Preparation of arctigenin derivative and application of arctigenin derivative in treatment of diabetic peripheral neuropathy

Abstract

The invention discloses an application of an arctigenin derivative or a pharmaceutically acceptable salt thereof in preparation of drugs for treating diabetic peripheral neuropathy. A large number of experimental screening results show that the arctigenin derivative and the pharmaceutically acceptable salt thereof can significantly improve the nerve conduction velocity and sensory deficiency symptoms of diabetic rats, thereby achieving the effect of treating peripheral neuropathy.

Description

Technical Field

[0001] The invention relates to the technical field of medicines, and in particular to arctigenin derivatives and applications thereof in preparing medicines for treating diabetic peripheral neuropathy. Background Art

[0002] Diabetic peripheral neuropathy (DPN) refers to the symptoms related to peripheral nerve dysfunction in diabetic patients when other causes are excluded. Clinically, it presents with symmetrical pain and paresthesia, and symptoms in the lower limbs are more common than in the upper limbs. Paresthesias include numbness, ants crawling, insects crawling, fever, and electric shock-like sensations, which often extend from the distal toes to above the knees. Cases with severe sensory impairment may develop lower limb arthritis and ulcers. The pain is tingling, burning, and drilling pain, and seems to be deep in the bone marrow. Sometimes it is severe pain like amputation, which is lighter during the day and heavier at night. When motor nerves are affected, muscle strength often decreases to varying degrees, and in the late stage there is malnutrition-related muscle atrophy. Peripheral neuropathy can be bilateral, unilateral, symmetrical, or asymmetrical, but bilateral symmetry is more common.

[0003] According to the International Diabetes Federation (IDF), there are currently about 537 million people with diabetes worldwide, with a total prevalence of 6.1%. The number of people with diabetes in China accounts for 1 / 4 of the world, about 141 million. DPN is the most common chronic complication of diabetes, and about 50% of diabetic patients will develop DPN in the later stage. DPN first affects sensory neurons, and the main pathological changes are axonal atrophy and degeneration, even disappearance, segmental or diffuse shrinkage or demyelination of myelin sheaths, and changes in the length of the nodes of Ranvier caused by myelin regeneration. In DPN, the main feature is the loss of nerve fibers, which mainly occurs in ischemic areas. At present, a large number of peroneal nerve biopsies and autopsies have found that diabetic patients with clinical manifestations of distal symmetrical polyneuropathy also have segmental demyelination on the basis of primary Schwann cell abnormalities. This pathological change is common in large myelinated nerves such as the sural nerve, tibial nerve, and median nerve, which can cause shortening of the distance between nodes of Ranvier, slow nerve conduction velocity, and symptoms such as hypoesthesia and fatigue. Therefore, it is believed that the treatment effect of anti-diabetic peripheral neuropathy can be achieved by protecting and promoting the growth of sensory neuron processes. At present, the drugs used in clinical treatment of diabetic peripheral neuropathy can only slow down the symptoms of patients, but cannot block the progression of diabetic peripheral neuropathy. Therefore, there is an urgent need to discover new anti-diabetic peripheral neuropathy drugs that can block the pathological progression of diabetic peripheral neuropathy.

[0004] Arctigenin, its structural formula is:

[0005] Summary of the invention

[0006] The first aspect of the present invention provides an arctiin derivative or a pharmaceutically acceptable salt thereof.

[0007] The arctiin derivative has the following structure:

[0008]

[0009] Wherein, the R1 is H;

[0010] The R2 is selected from -(CH2)n-R3, C 5-8 Alkyl, C 3-6 Cycloalkyl;

[0011] The R3 is selected from NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, cyclopropyl, C 1-3 Alkoxy, C 4-8 Nitrogen-containing heterocyclic groups,

[0012] The n is selected from 1, 2 or 3.

[0013] In some embodiments, R2 is selected from cyclopropyl, cyclohexyl, isopentyl, n-hexyl, n-octyl, morpholine, piperidine, piperazine, -(CH2)3-NH2, -(CH2)3-N(CH3)2, -CH2-cyclopropyl, -(CH2)3-methoxy, -(CH2)2-morpholinyl,

[0014]

[0015] In some embodiments, R2 is selected from C 6-8 Alkyl, preferably C 6-8 Straight chain alkyl.

[0016] The arctiin derivatives of the present invention are selected from the following structures:

[0017]

[0018]

[0019] The second aspect of the present invention provides a pharmaceutical composition for treating diabetic peripheral neuropathy, the pharmaceutical composition comprising the arctiin derivative or a pharmaceutically acceptable salt thereof according to the first aspect of the present invention and a pharmaceutically acceptable excipient.

[0020] In some embodiments, the dosage form of the pharmaceutical composition can be selected from tablets, capsules, and injections.

[0021] The third aspect of the present invention provides use of the arctiin derivative or a pharmaceutically acceptable salt thereof according to the first aspect of the present invention and the pharmaceutical composition according to the second aspect of the present invention in the preparation of a drug for treating diabetic peripheral neuropathy.

[0022] In some embodiments, the diabetic peripheral neuropathy is caused by type I diabetes.

[0023] In some embodiments, the diabetic peripheral neuropathy is caused by type II diabetes.

[0024] In some embodiments, the treatment of diabetic peripheral neuropathy is to improve nerve conduction velocity and sensory loss symptoms in diabetic patients.

[0025] Beneficial Effects

[0026] The present invention optimizes the structure based on the natural compound arctiin, and obtains a series of arctiin derivatives, which have excellent neuroinflammation inhibitory effects, can significantly improve the motor nerve conduction velocity and sensory loss of diabetic peripheral neuropathy, and have great application value in the treatment of diabetic peripheral neuropathy. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is the effect of different compound interventions on the expression level of the inflammatory factor IL-1β in cells.

[0028] Specific implementation cases

[0029] The following embodiments can enable those skilled in the art to more fully understand the present invention, but the present invention is not limited to the scope of the embodiments.

[0030] Example 1 Synthesis of Arctigenin Derivatives

[0031]

[0032] Synthesis of compound 1

[0033]

[0034] 1mL propylenediamine and 0.2mmol (-) arctiin were placed in a 10mL microwave reaction vial. The microwave reactor was programmed to a temperature of 110°C, an arrival time of 3 minutes, and a duration of 1 hour. The microwave vial was then placed in a microwave generator to start the microwave reaction. After the program was completed, the reaction solution was cooled to room temperature, and then adjusted to pH = 7.0 with a 2M HCl solution. The reaction solution was then poured into an ethyl acetate (20mL) solution and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography to obtain 57mg of a colorless viscous liquid, (2R, 3R)-N-(3-aminopropyl)-3-(3,4-dimethoxybenzyl)-4-hydroxy-2-(4-hydroxy-3-methoxybenzyl)butyramide. The yield was: 63.58%. 1 H NMR(500MHz,Chloroform-d)δ8.13(s,1H),6.97-6.60(m,6H),6.49-6.08(m,2H), 3.86(d,J=15.0Hz,9H),3.77-3.18(m,3H),3.16-2.40(m,9H),2.29-1.91(m,2H). 13 C NMR(126MHz,Chloroform-d)δ175.7,161.9,148.9,146.5,144.2,132.6,131.3,121.5,1 21.1,114.4,112.3,111.7,111.3,60.6,55.9,53.0,44.5,37.5,35.8,35.6,34.3,29.3.

[0035] Synthesis of compound 2

[0036]

[0037] Under N2 protection, 2 mL DMF, 1 mL cyclopropylamine, and 0.2 mmol (-) arctiin were added to a 10 mL sealed tube and reacted at 140 ° C overnight. After the reaction was completed, the reaction solution was cooled to room temperature, and then adjusted to pH = 7.0 with 2M HCl solution. The reaction solution was then poured into ethyl acetate (20 mL) solution and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography to obtain 63 mg of colorless viscous liquid, (2R, 3R)-N-cyclopropyl-3-(3,4-dimethoxybenzyl)-4-hydroxy-2-(4-hydroxy-3-methoxybenzyl) butyramide. The yield was: 73.34%. 1H NMR (500 MHz, Chloroform-d) δ 6.80-6.77 (m, 2H), 6.70 (d, J = 5.0 Hz, 2H), 6.59 (d, J = 15.0 Hz, 2H), 5.65 (s, 1H), 3.94 (d, J = 10.0 Hz, 1H), 3.85 (d, J = 10.0 Hz, 9H), 3.72 (s, 2H), 3.54-3.51 (m, 1H), 3.03-2.96 (m, 1H), 2.84-2.71 (m, 2H), 2.69-2.56 (m, 2H), 2.42-2.34 (m, 1H), 2.00 (s, 1H), 0.69 (d, J = 7.2 Hz, 1H), 0.35-0.18 (m, 2H). Synthesis of compound 3

[0038]

[0039] Under N2 protection, 2 mL DMF, 1 mL cyclopropylmethylamine, and 0.2 mmol (-) arctiin were added to a 10 mL sealed tube and reacted at 140 ° C overnight. After the reaction was completed, the reaction solution was cooled to room temperature, and then adjusted to pH = 7.0 with 2M HCl solution. The reaction solution was then poured into ethyl acetate (20 mL) solution and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography to obtain 68 mg of colorless viscous liquid, (2R, 3R)-N-(cyclopropylmethyl)-3-(3,4-dimethoxybenzyl)-4-hydroxy-2-(4-hydroxy-3-methoxybenzyl)butanamide. The yield was: 76.66%. 1 H NMR (500 MHz, Chloroform-d) δ 6.81 (t, J = 10.0 Hz, 2H), 6.77-6.70 (m, 2H), 6.63 (d, J = 10.0 Hz, 2H), 5.68 (s, 2H), 5.51 (s, 1H), 4.37 (s, 1H), 3.99 (d, J = 20.0 Hz, 1H), 3.93-3.79 (m, 9H), 3.55 (d, J = 10.0 Hz, 1H), 3.14-3.00 (m, 4H), 2.97-2.92 (m, 1H), 2.86-2.77 (m, 2H), 2.70-2.65 (m, 1H), 2.46-2.42 (m, 1H), 2.00 (s, 3H). Synthesis of compound 4

[0040]

[0041] Under N2 protection, 2 mL DMF, 1 mL isopropylamine, and 0.2 mmol (-) arctiin were added to a 10 mL sealed tube and reacted at 120°C overnight. After the reaction was completed, the reaction solution was cooled to room temperature, and then adjusted to pH = 7.0 with 2M HCl solution. The reaction solution was then poured into ethyl acetate (20 mL) solution and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography to obtain 59 mg of colorless viscous liquid, (2R, 3R)-3-(3,4-dimethoxybenzyl)-4-hydroxy-2-(4-hydroxy-3-methoxybenzyl)-N-isopropylbutanamide, with a yield of 68.36%. 1 H NMR(500MHz,Chloroform-d)δ6.80(t,J=10.0Hz,2H),6.72(d,J=10.0Hz,2H),6.61(d,J=1 0.0Hz,2H),5.28(d,J=10.0Hz,1H),4.60(s,1H),4.00-3.96(m,2H),3.86-3.83(m,9H),3. 55-3.47(m,1H),3.47(s,1H),3.06-2.97(m,1H),2.84-2.74(m,2H),2.67-2.63(m,1H),2. 38(dt,J=10.0,10.0Hz,1H),1.99(s,1H),1.11(d,J=10.0Hz,3H),0.88(d,J=10.0Hz,3H).

[0042] Synthesis of compound 5

[0043]

[0044] Under N2 protection, 2 mL DMF, 1 mL n-butylamine, and 0.2 mmol (-) arctiin were added to a 10 mL sealed tube and reacted at 140 ° C overnight. After the reaction was completed, the reaction solution was cooled to room temperature, and then adjusted to pH = 7.0 with 2M HCl solution. The reaction solution was then poured into ethyl acetate (20 mL) solution and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography to obtain 77 mg of colorless viscous liquid, (2R, 3R)-N-butyl-3-(3,4-dimethoxybenzyl)-4-hydroxy-2-(4-hydroxy-3-methoxybenzyl) butyramide. The yield was: 86.41%. 1H NMR (500MHz, Methanol-d4) δ6.88(d,J=10.0Hz,1H),6.83(s,1H),6.79(d,J=10.0Hz,1H),6.74-6.67(m,2H),6.61(d,J=10.0Hz,1 H),3.81(s,9H),3.62-3.50(m,2H),3.18-2.57(m,7H),2.01(s,1H),1.33-1.24(m,2H),1.18-1.09(m,2H),0.85(t,J=10.0Hz,3H). 13 C NMR(126MHz,Methanol-d4)δ175.6,149.0,147.3,133.2,131.1,121.3,121.1,114.6,112 .9,112.3,111.7,60.3,55.2,55.0,54.9,50.7,44.3,38.6,35.8,33.9,31.0,19.6,12.7.

[0045] Synthesis of compound 6

[0046]

[0047] Under N2 protection, 2 mL DMF, 1 mL isopentylamine, and 0.2 mmol (-) arctiin were added to a 10 mL sealed tube and reacted at 140 ° C overnight. After the reaction was completed, the reaction solution was cooled to room temperature, and then adjusted to pH = 7.0 with 2M HCl solution. The reaction solution was then poured into ethyl acetate (20 mL) solution and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography to obtain 49 mg of colorless viscous liquid, (2R, 3R)-3-(3,4-dimethoxybenzyl)-4-hydroxy-2-(4-hydroxy-3-methoxybenzyl)-N-isopentylbutyramide. The yield was: 53.31%. 1H NMR(500MHz,Chloroform-d)δ6.78(t,J=15.0Hz,2H),6.71(d,J=10.0Hz,2H),6.60(d,J=10.0 Hz,2H),5.89(s,1H),5.47(t,J=5.7Hz,1H),4.62(s,1H),3.96-3.93(m,1H),3.91-3.78(m,9H) ,3.53-3.50(m,1H),3.21-3.06(m,2H),3.00(t,1H),2.82-2.75(m,2H),2.66-2.62(m,1H),2.4 5-2.41(m,1H),1.99(s,1H),1.43-1.33(m,1H),1.18(q,J=5.0Hz,2H),0.83(t,J=10.0Hz,6H). 13 C NMR(126MHz,Chloroform-d)δ175.2,147.4,146.5,144.3,132.7,131.2,121.2,121.0,114.5 ,112.2,111.7,111.2,60.8,55.9,55.9,52.8,44.1,38.2,37.9,37.5,35.6,25.6,22.3,22.3.

[0048] Synthesis of compound 7

[0049]

[0050] 1mL 3-methoxypropylamine and 0.2mmol (-) arctiin were placed in a 10mL microwave reaction vial. The microwave reactor was programmed to a temperature of 110°C, an arrival time of 3 minutes, and a duration of 1 hour. The microwave vial was then placed in a microwave generator to start the microwave reaction. After the program was completed, the reaction solution was cooled to room temperature, and then adjusted to pH = 7.0 with a 2M HCl solution. The reaction solution was then poured into an ethyl acetate (20mL) solution and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography to obtain 78mg of a colorless viscous liquid, (2R, 3R)-3-(3,4-dimethoxybenzyl)-4-hydroxy-2-(4-hydroxy-3-methoxybenzyl)-N-(3-methoxypropyl)butyramide. The yield was 84.50%. 1H NMR(500MHz,Chloroform-d)δ6.79-6.70(m,4H),6.19-5.98(m,1H),4.76(s,2H),3.96-3.75(m,10H),3.51-3.48(m,2H),3.36-3.14( m,7H),3.07-2.91(m,1H),2.81-2.74(m,2H),2.64-2.60(m,1H),2.43(dt,J=10.0,10.0Hz,1H),2.01-1.91(m,1H),1.65-1.53(m,2H). 13 C NMR(126MHz,Chloroform-d)δ175.1,148.9,147.4,146.5,144.2,132.7,131.3,121.3,121.0, 114.5,112.2,111.6,111.2,71.2,60.7,55.9,55.9,55.8,52.8,44.2,38.1,37.5,35.6,28.7.

[0051] Synthesis of compound 8

[0052]

[0053] 1mL cyclohexylamine and 0.2mmol (-) arctiin were placed in a 10mL microwave reaction vial. The microwave reactor was programmed to a temperature of 110°C, an arrival time of 3 minutes, and a duration of 1 hour. The microwave vial was then placed in a microwave generator to start the microwave reaction. After the program was completed, the reaction solution was cooled to room temperature, and then adjusted to pH = 7.0 with a 2M HCl solution. The reaction solution was then poured into an ethyl acetate (20mL) solution and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography to obtain 78mg of a colorless viscous liquid, (2R, 3R)-N-cyclohexyl-3-(3,4-dimethoxybenzyl)-4-hydroxy-2-(4-hydroxy-3-methoxybenzyl)butyramide. The yield was 48.77%. 1H NMR(500MHz,Chloroform-d)δ6.81(t,J=10.0Hz,2H),6.73(d,J=10.0Hz,2H),6.63(d,J=10.0Hz,2H),5 .59(s,1H),5.18(d,J=8.1Hz,1H),4.48(s,1H),4.02(d,J=15.0Hz,1H),3.92-3.81(m,9H),3.75-3.67(m ,1H),3.56-3.53(m,1H),3.06-3.01(m,1H),2.86-2.75(m,2H),2.67-2.63(m,1H),2.39-2.35(m,1H),2. 00-1.91(m,2H),1.70-1.66(m,4H),1.40-1.35(m,1H),1.16-1.04(m,2H),0.81(q,J=15.0,10.0Hz,1H). 13 CNMR (126MHz, Chloroform-d)δ174.2,149.0,146.3,144.2,132.6,131.3,121.3,121.0,114.3,112.1,111.6,111.2,61.0,55.9,55.9,55.9,52.8,48.5,44.06,37.7,35.8,33.0,32.7,25.4,24.7,24.6. Synthesis of compound 9

[0054]

[0055] 2mL 3-(dimethylamino)propylamine and 0.2mmol (-) arctiin were placed in a 10mL microwave reaction vial. The microwave reactor was programmed to a temperature of 110°C, an arrival time of 3 minutes, and a duration of 1 hour. The microwave vial was then placed in a microwave generator to start a microwave reaction. After the program was completed, the reaction solution was cooled to room temperature, and then adjusted to pH = 7.0 with a 2M HCl solution. The reaction solution was then poured into an ethyl acetate (20mL) solution and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography to obtain 76mg of a colorless viscous liquid, (2S, 3S)-3-(3,4-dimethoxybenzyl)-N-(3-(dimethylamino)propyl)-4-hydroxy-2-(4-hydroxy-3-methoxybenzyl)butyramide. The yield was 80.23%. 1H NMR (500MHz, Methanol-d4) δ6.89 (d, J = 10.0 Hz, 1H), 6.85 (s, 1H), 6.84-6.80 (m, 1H), 6.75-6.66 (m, 2H), 6.63-6, 61 (m, 1H), 3.82 (s, 9H), 3.61-3. 49(m,2H),3.18-3.13(m,1H),3.03-2.91(m,2H),2.86-2.70(m,3H),2.6 3-2.59(m,1H),2.17(s,6H),2.12-2.00(m,,3H),1.48(p,J=15.0Hz,2H). 13 CNMR(126MHz,Methanol-d4)δ147.4,144.5,133.1,131.0,121.3,121.1,114.7,112.9 ,112.1,111.6,60.3,56.5,55.1,55.0,54.9,50.6,44.3,43.9,37.0,35.8,33.8,26.4.

[0056] Synthesis of compound 10

[0057]

[0058] 2mL of n-hexylamine and 0.2mmol (-) arctiin were placed in a 10mL microwave reaction vial. The microwave reactor was programmed to a temperature of 110°C, an arrival time of 3 minutes, and a duration of 1 hour. The microwave vial was then placed in a microwave generator to start the microwave reaction. After the program was completed, the reaction solution was cooled to room temperature, and then adjusted to pH = 7.0 with a 2M HCl solution. The reaction solution was then poured into an ethyl acetate (20mL) solution and extracted 3 times. The organic phases were combined, dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography to obtain 88mg of a colorless viscous liquid, (2R, 3R)-3-(3,4-dimethoxybenzyl)-N-hexyl-4-hydroxy-2-(4-hydroxy-3-methoxybenzyl)butyramide. The yield was 92.90%. 1H NMR(500MHz,Methanol-d4)δ6.87(d,J=10.0Hz,1H),6.83(s,1H),6.79(d,J=10.0Hz ,1H),6.73-6.67(m,2H),6.61(d,J=10.0Hz,1H),4.62(s,1H),3.81(s,9H),3.61(dd, J=10.0,10.0Hz,1H),3.52(dd,J=10.0,10.0Hz,1H),3.12-2.97(m,2H),2.94-2.76(m ,3H),2.73-2.61(m,2H),2.08-1.96(m,1H),1.43-1.07(m,9H),0.89(t,J=10Hz,3H). 13 C NMR(126MHz,Methanol-d4)δ175.7,148.9,147.3,133.1,131.0,121.3,121.1,114.6,112.8,11 2.1,111.6,60.3,55.1,55.0,54.9,50.7,44.3,38.9,35.8,33.9,31.3,28.9,26.3,22.2,13.0.

[0059] Synthesis of compound 11

[0060]

[0061] 1 mL of n-octylamine and 0.2 mmol (-) arctiin were placed in a 10 mL microwave reaction vial. The microwave reactor was programmed to a temperature of 110 ° C, an arrival time of 3 minutes, and a duration of 1 hour. The microwave vial was then placed in a microwave generator to start the microwave reaction. After the program was completed, the reaction solution was cooled to room temperature, and then adjusted to pH = 7.0 with a 2M HCl solution. The reaction solution was then poured into an ethyl acetate (20 mL) solution and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography to obtain 91 mg of a colorless viscous liquid, (2R, 3R)-3-(3,4-dimethoxybenzyl)-4-hydroxy-2-(4-hydroxy-3-methoxybenzyl)-N-octylbutanamide. The yield was: 90.70%. 1H NMR(500MHz,Chloroform-d)δ6.79(t,J=10.0Hz,2H),6.72(d,J=15.0Hz,2H),6.61(s,2H),5. 46(s,1H),5.20(s,3H),3.97(d,J=11.7Hz,1H),3.88-3.81(m,9H),3.53(d,J=10.0Hz,1H),3.1 2(q,J=10.0Hz,2H),3.06-2.96(m,1H),2.83-2.75(m,2H),2.67-2.63(m,1H),2.44-2.40(m,1H ),2.01(dd,J=27.0,10.9Hz,3H),1.32-1.26(m,6H),1.17-1.13(m,2H),0.88(t,J=5.0Hz,4H). 13 C NMR(126MHz,Chloroform-d)δ175.2,146.5,144.2,132.6,131.2,121.2,121.0,114.4,112.2,111.6, 111.2,60.8,55.9,55.9,55.9,52.8,44.0,39.8,37.6,35.7,31.8,29.4,29.2,29.1,26.8,22.6,14.1.

[0062] Synthesis of compound 12

[0063]

[0064] 1mL N-(2-aminoethyl)morpholine and 0.2mmol (-) arctiin were placed in a 10mL microwave reaction vial. The microwave reactor was programmed to a temperature of 110°C, an arrival time of 3 minutes, and a duration of 1 hour. The microwave vial was then placed in a microwave generator to start a microwave reaction. After the program was completed, the reaction solution was cooled to room temperature, and then adjusted to pH = 7.0 with a 2M HCl solution. The reaction solution was then poured into an ethyl acetate (20mL) solution and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography to obtain 83mg of a colorless viscous liquid, (2R, 3R)-3-(3,4-dimethoxybenzyl)-4-hydroxy-2-(4-hydroxy-3-methoxybenzyl)-N-(2-morpholinoethyl)butyramide. The yield was 82.57%. 1H NMR(500MHz,Methanol-d4)δ6.89(d,J=10.0Hz,1H),6.87-6.78(m,2H),6.74 -6.67(m,2H),6.61(d,J=10.0Hz,1H),3.82(s,9H),3.71(t,J=5.0Hz,3H),3. 68-3.51(m,6H),3.39(t,J=10.0Hz,1H),3.19(q,J=10.0Hz,2H),2.96-2.68( m,4H),2.62-2.57(m,1H),2.55-2.27(m,9H),2.21-2.16(m,1H),2.00(s,1H). 13 C NMR(126MHz,Methanol-d4)δ162.5,149.0,147.5,147.4,133.2,131.0,121.4,121.2,114.6,112.9,112 .2,111.7,66.4,66.3,60.3,57.0,56.9,55.255.1,54.9,53.2,53.1,50.9,44.5,36.0,35.4,34.4,34.0.

[0065] Synthesis of compound 13

[0066]

[0067] 2mL 2-[2-(2-aminoethoxy)ethoxy]ethanol and 0.2mmol (-) arctiin were placed in a 10mL microwave reaction vial. The microwave reactor was programmed to a temperature of 110°C, an arrival time of 3 minutes, and a duration of 1 hour. The microwave vial was then placed in a microwave generator to start a microwave reaction. After the program was completed, the reaction solution was cooled to room temperature, and then adjusted to pH = 7.0 with a 2M HCl solution. The reaction solution was then poured into an ethyl acetate (20mL) solution and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography to obtain 76mg of a colorless viscous liquid, (2R, 3R)-3-(3,4-dimethoxybenzyl)-4-hydroxy-2-(4-hydroxy-3-methoxybenzyl)-N-(2-(2-(-hydroxyethoxy)ethoxy)ethyl)butyramide. The yield was 80.23%. 1H NMR (500MHz, Methanol-d4) δ6.89 (d, J=10.0Hz, 1H), 6.84 (s, 1H), 6.81 (d, J= 10.0Hz,1H),6.76-6.64(m,2H),6.61(d,J=10.0Hz,1H),3.82(s,9H),3.67-3. 64(m,2H),3.62-3.42(m,9H),3.31-3.19(m,3H),2.91(dd,J=13.4,5.2Hz,1H) ,2.87-2.76(m,2H),2.75-2.71(m,1H),2.67-2.61(m,1H),2.05-1.98(m,1H). 13 C NMR(126MHz,Methanol-d4)δ175.9,147.4,147.3,133.2,131.0,121.3,121.2,114.6,112.8,11 2.1,111.6,72.2,70.0,69.8,69.2,60.7,60.4,55.1,55.0,54.9,50.5,44.3,38.7,35.7,33.8.

[0068] Example 2 In vitro experiment on improving inflammation of diabetic peripheral neuropathy with arctigenin derivatives

[0069] The present invention detects the influence of arctigenin derivatives on inflammation-related transcription factors in an in vitro inflammation model induced by LPS / ATP. The experiment shows that arctigenin derivatives have a significant effect of improving inflammation.

[0070] 1. Experimental Principle

[0071] This experiment was based on the fact that patients with diabetic peripheral neuropathy will experience neuroinflammation, and the inflammation-related indicators were detected in RSC cells to evaluate the improving effect of arctigenin derivatives on neuroinflammation in peripheral neuropathy.

[0072] 2. Experimental Materials and Methods

[0073] On the first day, 1×10 5Schwann cells were planted at a density of 10 μg / mL. On the second day, LPS (1 μg / mL) was given to Schwann cells for six hours, and compounds 10 μM / ml and ATP (3 mM) were given for 30 minutes to induce the expression of inflammasomes. The total RNA in Schwann cells was extracted with RNAiso plus. The treated RSC cells were placed in a 1.5 mL EP tube, and 1 mL RNAisoplus was added to each tube for lysis for 3-5 minutes. After lysis, 200 μL of chloroform was added, and the tube was shaken upside down and left to stand for 5 minutes. Finally, it was placed in a centrifuge at 12000 rpm / min and centrifuged at 4°C for 15 minutes. After centrifugation, the sample was layered, and the upper layer was RNA. The RNA was sucked into a new EP tube, about 400 μL, and the middle layer must not be sucked. Then 500 μL of isopropanol was added, and the mixture was mixed upside down, left to stand for 10 minutes, and centrifuged in a centrifuge at 12000 rpm / min and 4°C for 10 minutes. After centrifugation, the EP tube was taken out and the supernatant was poured out. At this time, a small amount of precipitation would be produced at the bottom of the tube. Add 1mL of 75% ethanol to wash, place in a centrifuge and centrifuge at 12000rpm / min at 4℃ for 10min. Take out the supernatant and discard it, and repeat the washing once. Finally, open the lid of the EP tube and dry it. Add 30μLDEPC water to each tube and dissolve it at 55-60℃ for 10min. Finally, use a nucleic acid quantifier to measure the total RNA concentration. Generally, the A260 / A280 ratio is suitable between 1.8 and 2.0. In the next step, use a reverse transcription kit to reverse mRNA into cDNA, and set the reverse transcription program as: 37℃, 15min; 85℃, 5s; 10℃∞. The cDNA obtained by reverse transcription uses a SYBR Premix Ex Taq kit and performs real-time quantitative PCR in a BIO-RAD CFX connect real-time system instrument. The specific RT-PCR program is: 94°C, 1 min; 95°C, 30 s; 63°C, 45 s; 72°C, 45 s; 80°C, 1 s; read the plate; repeat the above steps for 44 cycles; 72°C, 10 min; gradually increase the temperature from 50 to 95°C, and read the plate once every 0.5°C increase; 10°C, 10 min to end the program.

[0074] 3. Experimental results

[0075] result Figure 1 As shown, the expression level of IL-1β in the model group after LPS / ATP treatment was significantly increased compared with the blank control group, while the expression level of IL-1β was significantly reduced after intervention with ATG (i.e., arctigenin) and compound 1, compound 3, compound 5-8, and compound 10-11 compared with the model group. Among them, compound 10 and compound 11 had the best inhibitory effect on inflammation, and they had a significant IL-1β-reducing effect relative to arctigenin.

[0076] Note: * indicates p<0.05, ** indicates p<0.01, *** Indicates p<0.001.

[0077] Example 3 Experiment on improving motor nerve conduction velocity and sensory loss in diabetic peripheral neuropathy by arctigenin derivatives

[0078] The present invention tests the effect of arctigenin derivatives on motor nerve conduction velocity and pain response of diabetic peripheral neuropathy in STZ-induced type 1 diabetic mice. The experiment shows that arctigenin derivatives have the effect of significantly improving motor nerve conduction velocity and sensory loss of diabetic peripheral neuropathy.

[0079] 1. Experimental Principle

[0080] This experiment is based on the fact that patients with diabetic peripheral neuropathy will experience symptoms such as slowed nerve conduction velocity, decreased sensation, and fatigue. Behavioral indicators such as motor nerve conduction velocity, mechanical pain threshold, and thermal pain reaction time were detected in diabetic peripheral neuropathy model mice to evaluate the improvement effect of arctiin derivatives on the individual behavioral level of peripheral neuropathy.

[0081] 2. Experimental Materials and Methods

[0082] 1) Animal grouping and drug administration

[0083] Construction of type I diabetic mouse model: Male 8-week-old C57BL / 6J mice were purchased from Beijing Weitong Lihua. After one week of adaptive feeding, STZ (150 mg / kg) was injected intraperitoneally. Blood glucose was measured 4-7 days later, and mice with random blood glucose greater than 16 mmol / L were selected. Six weeks after STZ injection, the mice were grouped according to body weight and blood glucose, and were divided into a control group (non-diabetic mice), a model group (DPN mice), and a drug-treated group (compound 10: 25 or 50 mg / kg, arctigenin 40 mg / kg), and were gavaged for 4 weeks. Mechanical pain and thermal pain sensitivity were tested before and after drug administration, respectively, and motor nerve conduction velocity was tested before modeling, before and after drug administration.

[0084] 2) Mechanical pain threshold experiment

[0085] This experiment is based on the principle that rodents' paws will retract reflexively when they are mechanically stimulated. The Vonfrey tactile measurement kit was purchased from Ugo Basile. Vonfrey fibers can provide a stimulation force of 0.008g-300g, and the thickness of the fiber determines the magnitude of the stimulation force. The experiment selected fibers of appropriate thickness based on actual conditions and vertically stimulated the skin. The stimulation force can be adjusted by replacing the fiber until the fiber bends and the mouse retracts its paw, thereby evaluating the mouse's response to pain. A mouse is measured six times to determine the threshold value, based on 50%threshold=(10^(x f The 50% mechanical pain threshold of mice was calculated by using kδ (K) / 10000.

[0086] 3) Thermal pain latency experiment

[0087] The infrared plantar analgesia instrument was purchased from Ugo Basile. A movable radiant heat source was placed directly on the sole of the mouse's hind paw for thermal stimulation. When the mouse lifted its foot or moved away from the heat source, the instrument automatically stopped radiating and recorded the duration. The thermal latency period was used to evaluate the mouse's sensitivity to thermal pain.

[0088] 4) Motor nerve conduction velocity test

[0089] ①Electrode placement: The stimulating electrode is placed on the nerve trunk, the recording electrode is placed on the muscle belly, and the reference electrode is placed on the tendon; the ground wire is placed between the stimulating electrode and the recording electrode. ②Calculation of motor nerve conduction velocity: Super-strong stimulation of the distal and proximal ends of the nerve trunk can record two compound muscle action potentials on the muscles innervated by the nerve, and their different latencies are measured. The distance between the distal and proximal ends is divided by the latency difference between the two points, which is the conduction velocity of the nerve. The calculation formula is: Nerve conduction velocity (m / s) = distance between two points (cm) × 10 / latency difference between two points (ms).

[0090] 3. Experimental results

[0091] The results are shown in Tables 1-3. Compound 10 can significantly improve the motor nerve conduction velocity and sensory loss symptoms in mice with type 1 diabetic peripheral neuropathy. * p<0.05, ** p<0.01, *** p < 0.001 represents model group vs. control group; # p<0.05, ## p<0.01, ### p<0.001 represents the drug-treated group vs. the model group (one-way analysis of variance).

[0092] Table 1 Motor nerve conduction velocity (Mean±SEM., n=8, m / s)

[0093]

[0094] Table 2 Sensory nerve conduction velocity (Mean ± SEM., n = 8, m / s)

[0095]

[0096] Table 3 50% mechanical pain threshold (Mean±SEM., n=8, g)

[0097]

[0098] Table 4 Thermal response (Mean ± SEM., n = 8, s)

[0099]

[0100] The above embodiments are only exemplary embodiments of the present invention and are not intended to limit the present invention. The protection scope of the present invention is defined by the claims. Those skilled in the art may make various modifications or equivalent substitutions to the present invention within the essence and protection scope of the present invention, and such modifications or equivalent substitutions shall also be deemed to fall within the protection scope of the present invention.

Claims

1. An arctiin derivative or a pharmaceutically acceptable salt thereof, wherein the arctiin derivative has the following structure: in, Said R1 is H; The R2 is selected from -(CH2)n-R3, C 5-8 Alkyl, C 3-6 Cycloalkyl; The R3 is selected from -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, cyclopropyl, C 1-3 Alkoxy, C 4-8 Nitrogen-containing heterocyclic groups, The n is selected from 1, 2 or 3.

2. The arctiin derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R2 is selected from cyclopropyl, cyclohexyl, isopentyl, n-hexyl, n-octyl, morpholine, piperidine, piperazine, -(CH2)3-NH2, -(CH2)3-N(CH3)2, -CH2-cyclopropyl, -(CH2)3-methoxy, -(CH2)2-morpholinyl, One of them.

3. The arctiin derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R2 is selected from C 6-8 Alkyl, preferably C 6-8 Straight chain alkyl.

4. An arctiin derivative or a pharmaceutically acceptable salt thereof, wherein the arctiin derivative is selected from the following structures:

5. A pharmaceutical composition for treating diabetic peripheral neuropathy, comprising the arctiin derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 and a pharmaceutically acceptable excipient.

6. The pharmaceutical composition according to claim 5, wherein the dosage form of the pharmaceutical composition is selected from tablets, capsules, and injections.

7. The pharmaceutical composition according to claim 5, wherein the diabetic peripheral neuropathy is caused by type I diabetes or type II diabetes.

8. Use of the arctiin derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 or the pharmaceutical composition according to claim 5 in the preparation of a drug for treating diabetic peripheral neuropathy.

9. The use according to claim 8, wherein the diabetic peripheral neuropathy is caused by type I diabetes or type II diabetes.

10. The use according to claim 8, wherein the treatment of diabetic peripheral neuropathy is to improve nerve conduction velocity and sensory loss symptoms in diabetic patients.

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