Combination of FBPase Inhibitors and Insulin Sensitizers for the Treatment of Diabetes

a technology of fbpase inhibitors and insulin sensitizers, which is applied in the direction of phosphorous compound active ingredients, biocide, heterocyclic compound active ingredients, etc., can solve the problems of reducing the insulin requirement and associated safety risks, and achieve the effects of improving peripheral insulin sensitivity, improving glycemic control, and enhancing insulin action

Inactive Publication Date: 2008-01-03
METABASIS THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0019] The instant invention is a combination therapy and a composition for the treatment for diabetes and diseases responding to improved glycemic control or to improve peripheral insulin sensitivity. The therapy requires administration of a insulin sensitizer agent, e.g. PPAR γ agonist, RXR ligand, or another agent known to enhance insulin action and an FBPase inhibitor either together or at a different time such that improved glycemic control is achieved. In another aspect of t...

Problems solved by technology

The combination therapy decreases the in...

Method used

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  • Combination of FBPase Inhibitors and Insulin Sensitizers for the Treatment of Diabetes
  • Combination of FBPase Inhibitors and Insulin Sensitizers for the Treatment of Diabetes
  • Combination of FBPase Inhibitors and Insulin Sensitizers for the Treatment of Diabetes

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of 5-diethylphosphono-2-furaldehyde (1)

[1099] Step A. A solution of 2-furaldehyde diethyl acetal (1 mmole) in THF (tetrahydrofuran) was treated with nBuLi (1 mmole) at −78° C. After 1 h, diethyl chlorophosphate (1.2 mmole) was added and the reaction was stirred for 40 min. Extraction and evaporation gave a brown oil.

[1100] Step B. The resulting brown oil was treated with 80% acetic acid at 90° C. for 4 h. Extraction and chromatography gave compound 1 as a clear yellow oil. Alternatively this aldehyde can be prepared from furan as described below.

[1101] Step C. A solution of furan (1 mmole) in diethyl ether was treated with TMEDA (N,N,N′N′-tetramethylethylenediamine) (1 mmole) and nBuLi (2 mmole) at −78° C. for 0.5 h. Diethyl chlorophosphate (1.2 mmole) was added to the reaction mixture and stirred for another hour. Extraction and distillation gave diethyl 2-furanphosphonate as a clear oil.

[1102] Step D. A solution of diethyl 2-furanphosphonate (1 mmole) in THF was tr...

example 2

Preparation of 5-diethylphosphono-2-[(1-oxo)alkyl]furans and 6-diethylphosphono-2-[(1-oxo)alkyl]pyridines

[1106] Step A. A solution of furan (1.3 mmole) in toluene was treated with 4-methyl pentanoic acid (1 mmole), trifluoroacetic anhydride (1.2 mmole) and boron trifluoride etherate (0.1 mmole) at 56° C. for 3.5 h. The cooled reaction mixture was quenched with aqueous sodium bicarbonate (1.9 mmole), filtered through a celite pad. Extraction, evaporation and distillation gave 2-[(4-methyl-1-oxo)pentyl]furan as a brown oil (bp 65-77° C., 0.1 mmHg).

[1107] Step B. A solution of 2-[(4-methyl-1-oxo)pentyl]furan (1 mmole) in benzene was treated with ethylene glycol (2.1 mmole) and p-toluenesulfonic acid (0.05 mmole) at reflux for 60 h while removing water via a Dean-Stark trap. Triethyl orthoformate (0.6 mmole) was added and resulting mixture was heated at reflux for an additional hour. Extraction and evaporation gave 2-(2-furanyl)-2-[(3-methyl)butyl]-1,3-dioxolane as an orange liquid.

[...

example 3

Preparation of 4-[2-(5-phosphono)furanyl]thiazoles, 4-[2-(6-phosphono)pyridyl]thiazoles and 4-[2-(5-phosphono)furanyl]selenazoles

[1124] Step A. A solution of compound 2.1 (1 mmole) in ethanol was treated with copper (II) bromide (2.2 mmole) at reflux for 3 h. The cooled reaction mixture was filtered and the filtrate was evaporated to dryness. The resulting dark oil was purified by chromatography to give 5-diethylphosphono-2-[(2-bromo-4-methyl-1-oxo)pentyl]furan as an orange oil.

[1125] Step B. A solution of 5-diethylphosphono-2-[(2-bromo-4-methyl-1-oxo)pentyl]furan (1 mmole) and thiourea (2 mmole) in ethanol was heated at reflux for 2 h. The cooled reaction mixture was evaporated to dryness and the resulting yellow foam was suspended in saturated sodium bicarbonate and water (pH=8). The resulting yellow solid was collected through filtration to give 2-amino-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole.

[1126] Step C. A solution of 2-amino-5-isobutyl-4-[2-(5-diethylphosphono...

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Abstract

Pharmaceutical compositions containing an FBPase inhibitor and an insulin sensitizer are provided as well as methods for treating diabetes and diseases responding to increased glycemic control, an improvement in insulin sensitivity, a reduction in insulin levels, or an enhancement of insulin secretion.

Description

RELATED APPLICATIONS [0001] This application is a continuation of U.S. application Ser. No. 10 / 780,948, filed Feb. 17, 2004, which is a divisional of U.S. application Ser. No. 09 / 470,649, filed Dec. 22, 1999, now U.S. Pat. No. 6,756,360, which claims benefit of U.S. Provisional Application No. 60 / 114,718, filed Dec. 24, 1998 and which are incorporated by reference herein in their entirety.BACKGROUND OF THE INVENTION [0002] A combination therapy of an insulin sensitizer and an FBPase inhibitor is disclosed for the treatment of diabetes, and other diseases where the control of blood glucose levels or an improvement in insulin sensitivity, reduction in insulin levels or an enhancement of insulin secretion is beneficial. Compositions used in the therapy are also disclosed. BACKGROUND OF THE INVENTION [0003] Diabetes mellitus (or diabetes) is one of the most prevalent diseases in the world today. Diabetes patients have been divided into two classes, namely type I or insulin-dependent dia...

Claims

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Application Information

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IPC IPC(8): A61K31/7076A61K31/7056A61K31/522A61K31/675A61K31/426A61K31/4439A61K45/06
CPCA61K31/426A61K31/4439A61K31/522A61K31/675A61K31/7056A61K45/06A61K31/7076A61K2300/00
Inventor ERION, MARK D.VAN POELJE, PAUL D.
Owner METABASIS THERAPEUTICS INC
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