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Use of pyrimidine-substituted phenylpropionic acid compound in preparing medicament for preventing and/or treating diabetes

A compound, the technology of phenylpropionic acid, which is applied in the field of medicinal chemistry and pharmacotherapeutics, can solve the problems of phenylpropionic acid compounds without pyrimidine substitution

Inactive Publication Date: 2009-04-22
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Although the Chinese Patent Application No. 200610025586.2 provides pyrimidine-substituted phenylpropionic acid derivative compounds, their preparation methods and uses in the treatment of polycystic kidney disease, there is no pyrimidine-substituted phenylpropionic acid compound as a PPAR-γ agonist Any reports on the treatment of diabetes

Method used

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  • Use of pyrimidine-substituted phenylpropionic acid compound in preparing medicament for preventing and/or treating diabetes
  • Use of pyrimidine-substituted phenylpropionic acid compound in preparing medicament for preventing and/or treating diabetes
  • Use of pyrimidine-substituted phenylpropionic acid compound in preparing medicament for preventing and/or treating diabetes

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Example 1 3-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidinyl-4-oxo]-phenyl}-2-ethane Oxy-phenylpropionic acid (Compound 1)

[0072]

[0073] P(OEt) 2 (2-Ethoxy-2-(diethoxyphosphoryl)-ethyl acetate) was added to a mixed solution of methyl tert-butyl ether (55mL) and tert-butyl potassium (4.65g) under nitrogen protection , p-benzyloxybenzaldehyde (4.61g) was added to the mixture at 5°C, then tert-butanol (6.70g) was added, and the reaction was carried out at 15°C for about 30min. TLC detected that the reaction was complete, and water (30mL ), rotary evaporated the organic phase, added ethanol (30mL), recrystallized, washed with ethanol / water (1:1v / v), and dried to obtain 2-ethoxy-1-(4-benzyl)phenylacrylic acid ethyl Esters, 92% yield.

[0074] 1 HNMR, 400MHz (acetone-d6): δ1.12(t, J=7Hz), 1.32(t, J=7Hz), 1.33(t, J=7Hz), 3.91(q, J=7Hz), 4.12(q , J=7Hz), 4.24(q, J=7Hz), 5.12(s), 5.17(s), 6.10(s), 6.93(s), 6.94(d, J=9Hz), 7.05(d, J= 9Hz), 7.15(d, J=9Hz), 7.32~7...

Embodiment 2

[0079] Example 2 3-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidinyl-4-oxo]-phenyl}-2-methyl yl-2-phenoxypropionic acid (compound 2)

[0080]

[0081] Dissolve ethyl 2-phenoxypropionate (15g) in anhydrous THF, add lithium diisopropylamide (26ml) at -78°C, stir for half an hour, add p-benzyloxybenzaldehyde ( 10 g), stirred overnight under nitrogen protection. Add NH at room temperature 4 Cl saturated liquid until there are no bubbles, the aqueous layer is extracted twice with ethyl acetate, the organic phases are combined, rotary evaporated, passed through the column, PE:EA=10:1 to 4:1, and a light yellow solid 3-(4-benzyl Oxy)phenyl-3-hydroxy-2-methyl-2-phenoxypropanoic acid ethyl ester, 50% yield. Under ice-cooling, add 3-(4-benzyloxy)phenyl-3-hydroxy-2-methyl-2-phenoxy ethyl propionate (10g) and dichloromethane into the three-necked flask, Slowly drive the barrel into the BF 3 -Et 2 O(3.06ml) and (C 2 h 5 ) 3 SiH (4.08ml), into a blood-red liquid, overnight,...

Embodiment 3

[0088] Example 3 S-3-{4-[2-amino-6-(4-benzyl-piperazin-1-yl)-pyrimidinyl-4-oxo]-phenyl}-2- Methyl-2-phenoxypropionic acid (Compound 3)

[0089]

[0090] 3-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidinyl-4-oxo]-phenyl}-2-methyl-2-phenoxy Ethyl propionate was resolved by chiral preparative column to obtain S-3-{4-[2-amino-6-(4-benzyl-piperazin-1-yl)-pyrimidinyl-4-oxo]- Ethyl phenyl}-2-methyl-2-phenoxypropionate. ee: 99% (AD-H: 0.46 cm I.D. x 25 cm).

[0091]S-3-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidinyl-4-oxo]-phenyl}-2-methyl Dissolve ethyl-2-phenoxypropionate (1 mmol), add KOH supersaturated solution, overnight, rotary evaporate THF and methanol, add HCl to adjust pH = 6, a white solid precipitates, filter, wash with a small amount of water, use the water layer THF was extracted twice, the organic layers were combined and rotary evaporated to obtain a white solid, which was recrystallized from methanol to obtain S-3-{4-[2-amino-6-(4-benzyl-piperazin-1-yl...

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Abstract

The invention provides a pyrimidine substituted phenylpropionic acid compound shown in formula (I), and application of enantiomer, racemic modification, a pharmaceutically acceptable salt of the compound, or a mixture of the enantiomer, the racemic modification and the pharmaceutically acceptable salt of the compound to preparation of medicine for preventing and / or treating diabetes mellitus. The compound as PPAR-gamma excitant can participate in the regulation of genetic transcription through activating PXR / PPAR heterodimer, thereby effectively treating and / or preventing the diabetes mellitus. The invention also provides a medicine composition which contains the compound and has the effect of preventing and / or treating the diabetes mellitus.

Description

technical field [0001] The invention relates to the fields of medicinal chemistry and pharmacotherapeutics, in particular to the application of a class of pyrimidine-substituted phenylpropionic acid compounds in the prevention and / or treatment of diabetes. Background technique [0002] Diabetes mellitus (DM, Diabetes Mellitus) is a term that describes a metabolic disease with multiple etiologies, characterized by chronic hyperglycemia, accompanied by disorders of sugar, fat and protein metabolism caused by defects in insulin (Insulin) secretion and / or action, and is caused by genetic Clinical syndromes (chronic, systemic, metabolic diseases) caused by interactions with environmental factors. Most of them are caused by the absolute or relative lack of insulin in the human body, with hyperglycemia as the main feature, and it is a lifelong disease. [0003] There are two main types of diabetes, type 1 and type 2. Type 2 diabetes is more harmful, and its patients account for m...

Claims

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Application Information

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IPC IPC(8): A61K31/496A61K9/08A61K9/10A61K9/12A61K9/16A61K9/20A61K9/48A61P3/10
Inventor 沈建华冷颖蒋华良叶阳亮
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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