COMPOSITIONS, SYNTHESIS, AND METHODS OF UTILIZING QUINAZOLINEDIONE DERIVATIVES

• US 20100222359A1
• Filed: 02/26/2010
• Published: 09/02/2010
• Est. Priority Date: 02/26/2009
• Status: Active Grant

• Current Assignee: Reviva Pharmaceuticals, Inc.
• Original Assignee: Reviva Pharmaceuticals, Inc.
• Inventors: Dadiboyena, Sureshbabu, Bhat, Laxminarayan, Mohapatra, Prabhu Prasad, Adiey, Kouacou
• Granted Patent: US 8,575,185 B2
• Time in Patent Office: Days
• US Class Current: 514/252.170
• CPC Class Codes: A61K 31/538 ortho- or peri-condensed with carbocyclic ring systems
• 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 265/36 condensed with one six-membered ring
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links

Abstract

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

Claims

1. A compound according to Formula (1):

2. The compound of claim 1 having Formula 1a:

3. The compound of claim 1 having Formula 1b:

4. The compound of claim 1, 2 or 3 wherein A is —

(CH₂)₂—

.

5. The compound of claim 1, 2 or 3 wherein A is —

O—

(CH₂)_n—

, —

S—

(CH₂)_n—

, —

CH₂—

O—

(CH₂)_n—

, —

(CH₂)_n—

O—

CH₂—

CH₂—

, —

CH₂—

S—

(CH₂)_n—

, or —

(CH₂)_n—

S—

CH₂—

CH₂—

.

6. The compound of claim 1, 2 or 3 wherein A is —

NH—

C(O)—

(CH₂)_n—

, —

CH₂—

NH—

C(O)—

(CH₂)_n—

, —

CH₂—

C(O)—

NH—

(CH₂)_n—

or —

(CH₂)_n—

C(O)—

NH—

CH₂—

CH₂—

.

7. The compound of claim 3 wherein R⁴ is hydrogen.

8. The compound of claim 1, 2 or 3 wherein one or both of R¹ and R² are independently halogen, haloalkyl or alkoxy.

9. The compound of claim 1, 2 or 3 wherein the compound is characterized by:

an affinity for dopamine D₂ receptors;

an affinity for serotonin 5-HT_1A receptors;

an affinity for serotonin 5-HT_2A receptors;

having at least one hydrolysable bond that can be cleaved non-oxidatively by hydrolytic enzymes;

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

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;

lacing or having reduced incidence of metabolic drug-drug interaction when co-administered with other drugs;

not substantially elevating liver function test values when administered alone;

or

having oral bioavailability.

10. A pharmaceutical composition comprising the compound of any one of claims 1-9.

11. A method of treating one of psychoses, schizophrenia, acute mania, bipolar disorder, autistic disorder or depression comprising administering to a patient in need thereof the compound of any one of claims 1-9.

12. A method of treating schizophrenia comprising administering to a patient in need thereof the compound of any one of claims 1-9.

13. A method of treating bipolar disorder comprising administering to a patient in need thereof the compound of any one of claims 1-9.

14. The use of the compound of any one of claims 1-9 for the treatment of any one of psychoses, schizophrenia, acute mania, bipolar disorder, autistic disorder or depression.

15. The use of claim 14 wherein the use comprises the treatment of schizophrenia.

16. The use of claim 14 wherein the use comprises the treatment of bipolar disorder.

17. The use of any one of the compounds of claims 1-9 in the manufacture of a medicament for use in treatment of one of psychoses, schizophrenia, acute mania, bipolar disorder, autistic disorder or depression.

18. The use of any one of the compounds of claims 1-9 in the manufacture of a medicament for use in treatment of schizophrenia.

19. The use of any one of the compounds of claims 1-9 in the manufacture of a medicament for use in treatment of bipolar disorder.