Preparation method and application of aminonicotinic acid triester of chebulagic acid

Abstract

This invention belongs to the field of pharmaceutical technology, specifically relating to a chebula acid amino acid triester with the following general structural formula: The method for preparing the chebula acid amino acid triester is characterized by the following steps: S1, L-histidine and L-tyrosine are first protected with carboxyl groups, and then reacted with chebula acid to obtain a chebula acid-amino acid ester; S2, under ionic conditions, the carboxyl protecting groups on the amino acids are removed to obtain the chebula acid-amino acid triester. This invention addresses the problems existing in the prior art by using L-histidine and L-tyrosine to modify chebula acid, improving its absorption and taste in the gastrointestinal tract.

Description

Technical Field

[0001] This invention relates to a method for preparing and applying a chebulic acid amino acid triester, belonging to the field of pharmaceutical technology. Background Technology

[0002] Terminalia cathartica, a plant belonging to the genus Rhamnus in the family Combretaceae, is a traditional medicinal herb listed in the Pharmacopoeia of the People's Republic of China and is abundant in my country. It is not only a commonly used drug in traditional Chinese medicine but also in Mongolian and Tibetan medicine, and is known as the "King of Mongolian Medicine." Terminalia cathartica has a wide range of applications. It is neutral in nature, bitter and astringent in taste, and has the effects of astringing the intestines and stopping diarrhea, reducing internal heat and soothing the throat, and astringing the lungs and relieving cough. Terminalia cathartica is rich in chemical components, mainly including tannins, phenolic acids, and triterpenoids. Terminalia cathartica extracts possess various biological activities, including antibacterial, anti-inflammatory, antiviral, antioxidant, and antitumor effects.

[0003] Terminaliacetic acid is a monomeric component isolated from Terminalia chebula extract. It belongs to the polyhydroxyphenol class and is highly hydrophilic, but its absorption through the gastrointestinal tract is poor, limiting its application in pharmaceutical preparations. Furthermore, although terminaliacetic acid has a certain astringent effect, its sour and astringent taste when taken orally also limits its pharmaceutical use. Summary of the Invention

[0004] This invention addresses the problems existing in the prior art by modifying chebulic acid with L-histidine and L-tyrosine, thereby improving its absorption and taste in the gastrointestinal tract.

[0005] The specific technical solution adopted in this invention is as follows:

[0006] A chebulic acid amino acid triester has the following general structural formula:

[0007] .

[0008] Wherein, R is L-tyrosine or L-histidine, and their chemical formulas are as follows:

[0009] .

[0010] A method for preparing a chebulic acid amino acid triester, characterized by comprising the following steps:

[0011] S1, L-histidine and L-tyrosine are first carboxyl protected (L-tyrosine also protects the phenolic hydroxyl group), and then reacted with chebulic acid to prepare chebulic acid-amino acid ester.

[0012] S2. Under ionic conditions, the carboxyl protecting group on the amino acid is removed to obtain chebulic acid-amino acid triester.

[0013] In step S1, the carboxyl group of L-histidine is protected, including the following steps:

[0014] (1) Add 50 mL of water and 7.75 g (0.05 mol) of L-histidine (substance 1) to a 150 mL three-necked flask, stir to dissolve, and then heat to 90 °C;

[0015] (2) Add 45 ml of acetic anhydride (dropping rate 1.5 ml / min). After the addition is complete, stir and reflux at this temperature for 2 h. After the reaction is complete, the solution turns pale yellow and is cooled to room temperature naturally. Remove excess acetic acid and water by vacuum evaporation to obtain the remaining pale yellow viscous substance in the flask.

[0016] (3) After dissolving the above viscous substance in 50 mL of acetone, filter to remove unreacted L-tyrosine; remove the acetone in the filtrate in a vacuum evaporator at 40 °C to obtain a solid residue;

[0017] (4) Add 50 mL of water to the residue to dissolve it, then add 0.1 mol / L barium carbonate solution to neutralize the remaining acetic acid and make the solution neutral; then add 19.93 g of barium hydroxide solid and stir for 0.5 h; add 12.6 g of dimethyl sulfate dropwise at 30-40 °C; then reflux the above mixed solution at 85-95 °C for 2 h.

[0018] (5) Filter to remove insoluble matter, slowly pour the filtrate into a boiling solution consisting of 10g concentrated sulfuric acid (98% by mass) and 50mL water, cool and age overnight; filter to remove the precipitated barium sulfate solid; place in a refrigerator at 4℃ to cool and crystallize; precipitate compound (3) 4.79g of flaky or rod-shaped crystals.

[0019] (6) Add 3.0 g of compound (3) and 15 mL of 18% hydrochloric acid solution to a 100 mL three-necked flask and stir and reflux for 2 h;

[0020] (7) Place the flask in an ice-water mixture and cool for 1 hour; filter to obtain a solid, wash with cold 18% dilute hydrochloric acid to obtain 2.16 g of compound (4).

[0021] (8) Take another 20 ml of methanol solution (0 °C), stir vigorously, add 2.0 mL of thionyl chloride dropwise to methanol, then add 2∙0 g of compound (4) and stir under reflux for 3 h; evaporate the above reaction mixture under vacuum at 30 °C to constant weight to obtain 2∙0 g of white solid compound (5).

[0022] (9) The product of step (8) was recrystallized from methanol-chloroform (volume ratio 10:1) to obtain white needle-like crystals; the crystals in reaction (21) were then dissolved in 5-10 ml of water and neutralized with 10% ammonia water; then extracted three times with ether (50 mL) to obtain 1.59 g of compound (6).

[0023] The chemical reaction formulas for the above steps are as follows:

[0024] .

[0025] Based on the above technical solution, step S1 also includes the following steps:

[0026] (1) 3.56 g (0.01 mol) chebulic acid (7) and 6.00 g (0.05 mol) thionyl chloride were added to a 200 ml three-hole flask, and 50 mL of dimethylformamide (DMF) was added. The mixture was refluxed at room temperature for about 4 h. After the reaction was completed, the solvent was evaporated to dryness (at room temperature) to obtain 2.83 g of compound (8).

[0027] (2) At 0°C, take 9.35 g (0.05 mol) of dried compound (8), dissolve it in 10 ml of dichloromethane (DCM), add 6.06 g (0.06 mol) of triethylamine (Et-N) and 12.75 g (0.075 mol) of compound (6), and stir the reaction mixture at 0°C to 25°C for two hours;

[0028] (3) The resulting reaction mixture was diluted with 10 ml of dichloromethane (DCM), washed with 2 mol / L hydrochloric acid, and filtered; then washed with 100 ml of saturated NaHCO3 solution and filtered; then washed with saturated sodium chloride solution and filtered; and then the resulting solution was dried with sodium sulfate (Na2SO4) solid.

[0029] (4) The solid obtained in the above steps was purified with dichloromethane / petroleum ether (volume ratio 95:5) to obtain a white solid compound (9).

[0030] (5) Place 40.45 g (0.05 mol) of compound (9), 20 mL of ionic liquid (a 0.1 mol / L pyridine bromate PyHBr / aluminum trichloride mixed solution, molar ratio 0.33:0.67), and 2 mL of ethyl acetate (EtOAc) into a three-hole round-bottom flask equipped with a reflux condenser and a desiccator, heat to 140 °C, stir, and react for 3 hours;

[0031] (6) Cool the reaction mixture to room temperature and add 30 mL of anhydrous diethyl ether (Et2O). Separate the organic phase and dry with Na2SO4. Evaporate the solvent to obtain the crude product, and dry and crystallize to obtain 30.10 g of the target compound (10).

[0032] The chemical reaction formulas for the above steps are as follows:

[0033] .

[0034] In step S1, the carboxyl group of L-tyrosine is protected, including the following steps:

[0035] (1) Add 9.05g (0.05mol) L-tyrosine (substance 11) and 50mL of water to a 150mL three-necked flask, stir to dissolve, and then heat to 90℃;

[0036] (2) Add 45 ml of acetic anhydride (dropping rate 1.5 ml / min). After the addition is complete, stir and reflux at this temperature for 2 h. After the reaction is complete, the solution turns pale yellow and is cooled to room temperature naturally. Remove excess acetic acid and water by vacuum evaporation to obtain the remaining pale yellow viscous substance in the flask.

[0037] (3) After dissolving the above viscous substance in 50 mL of acetone, filter to remove unreacted L-tyrosine; remove the acetone in the filtrate in a vacuum evaporator at 40℃ to obtain a solid residue; add 50 mL of water to the residue to dissolve it, then add 0.1 mol / L barium carbonate solution to neutralize the remaining acetic acid and make the solution neutral; then add 19.93 g of barium hydroxide solid and stir for 0.5 h.

[0038] (4) Add 12.6 g of dimethyl sulfate dropwise at 30-40℃; then reflux the above mixed solution at 85-95℃ for 2 hours; filter to remove insoluble matter; slowly pour the filtrate into a boiling solution composed of 10 g of concentrated sulfuric acid (98% by mass) and 50 mL of water; cool and age overnight; filter to remove the precipitated barium sulfate solid; place in a refrigerator at 4℃ to cool and crystallize; precipitate 5.9 g of compound (13) in the form of flakes or rods;

[0039] (5) In addition, add 3.3 g of compound (13) and 15 mL of 18% hydrochloric acid solution to a 100 mL three-necked flask, and stir and reflux for 2 h;

[0040] (6) Add 3.0g of compound (3) and 15 mL of 18% hydrochloric acid solution to a 100mL three-necked flask and stir and reflux for 2h; place the flask in an ice-water mixture to cool for 1h; filter to obtain a solid, wash with cold 18% dilute hydrochloric acid to obtain 2.16g of compound (4);

[0041] (7) Take another 20 ml of methanol solution (0℃), stir vigorously, add 2.0 mL of thionyl chloride dropwise to methanol, then add 20 g of compound (4) and stir under reflux for 3 h; evaporate the above reaction mixture under vacuum at 30℃ to constant weight to obtain 2.0 g of white solid compound (5), then recrystallize it with methanol-chloroform (volume ratio 10:1) to obtain white needle-like crystals; extract it three times with diethyl ether (50 mL) to obtain 1.8 g of compound (16).

[0042] The chemical reaction formulas for the above steps are as follows:

[0043] .

[0044] Based on the above technical solution, step S1 further includes the following steps:

[0045] (1) At °C, take 9.35 g (0.05 mol) of compound (8) obtained in the previous experiment, dissolve it in 10 ml of dichloromethane (DCM), add 6.06 g (0.06 mol) of triethylamine (Et-N) and 15.675 g (0.075 mol) of compound (16), and stir the reaction mixture at 0 °C to 25 °C for two hours;

[0046] (2) The resulting reaction mixture was diluted with 10 ml of dichloromethane (DCM), washed with 2 mol / L hydrochloric acid, and filtered; then washed with 100 ml of saturated NaHCO3 solution and filtered; then washed with saturated sodium chloride solution and filtered; then the resulting solution was dried with sodium sulfate (Na2SO4) solid; the resulting solid was purified with dichloromethane / petroleum ether (volume ratio 95:5) to obtain a white solid compound (19);

[0047] (3) 46.5 g (0.05 mol) of compound (19), 20 mL of ionic liquid (0.1 mol / L pyridine bromate PyHBr / aluminum trichloride mixed solution, molar ratio 0.33:0.67), and 2 mL of ethyl acetate (EtOAc) were placed in a three-hole round-bottom flask equipped with a reflux condenser and a desiccator, heated to 140 °C, stirred, and reacted for 3 hours;

[0048] (4) Cool the reaction mixture to room temperature, add 30 mL of anhydrous diethyl ether (Et2O), separate the organic phase and dry with Na2SO4.

[0049] (5) Evaporate the solvent to obtain the crude product, dry and crystallize to obtain the target compound (20) 34.22g.

[0050] The chemical reaction formulas for the above steps are as follows:

[0051] .

[0052] In this application, the textual description "compound (n), where n represents the compound number in the chemical reaction formula" refers to the raw material or product corresponding to the number in the chemical reaction formula.

[0053] The purpose of the chebulic acid amino acid triester described in this invention is to prepare a drug for treating or adjuvant treatment of diarrhea.

[0054] In this invention, the chebulic acid-L-histidine triester contains -NH, which alters the acidity / alkalinity of chebulic acid and changes its taste; the chebulic acid-L-tyrosine triester contains a benzene ring and a phenolic hydroxyl group, which alters its lipid solubility and makes it more easily absorbed. Further research found that both chebulic acid amino acid triesters significantly improved the efficacy in treating animal diarrhea and increased feed intake compared to chebulic acid.

[0055] The beneficial effects of this invention are as follows:

[0056] The L-histidine of this invention can reduce gastric acidity, alleviate pain from gastrointestinal surgery, reduce vomiting and heartburn during pregnancy, inhibit digestive tract ulcers caused by autonomic nervous system tension, and is also effective for allergic diseases such as asthma. Furthermore, L-histidine is a basic amino acid. L-tyrosine is an aromatic amino acid, very slightly soluble in water, and is commonly used clinically in nutritional supplements. Attached Figure Description

[0057] Figure 1 shows the 13C NMR spectrum of the target compound (10):

[0058] 13 C NMR (125 MHz, (CD3)2SO) δ 177.11, 174.39, 173.67, 168.45, 164.95,146.89, 145.33, 137.63 (s, 1H), 134.67, 127.36, 124.78, 123.59, 121.17,110.11, 77.33, 51.19, 48.86 (s, 2H), 44.71, 37.79, 28.50.

[0059] Figure 2 shows the (10) 1H NMR spectrum:

[0060] 1H NMR (500 MHz, (CD3)2SO) δ 7.84 (s, 1H), 7.75 (s, 1H), 7.11 (s, 1H), 7.05 – 6.94 (m, 4H), 6.94 – 6.84 (m, 2H), 6.79 – 6.61 (m, 6H), 6.56 (s, 1H),5.89 (s, 1H), 5.75 (s, 1H), 5.63 (s, 3H), 5.50 (s, 1H), 5.04 – 4.95 (m, 3H),4.66 (s, 1H), 3.87 (s, 1H), 3.15 (t, J = 11.8 Hz, 3H), 3.02 (s, 1H), 2.88(dd, J = 36.1, 16.9 Hz, 4H), 2.63 (s, 1H).

[0061] Figure 3 shows the target compound (20). 13 CNMR spectrum:

[0062] 13 C NMR (125 MHz, (CD3)2SO) δ 177.11, 174.49, 173.67, 168.45, 164.95,156.30, 146.89, 145.33, 137.63, 130.65, 129.65, 123.59, 121.17, 115.93,110.11, 77.33, 54.80, 48.86, 44.71 (s, 1H), 37.79 (s, 1H), 37.42.

[0063] Figure 4 It is the target compound (20). 1 H NMR spectrum:

[0064] 1H NMR (500 MHz, (CD3)2SO) δ 7.84 (s, 1H), 7.75 (s, 1H), 7.11 (s, 1H), 7.05 – 6.94 (m, 4H), 6.94 – 6.84 (m, 2H), 6.79 – 6.61 (m, 6H), 6.56 (s, 1H),5.89 (s, 1H), 5.75 (s, 1H), 5.63 (s, 3H), 5.50 (s, 1H), 5.04 – 4.95 (m, 3H),4.66 (s, 1H), 3.87 (s, 1H), 3.15 (t, J = 11.8 Hz, 3H), 3.02 (s, 1H), 2.88(dd, J = 36.1, 16.9 Hz, 4H), 2.63 (s, 1H). Detailed Implementation

[0065] Example 1: Treatment of diarrhea in mice

[0066] One hundred and twenty-five 7-week-old BALB / c mice (weighing 37±1g) were randomly divided into five groups of 25 mice each: control group, model group, chebulic acid group (HZ group), chebulic acid-L-histidine ester group (HH group), and chebulic acid-L-tyrosine ester group (HT group).

[0067] After the mice adapted to the environment, except for the control group which was injected intraperitoneally with sterile saline, the other groups of mice were injected intraperitoneally with a suspension of *E. coli* (bacterial concentration 1.0 × 10⁻⁶). 9 CFU / mL), dose 0.1 mL / 10 g. Four hours after challenge, mice developed diarrhea. Mice in each group were orally administered the drugs: control and model groups received 0.1 mL / mouse of physiological saline; HZ group received 0.1 mL / mouse of chebulic acid (10 mg / mL); HH group received 0.1 mL / mouse of chebulic acid-L-histidine ester (10 mg / mL); and HT group received 0.1 mL / mouse of chebulic acid-L-tyrosine ester (10 mg / mL). Administered every 6 hours for a total of 3 times. Mice in each group were housed separately to prevent cross-infection. The health status of mice in each group was recorded and analyzed. Observation indicators: diarrhea rate and survival rate after 3 days. (Diarrhea rate (%) = [number of diarrheal mice in each group / total number of mice in each group] x 100%; Survival rate (%) = [number of surviving mice in each group / total number of mice in each group] x 100%).

[0068] Table 1: Diarrhea rate and survival rate in mice 3 days after drug administration

[0069] Group control group Model group HZ Group HH Group HT group Diarrhea rate % 0% 100% 48% 8% 12% Survival rate % 100% 50% 88% 100% 100% .

[0070] Data showed that the diarrhea rate in mice in the HH and HT groups was significantly lower than that in the HZ group, and no mice died, indicating that the modified drug was significantly more effective than chebulic acid in treating diarrhea caused by Escherichia coli infection.

[0071] Example 2: Treatment of diarrhea in rats

[0072] One hundred 30-day-old SD rats, weighing 70±5g each, with equal numbers of males and females, were randomly divided into five groups: control group, model group, chebulic acid group (HZ group), chebulic acid-L-histidine group (HH group), and chebulic acid-L-tyrosine group (HT group), with 10 rats in each group, equal numbers of males and females. Except for the control group rats, which were orally administered 0.5ml / rat of sterile saline, the other rats were orally administered senna leaf decoction (equivalent to a crude drug concentration of 0.3g / ml) once daily for 3 consecutive days. Six hours after oral administration of senna leaf decoction, rats in both the control and model groups received oral administration of the following drugs: 0.5 ml / rat of physiological saline in the control and model groups; 0.5 ml / rat (10 mg / mL) of chebulic acid in the HZ group; 0.5 ml / rat (10 mg / mL) of chebulic acid-L-histidine ester in the HH group; and 0.5 ml / rat (10 mg / mL) of chebulic acid-L-tyrosine ester in the HT group. Administered at the same time daily for three consecutive days. Rats in each group were housed separately to prevent cross-infection. The health status of rats in each group was recorded and analyzed. One day after drug withdrawal, the health status of rats in each group was recorded and analyzed. The diarrhea rate of rats one day after drug withdrawal was recorded. The results are shown in Table 2.

[0073] Table 2: Diarrhea Rate in Rats

[0074] Group control group Model group HZ Group HH Group HT group Diarrhea rate % 0% 100% 45% 5% 0% .

[0075] Data showed that the diarrhea rate in rats in the HH and HT groups was significantly lower than that in the HZ group, indicating that the modified drug was significantly more effective than chebulic acid in treating senna-induced diarrhea in rats.

[0076] Example 3: Treatment of diarrhea in weaned piglets

[0077] Fifty healthy, castrated 21-day-old crossbred piglets, with an average weight of 6.5 kg ± 0.5 kg, were selected. All piglets had normal body temperature, respiration, and heart rate. They were randomly divided into five groups: control group, model group, chebulic acid group (HZ group), chebulic acid-L-histidine group (HH group), and chebulic acid-L-tyrosine group (HT group), with 10 piglets in each group.

[0078] On day 2 of feeding, all groups of piglets underwent the same treatment: each group of piglets was orally administered 1.0 × 10⁻⁶ ETEC5 standard E. coli. 11 A diarrhea model was established using 5 mL of CFU / mL solution, while the control group was administered the same volume of sterile saline. The diarrhea status of piglets was observed, and the criteria for diarrhea assessment are shown in Table 3.

[0079] Table 3: Criteria for Judging Diarrhea in Weaned Piglets

[0080] fecal characteristics score Normal shape, granular, normal moisture content 0 Soft stool, unformed 1 Yellow water sample 2 Black water sample 3 .

[0081] Piglets in each group were fed different diets starting on the second day after viral challenge, and fed for three consecutive days: Control group: fed diet with the same amount of glucose; Model group: fed diet with the same amount of glucose; Terminalia chebula acid (HZ) group: fed diet with 20 mg / kg terminalia chebula acid; Terminalia chebula acid-L-histidine group (HH group): fed diet with 20 mg / kg terminalia chebula acid-L-histidine; Terminalia chebula acid-L-tyrosine group (HT group): fed diet with 20 mg / kg terminalia chebula acid-L-tyrosine. Piglets in each group were kept in separate pens to prevent cross-infection.

[0082] Observe the diarrhea index of piglets in each group on the second day after drug withdrawal (diarrhea index = sum of diarrhea scores / (number of experimental pigs x number of experimental days)). The results are shown in Table 4.

[0083] Group control group Model group HZ Group HH Group HT group Diarrhea score in weaned piglets 0.89±0.24 2.62±0.32 1.88±0.42 0.93±0.46 0.82±0.13 .

[0084] The results showed that the diarrhea index of weaned piglets in the HH and HT groups was significantly lower than that in the HZ group, indicating that the modified drug had a higher improvement in the treatment of diarrhea caused by Escherichia coli infection than chebulic acid.

[0085] Implementation Case 4: Impact on Feed Intake of Weaned Piglets

[0086] Thirty healthy, castrated piglets, aged 30 days, from a two-way crossbreed, were selected and weighed between 9.5 kg and 0.7 kg. All piglets had normal body temperature, respiration, and heart rate. They were randomly divided into five groups: a control group, a chebulic acid group (HZ group), a chebulic acid-L-histidine group (HH group), and a chebulic acid-L-tyrosine group (HT group), with six piglets in each group.

[0087] Piglets in each group were fed different diets for 3 consecutive days: Control group: no medication added to the feed; Terminalia chebula acid (HZ) group: fed diet supplemented with 20 mg / kg terminalia chebula acid; Terminalia chebula acid-L-histidine group (HH group): fed diet supplemented with 20 mg / kg terminalia chebula acid-L-histidine; Terminalia chebula acid-L-tyrosine group (HT group): fed diet supplemented with 20 mg / kg terminalia chebula acid-L-tyrosine. Piglets in each group were kept in separate pens, with each group receiving 5 kg of feed. After 20 minutes of feeding, the remaining feed from each group was collected, and feed intake was recorded. The results are shown in Table 5.

[0088] Group control group / g HZ group / g HH group / g HT group / g Day 1 548±8.2 501±10.1 580±7.2 588±9.4 Day 2 554±7.5 492±11.2 593±5.3 599±7.7 Day 3 558±9.6 522±8.4 589±6.4 601±11.1 .

[0089] The results showed that the feed intake of piglets in the HH and HT groups was significantly higher than that in the HZ group, and even higher than that in the control group, indicating that chebulic acid-L-histidine ester and chebulic acid-L-tyrosine ester have the effect of promoting feed intake in weaned piglets.

[0090] Example 5: Treatment of calf diarrhea

[0091] Sixty healthy Holstein calves (average weight 43.21 ± 1.13 kg) were selected and randomly divided into five groups: control group, model group, chebulic acid group (HZ group), chebulic acid-L-histidine group (HH group), and chebulic acid-L-tyrosine group (HT group), with 12 calves in each group. The calves in each group were raised and managed according to the traditional farm feeding and management model.

[0092] On day 5 of feeding, calves in each group were treated as follows: except for the control group, calves in each group were orally administered 1.0 × 10⁻⁶ ETEC5 standard Escherichia coli. 11 A diarrhea model was established using 10 mL of CFU / mL. Control group calves were administered the same volume of sterile saline. Starting at 5 days of age, fecal samples were photographed and recorded daily for each group. A fecal score greater than 3 was considered indicative of diarrhea.

[0093] In addition to normal feeding, calves in each group received the following treatments on day 6: Control group: 500ml of physiological saline orally; Model group: 500ml of physiological saline orally; Terminaliacetic acid group (HZ group): 500ml of physiological saline solution containing 200mg of terminaliacetic acid; Terminaliacetic acid-L-histidine group (HH group): 500ml of physiological saline solution containing 200mg of terminaliacetic acid-L-histidine; Terminaliacetic acid-L-tyrosine group (HT group): 500ml of physiological saline solution containing 200mg of terminaliacetic acid-L-tyrosine, for 5 consecutive days. The number of days with diarrhea, the number of calves with diarrhea, and the duration of diarrhea were recorded. The interval between the first observation of diarrhea and the first observation of no diarrhea was defined as the duration of diarrhea. Calves in each group were housed separately to prevent cross-infection. The criteria for judging diarrhea are shown in Table 6.

[0094] Table 6: Criteria for Judging Diarrhea in Calves

[0095] Senses score Stools are either in the shape of strips or in pellets. 1 The stool is formed, but the texture is relatively soft. 2 The stool is unformed and quite watery. 3 The feces and water are clearly separated, but the color is normal. 4 The feces and water are clearly separated, and the color is abnormal. 5 .

[0096] The experimental results were summarized after 30 days of age. The results are shown in Table 7.

[0097] Table 7: Treatment status of calves with diarrhea in each group

[0098] Group control group Model group HZ Group HH Group HT group Diarrhea score for infants aged 5-30 days 1.54±0.23 4.53±0.19 2.18±0.45 1.67±0.24 1.59±0.19 .

[0099] The results showed that the diarrhea index was significantly lower in the HH and HT groups than in the HZ group, indicating that the modified drug had a higher improvement in the treatment of calf diarrhea caused by Escherichia coli infection than chebulic acid.

Claims

1. A chebulic acid amino acid triester, selected from compounds shown in formula (10) or formula (20): 。 2. The method for preparing the chebulic acid amino acid triester according to claim 1, characterized in that, The compound shown in formula (10) is prepared according to the following chemical reaction steps: 。 3. The method for preparing the chebulic acid amino acid triester according to claim 1, characterized in that, The compound shown in formula (20) is prepared according to the following chemical reaction steps: 。 4. The use of the chebulic acid amino acid triester according to claim 1, characterized in that, The chebulic acid amino acid triester is used to prepare a drug for treating diarrhea.

Images