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Novel phosphorus-containing thyromimetics

A pharmaceutical, prodrug technology, applied in the field of new phosphorus-containing thyromimetic drugs, which can solve the problems of limited therapeutic application, increased heart organ weight, increased protein synthesis, etc.

Inactive Publication Date: 2008-05-28
METABASIS THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Increased protein synthesis and increased cardiac organ weights are readily observed in T3-treated animals and exhibit negative effects of T3 which limit therapeutic applications

Method used

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  • Novel phosphorus-containing thyromimetics
  • Novel phosphorus-containing thyromimetics
  • Novel phosphorus-containing thyromimetics

Examples

Experimental program
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Effect test

preparation example Construction

[1293] Preparation of phosphonate prodrugs

[1294] Prodrugs can be introduced at various stages of synthesis. Most often, these prodrugs are prepared from phosphonic acids of formula I due to their stability.

[1295] Phosphonic acids of formula I can be alkylated with electrophiles such as alkyl halides and alkyl sulfonates under nucleophilic substitution conditions to give phosphonates. For example, where YR 11 Compounds of formulae I-VII of the formula acyloxyalkyl group can be in a suitable solvent such as DMF (J. Med Chem. 37: 1875 (1994)) in a suitable base (eg, pyridine, TEA, diisopropyl Direct alkylation of compounds of formulae I-VII with appropriate acyloxyalkyl halides (eg, Cl, Br, I; Phosphorus Sulfur, 54:143 (1990); Synthesis 62 (1988)) in the presence of ethylamine) Prepare. The carboxylate moieties of these acyloxyalkyl halides include, but are not limited to, acetates, propionates, isobutyrates, valerates, benzoates, carbonates and other carboxylates.

[...

Embodiment 1

[1411] Compound 1: N-[3,5-Dimethyl-4-(3'-isopropyl-4'-hydroxyphenoxy)]carbamoylphosphonic acid

[1412]

[1413] Step a:

[1414] 3,5-Dimethyl-4-(3'-isopropyl-4'-methoxyphenoxy)aniline (J.Med.Chem.38: A mixture of 695 (1995), 0.1 g, 0.35 mmol) and diphosgene (0.04 g, 0.19 mmol) was heated at 60 °C for 3 h.

[1415] The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. To the residue was added a solution of diethyl phosphinate (0.06 g, 0.42 mmol) in hexanes (1.0 mL, 3 drops of triethylamine were added) 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 give diethyl phosphonate as an oil (0.1 g, 64%): 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,...

Embodiment 2

[1419] Compound 2: 1-Amino-2-[3,5-diiodo-4-(4'-hydroxy-3'-iodophenoxy)phenyl]ethylphosphonic acid

[1420]

[1421] Step a:

[1422] To a solution of 4-benzyloxyphenylacetyl chloride (4.0 g, 16.2 mmol) in THF (10.0 mL) was slowly added triethyl phosphinate (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 column chromatography on silica gel eluting with ethyl acetate-hexane (7:3) to give 2-(4-benzyloxyphenyl)-1-( as a colorless oil Diethyl hydroxyimino)ethylphosphonate (5.2 g, 85%): 1 H NMR (300MH...

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Abstract

The present invention relates to compounds containing T3 mimetics of phosphonic acid and monoesters, stereoisomers, pharmaceutically acceptable salts, co-crystals thereof, and prodrugs thereof and pharmaceutically acceptable salts and co-crystals of prodrugs thereof, and Their preparation and use in the prevention and / or treatment of metabolic diseases such as obesity, nonalcoholic steatohepatitis (NASH), hypercholesterolemia and hyperlipidemia, and related conditions such as atherosclerosis, coronary Cardiac disease, impaired glucose tolerance, metabolic syndrome x, and diabetes uses.

Description

[0001] Cross-reference of related patents [0002] This application claims the benefit of US Application No. 11 / 137,773, filed May 26, 2005, which is a continuation-in-part of PCT / US2004 / 039024, filed November 19, 2004, based on 35 U.S.C. §119 ( e), claiming the benefit of earlier filed applications such as US Provisional Application No. 60 / 598,524, filed August 3, 2004, and US Provisional Application No. 60 / 523,830, filed November 19, 2003. This application also claims the benefit of US Provisional Application No. 60 / 725,170, filed October 6, 2005. The entire contents of these applications, including the figures, are incorporated herein by reference. technical field [0003] The present invention relates to phosphonic acid-containing compounds as thyroid receptor ligands and their monoesters, pharmaceutically acceptable salts, and prodrugs of these compounds and their preparation and use in the prevention and / or treatment of metabolic diseases such as obesity, Nonalcoholic ...

Claims

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Application Information

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IPC IPC(8): C07F9/02C07F9/30C07F9/38C07F9/40C07F9/44C07F9/572C07F9/58C07F9/6571
CPCC07F9/4056C07F9/4006C07F9/4407C07F9/36C07F9/4075C07F9/3882C07F9/4465C07F9/3808C07F9/65517C07F9/657181C07F9/3211C07F9/4426A61P1/16A61P3/04A61P3/06A61P3/08A61P3/10A61P5/14A61P9/10A61P9/12A61P43/00
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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