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Novel phosphinic acid-containing thyromimetics

A halogen and trifluoromethyl technology, which is applied in the field of new phosphinic acid-containing thyromimetic drugs, can solve problems such as complex curative effect

Inactive Publication Date: 2008-05-14
METABASIS THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] Efficacy of TH therapy is complicated by the need for supraphysiological doses of T3 and associated side effects including cardiac problems, muscle weakness, and physical impairment

Method used

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  • Novel phosphinic acid-containing thyromimetics
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  • Novel phosphinic acid-containing thyromimetics

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[1667] Preparation of phosphonate prodrugs

[1668] Prodrugs can be introduced at various stages of synthesis. Most frequently, these prodrugs are prepared from phosphonic acids of formula I (due to their stability).

[1669] Phosphonic acids of formula I can be alkylated under nucleophilic substitution conditions with electrophiles such as alkyl halides and alkyl sulfonates to give phosphonates. For example, where YR 11 Compounds of formula I which are acyloxyalkyl groups can be dissolved in a suitable solvent such as DMF (J.Med.Chem.37:1875 (1994)) in a suitable base (for example, pyridine, TEA, diisopropylethylamine ) in the presence of an appropriate acyloxyalkyl halide (eg, Cl, Br, I; Phosphorus Sulfur 54:143 (1990); Synthesis 62 (1988)) by direct alkylation of compounds of formula I. The carboxylate component of these acyloxyalkyl halides includes, but is not limited to, acetates, propionates, isobutyrates, valerates, benzoates, and other carboxylates.

[1670] Dimet...

example 1

[1797] Compound 1: N-[3,5-Dimethyl-4-(3′-isopropyl-4′-hydroxyphenoxy)]carbamoylphosphonic acid

[1798]

[1799] Step a:

[1800] 3,5-Dimethyl-4-(3'-isopropyl-4'-methoxyphenoxy)aniline (J.Med.Chem.38: 695 (1995), 0.1 g, 0.35 mmol) and diphosgene (0.04 g, 0.19 mmol) were heated at 60° C. for 3 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. To the residue was added a solution of phosphite (0.06 g, 0.42 mmol) in hexane (1.0 mL, added 3 drops of triethylamine), and the reaction mixture was heated at reflux for 3 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexane (1:3), to obtain diethylphosphonate (0.1 g, 64%) as an oil: 1 H NMR (300MHz, CDCl 3 ): δ8.44(s, 1H), 7.17(s, 2H), 6.10-6.60(m, 3H), 4.10(m, 4H), 3.58(s, 3H), 3.07(m, 1H), 1.92( s, 3H), 1.93 (s, 3H...

example 2

[1804] Compound 2: 1-amino-2-[3,5-diiodo-4-(4'-hydroxy-3'-iodophenoxy)phenyl]ethylphosphonic acid

[1805]

[1806] Step a:

[1807]To 4-benzyloxyphenylacetyl chloride (4.0 g, 16.2 mmol) in THF (10.0 mL) was slowly added triethyl phosphite (3.33 mL, 19.5 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h and the solvent was removed under reduced pressure. The residue was treated with hexane (20 mL) and the mixture was filtered. The white solid was collected and air dried. The solid was dissolved in pyridine (25.0 mL) and hydroxylamine hydrochloride (1.96 g, 28 mmol) was added. The reaction mixture was stirred at room temperature for 72 h, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography eluting with ethyl acetate-hexane (7:3) to obtain 2-(4-benzyloxyphenyl)-1-(hydroxyimino) as colorless oil Diethyl ethyl phosphonate (5.2 g, 85%): 1 H NMR (300MHz, CDCl 3 ): δ7.1...

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Abstract

The present invention relates to compounds of phosphonic acid-containing T3 mimetics and monoesters thereof, stereoisomers, pharmaceutically acceptable salts, co-crystals, and prodrugs thereof and pharmaceutically acceptable salts and co-crystals of the prodrugs, as well as their preparation and uses for preventing and / or treating metabolic diseases such as obesity, NASH, hypercholesterolemia and hyperlipidemia, as well as associated conditions such as atherosclerosis, coronary heart disease, impaired glucose tolerance, metabolic syndrome x and diabetes.

Description

[0001] Cross References to Related Applications [0002] Pursuant to 35 U.S.X. §119(e), this application claims the earlier filing date of U.S. Provisional Application No. 60 / 684,573, filed May 26, 2005, and 60 / 725,169, filed October 6, 2005 Priority, the entire contents of which including the drawings are hereby incorporated by reference. technical field [0003] The present invention relates to phosphinic acid-containing compounds, pharmaceutically acceptable salts, and prodrugs of these compounds that are thyroid receptor ligands, as well as their preparation and use, for the prevention and / or treatment of metabolic diseases such as obesity, NASH, hyperlipidemia Cholesterolemia and hyperlipidemia, and related conditions such as atherosclerosis, coronary heart disease, impaired glucose tolerance and diabetes. The invention also relates to the liver-specific delivery of thyroid receptor ligands and the use of these compounds for the prevention and treatment of diseases respo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P5/14A61K31/662C07F9/30C07F9/40C07F9/572C07F9/32C07F9/655C07F9/36C07F9/48C07F9/6571
Inventor 马克·D·埃里安姜洪建塞尔日·H·布瓦耶
Owner METABASIS THERAPEUTICS INC
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