Preparation method and application of novel lappaconitine derivative

Abstract

The invention relates to a preparation method and application of a novel lappaconitine derivative, and the novel lappaconitine derivative obtained by an acylation preparation method enriches the structure of diterpenoid alkaloid. The structural formula of the compound is shown as a formula I. The analgesic activity of the compound is superior to that of lappaconitine, and the toxicity of the compound is lower than that of the lappaconitine, so that the synthesized lappaconitine derivative has a good treatment effect in pain treatment. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicine and relates to a preparation method and use of a novel lappaconitine derivative. Background Art

[0002] Lappaconitine is a monoesters diterpenoid alkaloid first isolated from the roots of the natural plant Aconitum sinomontanum Nakai, which is the main active ingredient of Aconitum sinomontanum Nakai. Also known as acanthine and labaconitine, it belongs to C18-diterpenoid alkaloids. Lappaconitine has a wide range of biological activities, including analgesia, anti-arrhythmia, inhibition of epileptiform activity in hippocampal neurons, anti-inflammatory, antioxidant and anti-cancer effects. Its analgesic effect is particularly significant, 7 times that of aminopyrine, equivalent to pethidine, and it is a commonly used alternative drug to tramadol.

[0003] Although lappaconitine has the advantages of strong analgesic effect and non-addictive properties, as a diterpenoid alkaloid, lappaconitine, like other aconite alkaloids, has high toxicity. Toxicity may occur when used in small doses, and allergic reactions such as arrhythmia, respiratory depression, convulsions, and ototoxicity may also occur. Secondly, lappaconitine has poor water solubility, resulting in slow or incomplete drug dissolution after oral administration of ordinary tablets, low bioavailability, slow onset of analgesic activity, and difficulty in meeting clinical analgesic needs, thus limiting its widespread application. Therefore, it is of great significance to conduct structural modification research on lappaconitine (LA) and develop lappaconitine (LA) derivatives with high activity, low toxicity, high water solubility and high bioavailability. Summary of the Invention

[0004] One object of the present invention is to provide a class of lappaconitine compounds represented by the general formula (I).

[0005] Another object of the present invention is to provide a preparation method of the compound of the general formula (I).

[0006] Another object of the present invention is to provide the use of the compound of the general formula (I) in the medicine for treating pain-related diseases.

[0007] In order to achieve the above technical objects, the technical solutions provided by the present invention are as follows:

[0008] The present invention provides a novel lappaconitine derivative, characterized in that the structure of the novel lappaconitine derivative is as shown in formula I:

[0009]

[0010] Wherein:

[0011] R is selected from alkyl, aryl, azacycle, aralkyl, alkoxy, aryloxy, heterocyclic group, phenyl, halogen-substituted C1-6 alkyl, monosaccharide chain, polysaccharide chain.

[0012] In some embodiments, the R group is selected from, but not limited to:

[0013] The lappaconitine derivatives described in the present invention are selected from, but not limited to

[0014]

[0015]

[0016] In some embodiments, the compound is

[0017]

[0018] On the other hand, the present invention provides a method for preparing lappaconitine derivatives, including using lappaconitine as a raw material, refluxing in a dilute sulfuric acid solution to hydrolyze the amide bond, adjusting the pH with 1%-10% potassium hydroxide, and separating and purifying to obtain N-deacetyl lappaconitine. On this basis, acylation is carried out to obtain a series of N-deacetyl lappaconitine derivatives, and the obtained derivatives are evaluated for activity by the hot plate method and the acetic acid writhing method.

[0019] The reaction general formula:

[0020]

[0021] The R group is as described above.

[0022] In the third aspect of the present invention, there is provided the use of the above compound in the preparation of drugs for treating mild, moderate and severe pain.

[0023] In the fourth aspect of the present invention, there is provided a pharmaceutical composition, which comprises the above compound and at least one pharmaceutically acceptable excipient.

[0024] According to the usual method, the pharmaceutical composition can be made into dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, sprays and other oral preparations, external preparations, suppositories and sterile injection solutions for use.

[0025] The non-drug active ingredients such as carriers, excipients and diluents that can be included are well-known in the art, and those of ordinary skill in the art can determine that they meet clinical standards.

[0026] Obviously, based on the above content of the present invention, and in accordance with the common general technical knowledge and useful means in the art, without departing from the above basic technical idea of the present invention, various other forms of modifications, substitutions or changes can also be made. Description of the Drawings

[0027] Figure 1 It is the result of the acute toxicity test. Detailed Embodiments

[0028] The following is a further detailed description of the above content of the present invention through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention.

[0029] Example 1

[0030] Preparation of Compound II

[0031]

[0032] Using lappaconitine as the raw material, reflux in a 3% aqueous solution of dilute sulfuric acid to hydrolyze the amide bond, adjust the pH to 9 - 10 with 1% - 10% potassium hydroxide. After detecting the completion of the reaction by TLC, separate and purify to obtain N - deacetyl lappaconitine (Compound II).

[0033] Example 2

[0034] Preparation of Compound 1

[0035]

[0036] Under anhydrous and anaerobic conditions, dissolve Compound II in DMSO, add 4 - biphenylcarbonyl chloride under ice - bath conditions, react at room temperature for 1 - 4 h. After detecting the completion of the reaction by TLC, extract the reaction solution with dichloromethane, then concentrate under reduced pressure to obtain the crude product of solid Compound 1, and further purify it by recrystallization to obtain Compound 1: white solid.

[0037] 11H NMR (400 MHz, Chloroform-d) δ 12.10 (s, 1H), 8.91 (dd, J = 8.5, 1.2 Hz, 1H), 8.21–8.07 (m, 2H), 7.99 (dd, J = 8.0, 1.7 Hz, 1H), 7.80–7.73 (m, 2H), 7.70–7.63 (m, 2H), 7.58 (m, J = 8.7, 7.3, 1.7 Hz, 1H), 7.48 (m, J = 7.2, 6.2, 1.3 Hz, 2H), 7.39 (t, J = 7.2 Hz 1H), 7.08 (t, J = 8.0 Hz, 1H), 3.62 (d, J = 11.4 Hz, 1H), 3.57 (s, 1H), 3.45 (d, J = 4.8 Hz, 1H), 3.41 (s, 3H), 3.31 (s, 3H), 3.30 (s, 3H) 3.21 (dd, J = 10.0, 7.2 Hz, 1H), 3.02 (s, 1H), 2.75 - 2.67 (m, 2H), 2.61 - 2.48 (m, 4H), 2.47 - 2.44 (m, 1H), 2.43 - 2.35 (m, 2H), 2.35 - 2.28 (m, 2H), 2.18 (t, J = 7.9 Hz, 2H), 2.12 (dd, J = 12.4, 4.4 Hz, 1H), 2.07 - 1.93 (m, 2H), 1.87 (s, J = 13.1 Hz, 1H), 1.80 (s, 1H) 1.63 (dd, J = 15.1, 8.3 Hz, 1H), 1.13 (t, J = 7.1 Hz, 3H).

[0038] 13 13C NMR (100 MHz, Chloroform-d) δ 167.75, 165.44, 144.56, 141.93, 140.04, 134.48, 133.66, 131.21, 128.89, 128.86, 128.14, 127.99, 127.98, 127.43, 127.22, 127.14, 127.12, 122.54, 120.44, 116.28, 90.13, 84.72, 84.18, 82.91, 78.58, 75.64, 61.48, 57.92, 56.53, 56.12, 55.53, 51.00, 49.81, 48.98, 48.43, 47.59, 44.84, 36.32, 31.81, 26.81, 26.25, 24.11, 13.54.

[0039] Example 3

[0040] Preparation of Compound 2

[0041]

[0042] Under anhydrous and anaerobic conditions, dissolve Compound II in DMSO. Under an ice bath condition, add n-butyryl chloride and react at 25 °C for 1 - 4 h. After detecting the completion of the reaction by TLC, extract with dichloromethane three times, combine the organic phases, wash with water, and concentrate under reduced pressure to obtain the crude product of Compound 2. Pure Compound 2 is obtained by column chromatography.

[0043] 1 H NMR (400 MHz, Chloroform-d) δ 11.05 (s, 1H), 8.68 (dd, J = 8.5, 1.2 Hz, 1H), 7.90 (dd, J = 8.0, 1.7 Hz, 1H), 7.47 (m, J = 8.7, 7.3, 1.7 Hz, 1H), 7.00 (m, J = 8.4, 7.3, 1.3 Hz, 1H), 3.57 (d, J = 11.4 Hz, 2H), 3.45–3.40 (m, 1H), 3.39 (s, 3H), 3.29 (d, J = 6.0 Hz, 6H), 3.17 (dd, J = 10.3, 7.0 Hz, 1H), 2.99 (s, 1H), 2.73–2.61 (m, 2H), 2.55–2.48 (m, 4H), 2.52–2.44 (m, 1H), 2.43–2.31 (m, 5H), 2.26 (m, J = 15.1, 8.5, 3.7 Hz, 1H), 2.20–1.90 (m, 6H), 1.86–1.76 (m, 1H), 1.79–1.70 (m, 2H), 1.58 (dd, J = 15.0, 8.3 Hz, 1H), 1.11 (t, J = 7.1 Hz, 3H), 0.99 (t, J = 7.4 Hz, 3H).

[0044] 13 C NMR (100 MHz, Chloroform-d) δ 172.09, 167.40, 141.69, 134.31, 131.46, 122.18, 120.25, 115.80, 90.11, 84.53, 84.17, 82.88, 78.56, 75.60, 61.50, 57.89, 56.51, 56.09, 55.49, 50.95, 49.82, 48.96, 48.49, 47.58, 44.79, 40.56, 36.29, 31.81, 26.77, 26.21, 24.09, 19.04, 13.82, 13.72.

[0045] Example 4

[0046] Preparation of Compound 3

[0047]

[0048] Under anhydrous and anaerobic conditions, dissolve Compound II in DMSO. Under an ice bath condition, add chloroacetyl chloride and react at 25 °C for 1 - 4 h. After the reaction is completed as detected by TLC, quench the reaction with water. Extract with dichloromethane, combine the organic phases, and purify by concentration under reduced pressure to obtain Compound 3.

[0049] Example 5

[0050] Preparation of Compound 4

[0051]

[0052] Under anhydrous and anaerobic conditions, dissolve Compound II (542 mg, 1 mmol) in DMSO. Under an ice bath condition, sequentially add pyridine (118.5 mg, 1.5 mmol) and bromoacetyl bromide (180.9 mg, 0.9 mmol), and react at 25 °C for 1 - 4 h. After the reaction is completed as detected by TLC, quench the reaction with water. Extract with dichloromethane, combine the organic phases, and purify by concentration under reduced pressure to obtain Compound 4 (386.45 mg, yield 58.35%).

[0053] 1 H NMR (400 MHz, Chloroform - d) δ 11.83 (s, 1H), 8.63 (d, J = 8.5 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 7.9 Hz, 1H), 7.08 (t, J = 7.7 Hz, 1H), 4.17 (s, 2H), 3.58 (d, J = 11.5 Hz, 1H), 3.42 (d, J = 4.9 Hz, 1H), 3.39 (s, 3H), 3.28 (d, J = 6.8 Hz, 7H), 3.22–3.13 (m, 1H), 2.99 (s, 1H), 2.68 (m, J = 15.3, 8.6 Hz, 2H), 2.51 (m, J = 14.1, 6.0 Hz, 4H), 2.43–2.24 (m, 5H), 2.14 (d, J = 8.4 Hz, 3H), 2.03 (m, J = 32.3, 16.4, 10.6 Hz, 3H), 1.58 (dd, J = 15.1, 8.2 Hz, 1H), 1.23 (s, 1H), 1.10 (t, J = 7.1 Hz, 3H).

[0054] 1313C NMR (151 MHz, Chloroform-d) δ 166.96, 165.23, 140.32, 134.19, 131.10, 123.35, 120.36, 117.01, 90.10, 84.70, 84.10, 82.87, 78.55, 75.61, 61.44, 57.89, 56.49, 56.10, 55.43, 50.96, 49.80, 48.95, 48.44, 47.56, 44.80, 43.28, 36.28, 31.73, 26.73, 26.22, 24.09, 13.48.

[0055] Example 6

[0056] Preparation of Compound 10

[0057]

[0058] Under anhydrous and anaerobic conditions, Compound II was dissolved in DMSO. Under ice bath conditions, 3-trifluoromethylbenzoyl chloride was added, and the reaction was carried out at room temperature for 2 - 5 h. After the reaction was completed as detected by TLC, the reaction was quenched with water. Extracted with dichloromethane, the organic phases were combined, concentrated under reduced pressure, and recrystallized to obtain Compound 10.

[0059] 1 1H NMR (400 MHz, Chloroform-d) δ 12.20 (s, 1H), 8.85 (d, J = 8.5 Hz, 1H), 8.34 (s, 1H), 8.18 (d, J = 7.8 Hz, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.58 (t, J = 7.9 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 3.61 (d, J = 11.4 Hz, 1H), 3.44 (d, J = 4.8 Hz, 1H), 3.41 (s, 3H), 3.31 (d, J = 4.5 Hz, 6H), 3.20 (dd, J = 10.4, 6.9 Hz, 1H), 3.02 (s, 1H), 2.69 (m, J = 14.4, 12.8, 5.7 Hz, 2H), 2.60–2.46 (m, 4H), 2.46–2.35 (m, 3H), 2.39–2.24 (m, 2H), 2.15 (m, J = 27.8, 7.6 Hz, 3H), 2.02 (dd, J = 14.8, 7.2 Hz, 2H), 1.91–1.80 (m, 1H), 1.61 (dd, J = 15.1, 8.2 Hz, 1H), 1.25 (s, 1H), 1.13 (t, J = 7.1 Hz, 3H).

[0060] 13 13C NMR (100 MHz, Chloroform-d) δ 167.87, 164.14, 141.52, 134.58, 131.48, 131.27, 131.24, 130.19, 129.38, 128.37, 124.99, 122.96, 122.84, 120.40, 116.38, 90.13, 85.01, 84.12, 82.88, 78.57, 75.64, 61.51, 57.91, 56.51, 56.11, 55.47, 51.01, 49.80, 48.97, 48.47, 47.55, 44.87, 36.31, 31.81, 26.79, 26.22, 24.13, 13.46.

[0061] Example 7

[0062] Preparation of Compound 8

[0063]

[0064] Under anhydrous and anaerobic conditions, Compound II was dissolved in tetrahydrofuran reagent. Using triethylamine as a catalyst, 2-naphthoyl chloride was added under an ice bath condition, and the reaction was carried out at 0 °C for 5 - 6 h. After the reaction was completed as detected by TLC, the reaction was quenched with water. After extraction with dichloromethane, the organic phases were combined, concentrated under reduced pressure, and Compound 8 was obtained by recrystallization.

[0065] Example 8

[0066] Preparation of Compound 11

[0067]

[0068] Under anhydrous and anaerobic conditions, Compound II was dissolved in DMSO. Using pyridine as a catalyst, 4-fluoro-3-(trifluoromethyl)benzoyl chloride was added under an ice bath condition, and the reaction was carried out at 0 °C for 1 - 5 h. After the reaction was completed as detected by TLC, the reaction was quenched with water. After extraction with dichloromethane, the organic phases were combined, concentrated under reduced pressure, and Compound 11 was obtained by recrystallization.

[0069] 11H NMR (400 MHz, Chloroform-d) δ 12.19 (s, 1H), 8.82 (dd, J = 8.5, 1.2 Hz, 1H), 8.35 (dd, J = 6.9, 2.3 Hz, 1H), 8.20 (m, J = 8.6, 4.6, 2.4 Hz, 1H), 7.99 (dd, J = 8.0, 1.7 Hz, 1H), 7.58 (m, J = 8.7, 7.3, 1.7 Hz, 1H), 7.37 (t, J = 9.2 Hz, 1H), 7.11 (m, J = 8.3, 7.4, 1.2 Hz, 1H), 3.61 (d, J = 11.4 Hz, 1H), 3.44 (d, J = 4.8 Hz, 1H), 3.41 (s, 3H), 3.31 (d, J = 4.5 Hz, 6H), 3.20 (dd, J = 10.4, 6.9 Hz, 1H), 3.02 (s, 1H), 2.69 (m, J = 14.4, 12.8, 5.7 Hz, 2H), 2.60–2.46 (m, 4H), 2.46–2.35 (m, 3H), 2.39–2.24 (m, 2H), 2.15 (m, J = 27.8, 7.6 Hz, 3H), 2.02 (dd, J = 14.8, 7.2 Hz, 2H), 1.91–1.80 (m, 1H), 1.61 (dd, J = 15.1, 8.2 Hz, 1H), 1.25 (s, 1H), 1.13 (t, J = 7.1 Hz, 3H).

[0070] 13 13C NMR (100 MHz, Chloroform-d) δ 167.96, 163.11, 141.44, 134.65, 132.88, 132.82, 131.46, 131.26, 127.51, 123.05, 120.32, 117.51, 117.37, 116.31, 90.12, 85.13, 84.06, 82.87, 78.56, 75.65, 61.51, 57.92, 56.51, 56.12, 55.48, 51.02, 49.79, 48.98, 48.37, 47.54, 44.87, 36.30, 31.79, 29.66, 26.76, 26.22, 24.12, 13.44.

[0071] The beneficial effects of the compounds of the present invention are demonstrated by the following test examples.

[0072] Test Example 1: Analgesic Activity of the Lappaconitine Derivatives of the Present Invention

[0073] a. Experimental study on the pain model of mice with hot plate by lappaconitine derivatives:

[0074] 1. Experimental principle: Place the mice on a hot plate apparatus. The heat stimulates the mice's feet to produce a pain response, and record the time from when the mice are exposed to the heat stimulus until they show a pain response (such as licking the hind paw). By comparing the pain response times before and after drug treatment, the analgesic effect of the drug can be evaluated.

[0075] 2. Drug preparation: Prepare 0.1M HCl with physiological saline for dissolving lappaconitine and other derivatives, and the initial concentration is 1mg / mL for all.

[0076] 3. Dosage and administration method: The dosage of lappaconitine and its derivatives is 10mg / kg, and the administration volume is 10mL / kg for all.

[0077] 4. Experimental method: Before administration, measure the time required for the mice to lick the hind paw on the hot plate apparatus twice (with a 5-minute interval each time), and record them as S1 and S2 respectively. The average value of S1 and S2 in each drug administration group is the time for the mice to lick the hind paw before administration, that is, the time for the blank control group to lick the hind paw. Each group of mice is injected subcutaneously with physiological saline or the sample, and measure the time required for the mice to lick the hind paw on the hot plate apparatus at 15min, 30min, 45min, and 60min after administration respectively, and record them as S3, S4, S5, and S6. If it exceeds 60s, immediately take out the mice to avoid scalding. The analgesic activity is expressed as the percentage change in the time for the mice in the blank control group to lick the hind paw.

[0078] 5. Results of analgesic activity:

[0079] The analgesic activity of lappaconitine derivatives was studied using the hot plate method. The time required for the mice to lick the hind paw before and after administration is shown in Table 1. After administration, there was a significant difference between the positive control drug lappaconitine and the physiological saline group (P<0.01). Administering lappaconitine can significantly increase the time required for the mice to lick the hind paw, indicating that the established model is real and effective. When the initial screening dose of compound 2 was 10mg / kg, deaths occurred in the experimental animals. By reducing the dosage, the analgesic activity data were finally measured.

[0080] Table 1 Effects of lappaconitine derivatives on the time of licking the paw in the hot plate pain model

[0081]

[0082]

[0083] Continued Table 1 Effects of lappaconitine derivatives on the time of licking the paw in the hot plate pain model

[0084] The analgesic rates of lappaconitine derivatives at different time points are shown in Table 2. Analgesic rate = (average licking hind paw time after administration - average licking hind paw time before administration) / average licking hind paw time before administration × 100%. Positive control lappaconitine showed analgesic activity 15 min after administration, and the effect was the best at 30 min. Among the tested compounds, 4, 5, 7, 11, 13, 14 and 16 showed good analgesic activity. The analgesic activity of compound 4 was higher than that of lappaconitine 15 minutes after administration. Compound 5 showed good analgesic activity at 30 minutes, with a relatively late onset, and the analgesic activity almost disappeared after 60 minutes.

[0085] Table 2 Analgesic rates of lappaconitine derivatives at different time points observed by hot plate method

[0086]

[0087] Continued Table 2 Analgesic rates of lappaconitine derivatives at different time points observed by hot plate method

[0088]

[0089] b. Experimental study on the pain model of acetic acid-induced writhing behavior in mice by lappaconitine derivatives:

[0090] 1. Analgesic experiment: The acetic acid-induced writhing behavior pain model in mice was used to evaluate the analgesic activity of the compounds. After injecting a certain volume and concentration of acetic acid solution into the abdominal cavity of mice, it can stimulate the visceral and parietal peritoneum of mice, resulting in mouse writhing behavior reactions such as abdominal indentation, stretching of the body and hind limbs, and elevation of the buttocks. Compounds with analgesic activity can significantly reduce the number of writhing behaviors of pain model mice;

[0091] 2. Drug preparation: Prepare 0.7% acetic acid solution with normal saline and use it immediately; prepare 0.1 M HCl with normal saline for dissolving lappaconitine and other derivatives, and the initial concentration is 1 mg / mL for all;

[0092] 3. Administration dose and method: The administration volume of 0.7% glacial acetic acid solution is 10 mL / kg, and the administration method is intraperitoneal injection; the administration dose of lappaconitine is 3 mg / kg, and the administration volume is 10 mL / kg; the administration doses of derivatives are all 10 mg / kg, and the administration volumes are all 10 mL / kg;

[0093] 4. Experimental method: The mice were randomly grouped, weighed, and labeled with picric acid. The animals were first subcutaneously administered the test substance or normal saline. After 15 minutes, a 0.7% aqueous solution of glacial acetic acid was intraperitoneally injected. Then the mice were placed alone, and the total number of abdominal contractions and body wriggles of the mice within 15 minutes was observed and recorded. The group subcutaneously injected with normal saline was used as the blank control group, and the group subcutaneously injected with the sample was used as the test group. Except that the test sample was replaced with normal saline, the control group animals received the same experimental treatment as the test group. The analgesic activity inhibition rate was expressed as the percentage reduction in the number of writhing compared with the blank control group. The room temperature in the observation room was controlled at 25 - 27 °C; Analgesic percentage (%) = (Number of writhing in the blank control group - Number of writhing in the drug-administered group) / Number of writhing in the blank control group × 100%.

[0094] 5. Results of analgesic activity:

[0095] The analgesic activities of compounds 1 - 17 were tested using the acetic acid writhing method. The results are shown in Table 3. Inhibition rate = (Average number of writhing in the normal saline group - Average number of writhing after drug administration) / Average number of writhing in the normal saline group. From the results, it can be seen that all compounds have analgesic activity, and the analgesic activity range is wide (28.82% - 82.83%). According to the results of the hot plate experiment, the dosage of compound 2 was halved; when the initial screening dosage of compound 2 was 10 mg / kg, deaths occurred in the test animals. By reducing the dosage multiple times, the analgesic activity data were finally measured. When testing the analgesic activity of lappaconitine, when the dosage was 10 mg / kg, the experimental animals showed poisoning phenomena such as listlessness, dyspnea, and weakness in the limbs. Compounds 4 and 15 have good analgesic activity. Especially when the dosages were 10 mg / kg respectively, the inhibition rates of compounds 4 and 15 were as high as 77.31% and 82.83% respectively.

[0096] Table 3 Analgesic activities of lappaconitine derivatives studied by the acetic acid writhing method

[0097]

[0098] Continued Table 3 Analgesic activities of lappaconitine derivatives studied by the acetic acid writhing method

[0099]

[0100] For further in-depth study, derivatives 4 and 15 with better initial screening results were selected, and their ED 50 values were studied by the acetic acid writhing method. At safe dosages, within the safe dosage range, the inhibition rates of 5 compounds against acetic acid-induced pain in mice increased with increasing concentration. The ED 50 of compound 4 was 2.578 mg / kg (1.597 - 3.678 mg / kg, 95% confidence interval), and the ED 50It was 2.620 mg / kg (2.049 - 3.241 mg / kg, 95% confidence interval).

[0101] Test Example 2: Acute Toxicity Study of Lappaconitine Derivatives

[0102] Toxicity is one of the most important indicators for evaluating drugs. To evaluate the toxicity of the compound, derivative 4 with good performance in the primary screening was selected for the acute toxicity test. The relationship between the dosing dose of the compound and the number of surviving mice is as Figure 1 , and the animals were observed for 24 hours, and the mortality of each group of animals was recorded. The ED50 value and LD50 value were both calculated by the software SPSS.

[0103] Based on the primary screening at 10 mg / kg, the dosing dose was increased by 10 times, that is, when it was 100 mg / kg, 1 out of 4 mice injected with compound 4 died. When the dosing dose was 200 mg / kg, all 4 mice died. By reducing the dosing dose multiple times, the lethality rates at five concentrations were obtained. After calculation, the LD 50 of compound 4 was 144.348 mg / kg (103.781 - 249.386 mg / kg, 95% confidence interval)

[0104] In summary, the present invention provides a novel lappaconitine derivative. The analgesic activity of this kind of compound is better than that of lappaconitine, and the toxicity is less than that of lappaconitine, broadening the therapeutic window of lappaconitine. Therefore, the synthesized lappaconitine derivatives have good therapeutic effects in the treatment of pain.

[0105] The above embodiments are only for illustrating the technical concept and features of the present invention, and the purpose is to enable those skilled in the art to understand the content of the present invention and implement it accordingly, and it should not be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.

Claims

1. A lappaconitine derivative, characterized in that, The structure of the lappaconitine derivative is shown in Formula I: Wherein: R is selected from alkyl, aryl, azacycle, aralkyl, alkoxy, aryloxy, heterocyclic group, phenyl, halogen-substituted C1-6 alkyl, monosaccharide chain, polysaccharide chain.

2. The lappaconitine derivative according to claim 1, wherein the R group is selected from:

3. The lappaconitine derivative according to claim 1 is selected from:

4. The lappaconitine derivative according to claim 1, wherein the compound is 5. Use of the lappaconitine derivative according to any one of claims 1-4 in the preparation of a medicament for treating pain.

6. A pharmaceutical composition comprising the lappaconitine derivative according to any one of claims 1-4 and at least one pharmaceutically acceptable excipient.

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