Compound salt commiphor furan lactone, its preparation method and pharmaceutical composition and its use in analgesia, anti-inflammatory

Abstract

The application belongs to the field of medicine, and discloses a compound, rhusenol, a preparation method and a pharmaceutical composition of the compound, and an application of the compound in analgesia and anti-inflammation. The rhusenol is shown as formula (I), has analgesic and anti-inflammatory effects, prolongs the reaction time of a mouse in pain caused by light heat induction, and improves the effect of tinea urticae oil-induced mouse ear swelling. The rhusenol can relieve and / or treat diseases related to analgesic and anti-inflammatory effects, such as rheumatoid arthritis, osteoarthritis, rheumatic arthritis, gouty arthritis, and lupus erythematosus syndrome.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to the compound sumac furanolactone, its preparation method, pharmaceutical compositions, and its use in analgesia and anti-inflammation. Background Technology

[0002] sumac ( Rhus chinensis Mill. belongs to the genus *Rhus* of the family Anacardiaceae. Rhus This genus comprises approximately 250 species worldwide, with 6 species and 3 varieties found in my country. They mostly grow in limestone mountain shrublands and sparse forests at altitudes of 350-2300 meters, and are widely distributed throughout China (except Heilongjiang, Jilin, Liaoning, Xinjiang, and Qinghai). *Rhus chinensis* (Salix salsa) R. Chinese As a medicinal plant, *Rhus chinensis* (Salvia splendens) was first recorded in the *Kaibao Materia Medica* of the Song Dynasty, and is currently included in publications such as the *National Compendium of Chinese Herbal Medicine* and the *Dictionary of Chinese Materia Medica*. *Rhus chinensis* has the effects of clearing heat and detoxifying, dispersing blood stasis and stopping bleeding, and is commonly used for colds with fever, bronchitis, cough with hemoptysis, diarrhea, dysentery, and hemorrhoidal bleeding. Modern pharmacological studies have shown that *Rhus chinensis* possesses antiviral, anti-inflammatory, analgesic, antioxidant, cytotoxic, and anti-ulcer pharmacological activities.

[0003] Pain is a protective response of the body to noxious stimuli, often accompanied by emotions such as fear, tension, and anxiety. Pain is also a symptom of certain diseases, causing distress. Severe pain, in addition to sensory suffering and emotional unease, can lead to physiological dysfunction, insomnia, and even induce shock, endangering life. Modern medicine has listed pain as the fifth vital sign after respiration, pulse, blood pressure, and body temperature. Therefore, the appropriate use of analgesics in clinical practice to relieve severe pain and prevent shock is necessary and plays a significant role in disease treatment and trauma care.

[0004] Inflammation is a bodily response to injury, a mechanism used by higher animals to combat infection and trauma. It clears harmful factors and damaged tissues, repairing them and restoring them to normal. Many factors can cause inflammation, such as microorganisms, metabolic products, harmful chemicals, abnormal immune responses, and dead tissue. Common symptoms of inflammation include redness, swelling, heat, pain, and impaired function. The body's inflammatory response can both fight off external invasions and cause internal damage. If the inflammatory response exceeds a certain limit, it can lead to various diseases. Therefore, the appropriate use of anti-inflammatory drugs is crucial for relieving symptoms and eliminating the underlying cause.

[0005] The compound involved in this study is a novel compound that has been found to have analgesic and anti-inflammatory activities. To date, no patents or literature reports have been found on the above research results.

[0006] The purpose of this invention is to make full use of my country's unique plant resources, conduct in-depth research and development, and search for compounds with unique chemical structures, high activity, and low toxicity, in order to provide new analgesic and anti-inflammatory drugs for clinical research to alleviate and / or treat analgesic and anti-inflammatory related diseases such as rheumatoid arthritis, osteoarthritis, rheumatic arthritis, gouty arthritis, lupus syndrome, etc. Summary of the Invention

[0007] The problem addressed by this invention is to provide the compound sumata furanolactone, its preparation method, pharmaceutical compositions, and their uses in analgesia and anti-inflammation. To solve the technical problem of this invention, the following technical solution is provided:

[0008] The first aspect of the present invention is to provide the compound sumata furanolactone and its pharmaceutically acceptable salt, characterized in that: the chemical structural formula is as follows:

[0009]

[0010] Rhus chinensis furanolactone structure

[0011] The second aspect of the present invention is to provide a method for preparing the compound sumata furanolactone described in the first aspect, characterized in that:

[0012] 1) The dried roots of Rhus chinensis were extracted twice by heating and refluxing with 95% ethanol-water for 2 hours each time. The extracts were combined and the ethanol was recovered under reduced pressure to obtain the extract.

[0013] 2) The extract was separated using a Diaion HP-20 macroporous resin column (140 × 15 cm) and eluted with water, 10% ethanol-water, 30% ethanol-water, 50% ethanol-water, 70% ethanol-water and 95% ethanol-water respectively. The eluents were then evaporated to dryness.

[0014] 3) The macroporous resin eluted with 95% water was subjected to silica gel column chromatography with a gradient elution of petroleum ether-ethyl acetate (98:2 – 50:50). After combining the fractions, six fractions (Fr.1 to Fr.6) were obtained. Fraction Fr.6 was subjected to silica gel column chromatography with petroleum ether:ethyl acetate elution, followed by reversed-phase C24 chromatography. 18 Semi-preparative column (250 × 9.4 mm, 5) m m; YMC-C 18 Purification was performed using a column (flow rate 12 mL / min) with acetonitrile:0.1% formic acid / water as the mobile phase (85:15). R The compound was obtained after 21 min.

[0015] A third aspect of the present invention is to provide a pharmaceutical composition, characterized in that: the pharmaceutical composition contains the compound furanolol described in the first aspect, its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier or excipient.

[0016] The fourth aspect of the present invention is to provide the use of the compound furanolol described in the first aspect and its pharmaceutically acceptable salt in the preparation of anti-inflammatory or analgesic drugs.

[0017] Beneficial technical effects:

[0018] The compound described in this invention, sumac furanolactone, is a novel compound, and experiments have demonstrated that it possesses anti-inflammatory and analgesic pharmacological activities. Attached Figure Description

[0019] Figure 1 Structure of the compound sumac furanolactone

[0020] Figure 2 High-resolution mass spectrum of the compound sumac furanolactone

[0021] Figure 3 UV spectrum of the compound sumac furanolactone

[0022] Figure 4 IR spectrum of the compound sumac furanolactone

[0023] Figure 5 The compound sumac furanolactone 1 1H NMR (400 MHz, CDCl3) spectrum

[0024] Figure 6 The compound sumac furanolactone 13 C NMR (100 MHz, CDCl3) spectrum

[0025] Figure 7 HSQC spectrum of the compound sumac furanolactone

[0026] Figure 8 HMBC spectrum of the compound sumac furanolactone

[0027] Figure 9 NOE spectrum of the compound sumac furanolactone

[0028] Figure 10 Three-dimensional simulation diagram (a) of the compound sumac furanolactone: the double bond C3-C10 configuration is as follows E (b): The double bond C3-C10 configuration is Z Detailed Implementation

[0029] Example: Isolation of the compound sumac furanolactone

[0030] 20 kg of dried roots of *Rhus chinensis* were extracted twice by heating and reflux with 95% ethanol-water for 2 hours each time. The extracts were combined, and the ethanol was recovered under reduced pressure to obtain 2.1 kg of extract. The extract was separated using a Diaion HP-20 macroporous resin column (140 × 15 cm), eluted with water, 10% ethanol-water, 30% ethanol-water, 50% ethanol-water, 70% ethanol-water, and 95% ethanol-water, respectively. The eluents were evaporated to dryness. The 95% ethanol-water eluent (320 g) from the macroporous resin was subjected to silica gel column chromatography with a gradient elution of petroleum ether-ethyl acetate (98:2–50:50). The fractions were combined to obtain 6 fractions (Fr.1 to Fr.6). The Fr.6 fraction (7 g) was subjected to silica gel column chromatography with petroleum ether:ethyl acetate elution, followed by reversed-phase C24 chromatography. 18 Preparation column (250 × 20 mm, 5) m m;YMC-C 18 Purification was performed using a column (12 mL / min) with acetonitrile:0.1% formic acid / water (85:15) as the mobile phase, at t R =21 min yielded the compound sumata furanolactone (3 g).

[0031] The compound, sumac furanolactone, is an orange amorphous powder. UV l max 369 (3.91), 262 (3.56), 237 (3.65), and 204 (4.28) nm indicate absorption bands of long conjugated aromatic compounds in the structure. IR n max 3454, 3250cm -1 The absorption peak is for hydroxyl groups, at 1726 cm⁻¹. -1 The peak is the carbonyl absorption peak at 1616 cm⁻¹. -1 The absorption peak for the benzene ring is at 1480 cm⁻¹. -1 The presence of a double bond is indicated. A quasi-molecular ion peak is given by high-resolution mass spectrometry (-HR-ESI-MS). m / z 529.2960 [MH] - (calcd. forC) 34 H 41 O5, 529.2959), the molecular formula is determined to be C 34 H 42 O5 has an unsaturation degree of 14.

[0032] 1 H-NMR spectrum (in CDCl3, 400 MHz, dppm): There are two meta-coupled benzene ring hydrogen signals in the low field region. d H 7.77 (1H, d, J = 2.8 Hz, H-5) and d H 6.73 (1H, d, J = 2.8 Hz, H-7), a single peak hydrogen signal of a double bond in d H 7.31 (1H, s, H-10), two ortho-coupled furan ring hydrogen signals in d H 6.80 (1H, d, J = 3.2 Hz, H-12) and d H 6.49 (1H, d, J = 3.2 Hz, H-13), the multiplet hydrogen signal of 4 non-conjugated double bonds in d H 5.32 (1H, m, H-2′) and d H 5.09 (3H, m, H-6′, H-10′, H-14′); a single-peak methylene signal exists in the high-field region. d H 4.80 (2H, s, H-15), a set of bimodal methylene hydrogen signals at d H 3.35 (2H, d, J = 7.2 Hz, H-1′), 6 sets of methylene multiplet hydrogen signals in d H 2.11–1.94 (12H, m, H-4′, H-5′, H-8′, H-9′, H-12′, H-13′), 5 groups of broad single-peak hydrogen signals of methyl groups in d H 1.73 (3H, br s, H-19′), 1.66 (3H, br s, H-16′), 1.59 (3H, br s, H-18′), 1.58 (6H, br s, H-17′, H-20′).

[0033] 13 C-NMR (in CDCl3, 100 MHz, d The ppm spectrum showed 34 carbon signals, of which 21 carbon signals were present in the low field region: 1 ester carbonyl carbon signal ( d C170.8), 4 furan ring carbon signals ( d C 157.7, 151.5, 121.6, 112.0), 6 carbon signals of the benzene ring ( d C 152.5, 146.5, 125.7, 122.2, 118.1, 109.1), 10 double bond carbon signals ( d C 137.7, 135.3, 135.0, 131.4, 124.5, 124.3, 124.1, 122.6, 120.7, 118.5; 8 methylene carbon signals were observed in the high-field region ( d C 57.5, 39.8×3, 27.7, 26.9, 26.8, 26.7, and 5 methyl carbon signals ( d C 25.8, 17.8, 16.4, 16.2, 16.1).

[0034] The above signal is basically consistent with that of the known compound cannabifolactone A, the only difference being that the compound sumata furanolactone has an additional geraniol geraniol fragment at C-8.

[0035] HSQC spectral correlation analysis determined the correspondence between carbon and hydrogen.

[0036] HMBC spectrum shows H-1′ ( d H 3.35) and C-9 ( d C 146.5), C-3′ ( d C 137.7) and C-7 ( d C 118.1) is related, indicating that the geraniol group is connected to the C-8 position of the B ring; H-10 ( d H 7.31) and C-2 ( d C 170.8), C-4 ( d C 122.2) and C-12 ( d C (121.6) Related to this, it is explained that the 2-hydroxymethylfuran group is connected to the A ring at the C-3 position via a carbon-carbon double bond through the C-10 position.

[0037] NOE spectrum shows irradiation of H-5 ( d H 7.77), then H2-15 ( d H4.80) has gain, similarly, irradiation of H2-15 ( d H 4.80), then H-5 ( d H 7.77) also has gain. In the ChemDraw 3D simulation, when the double bond configuration is E When the distance between H-5 and H2-15 is 3.2 Å, NOE exists; when the double bond configuration is Z At that time, the distance between H-5 and H2-15 was 7.8 Å, and there was no NOE. Therefore, it can be determined that the double bond C3-C10 is... E The configuration is consistent with the double bond configuration of the known compound cannabifolactone A.

[0038] In conclusion, the compound has been identified as sumac furanolactone.

[0039] Table 1. Compounds of sumac furanolactone 1 H NMR and 13 C NMR data

[0040]

[0041] Pharmacological experiments

[0042] Experimental Example 1: Effect of the compound sumac furanolactone on photothermal-induced pain in mice

[0043] Experimental Methods: Male Kunming mice, weighing 18–23 g, were administered the compound sumatafructolide, dissolved in physiological saline, via subcutaneous injection at doses of 50 mg / kg, 100 mg / kg, and 200 mg / kg. The control group received the same dose of physiological saline. One hour after administration, an analgesia experiment was conducted using a photosensitizer. The pain response time (in seconds) was recorded based on the tail-flick response of the mice, and the prolongation rate of the pain response time was calculated as follows: Prolongation rate (%) = (Average tail-flick time in the administered group - Average tail-flick time in the control group) / Average tail-flick time in the administered group × 100%.

[0044] Experimental results:

[0045] The results showed that the compound sumata furanolide had a significant analgesic effect in vivo: subcutaneous injection of 200 mg / kg of sumata furanolide prolonged the pain response time by 48.55% compared with the blank control group, indicating that this compound can significantly prolong the pain response time in mice. p <0.05), exhibiting significant in vivo analgesic activity (as shown in Table 2).

[0046] Table 2. Effects of the compound sumac furanolactone on photothermal-induced pain response in mice.

[0047]

[0048] Experimental Example 2: Effect of the compound sumac furanolactone on croton oil-induced otitis media in mice

[0049] Experimental Methods: Male Kunming mice, weighing 18–23 g, were administered 50 mg / kg and 100 mg / kg of the compound sumammonia furanolide subcutaneously in physiological saline. The control group received the same dose of physiological saline. One hour after administration, 50 μL of a 4% croton oil solution was applied to one ear to induce otitis. Four hours later, the mice were euthanized by dislocation, and both ears were cut off along the auricle. Circular ear pieces were punched at the same location (along the ear margin) in both ears using an 8 mm diameter punch. The weight difference (mg) between the left and right ear pieces was recorded. Ear swelling inhibition rate was calculated as follows: Ear swelling inhibition rate (%) = (Average ear swelling in the model group - Average ear swelling in the administered group) / Average ear swelling in the model group × 100%.

[0050] Experimental results:

[0051] The results showed that the compound sumata furanolide significantly improved ear swelling in a mouse model of croton oil-induced otitis media: Subcutaneous injection of 100 mg / kg of sumata furanolide inhibited ear swelling by 44.03% compared to the control group, indicating that this compound significantly improved the degree of ear swelling in the croton oil-induced mouse model of otitis media. p <0.05), exhibiting significant in vivo anti-inflammatory activity (as shown in Table 3).

[0052] Table 3. Inhibition of ear swelling in a croton oil-induced mouse otitis model by the compound sumac furanolactone.

[0053]

[0054] In conclusion, the compound sumac furanolactone can significantly inhibit photothermal-induced pain response in mice and croton oil-induced otitis in mice, indicating that it has significant analgesic and anti-inflammatory activities.

Claims

1. A compound as shown in formula (I) and a pharmaceutically acceptable salt thereof, characterized in that: （I）。 2. The method for preparing the compound according to claim 1, characterized in that: 1) The dried roots of Rhus chinensis were extracted twice by heating and refluxing with 95% ethanol-water for 2 hours each time. The extracts were combined and the ethanol was recovered under reduced pressure to obtain the extract. 2) The extract was separated using a Diaion HP-20 macroporous resin column (140 × 15 cm). The extract was eluted with water, 10% ethanol-water, 30% ethanol-water, 50% ethanol-water, 70% ethanol-water and 95% ethanol-water respectively. The eluents were then evaporated to dryness. 3) The macroporous resin eluted with 95% ethanol-water was subjected to silica gel column chromatography, eluted with a gradient of petroleum ether-ethyl acetate (98:2 – 50:50). The fractions were combined to obtain six fractions, numbered Fr.1 to Fr.

6. Fraction Fr.6 was subjected to silica gel column chromatography, eluted with petroleum ether:ethyl acetate, and then subjected to reversed-phase C24 chromatography. 18 Semi-preparative column, column size 250 × 9.4 mm, column particle size 5. μ m, column model is YMC-C 18 Purification was performed using a column at a flow rate of 12 mL / min, with an acetonitrile:0.1% formic acid aqueous solution as the mobile phase and an elution ratio of 85:

15. R =21 min to obtain the compound shown in formula (I).

3. A pharmaceutical composition, characterized in that: The pharmaceutical composition comprises the compound of claim 1, its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier or excipient.

4. The use of the compound of claim 1 and its pharmaceutically acceptable salt in the preparation of anti-inflammatory or analgesic drugs.

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