3-amino-4-(2, 4, 5-trifluorophenyl) bornyl butyrate as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicinal chemistry, and relates to 3-amino-4-(2, 4, 5-trifluorophenyl) bornyl butyrate as well as a preparation method and application thereof. The 3-amino-4-(2, 4, 5-trifluorophenyl) bornyl butyrate has the following structure: the 3-amino-4-(2, 4, 5-trifluorophenyl) bornyl butyrate provided by the invention has an excellent hypoglycemic effect, has a low toxic effect on AC16 cells, and provides a treatment choice with better efficiency and higher safety for diabetics.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry technology, specifically relating to borneol ester of 3-amino-4-(2,4,5-trifluorophenyl)butyrate, its preparation method, and its application. Background Technology

[0002] In recent years, the incidence of diabetes has been on a continuous upward trend. There is an urgent need to explore new avenues, establish new technologies, and develop safe and effective new antidiabetic drugs to achieve efficient prevention and treatment of diabetes. Summary of the Invention

[0003] The purpose of this invention is to provide a novel compound with hypoglycemic activity.

[0004] The present invention employs the following technical solutions to achieve its objective:

[0005] One aspect of the present invention provides a novel compound: borneol ester of 3-amino-4-(2,4,5-trifluorophenyl)butyrate, having a structure as shown in formula (I):

[0006]

[0007] A second aspect of this invention provides a method for preparing borneol ester of 3-amino-4-(2,4,5-trifluorophenyl)butyrate, comprising the following steps:

[0008] 3-((tert-butoxycarbonyl)amino)-4-(2,4,5-trifluorophenyl)butyric acid and borneol were subjected to a dehydration condensation reaction in the presence of a catalyst, followed by post-treatment to obtain borneol ester of 3-amino-4-(2,4,5-trifluorophenyl)butyric acid.

[0009] Preferably, the molar ratio of 3-((tert-butoxycarbonyl)amino)-4-(2,4,5-trifluorophenyl)butyric acid to borneol is 0.8 to 1.5:1. More preferably, it is 1.1 to 1.5:1.

[0010] Preferably, the molar ratio of the catalyst to borneol is 1 to 5:1.

[0011] Preferably, the catalyst is one or more of the DCC / DMAP system, EDC / DMAP system, and DIC / DMAP system.

[0012] Further preferably, the catalyst is a DCC / DMAP system (i.e., a mixture of DCC and DMAP). The molar ratio of dicyclohexylcarbodiimide (DCC) to 4-dimethylaminopyridine (DMAP) is 5–20:1.

[0013] Preferably, the dehydration condensation reaction is carried out in an organic solvent, which is one or more of dichloromethane (DCM), tetrahydrofuran (THF), N,N-dimethylformamide (DMF), acetonitrile, etc.

[0014] Preferably, the dehydration condensation reaction is carried out at a temperature of 10–40°C for 1–10 h. By monitoring the reaction progress using thin-layer chromatography (TLC), it is possible to quickly determine whether the reactants have been completely converted and whether the target product has been formed, thereby ensuring the smooth progress of the reaction and controlling the formation of byproducts.

[0015] Preferably, the post-processing includes: filtering after the reaction stops, washing and drying the obtained filtrate, then dissolving it in a good solvent, subsequently adding hydrogen chloride to remove the Boc group, filtering and removing the solvent, then adding a poor solvent to slurry to promote product precipitation, and finally filtering and drying to obtain a powdered solid.

[0016] The post-treatment includes washing with 0.2–3 mol / L HCl, saturated NaHCO3 solution, and saturated NaCl solution in sequence.

[0017] A good solvent is an organic solvent used to dissolve the target compound, such as one or more of alcohols, esters, ketones, ethers, and halogenated hydrocarbons; ethyl acetate is an example. A bad solvent is a solvent used for precipitating or recrystallizing the target compound, such as low-polarity ethers and hydrocarbon solvents; isopropyl ether is an example.

[0018] Hydrogen chloride is added in the form of a good hydrogen chloride solvent solution, which is formed by dissolving hydrogen chloride in a good solvent. The concentration of the good hydrogen chloride solvent solution is 0.5–5 mol / L.

[0019] Preferably, the post-processing steps specifically include: filtering after the reaction stops, washing the obtained filtrate sequentially with 0.2-3 mol / L HCl, saturated NaHCO3 solution, and saturated NaCl solution, drying with anhydrous sodium sulfate, evaporating the solvent, dissolving in a good solvent, adding dropwise 0.5-5 mol / L hydrogen chloride good solvent solution, stirring and filtering at room temperature, evaporating the solvent, adding a poor solvent to slurry, filtering and drying to obtain a powdered solid.

[0020] Preferably, the preparation method of 3-((tert-butoxycarbonyl)amino)-4-(2,4,5-trifluorophenyl)butyric acid includes the following steps:

[0021] S1. The raw materials 2,4,5-trifluorophenylacetic acid and 2,2-dimethyl-1,3-dioxane-4,6-dione are subjected to a condensation reaction to generate a diketone compound.

[0022] S2. The diketone compound obtained in S1 is subjected to a reflux decarboxylation reaction with trifluoroacetic acid to obtain β-keto acid;

[0023] S3. The β-keto acid obtained in S2 is reacted with tert-butyl carbamate to obtain an enamine;

[0024] S4. The enamine obtained in S3 was reduced by an asymmetric reduction catalyst to prepare 3-((tert-butoxycarbonyl)amino)-4-(2,4,5-trifluorophenyl)butyric acid.

[0025] A third aspect of the present invention provides the use of 3-amino-4-(2,4,5-trifluorophenyl)butyric acid borneol ester in the preparation of any of the following:

[0026] Drugs that have a hypoglycemic effect;

[0027] Health supplements with blood sugar lowering effects;

[0028] Antidiabetic drugs.

[0029] The drug or health product contains borneol ester of 3-amino-4-(2,4,5-trifluorophenyl)butyrate and / or its salt-forming components.

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] 1. This invention utilizes a combination of traditional Chinese medicine molecular chemical design strategies and a combination of Chinese and Western medicine methods to chemically link 3-amino-4-(2,4,5-trifluorophenyl)butyric acid with borneol to synthesize 3-amino-4-(2,4,5-trifluorophenyl)butyric acid borneol ester. It has the effects of promoting insulin secretion and lowering blood sugar. Compared with existing clinical anti-type 2 diabetes drugs such as metformin, it has the characteristics of multi-target synergistic effect, realizing multi-target treatment of type 2 diabetes and providing candidate drug molecules for the clinical development of superior anti-diabetic drugs.

[0032] 2. By introducing borneol into the structure, this invention not only utilizes its pharmacological advantages such as promoting blood circulation, enhancing permeability, and facilitating drug crossing of the blood-brain barrier, but may also help improve common neurological microcirculatory disorders in diabetes. This novel molecule thus holds promise for achieving a combined effect of "lowering blood sugar + neuroprotection," thereby promoting insulin secretion and protecting the nervous system, meeting the clinical need for integrated prevention and treatment of diabetes and its chronic complications.

[0033] 3. The novel compound 3-amino-4-(2,4,5-trifluorophenyl)butyrate borneol ester provided by this invention has low toxicity to AC16 cells. Compared with the compound 3-amino-4-(2,4,5-trifluorophenyl)butyrate menthol ester previously studied by the inventors, AC16 cells have a higher survival rate, providing a safer treatment option for diabetic patients.

[0034] 4. This "integration of Chinese and Western medicine" design concept not only provides a new paradigm for the development of antidiabetic drugs, but also provides a theoretical framework that can be referenced for the design of multi-target drugs for other chronic diseases (such as cardiovascular diseases and neurodegenerative diseases), which is of great significance for the development of drugs for the prevention and treatment of other chronic diseases. Attached Figure Description

[0035] Figure 1 Borneol ester of 3-amino-4-(2,4,5-trifluorophenyl)butyrate prepared in Example 1 1 HNMR spectrum.

[0036] Figure 2 The mass spectrum of borneol ester of 3-amino-4-(2,4,5-trifluorophenyl)butyrate prepared in Example 1. Detailed Implementation

[0037] The technical solution of the present invention will be further described and illustrated below with reference to specific embodiments and accompanying drawings. It should be understood that the specific embodiments described herein are only for the purpose of helping to understand the present invention and are not intended to limit the specific scope of the present invention. Furthermore, the accompanying drawings used herein are merely for better illustrating the content disclosed in the present invention and do not limit the scope of protection. Unless otherwise specified, the raw materials used in the embodiments of the present invention are all commonly used in the art, and the methods used in the embodiments are all conventional methods in the art.

[0038] In the description of this invention, unless otherwise stated, the numerical range "a~b" represents a shortened representation of any combination of real numbers between a and b, and includes both a and b. "Multiple" includes two, three, four, five, or more.

[0039] Example 1

[0040] The reaction route for preparing borneol ester of 3-amino-4-(2,4,5-trifluorophenyl)butyrate is as follows:

[0041]

[0042] The specific preparation method is as follows:

[0043] Preparation of S1 and Compound 3

[0044] In a 500 mL three-necked flask, tetrahydrofuran (240 mL) was added first, followed by 2,4,5-trifluorophenylacetic acid (20 g, 105.2 mmol), and stirred until completely dissolved. The mixture was kept at a constant temperature of 30 °C, and N,N-carbonyldiimidazole (25.6 g, 157.8 mmol) was slowly added in four portions, followed by 4-dimethylaminopyridine (1.92 g, 15.78 mmol). After stirring for 2.5 h, McFarland acid (2,2-dimethyl-1,3-dioxazolidine-4,6-dione) (18.2 g, 126.2 mmol) was added. The temperature was raised to 50 °C, and the reaction was stopped after 7 h. The reactants were removed by rotary evaporation to remove the solvent. 100 mL of 10% hydrochloric acid was added to the remaining species, and the mixture was extracted twice with 450 mL of dichloromethane. The combined organic phases were rotary evaporated to obtain a pale yellow oil, which was used directly in the next reaction.

[0045] Preparation of S2 and Compound 4

[0046] In a 1L three-necked flask, the product obtained in the previous step was dissolved in methanol (380mL), and trifluoroacetic acid (4mL) was slowly added dropwise. The mixture was refluxed for 5 hours, after which the reaction was stopped. After removing methanol by rotary evaporation, the mixture was extracted twice with water (200mL) and ethyl acetate (450mL). The organic phases were combined, washed twice with saturated sodium chloride solution (200mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 24.2g of a light yellow viscous oil, which was used directly in the next step of the reaction.

[0047] Preparation of S3 and Compound 5

[0048] In a 500 mL three-necked flask, 250 mL of methanol was added, followed by the previously obtained pale yellow viscous oily compound 4 (24.2 g, approximately 104.2 mmol). The mixture was stirred until completely dissolved, then tert-butyl carbamate (NH₂Boc, 104.2 mmol) was added, followed by p-toluenesulfonic acid (PTSA, 2.2 g, 12.6 mmol) and anhydrous magnesium sulfate (12.5 g, 104.2 mmol). The mixture was heated under reflux for 12 h. The reaction solution was filtered, and the solvent was removed by rotary evaporation to obtain a white solid. Recrystallization from a mixture of methanol and water yielded 13.8 g of a white powder.

[0049] Preparation of S4 and Compound 6

[0050] In a 1L reactor, 150ml of tetrahydrofuran was added, followed by compound 5 (6.5g, 19.7mmol) obtained in the previous step. After complete dissolution, 46mg of the asymmetric reduction catalyst TangPhosRh(COD)BF4 was added, hydrogen gas was introduced, and the reaction was carried out at a pressure of 10 atm for 18h at room temperature. The solvent was removed by rotary evaporation, and the crude product was recrystallized from a mixed solution of ethyl acetate and n-hexane. After filtration and vacuum drying, 5.2g of a white solid was obtained.

[0051] Preparation of S5, 3-amino-4-(2,4,5-trifluorophenyl)butyrate borneol ester (BHC)

[0052] In a 250 mL three-necked flask, borneol (1.98 g, 12.8 mmol), compound 6 (5.2 g, 15.4 mmol), dicyclohexylcarbodiimide (DCC) (5.3 g, 25.6 mmol), and 4-dimethylaminopyridine (DMAP) (0.3 g, 2.5 mmol) were weighed out and added to 100 mL of dichloromethane solution. The mixture was stirred at room temperature (25 °C) for 5 hours, and the reaction was monitored by TLC. After the reaction was stopped, the reaction solution was filtered, and the filtrate was washed successively with 1 mol / L HCl, saturated NaHCO3 solution, and saturated NaCl solution. The solution was then dried over anhydrous sodium sulfate, the solvent was evaporated, and the solution was dissolved in 30 mL of ethyl acetate. 10 mL of 2.3 mol / L ethyl hydrochloride solution was added dropwise, and the mixture was stirred and filtered at room temperature. The solvent was evaporated, and the solution was slurried with isopropyl ether, filtered, and dried to obtain a white powdery solid with a molecular weight of 4.17 g.

[0053] I. Structural Assessment

[0054] Figure 1 Borneol ester of 3-amino-4-(2,4,5-trifluorophenyl)butyrate prepared in Example 1 1 HNMR spectrum. Structural analysis is as follows: 1 ¹H NMR (CD3OD-d6, 400MHz) δ (ppm): 0.6–1.5 (¹⁵H, hydrogen on the methyl and methylene groups of the borneol structure (excluding hydrogen on -CH(-O) and tertiary hydrogen); δ: 2.3–2.5 (¹H, -CH- on the borneol structure); δ: 2.6–2.8 and 3.0–3.2 (¹H, hydrogen at positions 2 and 4); δ: 3.8–4.0 (¹H, hydrogen on the carbon atom of the ester group attached to the borneol; δ: 4.7–45.0 (¹H, hydrogen on the tertiary methyl group of the NH₂(-CH) structure); δ: 7.2–7.4 (²H, hydrogen on the benzene ring).

[0055] Figure 2 The mass spectrum of borneol ester of 3-amino-4-(2,4,5-trifluorophenyl)butyrate prepared in Example 1. ESI-MS (m / z): 370.6 [M+H] + .

[0056] II. Experimental Study on Antidiabetic Activity

[0057] 2.1 Experimental Materials

[0058] 2.1.1 Laboratory Animals

[0059] Species and strain: N000180BKS.Cg-Dock7m+ / +Leprdb / Nju mouse;

[0060] Source: Nanjing University - Nanjing Institute of Biomedicine;

[0061] Age: 6-8 weeks;

[0062] Sex: Male;

[0063] Householding conditions: SPF facility.

[0064] 2.1.2 Instruments

[0065] Portable blood glucose meter and test strips.

[0066] 2.2.3 Test methods:

[0067] 2.2.3.1 Grouping of animals:

[0068] Experimental mice were randomly divided into 5 groups according to their body weight, with 4 mice in each group. The specific grouping is as follows:

[0069] Model control group: Oral administration of physiological saline;

[0070] Positive control group: Metformin, 200 mg / kg;

[0071] Administration groups: The 3-amino-4-(2,4,5-trifluorophenyl)butyric acid borneol ester prepared in Example 1 was administered to three groups of mice at low, medium and high doses, respectively. The specific dosage distribution is as follows: low dose group (100 mg / kg), medium dose group (200 mg / kg), and high dose group (400 mg / kg).

[0072] 2.2.3.2. Glucose tolerance test:

[0073] Animals were used to model hyperglycemia, divided into a hyperglycemic control group, a metformin positive control group, and three sample dosage groups, with four mice in each group. After fasting for 5 hours, the dosage groups were given high, medium, and low doses of the test substance, respectively, while the hyperglycemic control group was given physiological saline. Twenty minutes later, each mouse was orally administered glucose at 2.0 g / kg body weight. Blood glucose levels were measured at 0, 0.5, and 2 hours after glucose administration, and the area under the blood glucose curve at these three time points was compared between each dosage group and the hyperglycemic control group.

[0074] 2.2.3.3. Results

[0075] Data from glucose tolerance tests in a hyperglycemic model mouse showed that the area under the blood glucose curve (AUC) of the test substance at medium and high doses was significantly different from that of the solvent control group (p<0.05). Furthermore, a clear linear relationship existed between the high, medium, and low dose groups, indicating that the test substance had a significant hypoglycemic effect under these experimental conditions, and was slightly superior to the positive control drug metformin at the same dose. Relevant data are shown in Table 1.

[0076] Table 1. Experimental data on the hypoglycemic effect of each treatment group on hyperglycemic mice.

[0077]

[0078]

[0079] Based on the data analysis in Table 1, preliminary results indicate that the three groups of test drug administration have significant hypoglycemic effects on N000180BKS.Cg-Dock7m+ / +Leprdb / Nju hyperglycemic mice, and at the same experimental dose, the hypoglycemic effect is slightly better than that of the positive control drug metformin (200mg / kg / d).

[0080] III. Apoptosis Experiment

[0081] 3.1 Main Reagents and Instruments

[0082] Main reagents

[0083] MEM basal culture medium: Wuhan Pronosai Life Science Technology Co., Ltd.;

[0084] Trypsin digestion solution: NCM Biotech;

[0085] PBS buffer: Shanghai Dalthhill Biotechnology Co., Ltd.;

[0086] Penicillin-Streptomycin Mixture: Beijing Solarbio Technology Co., Ltd.;

[0087] Fetal bovine serum: Gibco;

[0088] Annexin V-FITC Apoptosis Detection Kit: Beijing Solarbio Science & Technology Co., Ltd.;

[0089] Cell line: AC16 cells, purchased from Cybio (Shanghai) Biotechnology Co., Ltd.;

[0090] Other reagents: None were further purified; all were commercially available analytical grade.

[0091] Main instruments

[0092] Clean bench: Suzhou Bolair Instrument Co., Ltd.;

[0093] Digital display constant temperature water bath: Shanghai Lichen Bangxi Instrument Technology Co., Ltd.

[0094] Inverted optical microscope: Shanghai Qianxin Instruments Co., Ltd.;

[0095] Flow cytometer: Changzhou Bidaco Biotechnology Co., Ltd.

[0096] 3.2 Proliferation and Culture of AC16 Cells

[0097] AC16 cell lines were cultured in vitro. First, frozen cells were rapidly thawed in a 37°C water bath and then transferred to MEM medium containing 10% fetal bovine serum. The cells were then cultured in a 37°C, 5% CO2 incubator using standard methods until they were fully adhered, evenly distributed, and morphologically sound. Once the cells reached a suitable density, 2 mL of DPBS balanced salt solution was added to the culture flask to gently wash the cells, followed by 1 mL of digestion solution. The flask was then incubated for 1 minute. After incubation, the cells were observed under a microscope to confirm complete detachment. 1 mL of serum was then added to the medium to terminate the digestion reaction. The cell suspension was transferred to centrifuge tubes and centrifuged at 1000 rpm for 5 minutes. The supernatant was discarded, and the cells were resuspended in 6 mL of fresh medium. The cells were then transferred to six-well plates, with 1 mL of medium added to each well. Finally, the six-well plates were incubated until the cells were fully adhered and entered the logarithmic growth phase.

[0098] 3.3 Preparation of 16.67 g / L BHC solution

[0099] Accurately weigh 0.0500 g of the BHC compound and transfer it to a clean glass beaker. Using a pipette, accurately add 3000 μL of dimethyl sulfoxide (DMSO) solution and gently shake for 2 minutes until completely dissolved and the solution is clear and free of suspended particles. In a laminar flow hood, use a sterile syringe to aspirate the dissolved solution and filter it through a Φ25, 0.45 μm filter into a sterile container. Seal the container with sealing film and refrigerate for later use.

[0100] 3.4. AC16 Cell Apoptosis Assay

[0101] In six-well plates, 10 μL, 32.5 μL, 55 μL, 77.5 μL, and 100 μL of 16.67 g / L BHC solution were added, respectively, to set up a blank control group (no drug added). After 24 hours, the supernatant was discarded, and each well was washed twice with 2 mL of PBS buffer to remove residual culture medium. Subsequently, 400 μL of trypsin cell digestion solution was added to each well, and the plates were incubated at 37°C, 5% CO2 for 1 minute to allow complete cell detachment. After digestion, 1 mL of culture medium was added to each well to neutralize the digestion solution. The cell suspension in the six-well plates was transferred to centrifuge tubes and centrifuged at 1000 rpm for 5 minutes, and the supernatant was discarded. The cells were resuspended in 1 mL of PBS buffer in each cell pellet, and 100 μL of the cell suspension was added to six flow cytometry tubes. Add 5 μL of Annexin V-FITC staining solution to each tube, incubate in the dark for 5 minutes, then add 5 μL of propidium iodide (PI) staining solution, and finally dilute with 400 μL of PBS buffer. Following the method described in the literature, apoptosis was detected in each group of cells using flow cytometry to analyze the apoptosis rate. The experimental results are shown in Table 2.

[0102] Table 2. Results of cell experiments in each group

[0103] blank 10μL 32.5μL 55μL 77.5μL 100μL normal cells 99.86％ 99.56％ 99.72％ 98.61％ 99.50％ 98.88％ Early apoptosis 0.05％ 0.00％ 0.00％ 0.00％ 0.08％ 0.00％ Late apoptosis 0.00％ 0.10％ 0.00％ 0.75％ 0.17％ 0.47％ Damaged cells 0.00％ 0.25％ 0.28％ 0.64％ 0.26％ 0.65％ Cell count 2216 1579 717 932 1205 1700

[0104] As can be seen from the cell experiment results in Table 2, compared with the blank group, the overall cell survival rate of the BHC treatment group was higher, indicating that BHC had a smaller toxic effect on AC16 cells.

[0105] All aspects, embodiments, and features of this invention should be considered illustrative in all respects and not limiting of the invention; the scope of the invention is defined only by the claims. Other embodiments, modifications, and uses will become apparent to those skilled in the art without departing from the spirit and scope of the invention as claimed.

[0106] In the preparation method of this invention, the order of the steps is not limited to the listed order. For those skilled in the art, variations in the order of the steps without creative effort are also within the scope of protection of this invention. Furthermore, two or more steps or actions can be performed simultaneously.

[0107] Finally, it should be noted that the specific embodiments described herein are merely illustrative examples of the invention and are not intended to limit the implementation of the invention. Those skilled in the art can make various modifications or additions to the described specific embodiments or use similar methods to replace them; it is neither necessary nor possible to exemplify all embodiments here. However, these obvious variations or modifications derived from the essential spirit of the invention still fall within the scope of protection of the invention, and interpreting them as any additional limitation would contradict the spirit of the invention.

Claims

1. 3-Amino-4-(2,4,5-trifluorophenyl)butyric acid borneol ester, characterized in that, It has a structure as shown in equation (I):

2. The method for preparing borneol ester of 3-amino-4-(2,4,5-trifluorophenyl)butyrate as described in claim 1, characterized in that, Includes the following steps: 3-((tert-butoxycarbonyl)amino)-4-(2,4,5-trifluorophenyl)butyric acid and borneol were subjected to a dehydration condensation reaction in the presence of a catalyst, followed by post-treatment to obtain borneol ester of 3-amino-4-(2,4,5-trifluorophenyl)butyric acid.

3. The preparation method according to claim 2, characterized in that, The molar ratio of 3-((tert-butoxycarbonyl)amino)-4-(2,4,5-trifluorophenyl)butyric acid to borneol is 0.8–1.5:

1.

4. The preparation method according to claim 2, characterized in that, The molar ratio of catalyst to borneol is 1 to 5:

1.

5. The preparation method according to claim 2, characterized in that, The catalyst is one or more of the DCC / DMAP system, EDC / DMAP system, and DIC / DMAP system.

6. The preparation method according to claim 2 or 5, characterized in that, The catalyst is a DCC / DMAP system; wherein the molar ratio of DCC to DMAP is 5 to 20:

1.

7. The preparation method according to claim 2, characterized in that, The dehydration condensation reaction is carried out in an organic solvent, which is one or more of dichloromethane, tetrahydrofuran, N,N-dimethylformamide, and acetonitrile.

8. The preparation method according to claim 2, characterized in that, The temperature for the dehydration condensation reaction is 10–40℃, and the reaction time is 1–10 h.

9. The preparation method according to claim 2, characterized in that, The post-processing includes: filtering after the reaction stops, washing and drying the obtained filtrate, dissolving it in a good solvent, then adding hydrogen chloride to remove the Boc group, filtering and removing the solvent, then adding a poor solvent to slurry to promote product precipitation, and finally filtering and drying to obtain a powdered solid.

10. The use of 3-amino-4-(2,4,5-trifluorophenyl)butyric acid borneol ester as described in claim 1 in the preparation of any of the following: Drugs that have a hypoglycemic effect; Health supplements with blood sugar lowering effects; Antidiabetic drugs.

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