A nicotinic acid biphenyl diester derivative, formulation and use

Abstract

This invention belongs to the field of pharmaceutical technology, specifically relating to a nicotinic acid biphenyl diester derivative, its formulation, and its uses. The structure of the nicotinic acid biphenyl diester derivative is as follows: ; R1, R2, R3, R4, and R5 are each independently selected from H, halogen, hydroxyl, C1-3 alkyl, C1-3 alkoxy, or cyclopropane; at least one of R1, R2, R3, R4, and R5 is R; R6, R7, R8, R9, and R... 10 Each is independently selected from H, halogen, hydroxyl, C1-3 alkyl, C1-3 alkoxy, or cyclopropane; R6, R7, R8, R9, R 10 At least one of them is R; R is; This invention has lipid-lowering, blood sugar-lowering and antibacterial effects, and the effect is good.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a nicotinic acid biphenyl diester derivative, its formulation, and its uses. Background Technology

[0002] Niacin is an essential nutrient for the human body, playing a vital role in promoting normal growth and development. It can enhance the excitability of the central nervous system, protect the cardiovascular system, prevent and alleviate severe migraines, and lower cholesterol and triglycerides, among other benefits.

[0003] Research progress on the synthesis and application of nicotinic acid, Wang Jia et al., Anhui Chemical Industry, 2019, 45: 13-15, discloses the uses of nicotinic acid. CN201210365392.2 discloses a method for manufacturing a class of derivatives containing nicotinic acid and acetylsalicylic acid curcumin ester and their uses, which have the effects of regulating blood lipids, lowering blood sugar, lowering blood pressure, anticancer, anti-inflammatory, antithrombotic, antiviral, neuroprotective and therapeutic effects on Alzheimer's disease. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide a nicotinic acid biphenyl diester derivative, preparation and use, which has lipid-lowering, blood sugar-lowering and antibacterial effects, and the effect is good.

[0005] This invention provides a nicotinic acid biphenyl diester derivative, the structure of which is as follows: ;

[0006] R1, R2, R3, R4, and R5 are each independently selected from H, halogen, hydroxyl, C1-3 alkyl, C1-3 alkoxy, or cyclopropane; at least one of R1, R2, R3, R4, and R5 is R.

[0007] The R6, R7, R8, R9, R 10 Each is independently selected from H, halogen, hydroxyl, C1-3 alkyl, C1-3 alkoxy, or cyclopropane; R6, R7, R8, R9, R 10 At least one of them is R;

[0008] R is .

[0009] Preferably, one of R1, R2, R3, R4, and R5 is R; R6, R7, R8, R9, and R 10 One of them is R.

[0010] Preferably, R1, R2, R3, R4, and R5 are each independently selected from H; one of R1, R2, R3, R4, and R5 is R; R6, R7, R8, R9, and R 10Each is independently selected from H; R6, R7, R8, R9, R 10 One of them is R.

[0011] Preferably, the nicotinic acid biphenyl diester derivative is 2,4′-nicotinic acid biphenyl diester, 3,4′-nicotinic acid biphenyl diester, 4,4′-nicotinic acid biphenyl diester, 2,3′-nicotinic acid biphenyl diester, 3,3′-nicotinic acid biphenyl diester or 2,2′-nicotinic acid biphenyl diester.

[0012] Preferably, the nicotinic acid biphenyl diester derivative is 3,4′-nicotinic acid biphenyl diester.

[0013] This invention provides a formulation comprising the aforementioned nicotinic acid biphenyl diester derivative.

[0014] Preferably, the dosage form of the preparation is tablets, capsules, pills, granules, syrups, emulsions, or suspensions.

[0015] This invention provides a use of the nicotinic acid biphenyl ester derivative, which is used to prepare lipid-regulating drugs.

[0016] This invention provides a use of the nicotinic acid biphenyl ester derivative, which is used to prepare a hypoglycemic drug.

[0017] This invention provides a use of the nicotinic acid biphenyl diester derivative, which is used to prepare antibacterial drugs.

[0018] The method for preparing the nicotinic acid biphenyl diester derivative of the present invention involves reacting the biphenyl hydroquinone and its derivative with nicotinic acid in a solvent at 55-80°C for 2-20 hours to obtain the target product. The solvent is thionyl chloride or acetyl chloride.

[0019] The nicotinic acid biphenyl diester derivative is reacted with an acid at 5-90°C to obtain the salt of the compound of the present invention, wherein the acid is hydrochloric acid, hydrobromic acid or hydroiodic acid, preferably hydrochloric acid.

[0020] The beneficial effects of this invention are that the invention has conducted experiments on the lipid-regulating, blood glucose-lowering, and antibacterial properties of various compounds. The experimental results show that compounds 101, 102, 104, or 105 can significantly reduce plasma LDL-C levels and also have a certain reducing effect on TG and TC; at the same time, they also have the effect of increasing HDL-C, and their efficacy is comparable to that of lovastatin.

[0021] Compounds 102, 103, 104, or 106 significantly reduced fasting blood glucose levels in db / db mice, with efficacy comparable to metformin.

[0022] Compounds 102, 103, 104, or 105 exhibit significant antibacterial activity.

[0023] This invention also included an acute toxicity experiment, in which mice were administered a single high dose of compounds 101, 105, and 106 via gavage. Behavioral activity and the degree of toxic reaction were continuously observed. At the end of the experiment, the mice were euthanized and dissected to obtain toxicity data for compounds 101, 105, and 106. After 14 days of continuous observation, no significant behavioral abnormalities or deaths were observed in the mice. The highest dose set in the experiment, 500 mg / kg, and doses below this level showed no significant toxicity to the mice.

[0024] Pharmacological experiments have demonstrated that the compounds of this invention have varying degrees of lipid-regulating, blood sugar-lowering, and antibacterial effects, and exhibit low toxicity.

[0025] Therefore, the compounds and their salts of the present invention can be used to prepare drugs for regulating blood lipids, lowering blood sugar, and antibacterial purposes.

[0026] The compounds of the present invention can be administered to patients in need of treatment in the form of a composition comprising a therapeutically effective amount of the compounds of the present invention, their salts, and a pharmaceutically acceptable carrier, said carrier comprising a diluent such as water, a filler such as starch, a wetting agent such as glycerin, a binder such as a cellulose derivative, etc., and prepared into tablets, capsules, pills, granules, syrups, emulsions, suspensions, and solutions by methods known in the art, administered conventionally, preferably orally, at a dose of 0.001 to 75 mg / kg body weight.

[0027] The compounds of this invention possess excellent lipid-regulating, blood sugar-lowering, and antibacterial effects, with low toxicity. They are easy to prepare, suitable for industrial production, and can meet the needs of the pharmaceutical field. The compounds of this invention have advantages such as high efficacy and low toxicity. Detailed Implementation

[0028] Example 1

[0029] Preparation of 2,4′-nicotinic acid biphenyl diester (code 101):

[0030] 0.01 mol of 2,4′-biphenyldiol was reacted with 0.03 mol of nicotinic acid in 10 mL of thionyl chloride at 72 °C for 9 hours. The mixture was then transferred to an ice-water bath, extracted three times with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and finally purified by column chromatography with ethyl acetate:petroleum ether = 1:3 to obtain the target product, 2,4′-nicotinic acid biphenyl diester (code 101). Relevant data are as follows:

[0031] MS (EI, 70ev) m / z: 396;Anal. Calcd. for C24 H 16 NO4: C, 72.72, H, 4.06, N7.07; Found C, 72.71, H, 4.07, N 7.06.

[0032] Example 2

[0033] Preparation of 3,4′-nicotinic acid biphenyl diester (code 102):

[0034] 0.01 mol of 3,4′-biphenylhydrazine was reacted with 0.03 mol of nicotinic acid in 10 mL of thionyl chloride at 72 °C for 9 hours. The mixture was then poured into an ice-water bath, extracted three times with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and finally purified by column chromatography with ethyl acetate:petroleum ether = 1:3 to obtain the target product, 4,4′-nicotinic acid biphenyl diester (code 102). Relevant data are as follows:

[0035] MS (EI, 70ev) m / z: 396;Anal. Calcd. for C 24 H 16 NO4: C, 72.72, H, 4.06, N7.07; Found C, 72.72, H, 4.06, N 7.07.

[0036] Example 3

[0037] Preparation of 4,4′-nicotinic acid biphenyl diester (code 103):

[0038] 0.01 mol of 4,4′-biphenylhydrazine was reacted with 0.03 mol of nicotinic acid in 10 mL of thionyl chloride at 72 °C for 9 hours. The mixture was then poured into an ice-water bath, extracted three times with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and finally purified by column chromatography with ethyl acetate:petroleum ether = 1:3 to obtain the target product, 4,4′-nicotinic acid biphenyl diester (code 103). Relevant data are as follows:

[0039] MS (EI, 70ev) m / z: 396;Anal. Calcd. for C 24 H 16 NO4: C, 72.72, H, 4.06, N7.07; Found C, 72.72, H, 4.07, N 7.06.

[0040] The reaction route is as follows:

[0041] ,

[0042] The substituent mentioned above is H.

[0043] Example 4

[0044] Preparation of 2,3′-nicotinic acid biphenyl diester (code 104):

[0045] 0.01 mol of 2,3′-biphenylhydrazine was reacted with 0.03 mol of nicotinic acid in 10 mL of thionyl chloride at 72 °C for 9 hours. The mixture was then transferred to an ice-water bath, extracted three times with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and finally purified by column chromatography with ethyl acetate:petroleum ether = 1:3 to obtain the target product, 2,3′-nicotinic acid biphenyl diester (code 104). Relevant data are as follows:

[0046] MS (EI, 70ev) m / z: 396;Anal. Calcd. for C 24 H 16 NO4: C, 72.72, H, 4.06, N7.07; Found C, 72.71, H, 4.06, N 7.06.

[0047] The reaction route is as follows:

[0048] ,

[0049] The substituent mentioned above is H.

[0050] Example 5

[0051] Preparation of 3,3′-nicotinic acid biphenyl diester (code 105):

[0052] 0.01 mol of 3,3′-biphenylhydrazine was reacted with 0.03 mol of nicotinic acid in 10 mL of thionyl chloride at 72 °C for 9 hours. The mixture was then transferred to an ice-water bath, extracted three times with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and finally purified by column chromatography with ethyl acetate:petroleum ether = 1:3 to obtain the target product, 3,3′-nicotinic acid biphenyl diester (code 105). Relevant data are as follows:

[0053] MS (EI, 70ev) m / z: 396;Anal. Calcd. for C 24 H 16 NO4: C, 72.72, H, 4.06, N7.07; Found C, 72.71, H, 4.06, N 7.07.

[0054] The reaction route is as follows:

[0055] ,

[0056] The substituent mentioned above is H.

[0057] Example 6

[0058] Preparation of 2,2′-nicotinic acid biphenyl diester (code 106):

[0059] 0.01 mol of 2,2′-biphenylhydrazine was reacted with 0.03 mol of nicotinic acid in 10 mL of thionyl chloride at 72 °C for 9 hours. The mixture was then transferred to an ice-water bath, extracted three times with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and finally purified by column chromatography with ethyl acetate:petroleum ether = 1:3 to obtain the target product, 2,2′-nicotinic acid biphenyl diester (code 106). Relevant data are as follows:

[0060] 2,2′-Nicotinic acid biphenyl diester (code 106): MS (EI, 70ev) m / z: 396; Anal. Calcd. for C 24 H 16 NO4: C, 72.72, H, 4.06, N 7.07; Found C, 72.72, H, 4.06, N 7.06.

[0061] Example 7

[0062] Using a HITACHI 7060 fully automated biochemical analyzer, based on enzymatic detection technology, the susceptibility of the compounds of this invention to ApoE was systematically evaluated. - / - The lipid-lowering effect of gene knockout atherosclerosis model mice was investigated using the following method: 8-week-old male ApoE mice were selected. - / - In mice, a atherosclerosis model was successfully established by administering a fat emulsion for 12 weeks and measuring plasma total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels (LDL-C ≥ 10 mmol / L) through blood collection from the orbital venous plexus.

[0063] Mice that successfully modeled the disease were randomly divided into a model control group and various compound intervention groups. The compound intervention groups received 50 mg / kg / day (carboxymethyl cellulose sodium suspension prepared by ultrasonic dispersion) via gavage and maintained a high-fat diet. The model control group received an equal volume of 0.5% carboxymethyl cellulose solution and maintained a high-fat diet. The lovastatin group received 20 mg / kg / day (carboxymethyl cellulose sodium suspension prepared by ultrasonic dispersion) via gavage and maintained a high-fat diet. All groups continued treatment for 4 weeks. Plasma samples were collected after a 12-hour fast following the last administration. Total cholesterol (TC) was measured using the cholesterol oxidase-peroxidase method (COD-PAP method, detection wavelength 500 nm) on a HITACHI 7060 analyzer. LDL-C and high-density lipoprotein cholesterol (HDL-C) were measured using a direct method (homogeneous enzymatic method, detection wavelength 546 nm). Triglycerides (TG) were measured using the glycerol phosphate oxidase method (GPO-PAP method, detection wavelength 546 nm). One-way ANOVA was performed using SPSS 26.0 software. ANOVA was used for intergroup comparisons, and Tukey's test was used. A p-value < 0.05 was considered statistically significant. Specific experimental results are shown in Table 1.

[0064] Table 1. Effects of various compounds on atherosclerotic mice (ApoE) - / - The effect of blood lipids

[0065]

[0066] Compared with the model control group: * indicates P < 0.05.

[0067] Among them, TC is total cholesterol, TG is triglycerides, LDL-C is low-density lipoprotein cholesterol, and DL-C is low-density lipoprotein cholesterol.

[0068] The experimental results show that compounds 101, 102, 104, and 105 can significantly reduce plasma LDL-C levels and also have a certain reducing effect on TG and TC; at the same time, they also have the effect of increasing HDL-C, and their efficacy is comparable to that of lovastatin.

[0069] Example 8

[0070] The effects of the compound of this invention on fasting blood glucose in db / db mice were systematically evaluated. The specific methods are as follows: After one week of acclimatization feeding, fasting blood glucose levels were measured. db / db mice were randomly divided into groups of 10 mice per group. The groups included: a model control group, a metformin group (50 mg / kg), a compound group (50 mg / kg), and a normal control group (age-matched normal mice). Each group was administered the compound once daily by gavage for 4 weeks. The normal control group and the model group were given an equal volume of 0.5% carboxymethyl cellulose solution. After 4 weeks, blood samples were collected from the tail vein of the mice. Approximately 50 μL of fresh blood was added to test strips, and glucose levels were measured using a glucometer. The results are shown in Table 2.

[0071] Table 2 Fasting blood glucose (mmol / L) after 4 weeks of intervention

[0072]

[0073] Compared with the model control group: * indicates P < 0.05.

[0074] The experimental results show that compounds 102, 103, 104, and 106 can significantly reduce fasting blood glucose in db / db mice, and their efficacy is comparable to that of metformin.

[0075] Example 9

[0076] The antibacterial effect of the compound of this invention against three tested bacteria—Escherichia coli, Pseudomonas aeruginosa ATCC27853, and Staphylococcus aureus ATCC6538—was determined using the filter paper disc method. A solution of the compound of this invention with a mass concentration of 50 mg / mL was prepared. Dimethyl sulfoxide (DMSO) was used as a negative control, and gentamicin susceptibility testing discs, typically containing 10 μg of the drug per disc, were used as a positive control. Double-layered sterilized filter paper discs (d = 6 mm) were placed between the culture plates containing different bacterial species. 10 μL of the sample solution (containing 0.5 mg of the drug) was added using a pipette, and the plates were incubated at 37°C for 24 h. Three parallel experiments were performed for each sample, and the diameter of the inhibition zone was measured using the cross-sectional method.

[0077] Table 3 Antibacterial activity of the compounds

[0078]

[0079] The experimental results showed that compounds 102, 103, 104, and 105 had antibacterial effects comparable to gentamicin. Compound 105 exhibited the strongest inhibitory effect against *Escherichia coli* and *Pseudomonas aeruginosa*, while compound 103 showed the best inhibitory effect against *Staphylococcus aureus*. Compounds 101 and 106, however, showed no significant antibacterial effects.

[0080] Example 10

[0081] Tablets containing nicotinic acid biphenyl diester derivatives have the following composition:

[0082] Nicotinic acid biphenyl diester derivative 75mg

[0083] Magnesium stearate 6mg

[0084] 4mg talc

[0085] Lactose 25mg

[0086] Starch 40mg.

[0087] Example 11

[0088] Capsules containing nicotinic acid biphenyl diester derivatives have the following composition:

[0089] Nicotinic acid biphenyl diester derivative 60mg

[0090] Magnesium stearate 10mg

[0091] 10mg talc

[0092] 30mg lactose

[0093] Starch 30mg

[0094] Polyvinylpyrrolidone 10mg.

[0095] Those skilled in the art should understand that the discussion of any of the above embodiments is merely exemplary and is not intended to imply that the scope of protection of this application is limited to these examples; within the framework of this application, the technical features of the above embodiments or different embodiments can also be combined, the steps can be implemented in any order, and there are many other variations of different aspects of one or more embodiments of this application as described above, which are not provided in detail for the sake of brevity.

[0096] One or more embodiments in this application are intended to cover all such substitutions, modifications, and variations that fall within the broad scope of this application. Therefore, any omissions, modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of one or more embodiments in this application should be included within the protection scope of this application.

Claims

1. A nicotinic acid biphenyl diester derivative, characterized in that, The nicotinic biphenyl diester derivative is 2,4′-nicotinic biphenyl diester, 3,4′-nicotinic biphenyl diester, 4,4′-nicotinic biphenyl diester, 2,3′-nicotinic biphenyl diester, 3,3′-nicotinic biphenyl diester or 2,2′-nicotinic biphenyl diester.

2. The nicotinic acid biphenyl diester derivative as described in claim 1, characterized in that, The nicotinic acid biphenyl diester derivative is 3,4′-nicotinic acid biphenyl diester.

3. A formulation characterized in that, Including the nicotinic acid biphenyl diester derivative as described in any one of claims 1-2.

4. The formulation as described in claim 3, characterized in that, The dosage form of the preparation is tablets, capsules, pills, granules, syrups, emulsions, or suspensions.

5. Use of a nicotinic acid biphenyl diester derivative as described in any one of claims 1-2, characterized in that, The nicotinic acid biphenyl diester derivative is used to prepare lipid-lowering drugs.

6. Use of a nicotinic acid biphenyl diester derivative as described in any one of claims 1-2, characterized in that, The nicotinic acid biphenyl diester derivative is used to prepare hypoglycemic drugs.

7. Use of a nicotinic acid biphenyl diester derivative as described in any one of claims 1-2, characterized in that, The nicotinic acid biphenyl diester derivative is used to prepare antibacterial drugs.

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