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Methyl analogs of simvastatin as novel HMG-CoA reductase inhibitors

A technology of simvastatin and methyl, applied in the field of novel methyl analogs, can solve problems such as unreported mevalonate analogs

Inactive Publication Date: 2004-10-06
RANBAXY LAB LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0022] However, mevalonate analogues substituted with a methyl group at the 3-position of the β-hydroxypyrone ring have not been reported in the literature

Method used

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  • Methyl analogs of simvastatin as novel HMG-CoA reductase inhibitors
  • Methyl analogs of simvastatin as novel HMG-CoA reductase inhibitors
  • Methyl analogs of simvastatin as novel HMG-CoA reductase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] 6(R)-[2-[8(S)-[[2,2-dimethylbutyryl]oxy]-2(S),6(R)-dimethyl-1,2,6, 7,8,8a(R)-hexahydro-1(S)-naphthyl]ethyl]-3(S)-methyl, 4(R)-hydroxyl-3,4,5,6-tetrahydro- 2H-pyran-2-one (VIIc)

[0054] Lithium hexamethyldisilazane (0.3M, dissolved in hexane, 55.14ml, 0.05mol) was added via syringe to a THF solution (130ml) of simvastatin (10g, 0.023mol), and the above process was carried out under nitrogen , the temperature is maintained at -40°C to -45°C. The mixture was stirred at this temperature for 1 hour. Iodomethane (3.72 g, 0.026 mol) was added via syringe keeping the temperature below -30°C. The mixture was stirred at -40 to -45°C for a further 1 hour and quenched by adding water (50ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (50ml x 2). The combined organic layers were washed with pre-cooled 2N hydrochloric acid (25ml) and then with water (30ml). The organic layer was concentrated to an oil which was crystallized from ethyl acet...

Embodiment 2

[0058] 6(R)-[2-[8(S)-[[2,2-dimethylbutyryl]oxy]-2(S),6(R)-dimethyl-1,2,6, 7,8,8a(R)-hexahydro-1(S)-naphthyl]ethyl]-3(R)-methyl, 4(R)-hydroxyl-3,4,5,6-tetrahydro- 2H-pyran-2-one (VIIa)

[0059] To a THF solution (15 ml) of pyrrolidine (2.73 g, 0.038 mol) was added N-butyllithium (1.6 M, 23 ml, 0.036 mol) via syringe at -30 to -25 °C under nitrogen. The mixture was stirred at -25°C for 30 minutes, and simvastatin solution (5 g, 0.012 mol) was added at -40°C. The mixture was stirred at -30°C for about 1 hour and iodomethane (5.12 g, 0.036 mol) was added. The mixture was stirred for a further 1 hour at -30°C and then for 20 minutes at -15°C. The reaction was quenched by adding water (50ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (20ml). The combined organic layers were washed with 1N hydrochloric acid (30ml) and evaporated in vacuo to give an oil (4.2g). Assays were performed by HPLC and the oil was found to be a mixture of (VIIa) an...

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Abstract

The present invention relates to a novel methyl analog of simvastatin, which has the ability to inhibit the synthesis of cholesterol. The compound of the present invention holds promise for the treatment and prophylaxis of hypercholesterolemia and of various cardiac disorders. The invention also relates to a process for making the novel compound.

Description

field of invention [0001] The present invention relates to a novel methyl analogue of simvastatin which is capable of inhibiting cholesterol synthesis. The compounds of the present invention are expected to be used in the treatment and prevention of hypercholesterolemia and various heart diseases. The invention also relates to methods of making the novel compounds. Background of the invention [0002] Hypercholesterolemia is known to be a major risk factor for arteriosclerosis. High serum cholesterol is also a major risk factor for ischemic heart disease and, therefore, there is a need for drugs that can effectively lower blood cholesterol levels. [0003] Over the past few years, a number of structurally related antihypercholesterolemic agents that act by inhibiting 3-hydroxy-3-methylglutaryl coenzyme (HMG-CoA) have been developed and are now Commercially available. These compounds are from natural fermentation product, i.e. the compactin of structural formula I (a kind...

Claims

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Application Information

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IPC IPC(8): A61K31/22A61K31/366A61P3/06A61P9/00C07C67/293C07C67/52C07C67/58C07C69/013C07C69/03C07C69/30C07D309/30
CPCC07C69/30C07D309/30C07C2102/28C07C2602/28A61P3/00A61P3/06A61P9/00
Inventor R·K·哈珀S·M·D·库马Y·库马
Owner RANBAXY LAB LTD
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