Quinolines and related analogs as sirtuin modulators

• US 8,685,970 B2
• Filed: 04/30/2009
• Issued: 04/01/2014
• Est. Priority Date: 05/01/2008
• Status: Active Grant

• Current Assignee: GlaxoSmithKline LLC (GlaxoSmithKline PLC)
• Original Assignee: GlaxoSmithKline LLC (GlaxoSmithKline PLC)
• Inventors: Vu, Chi B., Disch, Jeremy S., Springer, Stephanic K., Blum, Charles A., Perni, Robert B.
• Primary Examiner(s): ANDERSON, REBECCA L
• Application Number:
  US12/990,339
• Publication Number:
  US 20110046110A1
• Time in Patent Office: 1,797 Days
• Field of Search: 427/2.26, 514/235.2, 544/128
• US Class Current: 514/235.2
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• 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 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 27/02 Ophthalmic agents
• 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 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• 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: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 215/12 : with substituted hydrocarbon radicals attached to ring carbon atoms
• CPC Class Codes: C07D 215/40 : attached in position 8
• CPC Class Codes: C07D 215/48 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 453/02 : containing not further condensed quinuclidine ring systems
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

Abstract

Provided herein are novel sirtuin-modulating compounds and methods of use thereof. The sirtuin-modulating compounds may be used for increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders including, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular disease, blood clotting disorders, inflammation, cancer, and/or flushing as well as diseases or disorders that would benefit from increased mitochondrial activity. Also provided are compositions comprising a sirtuin-modulating compound in combination with another therapeutic agent.

Claims

1. A compound represented by the formula:

2. The compound of claim 1, wherein:

X is selected from —

NH—

C(═

O)-†

, —

C(═

O)—

NH-†

, —

NH—

C(═

S)-†

, —

C(═

S)—

NH-†

, —

NH—

S(═

O)-†

, —

S(═

O)—

NH-†

, —

S(═

O)₂—

NH-†

, —

NH—

S(O)₂—

NR¹⁵-†

, —

NR¹⁵—

S(O)₂—

NH-†

, —

NH—

C(═

O)O-†

, O—

C(═

O)—

NH-†

, —

NH—

C(═

O)NH-†

, —

NH—

C(═

O)NR¹⁵-†

, —

NR¹⁵—

C(═

O)NH-†

, —

NH—

NR¹⁵-†

, —

NR¹⁵—

NH-†

, —

O—

NH-†

, —

NH—

O-†

, —

NH—

C(═

NR¹⁵)-†

, —

C(═

NR¹⁵)—

NH-†

, —

CR¹⁵R¹⁶—

NH—

C(O)-†

, —

NH—

C(═

S)—

CR¹⁵R¹⁶-†

, —

CR¹⁵R¹⁶—

C(═

S)—

NH-†

, —

NH—

S(O)—

CR¹⁵R¹⁶-†

, —

CR¹⁵R¹⁶—

S(O)—

NH-†

, —

NH—

S(O)₂—

CR¹⁵R¹⁶-†

, —

CR¹⁵R¹⁶—

S(O)₂—

NH-†

, —

NH—

C(═

O)—

O—

CR¹⁵R¹⁶-†

, —

CR¹⁵R¹⁶—

O—

C(═

O)—

NH-†

, —

NH—

C(═

O)—

NR¹⁴—

CR¹⁵R¹⁶-†

, —

NH—

C(═

O)—

CR¹⁵R¹⁶-†

, and —

CR¹⁵R¹⁶—

NH—

C(═

O)—

O-†

.

3. The compound of claim 1, wherein R¹² is selected from aryl and heteroaryl.

4. The compound of claim 3, wherein R¹² is selected from:

5. The compound of claim 1, selected from any one of:

6. The compound of claim 5, wherein the compound is represented by a Structural Formula selected from IIIa, IIIi, IIIj, IIIk, or IIIl.

7. The compound of claim 6, wherein the compound is represented by Structural Formula IIIa.

8. The compound of claim 1, wherein X is —

NH—

C(═

O)-†

or —

C(═

O)—

NH-†

.

9. The compound of claim 1, wherein R¹¹ is selected from:

10. The compound of claim 9, represented by the formula:

11. The compound of claim 1, wherein the compound is selected from any one of:

12. The compound of claim 1, wherein the salt is a pharmaceutically acceptable salt.

13. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

14. The pharmaceutical composition of claim 13, comprising a first active agent comprising a compound of claim 1 and further comprising an additional active agent.

15. A method for treating a subject suffering from insulin resistance, metabolic syndrome, or diabetes, or for increasing insulin sensitivity in a subject, comprising administering to the subject in need thereof a composition of claim 13.