A kind of medicine for lowering blood fat and preparation method thereof

A technology of medicine and pharmacy, which is applied in the field of preparing medicines for lowering blood lipids and/or treating atherosclerosis, and can solve the problems of affecting bioavailability and the like

Inactive Publication Date: 2018-11-23
MUDANJIANG MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are certain defects in these drugs themselves, such as fenofibrate, because it is almost insoluble in water, only special pharmaceutical preparations are made to ensure good bioavailability, but due to the insolubility of fenofibrate in water, the preparation releases There is a tendency to recrystallize during the process, affecting bioavailability

Method used

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  • A kind of medicine for lowering blood fat and preparation method thereof
  • A kind of medicine for lowering blood fat and preparation method thereof
  • A kind of medicine for lowering blood fat and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] Example 1: 1-((3-methoxy-4-methyl-6-oxo-4,5,6,7-tetrahydro-2H-pyrazol[3,4-b]pyridine-2- Base) methyl) -3- (piperidin-1-yl) urea (compound I)

[0075]

[0076]Step 1: Bromomethylhydrazine (2.46 g, 20.0 mmol) was added to a solution of methyl 2-cyanoacetate (1.98 g, 20.0 mmol) in ethanol (100 mL), and the mixture was stirred at 50° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was separated into an organic layer and an aqueous layer by adding saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized with chloroform to obtain 1-(bromomethyl)-5-methoxy-1H-pyrazol-3-amine 2.93 g, yield: 72%, content 99%. ESI-MS: 205.99[M+H] + .

[0077] Step 2: Add acetaldehyde methyl hemiacetal (0.76g, 20.mmol) to the 1-(bromomethyl)-5-methoxy-...

Embodiment 2

[0082] Example 2: 1-((3-((2H-1,2,3-triazol-2-yl)methyl)-4-(fluoromethyl)-6-oxo-4,5,6, 7-tetrahydro-2H-pyrazol[3,4-b]pyridin-2-yl)methyl)-3-thiomorpholinourea (Compound II)

[0083]

[0084] According to the method of Example 1, with 3-oxo-4-(2H-1,2,3-triazol-2-yl)butyronitrile instead of methyl 2-cyanoacetate, 1-fluoroacetaldehyde methyl semi Acetal in place of acetaldehyde methyl hemiacetal and 1-(thiomorpholin-4-yl)urea in place of 1-(piperazin-1-yl)urea afforded the title compound as a pale yellow solid, the total product of three steps rate of 38%.

[0085] ESI-MS: 424.16[M+H] +

[0086] Elemental analysis: theoretical value / measured value, C(45.38 / 45.48), H(5.24 / 5.29), F(4.49 / 4.53), N(29.77 / 29.64), O(7.56 / 7.51), S(7.57 / 7.55)

[0087] 1 H NMR(400MHz,DMSO-D6)δ8.04(s,1H),7.62(d,2H),6.03(s,1H),5.97(s,1H),5.61(s,2H),4.99(s, 2H), 4.55(q, 1H), 4.25(q, 1H), 3.25(m, 1H), 2.91(t, 4H), 2.72(t, 4H), 2.61(q, 1H), 2.31(q, 1H ).

Embodiment 3

[0088] Example 3: 1-(3-chloropyridin-2-yl)-3-((3-(2-ethoxyethyl)-6-oxo-4-(trifluoromethyl)-4,5 ,6,7-tetrahydro-2H-pyrazol[3,4-b]pyridin-2-yl)methyl)urea (compound III)

[0089]

[0090] According to the method of Example 1, replace methyl 2-cyanoacetate with 5-ethoxyl-3-oxovaleronitrile, trifluoroacetaldehyde methyl hemiacetal instead of acetaldehyde methyl hemiacetal, use 1- (3-Chloro-pyridin-2-yl)urea in place of 1-(piperazin-1-yl)urea afforded the title compound as a white solid in 35% overall yield over three steps.

[0091] ESI-MS: 461.12[M+H] +

[0092] Elemental analysis: theoretical value / measured value, C(46.91 / 46.78), H(4.37 / 4.31), Cl(7.69 / 7.78), F(12.37 / 12.47), N(18.24 / 18.34), O(10.42 / 7.32)

[0093] 1 H NMR (400MHz, DMSO-D6) δ9.54(s,1H),8.04(s,1H),8.12(d,1H),7.62(d,1H),6.81(q,1H),6.08(s, 1H),5.63(s,2H),3.89(q,1H),3.55(t,2H),3.47(q,2H),2.75(t,2H),2.61(q,1H),2.32(q,1H ), 1.11(t,3H).

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Abstract

The invention relates to a drug used for reducing blood fat, and a preparation method thereof. The drug is used for treating hyperlipidemia and / or atherosclerosis. The drug is capable of increasing the uptake ratio of hepatocytes on low density lipoprotein, and reducing serum total cholesterol, serum triglyceride, and serum low density lipoprotein cholesterol of mouse obviously; the effect of the drug is similar to that of simvastatin; it is shown that the drug possesses excellent blood fat reducing activity, and can be used in treatment of hyperlipidemia and atherosclerosis.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and more specifically relates to a new class of heterocyclic compounds with blood lipid-lowering activity, its preparation method and its use in the preparation of drugs for reducing blood fat and / or treating atherosclerosis. Background technique [0002] Hyperlipidemia (hyperlipidemia, HLP) is a disorder of lipid metabolism in the human body, and one or more lipid components in plasma are abnormally increased. Hyperlipidemia can cause abnormalities in the body's antioxidant capacity and hemorheology, and these abnormal factors can be used as an intermediate link or promoting factor of hyperlipidemia, causing damage to arterial endothelial function, causing endothelial cell dysfunction or Damage to the function and structure of the blood vessel wall affects the function of the blood vessel, aggravates and promotes the pathological changes and clinical symptoms caused by hyperlipidemia. Studies...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61K31/496A61K31/541A61K31/444A61P3/06A61P9/10
CPCC07D471/04
Inventor 姚冬杰梁爽崔江河安宁张宇战海艳
Owner MUDANJIANG MEDICAL UNIV
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