CN102250019A - (Thio) barbituric acid compound and application thereof - Google Patents

(Thio) barbituric acid compound and application thereof Download PDF

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CN102250019A
CN102250019A CN2010101795690A CN201010179569A CN102250019A CN 102250019 A CN102250019 A CN 102250019A CN 2010101795690 A CN2010101795690 A CN 2010101795690A CN 201010179569 A CN201010179569 A CN 201010179569A CN 102250019 A CN102250019 A CN 102250019A
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methyl
fluorine
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nitro
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CN102250019B (en
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陈俐娟
魏于全
罗有福
蒋维
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Sichuan University
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Sichuan University
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Abstract

The invention relates to a new (thio) barbituric acid compound and an application thereof, and belongs to the field of chemical medicine. Particularly, the invention relates to a compound as shown in formula I and an application thereof, wherein R1 is hydrogen or methyl; R2 is a benzene ring containing different substituents, a pyridine ring containing different substituents, cyclohexyl, pyrimidinyl, benzyl or a naphthalene ring group; R3, R4, R5, R6 and R7is hydrogen or a methyl; X is oxygen or sulfur atom. Tests show that the compound as shown in formula I has good effect on treating metabolic diseases such as diabetes, obesity, and the like, and provides a new choice for the preparation of drugs for treating metabolic diseases.

Description

(sulfo-) barbituric acid compounds and uses thereof
Technical field
The present invention relates to new (sulfo-) barbituric acid compounds of a class and uses thereof, be specifically related to 2-(4-(((sulfo-) barbituric acid-5 (2H)-methylene radical) methyl) phenoxy group) acetamide derivative, and the purposes in metabolism disease medicaments such as preparation prevention and treatment obesity, belong to chemical field of medicaments.
Technical background
The World Health Organization is decided to be disease with obesity, is the third-largest enemy who after cardiovascular and cerebrovascular disease and cancer human health is threatened at present.Diseases such as hypertension, coronary heart disease, fatty liver, diabetes, hyperlipidemia, gout easily take place in the obese person.Simple obesity patient is by clinical assay, and endocrine regulation appears in most patients, and especially hyperinsulinemia, sugar tolerance experiment are unusually, sex hormone level is disorderly, adrenocortical hormone is higher, leptin increases or the like;
Obesity generally is divided into two big classes, one class is the obesity that due to illness causes, it is that (encephalitis, brain tumor, sacroiliitis maybe need take the chronic disease of hormone or because of the sick hormone of taking) causes the obesity that endocrine regulation causes because disease, and this obesity is called symptomatic obesity.This class adiposis patient accounts for about 5% of whole fat number.
Another kind of obesity then is because the heat of being taken in diet processes, substantially exceed the heat that itself consumes, and make unnecessary fat and other nutriment put aside the formation adipocyte in vivo, and cause fat, the people who belongs to this class obesity claims simple obesity, and the fat number of this class accounts for more than 90% of obese people's sum.
General obese person need pass through dietary control, motion, fat-reducing even pharmacological agent, adds the kinesitherapy nonresponder as occurring through dietary control, can consider pharmacological agent.There have report can reply sugar tolerance through the patient of dietary control+motion+drug intervention about 75% to be normal.The medicine of treatment obesity is a lot, can be divided into the depress appetite medicine, increases the energy expenditure medicine, suppress the intestinal absorption medicine by its mechanism of action.The ideal slimming medicine should be able to reduce energy intake, increases energy expenditure, and improves fat relevant cardiovascular disorder risk factor.Diet pill commonly used have: one, the medicine of depress appetite: 1. act on the medicine of norepinephrine, the untoward reaction of this type of medicine comprises insomnia, dry, constipation, floaty euphoria, palpitaition and hypertension.Lack the good long term curative effect.2.5 hydroxy-tryptamine (5-HT) receptor stimulant, the release by promoting 5-HT and (or) suppress its re-uptake and reach the fat-reducing purpose.Studies show that this type of medicine has the slimming effect of part, curative effect is similar with the medicine that acts on norepinephrine, but lacks the good long term curative effect equally.3. neurotransmitter re-uptake, by suppressing the re-uptake of NE and 5-HT, minimizing is ingested, and reduces body weight.This type of medicine is not induced the release of 5-HT, thereby puts and think irrelevant with the generation of cardiovascular disorder.Two, increase the medicine of energy expenditure.Three, the medicine that suppresses intestinal absorption.These medicines all more or less have abdomen epilepsy, flatulence, watery stool, soft stool, rectum carbuncle, gum discomfort etc., and idol has untoward reactions such as headache, fash.
Because the exploitation of obesity treatment medicine is subjected to the puzzlement of variety of issue always, great majority are relevant with effect finite sum significant side effects.The more medicine of exploitation is badly in need of in this area, for diseases such as obesity provide more better choice.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of new selection for metabolism class treatment of diseases such as obesity, diabetes, hypertension, hyperlipidemia, hyperglycemia or non-alcoholic fatty liver diseases.
The invention provides a kind of new (sulfo-) barbituric acid compounds, this compound is used for the treatment of metabolism class diseases such as obesity, diabetes, hypertension, hyperlipidemia, hyperglycemia or non-alcoholic fatty liver disease and has significant curative effect, particularly in management of body weight, triglyceride level, index aspect effects such as cholesterol are remarkable.
Compound of the present invention mechanism is suc as formula shown in the I:
Figure GDA0000021616990000021
Wherein,
R 1For-H or-CH 3
R 2For-H,
R 3For-H or-CH 3R 4For-H or-CH 3R 5For-H or-CH 3R 6For-H or any C 1-7Alkane; R 7For-H or any C 1-7Alkane; X is O or S.
Further, R 1During for hydrogen,
R 2For replacing or not removing phenyl, the replacement in generation or the pyridyl that does not replace, cyclohexyl, benzyl or naphthalene nucleus group; R 3, R 4, R 5, R 6, R 7Be respectively hydrogen or methyl.
Further,
Figure GDA0000021616990000023
Wherein, hydrogen, 2-methyl, 3-methyl, 4-methyl, 2-methoxyl group, 3-methoxyl group, 4-methoxyl group, 3,4-dimethoxy, 3,4,5-trimethoxy, 4-trifluoromethyl, 3-formyl radical, 4-formyl radical, 2-ethanoyl, 3-ethanoyl, 4-ethanoyl, 2-is fluorine-based, 3-is fluorine-based, 4-is fluorine-based, 2-chloro, 3-chloro, 4-chloro, 3-bromo, 4-bromo, 2,4-dichloride base, 3, and 4-is fluorine-based for 5-dichloride base, 3-chloro-, 3,4-is two fluorine-based, 2-nitro, 3-nitro, 4-nitro;
Figure GDA0000021616990000024
Wherein, R 9Be hydrogen, 3-carboxyl, 4-carboxyl, 5-carboxyl, 3-nitro, 4-nitro, 5-nitro, 3-chlorine, 4-chlorine, 5-chlorine, 3-fluorine, 4-fluorine, 5-fluorine, 3-methyl, 4-methyl, 3-methoxyl group, 4-methoxyl group, 5-methoxyl group, 3,4,5-trimethoxy or 5-methyl.
R 2Be cyclohexyl, pyrimidyl, benzyl or naphthalene nucleus.
Further, work as R 1During for methyl,
R 8Be hydrogen, 4-methyl, 4-methoxyl group or 3,4-dimethoxy; R 3For-H or-CH 3
R 4For-H or-CH 3R 5For-H or-CH 3R 6For-H or-CH 3R 7For-H or-CH 3
Further, R 8Be hydrogen.
Compound of the present invention can be the compound shown in the formula II:
Figure GDA0000021616990000032
Can be following compound particularly:
Figure GDA0000021616990000033
Figure GDA0000021616990000041
Compound of the present invention can be the compound shown in the formula III:
Figure GDA0000021616990000042
Can be following compound particularly:
Figure GDA0000021616990000043
Figure GDA0000021616990000051
Compound of the present invention can be the compound shown in the formula IV:
Figure GDA0000021616990000052
Can be following compound particularly:
Figure GDA0000021616990000053
Figure GDA0000021616990000061
Compound of the present invention can be the compound shown in the formula V
Figure GDA0000021616990000062
Can be following compound particularly:
Figure GDA0000021616990000071
Wherein, above-claimed cpd can be used for preparation prevention and treatment metabolism class disease with the form of its pharmacologically acceptable salt, solvate, amidate, carboxylate, N-oxide compound, chemoproection form, prodrug or pharmaceutical composition or the like.
The preparation method of above-claimed cpd is as follows:
The first step is a raw material with various amine, does alkali at triethylamine, and methylene dichloride is done under the condition of solvent, obtains 2-chloro-N-substituting group ethanamide with the chloroacetyl chloride room temperature in 5 to 6 hours in reaction.
Wherein alkali can be organic bases and mineral alkali, preferred triethylamine, N, N-diethyl Isopropylamine, salt of wormwood, yellow soda ash, saleratus; The preferred methylene dichloride of solvent, acetone, ethyl acetate;
Second step, do alkali at salt of wormwood, potassiumiodide makes catalyzer and acetone is done under the condition of solvent, the 2-chloro-N-substituting group ethanamide of the first step and p-Hydroxybenzaldehyde reaction, refluxing obtained 2-(4-aldehyde radical benzene oxygen)-N-substituting group ethanamide in 12 hours.The preferred salt of wormwood of alkali wherein, saleratus, yellow soda ash, sodium bicarbonate; The preferred potassiumiodide of catalyzer, the tetra-tert brometo de amonio; The preferred acetone of solvent, ethyl acetate;
In the 3rd step, in water and ethanol mixed solvent, the aldehyde of intermediate and barbituric acid or thiobarbituricacid react and obtained final product in 3-4 hour under 60 degree conditions.Solvent preferably water and alcoholic acid equal-volume mixed solvent.
Figure GDA0000021616990000081
The invention has the beneficial effects as follows: the creative 2-shown in the formula I (4-(((sulfo-) barbituric acid-5 (2H)-methylene radical) methyl) phenoxy group) acetamide derivative that proved by experiment has the effect of excellent prevention and metabolism diseases such as treatment diabetes, obesity, for the preparation of such medicine provides a kind of new selection.
Description of drawings
Fig. 1 compound N-(pyridine-2)-2-(4-((2,4,6-trioxy-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide H﹠amp; E and oil red colored graph.
Embodiment
The preparation method is as follows:
Figure GDA0000021616990000082
Below mode by specific embodiment the present invention is further described, be limitation of the present invention but should not be construed as.
The preparation of embodiment 1 " N-phenyl-2-(4-((2,4,6-trioxy-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide ".
Step 1: 2-chloro-N-phenylacetamide synthetic.
Under ice bath stirs, aniline (1.86g, 20mmol) and triethylamine (24mmol 3.3ml) is dissolved in the anhydrous methylene chloride (20ml), and (2.71g 24mmol) is added drop-wise in the above-mentioned solution lentamente chloroacetyl chloride then.Mixture stirred 12 hours at ambient temperature.Solvent is removed in decompression then, and the solid that obtains filters with frozen water (100ml) washing, and last thick product obtains white solid 3.1g (productive rate 92%) with ether/sherwood oil mixed solvent recrystallization.
Nuclear-magnetism: (400MHz, CDCl 3) δ 8.232 (s, 1H), 7.562-7.540 (m, 2H), 7.385-7.341 (m, 2H), 7.199-7.156 (m, 1H), 4.195 (s, 2H);
Mass spectrum: 170.01[M+H] +
Synthesizing of step 2: 2-(4-aldehyde radical benzene oxygen)-N-phenylacetamide.
In the anhydrous propanone solvent, add respectively 2-chloro-N-phenylacetamide (1.69g, 10mmol) and p-Hydroxybenzaldehyde (1.34g, 11mmol), add respectively again after the stirring and dissolving Anhydrous potassium carbonate (2.76g, 20mmol) and potassiumiodide (166mg, 1mmol).Reaction mixture stirring and refluxing 24 hours is cool to room temperature then.Remove by filter and do not allow solid, the solvent acetone that reduces pressure away obtains crude product.Obtain faint yellow solid 2.3g (productive rate 88.6%) with ethyl alcohol recrystallization at last.
Nuclear-magnetism: (400MHz, CDCl 3) δ 9.943 (s, 1H), 8.173 (s, 1H), 7.937-7.902 (m, 2H), 7.587 (d, 2H, J=7.6Hz), 7.393-7.349 (m, 2H), 7.199-7.7.162 (m, 1H), 7.150-7.116 (m, 2H), 4.708 (s, 2H);
Mass spectrum: 254.09[M+H] -
Step 3: N-phenyl-2-(4-((2,4,6-trioxy-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide synthetic.
In the mixed solvent of 4ml ethanol and 4ml water, (56.2mg, 0.22mmol), (33.8mg, 0.264mmol 1.2equiv), stir and are warming up to 60 ℃ to barbituric acid, react 4 hours to add 2-(4-aldehyde radical benzene oxygen)-N-phenylacetamide respectively.Have solid to separate out this moment, is cooled to room temperature, filter and water, and ethanol, ether washing solid, drying obtains faint yellow solid 71.85mg (productive rate 89.4%) then.
Nuclear-magnetism: (400MHz, DMSO-d 6) δ 11.316 (s, 1H), 11.191 (s, 1H), 10.172 (s, 1H), 8.360 (d, 2H, J=8.8Hz), 8.253 (s, 1H), 7.630 (d, 2H, J=7.6Hz), 7.331 (t, 2H, J=8.0Hz), 7.125-7.069 (m, 2H), 4.864 (s, 2H);
Mass spectrum: 364.18[M+H] -
The preparation of embodiment 2 " 2-(4-((4,6-dioxo-2-sulfo-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group)-N-phenylacetamide "
Figure GDA0000021616990000101
Step 1: 2-chloro-N-phenylacetamide synthetic.
Under ice bath stirs, aniline (1.86g, 20mmol) and triethylamine (24mmol 3.3ml) is dissolved in the anhydrous methylene chloride (20ml), and (2.71g 24mmol) is added drop-wise in the above-mentioned solution lentamente chloroacetyl chloride then.Mixture stirred 12 hours at ambient temperature.Solvent is removed in decompression then, and the solid that obtains filters with frozen water (100ml) washing, and last thick product obtains white solid 3.1g (productive rate 92%) with ether/sherwood oil mixed solvent recrystallization.
Nuclear-magnetism: (400MHz, CDCl 3) δ 8.232 (s, 1H), 7.562-7.540 (m, 2H), 7.385-7.341 (m, 2H), 7.199-7.156 (m, 1H), 4.195 (s, 2H);
Mass spectrum: 170.01[M+H] +
Synthesizing of step 2: 2-(4-aldehyde radical benzene oxygen)-N-phenylacetamide.
In the anhydrous propanone solvent, add respectively 2-chloro-N-phenylacetamide (1.69g, 10mmol) and p-Hydroxybenzaldehyde (1.34g, 11mmol), add respectively again after the stirring and dissolving Anhydrous potassium carbonate (2.76g, 20mmol) and potassiumiodide (166mg, 1mmol).Reaction mixture stirring and refluxing 24 hours is cool to room temperature then.Remove by filter and do not allow solid, the solvent acetone that reduces pressure away obtains crude product.Obtain faint yellow solid 2.3g (productive rate 88.6%) with ethyl alcohol recrystallization at last.
Nuclear-magnetism: (400MHz, CDCl 3) δ 9.943 (s, 1H), 8.173 (s, 1H), 7.937-7.902 (m, 2H), 7.587 (d, 2H, J=7.6Hz), 7.393-7.349 (m, 2H), 7.199-7.7.162 (m, 1H), 7.150-7.116 (m, 2H), 4.708 (s, 2H);
Mass spectrum: 254.09[M+H] -
Synthesizing of step 3: 2-(4-((4,6-dioxo-2-sulfo-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group)-N-phenylacetamide.
In the mixed solvent of 4ml ethanol and 4ml water, (56.2mg, 0.22mmol), (38.01mg, 0.264mmol 1.2equiv), stir and are warming up to 60 ℃ to thiobarbituricacid, react 3 hours to add 2-(4-aldehyde radical benzene oxygen)-N-phenylacetamide respectively.Have solid to separate out this moment, is cooled to room temperature, filter and water, and ethanol, ether washing solid, drying obtains faint yellow solid 72.4mg (productive rate 86.3%) then.
Nuclear-magnetism: (400MHz, DMSO-d 6) δ 11.316 (s, 1H), 11.191 (s, 1H), 10.172 (s, 1H), 8.360 (d, 2H, J=8.8Hz), 8.253 (s, 1H), 7.630 (d, 2H, J=7.6Hz), 7.331 (t, 2H, J=8.0Hz), 7.125-7.069 (m, 2H), 4.864 (s, 2H);
Mass spectrum: 364.18[M+H] -
Preparation method of following examples and embodiment 1 or embodiment 2 are similar.
The preparation of embodiment 3 " N-is to Toluene-2,4-diisocyanate-(4-((2,4,6-trioxy-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide "
Figure GDA0000021616990000111
Productive rate: 78.0%; Purity: 98.39%; Yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6): δ 11.319 (s, 1H), 11.194 (s, 1H), 10.084 (s, 1H), 8.358 (d, 2H, J=9.2Hz), 8.251 (s, 1H), 7.510 (d, 2H, J=8.4Hz), 7.120 (t, 4H, J=8.0Hz), 4.838 (s, 2H), 2.257 (s, 3H);
Mass spectrum: 378.15[M+H] -
Embodiment 4N-(4-p-methoxy-phenyl)-2-(4-((2,4,6-trioxy-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide
Figure GDA0000021616990000112
Productive rate: 89.4%; Purity: 98.54%; Yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6): δ 11.319 (s, 1H), 11.194 (s, 1H), 10.033 (s, 1H), 8.361 (d, 2H, J=10.2Hz), 8.253 (s, 1H), 7.536 (d, 2H, J=10.2Hz), 7.113 (d, 2H, J=8.4Hz), 6.903 (d, 2H, J=7.2Hz), 4.824 (s, 2H), 3.725 (s, 3H); Mass spectrum: 394.20[M+H] -
Embodiment 5N-(3, the 4-Dimethoxyphenyl)-2-(4-((2,4,6-trioxy-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide
Productive rate: 76.0%; Purity: 99.80%; Yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6): δ 11.319 (s, 1H), 11.194 (s, 1H), 10.024 (s, 1H), 8.366 (d, 2H, J=8.8Hz), 8.255 (s, 1H), 7.325 (d, 1H, J=2.0Hz), 7.173-7.104 (m, 3H), 6.906 (d, 1H, J=8.8Hz), 4.826 (s, 2H), 3.722 (s, 6H); Mass spectrum: 424.07[M+H] -
Embodiment 6N-(4-trifluoromethyl)-2-(4-((2,4,6-trioxy-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide.
Figure GDA0000021616990000114
Productive rate: 83.1%; Purity: 99.52%; Yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6): δ 11.316 (s, 1H), 11.189 (s, 1H), 10.541 (s, 1H), 8.351 (d, 2H, J=8.8Hz), 8.246 (s, 1H), 7.849 (d, 2H, J=8.0Hz), 7.700 (d, 2H, J=8.4Hz), 7.111 (d, 2H, J=8.8Hz), 4.911 (s, 2H); Mass spectrum: 464.08[M+MeOH] -.
Embodiment 7N-(4-acetylphenyl)-2-(4-((2,4,6-trioxy-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide
Productive rate: 97.5%; Purity: 99.39%; Yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6): δ 11.319 (s, 1H), 11.192 (s, 1H), 10.520 (s, 1H), 8.354 (d, 2H, J=8.8Hz), 8.249 (s, 1H), 7.951 (d, 2H, J=8.4Hz), 7.773 (d, 2H, J=8.8Hz), 7.114 (d, 2H, J=9.2Hz), 4.914 (s, 2H), 2.531 (s, 3H); Mass spectrum: 438.26[M+MeOH] -.
Embodiment 8N-(3-fluorophenyl)-2-(4-((2,4,6-trioxy-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide
Productive rate: 88.7%; Purity: 97.33%; Light yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6): δ 11.313 (s, 1H), 11.187 (s, 1H), 10.379 (s, 1H), 8.349 (d, 2H, J=8.8Hz), 8.245 (s, 1H), 7.603 (d, 1H, J=11.6Hz), 7.369-7.353 (m, 2H), 7.104 (d, 2H, J=8.8Hz), 6.916-6.897 (m, 1H), 4.874 (s, 2H); Mass spectrum: 414.11[M+MeOH] -.
Embodiment 9N-(4-fluorophenyl)-2-(4-((2,4,6-trioxy-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide
Figure GDA0000021616990000123
Productive rate: 86.1%; Purity: 99.41%; Yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6): δ 11.319 (s, 1H), 11.193 (s, 1H), 10.231 (s, 1H), 8.358 (d, 2H, J=9.2Hz), 8.253 (s, 1H), 7.670-7.634 (m, 2H), 7.175 (t, 2H, J=8.8Hz), 7.113 (d, 2H, J=8.0Hz), 4.856 (s, 2H); Mass spectrum: 414.19[M+MeOH] -.
Embodiment 10N-(3-chloro-phenyl-)-2-(4-((2,4,6-trioxy-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide
Productive rate: 95.0%; Purity: 99.87%; Light yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6): δ 11.314 (s, 1H), 11.188 (s, 1H), 10.351 (s, 1H), 8.349 (d, 2H, J=8.8Hz), 8.246 (s, 1H), 7.826 (s, 1H), 7.521 (d, 1H, J=8.0Hz), 7.357 (t, 1H, J=8.0Hz), 7.154-7.096 (m, 3H), 4.874 (s, 2H); Mass spectrum: 430.13[M+MeOH] -.
Embodiment 11N-(4-chloro-phenyl-)-2-(4-((2,4,6-trioxy-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide
Productive rate: 45.0%; Purity: 99.91%; Yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6): δ 11.321 (s, 1H), 11.194 (s, 1H), 10.316 (s, 1H), 8.356 (d, 2H, J=8.8Hz), 8.251 (s, 1H), 7.670 (d, 2H, J=8.4Hz), 7.392 (d, 2H, J=8.8Hz), 7.111 (d, 2H, J=8.8Hz), 4.870 (s, 2H); Mass spectrum: 398.11[M+H] -.
Embodiment 12N-(4-bromophenyl)-2-(4-((2,4,6-trioxy-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide
Figure GDA0000021616990000132
Productive rate: 95.6%; Purity: 98.47%; Yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6): δ 11.316 (s, 1H), 11.189 (s, 1H), 10.306 (s, 1H), 8.348 (d, 2H, J=8.8Hz), 8.244 (s, 1H), 7.610 (d, 2H, J=8.8Hz), 7.510 (s, 2H, J=8.8Hz), 7.103 (d, 2H, J=8.8Hz), 4.860 (s, 2H); Mass spectrum: 442.02[M+H] -.
Embodiment 13N-(2,4 dichloro benzene base)-2-(4-((2,4,6-trioxy-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide
Figure GDA0000021616990000133
Productive rate: 87.3%; Purity: 99.60%; Light yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6): δ 11.328 (s, 1H), 11.202 (s, 1H), 9.840 (s, 1H), 8.363 (d, 2H, J=8.8Hz), 8.259 (s, 1H), 7.813 (d, 1H, J=8.4Hz), 7.467-7.440 (m, 1H), 7.167-7.698 (m, 1H), 7.133 (d, 2H, J=8.8Hz), 4.950 (s, 2H); Mass spectrum: 464.19[M+MeOH] -.
Embodiment 14N-(3, the 5-dichlorophenyl)-2-(4-((2,4,6-trioxy-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide
Figure GDA0000021616990000134
Productive rate: 92.1%; Purity: 99.78%; Yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6): δ 11.329 (s, 1H), 11.203 (s, 1H), 10.492 (s, 1H), 8.358 (d, 2H, J=8.8Hz), 8.257 (s, 1H), 7.737 (d, 2H, J=1.6Hz), 7.328 (s, 1H), 7.122 (d, 2H, J=9.2Hz), 4.897 (s, 2H); Mass spectrum: 465.94[M+MeOH] -.
Embodiment 15N-(3-chlorine, 4-fluorophenyl)-2-(4-((2,4,6-trioxy-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide
Productive rate: 98.7%; Purity: 99.96%; Yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6): δ 11.319 (s, 1H), 11.192 (s, 1H), 10.375 (s, 1H), 8.351 (d, 2H, J=8.8Hz), 8.249 (s, 1H), 7.953-7.931 (m, 1H), 7.575-7.537 (m, 1H), 7.399 (d, 1H, J=8.8Hz), 7.114 (d, 2H, J=8.8Hz), 4.869 (s, 2H); Mass spectrum: 416.09[M+H] -.
Embodiment 16N-(3, the 4-difluorophenyl)-2-(4-((2,4,6-trioxy-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide
Figure GDA0000021616990000142
Productive rate: 94.4%; Purity: 99.80%; Light yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6): δ 11.315 (s, 1H), 11.188 (s, 1H), 10.393 (s, 1H), 8.347 (d, 2H, J=8.8Hz), 8.245 (s, 1H), 7.818-7.769 (m, 1H), 7.466-7.380 (m, 2H), 7.106 (d, 2H, J=8.4Hz), 4.865 (s, 2H); Mass spectrum: 432.27[M+MeOH] -.
Embodiment 17N-methyl-N-phenyl-2-(4-((2,4,6-trioxy-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide
Figure GDA0000021616990000143
Productive rate: 83.8%; Purity: 99.80%; Yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6): δ 11.297 (s, 1H), 11.172 (s, 1H), 8.298 (d, 2H, J=8.4Hz), 8.222 (s, 1H), 7.500-7.408 (m, 5H), 6.892 (s, 2H), 4.587 (s, 2H), 3.200 (s, 3H); Mass spectrum: 410.28[M+MeOH] -.
Embodiment 18N-cyclohexyl-2-(4-((2,4,6-trioxy-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide
Figure GDA0000021616990000144
Productive rate: 87.8%; Purity: 99.90%; Light yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6) δ 11.312 (s, 1H), 11.186 (s, 1H), 8.343 (d, 1H, J=8.8Hz), 8.245 (s, 1H), 7.980 (d, 1H, J=8.0Hz), 7.047 (d, 2H, J=9.2Hz), 4.602 (s, 2H), 3.613 (t, 1H, J=4.4Hz), 1.741-1.676 (m, 4H), 1.579-1.547 (m, 1H), 1.315-1.186 (m, 4H), 1.150-1.057 (m, 1H); Mass spectrum: 402.14[M+MeOH] -.
Embodiment 19N-benzyl-2-(4-((2,4,6-trioxy-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide
Figure GDA0000021616990000151
Productive rate: 85.9%; Purity: 99.59%; Light yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6): δ 11.314 (s, 1H), 11.188 (s, 1H), 8.725 (t, 1H, J=6.0Hz), 8.343 (d, 2H, J=8.4Hz), 8.245 (s, 1H), 7.327-7.211 (m, 5H), 7.075 (d, 2H, J=8.4Hz), 4.710 (s, 2H), 4.348 (d, 2H, J=6.0Hz); Mass spectrum: 410.22[M+MeOH] -.
Embodiment 20N-(pyridine-2)-2-(4-((2,4,6-trioxy-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide
Figure GDA0000021616990000152
Productive rate: 84.9%; Purity: 99.10%; Light yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6) δ 11.315 (s, 1H), 11.192 (s, 1H), 10.659 (s, 1H), 8.348 (d, 3H, J=8.8Hz), 8.247 (s, 1H), 8.043 (d, 1H, J=8.4Hz), 7.826-7.782 (m, 1H), 7.158-7.128 (m, 1H), 7.085 (d, 2H, J=8.4Hz), 4.961 (s, 2H); Mass spectrum: 397.11[M+MeOH] -.
Embodiment 21N-(5-picoline-2)-2-(4-((2,4,6-trioxy-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide
Figure GDA0000021616990000153
Productive rate: 89.4%; Purity: 98.70%; Light yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6) δ 11.316 (s, 1H), 11.1932 (s, 1H), 10.561 (s, 1H), 8.347 (d, 2H, J=8.8Hz), 8.247 (s, 1H), 8.182 (s, 1H), 7.947 (d, 1H, J=7.6Hz), 7.625 (dd, 1H, J=8.4Hz), 7.083 (d, 2H, J=9.2Hz), 4.935 (s, 2H), 2.256 (s, 3H); MS (ESI), m/z:411.13[M+MeOH] -.
Embodiment 22N-(naphthalene-1)-2-(4-((2,4,6-trioxy-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide
Figure GDA0000021616990000154
Productive rate: 89.2%; Purity: 99.15%; Light yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6): δ 11.320 (s, 1H), 11.197 (s, 1H), 10.226 (s, 1H), 8.386 (d, 2H, J=8.8Hz), 8.269 (s, 1H), 8.008-7.945 (m, 2H), 7.808 (d, 1H, J=8.0Hz), 7.667-7.651 (m, 1H), and 7.547-7.491 (m, 3H), 7.184 (d, 2H, J=8.0Hz), 5.034 (s, 2H); Mass spectrum: 4446.16[M+MeOH] -.
Embodiment 23N-(naphthalene-2)-2-(4-((2,4,6-trioxy-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide
Figure GDA0000021616990000161
Productive rate: 96.3%; Purity: 99.54%; Light yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6) δ 11.325 (s, 1H), 11.201 (s, 1H), 10.402 (s, 1H), 8.374 (d, 2H, J=8.8Hz), 8.317 (s, 1H), 8.264 (s, 1H), and 7.906-7.820 (m, 3H), 7.673-7.646 (m, 1H), and 7.501-7.403 (m, 2H), 7.151 (d, 2H, J=8.8Hz), 4.937 (s, 2H); MS (ESI), m/z:[M+MeOH] -.
Embodiment 242-(4-((4,6-dioxo-2-sulfo-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group)-N-is to the toluene ethanamide
Figure GDA0000021616990000162
Productive rate: 80.9%; Purity: 98.20%; Yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6): δ 12.401 (s, 1H), 12.307 (s, 1H), 10.091 (s, 1H), 8.411 (d, 2H, J=9.2Hz), 8.269 (s, 1H), 7.510 (d, 2H, J=8.4Hz), 7.138-7.115 (m, 4H), 4.856 (s, 2H), 2.258 (s, 3H); Mass spectrum: 426.17[M+MeOH] -.
Embodiment 252-(4-((4,6-dioxo-2-sulfo-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group)-N-(4-p-methoxy-phenyl) ethanamide
Figure GDA0000021616990000163
Productive rate: 85.0%; Purity: 98.70%; Yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6): δ 12.401 (s, 1H), 12.308 (s, 1H), 10.041 (s, 1H), 8.413 (d, 2H, J=10.2Hz), 8.271 (s, 1H), 7.546-7.515 (m, 2H), 7.130 (d, 2H, J=10.2Hz), 6.923-6.883 (m, 2H), 4.841 (s, 2H), 3.724 (s, 3H); Mass spectrum: 442.10[M+MeOH] -.
Embodiment 26N-(3, the 4-Dimethoxyphenyl)-2-(4-((4,6-dioxo-2-sulfo-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide
Figure GDA0000021616990000164
Productive rate: 77.5%; Purity: 97.90%; Yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6): δ 12.400 (s, 1H), 12.308 (s, 1H), 10.032 (s, 1H), 8.414 (d, 2H, J=9.2Hz), 8.273 (s, 1H), 7.324 (d, 1H, J=2.4Hz), and 7.172-7.121 (m, 3H), 6.907 (d, 1H, J=8.8Hz), 4.843 (s, 2H), 3.725 (s, 3H), 3.721 (s, 3H); Mass spectrum: 440.11[M+H] -.
Embodiment 272-(4-((4,6-dioxo-2-sulfo-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group)-N-(4-trifluoromethyl) ethanamide
Figure GDA0000021616990000171
Productive rate: 80.2%; Purity: 99.30%; Yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6): δ 12.396 (s, 1H), 12.300 (s, 1H), 10.548 (s, 1H), 8.401 (d, 2H, J=8.8Hz), 8.263 (s, 1H), 7.848 (d, 2H, J=8.4Hz), 7.701 (d, 2H, J=8.4Hz), 7.128 (d, 2H, J=8.4Hz), 4.927 (s, 2H); Mass spectrum: 480.06[M+MeOH] -.
Embodiment 28N-(4-acetylphenyl)-2-(4-((4,6-dioxo-2-sulfo-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide
Productive rate: 100%; Purity: 98.70%; Yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6): δ 12.399 (s, 1H), 12.304 (s, 1H), 10.525 (s, 1H), 8.406 (d, 2H, J=9.2Hz), 8.266 (s, 1H), 7.950 (d, 2H, J=8.8Hz), 7.772 (d, 2H, J=8.4Hz), 7.130 (d, 2H, J=8.8Hz), 4.909 (s, 2H), 2.531 (s, 3H); Mass spectrum: 454.32[M+MeOH] -.
Embodiment 292-(4-((4,6-dioxo-2-sulfo-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group)-N-(3-fluorophenyl) ethanamide
Productive rate: 86.9%; Purity: 97.99%; Yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6): δ 12.395 (s, 1H), 12.300 (s, 1H), 10.388 (s, 1H), 8.401 (d, 2H, J=8.8Hz), 8.263 (s, 1H), 7.602 (d, 1H, J=10.4Hz), 7.369-7.353 (m, 2H), 7.121 (d, 2H, J=8.8Hz), 6.914-6.897 (m, 1H), 4.891 (s, 2H); Mass spectrum: 430.09[M+MeOH] -.
Embodiment 302-(4-((4,6-dioxo-2-sulfo-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group)-N-(4-fluorophenyl) ethanamide
Figure GDA0000021616990000181
Productive rate: 82.6%; Purity: 99.60%; Yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6): δ 12.403 (s, 1H), 12.309 (s, 1H), 10.241 (s, 1H), 8.411 (d, 2H, J=9.2Hz), 8.271 (s, 1H), 7.668-7.633 (m, 2H), 7.198-7.176 (m, 2H), 7.131 (d, 2H, J=8.8Hz), 4.874 (s, 2H); Mass spectrum: 430.19[M+MeOH] -.
Embodiment 31N-(3-chloro-phenyl-)-2-(4-((4,6-dioxo-2-sulfo-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide
Figure GDA0000021616990000182
Productive rate: 84.1%; Purity: 99.80%; Yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6): δ 12.394 (s, 1H), 12.300 (s, 1H), 10.359 (s, 1H), 8.401 (d, 2H, J=8.8Hz), 8.263 (s, 1H), 7.824 (s, 1H), 7.514 (d, 1H, J=8.4Hz), 7.258 (t, 1H, J=8.0Hz), 7.156-7.112 (m, 3H), 4.856 (s, 2H); Mass spectrum: 446.09[M+MeOH] -.
Embodiment 32N-(4-chloro-phenyl-)-2-(4-((4,6-dioxo-2-sulfo-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide
Figure GDA0000021616990000183
Productive rate: 45.7%; Purity: 99.73%; Yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6): δ 12.400 (s, 1H), 12.305 (s, 1H), 10.320 (s, 1H), 8.408 (d, 2H, J=8.8Hz), 8.269 (s, 1H), 7.663 (d, 2H, J=8.8Hz), 7.392 (d, 2H, J=8.8Hz), 7.128 (d, 2H, J=8.8Hz), 4.863 (s, 2H); Mass spectrum: 446.09[M+MeOH] -.
Embodiment 33N-(4-bromophenyl)-2-(4-((4,6-dioxo-2-sulfo-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide
Figure GDA0000021616990000184
Productive rate: 98.9%; Purity: 98.86%; Yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6): δ 12.397 (s, 1H), 12.302 (s, 1H), 10.314 (s, 1H), 8.401 (d, 2H, J=8.8Hz), 8.263 (s, 1H), 7.610 (d, 2H, J=8.8Hz), 7.513 (d, 2H, J=8.4Hz), 7.120 (d, 2H, J=8.8Hz), 4.855 (s, 2H); Mass spectrum: 458.22[M+H] -.
Embodiment 34N-(2,4 dichloro benzene base)-2-(4-((4,6-dioxo-2-sulfo-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide
Productive rate: 91.3%; Purity: 99.60%; Yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6): δ 12.410 (s, 1H), 12.315 (s, 1H), 9.855 (s, 1H), 8.415 (d, 2H, J=9.2Hz), 8.276 (s, 1H), 7.812 (d, 1H, J=8.8Hz), 7.714 (d, 1H, J=2.6Hz), and 7.467-7.440 (m, 1H), 7.147 (d, 2H, J=9.2Hz), 4.944 (s, 2H); Mass spectrum: 480.16[M+MeOH] -.
Embodiment 35N-(3, the 5-dichlorophenyl)-2-(4-((4,6-dioxo-2-sulfo-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide.
Productive rate: 100%; Purity: 97.60%; Yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6): δ 12.406 (s, 1H), 12.312 (s, 1H), 10.500 (s, 1H), 8.408 (d, 2H, J=8.8Hz), 8.272 (s, 1H), 7.734 (d, 2H, J=2.0Hz), 7.332 (t, 1H, J=2.0Hz), 7.135 (d, 2H, J=9.2Hz), 4.911 (s, 2H); Mass spectrum: 480.12[M+MeOH] -.
Embodiment 36N-(3-chlorine, 4-fluorophenyl)-2-(4-((4,6-dioxo-2-sulfo-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide
Figure GDA0000021616990000193
Productive rate: 86.4%; Purity: 98.70%; Yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6): δ 12.401 (s, 1H), 12.306 (s, 1H), 10.384 (s, 1H), 8.403 (d, 2H, J=8.8Hz), 8.266 (s, 1H), 7.952-7.930 (m, 1H), 7.573-7.535 (m, 1H), 7.399 (t, 1H, J=8.8Hz), 7.128 (d, 2H, J=8.8Hz), 4.885 (s, 2H); Mass spectrum: 464.20[M+MeOH] -.
Embodiment 37N-(3, the 4-difluorophenyl)-2-(4-((4,6-dioxo-2-sulfo-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide
Figure GDA0000021616990000201
Productive rate: 72.4%; Purity: 98.90%; Yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6): δ 12.395 (s, 1H), 12.300 (s, 1H), 10.400 (s, 1H), 8.399 (d, 2H, J=8.8Hz), 8.263 (s, 1H), 7.816-7.767 (m, 1H), 7.466-7.379 (m, 2H), 7.122 (d, 2H, J=8.8Hz), 4.882 (s, 2H); Mass spectrum: 448.24[M+MeOH] -.
Embodiment 382-(4-((4,6-dioxo-2-sulfo-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group)-N-methyl-phenyl acetanilide,Phenacetylaniline
Figure GDA0000021616990000202
Productive rate: 79.4%; Purity: 97.98%; Yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6): δ 12.379 (s, 1H), 12.285 (s, 1H), 8.348 (d, 2H, J=8.0Hz), 8.240 (s, 1H), 7.501-7.408 (m, 5H), 6.908 (s, 2H), 4.603 (s, 2H), 3.200 (s, 3H); Mass spectrum: 426.23[M+MeOH] -.
Embodiment 39N-cyclohexyl-2-(4-((4,6-dioxo-2-sulfo-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide
Productive rate: 87.8%; Purity: 99.19%; Yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6) δ 12.395 (s, 1H), 12.299 (s, 1H), 8.395 (d, 1H, J=9.2Hz), 8.262 (s, 1H), 7.992 (d, 1H, J=8.0Hz), 7.064 (d, 2H, J=9.2Hz), 4.618 (s, 2H), 3.622-3.604 (m, 1H), 1.741-1.642 (m, 4H), 1.577-1.546 (m, 1H), 1.314-1.185 (m, 4H), 1.149-1.057 (m, 1H); Mass spectrum: 418.11[M+MeOH] -.
Embodiment 40N-benzyl-2-(4-((4,6-dioxo-2-sulfo-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide
Figure GDA0000021616990000204
Productive rate: 77.4%; Purity: 99.32%; Yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6): δ 12.395 (s, 1H), 12.301 (s, 1H), 8.733 (t, 1H, J=5.6Hz), 8.395 (d, 2H, J=8.4Hz), 8.263 (s, 1H), 7.327-7.211 (m, 5H), 7.091 (d, 2H, J=8.4Hz), 4.727 (s, 2H), 4.349 (d, 2H, J=5.6Hz); Mass spectrum: 426.17[M+MeOH] -.
Embodiment 412-(4-((4,6-dioxo-2-sulfo-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group)-N-(ethanamide of pyridine-2-)
Figure GDA0000021616990000211
Productive rate: 88.9%; Purity: 98.56%; Yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6) δ 12.399 (s, 1H), 12.306 (s, 1H), 10.730 (s, 1H), 8.401 (d, 2H, J=9.2Hz), 8.363-8.355 (m, 1H), 8.270 (s, 1H), 8.030 (d, 1H, J=8.4Hz), 7.853-7.810 (m, 1H), and 7.180-7.150 (m, 1H), 7.106 (d, 2H, J=9.2Hz), 4.986 (s, 2H); Mass spectrum: 413.06[M+MeOH] -.
Embodiment 422-(4-((4,6-dioxo-2-sulfo-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group)-N-(ethanamide of 5-picoline-2-)
Figure GDA0000021616990000212
Productive rate: 78.2%; Purity: 99.60%; Yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6) δ 12.396 (s, 1H), 12.304 (s, 1H), 10.572 (s, 1H), 8.398 (d, 1H, J=8.8Hz), 8.265 (s, 1H), 8.182 (s, 1H), 7.944 (d, 1H, J=8.0Hz), 7.626 (dd, 1H, J=8.4Hz), 7.100 (d, 2H, J=8.8Hz), 4.951 (s, 2H), 2.256 (s, 3H); Mass spectrum: 427.15[M+MeOH] -.
Embodiment 432-(4-((4,6-dioxo-2-sulfo-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group)-N-(ethanamide of naphthalene-1-)
Figure GDA0000021616990000213
Productive rate: 88.6%; Purity: 99.90%; Yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6) δ 12.403 (s, 1H), 12.311 (s, 1H), 10.235 (s, 1H), 8.441 (d, 2H, J=8.0Hz), 8.287 (s, 1H), 8.030-7.943 (m, 2H), 7.812 (d, 1H, J=8.0Hz), 7.669-7.651 (m, 1H), and 7.556-7.493 (m, 3H), 7.201 (d, 2H, J=8.4Hz), 5.052 (s, 2H); Mass spectrum: 462.09[M+MeOH] -.
Embodiment 442-(4-((4,6-dioxo-2-sulfo-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group)-N-(ethanamide of naphthalene-2-)
Figure GDA0000021616990000214
Productive rate: 89.3%; Purity: 99.30%; Yellow solid; Nuclear-magnetism (400MHz, DMSO-d 6) δ 12.405 (s, 1H), 12.312 (s, 1H), 10.406 (s, 1H), 8.425 (d, 2H, J=9.2Hz), 8.318 (s, 1H), 8.281 (s, 1H), and 7.906-7.821 (m, 3H), 7.672-7.645 (m, 1H), and 7.501-7.404 (m, 2H), 7.163 (d, 2H, J=8.8Hz), 4.937 (s, 2H); Mass spectrum: 462.10[M+MeOH] -.
The pharmacodynamics test part
Test example 1,2-(4-(((sulfo-) barbituric acid-5 (2H)-methylene radical) methyl) phenoxy group) cytotoxicity experiment (table 1) of acetamide derivative on the HepG2 cell
Experimental technique: detect the cytotoxicity of derivative on HepG2 by the MTT method.
The cytotoxicity experiment of table 1HepG2 cell
No. IC 50(μmol/L) No. IC 50(μmol/L) No. IC 50(μmol/L)
Example 1 ≥150 Example 17 ≥150 Example 31 ≥150
Example 3 ≥150 Example 18 126.21 Example 32 ≥150
Example 4 142.60 Example 19 ≥150 Example 33 126.31
Example 5 ≥150 Example 20 ≥150 Example 34 ≥150
Example 6 143.34 Example 21 ≥150 Example 35 ≥150
Example 7 ≥150 Example 22 ≥150 Example 36 ≥150
Example 8 ≥150 Example 23 135.19 Example 37 142.32
Example 9 ≥150 Example 2 ≥150 Example 38 ≥150
Example 10 90.36 Example 24 ≥150 Example 39 ≥150
Example 11 ≥150 Example 25 ≥150 Example 40 113.01
Example 12 67.05 Example 26 94.82 Example 41 ≥150
Example 13 ≥150 Example 27 ≥150 Example 42 ≥150
Example 14 128.20 Example 28 149.05 Example 43 ≥150
Example 15 ≥150. Example 29 ≥150 Example 44 ≥150
Example 16 85.22 Example 30 114.21
〉=150 expression compounds do not detect ancestral cell toxicity under 150 μ M concentration.
The cytotoxicity screening of series compound shows that (sulfo-) barbiturates compound cytotoxicity is all very little.
The hypoglycemic experiment (table 2,3,4 and 5) on the HepG2 cell of test example 2,2-(4-(((sulfo-) barbituric acid-5 (2H)-methylene radical) methyl) phenoxy group) acetamide derivative
Experimental technique: the HepG2 cell is provided by biotherapy National Key Laboratory of Sichuan University.Cell is grown under the substratum of the sugar that contains 10% bovine serum (5.5mM glucose).Before the experiment, with cell transfer in 96 hollow plates, and replacing contains the substratum of different concns glucose, add 2-(4-(((sulfo-) barbituric acid-5 (2H)-methylene radical) methyl) phenoxy group) acetamide derivative (100 μ M) DMEM solution then, detect the glucose consumption amount with method of cracking at last.
Test example 3,2-(4-(((sulfo-) barbituric acid-5 (2H)-methylene radical) methyl) phenoxy group) adiponectin and the leptin screening experiment (table 2,3,4 and 5) of acetamide derivative on the 3T3-L1 cell
Experimental technique: adipocyte is grown in containing the DMEM substratum of 10% bovine serum before the 3T3-L1 of mouse, and upgrades a subculture every three days, is induced lipoblast up to 90% preceding adipocyte.The DMEM solution that adds 2-(4-(((sulfo-) barbituric acid-5 (2H)-methylene radical) methyl) phenoxy group) acetamide derivative (100 μ M) then after 24 hours, detects adiponectin and leptin by the Elisa test kit.
The result of table 2, table 3, table 4 and table 5 is as follows: wherein the structural formula of representation compound is:
Table 2
Figure GDA0000021616990000231
Table 3
Figure GDA0000021616990000232
Table 4 Table 5
Figure GDA0000021616990000234
Table 2
Figure GDA0000021616990000235
Figure GDA0000021616990000241
Table 3
Figure GDA0000021616990000242
Table 4
Figure GDA0000021616990000243
Figure GDA0000021616990000251
Table 5
Annotate: N.T is not for detecting activity.
Series compound is in the hypoglycemic screening, and example 20 compound effects are obvious, and two regulatory factor adiponectins of Regular Insulin and leptin are all had regulating and controlling effect.
Test example 4, compound N-(pyridine-2)-2-(4-((2,4,6-trioxy-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) action effect (table 6) of ethanamide (example 20) on fat animal model
Test method and material: the male Wistar rats of normal heavy 140-180g is bought from only one group of experimentation on animals center, West China .10, totally 3 groups, set up fat model comprising control group G1 and two treatment group G2. by the high lipid food nursing, approximately about nursing all around.By oral compound N-(pyridine-2)-2-(4-((2,4,6-trioxy-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide of taking, every day, each oral dosage 50mg/kg treated 4 time-of-weeks to G2 respectively then.
The every Biological indicators of table 6 compound example 20 after the fat animal model treatment
Figure GDA0000021616990000261
Test example 5, compound N-(pyridine-2)-2-(4-((2,4,6-trioxy-tetrahydropyrimidine-5 (2H)-methylene radical) methyl) phenoxy group) ethanamide (20) H﹠amp; E and oil red colored graph are seen Fig. 1, and compound 20 has significantly reduced fatty deposition, have improved the structure of pathology fat, and the metabolic syndrome that insulin resistant is caused has tangible curative effect as obesity, diabetes and hyperlipidemia, hypertension.

Claims (13)

1. the compound shown in the formula I prevents and the purposes for the treatment of in the metabolism class disease medicament in preparation,
Figure FDA0000021616980000011
Wherein,
R 1For-H or-CH 3
R 2For-H,
Figure FDA0000021616980000012
Figure FDA0000021616980000013
R 3For-H or-CH 3
R 4For-H or-CH 3
R 5For-H or-CH 3
R 6For-H or any C 1-7Alkane;
R 7For-H or any C 1-7Alkane;
X is O or S.
2. purposes according to claim 1 is characterized in that:
R 1Be hydrogen, R 2For replacing or phenyl, the replacement that does not replace or the pyridyl that does not replace, cyclohexyl, pyrimidyl, benzyl or naphthalene nucleus base; R 3, R 4, R 5, R 6, R 7Be respectively hydrogen or methyl; As:
Wherein,
R 8Be hydrogen, 2-methyl, 3-methyl, 4-methyl, 2-methoxyl group, 3-methoxyl group, 4-methoxyl group, 3,4-dimethoxy, 3,4,5-trimethoxy, 4-trifluoromethyl, 3-formyl radical, 4-formyl radical, 2-ethanoyl, 3-ethanoyl, 4-ethanoyl, 2-is fluorine-based, 3-is fluorine-based, 4-is fluorine-based, 2-chloro, 3-chloro, 4-chloro, 3-bromo, 4-bromo, 2,4-dichloride base, 3,4-is fluorine-based for 5-dichloride base, 3-chloro-, and 3,4-is two fluorine-based, 2-nitro, 3-nitro, 4-nitro;
Figure FDA0000021616980000015
Wherein, R 9Be hydrogen, 3-carboxyl, 4-carboxyl, 5-carboxyl, 3-nitro, 4-nitro, 5-nitro, 3-chlorine, 4-chlorine, 5-chlorine, 3-fluorine, 4-fluorine, 5-fluorine, 3-methyl, 4-methyl, 3-methoxyl group, 4-methoxyl group, 5-methoxyl group, 3,4,5-trimethoxy or methyl; Or
R 2Be cyclohexyl, pyrimidyl, benzyl or naphthalene nucleus.
3. purposes according to claim 1 is characterized in that:
R 1Be methyl,
Figure FDA0000021616980000021
R 8Be hydrogen, 4-methyl, 4-methoxyl group or 3,4-dimethoxy; Preferred R 8Be hydrogen;
R 3For-H or-CH 3
R 4For-H or-CH 3
R 5For-H or-CH 3
R 6For-H or-CH 3
R 7For-H or-CH 3
4. according to each described purposes of claim 1-3, it is characterized in that described metabolism class disease is obesity, diabetes, hypertension, hyperlipidemia, hyperglycemia or non-alcoholic fatty liver disease.
5. the compound shown in the formula I,
Wherein,
R 1For-H or-CH 3
R 2For
Figure FDA0000021616980000023
R 3For-H or-CH 3
R 4For-H or-CH 3
R 5For-H or-CH 3
R 6For-H or any C 1-7Alkane;
R 7For-H or any C 1-7Alkane;
X is O or S.
6. compound according to claim 5 is characterized in that:
R 1Be hydrogen or methyl, R 2For replacing or phenyl, the replacement that does not replace or the pyridyl that does not replace, cyclohexyl, pyrimidyl, benzyl or naphthalene nucleus group; R 3, R 4, R 5, R 6, R 7Be respectively hydrogen or methyl.
7. compound according to claim 6 is characterized in that:
Figure FDA0000021616980000031
Structural formula of compound is described suc as formula II or IV formula:
Figure FDA0000021616980000032
Wherein,
R 8Be hydrogen, 2-methyl, 3-methyl, 4-methyl, 2-methoxyl group, 3-methoxyl group, 4-methoxyl group, 3; 4-dimethoxy, 3; 4; 5-trimethoxy, 4-trifluoromethyl, 3-formyl radical, 4-formyl radical, 2-ethanoyl, 3-ethanoyl, 4-ethanoyl, 2-is fluorine-based, 3-is fluorine-based, 4-is fluorine-based, 2-chloro, 3-chloro, 4-chloro, 3-bromo, 4-bromo, 2; 4-dichloride base, 3; 4-is fluorine-based for 5-dichloride base, 3-chloro-, and 3,4-is two fluorine-based, 2-nitro, 3-nitro, 4-nitro.
8. compound according to claim 6 is characterized in that:
Figure FDA0000021616980000033
Wherein, R 9Be hydrogen, 3-carboxyl, 4-carboxyl, 5-carboxyl, 3-nitro, 4-nitro, 5-nitro, 3-chlorine, 4-chlorine, 5-chlorine, 3-fluorine, 4-fluorine, 5-fluorine, 3-methyl, 4-methyl, 3-methoxyl group, 4-methoxyl group, 5-methoxyl group, 3,4,5-trimethoxy or methyl.
9. compound according to claim 6 is characterized in that:
R 1Be hydrogen,
Figure FDA0000021616980000034
R 8Be hydrogen, 2-methyl, 3-methyl, 4-methyl, 2-methoxyl group, 3-methoxyl group, 4-methoxyl group, 3; 4-dimethoxy, 3; 4; 5-trimethoxy, 4-trifluoromethyl, 3-formyl radical, 4-formyl radical, 2-ethanoyl, 3-ethanoyl, 4-ethanoyl, 2-is fluorine-based, 3-is fluorine-based, 4-is fluorine-based, 2-chloro, 3-chloro, 4-chloro, 3-bromo, 4-bromo, 2; 4-dichloride base, 3; 4-is fluorine-based for 5-dichloride base, 3-chloro-, and 3,4-is two fluorine-based, 2-nitro, 3-nitro, 4-nitro.
10. compound according to claim 6 is characterized in that:
R 1Be hydrogen,
R 2For: the pyridyl, cyclohexyl, pyrimidyl, benzyl or the naphthalene nucleus that replace or do not replace, its structural formula is:
11. compound according to claim 7 is characterized in that:
R 1Be methyl,
Figure FDA0000021616980000042
R 8Be hydrogen, 4-methyl, 4-methoxyl group or 3,4-dimethoxy; Preferred R 8Be hydrogen;
R 3For-H or-CH 3
R 4For-H or-CH 3
R 5For-H or-CH 3
R 6For-H or-CH 3
R 7For-H or-CH 3
12. compound according to claim 11 is characterized in that: R 1, R 3, R 4, R 5, R 6, R 7Be respectively hydrogen.
13. the pharmacologically acceptable salt of the described compound of claim 5-12, solvate, amidate, carboxylate, N-oxide compound.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111004186A (en) * 2019-12-26 2020-04-14 温州医科大学 Small-molecule fluorescent probe and preparation method and application thereof

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