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Combinations of a squalene synthase inhibitor and a HMG-CoA reductase inhibitor for treating hyperlipidemia

A technology of reductase inhibitors and synthase inhibitors, which is applied in the direction of drug combinations, medical preparations containing active ingredients, active ingredients of heterocyclic compounds, etc., can solve the problems of increasing toxicity and achieve the effect of improving serum lipids

Inactive Publication Date: 2008-05-28
TAKEDA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

On the other hand, there is concern that high-dose therapy with HMG-CoA reductase inhibitors will increase the risk of developing toxicities such as hepatotoxicity
Furthermore, an increased risk of muscle toxicity such as rhabdomyolysis has been reported for combinations of HMG-CoA reductase inhibitors and fibrates for lowering triglycerides

Method used

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  • Combinations of a squalene synthase inhibitor and a HMG-CoA reductase inhibitor for treating hyperlipidemia
  • Combinations of a squalene synthase inhibitor and a HMG-CoA reductase inhibitor for treating hyperlipidemia
  • Combinations of a squalene synthase inhibitor and a HMG-CoA reductase inhibitor for treating hyperlipidemia

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0473] Example 1: Lowering Effect of Plasma Triglycerides Using the Combination of Compound X and Atorvastatin

[0474] Detection method:

[0475] For Wistar Fatty rats (19 weeks old, female, N=6), 10mL / kg dose of vehicle (vehicle), compound X (30mg / kg) alone, atorvastatin (30mg / kg) alone or both The combination of drugs was administered orally once a day for 8 days. On the morning of the first day after the eighth administration, blood was collected under an overnight fast, and the plasma triglyceride concentration was measured.

[0476] result:

[0477] treat

Plasma triglyceride value (mg / dL)

solvent

519.7±43.5

Compound X (30mg / kg)

376.5±22.0

Atorvastatin (30mg / kg)

192.1±15.2

Atorvastatin (30mg / kg) + Compound X

(30mg / kg) combination

142.9±15.3

[0478] Mean ± standard error (N = 6)

[0479] in conclusion:

[0480] An additional plasma triglyceride lowering effect was observed b...

Embodiment 2

[0481] Example 2: Plasma Cholesterol Lowering Effect Using Compound X and Atorvastatin in Combination

[0482] method:

[0483] For Hartley guinea pigs (5 weeks old, male, N=12), fed with RC-4 food containing 0.05% cholesterol and 10% corn oil for 3 weeks, orally administered for 14 days, once a day, 10-mL / kg dose Vehicle, compound X (30 mg / kg) alone, atorvastatin (3, 10, 30 mg / kg) alone or a combination of atorvastatin (3, 10, 30 mg / kg) and compound X (30 mg / kg) . On the morning of the first day after the 14th administration, blood was collected, and total cholesterol in plasma was measured.

[0484] Test results:

[0485] treat

Total cholesterol level (mg / dL)

solvent

56.3±4.1

Compound X (30mg / kg)

44.4±4.1

Atorvastatin (3mg / kg)

46.1±3.3

Atorvastatin (10mg / kg)

37.4±4.1

Atorvastatin (30mg / kg)

33.5±2.8

Atorvastatin (3mg / kg) + Compound X

(30mg / kg) combination

39.2±...

Embodiment 3

[0489] Example 3: Plasma Cholesterol Lowering Effect Using Compound X and Simvastatin Combination

[0490] Detection method:

[0491] For Hartley guinea pigs (5 weeks old, male, N=12), fed with RC-4 food containing 0.05% cholesterol and 10% corn oil for 3 weeks, orally administered for 14 days, once a day, 10-mL / kg dose Vehicle, compound X (30 mg / kg) alone, simvastatin (10, 30, 100 mg / kg) alone or a combination of simvastatin (10, 30, 100 mg / kg) and compound X (30 mg / kg) . On the morning of the first day after the 14th dose, blood was collected and total cholesterol in plasma was measured.

[0492] Test results

[0493] treat

Total cholesterol level (mg / dL)

solvent

56.9±4.8

Compound X (30mg / kg)

40.2±4.7

Simvastatin (10mg / kg)

41.0±3.6

Simvastatin (30mg / kg)

43.4±2.2

Simvastatin (100mg / kg)

31.7±2.6

Simvastatin (10mg / kg) + Compound X

(30mg / kg)

40.0±3.0

S...

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PUM

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Abstract

A pharmaceutical composition useful for the prevention and / or treatment of hyperlipidemia, which comprises combining an effective amount of a squalene synthase inhibitor and a HMG-CoA reductase inhibitor is provided. Furthermore, a method for preventing and / or treating hepatic toxicity caused by the administration of a HM6-C0A veductase inhibitor, which comprisis adminisvering an effective amount of a sgualence synthase inhibitor, is provided .

Description

technical field [0001] The present invention is based on the discovery that N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-di Methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-acetic acid (abbreviated below Compound X) is a squalene synthase inhibitor (hereinafter referred to as "SSI") and can be used as a preventive and / or therapeutic agent for hyperlipidemia, which can enhance the effect of HMG-CoA reductase inhibitors, HMG -CoA reductase inhibitors, also known as "statins" (for example, atorvastatin, lovastatin, simvastatin, pravastatin, etc.), are now widely used clinically as hyperlipidemia Preventive and / or therapeutic agents for hyperemia. The present invention also relates to a method for treating hyperlipidemia and the like in mammals, including animals or humans, by using a squalene synthase inhibitor and an HMG-CoA reductase inhibitor in combination. Background technique [0002] Hyperlipidemia refers to a state in ...

Claims

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Application Information

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IPC IPC(8): A61K31/366A61K31/397A61K31/40A61K31/553A61K45/06A61P1/16A61P3/06
Inventor 西本诚之兔泽隆一和田岳夫石川英一郎西俊哉山川弘子
Owner TAKEDA PHARMA CO LTD
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