Preparation of arctiin aglycone derivatives and application thereof in treating diabetic peripheral neuropathy

Abstract

The application discloses application of arctigenin derivative or a pharmaceutically acceptable salt thereof in preparation of a medicament for treating peripheral neuropathy in diabetes. The application shows through a large number of experiments that the arctigenin derivative and the pharmaceutically acceptable salt thereof can obviously improve nerve conduction velocity and sensory loss symptoms of diabetic mice, thereby achieving the effect of treating peripheral neuropathy.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to arctigenin derivatives and their application in the preparation of drugs for treating diabetic peripheral neuropathy. Background Technology

[0002] Diabetic peripheral neuropathy (DPN) refers to the symptoms associated with peripheral nerve dysfunction in diabetic patients after excluding other causes. Clinically, it presents as symmetrical pain and sensory abnormalities, with lower extremity symptoms being more common than upper extremity symptoms. Sensory abnormalities include numbness, tingling, crawling sensations, burning sensations, and electric shock-like sensations, often ascending from the toes to above the knee. Severe cases of sensory impairment may lead to lower extremity joint disease and ulcers. The pain is described as stabbing, burning, or drilling pain, seemingly radiating deep into the bone marrow, sometimes excruciating like amputation pain, and is worse at night than during the day. When motor nerves are involved, muscle strength often declines to varying degrees, and in later stages, dystrophic muscle atrophy occurs. Peripheral neuropathy can be bilateral or unilateral, symmetrical or asymmetrical, but bilateral symmetrical cases are more common.

[0003] Peripheral neuropathy (DPN) is the most common chronic complication of diabetes, affecting approximately 50% of diabetic patients in its later stages. DPN primarily affects sensory neurons, with main pathological changes including axonal atrophy, degeneration, and even disappearance; segmental or diffuse myelin sheath shrinkage or demyelination; and alterations in the internode length of Ranvier's nodes due to myelin regeneration. DPN is characterized by the loss of nerve fibers, primarily occurring in ischemic sites. Extensive peroneal nerve biopsies and autopsies have revealed that diabetic patients presenting with distal symmetrical polyneuropathy exhibit segmental demyelination in addition to primary Schwann cell abnormalities. This pathological change is commonly seen in myelinated major nerves such as the sural, tibial, and median nerves, leading to shortened internode spacing, slowed nerve conduction velocity, and symptoms such as sensory loss and weakness. Therefore, it is believed that protecting and promoting the growth of sensory neuronal processes can provide a therapeutic effect against diabetic peripheral neuropathy. Currently, drugs used in clinical practice to treat diabetic peripheral neuropathy can only slow down the symptoms and cannot stop the progression of diabetic peripheral neuropathy. Therefore, there is an urgent need for the discovery of new anti-diabetic peripheral neuropathy drugs that can block the pathological process of diabetic peripheral neuropathy.

[0004] Arctiocarboxylic acid, its structural formula is:

[0005] Summary of the Invention

[0006] The first aspect of this invention provides an arctiin derivative or a pharmaceutically acceptable salt thereof. The arctiin derivative has the structure of Formula I.

[0007]

[0008] Wherein, R1 is H;

[0009] The R2 is selected from -(CH2)n-R3, C 5-8 Alkyl, C 3-6 cycloalkyl;

[0010] 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,

[0011] The number n is selected from 1, 2, or 3.

[0012] 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,

[0013] In some implementations, R2 is selected from C 6-8 Alkyl group, preferably C 6-8 Straight-chain alkyl groups.

[0014] The arctiin derivatives of this invention are selected from the following structures:

[0015]

[0016]

[0017] A second aspect of the present invention provides a pharmaceutical composition for treating diabetic peripheral neuropathy, the pharmaceutical composition comprising an arctiin derivative or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient of the first aspect of the present invention.

[0018] In some embodiments, the dosage form of the pharmaceutical composition may be selected from tablets, capsules, or injections.

[0019] The third aspect of the present invention provides the use of the arctiin derivative of the first aspect of the present invention or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of the second aspect of the present invention in the preparation of a medicament for treating diabetic peripheral neuropathy.

[0020] In some implementations, the diabetic peripheral neuropathy is caused by type 1 diabetes.

[0021] In some implementations, the diabetic peripheral neuropathy is caused by type 2 diabetes.

[0022] In some implementations, the treatment of diabetic peripheral neuropathy aims to improve nerve conduction velocity and sensory loss symptoms in diabetic patients.

[0023] Beneficial effects

[0024] This invention optimizes the structure of the natural compound arctigenin to obtain a series of arctigenin derivatives, which have excellent inhibitory effects on neuroinflammation and can significantly improve the motor nerve conduction velocity and sensory loss in diabetic peripheral neuropathy. They have great application value in the treatment of diabetic peripheral neuropathy. Attached Figure Description

[0025] Figure 1 To investigate the effects of different compound interventions on the expression level of the inflammatory cytokine IL-1β in cells.

[0026] Specific Implementation Cases

[0027] The following embodiments are intended to enable those skilled in the art to more fully understand the present invention, but are not intended to limit the invention to the scope of the embodiments described.

[0028] Example 1: Synthesis of Arctium aglycone derivatives

[0029] Synthesis of Compound 1

[0030]

[0031] 1 mL of propylenediamine and 0.2 mmol (-) arctigenin were added to a 10 mL microwave-safe reaction vial. The microwave reactor was programmed to reach 110 °C for 3 minutes and last for 1 hour. The vial was then placed in the microwave generator to begin the microwave reaction. After the program ended, the reaction solution was cooled to room temperature and then adjusted to pH 7.0 with 2 M HCl solution. The reaction solution was then extracted three times with 20 mL of ethyl acetate solution. The organic phases were combined, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography to obtain 57 mg 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.

[0032] Synthesis of Compound 2

[0033]

[0034] Under N2 protection, 2 mL of LDM, 1 mL of cyclopropylamine, and 0.2 mmol of (-) arctigenin were added to a 10 mL sealed tube, and the reaction was carried out overnight at 140 °C. After the reaction was complete, the reaction solution was cooled to room temperature, and then the pH was adjusted to 7.0 with 2 M HCl solution. The reaction solution was then extracted three times with 20 mL of ethyl acetate solution. The organic phases were combined, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography to obtain 63 mg of a colorless viscous liquid, (2R,3R)-N-cyclopropyl-3-(3,4-dimethoxybenzyl)-4-hydroxy-2-(4-hydroxy-3-methoxybenzyl)butyramide. The yield was 73.34%. 1 H NMR(500MHz,Chloroform-d)δ6.80-6.77(m,2H),6.70(d,J=5.0Hz,2H),6.59(d, J=15.0Hz,2H),5.65(s,1H),3.94(d,J=10.0Hz,1H),3.85(d,J=10.0Hz,9H),3.7 2(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=7.2Hz,1H),0.35-0.18(m,2H).

[0035] Synthesis of Compound 3

[0036]

[0037] Under N2 protection, 2 mL of LDM, 1 mL of cyclopropylmethylamine, and 0.2 mmol of (-)arbuscular aglycone were added to a 10 mL sealed tube, and the reaction was carried out overnight at 140 °C. After the reaction was complete, the reaction solution was cooled to room temperature, and then the pH was adjusted to 7.0 with 2 M HCl solution. The reaction solution was then extracted three times with 20 mL of ethyl acetate solution. The organic phases were combined, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography to give 68 mg of a colorless viscous liquid, (2R,3R)-N-(cyclopropylmethyl)-3-(3,4-dimethoxybenzyl)-4-hydroxy-2-(4-hydroxy-3-methoxybenzyl)butyramide. The yield was 76.66%. 1 H NMR(500MHz,Chloroform-d)δ6.81(t,J=10.0Hz,2H),6.77-6.70(m,2H),6.63 (d,J=10.0Hz,2H),5.68(s,2H),5.51(s,1H),4.37(s,1H),3.99(d,J=20.0Hz, 1H),3.93-3.79(m,9H),3.55(d,J=10.0Hz,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).

[0038] Synthesis of Compound 4

[0039]

[0040] Under N2 protection, 2 mL of DMF, 1 mL of isopropylamine, and 0.2 mmol (-) arctigenin were added to a 10 mL sealed tube, and the reaction was carried out overnight at 120 °C. After the reaction was complete, the reaction solution was cooled to room temperature, and then the pH was adjusted to 7.0 with 2 M HCl solution. The reaction solution was then extracted three times with 20 mL of ethyl acetate solution. The organic phases were combined, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography to obtain 59 mg of a colorless viscous liquid, (2R,3R)-3-(3,4-dimethoxybenzyl)-4-hydroxy-2-(4-hydroxy-3-methoxybenzyl)-N-isopropylbutyramide, with a yield of 68.36%. 1H 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).

[0041] Synthesis of Compound 5

[0042]

[0043] Under N2 protection, 2 mL of LDM, 1 mL of n-butylamine, and 0.2 mmol of (-) arctigenin were added to a 10 mL sealed tube, and the reaction was carried out overnight at 140 °C. After the reaction was complete, the reaction solution was cooled to room temperature, and then the pH was adjusted to 7.0 with 2 M HCl solution. The reaction solution was then extracted three times with 20 mL of ethyl acetate solution. The organic phases were combined, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography to obtain 77 mg of a colorless viscous liquid, (2R,3R)-N-butyl-3-(3,4-dimethoxybenzyl)-4-hydroxy-2-(4-hydroxy-3-methoxybenzyl)butyramide. The yield was 86.41%. 1 H 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). 13C 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.

[0044] Synthesis of Compound 6

[0045]

[0046] Under N2 protection, 2 mL of LDM, 1 mL of isoamylamine, and 0.2 mmol of (-) arctigenin were added to a 10 mL sealed tube, and the reaction was carried out overnight at 140 °C. After the reaction was complete, the reaction solution was cooled to room temperature, and then the pH was adjusted to 7.0 with 2 M HCl solution. The reaction solution was then extracted three times with 20 mL of ethyl acetate solution. The organic phases were combined, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography to obtain 49 mg of a colorless viscous liquid, (2R,3R)-3-(3,4-dimethoxybenzyl)-4-hydroxy-2-(4-hydroxy-3-methoxybenzyl)-N-isoamylbutyramide. The yield was 53.31%. 1 H 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.

[0047] Synthesis of Compound 7

[0048]

[0049] 1 mL of 3-methoxypropylamine and 0.2 mmol (-) arctigenin were added to a 10 mL microwave-safe reaction vial. The microwave reactor was programmed to reach 110 °C for 3 minutes and last for 1 hour. The vial was then placed in the microwave generator to begin the microwave reaction. After the program ended, the reaction solution was cooled to room temperature and then adjusted to pH 7.0 with 2 M HCl solution. The reaction solution was then extracted three times with 20 mL of ethyl acetate solution. The organic phases were combined, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography to obtain 78 mg 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%. 1 H 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 CNMR(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.

[0050] Synthesis of Compound 8

[0051]

[0052] 1 mL of cyclohexylamine and 0.2 mmol (-) arctigenin were added to a 10 mL microwave-safe reaction vial. The microwave reactor was programmed to reach 110 °C for 3 minutes and last for 1 hour. The vial was then placed in the microwave generator to begin the microwave reaction. After the program ended, the reaction solution was cooled to room temperature and then adjusted to pH 7.0 with 2 M HCl solution. The reaction solution was then extracted three times with 20 mL of ethyl acetate solution. The organic phases were combined, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography to obtain 78 mg 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%. 1 H 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 C NMR(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.

[0053] Synthesis of Compound 9

[0054]

[0055] 2 mL of 3-(dimethylamino)propylamine and 0.2 mmol of (-)arbuscular aglycone were added to a 10 mL microwave-safe reaction vial. The microwave reactor was programmed to reach 110 °C for 3 minutes and last for 1 hour. The vial was then placed in the microwave generator to begin the microwave reaction. After the program ended, the reaction solution was cooled to room temperature and then adjusted to pH 7.0 with 2 M HCl solution. The reaction solution was then extracted three times with 20 mL of ethyl acetate solution. The organic phases were combined, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography to obtain 76 mg 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%. 1 H NMR (500MHz, Methanol-d4) δ6.89 (d, J = 10.0Hz, 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 C NMR(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] 2 mL of n-hexylamine and 0.2 mmol (-) arctigenin were added to a 10 mL microwave-safe reaction vial. The microwave reactor was programmed to reach 110 °C for 3 minutes and last for 1 hour. The vial was then placed in the microwave generator to begin the microwave reaction. After the program ended, the reaction solution was cooled to room temperature and then adjusted to pH 7.0 with 2 M HCl solution. The reaction solution was then extracted three times with 20 mL of ethyl acetate solution. The organic phases were combined, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography to obtain 88 mg 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%. 1 H 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 C10 NMR (126 MHz, Methanol-d4) δ 175.7, 148.9, 147.3, 133.1, 131.0, 121.3, 121.1, 114.6, 112.8, 112.1, 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. Synthesis of Compound 11

[0059]

[0060] 1 mL of n-octylamine and 0.2 mmol (-) arctigenin were added to a 10 mL microwave-safe reaction vial. The microwave reactor was programmed to reach 110 °C for 3 minutes and last for 1 hour. The vial was then placed in the microwave generator to begin the microwave reaction. After the program ended, the reaction solution was cooled to room temperature and then adjusted to pH 7.0 with 2 M HCl solution. The reaction solution was then extracted three times with 20 mL of ethyl acetate solution. The organic phases were combined, dried over anhydrous sodium sulfate, evaporated to dryness, 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-octylbutyramide. The yield was 90.70%. 1 H 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.

[0061] Synthesis of Compound 12

[0062]

[0063] 1 mL of N-(2-aminoethyl)morpholine and 0.2 mmol of (-)arbuscular aglycone were added to a 10 mL microwave-safe reaction vial. The microwave reactor was programmed to reach 110 °C for 3 minutes and last for 1 hour. The vial was then placed in the microwave generator to begin the microwave reaction. After the program ended, the reaction solution was cooled to room temperature and then adjusted to pH 7.0 with 2 M HCl solution. The reaction solution was then extracted three times with 20 mL of ethyl acetate solution. The organic phases were combined, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography to obtain 83 mg 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%. 1 H 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.

[0064] Synthesis of Compound 13

[0065]

[0066] 2 mL of 2-[2-(2-aminoethoxy)ethoxy]ethanol and 0.2 mmol of (-)arbuscular aglycone were added to a 10 mL microwave-safe reaction vial. The microwave reactor was programmed to reach 110 °C for 3 minutes and last for 1 hour. The vial was then placed in the microwave generator to begin the microwave reaction. After the program ended, the reaction solution was cooled to room temperature and then adjusted to pH 7.0 with 2 M HCl solution. The reaction solution was then extracted three times with 20 mL of ethyl acetate solution. The organic phases were combined, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography to obtain 76 mg 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%. 1 HNMR(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.

[0067] Example 2: In vitro experiment on the improvement of inflammation in diabetic peripheral neuropathy by arctiinogen derivatives

[0068] This invention investigates the effects of arctigenin derivatives on inflammation-related transcription factors in an LPS / ATP-induced in vitro inflammation model. Experiments show that arctigenin derivatives significantly improve inflammation.

[0069] 1. Experimental Principle

[0070] This experiment was conducted based on the fact that patients with diabetic peripheral neuropathy experience neuroinflammation. In RSC cells, inflammation-related indicators were detected to evaluate the ameliorative effect of arctigenin derivatives on neuroinflammation in peripheral neuropathy.

[0071] 2. Experimental Materials and Methods

[0072] The first day with 1×10 5 Schwann cells were seeded at a specific density. The next day, the cells were treated with LPS (1 μg / mL) for six hours, followed by 10 μM / mL of a compound and ATP (3 mM) for 30 minutes to induce inflammasome expression. Total RNA was extracted from the Schwann cells using RNAisoplus. The treated RSC cells were placed in 1.5 mL EP tubes, and 1 mL of RNAisoplus was added to each tube for lysis for 3-5 minutes. After lysis, 200 μL of chloroform was added, the tube was vigorously shaken upside down 15 times, and allowed to stand for 5 minutes. Finally, the tubes were centrifuged at 12000 rpm / min at 4°C for 15 minutes. After centrifugation, the sample separated into layers, with RNA on the top layer. Approximately 400 μL of RNA was transferred to a new EP tube, being careful not to aspirate the middle layer. Then, 500 μL of isopropanol was added, the tubes were mixed by inverting, allowed to stand for 10 minutes, and then centrifuged at 12000 rpm / min at 4°C for 10 minutes. After centrifugation, the EP tubes were removed, and the supernatant was discarded. A small amount of precipitate was expected at the bottom of the tube. Add 1 mL of 75% ethanol for washing, then centrifuge at 12000 rpm / min, 4°C for 10 min. Discard the supernatant and repeat the washing process once more. Finally, open the EP tube cap and allow it to air dry. Add 30 μL of LEPC water to each tube and incubate at 55-60°C for 10 min to aid dissolution. Measure the total RNA concentration using a nucleic acid quantification instrument; an A260 / A280 ratio between 1.8 and 2.0 is generally suitable. Next, reverse transcription is used to convert mRNA into cDNA. The reverse transcription program is: 37°C, 15 min; 85°C, 5 s; 10°C to infinity. The cDNA obtained from reverse transcription is then used in real-time quantitative PCR on a BIO-RAD CFX connect real-time system using the SYBR Premix Ex Taq kit. The specific RT-PCR program is as follows: 94℃, 1 min; 95℃, 30 s; 63℃, 45 s; 72℃, 45 s; 80℃, 1 s; read the plate; repeat the above steps for 44 cycles; 72℃, 10 min; gradually increase the temperature to 50-95℃, reading the plate once for every 0.5℃ increase; 10℃, 10 min to end the program.

[0073] 3. Experimental Results

[0074] result Figure 1As shown, the LPS / ATP-treated model group exhibited a significantly increased IL-1β expression level compared to the blank control group. However, intervention with ATG (arbuscular aglycone) and compounds 1, 3, 5-8, and 10-11 resulted in a significantly decreased IL-1β expression level compared to the model group. Among these, compounds 10 and 11 showed the best anti-inflammatory effects, exhibiting a significantly lower IL-1β expression level relative to aglycone.

[0075] Note: * ** indicates p < 0.05, ** indicates p < 0.01, and *** indicates p < 0.001.

[0076] Example 3: Experiment on the improvement of motor nerve conduction velocity and sensory loss in diabetic peripheral neuropathy by arctiinogen derivatives.

[0077] This invention investigated the effects of arctigenin derivatives on motor nerve conduction velocity and pain response in diabetic peripheral neuropathy in STZ-induced type 1 diabetic mice. The results showed that arctigenin derivatives significantly improved motor nerve conduction velocity and sensory loss in diabetic peripheral neuropathy.

[0078] 1. Experimental Principle

[0079] This experiment is based on the symptoms of diabetic peripheral neuropathy, such as slowed nerve conduction velocity, decreased sensation, and fatigue. Behavioral indicators such as motor nerve conduction velocity, mechanical pain threshold, and thermal pain response time were measured in diabetic peripheral neuropathy model mice to evaluate the ameliorative effect of arctigenin derivatives on the individual behavioral level of peripheral neuropathy.

[0080] 2. Experimental Materials and Methods

[0081] 1) Animal grouping and administration

[0082] Establishment of a type 1 diabetic mouse model: Male 8-week-old C57BL / 6J mice were purchased from Vital River Pharmaceuticals in Beijing. After one week of acclimatization, they were intraperitoneally injected with STZ (150 mg / kg). Blood glucose levels were measured 4-7 days later, and mice with random blood glucose levels greater than 16 mmol / L were selected. Six weeks after STZ injection, mice were grouped according to body weight and blood glucose levels into a control group (non-diabetic mice), a model group (DPN mice), and a treatment group (compound 10:25 or 50 mg / kg, arctigenin 40 mg / kg), administered by gavage for 4 weeks. Mechanical pain and thermal pain sensitivity were measured weekly before and after drug administration, respectively. Motor nerve conduction velocity was measured before model establishment, before drug administration, and after drug administration.

[0083] 2) Mechanical pain threshold test

[0084] This experiment is based on the principle of the retraction reflex in rodents when their claws are mechanically stimulated. The Vonfrey tactile measurement kit was purchased from Ugo Basile. Vonfrey fibers can provide a stimulating force ranging from 0.008g to 300g, with the thickness of the fiber determining the magnitude of the force. The experiment used fibers of appropriate thickness selected according to the actual situation, stimulating the skin vertically. The stimulation force was adjusted by changing the fibers until the fibers bent, causing the mouse to exhibit a paw withdrawal response. This was used to assess the mouse's response to pain. Each mouse was measured six times to determine the threshold, based on the formula 50% threshold = (10^(x)). f +kδ)) / 10000 calculates the 50% mechanical pain threshold of mice.

[0085] 3) Thermal pain latency test

[0086] The infrared plantar pain meter was purchased from Ugo Basile. A portable heat source was placed directly on the sole of the mouse's hind paw for thermal stimulation. When the mouse lifted its paw or moved away from the heat source, the instrument automatically stopped radiating and recorded the duration. The duration of this thermal latency was used to assess the mouse's sensitivity to thermal pain.

[0087] 4) Motor nerve conduction velocity detection experiment

[0088] ① Electrode Placement: The stimulating electrode is placed on the nerve trunk, the recording electrode on the muscle belly, and the reference electrode on the tendon; the ground wire is placed between the stimulating and recording electrodes. ② Calculation of Motor Nerve Conduction Velocity: Strong stimulation of the distal and proximal ends of the nerve trunk will record two compound muscle action potentials on the muscles innervated by this nerve. The different latencies are measured, and the nerve conduction velocity is calculated by dividing the distance between the distal and proximal ends by the difference in latency between the two points. The formula is: Nerve conduction velocity (m / s) = Distance between two points (cm) × 10 / Latency difference between two points (ms).

[0089] 3. Experimental Results

[0090] The results are shown in Tables 1-3. Compound 10 significantly improved 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 the model group vs. the control group; # p<0.05, ## p<0.01, ### p<0.001 represents the treatment group vs. the model group (one-way ANOVA).

[0091] Table 1. Motor nerve conduction velocity (Mean±SEM., n=8, m / s)

[0092]

[0093] Table 2 Sensory nerve conduction velocities (Mean±SEM., n=8, m / s)

[0094]

[0095]

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

[0097]

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

[0099]

[0100]

[0101] The above embodiments are merely exemplary embodiments of the present invention and are not intended to limit the present invention. The scope of protection of the present invention is defined by the claims. Those skilled in the art can make various modifications or equivalent substitutions to the present invention within its spirit and scope of protection, and such modifications or equivalent substitutions should also be considered to fall within the scope of protection of the present invention.

Claims

1. An arctiin derivative or a pharmaceutically acceptable salt thereof, said arctiin derivative having the structure of Formula I: in, 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; The number 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, -(CH2)3-NH2, -(CH2)3-N(CH3)2, -CH2-cyclopropyl, -(CH2)3-methoxy.

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

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

5. An arctiin derivative or a pharmaceutically acceptable salt thereof, said arctiin derivative being selected from the following structures:

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

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

8. Use of the arctiin derivative of any one of claims 1-5 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 6 in the preparation of a medicament for treating diabetic peripheral neuropathy.

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