Glucokinase activators and methods of using same

• US 8,273,777 B2
• Filed: 08/30/2010
• Issued: 09/25/2012
• Est. Priority Date: 07/27/2007
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Shi, Yan, Cheng, Peter T. W., Wang, Ying, Ryono, Denis E.
• Primary Examiner(s): Kosack, Joseph
• Assistant Examiner(s): COUGHLIN, MATTHEW P
• Application Number:
  US12/871,226
• Publication Number:
  US 20100324071A1
• Time in Patent Office: 757 Days
• Field of Search: 548/200, 514/365
• US Class Current: 514/365
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• 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 27/06 Antiglaucoma agents or miotics
• 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 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: C07C 317/22 with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
• CPC Class Codes: C07D 213/81 Amides; Imides
• CPC Class Codes: C07D 231/14 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/90 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 241/24 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 249/10 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 277/56 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 277/68 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems

Abstract

Compounds are provided which are activators of the enzyme glucokinase and thus are useful in treating diabetes and related diseases, which compounds have the structure

where Q is

and R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined herein
or a pharmaceutically acceptable salt thereof.

A method for treating diabetes and related diseases employing the above compounds is also provided.

Claims

1. A compound of the structure

2. The compound as defined in claim 1 wherein R⁴ and R⁵ are the same or different and are independently selected from the group consisting of H, alkyl, arylalkyl, alkoxycarbonyl and carboxyl, or a pharmaceutically acceptable salt thereof, and all stereoisomers thereof, including enantiomers and diastereomers thereof.

3. The compound as defined in claim 2 wherein Q is

4. The compound as defined in claim 1 wherein the R² is Y—

Z—

, where Z is O or a bond; and

Y is C_1-6alkyl-Z¹—

where Z¹ is a bond,

aryl-Z¹—

where Z¹ is a bond,

heterocyclyl-Z¹—

where Z¹ is a bond, or

heteroaryl-Z¹—

where Z¹ is a bond,

and R⁶ is hydrogen,

or a pharmaceutically acceptable salt thereof, and all stereoisomers thereof, including enantiomers and diastereomers thereof.

5. The compound as defined in claim 4 wherein the R² group is selected from the group consisting of

6. The compound as defined in claim 1 wherein

R³ is Y—

Z—

where Z is a bond, and

Y is aryl Z¹ where Z¹ is a bond,

or a pharmaceutically acceptable salt thereof, and all stereoisomers thereof, including enantiomers and diastereomers thereof.

7. The compound as defined in claim 6 wherein R³ is

8. The compound as defined in claim 1 wherein

10. A pharmaceutical composition comprising a compound as defined in claim 1, or a pharmaceutically acceptable salt thereof, and all stereoisomers thereof, including enantiomers and diastereomers thereof, and a pharmaceutically acceptable carrier thereof.

11. A pharmaceutical composition comprising a compound as defined in claim 1, or a pharmaceutically acceptable salt thereof, and all stereoisomers thereof, including enantiomers and diastereomers thereof, and another therapeutic agent which is an anti-diabetic agent, anti-hyperglycemic agent, anti-hyperinsulinemic agent, anti-retinopathic agent, anti-neuropathic agent, anti-nephropathic agent, anti-atherosclerotic agent, anti-infective agent, anti-ischemic agent, anti-hypertensive agent, anti-obesity agent, anti-dyslipidemic agent, anti-hyperlipidemic agent, anti-hypertriglyceridemic agent, anti-hypercholesterolemic agent, anti-ischemic agent, anti-cancer agent, anti-cytotoxic agent, anti-restenotic agent, anti-pancreatic agent, lipid lowering agent, appetite suppressant, memory enhancing agent, or cognitive agent.

9. A compound of the structure