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Indole and indazole analogs as glycogen synthase activators

a technology of glycogen synthase and indole, which is applied in the direction of biocide, drug composition, metabolic disorder, etc., can solve the problems of weight gain, loss of effectiveness, and inability to control disease,

Inactive Publication Date: 2011-05-12
F HOFFMANN LA ROCHE INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these factors are often unable to control the disease, and there are a number of drug treatments available, including insulin, metformin, sulfonylureas, acarbose, and thiazolidinediones.
Each of these treatments has disadvantages and there is an ongoing need for new drugs to treat diabetes.
However, it loses its effectiveness over a period of years [Turner, R. C. et al.
One disadvantage associated with the use of thiazolidinediones is weight gain.
A further problem often encountered in patients treated with sulfonylureas is hypoglycemia [Salas, M. and Caro, J. J. Adv. Drug React. Tox. Rev. 2002, 21, 205-217].
It has lower efficacy than metformin or the sulfonylureas, and it causes intestinal discomfort and diarrhea which often lead to the discontinuation of its use [Inzucchi, S. E. JAMA 2002, 287, 360].
However, none of these known compounds have been associated with either the treatment of diseases mediated by the activation of the glycogen synthase enzyme or to any pharmaceutical composition for the treatment of diseases mediated by the activation of the glycogen synthase enzyme.

Method used

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  • Indole and indazole analogs as glycogen synthase activators
  • Indole and indazole analogs as glycogen synthase activators
  • Indole and indazole analogs as glycogen synthase activators

Examples

Experimental program
Comparison scheme
Effect test

example 1

4-(4′,5′-Difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1H-indazole

[0085]

[0086]3-Amino-2-methyl benzyl alcohol (0.82 g, 5.98 mmol), acetic anhydride (1.68 mL, 17.8 mmol), potassium acetate (1.75 g, 17.8 mol), isoamyl nitrite (1.82 mL, 13.7 mmol) and 18-crown-6 (79 mg, 0.3 mmol) in 25 mL CHCl3 were reacted as described in EP99 / 07620. The crude product was purified by flash chromatography with a gradient from 0-35% ethyl acetate in hexanes to yield acetic acid 1-acetyl-1H-indazol-4-ylmethyl ester.

[0087]Acetic acid 1-acetyl-1H-indazol-4-ylmethyl ester was treated with 6 mL 48% HBr with stirring overnight and then refluxed for 5 hrs. The reaction mixture was concentrated, diluted with CH3CN and the precipitated solid was filtered off. The residue was treated with dihydropyran (0.53 g, 6.28 mmol) in 25 mL THF and heated to reflux for 5 hrs. The reaction was cooled and distributed between CH2Cl2 and saturated NaHCO3. The organic layer was separated, washed with H2O and concentrated in vacuo....

example 2

3-[4-(4′,5′-Difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indazol-1-yl]-propionic acid

[0090]

[0091]4-(4′,5′-Difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1H-indazole (0.09 g, 0.245 mmol), ethyl bromopropionate (0.045 g, 0.245 mmol), cesium carbonate (81 mg, 0.294 mmol) in 6 mL DMF was stirred at RT overnight and then heated to 90° C. for 35 min. The reaction was cooled and distributed between EtOAc and H2O. The organic layer was separated and concentrated in vacuo. The crude product was purified by flash chromatography with a gradient from 0-30% ethyl acetate in hexanes to yield 3-[4-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indazol-1-yl]-propionic acid ethyl ester as a white solid (98 mg, 85.7%).

[0092]3-[4-(4′,5′-Difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indazol-1-yl]-propionic acid ethyl ester (0.095 g, 0.204 mmol) and lithium hydroxide hydrate (10 mg, 0.245 mmol) in 5 mL THF / 1 mL H2O was stirred at RT for 3 hrs. The reaction was distributed between EtOAc and H2O. The water ...

example 3

6-(4′,5′-Difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1H-indazole

[0093]

[0094]6-(4′,5′-Difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1H-indazole was prepared from 3-amino-4 methyl benzyl alcohol (1 g, 0.729 mmol), as described above for 4-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1H-indazole, to yield 510 mg of product. LC-MS (ES) calculated for C21H16F2N2O2, 366.37. Found m / z 367 [M+H]+.

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Abstract

Provided herein are compounds of the formula (I):as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of metabolic diseases and disorders such as, for example, type II diabetes mellitus.

Description

PRIORITY TO RELATED APPLICATION(S)[0001]This application claims the benefit of U.S. Provisional Application No. 61 / 260,059, filed Nov. 11, 2009, which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION[0002]The invention is directed to compounds, salts and pharmaceutical compositions useful as activators of glycogen synthase for the treatment of metabolic diseases and disorders.[0003]All documents cited or relied upon below are expressly incorporated herein by reference.BACKGROUND OF THE INVENTION[0004]Diabetes mellitus is a common and serious disorder, affecting 10 million people in the U.S. [Harris, M. I. Diabetes Care 1998 21 (3S) Supplement, 11C], putting them at increased risk of stroke, heart disease, kidney damage, blindness, and amputation. Diabetes is characterized by decreased insulin secretion and / or an impaired ability of peripheral tissues to respond to insulin, resulting in increased plasma glucose levels. The incidence of diabetes is increasing...

Claims

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Application Information

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IPC IPC(8): A61K31/416C07D231/56A61K31/405C07D209/12C07D209/08A61K31/404A61P3/00
CPCC07D231/56C07D209/08A61P3/00
Inventor BOLIN, DAVID ROBERTHAMILTON, MATTHEW MICHAELMCDERMOTT, LEE APOSTLEYI, LIN
Owner F HOFFMANN LA ROCHE INC
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