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A combination of FBPase Inhibitors and insulin sensitizers for the treatment of diabetes

A technology of insulin and sensitizers, applied in the field of therapeutic compositions, can solve problems such as weak activity, inability to inhibit glucose production, and poor cell penetration

Inactive Publication Date: 2002-05-22
METABASIS THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these compounds were rather weakly active and failed to inhibit glucose production in hepatocytes (presumably due to poor cell penetration)

Method used

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  • A combination of FBPase Inhibitors and insulin sensitizers for the treatment of diabetes
  • A combination of FBPase Inhibitors and insulin sensitizers for the treatment of diabetes

Examples

Experimental program
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Effect test

Embodiment

[0770] Compounds of formula VI are prepared according to modified literature methods and other methods well known to those skilled in the art. These compounds are generally synthesized by the method of Srivastava, J. Med. Chem. (1976). Wood et al., J. Med. Chem. 28: 1198-1203 (1985); Sagi et al., J. Med. Chem. 35: 4549-4556 (1992); Paul, Jr. J. Med. Chem. 28: 1704-1716 (1985); Cohen et al., J. Am. Chem. Soc. 95:4619-4624 (1973). Other methods are described.

[0771] Compounds of formula II-IV were prepared according to the methods described in PCT publications WO 98 / 39344, WO 98 / 39343, and WO 98 / 39342. Part 1 Synthetic formula I compound

[0772] Synthesis of compounds within the scope of this invention generally includes some or all of the following general steps: (1) preparation of phosphonate prodrugs; (2) deprotection of phosphonate; (3) modification of heterocycle; Ring coupling with phosphonate moieties; (5) construction of heterocycles; (6) ring closure to construct ...

Embodiment Embodiment 1 preparation 5- 2 -2-(1)A.  -78℃，2- 2 (1mmol)THF( 4 )nBuLi(1mmol)。1， 2 (1.2mmol)，40。，。B.  90℃80％4。，1，。 or preparation 。C.  -78℃，(1mmol)TMEDA(N，N，N’，N’- 4 2 )(1mmol) and nBuLi(2mmol)0.5。 2 (1.2mmol)，1。，2- 2 ，。D.  -78℃，2- 2 (1mmol)THFLDA(1.12mmol，N，N- 2 )20。(1.5mmol)，1。，1，。2- preparation 。E.  2-(1mmol) and N，N’- 2 2 (1mmol)，-。2，，，-2-(N，N’- 2 )，。bp 59-61℃(3mmHg)。F.-40℃--48℃，-2-(N， N’- 2 )(1mmol) and TMEDA(1mmol)THFnBuLi(1.3mmol)。0℃1.5， to -55℃， 2 (1.1mmol)THF。25℃12，，，5- 2 -2-(N，N’- 2 )，。G.  5- 2 -2-(N，N’- 2 )(1mmol) to pH＝1。，1，。 Embodiment 2

[0822]Examples Example 1 Preparation of 5-diethylphosphono-2-furfuraldehyde (1) Step A. At -78°C, a solution of 2-furfuraldehyde diethyl acetal (1 mmol) in THF (tetrahydrofuran) was washed with nBuLi (1 mmol) treatment. After 1 hour, diethyl chlorophosphate (1.2 mmol) was added and the reaction was stirred for 40 minutes. After extraction and evaporation, a brown oil was obtained. Step B. The resulting brown oil was treated with 80% acetic acid at 90°C for 4 hours. After extraction and chromatographic purification, compound 1 was obtained as a clear yellow oil. Alternatively the aldehyde can be prepared from furan as described below. Step C. A solution of furan (1 mmol) in ether was treated with TMEDA (N,N,N',N'-tetramethylethylenediamine) (1 mmol) and nBuLi (2 mmol) at -78°C for 0.5 h. Diethyl chlorophosphate (1.2 mmol) was added to the reaction mixture and stirred for another 1 hour. Extraction and distillation afforded diethyl 2-furanphosphonate as a clear oil. Step D...

Embodiment 3

[0828] The following compounds were prepared according to this method: (2.4) 5-diethylphosphono-2-(2-ethoxycarbonylacetyl) furan (2.5) 5-diethylphosphono-2-(2- Methylthioacetyl)furan (2.6) 6-diethylphosphono-2-acetylpyridine Example 3. Preparation of 4-[(2-(5-phosphono)furyl]thiazole, 4-[2- (6-phosphono)pyridyl]thiazole and 4-[2-(5-phosphono)furyl]selenazole Step A. A solution of compound 2.1 (1 mmol) in ethanol was treated with copper(II) bromide (2.2 mmol) was treated under reflux conditions for 3 hours. The cooled reaction mixture was filtered and the filtrate was evaporated to dryness. The resulting dark oil was purified by chromatography to obtain 5-diethylphosphono-2-[(2- Bromo-4-methyl-1-oxo)pentyl]furan as an orange oil. Step B. Adding 5-diethylphosphono-2-[(2-bromo-4-methyl-1-oxo A solution of pentyl]furan (1 mmol) and thiourea (2 mmol) in ethanol was heated to reflux for 2 hours. The cooled reaction mixture was evaporated to dryness and the resulting yellow foam was...

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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

[0001] Related Application Introduction [0002] This application is a continuation of Provisional Application No. 60 / 114,718, filed December 23, 1998, which is hereby incorporated by reference in its entirety. field of invention [0003] The present invention discloses combination therapy with insulin sensitizers and FBPase inhibitors for the treatment of diabetes mellitus and other diseases that would benefit from controlling blood glucose levels or improving insulin sensitivity, lowering insulin levels or increasing insulin secretion disease. The invention also discloses compositions for said treatment. Background of the invention [0004] Diabetes is one of the most prevalent diseases in the world today. Diabetics have been divided into two categories, Type I or insulin-dependent diabetes mellitus and Type II or non-insulin-dependent diabetes mellitus (NIDDM). NIDDM accounts for approximately 90% of all diabe...

Claims

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Application Information

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IPC IPC(8): A61K45/06A61K31/192A61K31/203A61K31/421A61K31/426A61K31/427A61K31/4439A61K31/661A61K31/662A61K31/664A61K31/665A61K31/675A61K31/7056A61K33/00A61P3/00A61P3/04A61P3/08A61P3/10A61P9/12A61P15/00
CPCA61K31/675A61K45/06A61P15/00A61P3/00A61P3/04A61P3/08A61P5/50A61P9/12A61P3/10A61K31/425A61K2300/00
Inventor M·D·埃里安P·范佩耶
Owner METABASIS THERAPEUTICS INC
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