Novel natural bornyl ester derivative as well as preparation method and application thereof

Abstract

The invention relates to the technical field of natural medicines, in particular to a novel natural bornyl ester derivative as well as a preparation method and application thereof. According to the invention, natural borneol is taken as a raw material, a series of natural borneol ester compounds with novel structures are designed and synthesized, and the natural borneol ester compounds are subjected to structural characterization and application research in the field of anti-inflammatory activity. The method has the characteristics of easily available raw materials, simplicity and convenience in operation and high yield, and can be used for quickly synthesizing a target compound. The bornyl ester derivative provided by the invention has remarkable pharmaceutical activity, and the unique alkyl structure fragment of natural borneol provides unique bidirectional regulation and protection effects for a novel medicine, so that the absorption and anti-inflammatory and analgesic effects of the medicine are remarkably enhanced.

Description

Technical Field

[0001] This invention relates to the field of natural medicine technology, specifically to a novel natural borneol ester derivative, its preparation method, and its application. Background Technology

[0002] Inflammation is a stress-induced immune response that occurs when the body is injured or infected, and it is a relatively common clinicopathological process. Many chronic and acute diseases are characterized by inflammation, including autoimmune diseases (such as rheumatoid arthritis and lupus), cardiovascular diseases, neurodegenerative diseases (such as Alzheimer's disease), various types of cancer, diabetes, inflammatory bowel disease, and age-related neurological disorders. If an excessive inflammatory response occurs in a patient, known as a "cytokine storm," it can cause damage to lung tissue and multiple organs, leading to progression from severe to critical illness and ultimately death.

[0003] Natural borneol is a natural stimulant that effectively promotes drug absorption. It also possesses analgesic, antibacterial, and anti-inflammatory properties. It is cool in nature, pungent and bitter in taste, and enters the heart, spleen, and lung meridians. It has the effects of opening the orifices and refreshing the mind, clearing heat and relieving pain. Natural borneol has a bidirectional regulatory and protective effect on the central nervous system: firstly, it has a bidirectional regulatory effect on the central nervous system, both calming the mind and refreshing the brain; secondly, it has a protective effect on the central nervous system. Furthermore, natural borneol can significantly inhibit the increase in peritoneal capillary permeability in mice induced by acetic acid, exhibiting anti-inflammatory effects; it can significantly prolong the time and duration of pain response induced by heat stimulation in mice, exhibiting analgesic effects.

[0004] Carboxylic acids, especially aryl propionic acid derivatives and other nonsteroidal anti-inflammatory drugs (NSAIDs), are a class of drugs with antipyretic and analgesic effects, and also have anti-inflammatory effects when administered at higher doses. However, these drugs are prone to causing side effects such as gastrointestinal bleeding and ulcers.

[0005] This invention aims to improve the pharmacokinetic properties of compounds, develop a broad-spectrum oral drug, and enhance its anti-inflammatory activity and in vivo efficacy. It utilizes the twinning principle to obtain a series of novel structures of natural borneol ester compounds. This development of safe and effective novel natural borneol ester anti-inflammatory drugs has significant theoretical and practical implications. Summary of the Invention

[0006] In view of this, the purpose of this invention is to provide a novel natural borneol ester derivative, its preparation method and application, so as to provide a novel natural borneol ester derivative with good anti-inflammatory effect.

[0007] To achieve the above objectives, the present invention provides a novel natural borneol ester derivative, the chemical structural formula of which is shown in Formula I:

[0008]

[0009] Wherein, R is one of benzene, benzene derivatives, naphthalene, or naphthalene derivatives.

[0010] Preferably, R is one of 2-fluoro-[1,1'-biphenyl], 4-benzoylphenyl, 4-isobutylphenyl, 6-methoxynaphth-2-yl, and 4-trifluoromethoxyphenyl.

[0011] Furthermore, the present invention also provides a method for preparing a novel natural borneol ester derivative, the specific preparation steps of which are as follows:

[0012] A carboxylic acid compound was placed in a solvent, and DMF was added under ice bath conditions. Oxaloyl chloride was added dropwise while stirring. After the addition was complete, the reaction was carried out for 30 minutes. The mixture was then concentrated under reduced pressure to obtain a concentrated solution of the acyl chloride compound. Natural borneol was then dissolved in dichloromethane, and triethylamine was added under ice bath conditions. The concentrated solution of the acyl chloride compound was then added, and the reaction was carried out at room temperature for 30 minutes. The mixture was then purified to obtain a novel natural borneol ester derivative.

[0013] Preferably, the carboxylic acid compound is an aromatic group containing a carboxylic acid substituent group or a substituted aromatic group.

[0014] Furthermore, the carboxylic acid compound is an arylpropionic acid compound.

[0015] Preferably, the oxalyl chloride can also be replaced by thionyl chloride.

[0016] Furthermore, when thionyl chloride is used to replace oxalyl chloride, the molar amount added is the same as the molar amount of oxalyl chloride.

[0017] Preferably, the solvent is one of dichloromethane, tetrahydrofuran, and carbon tetrachloride.

[0018] Preferably, the molar ratio of the carboxylic acid compound, oxalyl chloride, and natural borneol is 1:1.2-1.5:1-1.1.

[0019] Preferably, the amount of triethylamine added is twice the molar amount of the carboxylic acid compound.

[0020] Preferably, the triethylamine can also be replaced by the organic base diisopropylethylamine or the inorganic bases sodium carbonate or potassium carbonate.

[0021] Furthermore, when diisopropylethylamine is used to replace triethylamine, the molar amount added is the same as the molar amount of triethylamine.

[0022] Preferably, the natural borneol is derived from natural plant extracts, and its purity is required to be greater than 96.0%.

[0023] Furthermore, the present invention also provides a pharmaceutical composition, wherein the pharmaceutical composition uses a natural borneol ester derivative as the active ingredient or the main active ingredient, and is formulated into a pharmaceutically acceptable dosage form with a pharmaceutically acceptable carrier.

[0024] Preferably, the dosage form is any one of tablets, pellets, capsules, powder syrups, liquids, suspensions, lyophilized powder injections or injections, or nano-preparations.

[0025] Furthermore, the present invention also provides an application of a pharmaceutical composition in the preparation of an anti-inflammatory drug.

[0026] The beneficial effects of this invention are:

[0027] The novel natural borneol ester derivatives of this invention have significant pharmacological activity. The unique alkyl structural fragment of natural borneol provides unique bidirectional regulatory and protective effects for the novel drug, significantly enhancing drug absorption and anti-inflammatory and analgesic effects. It can effectively inhibit NO production in RAW264.7 cells, exhibiting significant anti-inflammatory activity, and its anti-inflammatory effect is superior to that of natural borneol and indomethacin.

[0028] This invention relates to novel natural borneol ester derivatives, utilizing the twinning principle to obtain a series of novel structures of natural borneol ester compounds. Furthermore, it has significant theoretical and practical implications for the development of safe and effective novel natural borneol ester anti-inflammatory drugs.

[0029] The novel natural borneol ester derivatives of the present invention are characterized by readily available raw materials, simple operation, and high yield, and can rapidly synthesize the target compound. Attached Figure Description

[0030] To more clearly illustrate the technical solutions in this invention or the prior art, the accompanying drawings used in the description of the embodiments or the prior art will be briefly introduced below.

[0031] Figure 1 The chemical structural formula of the natural borneol ester derivatives in this embodiment of the invention;

[0032] Figure 2 This is a synthetic route diagram of the natural borneol ester derivatives in the embodiments of the present invention. Detailed Implementation

[0033] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments.

[0034] Example 1: The carboxylic acid compound used in this example is an aryl propionic acid compound: flurbiprofen. The structural formula of the obtained natural borneol ester derivative is as follows:

[0035]

[0036] Its name is (4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl-2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionate, and the specific preparation steps are as follows:

[0037] Weigh 2.44 g (10 mmol 1.0 eq) of flurbiprofen and add it to 50 mL of dichloromethane. Under ice bath conditions, add 2-3 drops of DMF and, while stirring, add 1.91 g (15 mmol 1.5 eq) of oxaloyl chloride. After the addition is complete, transfer to room temperature and continue the reaction for 30 min. After the starting material is completely eliminated by TLC, concentrate the solution and add another 50 mL of dichloromethane to concentrate twice under reduced pressure to remove residual oxaloyl chloride, obtaining a concentrated solution of the acyl chloride compound. Then, weigh 1.62 g (10.5 mmol 1.05 eq) of natural borneol and dissolve it in 50 mL of dichloromethane. Under ice bath conditions, add 2.02 g of triethylamine (20 mmol) After stirring for 10 min, the concentrated acyl chloride compound was added dropwise to the reaction system. After complete addition, the mixture was allowed to rise to room temperature and reacted for 30 min until the starting material was completely eliminated. The resulting compound was purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether = 1:10) to obtain 3.32 g (8.73 mmol, yield 87.3%) of the target compound, which was then characterized.

[0038] 1H NMR (500MHz, CDCl3) δ7.57 (dq, J=8.2, 1.4Hz, 2H), 7.49-7.43 (m, 2H), 7.43-7.36 (m, 2H), 7.22-7.1 4(m,2H), 4.92(dddd,J=13.3,9.9,3.5,2.1Hz,1H), 3.80(qd,J=7.2,2.9Hz,1H), 2.36(dddd,J=14 .7,13.5,9.9,4.8,3.3Hz,1H),1.92-1.81(m,1H),1.78-1.64(m,3H),1.58(dd,J=7.2,2.0Hz,3H), 1.35-1.19(m,2H),1.11(ddd,J=12.2,9.5,4.5Hz,1H),0.88(s,3H),0.87(s,3H),0.85(s,3H),13C NMR (126MHz, CDCl3) δ174.16,160.64,135.57,130.68,130.65,128.97,128.95,128.44,127.63,123.60,123.57,115.36,115.1 7,80.52,48.81,47.87,45.29,44.80,36.70,27.94,27.09,19.67,18.85,18.05,13.53.HR-ESI-MSm / z:380.2205[M+H]+(Calcd forC 25 H 29 FO2:381.2205).

[0039] Example 2: The carboxylic acid compound used in this example is an aryl propionic acid compound: ketoprofen. The structural formula of the obtained natural borneol ester derivative is as follows:

[0040]

[0041] Its name is (4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl-2-(4-benzoylphenyl)propionate, and the specific preparation steps are as follows:

[0042] The difference from Example 1 is that the carboxylic acid compound used was ketoprofen, and the final yield of the target compound was 3.42 g (8.76 mmol, yield 87.6%), which was then characterized.

[0043] 1H NMR (500MHz, CDCl3) δ7.88-7.86(m,4H),7.76(d,J=8.7Hz,1H),7.67-7.63(m,2H),7.55(t,J =7.8Hz,2H),4.97(ddt,J=20.2,9.9,2.9Hz,1H),3.91(dt,J=7.4,3.7Hz,1H),2.40(tdt,J=13 .9,10.0,4.0Hz,1H),1.92-1.81(m,1H),1.78-1.64(m,3H),1.58(dd,J=7.2,2.0Hz,3H),1.35 -1.19(m,2H),1.11(ddd,J=12.2,9.5,4.5Hz,1H),0.88(s,3H),0.87(s,3H),0.85(s,3H),13C NMR (151MHz, CDCl3) δ196.47,174.17,141.25,141.08,137.60,132.48,131.55,130.04,130.04,129.25,128.87,128.48,128.32,1 28.32,80.44,47.86,45.82,45.67,44.82,36.74,19.69,18.86,18.16,18.15,13.53,13.41.HR-ESI-MSm / z:390.2204[M+H]+(Calcd for C 26 H 30 O3:391.2204).

[0044] Example 3: The carboxylic acid compound used in this example: ibuprofen (isobutylphenylpropionic acid), the structural formula of the obtained natural borneol ester derivative is as follows:

[0045]

[0046] Its name is (4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl-2-(4-isobutylphenyl)propionate, and the specific preparation steps are as follows:

[0047] The difference from Example 1 is that the carboxylic acid compound used was ibuprofen (isobutylphenylpropionic acid), and 3.05 g (8.91 mmol, yield 89.1%) of the target compound was finally obtained and characterized.

[0048] 1H NMR (500MHz, DCl3) δ7.31 (dd, J=8.1, 2.2Hz, 2H), 7.18 (dd, J=8.1, 2.2Hz, 2H), 5.02-4. 89(m,1H),3.86-3.76(m,1H),2.57-2.53(m,2H),2.39(dddd,J=21.5,13.9,10.3,5.5H z,1H),1.92(tdt,J=13.3,9.4,5.4Hz,2H),1.80-1.72(m,2H),1.62-1.56(m,4H),1.59 (d,J=2.3Hz,1H),0.99-0.95(m,6H),0.93(s,3H),0.91(s,3H),0.87-0.83(m,3H); 13C NMR (151MHz, CDCl3) δ174.90,140.37,138.01,129.23,129.23,127.26,127.26,80.07,47.85,45.10,45.10,44.87,3 6.68,30.28,27.10,20.16,19.73,18.90,18.04,18.01,13.54,13.32,11.42.HR-ESI-MSm / z:342.2610[M+H]+(Calcd for C 23 H 34 O2:343.2610).

[0049] Example 4: The carboxylic acid compound used in this example is 2-(6-methoxy-2-naphthyl)propionic acid, and the structural formula of the obtained natural borneol ester derivative is as follows:

[0050]

[0051] Its name is (4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl-2-(6-methoxynaphthalene-2-yl)propionate, and the specific preparation steps are as follows:

[0052] The difference from Example 1 is that the carboxylic acid compound used was 2-(6-methoxy-2-naphthyl)propionic acid, ultimately yielding 3.37 g (9.20 mmol, 92.0% yield) of the target compound, which was then characterized.

[0053] 1H NMR (500MHz, CDCl3) δ7.78-7.74(m,3H),7.51(dd,J=8.5,1.8Hz,1H), 7.21(ddJ=8.5,1.8Hz, 1H),7.17(d,J=1.8Hz,1H),4.98(ddt,J=20.6,10.0,2.3Hz,1H),3.94(s,3H),3.76-3.71(m, 1H), 2.45-2.32(m,1H),1.98-1.87(m,2H),1.861.69(m,2H),1.66(d,J=2.0Hz,3H),1.63-1. 50(m,1H),1.36-1.14(m,1H),0.95(s,3H),0.93(s,3H),0.91(s,3H),0.87-0.83(m,3H); 13C NMR (151MHz, CDCl3) δ174.87,157.65,133.73,129.32,129.30,127.05,126.46,126.44,125.99,118.96,105.68,80.25,55 .29,47.89,45.94,45.76,44.98,44.88,36.75,27.08,19.71,18.91,13.61,13.44.HR-ESI-MSm / z:366.2218[M+H]+(Calcd for C 24 H 30 O3:367.2218).

[0054] Performance testing

[0055] Anti-inflammatory activity experiment:

[0056] RAW264.7 (mouse mononuclear macrophage leukemia cells) were selected, and 100 μL of a concentration of 5 × 10⁶ cells was seeded into 96-well flat-bottom cell culture plates. 4Cells were cultured at 37°C, 5% CO2, and above 90% humidity for 24 hours. Afterward, 50 μL of prepared test compound solutions (100 μM, 50 μM, 25 μM, 12.5 μM, 6.25 μM, 3.125 μM) were added, and the cells were cultured under the same conditions. After 1 hour, 50 μL of prepared LPS solution (final concentration 500 ng / mL) was added. After 24 hours, 100 μL of supernatant was collected from each well into a new 96-well plate. Then, 100 μL (40 mg / mL) of Griess reagent was added to each well, and the absorbance was measured and recorded at 540 nm using a microplate reader. The NO inhibition rate was calculated using the following formula. The control group was indomethacin, and the negative control group was DMSO. The test compound was diluted 5 times at five different concentrations. The IC50 value of the test compound was calculated by plotting the test compound concentration on the x-axis and the inhibition rate on the y-axis.

[0057] Inhibition rate (%) = (C2-C1) / (C2-C0) × 100%;

[0058] Wherein, C0, C1, and C2 are the absorbance values ​​of the blank control group (without LPS), experimental group, and negative control group (with LPS), respectively, measured at 540 nm. The inhibition rate at each concentration was calculated and a compound concentration-inhibition rate curve was plotted. The half-maximal inhibitory concentration (IC50) of the compound on LPS-induced NO production from RAW264.7 was calculated. The results are shown in Table 1.

[0059] Table 1. Experimental data on anti-inflammatory effects

[0060] IC50±SDμM Example 1 13.51±1.11* Example 2 15.44±0.86* Example 3 18.21±1.10* Example 4 22.44±1.35* Natural borneol a 82.15±3.05 Indomethacin A 52.30±5.11

[0061] Among them, a is the positive control, *P<0.05 vs positive control group.

[0062] As can be seen from the data in Table 1, the above compounds can effectively inhibit the production of NO in RAW264.7 cells, showing significant anti-inflammatory activity, which is superior to the positive control natural borneol and indomethacin.

[0063] 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 the invention is limited to these examples; within the framework of the invention, 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 the different aspects of the invention as described above, which are not provided in detail for the sake of brevity.

Claims

1. A novel natural borneol ester derivative, characterized in that, The chemical structural formula of the natural borneol ester derivative is shown in Formula I: Wherein, R is one of benzene, benzene derivatives, naphthalene, or naphthalene derivatives.

2. The natural borneol ester derivative according to claim 1, characterized in that, R is one of 2-fluoro-[1,1'-biphenyl], 4-benzoylphenyl, 4-isobutylphenyl, 6-methoxynaphth-2-yl, and 4-trifluoromethoxyphenyl.

3. A method for preparing a novel natural borneol ester derivative according to any one of claims 1-2, characterized in that, The specific preparation steps are as follows: A carboxylic acid compound was placed in a solvent, and DMF was added under ice bath conditions. Oxaloyl chloride was added dropwise while stirring. After the addition was complete, the reaction was carried out for 30 minutes. The mixture was then concentrated under reduced pressure to obtain a concentrated solution of the acyl chloride compound. Natural borneol was then dissolved in dichloromethane, and triethylamine was added under ice bath conditions. The concentrated solution of the acyl chloride compound was then added, and the reaction was carried out at room temperature for 30 minutes. The mixture was then purified to obtain a novel natural borneol ester derivative.

4. The method for preparing the novel natural borneol ester derivative according to claim 3, characterized in that, The carboxylic acid compound is one of benzene, benzene derivatives, naphthalene, or naphthalene derivatives containing a carboxylic acid substituent group.

5. The method for preparing the novel natural borneol ester derivative according to claim 3, characterized in that, The solvent is one of dichloromethane, tetrahydrofuran, and carbon tetrachloride; the molar ratio of the carboxylic acid compound, oxalyl chloride, and natural borneol is 1:1.2-1.5:1-1.

1.

6. The method for preparing the novel natural borneol ester derivative according to claim 3, characterized in that, The natural borneol is derived from natural plant extracts, and its purity is required to be greater than 96.0%.

7. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a natural borneol ester derivative as the active ingredient or main active ingredient, formulated into a pharmaceutically acceptable dosage form with a pharmaceutically acceptable carrier.

8. The pharmaceutical composition according to claim 7, characterized in that, The dosage form is any one of tablets, pellets, capsules, powder syrups, liquids, suspensions, lyophilized powder injections or injections, or nano-preparations.

9. The use of a pharmaceutical composition according to any one of claims 7-8, characterized in that, Applications in the preparation of anti-inflammatory drugs.

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