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3-(1H-indazole)-tetrahydropyrimidine-2-one compounds, preparation method, and application thereof

A compound and composition technology, applied in the field of 3-tetrahydropyrimidin-2-one compounds, can solve the problems of no prevention and treatment of cardiovascular and cerebrovascular diseases, diabetes, etc., achieve good application and development prospects, and protect blood vessels Function, the effect of promoting glucose consumption

Active Publication Date: 2017-12-01
INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The 3-(1H-indazole)-tetrahydropyrimidin-2-one compound of the present invention is a new compound, and there is no relevant report on the application of the prevention and treatment of cardiovascular and cerebrovascular diseases, diabetes and its complications

Method used

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  • 3-(1H-indazole)-tetrahydropyrimidine-2-one compounds, preparation method, and application thereof
  • 3-(1H-indazole)-tetrahydropyrimidine-2-one compounds, preparation method, and application thereof
  • 3-(1H-indazole)-tetrahydropyrimidine-2-one compounds, preparation method, and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1-16

[0044] The preparation of embodiment 1-16 intermediate:

[0045] Step A: 5-aminoindazole (474mg, 3.56mmol), 6ml of anhydrous pyridine in dichloromethane (6ml) was added to a 25ml round bottom flask, and methyl chlorobenzoate (0.45ml, 3.56ml) was slowly added dropwise at 80°C. mmol). The reaction was stirred at room temperature. After reacting for about 6 hours, TLC showed that the starting material basically disappeared, so the reaction was stopped, and the solvent was removed under reduced pressure. Silica gel column chromatography (dichloromethane: ethyl acetate = 50:1) gave 812 mg of the product with a yield of 90%.

[0046]

[0047] 1 H NMR (400MHz, DMSO, δppm) 12.98(s, 1H), 10.17(s, 1H), 8.01(s, 1H), 7.92(s, 1H), 7.50(d, J=8.8Hz, 1H), 7.42 (t,J=8.4Hz,3H),7.24(m,3H).

[0048] HR-MS(ESI)m / z(M+H) + calcd for C 14 h 12 N 3 o 2 :254.09240; Found: 254.09120.

[0049] Step B: add compound 17 (100mg, 0.4mmol) in 10ml round bottom flask, 2ml anhydrous THF (6ml), stir...

Embodiment 1

[0058] The synthesis of embodiment 1 compound 1

[0059] Step A: Add compound 19 (200mg, 0.67mmol), 4ml of anhydrous 1,4-dioxane to a 25ml round bottom flask, add NaH (44mg, 1.82mmol) at 0°C, benzyl bromide (124mg, 0.73ml ). Stirring at room temperature for about 3 hours, TLC showed that the starting material basically disappeared, the reaction was stopped, and the solvent was removed under reduced pressure. Dilute with dichloromethane, wash with saturated sodium bicarbonate solution, water and saturated sodium chloride solution successively, and dry over anhydrous sodium sulfate. Filtration, concentration, and silica gel column chromatography (dichloromethane:methanol=100:1) gave 223 mg of the product with a yield of 86%.

[0060]

[0061] 1 H NMR (400MHz,DMSO,δppm)8.05(s,1H),7.63(m,2H),7.35(m,3H),7.28(m,3H),5.81(m,1H),4.51(s,2H) ,3.85(m,1H),3.71(m,3H),3.28(m,2H),2.40(m,1H),1.97(m,4H),1.73(m,1H),1.57(m,2H).

[0062] HR-MS(ESI)m / z(M+H) + calcd for C 23 h 27 N 4 o ...

Embodiment 2

[0067] The synthesis of embodiment 2 compound 2

[0068] Step A: Add compound 19 (80mg, 0.27mmol), 4ml of anhydrous 1,4-dioxane to a 25ml round bottom flask, add NaH (10mg, 0.40mmol) at 0°C, p-methylbenzyl bromide (59mg , 0.32 mmol). Stirring at room temperature for about 3 hours, TLC showed that the starting material basically disappeared, the reaction was stopped, and the solvent was removed under reduced pressure. Dilute with dichloromethane, wash with saturated sodium bicarbonate solution, water and saturated sodium chloride solution successively, and dry over anhydrous sodium sulfate. After filtration, concentration, and silica gel column chromatography (dichloromethane:methanol=100:1), 78mg of the product was obtained with a yield of about 72%.

[0069]

[0070] 1H NMR (400MHz, DMSO, δppm) δ8.04(s, 1H), 7.64(d, J=9.0Hz, 1H), 7.60(s, 1H), 7.35(d, J=9.0Hz, 1H), 7.17 (m,4H),5.82(d,J=10.0Hz,1H),4.45(s,2H),4.07(q,J=5.3Hz,1H),3.87(d,J=11.4Hz,1H),3.73 (q,J=5.9,5.0Hz,1H)...

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Abstract

The invention discloses a series of 3-(1H-indazole)-tetrahydropyrimidine-2-one compounds (represented as the general formula I), a preparation method, and a medicinal application thereof. The novel 3-(1H-indazole)-tetrahydropyrimidine-2-one compounds have effects of inhibiting activity of Rho kinase, have the functions of relaxing aorta vessels, brain base arteriole and mesenteric vessels and protecting vascular function and pharmacological effects of promoting consumption of glucose in cells. These novel compounds have important applications in the field of preparing medicines used for preventing and / or treating cardia-cerebrovascular diseases such as hypertension, atherosclerosis, cerebral angiospasm, coronarospasm, myocardial infarction, cardiac failure, diabetes and the like, and diabetes as well as complications thereof, such as diabetic cardiovascular complication, diabetic cerebro-vascular complication and the like.

Description

technical field [0001] The present invention relates to 3-(1H-indazole)-tetrahydropyrimidin-2-one compound or pharmaceutically acceptable salt, its preparation method and its pharmaceutical use. Specifically related to new compounds, new drug effects and their use in the preparation of cardiovascular and cerebrovascular diseases such as prevention, alleviation and / or treatment of hypertension, atherosclerosis, cerebral vasospasm, coronary artery spasm, myocardial infarction, heart failure and diabetic complications , diabetes or symptoms of medicines and health care products, belonging to the field of innovative medicine research technology. technical background [0002] As we all know, cardiovascular and cerebrovascular diseases are the number one killer threatening human health, and the incidence group is gradually getting younger, and the morbidity and mortality are also rising. The main etiology of these diseases are changes in the structure and function of central or p...

Claims

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Application Information

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IPC IPC(8): C07D403/04A61K31/513A61P9/12A61P9/10A61P3/10A61P9/04A61P9/00A61P9/08A23L33/10
CPCC07D403/04Y02P20/55
Inventor 方莲花焦晓臻杜冠华谢平袁天翊姚阳阳陈俞材张惠芳
Owner INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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