Novel compounds, their preparation and use

A compound and mixture technology, applied in the fields of dicarboxylic acid derivatives, their preparation and therapeutic applications, can solve the problems of inability to overcome macrovascular complications and the like

Inactive Publication Date: 2005-01-26
NOVO NORDISK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Glucose lowering as a single approach does not overcome macrovascular complications associated with type 2 diabetes and metabolic syndrome

Method used

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  • Novel compounds, their preparation and use
  • Novel compounds, their preparation and use
  • Novel compounds, their preparation and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0532] Embodiment 1 (general method A)

[0533] (E)(E)(S)(S)2-Ethoxy-3-{4-[5-(4-{5-[4-(2-ethoxy-2-ethoxycarbonylethyl) )-phenoxy]-pent-3-en-1-ynyl}-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-propionic acid ethyl ester

[0534]

[0535] Steps A-B:

[0536] To a solution of 1,4-diiodobenzene (1.32 g, 4.0 mmol) in diisopropylamine (12 mL) was added copper(I) iodide (60 mg, 0.3 mmol) and tetra (Triphenylphosphine)palladium (80 mg, 0.07 mmol). After stirring the mixture for 1 h, a solution of 2-penten-4-yn-1-ol (1.0 g, 12.0 mmol) in diisopropylamine (7 mL) was added. After stirring at 60 °C for 8 h under nitrogen atmosphere, the reaction mixture was filtered and the filtrate was evaporated to dryness. The product was purified by flash chromatography using toluene / ethyl acetate (2:1) gradually transitioning to ethyl acetate as eluent to give 520 mg (55%) of (E)(E)5-[4-(5-hydroxy -pent-3-en-1-ynyl)-phenyl]-pent-2-en-4-yn-1-ol.

[0537] 1 H NMR (CDCl 3 ): δ1.47(2H, bs), 4.28(2H, ...

Embodiment 2

[0541] Embodiment 2 (general method E)

[0542] (E)(E)(S)(S)3-{4-[5-(4-{5-[4-(2-carboxy-2-ethoxy-ethyl)-phenoxy]-pentane -3-en-1-ynyl}-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid

[0543]

[0544] Step A:

[0545] To (E)(E)(S)(S)2-ethoxy-3-{4-[5-(4-{5-[4-(2-ethoxy-2-ethoxycarbonylethyl Base)-phenoxy]-pent-3-en-1-ynyl}-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-propionic acid ethyl ester (Example 1 ) (88 mg 0.13 mmol) in THF (3 mL) and ethanol (3 mL) was added 1N sodium hydroxide (2 mL). After stirring at room temperature for 1 h, the reaction mixture was concentrated under reduced pressure, and water and 1N hydrochloric acid were added until the pH value was 1. The product was extracted three times with dichloromethane, and the combined organic phases were washed with magnesium sulfate (MgSO 4 ), filtered and concentrated under reduced pressure to give the title compound as a crystalline product. The product was recrystallized from ethyl acetate and petrole...

Embodiment 3

[0547] Embodiment 3 (general method A)

[0548] (E)(E)3-Chloro-4-(5-4-[5-(3-chloro-4-ethoxycarbonylmethyl-phenoxy)-pent-3-en-1-ynyl ]-phenyl}-pent-2-en-4-ynyloxy)-phenyl]-ethyl acetate

[0549]

[0550] Step C:

[0551] Under nitrogen atmosphere, azodicarboxylic acid dipiperidine amide (504mg, 2.0mmol) was added to tributylphosphine (404mg, 2.0mmol), (3-chloro-4-hydroxybenzene base) ethyl propionate (322 mg, 1.5 mmol) and (E)(E) 5-[4-(5-hydroxy-pent-3-en-1-ynyl)-phenyl]-pent-2-ene -4-Alkyn-1-ol (Example 1, Steps A-B) (120 mg, 0.5 mmol) in a stirred solution in dry THF (25 mL). After 1 h, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography using a gradual transition from toluene to toluene / ethyl acetate (1:1) as eluent. The product was recrystallized from ethyl acetate to give 150 mg (48%) of the title compound.

[0552] 1 H NMR (CDCl 3 ): δ1.24(6H, t), 3.53(4H, s), 4.15(4...

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Abstract

A novel class of dicarboxylic acid derivatives, the use of these compounds as phar-maceutical compositions, pharmaceutical compositions comprising the compounds and meth-ods of treatment employing these compounds and compositions. The present compounds may be useful in the treatment and / or prevention of conditions mediated by Peroxisome Prolifera-tor-Activated Receptors (PPAR).

Description

technical field [0001] The present invention relates to novel dicarboxylic acid derivatives, the use of these compounds as pharmaceutical compositions, pharmaceutical compositions comprising said compounds and methods of treatment using these compounds and compositions. More specifically, the compounds of the invention are useful in the treatment and / or prevention of peroxisome proliferator-activated receptor (PPAR) mediated conditions. Background technique [0002] Coronary artery disease (CAD) is fatal in patients with type 2 diabetes and the metabolic syndrome (i.e., those falling within the "fatal quartet" of impaired glucose tolerance, insulin resistance, hypertriglyceridemia, and / or obesity) the main cause of. [0003] The hypolipidemic fibrate and the antidiabetic thiazolidinediones, respectively, showed moderately potent triglyceride-lowering activity, although they were neither potent nor potent enough to be used alone in patients with type 2 diabetes or the metabo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/194A61K31/197A61K31/216A61K31/225A61P3/04A61P3/06A61P3/10A61P9/00A61P9/10A61P43/00C07C51/09C07C59/64C07C59/68C07C59/70C07C59/90C07C69/712C07C69/734C07C229/36C07C323/20C07C323/62
CPCC07C69/734C07C51/09C07C69/712C07C229/36C07C59/68C07C59/90C07C323/62C07C323/20A61P3/10A61P3/04A61P3/06A61P43/00A61P9/00A61P9/10
Inventor P·绍尔博格P·S·布里L·杰普森J·P·莫根森
Owner NOVO NORDISK AS
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