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Pyrimidine substituted benzenepropanoic acid derivative, its preparation method and use in curing polycystic kidney disease

A technology of compounds and mixtures, applied in the field of pyrimidine-substituted phenylpropionic acid derivatives, which can solve the problems of aggravating side effects of heart failure

Active Publication Date: 2007-10-17
SHENYANG SUNSHINE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Most patients with polycystic kidney disease are complicated with hypertension and cardiac hypertrophy in the middle and late stages. The side effects of such drugs aggravate heart failure pose a challenge to the clinical feasibility of treating polycystic kidney disease

Method used

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  • Pyrimidine substituted benzenepropanoic acid derivative, its preparation method and use in curing polycystic kidney disease
  • Pyrimidine substituted benzenepropanoic acid derivative, its preparation method and use in curing polycystic kidney disease
  • Pyrimidine substituted benzenepropanoic acid derivative, its preparation method and use in curing polycystic kidney disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0153] 2-Ethoxy-3-{4-[2-amino-4-oxo-6-(1-benzylpiperazinyl)]pyrimidinyl}phenylpropionic acid

[0154] 2-Ethoxy-2-(diethoxyphosphoryl)-ethyl acetate was added to a mixed solution of methyl tert-butyl ether (55 mL) and tert-butyl potassium (4.65 g) under nitrogen protection, Add p-benzyloxybenzaldehyde (4.61g) to the mixture at 5°C, then add tert-butanol (6.70g), react at 15°C for about 30min, TLC detects that the reaction is complete, add water (30mL) , rotary evaporated the organic phase, added ethanol (30mL), recrystallized, washed with ethanol / water (1:1 v / v), dried to obtain 2-ethoxy-1-(4-benzyl)phenylacrylic acid ethyl Esters, 92% yield.

[0155] 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), 7.32~7.42(m), 7.46~7.50(m), 7.81(d, J=9Hz).

[0156] Dissolve ethyl 2-ethoxy-1-(4-benzyl)phenylacrylate (20.0g) in ...

Embodiment 2

[0161] 2-Methyl-2-phenoxy-3-{4-[2-amino-4-oxo-6-(1-benzyl)piperazinyl]pyrimidinyl}phenylpropanoic acid

[0162] 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 the light yellow solid 2-methyl-2 -Ethyl phenoxy-3-hydroxy-3-(4-benzyloxy)phenylpropanoate, 50% yield. Under ice-cooling, add 2-methyl-2-phenoxy-3-hydroxyl-3-(4-benzyloxy)phenylpropionic acid ethyl ester (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, with saturated NaCO 3 The liquid was neutral...

Embodiment 3

[0169] 2-Methyl-2-phenoxy-3-{4-{2-amino-4-oxo-6-[1-(3,4-formalyl)benzyl]piperazinyl}pyrimidine phenylpropionic acid

[0170] With 2-amino-4-chloro-6-[1-(3,4-formyl) benzylpiperazinyl] pyrimidine replaces 2-amino-4-chloro-6-( 1-benzyl)piperazinylpyrimidine was prepared according to the preparation method described in Example 2.

[0171] 1 HNMR (300MHz, CD 3OD): δ1.40(s, 3H), 3.00(t, 4H), 3.20(q, 2H), 3.70(t, 4H), 4.05(s, 2H), 5.19(s, 1H), δ5.90 (d, 2H), 6.88-7.06 (m., 5H), 7.20-7.37 (m, 4H), 7.46-7.55 (m, 3H).

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Abstract

The present invention relates to a kind of pyrimidine substituted phenylpropionic acid derivative compounds of formula I which includes itsgeometric isomer, enantiomer, diastereoisomer, racemate, and mixture therefore or pharmaceutically acceptable salt thereof. The present invention also relates to the preparation method and use of such compound. Compounds of present invention are useful in the treatment of polycystic kidney disease.

Description

technical field [0001] The invention relates to the field of medicines, in particular to a pyrimidine-substituted phenylpropionic acid derivative compound for treating polycystic kidney disease and its preparation method and application. Background technique [0002] According to the mode of inheritance, polycystic kidney disease is divided into autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (autosomal recessive polycystic kidney disease, ARPKD). Among them, ADPKD is one of the most common and most harmful monogenic genetic diseases in humans, ranking first in hereditary kidney diseases. The disease is characterized by multiple fluid cysts of different sizes in the cortex and medulla of the bilateral kidneys, and can involve multiple extrarenal organs at the same time, forming polycystic liver, dilated pancreatic and bile ducts, colonic diverticulum, and intracranial arteries. Tumors, heart valve abnormalities, etc. T...

Claims

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Application Information

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IPC IPC(8): C07D403/04A61K31/513
Inventor 沈建华梅长林蒋华良戴兵叶阳亮熊锡山唐靖付莉莉
Owner SHENYANG SUNSHINE PHARMA
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