CN116283648B - Substituted benzene acryloyl or benzene propionyl phenethylamine compound and preparation method and application thereof - Google Patents

Substituted benzene acryloyl or benzene propionyl phenethylamine compound and preparation method and application thereof Download PDF

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CN116283648B
CN116283648B CN202310207274.7A CN202310207274A CN116283648B CN 116283648 B CN116283648 B CN 116283648B CN 202310207274 A CN202310207274 A CN 202310207274A CN 116283648 B CN116283648 B CN 116283648B
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田瑜
姜保平
尚海
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Institute of Medicinal Plant Development of CAMS and PUMC
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Abstract

The invention relates to the technical field of organic synthesis, in particular to a substituted benzene acryloyl or benzene propionyl phenethylamine compound, a preparation method and application thereof, wherein the structure of the compound is as follows, rn represents n substituents R, n=1-4, and R is at least one of hydrogen, hydroxyl, halogen, trifluoromethyl, methoxy and C1-C5 alkyl; ""represents a double bond or a single bond; r is R 1 Selected from H or C1-C5 alkyl; r is R 2 And R is 3 Each independently selected from C1-C3 alkyl; r is R 4 Is selected from H or C1-C10 alkyl, has easily available source and simple synthetic route, and has excellent effects on reducing blood sugar and improving obesity.

Description

Substituted benzene acryloyl or benzene propionyl phenethylamine compound and preparation method and application thereof
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a substituted benzene acryloyl or benzene propionyl phenethylamine compound, and a preparation method and application thereof.
Background
3, 4-dihydroxybenzene acrylic acid, also called caffeic acid, is a naturally occurring phenolic acid compound, widely existing in the plant kingdom of fruits, grains, vegetables and the like, and has been gradually applied to the fields of foods, medicines, cosmetics and the like in recent years. As a natural antioxidant, 3, 4-dihydroxybenzene acrylic acid has many biological activities such as cardiovascular protection, antibacterial, antiviral, antitumor, etc. Many natural or artificial derivatives of 3, 4-dihydroxybenzene acrylic acid also have pharmacological effects similar to those of caffeic acid, such as Caffeic Acid Phenethyl Ester (CAPE) extracted from propolis, which is a natural product containing 3, 4-dihydroxybenzene acryl fragments, and recent studies have found that it has anti-inflammatory, antioxidant, immunomodulatory and other biological activities similar to or even stronger than those of 3, 4-dihydroxybenzene acrylic acid.
In recent years, in the prevention and treatment of diseases of regulating blood sugar and blood lipid metabolism, the application share of traditional Chinese herbal medicines is heavier, and researchers are researching the active ingredients of the Chinese herbal medicines more and more. However, drugs are developed as natural products, which have relatively limited activity, retain biologically active fragments thereof, and are structurally modified based on their structure, which is advantageous for the discovery of more active compounds. The phenoxyacetic acid lipid regulating agent is used for regulating lipid metabolism disorder, has very good curative effects on obesity improvement and weight reduction, and phenoxyacetic acid or phenoxyacetate in the structure is an active essential group of the compound. And the clinically common hypoglycemic drugs such as thiazolidinedione hypoglycemic drug rosiglitazone and the like are easy to have side effects such as weight gain and the like.
Therefore, it is very necessary to develop a compound capable of solving the above technical problems.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a substituted benzene acryloyl or benzene propionyl phenethylamine substance which has the advantages of easily available source, simple synthetic route, excellent effect in reducing blood sugar and improving obesity and no side effect.
The invention prepares a substituted benzene acryloyl or benzene propionyl phenethylamine substance by synthesis, and further carries out the study of hypoglycemic bioactivity. For any natural compound, purely depending on natural plant resources, sustainable development is not facilitated, chemical transformation and synthesis paths are necessary, and meanwhile the problems of weak efficacy of natural products, large side effects of clinical hypoglycemic drugs and the like are solved.
The invention is realized by the following technical scheme:
a substituted benzene acryl or benzene propionyl phenethylamine compound, which has the following structure:
wherein Rn represents n substituents R, n=1 to 4, and R is at least one selected from hydrogen, hydroxy, halogen, trifluoromethyl, methoxy and C1-C5 alkyl;represented by a double bond or a single bond; r is R 1 Selected from H or C1-C5 alkyl; r is R 2 And R is 3 Each independently selected from C1-C3 alkyl; r is R 4 Selected from H or C1-C10 alkyl.
When Rn represents 2 or more substituents R, the types of substituents R at different positions may be the same or different.
Preferably, n=1 or 2.
Preferably, R is selected from at least one of hydrogen, hydroxy, halogen, trifluoromethyl, methoxy and methyl.
Preferably, R 1 Selected from H or methyl.
Preferably, R 2 And R is 3 Are all methyl groups.
Preferably, R 4 Selected from H or ethyl.
The invention also relates to a preparation method of the compound, which comprises the following steps:
a) Starting from compound A p-hydroxyphenylethylamine and (Boc) 2 O reacts to obtain an intermediate B;
b) Reacting the intermediate B with alpha substituted bromocarboxylate to obtain an intermediate C;
c) Removing Boc from the intermediate C under an acidic condition to obtain an intermediate D;
d) The intermediate D reacts with the compound P to obtain a compound CP, namely a substituted benzene acryloyl or benzene propionyl phenethylamine compound;
the structure of the compound P is as follows:
rn and R 1 Is as defined above.
The reaction route is as follows:
preferably, in step a), at least one of sodium bicarbonate, potassium bicarbonate, triethylamine, 4-dimethylaminopyridine and N, N-diisopropylethylamine is further added for reaction.
More preferably, the molar ratio of at least one of sodium bicarbonate, potassium bicarbonate, triethylamine, 4-dimethylaminopyridine, N-diisopropylethylamine to compound A is 1-5:1.
Preferably, in step b), the reaction is carried out under alkaline conditions. The alkaline condition may be provided by an organic base or an inorganic base.
More preferably, in step b), the alkaline condition is provided by at least one of potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide.
More preferably, in step B), the molar ratio of base to intermediate B providing alkaline conditions is between 1 and 5:1.
preferably, in step b), the alpha-substituted bromocarboxylic acid esters comprise 1 to 10 long chain or branched carbon substituted bromocarboxylic acid esters.
More preferably, the α -substituted bromocarboxylic acid esters include at least one of ethyl α -bromo-2-methylpropionate, ethyl α -bromopropionate, ethyl α -bromopentanoate, ethyl α -bromoisovalerate, ethyl α -bromoacetate, ethyl α -bromobutyrate, and ethyl α -bromophenylacetate.
Preferably, in step c), the Boc removal is achieved by hydrolysis by providing acidic conditions with at least one of trifluoroacetic acid, boron trifluoride etherate, zinc chloride.
Preferably, in step d) at least two of BOP, BOP-Cl, HOBt, HATU, HBTU, TBTU, TATU, EDCI, DMAP and N, N-diisopropylethylamine are also added and the reaction is carried out in a solvent.
More preferably, in step d), the solvent comprises at least one of DMF and DCM.
Preferably, when R 4 When the sample is not H, the method further comprises the step e): compound CP was hydrolyzed under alkaline conditions to give the corresponding carboxylic acid, which was prepared as follows:
the invention selects p-hydroxyphenylethylamine as a starting material, and synthesizes series of phenylpropenoyl or phenylpropionyl phenethylamine substances through amino protection, etherification reaction, removal of amino protecting groups, amide formation and hydrolysis.
The invention also relates to application of the compound or the compound prepared by the preparation method in preparation of medicines for reducing blood sugar and/or improving obesity.
The invention also relates to application of the compound or the compound prepared by the preparation method in preparing a medicament for treating obesity and/or type II diabetes.
Preferably, the obesity and/or type ii diabetes is induced by a high fat diet.
The inventor finds that the 3, 4-dihydroxybenzene acrylic ester derivative has good activity of regulating blood fat, blood sugar and the like in the early research process, and has the activity equivalent to that of a prototype natural product 3, 4-dihydroxybenzene acrylic acid, which indicates that the 3, 4-dihydroxybenzene acryloyl fragment has a certain activity of regulating glycolipid metabolism and the like.
The invention selects the natural product chlorogenic acid or caffeic acid active fragment (the structure of which comprises 3, 4-dihydroxyl benzene acryloyl fragment) widely existing in plants, combines the fibrate lipid regulating active fragment phenoxyacetic acid or phenoxyacetic ester based on the 3, 4-dihydroxyl benzene acryloyl fragment, adopts the split principle and the minimum structure modification principle of drug design, designs and synthesizes a series of phenylacryloyl or phenylacrylyl phenethylamine compounds CP 1-CP 32 for unhealthy diet induced blood sugar and weight increase by applying the bioisostere and prodrug principle, comprises compounds in which the hydroxyl group on the benzene ring is replaced by fluorine, chlorine and bromine, and compounds of phenoxyacetic ester fragment containing different substituents, and finally discovers a series of compounds with research value and good glycolipid regulating activity.
The anti-diabetes effect of the compound has good suggestion in an insulin resistance cell model and a high-fat diet induced type 2 diabetes animal model (hyperglycemia and/or glucose tolerance reduction caused by the insulin resistance of target tissues), is equivalent to that of thiazolidinedione hypoglycemic drugs, can effectively reduce the high-fat diet induced increase of fasting blood glucose of mice, improve impaired glucose tolerance and the decrease of insulin tolerance, increase insulin sensitivity, lighten hyperinsulinemia of the mice and delay the development of diabetes of the high-fat diet mice after being continuously used for 1 week. The product has stable effect of lowering blood sugar in animal model in 2-3 months experimental period. Animal researches indicate that compared with thiazolidinedione positive drugs, the product provided by the invention has the advantages that the blood sugar is reduced, the side effect of the thiazolidinedione drugs on animal weight increase is avoided, but the weight increase induced by high-fat diet can be effectively reduced, and the effects of increasing blood fat and accumulating liver fat are obviously improved, so that the product has very good development and application prospects in the aspects of high-fat high-sugar diet-induced type 2 diabetes and obesity.
The beneficial effects of the invention are as follows:
the invention takes p-hydroxyphenylethylamine as an initial raw material, takes fibrate lipid regulating active fragment phenoxyacetic acid as a base, combines 3, 4-dihydroxycinnamoyl fragments discovered by earlier-stage research in a laboratory, adopts the principle of splicing and minimum structure modification of a medicine design, adopts the principles of bioelectronics isostere and prodrug to replace hydroxyl groups on benzene rings by fluorine, chlorine and bromine, and adopts phenoxyacetic acid esters or carboxylic acid fragments containing different substituents to design and synthesize a series of phenylpropoyl or phenylpropionyl phenethylamine substances, and has simple synthesis method and high product purity. Compared with the lead caffeic acid, the benzene acryl or benzene propionyl phenethylamine substance provided by the invention has the following advantages: 1. the source is easy to obtain, and the synthetic route is simple and convenient; 2. has better bioactivity and stability compared with the prototype; 3. the structure is brand new; 4. meanwhile, the composition has excellent effects on reducing blood sugar and improving obesity, and has no side effect.
Drawings
FIG. 1 shows the results of in vitro screening of CP-series compounds for improving insulin resistance and promoting sugar absorption activity.
Figure 2 is the effect of CP11 compounds on the body weight of high fat diet mice.
Figure 3 is the effect of CP11 compounds on glucose and insulin resistance in high fat diet mice.
FIG. 4 is a graph showing the effect of CP11 compounds on the glucose-induced serum protein and insulin levels in hyperglycemic mice.
Detailed Description
The invention will be further described with reference to specific embodiments, and advantages and features of the invention will become apparent from the description. These examples are merely exemplary and do not limit the scope of the invention in any way. It will be understood by those skilled in the art that various changes and substitutions of details and forms of the technical solution of the present invention may be made without departing from the spirit and scope of the present invention, but these changes and substitutions fall within the scope of the present invention.
Example 1
1. Preparation of phenylpropenoyl or phenylpropionyl phenethylamines
1) Synthesis of intermediate B
48.0g (0.39 mol) of p-hydroxyphenylethylamine A was weighed out in a round-bottomed flask, dissolved by adding methanol thereto with stirring, and then 132.0g (1.57 mol) of sodium hydrogencarbonate was weighed out and added to the reaction liquid with stirring sufficiently. 98mL (Boc) was slowly added to the reaction under nitrogen 2 O, and stirred at room temperature for 12h. After the reaction was completed, sodium hydrogencarbonate solid was removed by suction filtration, the filtrate was removed by pressure-reduction, and the residue was purified by silica gel column chromatography, and petroleum ether-ethyl acetate (8:1) was eluted to give 79g of B intermediate as a yellow oil in 91% yield.
2) Synthesis of intermediate C
4.0g (18 mmol) of intermediate B, various alpha-substituted ethyl bromocarboxylates (ethyl alpha-bromo-2-methylpropionate, ethyl alpha-bromopropionate, ethyl alpha-bromopentanoate, ethyl alpha-bromoisovalerate, ethyl alpha-bromoacetate, ethyl alpha-bromobutyrate, ethyl alpha-bromophenylacetate) (22 mmol) and 7.0g (54 mmol) of anhydrous potassium carbonate solid were weighed accurately in a round bottom flask, and 150mL of anhydrous acetone was added and stirred well. Reflux reaction under argon protection until TLC monitoring reaction is finished, developing solvent is petroleum ether-ethyl acetate (4:1), cooling reaction to room temperature, suction filtering insoluble substances, and washing filter cake with acetone. The solvent was distilled off from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with petroleum ether-ethyl acetate (10:1) to give 7 colorless oily intermediates C1 to C7, respectively. 3) Synthesis of intermediate D1-D7 series compounds
Separately, accurately weighing the intermediates C1-C7 (15 mmol) in a round-bottom flask, adding 200mL of dichloromethane to dissolve, slowly adding 25mL (0.3 mmol) of trifluoroacetic acid under ice bath, and stirring at room temperature to react for 1h until Boc protection is removed. Evaporating the solvent, adding saturated sodium carbonate aqueous solution, extracting with chloroform, combining organic layers, drying with anhydrous magnesium sulfate, filtering, concentrating the filtrate, purifying the residue by silica gel column chromatography, and eluting with petroleum ether-ethyl acetate (2:1) to obtain 7 colorless oily intermediates D1-D7 respectively.
4) Synthesis of target Compounds CP1 to CP32
In a round bottom flask, 10mmol of Compound P was accurately weighed, 30mL of anhydrous DMF was added for dissolution, and DIEA 1.6mL (18 mmol) was added dropwise with stirring. The structure of compound P is as follows:
wherein Rn represents n substituents R, n=1 to 3, and R is at least one selected from hydrogen, hydroxy, halogen, trifluoromethyl, methoxy and C1-C3 alkyl; />Represented by a double bond or a single bond; r is R 1 Selected from H or C1-C3 alkyl.
Accurately weighing 2.3g (10 mmol) of BOP, dissolving the BOP in anhydrous dichloromethane, and then adding 2.2g (10 mmol) of intermediates D1-D7 respectively, and fully and uniformly stirring. The above dichloromethane solution containing BOP and intermediates D1-D7 was slowly added dropwise to the reaction flask in ice bath, then stirred at room temperature for reaction, TLC monitored the end of the reaction, and the developing solvent was dichloromethane-methanol (10:1). The solvent dichloromethane was distilled off, the residue was diluted with distilled water, extracted with ethyl acetate, and then washed with 1N HCl, saturated aqueous sodium bicarbonate and saturated brine in this order, the organic layers were combined, dried over anhydrous magnesium sulfate, suction filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography, dichloromethane-methanol (50:1) to give the objective products CP1 to CP32.
The hydrogen spectrum data of the prepared compounds CP1 to CP32 are as follows:
compound CP1 (Et represents ethyl):
pale yellow powder, yield 38.9%. 1 H-NMR(600MHz,DMSO)δ:8.42(1H,t,J＝6.0Hz),7.27(1H,d,J＝15.9Hz),7.17(2H,d,J＝8.6Hz),6.94(1H,d,J＝2.0Hz),6.83(1H,dd,J＝2.1Hz,8.2Hz),6.80(1H,d,J＝8.3Hz),6.76～6.73(3H,m),6.37(1H,d,J＝15.9Hz),4.30(2H,d,J＝5.9Hz),4.18～4.14(2H,m),1.50(6H,s),1.17(1H,t,J＝7.1Hz)。
Compound CP2:
white powder, yield 60.1%. 1 H-NMR(600MHz,CDCl 3 )δ:7.59(1H,d,J＝15.9Hz),7.48～7.47(1H,m),7.36～7.34(1H,m),7.32～7.28(2H,m),7.19～7.18(2H,m),6.82～6.80(2H,m),6.39(1H,d,J＝15.6Hz),5.90(1H,t),4.49(2H,d,J＝5.7Hz),4.23(2H,q,J＝7.1Hz),1.58(6H,s),1.26(1H,t,J＝7.2Hz)。
Compound CP3:
white powder, yield 52.9%. 1 H-NMR(600MHz,CDCl 3 )δ:7.58(1H,d,J＝15.7Hz),7.47～7.46(1H,m),7.34～7.33(1H,m),7.31～7.27(2H,m),7.18～7.17(2H,m),6.81～6.79(2H,m),6.41(1H,d,J＝15.6Hz),6.03(1H,t),4.48(2H,d,J＝5.6Hz),4.22(2H,q,J＝7.0Hz),1.58(6H,s),1.26(1H,t,J＝7.0Hz)。
Compound CP4:
white powder, yield 61.5%. 1 H-NMR(600MHz,CDCl 3 )δ:7.67(1H,d,J＝15.8Hz),7.50～7.49(2H,m),7.38～7.34(3H,m),7.21～7.19(2H,m),6.83～6.81(2H,m),6.39(1H,d,J＝15.4Hz),5.80(1H,t),4.51(2H,d,J＝5.7Hz),4.23(2H,q,J＝7.1Hz),1.59(6H,s),1.26(1H,t,J＝7.1Hz)。
Compound CP5:
white powder, yield 43.3%. 1 H-NMR(600MHz,CD 3 OD)δ:7.49(1H,d,J＝16.0Hz),7.21～7.17(3H,m),7.01～7.00(1H,m),6.98～6.97(1H,m),6.81～6.79(3H,m),6.57(1H,d,J＝15.9Hz),4.41(1H,t),4.19(2H,q,J＝7.2Hz),1.53(6H,s),1.22(1H,t,J＝7.3Hz)。
Compound CP6:
white powder, yield 46.7%. 1 H-NMR(600MHz,CDCl 3 )δ:7.73(1H,m),7.66(1H,d,J＝15.5Hz),7.63～7.57(2H,m),7.49～7.46(1H,m),7.19～7.16(2H,m),6.81～6.78(2H,m),6.49(1H,d,J＝15.9Hz),6.13(1H,t),4.48(2H,d,J＝5.5Hz),4.22(2H,q,J＝7.0Hz),1.57(6H,s),1.25(1H,t,J＝7.0Hz)。
Compound CP7:
white powder, yield 51.2%. 1 H-NMR(600MHz,CDCl 3 )δ:7.69(1H,d,J＝15.7Hz),7.62～7.58(4H,m),7.26～7.19(2H,m),6.83～6.81(2H,m),6.46(1H,d,J＝15.7Hz),5.91(1H,t),4.50(2H,d,J＝5.6Hz),4.23(2H,q,J＝7.1Hz),1.59(6H,s),1.26(1H,t,J＝7.1Hz)。
Compound CP8:
white powder, yield 39.9%. 1 H-NMR(600MHz,CDCl 3 )δ:7.38～7.36(3H,m),7.33～7.32(2H,m),7.30～7.28(2H,m),7.22～7.20(2H,m),6.84～6.81(2H,m),6.13(1H,t),4.49(2H,d,J＝5.6Hz),4.23(2H,q,J＝7.2Hz),2.11～2.10(3H,m),1.59(6H,s),1.26(1H,t,J＝7.1Hz)。
Compound CP9:
white powder, yield 41.5%. 1 H-NMR(600MHz,CDCl 3 )δ:7.60(2H,d,J＝15.6Hz),7.40～7.38(2H,m),7.20～7.19(2H,m),6.84～6.80(4H,m),6.25(2H,d,J＝15.6Hz),5.77(1H,t),4.50(2H,d,J＝5.6Hz),4.23(2H,q,J＝7.1Hz),1.58(6H,s),1.26(1H,t,J＝7.1Hz)。
Compound CP10:
white powder, yield 38.2%. 1 H-NMR(600MHz,CDCl 3 )δ:7.56(2H,d,J＝15.6Hz),7.17～7.16(2H,m),7.02(1H,d,J＝1.9Hz,8.3Hz),6.95(1H,d,J＝1.9Hz),6.87(1H,d,J＝8.2Hz),6.80～6.78(2H,m),6.28(2H,d,J＝15.6Hz),6.10(1H,s),6.04(1H,t),4.46(2H,d,J＝5.6Hz),4.21(2H,q,J＝7.0Hz),3.86(3H,s),1.57(6H,s),1.24(1H,t,J＝7.0Hz)。
Compound CP11:
white powder, yield 42.6%. 1 H-NMR(600MHz,CDCl 3 )δ:7.61(2H,d,J＝15.7Hz),7.44～7.42(2H,m),7.19～7.18(2H,m),6.88～6.87(2H,m),6.81～6.80(2H,m),6.27(2H,d,J＝15.6Hz),5.88(1H,t),4.82(2H,d,J＝5.6Hz),4.22(2H,q,J＝7.0Hz),3.82(3H,s),1.58(6H,s),1.25(1H,t,J＝7.1Hz)。
Compound CP12:
white powder, yield 39.4%. 1 H-NMR(600MHz,CDCl 3 )δ:7.63(2H,d,J＝15.6Hz),7.39～7.38(2H,m),7.19～7.15(4H,m),6.82～6.80(2H,m),6.35(2H,d,J＝15.6Hz),5.87(1H,t),4.49(2H,d,J＝5.6Hz),4.23(2H,q,J＝7.1Hz),2.36(3H,s),1.58(6H,s),1.25(1H,t,J＝7.1Hz)。
Compound CP13:
white powder, yield 34.6%. 1 H-NMR(600MHz,CDCl 3 )δ:7.31～7.28(2H,m),7.25～7.20(3H,m),7.03～7.01(2H,m),6.78～6.77(2H,m),5.75(1H,t),4.33(2H,d,J＝5.5Hz),4.25(2H,q,J＝7.2Hz),3.00(1H,t,J＝7.7Hz),2.52(1H,t,J＝7.7Hz),1.60(6H,s),1.28(1H,t,J＝7.0Hz)。
Compound CP14:
white powder, yield 30.2%. 1 H-NMR(600MHz,CD 3 OD)δ:6.99～6.97(2H,m),6.76～6.74(2H,m),6.67～6.65(2H,m),6.52～6.51(1H,m),4.24～4.19(4H,m),2.78(1H,t,J＝7.4Hz),2.45(1H,t,J＝7.5Hz),1.53(6H,s),1.23(1H,t,J＝7.0Hz)。
Compound CP15:
white powder, yield 55.5%. 1 H-NMR(400MHz,CD 3 OD)δ:7.41(1H,d,J＝15.7Hz),7.18～7.16(2H,m),7.01～7.00(1H,m),6.91～6.83(3H,m),6.77～6.75(1H,m),6.39(1H,d,J＝15.7Hz),4.39(2H,s),1.51(6H,s)。
Compound CP16:
white powder, yield 74.8%. 1 H-NMR(600MHz,CD 3 OD)δ:7.71(1H,m),7.50～7.47(3H,m),7.29～7.26(1H,m),7.22～7.21(2H,m),6.88～6.86(2H,m),6.63(1H,d,J＝15.7Hz),4.41(2H,s),1.54(6H,s)。
Compound CP17:
white powder, yield 72.8%. 1 H-NMR(600MHz,CD 3 OD)δ:7.61(1H,d,J＝15.5Hz),7.47(1H,m),7.35～7.29(3H,m),7.21～7.20(2H,m),6.91～6.89(2H,m),6.40(1H,d,J＝15.5Hz),5.98(2H,t),4.49(1H,d,J＝5.6Hz),1.60(6H,s)。
Compound CP18:
white powder, yield 65.3%. 1 H-NMR(600MHz,CDCl 3 )δ:7.49(1H,d,J＝15.7Hz),7.41～7.40(2H,m),7.22～7.20(2H,m),6.82～6.78(4H,m),6.44(1H,d,J＝15.7Hz),4.41(2H,s),1.54(6H,s)。
Compound CP19:
white powder, yield 69.0%. 1 H-NMR(600MHz,CD 3 OD)δ:7.58～7.54(3H,m),7.39～7.35(3H,m),7.23～7.22(2H,m),6.89～6.87(2H,m),6.83(1H,d,J＝15.5Hz),4.42(2H,s),1.54(6H,s)。
Compound CP20:
white powder, yield 51.5%. 1 H-NMR(600MHz,CD 3 OD)δ:7.49(1H,d,J＝15.6Hz),7.22～7.17(3H,m),7.02～6.97(2H,m),6.88～6.86(2H,m),6.81～6.79(1H,m),6.57(1H,d,J＝15.6Hz),4.41(2H,s),1.54(6H,s)。
Compound CP21:
white powder, yield 63.3%. 1 H-NMR(600MHz,CD 3 OD)δ:7.84～7.81(2H,m),7.66～7.57(3H,m),7.24～7.22(2H,m),6.89～6.87(2H,m),6.73(1H,d,J＝15.7Hz),4.43(2H,s),1.54(6H,s)。
Compound CP22:
white powder, yield 64.9%. 1 H-NMR(600MHz,CD 3 OD)δ:7.73～7.70(2H,m),7.66～7.65(2H,m),7.61～7.58(1H,m),7.23～7.21(2H,m),6.89～6.87(2H,m),6.74(1H,d,J＝15.7Hz),4.42(2H,s),1.54(6H,s)。
Compound CP23:
white powder, collectingThe rate was 53.9%. 1 H-NMR(600MHz,CD 3 OD)δ:7.39～7.35(4H,m),7.30～7.28(2H,m),7.24～7.23(2H,m),6.88～6.87(2H,m),4.42(2H,s),1.55(6H,s)。
Compound CP24:
white powder, yield 50.0%. 1 H-NMR(600MHz，CD 3 OD)δ:7.49(1H，d，J＝15.7Hz)，7.41～7.40(2H,m),7.21～7.20(2H,m),6.88～6.87(2H,m),6.79～6.78(2H,m),6.44(1H,d,J＝15.9Hz),4.41(2H,s),1.54(6H,s)。
Compound CP25:
white powder, yield 47.2%. 1 H-NMR(600MHz,CD 3 OD)δ:7.49(1H,d,J＝15.7Hz),7.20～7.19(2H,m),7.09(1H,d,J＝1.8Hz),7.01(1H,dd,J＝1.8Hz,8.2Hz),6.87～6.85(2H,m),6.79(1H,d,J＝8.2Hz),6.47(1H,d,J＝15.7Hz),4.40(2H,s),1.53(6H,s)。
Compound CP26:
white powder, yield 55.4%. 1 H-NMR(600MHz,CD 3 OD)δ:7.52～7.47(3H,m),7.22～7.20(2H,m),6.93～6.86(4H,m),6.79(1H,d,J＝8.2Hz),6.48(1H,d,J＝15.8Hz),4.41(2H,s),3.80(3H,s),1.54(6H,s)。
Compound CP27:
white powder, yield 59.4%. 1 H-NMR(600MHz,CD 3 OD)δ:7.53(1H,d,J＝15.9Hz),7.43～7.42(2H,m),7.22～7.17(4H,m),6.88～6.86(2H,m),6.57(1H,d,J＝15.9Hz),4.41(2H,s),2.33(3H,s),1.54(6H,s)。
Compound CP28:
white powder, yield 63.3%. 1 H-NMR(600MHz,CD 3 OD)δ:7.25～7.23(2H,m),7.21～7.18(2H,m),6.98～6.97(2H,m),6.80～6.78(2H,m),4.23(2H,s),2.92(1H,t,J＝7.6Hz),2.52(1H,t,J＝7.6Hz),1.53(6H,s)。
Compound CP29:
/>
white powder, yield 65.2%. 1 H-NMR(600MHz,MeOD)δ:7.42(1H,d,J＝15.6Hz,CH＝CH),7.23～7.21(2H,m,Ph′-H-2′,6′),7.00(1H,d,J＝2.0Hz,Ph-H-2),6.90(1H,d,J＝8.2Hz,1.9Hz,Ph-H-6),6.85～6.83(2H,m,Ph′-H-3′,5′),6.76(1H,d,J＝8.2Hz,Ph-H-5),6.39(1H,d,J＝15.7Hz,CH＝CH),4.45[1H,d,J＝5.4Hz,(CH 3 ) 2 CH-CH-COOEt],4.40(2H,s,NH-CH 2 ),4.18(1H,q,J＝7.1Hz,COOCH 2 CH 3 ),2.27～2.21[1H,m,(CH 3 ) 2 CH-CH-COOEt],1.23(3H,t,J＝7.1Hz,COOCH 2 CH 3 ),1.07～1.05[6H,m,(CH 3 ) 2 CH-CH-COOEt]。
Compound CP30:
white powder, yield 69.3%. 1 H-NMR(600MHz,MeOD)δ:7.42(1H,d,J＝15.7Hz,CH＝CH),7.25～7.24(2H,m,Ph′-H-2′,6′),7.01(1H,d,J＝1.8Hz,Ph-H-2),6.91～6.88(3H,m,Ph-H-6,Ph′-H-3′,5′),6.76(1H,d,J＝8.2Hz,Ph-H-5),6.39(1H,d,J＝15.6Hz,CH＝CH),4.67(2H,s,CH 2 -COOEt),4.41(2H,s,NH-CH 2 ),4.23(2H,q,J＝7.2Hz,COOCH 2 CH 3 ),1.27(3H,t,J＝7.2Hz,COOCH 2 CH 3 )。
Compound CP31:
white powder, yield 61.2%. 1 H-NMR(600MHz,MeOD)δ:7.43(1H,d,J＝15.7Hz,CH＝CH),7.23～7.21(2H,m,Ph′-H-2′,6′),7.01(1H,d,J＝1.9Hz,Ph-H-2),6.90(1H,dd,J＝8.2Hz,2.0Hz,Ph-H-6),6.84～6.83(2H,m,Ph′-H-3′,5′),6.77(1H,d,J＝8.2Hz,Ph-H-5),6.40(1H,d,J＝15.6Hz,CH＝CH),4.64～4.62(1H,m,CH 3 -CH 2 -CH-COOEt),4.39(2H,s,NH-CH 2 ),4.17(2H,q,J＝7.1Hz,COOCH 2 CH 3 ),1.98～1.88(2H,m,CH 3 -CH 2 -CH-COOEt),1.22(3H,t,J＝7.1Hz,COOCH 2 CH 3 ),1.04(3H,t,J＝7.5Hz,CH 3 -CH 2 -CH-COOEt)。
Compound CP32:
white powder, yield 57.6%. 1 H-NMR(600MHz,MeOD)δ:7.55～7.54(2H,m,Ph″-H-3″,5″),7.42(1H,d,J＝15.7Hz,CH＝CH),7.39～7.34(3H,m,Ph″-H-2″,4″,6″),7.23～7.21(2H,m,Ph′-H-2′,6′),7.01(1H,d,J＝1.9Hz,Ph-H-2),6.93～6.89(3H,m,Ph-H-6,Ph′-H-3′,5′),6.76(1H,d,J＝8.2Hz,Ph-H-5),6.38(1H,d,J＝15.6Hz,CH＝CH),5.75(1H,s,Ph″-CH-COOEt),4.39(2H,s,NH-CH 2 ),4.19～4.11(2H,m,COOCH 2 CH 3 ),1.22(3H,t,J＝7.1Hz,COOCH 2 CH 3 )。
EXAMPLE 2 pharmacological part
1. Experimental method
1.1 in vitro cell experiment screening method
Human normal liver cell (L02) strain, taking L02 cells with good growth state and in exponential growth phase, inoculating into 96-well plate at a certain concentration, culturing in RPMI1640 medium containing 10% fetal bovine serum and 1% penicillin/1% streptomycin, and culturing in incubator with 5% carbon dioxide at 37deg.C. After the cells are fused to 80%, the culture medium is changed into 2% fetal bovine serum and 25mol/L lithocholic acid (LCA) to stimulate the cells for 24 hours, so as to prepare a hepatocyte insulin resistance model; subsequently, treatments with different caffeic acid derivatives, compounds CP 1-CP 32 (10 or 100. Mu. Mol/L), were applied, a Control group (Control) and Model group (Model) were set, each group was set with 10 duplicate wells, and incubated for 24h. The liquid in the wells was then aspirated, washed 2 times with PBS buffer, cells were treated with 100mol/L2-NBDG containing 110-7mol/L insulin and incubated at 37℃for 30min, and the effect of the compound on glucose absorption by insulin stimulation was evaluated by changes in intracellular fluorescence intensity as detected at a full-automatic microplate reader excitation/emission wavelength (Ex/Em) of 488nm/520nm, and active compounds that improved LCA-induced insulin resistance-promoting glucose absorption were screened.
1.2 in vivo hypoglycemic Effect verification of active Compounds
After 50 male C57BL/6J mice of 6 weeks of age were fed for one week in a control group (CON, 10, standard diet Cat#D 12492) and a high fat diet group (40, high fat diet Cat#D1245 OJ) were fed for 6 weeks, and the high fat diet group was divided into 4 groups according to fasting blood glucose components: model group (HFD, high fat diet), caffeic acid group (CA, hfd+100mg/kg CA), active compound group (CP 11, hfd+100mg/kg CP 11), positive drug rosiglitazone group (ros., hfd+25mg/kg ros.), 10 groups each, 6 weeks of treatment. Body weight was measured weekly during animal feeding. OGTT and ITT experiments were performed at weeks 7 and 8 of the administration treatment for 12 hours and 4 hours, respectively, and intraperitoneal injection of 2g/kg glucose and 0.75U/kg insulin was performed, respectively, and tail vein blood sampling was performed for blood glucose for 0min, 30min, 60min, 90min and 120 min. The medicine is administrated by stomach irrigation, once a day for 9 weeks, fasted for 12 hours, anesthetized and blood taken, and is used for later biochemical index detection.
2. Experimental results
2.1 in vitro insulin resistance cell model screening Compounds for improving insulin resistance hypoglycemic action
The cell glucose uptake experimental result shows that the CP series compounds can improve cell insulin resistance and promote glucose absorption screening. Some derivatives can significantly improve LCA-induced L02 cell insulin resistance and significantly increase cellular glucose uptake. As shown in FIG. 1, compounds CP9 and CP14 significantly increased cellular glucose uptake when insulin resistant cells were treated at a concentration of 10. Mu. Mol/L for 24 hours; compounds CP7, CP10, CP11 and CP13 significantly increased cellular glucose uptake at concentrations of 10 and 100. Mu. Mol/L for 24 hours, with the compounds CP11 and CP13 having the most significant effects indicating that compounds CP11 and CP13 may have the effect of improving insulin resistance and treating type 2 diabetes.
In fig. 1, p <0.05 compared to control, p <0.01 compared to control, p <0.001 compared to control; * P <0.0001 compared to control group; p <0.05, # p <0.01 compared to model group, # p <0.001 compared to model group, # p <0.0001 compared to model group.
2.2 Effect of active Compound CP11 on body weight of high fat diet mice
As a result, as shown in fig. 2, the body weight of the mice in the control group, the model group and each of the administration groups increased gradually with the increase of the week old, and the body weight of the mice in the high-fat diet model group (HFD group) was significantly higher than that in the control group after receiving the high-fat diet for 9 weeks, and had a significant difference; high fat diet mice received drug treatment from week 6 (CA, CP11 and ros.), caffeic acid CA group, mice weighing comparable to HFD group; after 4 weeks of treatment of mice, the mice began to significantly increase in weight compared to HFD group, indicating that ros had the effect of increasing the weight of mice; whereas the body weight of the mice in the CP11 group was significantly lower than that of the HFD group after 5 weeks of treatment with CP11, indicating that CP11 significantly inhibited the weight gain of the mice caused by the high fat diet.
In fig. 2, p <0.05 compared to Control (CON); # compares p <0.05 to high fat diet group (HFD), # compares p <0.01 to HFD.
2.3 Effect of active Compound CP11 on high fat diet-induced hyperglycemia and insulin sensitivity in mice
As shown in a, B in fig. 3, the HFD group mice exhibited a significant glucose intolerance compared to the control group mice, and the glucose intolerance of the drug-interfered group mice was significantly improved compared to the HFD group; and CP11 mice exhibited better glucose tolerance than CA-combined ros. As shown in fig. 3c, d, the mice in the HFD group showed a slow and low blood glucose decrease after insulin injection compared to the mice in the control group, indicating that the mice developed significant insulin resistance; whereas insulin resistance was significantly improved in mice from the drug-interfered group compared to the HFD group.
In fig. 3, p <0.05 compared to Control (CON), p <0.01 compared to Control (CON), p <0.001 compared to CON, and p <0.0001 compared to CON; p <0.05, # compared to high fat diet group (HFD), p <0.01, # compared to HFD, p <0.001, # compared to HFD; +CA <0.05 compared to CP11, +CP11 <0.05 compared to Ros.
Consistent with this result, as shown in fig. 4, the serum of the mice in the CP11 and ros treatment groups had significantly reduced content of glycated serum protein compared to the HFD group, indicating that CP11 was effective in controlling the increase in blood glucose in high-fat diet mice and improving impaired fasting blood glucose in mice, and had excellent hypoglycemic effect. In addition, the serum of mice in the drug-treated group had significantly lower insulin content than that in the HFD group, wherein the decrease in insulin content was most pronounced in the CP11 treated group, and the insulin resistance index was significantly decreased and the insulin sensitivity index was significantly increased in the mice, indicating that the insulin sensitivity of the mice was significantly increased following drug intervention, particularly after CP11 treatment.
In fig. 4, p <0.0001, # p <0.05 compared to HFD, # p <0.01 compared to HFD, # p <0.001 compared to HFD, # p <0.0001 compared to HFD.
Conclusion:
the above in vivo and in vitro experimental results show that the CP11 compound can well improve the high-fat diet induced insulin resistance of mice, increase the insulin sensitivity of the mice, and well treat and control hyperglycemia caused by the high-fat diet, and the treatment effect is remarkable and slightly better than that of a positive drug ros (rosiglitazone), and most importantly: CP11 can also inhibit the weight gain of mice caused by high-fat diet effectively, and Ros can not inhibit the weight gain of mice caused by high-fat diet, but can obviously increase the weight of mice, so that the CP11 has the dual effects of reducing blood sugar and inhibiting weight gain, and has application prospect in treating obesity or high-fat diet-induced type 2 diabetes and obesity.
The foregoing detailed description is directed to one of the possible embodiments of the present invention, which is not intended to limit the scope of the invention, but is to be accorded the full scope of all such equivalents and modifications so as not to depart from the scope of the invention.

Claims (14)

1. A substituted benzene acryl or benzene propionyl phenethylamine compound, which has the following structure:
wherein Rn represents n substituents R, n=1 to 4, and R is at least one selected from hydrogen, hydroxy, halogen, trifluoromethyl, methoxy and C1-C5 alkyl;represented by a double bond or a single bond; r is R 1 Selected from H or C1-C5 alkyl; r is R 2 And R is 3 Each independently selected from C1-C3 alkyl; r is R 4 Selected from H or C1-C10 alkyl.
2. The compound of claim 1, wherein n = 1 or 2, r is selected from at least one of hydrogen, hydroxy, halogen, trifluoromethyl, methoxy, and methyl; r is R 1 Selected from H or methyl; the method comprises the steps of carrying out a first treatment on the surface of the R is R 2 And R is 3 Are all methyl groups; r is R 4 Selected from H or ethyl.
3. A process for the preparation of a compound as claimed in claim 1 or 2, comprising the steps of:
a) Starting from compound A p-hydroxyphenylethylamine and (Boc) 2 O reacts to obtain an intermediate B;
b) Reacting the intermediate B with alpha substituted bromocarboxylate to obtain an intermediate C;
c) Removing Boc from the intermediate C under an acidic condition to obtain an intermediate D;
d) The intermediate D reacts with the compound P to obtain a compound CP, namely a substituted benzene acryloyl or benzene propionyl phenethylamine compound;
the alpha-substituted bromocarboxylic acid ester is at least one selected from alpha-bromo-2-methylpropanoic acid ethyl ester, alpha-bromopropionic acid ethyl ester, alpha-bromopentanoic acid ethyl ester, alpha-bromoisovaleric acid ethyl ester, alpha-bromoacetic acid ethyl ester, alpha-bromobutyric acid ethyl ester and alpha-bromophenylacetic acid ethyl ester;
the structure of the compound P is as follows:
the reaction route is as follows:
4. the process according to claim 3, wherein in the step a), at least one of sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine, 4-dimethylaminopyridine and N, N-diisopropylethylamine is further added in an amount of 1 to 5 equivalents to carry out the reaction.
5. A process according to claim 3, wherein in step b) the reaction is carried out under alkaline conditions.
6. The method according to claim 5, wherein in the step b), alkaline conditions are provided by at least one of potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide; the molar ratio of the alkali to the intermediate B is 1-5:1.
7. A process according to claim 3, wherein in step B) the molar ratio of α -substituted bromocarboxylate to intermediate B is 1-3:1.
8. The process according to claim 3, wherein in step c), the Boc is removed by hydrolysis under acidic conditions provided by at least one of trifluoroacetic acid, boron trifluoride etherate and zinc chloride.
9. The process of claim 3, wherein in step d) at least two of BOP, BOP-Cl, HOBt, HATU, HBTU, TBTU, TATU, EDCI, DMAP and N, N-diisopropylethylamine are further added and the reaction is carried out in a solvent.
10. The method of claim 9, wherein in step d), the solvent comprises at least one of DMF and DCM.
11. The process according to claim 3, wherein when R 4 When the sample is not H, the method further comprises the step e): compound CP was hydrolyzed under alkaline conditions to give the corresponding carboxylic acid, which was prepared as follows:
12. use of a compound according to any one of claims 1-2 for the manufacture of a medicament for lowering blood glucose and/or ameliorating obesity.
13. Use of a compound according to any one of claims 1-2 for the manufacture of a medicament for the treatment of obesity and/or type ii diabetes.
14. The use according to claim 13, wherein the obesity and/or type ii diabetes is induced by a high fat diet.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5084466A (en) * 1989-01-31 1992-01-28 Hoffmann-La Roche Inc. Novel carboxamide pyridine compounds which have useful pharmaceutical utility
US5294643A (en) * 1989-07-05 1994-03-15 Kanegafuchi Kagaku Kogyo Kabushiki Cinnamamide derivative

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5084466A (en) * 1989-01-31 1992-01-28 Hoffmann-La Roche Inc. Novel carboxamide pyridine compounds which have useful pharmaceutical utility
US5294643A (en) * 1989-07-05 1994-03-15 Kanegafuchi Kagaku Kogyo Kabushiki Cinnamamide derivative

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