AZAQUINOLINONE DERIVATIVES AND USES THEREOF

• US 20100130540A1
• Filed: 11/13/2009
• Published: 05/27/2010
• Est. Priority Date: 11/13/2008
• Status: Active Grant

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Link Medicine Corp. (Astrazeneca PLC)
• Inventors: Duggan, Mark E.
• Granted Patent: US 8,343,996 B2
• Time in Patent Office: Days
• US Class Current: 514/300
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 519/00 : Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The present invention provides compounds and methods for treating or preventing the development of a disease, disorder, or condition in a subject or patient.

Claims

1. A compound of formula I:

2. The compound of claim 1, wherein V³ is N.

3. The compound of claim 1 of any one of formulae I-a, I-b, or I-c:

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein is a double bond.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R¹ is phenyl, and wherein R¹ is optionally substituted with 0-5 —

R^w.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R³ is a 5 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted with 1-2 R^x groups.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R⁴ is phenyl substituted with 0-3 R^y groups.

8. The compound of claim 1 of formula I-q:

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein at least one R^w group is independently selected from the group consisting of R, halogen, —

OR, —

N(R′

)₂, and —

C(R)₃.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R² is selected from the group consisting of —

OR, halogen, and —

N(R′

)₂.

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R⁵ is an acyclic C_1-12 aliphatic moiety.

12. The compound of claim 1 having any one of the following structures:

13. A pharmaceutical composition comprising a compound claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

14. A method of treating or preventing a proteinopathy, the method comprising administering the composition of claim 13 in a therapeutically effective amount to a subject in need thereof.

15. The method of claim 14, wherein the proteinopathy is selected from neurodegenerative disease, proliferative disease, inflammatory disease, and cardiovascular disease.

16. The method of claim 14, wherein the proteinopathy is a synucleinopathy.

17. The method of claim 14, wherein the proteinopathy is an amyloidopathy.

18. The method of claim 14, wherein the proteinopathy is a taupathy.

19. The method of claim 14, further comprising administering to the subject an amount of one or more non-farnesyl transferase inhibitor compounds effective to treat or prevent the proteinopathy.

20. The method of claim 14, wherein each non-farnesyl transferase inhibitor compound is selected from the group consisting of dopamine agonist, DOPA decarboxylase inhibitor, dopamine precursor, monoamine oxidase blocker, cathechol O-methyl transferase inhibitor, anticholinergic, and NMDA antagonist.