Heterocyclyl-substituted anti-hypercholesterolemic compounds

A compound and multi-substitution technology, applied in animal repellents, plant growth regulators, botanical equipment and methods, etc., can solve problems such as reducing the incidence and mortality of coronary heart disease

Inactive Publication Date: 2009-11-04
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although simvastatin substantially reduces the risk of coronary heart disease morbidity and mortality, the risk remains substantial in treated patients

Method used

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  • Heterocyclyl-substituted anti-hypercholesterolemic compounds
  • Heterocyclyl-substituted anti-hypercholesterolemic compounds
  • Heterocyclyl-substituted anti-hypercholesterolemic compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach A

[0053]

[0054] and pharmaceutically acceptable salts thereof, wherein variable (Ar 1 , R, R 1 , R 9 , R 12 , R 13 ) is as defined in Formula I or Embodiment A.

[0055] Another embodiment of the invention is a compound of formula I and embodiment A of formula Ib,

[0056]

[0057] and pharmaceutically acceptable salts thereof, wherein the variable (R 9 , R 12 , R 13 ) is as defined in Formula I or Embodiment A.

[0058] Another embodiment of the invention is a compound of formula I, Ia or embodiment A, wherein Ar 1 selected from aryl and R 4 Substituted aryl, where R 4 are 1-2 substituents at each occurrence independently selected from the following: -OR 5 , -O(CO)R 5 , -O(CO)OR 8 ,-O-C 1-5 Alkyl-OR 5 , -O(CO)NR 5 R 6 , -NR 5 R 6 , -NR 5 (CO)R 6 , -NR 5 (CO)OR 8 , -NR 5 (CO)NR 6 R 7 , -NR 5 SO 2 R 8 、-COOR 5 ,-CONR 5 R 6 、-COR 5 、-SO 2 NR 5 R 6 ,-S(O) t R 8 ,-O-C 1-10 Alkyl-COOR 5 ,-O-C 1-10 Alkyl-CONR 5 R 6 and fluoro groups. ...

Embodiment 1

[0317] (3R,4S)-4-{4-[3,4-Dihydroxy-3-(hydroxymethyl)butyl]phenyl}-3-[(3S)-3-(4-fluorophenyl)- 3-Hydroxypropyl]-1-{4-[3-(1H-1,2,4-triazol-1-yl)propyl]phenyl}azetidin-2-one

[0318] Step A : Preparation of 4-{[(1E)-(4-iodophenyl)methylene]amino}phenol

[0319]

[0320] Under a nitrogen atmosphere, iodobenzaldehyde (400 g, 1.724 mol) was added to a round bottom flask, and the radical was dissolved in 2-propanol (950 ml). 4-Hydroxyaniline was added and the resulting mixture was heated to 70°C. After heating at this temperature for 3 h, a tan precipitate formed in the dark brown solvent mixture. The reaction mixture was cooled, filtered and washed with 2-propanol followed by diethyl ether. The organics were evaporated in vacuo and the residue was dried under high vacuum overnight to give the title compound which was used without further purification. 1 HNMR (500MHz, DMSO-D6) δ: 9.55(s, 1H), 8.59(s, 1H), 7.85(d, 2H), 7.63(d, 2H), 7.2(d, 2H), 6.80(d, 2H ).

[0321] St...

Embodiment 2

[0353] (3R,4S)-4-{4-[3,4-Dihydroxy-3-(hydroxymethyl)butyl]phenyl}-3-[(3S)-3-(4-fluorobenzene Base)-3-hydroxypropyl]-1-{4-[2-(1H-1,2,4-triazol-5-yl)ethyl]phenyl}azetidine-2- ketone

[0354] Step A : Acetic acid (1S)-3-((2S,3R)-2-(4-{4-(acetyloxy)-3-[(acetoxy)methyl]-3- Hydroxybut-1-yn-1-yl}phenyl)-4-oxo-1-{4-[(trimethylsilyl)ethynyl]phenyl} Preparation of azetidin-3-yl)-1-(4-fluorophenyl)propyl ester

[0355]

[0356] Bubble nitrogen through (1S)-3-[(2S,3R)-2-(4-{4-(acetyloxy)-3-[(acetoxy)methyl]-3-hydroxybutyrate -1-yn-1-yl}phenyl)-4-oxo-1-(4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)azetidin-3-yl] -1-(4-fluorophenyl)propyl ester (9.77g, 12.8mmol; step F intermediate of Example 1), trimethylsilylacetylene (4.52mL, 32mmol), tetra-n-butylammonium iodide (4.72 g, 12.8 mmol) and triethylamine (8.92 mL, 64 mmol) in anhydrous DMF (100 mL) for 15 min. Add Pd(PPh 3 ) 4 (1.48g, 1.28mmol) and CuI (0.49g, 2.56mmol), the reaction mixture was heated at 50°C under nitrogen...

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PUM

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Abstract

This invention provides cholesterol absorption inhibitors of Formula I: and the pharmaceutically acceptable salts thereof, wherein R is a hydroxylated alkyl group and R contains a heterocyclic ring. The compounds are useful for lowering plasma cholesterol levels, particularly LDL cholesterol, and for treating atherosclerosis and preventing atherosclerotic disease events.

Description

Background of the invention [0001] The present invention relates to substituted 2-azetidinones (azetidinones) and pharmaceutically acceptable salts and esters thereof, and to their use alone or in combination with other active agents in the treatment of hypercholesterolemia and in the prevention, arrest or slowing of arterial Use in the development of atherosclerosis and related disorders and disease events. [0002] It has been established for decades that elevated blood cholesterol is a major risk factor for coronary heart disease, and many studies have shown that the risk of CHD events can be reduced with lipid-lowering therapy. Before 1987, lipid-lowering substances were basically limited to diets low in saturated fat and cholesterol, bile acid sequestrants (cholestyramine and colestipol), niacin (niacin), fibrates, and probucol. Unfortunately, all of these treatments have limited efficacy or / and tolerability. Substantial reductions in LDL (low density lipoprotein) chole...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A01N43/00A61K31/397
Inventor G·J·莫里洛R·J·德维塔C·R·莫耶斯
Owner MERCK & CO INC
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