Momordica derivative as well as preparation method and application thereof

Abstract

The invention discloses a charantin derivative as well as a preparation method and application thereof. The charantin derivative has the following molecular structure expression, the research finds that the charantin derivative not only shows excellent hypoglycemic activity, but also shows an obvious curative effect in the aspect of reducing blood fat.

Description

Technical Field

[0001] The present invention relates to a momordica charantia derivative, in particular to a momordica charantia derivative and a preparation method and application thereof. Background Art

[0002] According to epidemiological surveys, the incidence of dyslipidemia in the general population is 20% to 40%, while approximately 60% of diabetic patients experience it. This is because when lipid metabolism is abnormal, blood cholesterol and triglyceride levels are significantly higher than normal, while high-density lipoprotein cholesterol is lower. These metabolic changes can reduce insulin sensitivity and cause insulin resistance, which in turn leads to elevated blood sugar levels. Disrupted glucose metabolism in diabetic patients can further lead to disrupted lipid metabolism. Therefore, hyperglycemia and hyperlipidemia often coexist in clinical practice, a condition known as diabetes combined with dyslipidemia.

[0003] Significant progress has been made in the clinical treatment of diabetes mellitus with dyslipidemia. Commonly used oral hypoglycemic drugs include thiazolidinediones (TZDs) and biguanides, while commonly used lipid-lowering drugs include statins and fibrates. The combined use of hypoglycemic and lipid-regulating drugs has shown promising results in the treatment of metabolic syndrome and the prevention of cardiovascular and cerebrovascular events. However, both thiazolidinediones and biguanides, as well as statins and fibrates, are associated with numerous side effects, and the incidence of adverse reactions is high with long-term use. Therefore, developing novel drugs that simultaneously lower both blood sugar and lipids to reduce the number of oral medications is crucial for improving adverse reactions. However, such drugs with both functions are few and far between. Summary of the Invention

[0004] In order to solve the above technical problems, the present invention provides a momordica charantia derivative and a preparation method and application thereof.

[0005] To achieve the above object, the technical solutions adopted by the present invention are as follows:

[0006] According to the first aspect of the present invention, a momordica charantia derivative is provided, which has a novel molecular structure, and is expressed as follows:

[0007]

[0008] According to the second aspect of the present invention, there is also provided a method for preparing a momordica charantia derivative, comprising the following steps:

[0009]

[0010] a. reacting 4-(2-aminoethyl)benzenesulfonamide and Boc anhydride, and removing the optional solvent and excess starting material to obtain intermediate 1;

[0011] b. Mixing intermediate 1 and cyclohexyl isocyanate in a solvent, adding potassium carbonate catalyst and reacting to obtain intermediate 2;

[0012] c. Dissolve intermediate 2 and gradually add dilute hydrochloric acid, stirring and reacting for a period of time to obtain intermediate 3;

[0013] d. Mix the intermediate 3 and momordica charantia I in a solvent, add acetic acid catalyst and react to obtain the desired product.

[0014] The preparation method of the present invention uses 4-(2-aminoethyl)benzenesulfonamide as a raw material, first performs Boc protection on the amino group, then reacts the intermediate with cyclohexyl isocyanate and removes the protecting group, and then connects momordica charantia (terpenoid compound) to obtain a momordica charantia derivative with a novel structure. This preparation method utilizes a known and mature reaction mechanism and can obtain the target product with high efficiency and high yield.

[0015] As a preferred embodiment of the preparation method of the present invention, in step a, the molar ratio of 4-(2-aminoethyl)benzenesulfonamide to Boc anhydride is 1:(1-1.5), for example, 1:1.1, 1:1.2, 1:1.3, 1:1.4, etc.;

[0016] Preferably, the reaction solvent in step a is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, ethylene glycol monomethyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, and dimethyl carbonate;

[0017] Preferably, the reaction conditions in step a are stirring at room temperature for 2-5 hours, for example, 2 hours, 3 hours, 4 hours, 5 hours, etc.

[0018] After the reaction in step a is completed, water may be added and stirred, and floccules may be precipitated and then filtered, and the solid product may be collected and purified to obtain intermediate 1.

[0019] As a preferred embodiment of the preparation method of the present invention, in step b, the molar ratio of the intermediate 1 to cyclohexyl isocyanate is 1:(2-4), for example, 1:2.5, 1:3, 1:3.5, 1:4, etc.;

[0020] Preferably, the amount of potassium carbonate used is 1.5-3 times of 1 mole of the intermediate, for example, 2 times, 2.2 times, 2.4 times, 2.6 times, 2.8 times, etc.

[0021] As a preferred embodiment of the preparation method of the present invention, the reaction in step b is first carried out in acetone solvent, heated to 40-60°C for 1-2 hours, and then water is added in an amount not exceeding the amount of acetone to continue the reaction for 0.5-1 hour to terminate the reaction.

[0022] After the reaction in step b is completed, the insoluble matter is filtered out, washed with equal volumes of acetone and water, dried, and purified to obtain intermediate 2.

[0023] As a preferred embodiment of the preparation method of the present invention, in step c, the amount of dilute hydrochloric acid used is 1-2 times the amount of 2 moles of the intermediate, for example, 1.2 times, 1.4 times, 1.6 times, 1.8 times, etc.;

[0024] Preferably, the reaction solvent in step c is one or more of ethyl acetate, acetonitrile and ethanol.

[0025] As a preferred embodiment of the preparation method of the present invention, the reaction conditions in step c are: stirring the reaction at room temperature for 8-24 hours, for example, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, 22 hours, etc.

[0026] After the reaction in step c is completed, the solid is filtered, washed, and purified to obtain intermediate 3.

[0027] As a preferred embodiment of the preparation method of the present invention, in step d, the molar ratio of intermediate 3 to momordica charantia I is 1:(1-1.2), for example, 1:1.05, 1:1.1, 1:1.15, etc.;

[0028] Preferably, the amount of acetic acid used is 5-10 times the molar amount of the intermediate, for example, 6 times, 7 times, 8 times, 9 times, 10 times, etc.

[0029] As a preferred embodiment of the preparation method of the present invention, the reaction solvent in step d is one or more of ethyl acetate, acetonitrile, and ethanol;

[0030] Preferably, the reaction conditions in step d are stirring the reaction at room temperature for 8-24 hours, for example, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, 22 hours, etc.

[0031] After the reaction in step d is completed, the mixture is cooled to room temperature, the flocculent is filtered out, washed, and purified by recrystallization to obtain the target product.

[0032] According to the third aspect of the present invention, there is also provided a use of the momordica charantia derivative as described above or the momordica charantia derivative prepared by the method described above in a drug for lowering blood sugar and / or blood lipids, especially as a drug for diabetes combined with dyslipidemia.

[0033] The present invention unexpectedly discovered through research that the momordica charantia derivative not only exhibits excellent hypoglycemic activity, but also shows significant therapeutic effects in lowering blood lipids, especially the strongest effect on lowering TC and TG, and is particularly suitable for hypertriglyceridemia or mixed hyperlipidemia with elevated cholesterol as the main feature. DETAILED DESCRIPTION

[0034] The present invention will be further described below through specific examples. The examples of the present invention are only for illustration of the present invention and do not limit the scope of the present invention.

[0035] Unless otherwise specified, the raw materials and reagents used in the following examples of the present invention can be purchased from commercial sources.

[0036] [Example 1]

[0037] A method for preparing a momordica charantia derivative comprises the following steps:

[0038]

[0039] a. Mix 4-(2-aminoethyl)benzenesulfonamide (5 mmol) and Boc anhydride (5 mmol) in 12 mL of anhydrous DMF and stir at room temperature for 4 h. Add water and stir until a flocculent product precipitates, which is then filtered to obtain a white solid. Wash the solid several times with water and dry it to obtain Intermediate 1.

[0040] 1 H NMR (600MHz, Chloroform-d): δ7.79–7.73(m,2H),7.31–7.25(m,2H),7.24(s,2H),5. 14(t,J=4.9Hz,1H),3.35(q,J=5.2Hz,2H),2.79(tt,J=5.4,0.9Hz,2H),1.40(s,9H).

[0041] b. Dissolve intermediate 1 (5 mmol) and cyclohexyl isocyanate (20 mmol) in 15 mL of acetone solvent, add potassium carbonate catalyst (15 mmol), heat to 40°C and stir to react for 2 h, then add 20 mL of a mixed solution of water:acetone (volume ratio 1:1), and continue the reaction for 0.5 h. After the reaction is completed, filter out the insoluble matter, wash with equal volumes of acetone and water, and dry to obtain intermediate 2.

[0042] 1 H NMR (600MHz, Chloroform-d): δ7.84–7.78(m,2H),7.32–7.25(m,2H),6.35(s,1H),5.14(t,J=4.9Hz,1H),4.29(d,J=8.1Hz,1H),3.35( q,J=5.2Hz,2H),3.34–3.27(m,1H),2.79(tt,J=5.4,0.9Hz,2H),1.78–1.68(m,2H),1.67–1.55(m,2H),1.55–1.39(m,6H),1.40(s,9H).

[0043] c. Dissolve intermediate 2 (2 mmol) in 20 mL of ethyl acetate, gradually add hydrochloric acid (4 mmol) diluted with ethyl acetate, and stir at room temperature for 12 h. After the reaction is complete, filter to obtain a solid, wash with water, and dry to obtain intermediate 3.

[0044] 1 H NMR (600MHz, Chloroform-d): δ7.84–7.78(m,2H),7.34–7.27(m,2H),6.35(s,1H),4.29(d,J=8.0Hz,1H),3.31(dp,J=8.1,4.8Hz,1H),3 .03(tt,J=6.6,5.0Hz,2H),2.88(tt,J=5.0,0.9Hz,2H),2.67(t,J=6.6Hz,2H),1.78–1.68(m,2H),1.67–1.55(m,2H),1.55–1.39(m,6H).

[0045] d. Dissolve intermediate 3 (1 mmol) and momordica charantia I (1.2 mmol) in 20 mL of ethanol, add acetic acid catalyst (5 mmol), react at room temperature for 12 h, cool to room temperature, filter out the flocs, wash, and recrystallize to obtain the target product momordica charantia derivative.

[0046] 1H NMR (500MHz, Chloroform-d): δ7.84–7.78(m,2H),7.50(tq,J=2.0,1.0Hz,1H),7.34–7.27(m,2H),6.35(s,1H),5.65(dt,J=4.8,1.7Hz,1H),5.29(dddd,J =7.0,2.4,1.6,0.9Hz,1H),4.42(dtd,J=7.1,4.6,1.0Hz,1H),4.38–4.26(m, 2H),3.62(dtdd,J=6.7,5.4,2.9,1.5Hz,1H),3.59–3.47(m,2H),3.31(dp,J= 8.1,4.8Hz,1H),3.14(d,J=4.4Hz,1H),2.98(ddt,J=6.9,5.2,0.9Hz,2H),2. 77(d,J=6.6Hz,1H),2.46(dtt,J=7.3,2.7,1.5Hz,1H),2.16–2.10(m,2H),2. 03–1.91(m,1H),1.94–1.79(m,2H),1.82–1.53(m,20H),1.55–1.34(m,9H),1 .23(d,J=1.5Hz,3H),1.18(d,J=1.7Hz,3H),1.07(s,3H),1.03–0.96(m,6H).

[0047] [Example 2]

[0048] A method for preparing a momordica charantia derivative comprises the following steps:

[0049] a. Mix 4-(2-aminoethyl)benzenesulfonamide (5 mmol) and Boc anhydride (7.5 mmol) in 15 mL of anhydrous N-methylpyrrolidone and stir at room temperature for 2 h. Add water and stir until a flocculent product precipitates, which is then filtered to obtain a white solid. Wash the solid several times with water and dry it to obtain Intermediate 1.

[0050] b. Dissolve intermediate 1 (5 mmol) and cyclohexyl isocyanate (10 mmol) in 15 mL of acetone solvent, add potassium carbonate catalyst (7.5 mmol), heat to 60°C and stir to react for 1 h, then add 20 mL of a mixed solution of water:acetone (volume ratio 1:1), and continue the reaction for 0.5 h. After the reaction is completed, filter out the insoluble matter, wash with equal volumes of acetone and water, and dry to obtain intermediate 2.

[0051] c. Dissolve intermediate 2 (2 mmol) in 20 mL of ethyl acetate, gradually add hydrochloric acid (3 mmol) diluted with ethyl acetate, and stir at room temperature for 18 h. After the reaction is complete, filter to obtain a solid, wash with water, and dry to obtain intermediate 3.

[0052] d. Dissolve intermediate 3 (1 mmol) and momordica charantia I (1 mmol) in 20 mL of acetonitrile, add acetic acid catalyst (8 mmol), react at room temperature for 8 h, cool to room temperature, filter out the flocculent material, wash, and recrystallize to obtain the target momordica charantia derivative.

[0053] [Example 3]

[0054] A method for preparing a momordica charantia derivative comprises the following steps:

[0055] a. Mix 4-(2-aminoethyl)benzenesulfonamide (5 mmol) and Boc anhydride (6 mmol) in 20 mL of anhydrous tert-butyl methyl ether and stir at room temperature for 3 h. Add water and stir until a flocculent substance precipitates, which is then filtered to obtain a white solid. Wash the solid several times with water and dry it to obtain Intermediate 1.

[0056] b. Dissolve intermediate 1 (5 mmol) and cyclohexyl isocyanate (15 mmol) in 15 mL of acetone solvent, add potassium carbonate catalyst (10 mmol), heat to 50°C and stir to react for 1.5 h, then add 20 mL of a water:acetone (volume ratio 1:1) mixed solution and continue the reaction for 1 h. After the reaction is completed, filter out the insoluble matter, wash with equal volumes of acetone and water, and dry to obtain intermediate 2.

[0057] c. Dissolve intermediate 2 (2 mmol) in 20 mL of ethanol, gradually add hydrochloric acid (2 mmol) diluted with ethyl acetate, and stir at room temperature for 24 h. After the reaction is complete, filter to obtain a solid, wash with water, and dry to obtain intermediate 3.

[0058] d. Dissolve intermediate 3 (1 mmol) and momordica charantia I (1.1 mmol) in 20 mL of ethanol, add acetic acid catalyst (10 mmol), react at room temperature for 20 h, cool to room temperature, filter out the flocs, wash, and recrystallize to obtain the target momordica charantia derivative.

[0059] Application Examples

[0060] (1) Blood glucose test

[0061] Experimental Mouse Modeling: SPF male Sprague-Dawley rats of uniform weight were selected and evenly divided into five groups: blank group, model group, experimental group, positive control group, and raw material control group. All rats were first fed a basal diet (prepared in accordance with national standard GB14924-1994) for one week. Then, all rats except the blank group were switched to a high-fat, high-sugar diet consisting of 66.5% basal diet, 10% lard, 20% sucrose, 2.5% cholesterol, and 1% sodium cholate. After six weeks, all rats except the blank group received a single intraperitoneal injection of streptozotocin (STZ) (30 mg / kg / body weight) to establish a T2DM model.

[0062] Drug preparation: Using 0.8 wt % CMC-Na as solvent, prepare 4 mg / mL of momordica charantia derivative experimental group solution, metformin positive control group solution, and momordica charantia I raw material control group solution.

[0063] Drug administration: Each drug solution was administered to rats in the corresponding groups at a dose of 200 mg / kg by oral gavage for 8 consecutive weeks. The blank and model groups were gavaged with an equal volume of 0.8 wt% CMC-Na solution. Blood glucose levels were measured and recorded every 2 weeks. The results are shown in Table 1.

[0064] Table 1. Fasting blood glucose values ​​of rats (mmol / L)

[0065] 0 weeks 2 weeks 4 weeks 6 weeks 8 weeks Blank group 5.8±0.5 6.1±0.2 6.2±0.1 5.7±0.5 6.1±0.6 Model Group 17.6±0.6 21.2±0.3 22.5±0.5 24.8±0.7 24.7±0.6 Experimental group 20.4±0.2 21.3±0.5 19.2±0.4 16.3±0.7 14.3±0.5 Positive control group 19.7±0.5 21.7±0.3 19.4±0.5 17.6±0.4 16.7±0.7 Raw material control group 19.3±0.2 20.5±0.1 21.6±0.4 20.3±0.3 19.8±0.5

[0066] (2) Blood lipid test

[0067] Experimental Mouse Modeling: SPF-grade male SD rats of uniform weight were selected and evenly divided into five groups: blank group, model group, experimental group, positive control group, and raw material control group. All rats were first fed a basal diet (prepared in accordance with national standard GB14924-1994) for one week. Then, except for the blank group, all rats were switched to a high-fat, high-sugar diet consisting of 66.5% basal diet, 10% lard, 20% sucrose, 2.5% cholesterol, and 1% sodium cholate. The diet was continued for four weeks to establish a hyperlipidemia model.

[0068] Drug preparation: Using 0.8 wt % CMC-Na as solvent, prepare 4 mg / mL of the momordica charantia derivative experimental group solution, the bezafibrate positive control group solution, and the momordica charantia I raw material control group solution.

[0069] Drug feeding: Each drug solution was administered to the rats of the corresponding group at a dose of 400 mg / kg. The administration method was oral gavage for 28 consecutive days. Among them, the blank group and the model group were gavaged with an equal amount of 0.8wt% CMC-Na solution. After 28 days, the rats were fasted for 12 hours but not water, weighed, anesthetized, and then euthanized by carbon dioxide inhalation. Then blood was collected from the abdominal aorta, and the serum was separated by a high-speed centrifuge for 10 minutes (3000r / min). The serum was analyzed using a fully automatic biochemical analyzer. Among them, TC represents total cholesterol, TG represents total triglycerides, HDL-C represents high-density lipoprotein cholesterol, and LDL-C represents low-density lipoprotein cholesterol. The results of various analytical tests in the serum are shown in Table 2.

[0070] Table 2. Analysis and test results

[0071] Group TC / mmol / L TG / mmol / L HDL-C / mmol / L LDL-C / mmol / L Blank group 1.44±0.12 0.41±0.10 0.58±0.02 1.91±0.13 Model Group 5.80±0.53 0.90±0.13 0.25±0.01 5.25±0.26 Experimental group 3.01±0.42 0.42±0.11 0.36±0.05 4.33±0.28 Positive control group 4.21±0.82 0.51±0.15 0.39±0.03 4.25±0.19 Raw material control group 5.05±0.24 0.78±0.04 0.29±0.12 4.97±0.35

[0072] Note: The welfare of experimental animals and experimental procedures were carried out in strict accordance with the relevant provisions of the Guide for the Care and Use of Laboratory Animals, and every effort was made to minimize the suffering of the animals.

[0073] From the test results in Tables 1 and 2, it can be seen that the momordica charantia derivatives proposed in the present invention not only have excellent blood sugar lowering effects, but also have certain therapeutic effects in lowering blood lipids, and have the strongest effect on lowering TC and TG, and are particularly suitable for hypertriglyceridemia or mixed hyperlipidemia with elevated cholesterol as the main feature.

[0074] The above is only a preferred embodiment of the present invention. It should be pointed out that ordinary technicians in this field can make several improvements and supplements without departing from the method of the present invention. These improvements and supplements should also be considered within the scope of protection of the present invention.

Claims

1. A momordica charantia derivative, characterized in that Has the following molecular structure expression:

2. A method for preparing a momordica charantia derivative, characterized in that: The following steps are involved: a. reacting 4-(2-aminoethyl)benzenesulfonamide and Boc anhydride, and removing the optional solvent and excess starting material to obtain intermediate 1; b. Mixing intermediate 1 and cyclohexyl isocyanate in a solvent, adding potassium carbonate catalyst and reacting to obtain intermediate 2; c. Dissolve intermediate 2 and gradually add dilute hydrochloric acid, stirring and reacting for a period of time to obtain intermediate 3; d. Mix the intermediate 3 and momordica charantia I in a solvent, add acetic acid catalyst and react to obtain the desired product.

3. The method for preparing the momordica charantia derivative according to claim 2, wherein: In step a, the molar ratio of 4-(2-aminoethyl)benzenesulfonamide to Boc anhydride is 1:(1-1.5); Preferably, the reaction solvent in step a is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, ethylene glycol monomethyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, and dimethyl carbonate; Preferably, the reaction conditions in step a are stirring the reaction at room temperature for 2-5 hours.

4. The method for preparing the momordica charantia derivative according to claim 2 or 3, wherein: In step b, the molar ratio of intermediate 1 to cyclohexyl isocyanate is 1:(2-4); Preferably, the amount of potassium carbonate used is 1.5-3 times the amount of 1 mole of the intermediate.

5. The method for preparing the momordica charantia derivative according to any one of claims 1 to 4, characterized in that: In step b, the reaction is first carried out in acetone solvent, heated to 40-60° C. for 1-2 hours, and then water is added in an amount not exceeding the amount of acetone and the reaction is continued for 0.5-1 hour to terminate the reaction.

6. The method for preparing the momordica charantia derivative according to any one of claims 1 to 5, characterized in that: In step c, the amount of dilute hydrochloric acid used is 1-2 times the molar amount of the intermediate; Preferably, the reaction solvent in step c is one or more of ethyl acetate, acetonitrile and ethanol.

7. The method for preparing the momordica charantia derivative according to claim 6, wherein: The reaction conditions in step c are: stirring the reaction at room temperature for 8-24 hours.

8. The method for preparing the momordica charantia derivative according to any one of claims 1 to 7, characterized in that: In step d, the molar ratio of intermediate 3 to momordica charantia I is 1:(1-1.2); Preferably, the amount of acetic acid used is 5-10 times the molar amount of the intermediate.

9. The method for preparing the momordica charantia derivative according to claim 8, wherein: The reaction solvent in step d is one or more of ethyl acetate, acetonitrile, and ethanol; Preferably, the reaction conditions in step d are stirring the reaction at room temperature for 8-24 hours.

10. Use of the momordica charantia derivative according to claim 1 or the momordica charantia derivative prepared by the method according to any one of claims 1 to 9 in a drug for lowering blood sugar and / or blood lipids.

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