NOVEL GLUCOKINASE ACTIVATORS AND METHODS OF USING SAME

• US 20100324071A1
• Filed: 08/30/2010
• Published: 12/23/2010
• Est. Priority Date: 07/27/2007
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Cheng, Peter T. W., Wang, Ying, Shi, Yan, Ryono, Denis E.
• Granted Patent: US 8,273,777 B2
• Time in Patent Office: Days
• US Class Current: 514/255.06
• 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 having the structure

2. The compound as defined in claim 1 having the structure

3. The compound as defined in claim 2 wherein Q contains an R¹ ring which is an N-containing heteroaryl ring, or a pharmaceutically acceptable salt thereof, and all stereoisomers thereof, including enantiomers and diastereomers thereof.

5. The compound as defined in claim 3 wherein the R ring is a nitrogen containing a 5- or 6-membered monocyclic heteroaryl ring which optionally contains 1, 2 or 3 additional heteroatoms selected from sulfur, oxygen and/or nitrogen, or a pharmaceutically acceptable salt thereof, and all stereoisomers thereof, including enantiomers and diastereomers thereof.

6. The compound as defined in claim 5 wherein the heteroaryl ring contains a single nitrogen atom;

a nitrogen atom and a sulfur atom;

two nitrogen atoms, or three nitrogen atoms,

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

7. The compound as defined in claim 3 wherein the R¹ ring is a nitrogen containing 8- or 9-membered bicyclic heteroaryl ring which contains 1, 2 or 3 additional heteroatoms selected from sulfur, oxygen and/or nitrogen, or a pharmaceutically acceptable salt thereof, and all stereoisomers thereof, including enantiomers and diastereomers thereof.

8. The compound as defined in claim 7 wherein the 8- or 9-membered bicyclic heteroaryl ring contains two nitrogen atoms;

two nitrogen atoms and one sulfur atom;

or

one nitrogen atom and one sulfur atom,

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

9. The compound as defined in claim 3 wherein R⁴ and R⁵ are the same or different and are independently selected from alkyl, arylalkyl, alkoxycarbonyl or carboxyl, or a pharmaceutically acceptable salt thereof, and all stereoisomers thereof, including enantiomers and diastereomers thereof.

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

11. 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.

12. The compound as defined in claim 11 wherein the R² group is

13. The compound as defined in claim 1 wherein

R³ is Y—

Z—

where Z is a bond, and

Y is aryl<sub>—

Z</sub>¹ where Z¹ is a bond,

or a pharmaceutically acceptable salt thereof, and all stereoisomers thereof,

including enantiomers and diastereomers thereof.

14. The compound as defined in claim 13 wherein R³ is

16. The compound as defined in claim 3 wherein

R¹ is

17. The compound as defined in claim 1 wherein the compound is

18. 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.

19. 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.

20. A method for treating, preventing, or slowing the progression of a disease requiring glucokinase activator therapy or activating the enzyme glucokinase, which comprises administering to a mammalian patient in need of treatment a therapeutically effective amount of a compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof, and all stereoisomers thereof, including enantiomers and diastereomers thereof.

21. The method as defined in claim 20 wherein the disease is diabetes, hyperglycemia, impaired glucose tolerance, insulin resistance, hyperinsulinemia, retinopathy, neuropathy, nephropathy, delayed wound healing, atherosclerosis and its sequelae, abnormal heart function, myocardial ischemia, stroke, Metabolic Syndrome, hypertension, obesity, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, high LDL, non-cardiac ischemia, infection, cancer, vascular restenosis, pancreatitis, neurodegenerative disease, lipid disorders, cognitive impairment and dementia, bone disease, HIV protease associated lipodystrophy, and glaucoma.

23. A method of treating Type II diabetes, which comprises administering to a patient in need of treatment a compound as defined in claim 1, or a pharmaceutically acceptable salt thereof, and all stereoisomers thereof, including enantiomers and diastereomers thereof.

4. (canceled)

15. (canceled)

22. (canceled)