsubstituted ring.

32. The method of claim 29, wherein R⁷ and R⁸ form a 5- or 6-membered substituted or unsubstituted ring.

33. The method of claim 29, wherein the excipient is for oral, mucosal, rectal, parenteral, transdermal, or subcutaneous administration.

34. The method of claim 29, wherein the disease is psychoses, schizophrenia, acute manic, bipolar disorder, autistic disorder, or depression.

35. The method of claim 34, wherein the disease is schizophrenia.

36. The method of claim 34, wherein the disease is bipolar disorder.

37. The method of claim 34, wherein the disease is depression.

38. The method of claim 34, wherein the disease is acute manic.