CN108003218A - Limonin A ring ammonolysis derivative, its preparation method and medical usage - Google Patents

Abstract

The invention belongs to the field of medicinal chemistry, and in particular relates to limonin A ring aminolysis derivatives I and II, their preparation methods, and pharmaceutical compositions containing these compounds. Pharmacodynamic tests have proved that the compounds of the present invention have the ability to treat inflammation and pain aspects of use.

Description

Limonin A ring aminolysis derivative, its preparation method and medical application

technical field

The invention relates to the field of medicinal chemistry, in particular to a class of limonin A ring aminolysis derivatives and deoxylimonin A ring aminolysis derivatives, their preparation method and their analgesic and anti-inflammatory effects.

Background technique

Pain has been listed as the fifth vital sign after body temperature, pulse, respiration, and blood pressure by modern medicine. If it is not treated in time and effectively, it will seriously affect the quality of daily life and social stability. Analgesia has become an important task for medical workers . At present, the mainstream analgesics on the market can be mainly divided into opioid receptor agonists, non-steroidal anti-inflammatory drugs, and anticonvulsants according to their mechanism of action and structure. Although great progress has been made in the research of analgesics, both non-steroidal antipyretic analgesic and anti-inflammatory drugs for mild and moderate pain, and analgesics for moderate and severe pain all have their own side effects And limitations, on the other hand because the side effects caused by analgesic abuse also seriously endanger people's health. Therefore, it is of great practical and social significance to find analgesic drugs that are safe, effective, and have little side effects.

Limonin analogs are a class of highly oxidized secondary metabolites of tetracyclic triterpenoids, mainly found in Rutaceae and Meliaceae plant tissues, and have various biological activities such as analgesic, anti-inflammatory, anti-tumor, and insect antifeedant . However, the activity of limonin is not strong enough, its water solubility is poor, and its bioavailability is low, which limits its clinical application.

Contents of the invention

The invention discloses compounds of general formulas I and II. Pharmacological experiments prove that the compounds of the invention have relatively good analgesic and anti-inflammatory activities. Therefore, the compounds of the general formulas I and II of the present invention can be used for clinical pain relief and inflammation elimination.

Where R represents: H, C ₁ ~ C ₆ alkyl, R ¹ represents: H, C ₁ -C ₆ alkyl.

R ² represents: H, F, Cl, Br, CH ₃ , OCH ₃ , NH ₂ , NHCOCH ₃ , CONH ₂ , CN or NO ₂ , which can be monosubstituted or double substituted.

X stands for: CH ₂ , O, NH or NCH ₃ .

m=2 or 3.

n=1 or 2.

The general formula compound I of the present invention can be prepared by the following methods:

The above reaction is obtained by reacting limonin (1) with the corresponding amine (R-NH ₂ ) in a solvent, wherein R-NH ₂ is selected from the corresponding fatty amine or substituted aniline, and the solvent is selected from acetonitrile or tetrahydrofuran.

The general formula compound II of the present invention can be prepared by the following methods:

The above reaction is obtained by reacting deoxylimonin (2) with the corresponding amine (R-NH ₂ ) in a solvent, wherein R-NH ₂ is selected from the corresponding fatty amine or substituted aniline, and the solvent is selected from acetonitrile or tetrahydrofuran.

The compound (I) or (II) of the present invention can be added with a pharmaceutically acceptable carrier to make common pharmaceutical preparations, such as tablets, capsules, powders, syrups, liquids, suspensions, freeze-dried powder injections, For injection, common pharmaceutical excipients such as spices, sweeteners, liquid or solid fillers or diluents can be added.

Another object of the present invention is to provide the limonin derivatives of the general formula I or the deoxylimonin derivatives of the general formula II and their stereoisomers, hydrates, solvates or crystals of the present invention in the preparation of treating pain or Application in inflammatory drugs. Comprising the administration of a compound, stereoisomer, hydrate, solvate or crystal of or comprising a compound of formula I or II, stereoisomer, hydrate, solvent to a patient suffering from pain or inflammation Compounds or crystalline pharmaceutical compositions to effectively relieve symptoms in patients.

Some compounds provided by the invention are as follows:

Below are the pharmacological experiments and results of some compounds of the present invention:

(1) Mouse acetic acid writhing experiment

experimental method:

ICR mice, half male and half female, weighing 18-22 g, were randomly divided into a model group (0.5% CMC-Na solution) and each test drug group, with 8 mice in each group. Each administration group was suspended with 0.5% CMC-Na solution, and administered intragastrically at a dose of 0.1 mL/10 g. One hour after intragastric administration, 0.1 mL/10 g of 0.7% acetic acid was injected intraperitoneally, and the number of writhing times of mice within 15 minutes was recorded. The results are shown in Table 1.

Table 1 Effect of limonin A ring aminolysis derivatives on the number of writhing in mice

Note: ^* p<0.05, ^** p<0.01, ^*** p<0.001vs model group

The analgesic activity of the compound can be investigated by the mouse acetic acid writhing model. The results in Table 1 show that the analgesic activity of derivatives after aminolysis of ring A is improved compared with limonin or deoxylimonin, wherein compounds I-1, I-2, I-7, I-14, I-16, II-4, II-6, II-8-II-10, II-13, II-15 have an inhibition rate of more than 50% on mouse writhing, showing better analgesic activity. The inhibition rate of compound II-15 reached 68.75%, much higher than 46.02% of limonin.

(2) Xylene-induced mouse ear swelling experiment

experimental method:

ICR male mice, weighing 18-22 g, were randomly divided into a model group and each test drug group, with 8 mice in each group. The test group was administered with 0.5% CMC-Na solution after suspending the drug, and the model group was administered with 0.5% CMC-Na blank solution, and the dosage was 0.1ml/10g. After 90 minutes of administration in each group, smear 25ul of xylene on the right ear of the mouse to cause inflammation, pull the neck to kill after 30 minutes, punch both ears with an 8mm puncher, get the ears and weigh them, and calculate the swelling rate (%) and swelling Inhibition rate(%). The results are shown in Table 3 and Table 4.

Table 3 Effect of limonin A ring aminolysis derivatives on mouse ear swelling

Note: ^* p<0.05, ^** p<0.01, ^*** p<0.001vs model group

Through xylene-induced mouse ear swelling experiments, it can be seen that the anti-inflammatory activity of most of the modified derivatives has been improved to varying degrees, among which compounds I-4, I-7, II-7, II-10, II- 11. II-14 and II-15 showed extremely significant inhibitory activity on ear swelling in mice, and the inhibitory activity was not only stronger than that of limonin, but also stronger than that of naproxen, indicating that the modification of aminolysis of ring A is beneficial to the anti-inflammatory effect of the compound Increased activity.

Detailed ways

Example 1

Preparation of Compound I-1

Add limonin (1g, 2, 13mmol) and tetrahydrofuran (30mL) into a 100mL three-necked flask, add ammonia water (20mL) dropwise under ice bath conditions, remove the ice bath after dropping, and react at room temperature for 4 hours. Remove some solvent. Add 100 mL of water to the residue, adjust the pH to acidic with 5% dilute hydrochloric acid, extract the aqueous layer three times with dichloromethane (80 mL×3), combine the organic layers, wash with saturated brine three times (100 mL×3), and dry over anhydrous sodium sulfate . Filter and distill off the solvent under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol=100:1) to obtain 0.45 g of white solid (I-1), yield 43%, 160°C (decomposition). IR(KBr,υcm ^-1 ):3456,3359,2963,2351,1741,1710,1662,1594,1500,1387,1282,1163,1027,874,803. ¹ HNMR(500MHz,CDCl ₃ ),δ(ppm) :7.40(s,1H),7.39(dd,J ₁ =6.9Hz,J ₂ =0.8Hz,1H),6.38(brs,1H),6.37(dd,J ₁ =1.8Hz,J ₂ =0.8Hz, 1H),5.44(s,1H),5.32(brs,1H),4.55(dd,J ₁ =8.6Hz,J ₂ =5.7Hz,2H),3.83(brs,1H),3.81(s,1H), 2.86 (dd, J ₁ =15.8Hz, J ₂ =2.5Hz, 1H), 2.83 (d, J = 12.0Hz, 1H), 2.69 (dd, J ₁ =15.7Hz, J ₂ =9.3Hz, 1H), 2.31(dd, J ₁ =14.4Hz, J ₂ =3.6Hz, 2H), 2.50–2.07(m, 1H), 2.05(dd, J ₁ =29.8Hz, J ₂ =14.0Hz, 1H), 2.00–1.93 (m,1H),1.82(s,1H),1.67–1.74(m,1H),1.44–1.36(m,1H),1.31(s,3H),1.25(s,3H),1.12(s,3H ),1.05(s,3H) ^.13 C NMR(75MHz,CDCl ₃ ),δ(ppm):207.23,173.55,166.71,142.61,140.48,119.73,109.20,82.07,78.22,77.79,65.02,60.79,60.44, 52.65, 52.02, 50.58, 48.22, 38.55, 37.16, 35.97, 33.06, 29.35, 22.93, 21.82, 20.68, 15.44. HR-ESIMS m/z 488.2274[M+H] ⁺ (calcd for C ₂₆ H ₃₄ NO ₈ , 4988.2 ).

Example 2

Preparation of Compound I-2

Using limonin (1) and methylamine aqueous solution as raw materials, the operation was the same as that of I-1, and the crude product was purified by column chromatography (dichloromethane:methanol=100:1) to obtain 0.74 g of white solid (I-2). Yield 69%, 156°C (decomposition). IR(KBr,υcm ^-1 ):3386,3138,2955,1740,1705,1643,1543,1460,1384,1286,1163,1027,874,800,603. ¹ HNMR(500MHz,CDCl ₃ ),δ(ppm):7.40 (t, J = 0.7Hz, 1H), 7.39 (t, J = 1.7Hz, 1H), δ6.48 (d, J = 4.55Hz, 1H), 6.34 (dd, J ₁ = 1.7Hz, J ₂ = 0.7Hz, 1H), 5.43(s, 1H), 4.14(s, 2H), 3.80(s, 1H), 3.78(dd, J ₁ = 9.0Hz, J ₂ = 2.1Hz, 1H), 2.92–2.86( m, 2H), 2.81(d, J＝4.8Hz, 3H), 2.66(dd, J ₁ ＝15.8Hz, J ₂ ＝9.2Hz, 1H), 2.35–2.27(m, 2H), 2.14–2.04(m ,1H),2.04–1.95(m,3H),1.67–1.73(m,1H),1.46–1.38(m,1H),1.32(s,3H),1.25(s,3H),1.11(s,3H ),1.04(s,3H). ¹³ C NMR(75MHz,CDCl ₃ ),δ(ppm):207.28,171.92,166.67,142.62,140.46,119.73,109.17,82.33,78.27,77.82,65.01,60.79,60.32, 52.64,52.05,50.55,48.35,38.78,37.16,35.97,33.13,29.40,25.85,22.91,21.84,20.66,15.41. HR-ESIMS m/z 502.243[M+H] ⁺ (calcdfor C ₂₇ H ₃₆ NO ₈ , 502.2435).

Example 3

Preparation of Compound I-3

Using limonin (1) and ethylamine aqueous solution as raw materials, the operation was the same as that of I-1, and the crude product was purified by column chromatography (dichloromethane:methanol=100:1) to obtain 0.70 g of white solid (I-3). Yield 64%, 140°C (decomposition). IR(KBr,υcm ^-1 ):3386,3132,2961,1752,1708,1646,1540,1451,1387,1278,1166,1033,847,803. ¹ H NMR(500MHz,CDCl ₃ ),δ(ppm): 8.31(brs,1H),7.40(s,1H),7.38(t,J=1.7Hz,1H),6.45(brs,1H),6.34(s,1H),5.43(s,1H),4.14(s ,2H),3.80(s,1H),3.77(d,J=7.1Hz,1H),3.31–3.26(m,2H),2.85(t,J=15.1Hz,2H),2.65(dd,J ₁ =15.5Hz, J ₂ =8.5Hz,1H), 2.34–2.27(m,2H), 2.18–2.03(m,5H),1.71(dd,J ₁ =13.9Hz, J ₂ =6.8Hz,1H), 1.44–1.35(m,1H),1.31(s,3H),1.24(s,3H),1.14(t,J＝7.3Hz,3H),1.11(s,3H),1.04(s,3H). ¹³ C NMR(75MHz,CDCl ₃ ),δ(ppm):207.36,171.30,166.71,142.62,140.45,119.73,109.17,82.38,78.25,77.85,65.02,60.80,60.17,52.63,52.07,50.579,38.8 37.15,35.99,33.94,33.16,29.33,22.89,21.90,20.67,15.39,14.13. HR-ESIMS m/z 516.2592[M+H] ⁺ (calcd for C ₂₈ H ₃₈ NO ₈ ,516.2592).

Example 4

Preparation of Compound I-4

Limonin (1g, 2.13mmol), benzylamine (1.37g, 12.78mmol) and tetrahydrofuran (30mL) were added into a 100mL three-necked flask, and refluxed for 24 hours. TLC detected that the reaction was complete, and part of the solvent was distilled off under reduced pressure. Add 100 mL of water to the residue, adjust the pH to acidic with 5% dilute hydrochloric acid, extract the aqueous layer three times with dichloromethane (80 mL×3), combine the organic layers, wash with saturated brine three times (100 mL×3), and dry over anhydrous sodium sulfate . Filter and distill off the solvent under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol=100:1) to obtain 0.92 g of white solid (I-4), yield 75%, 230°C (decomposition). IR(KBr,υcm ^-1 ):3522,3421,3144,2979,1723,1678,1664,1540,1499,1451,1292,1157,1033,1004,877,827,727. ¹ HNMR(500MHz,DMSO),δ(ppm ):8.25(t,J=5.9Hz,1H),7.71(s,1H),7.65(t,J=1.7Hz,1H),7.31–7.26(m,4H),7.24–7.18(m,1H) ,6.49(d,J＝1.2Hz,1H),5.43(s,1H),4.28(qd,J ₁ ＝15.5Hz,J ₂ ＝6.0Hz,2H),4.02(d,J＝10.8Hz,1H) ,3.95–3.87(m,2H),3.83(s,1H),3.28(d,J＝11.85Hz,1H),3.18–3.15(m,1H),3.04(t,J＝15.0Hz,1H), 2.64 (dd, J ₁ =14.6Hz, J ₂ =2.25Hz, 1H), 2.28 (d, J = 10.9Hz, 1H), 2.19 (dd, J ₁ =14.4Hz, J ₂ =3.5Hz, 1H), 2.11(dd,J ₁ =15.7Hz,J ₂ =3.4Hz,1H),1.93–1.78(m,2H),1.70–1.63(m,1H),1.26(s,3H),1.15(s,3H) ,1.10(s,3H),0.96(s,3H). ¹³ C NMR(75MHz,DMSO),δ(ppm):209.66,171.01,167.74,143.78,142.08,140.15,128.52,127.41,126.99,120.69,110.67 m +H] ⁺ (calcd for C ₃₃ H ₄₀ NO ₈ ,578.2748).

Example 5

Preparation of Compound I-5

Using limonin (1) and p-fluorobenzylamine as raw materials, the operation is the same as that of I-4, and the crude product is purified by column chromatography (dichloromethane:methanol=100:1) to obtain 1.04 g of light yellow solid (I-5) , yield 82%, 226°C (decomposition). IR (KBr, υcm ^-1 ): 3533, 3433, 3150, 3115, 2973, 2879, 1723, 1675, 1602, 1543, 1507, 1446, 1345, 1292, 1227 , 1157, 1110, 1027, 1004, 915, 874, 818, 762, 715, 603. ¹ H NMR (500MHz, CDCl ₃ ), δ (ppm): 7.40 (s, 1H), 7.39 (s, 1H), 7.24 (s, 1H), 7.00 (t , J=8.6Hz, 2H), 6.78(d, J=5.5Hz, 1H), 6.34(s, 1H), 5.43(s, 1H), 4.41(qd, J ₁ =14.9Hz, J ₂ =5.8Hz ,2H),4.12(s,2H),3.80(s,1H),3.78(s,1H),2.94–2.77(m,2H),2.68(dd,J ₁ =15.4Hz,J ₂ =9.1Hz, 1H),2.39(s,1H),2.30(d,J＝11.1Hz,2H),2.15–2.03(m,1H),2.03–1.92(m,2H),1.69(dd, _J ＝13.9Hz, J ₂ =6.9Hz,1H),1.46–1.35(m,1H),1.31(s,3H),1.19(s,3H),1.11(s,3H),0.98(s,3H). ¹ H NMR( 500MHz, CDCl ₃ +D ₂ O), δ (ppm): 7.40 (s, 1H), 7.39 (t, J = 1.6Hz, 1H), 7.25 (dd, J ₁ = 8.4Hz, J ₂ = 2.9Hz, 2H), 7.00(t, J=8.6Hz, 2H), 6.82(t, J=5.6Hz, 1H), 6.34(s, 1H), 5.43(s, 1H), 4.41(qd, J ₁ = 14.9Hz ,J ₂ =5.7Hz,2H), 4.10(s,2H),3.80(s,1H),3.79(s,1H),2.94–2.76(m,2H),2.69(dd,J ₁ =15.4Hz, J ₂ ＝9.1Hz, 1H), 2.37–2.24(m, 2H), 2.08(dt, J ₁ ＝19.6Hz, J ₂ ＝13.0Hz, 1H), 2.03–1.90(m, 2H), 1.69(dd, J ₁ =14.0Hz, J ₂ =6.8Hz, 1H ),1.48–1.35(m,1H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.98(s,3H). ¹³ C NMR(126MHz,CDCl ₃ ),δ (ppm):207.63,171.39,167.13,163.13,143.09,140.98,133.96,129.26,129.19,120.25,115.57,115.40,109.69,82.81,78.64,78.28,65.51,61.29,60.90,53.18,52.51,51.14,48.71, 42.88,39.50,37.68,36.45,33.53,29.79,23.36,22.31,21.18,15.96. HR-ESIMS m/z 596.2657[M+H] ⁺ (calcdfor C ₃₃ H ₃₈ FNO ₈ ,596.2654).

Example 6

Preparation of Compound I-6

Using limonin (1) and p-methoxybenzylamine as raw materials, the operation is the same as that of I-4, and the crude product is purified by column chromatography (dichloromethane:methanol=100:1) to obtain a light yellow solid (I-6 ) 1.07g, yield 83%, 132°C (decomposition). IR(KBr,υcm ^-1 ):3386,3132,2961,2932,2825,1752,1646,1513,1457,1283,1239,1180,1113,1033,1004,827,809,771,597. ¹ H NMR(500MHz,CDCl ₃ ) ,δ(ppm):7.40(d,J=0.6Hz,1H),7.38(t,J=1.7Hz,1H),7.21(d,J=8.6Hz,2H),6.85(d,J=8.6Hz ,2H),6.69(t,J=5.4Hz,1H),6.34(d,J=1.1Hz,1H),5.43(s,1H),4.44–4.32(m,2H),4.11(s,2H) ,3.80(s,2H),3.79(s,3H),2.94–2.75(m,2H),2.67(dd,J ₁ =15.4Hz,J ₂ =8.8Hz,1H),2.37(s,1H), 2.30(dd, J ₁ =14.1Hz, J ₂ =3.3Hz, 2H), 2.16–2.03(m,1H), 2.02–1.93(m,2H), 1.69(dd,J ₁ =14.0Hz, J ₂ = 6.7Hz, 1H), 1.46–1.35(m, 1H), 1.31(s, 3H), 1.19(s, 3H), 1.11(s, 3H), 0.97(s, 3H). ¹ H NMR (500MHz, CDCl ₃ +D ₂ O),δ(ppm):7.40(s,1H),7.38(s,1H),7.21(d,J＝8.5Hz,2H),6.85(d,J＝8.5Hz,2H), 6.72(s,1H),6.34(s,1H),5.43(s,1H),4.44–4.31(m,2H),4.10(s,2H),3.80(s,2H),3.79(s,3H) ,2.94–2.76(m,2H),2.67(dd,J ₁ =15.4Hz,J ₂ =8.9Hz,1H),2.30(d,J=11.1Hz,2H),2.14–2.03(m,1H), 1.99(dd, J ₁ ＝21.4Hz, J ₂ ＝8.9Hz, 2H), 1.69(dd, J ₁ ＝13.8Hz, J ₂ ＝7.2Hz, 1H), 1.47–1.36(m, 1H), 1.30(s ,3H),1.19(s,3H),1.11(s,3H),0.97(s,3H). ¹³ C NMR(126MHz,CDCl ₃ ),δ(ppm):207.72,171.25,167.16,159.08,143.1 1,141.01,130.23,128.96,120.31,114.10,109.74,82.84,79.20,78.60,78.32,65.56,61.36,60.95,55.34,53.22,52.55,51.18,48.75,43.17,39.51,37.72,36.50,33.57,29.81,23.37, 22.34,21.21,16.01. HR-ESIMS m/z 608.2859[M+H] ⁺ (calcd for C ₃₄ H ₄₂ NO ₉ ,608.2854).

Example 7

Preparation of Compound I-7

Using limonin (1) and phenethylamine as raw materials, the operation was the same as that of I-4, and the crude product was purified by column chromatography (dichloromethane:methanol=100:1) to obtain 0.97 g of white solid (I-7). Yield 77%, 220°C (decomposition). IR(KBr,υcm ^-1 ):3427,3156,2961,2926,1734,1711,1655,1602,1525,1443,1387,1283,1166,1113,1027,874. ¹ HNMR(500MHz,CDCl ₃ ), δ(ppm):7.40(s,1H),7.39(s,1H),7.29(t,J=7.4Hz,2H),7.21(t,J=10.4Hz,3H),6.58(brs,1H), 6.34(s,1H),5.43(s,1H),4.10(s,2H),3.79(s,1H),3.66(d,J=8.7Hz,1H),3.62–3.50(m,2H),2.85 –2.78(m,4H),2.65–2.50(m,2H),2.33–2.24(m,2H),2.06–2.03(m,1H),1.98–1.90(m,2H),1.70–1.66(m, 1H),1.44–1.38(m,1H),1.30(s,3H),1.11(s,3H),1.01(s,3H),0.97(s,3H). ¹³ C NMR(75MHz,CDCl ₃ ), δ(ppm):207.27,171.31,166.65,142.63,140.46,138.30,128.24,128.12,126.07,119.74,109.18,82.23,78.20,77.82,64.98,60.73,60.28,52.64,52.03,50.51,48.31,39.93,38.90 ,37.15,35.95,34.91,33.14,29.20,22.83,21.85,20.68,15.40. HR-ESIMS m/z 592.2903[M+H] ⁺ (calcdfor C ₃₄ H ₄₂ NO ₈ ,592.2905).

Example 8

Preparation of Compound I-8

Using limonin (1) and p-fluorophenethylamine as raw materials, the operation is the same as that of I-4, and the crude product is purified by column chromatography (dichloromethane:methanol=100:1) to obtain a white solid (I-8) 1.09g, yield 84%, 160°C (decomposition). IR(KBr,υcm ^-1 ):3368,3150,2961,2920,2879,1734,1705,1652,1599,1537,1504,1451,1281,1219,1166,1113,1030,871,824,600. ¹ H NMR (500MHz , CDCl ₃ ), δ (ppm): 7.40 (s, 1H), 7.39 (d, J = 1.8Hz, 1H), 7.16 (dd, J ₁ = 8.4Hz, J ₂ = 5.5Hz, 2H), 6.98 ( t,J=17.2Hz,2H),6.34(s,1H),5.43(s,1H),4.11(s,2H),3.80(s,1H),3.68(d,J=9.1Hz,1H), 3.58–3.45(m,2H),2.87–2.74(m,4H),2.61(dd,J ₁ =15.8Hz,J ₂ =9.4Hz,2H),2.35–2.25(m,2H),2.11–2.01( m,1H),1.98–1.93(m,2H),1.69(dd,J ₁ =13.7Hz,J ₂ =7.3Hz,1H),1.44–1.36(m,1H),1.30(s,3H),1.13 (s,3H),1.11(s,3H),0.98(s,3H). ¹³ C NMR(75MHz,CDCl ₃ ),δ(ppm):207.68,171.79,167.13,163.27,160.03,143.11,140.95,134.42 ,130.17,130.06,120.22,115.50,115.22,109.67,82.76,78.71,78.30,65.50,61.22,60.76,53.14,52.50,51.02,48.80,40.50,39.41,37.65,36.43,34.67,33.59,29.72,23.34,22.32 ,21.14,15.89. HR-ESIMS m/z 610.2810[M+H] ⁺ (calcd for C ₃₄ H ₄₁ FNO ₈ ,610.2811).

Example 9

Preparation of Compound I-9

Using limonin (1) and m-methoxyphenethylamine as raw materials, the operation is the same as that of I-4, and the crude product is purified by column chromatography (dichloromethane:methanol=100:1) to obtain a white solid (I-9 ) 1.02g, yield 77%, 108°C (decomposition). IR(KBr,υcm ^-1 ):3362,3144,2973,2920,1743,1705,1649,1537,1448,1260,1163,1036,874,806,691,600,523. ¹ H NMR(500MHz,CDCl ₃ ),δ(ppm): 7.41(s,1H),7.39(d,J=1.6Hz,1H),7.21(t,J=7.8Hz,1H),6.80–6.76(m,2H),6.75(s,1H),6.61(t ,J=5.4Hz,1H),6.35(s,1H),5.43(s,1H),4.10(s,2H),3.80(s,1H),3.77(s,3H),3.67(d,J= 9.0Hz, 1H), 3.59–3.46(m, 2H), 2.86–2.75(m, 4H), 2.61(dd, J ₁ ＝15.9Hz, J ₂ ＝9.4Hz, 2H), 2.31–2.24(m, 2H ),2.07–2.01(m,1H),1.98–1.91(m,2H),1.68(dd,J ₁ =13.7Hz,J ₂ =7.1Hz,1H),1.44–1.36(m,1H),1.30( s,3H),1.11(s,3H),1.09(s,3H),0.97(s,3H). ¹³ C NMR(75MHz,CDCl ₃ ),δ(ppm):207.77,171.75,167.12,159.82,143.11 ,140.95,140.42,129.59,121.06,120.26,114.84,111.52,109.68,82.75,78.68,78.31,65.50,61.25,60.79,55.15,53.15,52.53,51.02,48.81,40.30,39.41,37.65,36.46,35.42,33.62 ,29.60,23.27,22.34,21.13,15.89. HR-ESIMS m/z 622.3008[M+H] ⁺ (calcd for C ₃₅ H ₄₄ NO ₉ ,622.3011).

Example 10

Preparation of Compound I-10

Using limonin (1) and 3,4-dimethoxyphenethylamine as raw materials, the operation is the same as that of I-4, and the crude product is purified by column chromatography (dichloromethane:methanol=100:1) to obtain a white solid (I-10) 1.13g, yield 82%, 126°C (decomposition). IR(KBr,υcm ^-1 ):3368,3126,2955,2926,1743,1708,1646,1593,1510,1460,1260,1166,877,809,635,597. ¹ H NMR(500MHz,CDCl ₃ ),δ(ppm): 7.40(s,1H),7.39(d,J=1.3Hz,1H),6.79(d,J=8.0Hz,1H),6.74–6.72(m,2H),6.46(brs,1H),6.40(s ,1H),5.43(s,1H),4.11(s,2H),3.86(s,3H),3.84(s,3H),3.80(s,1H),3.71(d,J=7.1Hz,1H) ,3.50(dd, _J1 =12.8Hz, _J2 =6.6Hz,2H),2.83(d,J=15.2Hz,2H),2.79–2.75(m,2H),2.57(dd, _J1 =15.6Hz ,J ₂ =9.0Hz,1H),2.31–2.26(m,2H),2.06–2.04(m,1H),1.97–1.93(m,2H),1.67(dd,J ₁ =13.8Hz,J ₂ = 7.0Hz, 1H), 1.43–1.38(m, 1H), 1.30(s, 3H), 1.11(s, 3H), 1.10(s, 3H), 0.97(s, 3H). ¹³ C NMR (75MHz, CDCl ₃ ),δ(ppm):207.65,171.53,167.09,149.12,147.84,143.09,140.96,131.29,120.66,120.25,112.06,111.43,109.69,82.74,78.59,78.27,77.21,65.48,61.29,60.89,55.96, 53.15,52.51,51.06,48.77,40.61,39.42,37.66,36.44,35.07,33.60,29.68,23.32,22.31,21.16,15.93. HR-ESIMS m/z 652.3115[M+H] ⁺ (calcd for C ₃₆ H ₄ NO ₁₀ ,652.3116).

Example 11

Preparation of Compound I-11

Add limonin (1g, 2.13mmol), N,N-dimethylethylenediamine (1.69g, 19.19mmol) and tetrahydrofuran (30mL) into a 100mL three-necked flask, and reflux for 4 hours. TLC detected that the reaction was complete, and part of the solvent was distilled off under reduced pressure. Add 100 mL of water to the residue, adjust the pH to acidic with 5% dilute hydrochloric acid, extract the aqueous layer three times with dichloromethane (80 mL×3), combine the organic layers, wash with saturated brine three times (100 mL×3), and dry over anhydrous sodium sulfate . Filter and distill off the solvent under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol=100:1) to obtain 0.68 g of white solid (I-11), yield 68%, mp 130-132°C. IR(KBr)υ(cm ^-1 ):3629,3411,2965,1743,1708,1654,1545,1465,1388,1285,1266,1163,1113,1029,1006,917,897,875,822,804,602,587. ¹ H NMRCl(500MHz ₃ ) δ7.40(s,1H),7.38(s,1H),7.13(s,1H),6.34(s,1H),5.43(s,1H),4.18(d,J＝11.3Hz,1H) ,4.11(d,J=11.5Hz,1H),3.85(d,J=8.0Hz,1H),3.80(s,1H),3.39(d,J=5.4Hz,2H),2.85(t,J= 14.9Hz, 2H), 2.67(dd, J＝15.6, 8.7Hz, 1H), 2.55(t, J＝5.5Hz, 2H), 2.34(s, 6H), 2.32(s, 1H), 2.30(s, 1H),2.26–2.17(m,2H),2.09–2.02(m,1H),2.01–1.95(m,1H),1.66–1.70(m,1H),1.45–1.37(m,1H),1.32( s,3H),1.23(s,3H),1.12(s,3H),1.03(s,3H). ¹³ C NMR(75MHz,CDCl ₃ )δ207.74,171.54,166.89,142.59,140.48,119.76,109.30,82.22 . .3016[M+H] ⁺ (calcd for C ₃₀ H ₄₃ N ₂ O ₈ :559.3014).

Example 12

Preparation of Compound I-12

Using limonin (1) and N,N-diethylethylenediamine as raw materials, the operation was the same as that of I-11, and the crude product was purified by column chromatography (dichloromethane:methanol=100:1) to obtain a white solid ( I-12) 0.45g, yield 43%, mp 118-120°C. ^{1 _} H NMR (500MHz, CDCl ₃ )δ7.40(s,1H),7.38(s,1H),7.10(brs,1H),6.34(s,1H),5.43(s,1H),4.17(d,J ＝11.4Hz,1H),4.12(d,J＝11.2Hz,1H),3.82–3.80(m,2H),3.43–3.33(m,2H),2.88–2.82(m,1H),2.68–2.63( m,1H),2.59–2.55(m,6H),2.32–2.29(m,2H),2.08–2.05(m,1H),2.04–1.91(m,3H),1.71–1.67(m,1H), 1.44–1.41(m,1H),1.32(s,3H),1.23(s,3H),1.11(s,3H),1.05–1.02(m,9H). ¹³ C NMR(75MHz,CDCl3)δ207.53,171.49 , 166.74,142.63,140.44,119.74,109.19,82.33,78.13,77.86,65.03, 60.84, 60.63,52.079,50.45,46.07 (2c) 22.94,21.92,20.67,15.38,11.01(2C).HR-ESIMS m/z587.3322[M+H] ⁺ (calcd for C ₃₂ H ₄₇ N ₂ O ₈ ,587.3327).

Example 13

Preparation of Compound I-13

Using limonin (1) and N-(2-aminoethyl)piperidine as raw materials, the operation is the same as that of I-11, and the crude product is purified by column chromatography (dichloromethane:methanol=100:1) to obtain a white solid (I-13) 0.54g, yield 79%, mp 150-152°C. ¹ H NMR (300MHz, CDCl ₃ )δ7.40(d,2H),7.18(s,1H),6.35(s,1H),5.43(s,1H),4.24–4.06(m,2H),3.90– 3.74(m,2H),3.39(d,J=5.0Hz,2H),2.86(t,J=14.8Hz,3H),2.68(dd,J=15.5,8.7Hz,2H),2.51(d,J ＝6.5Hz,5H),2.37–2.30(m,1H),2.29(s,1H),2.14–1.91(m,3H),1.73–1.56(m,5H),1.54–1.38(m,3H), 1.32(s,3H),1.25(s,3H),1.12(s,3H),1.04(s,3H). ¹³ C NMR(75MHz,CDCl ₃ )δ207.52,171.32,166.78,142.61,140.46,119.76,109.22 ,82.21,78.00,77.82,65.06,60.82,60.20,56.79,53.84(2C),53.78,52.66,52.05,50.50,48.31,38.70,37.16,36.04,35.67,33.12,29.47,25.691,2 20.67,15.43.IR(KBr)υ(cm ^-1 ):3854,3588,3567,3422,2938,2347,1735,1712,1654,1648,1560,1541,1535,1508,1458,1383,1284,1163 ,1122,1030,1006,875,802,602.HR-ESIMSm/z599.3324[M+H] ⁺ (calcd for C ₃₃ H ₄₇ N ₂ O ₈ :599.3327).

Example 14

Preparation of Compound I-14

Using limonin (1) and N-(2-aminoethyl)morpholine as raw materials, the operation is the same as that of I-11, and the crude product is purified by column chromatography (dichloromethane:methanol=100:1) to obtain a white solid (I-14) 0.74g, yield 69%, mp 125-127°C. IR(KBr)υ(cm ^-1 ):3400,2964,2924,2847,1743,1658,1642,1539,1465,1447,1340,1285,1275,1262,1246,1166,1121,1034,1024,1006 ,874,808. ¹ H NMR (500MHz, CDCl ₃ )δ7.40(s,1H),7.38(s,1H),6.34(s,1H),5.44(s,1H),4.19(d,J=11.4Hz ,1H),4.13(d,J＝11.6Hz,1H),3.88–3.70(m,6H),3.49–3.39(m,2H),2.90–2.81(m,2H),2.72–2.52(m,6H ),2.32–2.28(m,2H),2.20(s,1H),2.05(t,J＝8.0Hz,1H),1.99–1.89(m,1H),1.75–1.69(m,1H),1.62– 1.58(m,1H),1.40(dd,J＝8.9,3.4Hz,1H),1.31(s,3H),1.24(s,3H),1.12(s,3H),1.04(s,3H). ¹³ C NMR (75MHz, CDCl ₃ )δ207.30,171.23,166.69,142.63,140.46,119.73,109.20,82.26,78.07,77.80,66.26(2C),65.01,60.78,60.35,56.62,52.82.064,5 50.53,48.28,38.76,37.15,36.00,35.26,33.12,29.57,23.02,21.86,20.70,15.44. HR-ESIMS m/z 601.3115[M+H] ⁺ (calcd for C ₃₂ H ₄₅ N ₂ O ₉ ,601.312 ).

Example 15

Preparation of Compound I-15

Using limonin (1) and N-(3-aminopropyl)morpholine as raw materials, the operation is the same as that of I-11, and the crude product is purified by column chromatography (dichloroalkane:methanol=100:1) to obtain a white solid (I-15) 0.52g, yield 66%, mp 114-116°C. ^{1 _} H NMR (300MHz, CDCl ₃ )δ7.44–7.36(m,2H),7.13(t,J＝5.4Hz,1H),6.34(s,1H),5.43(s,1H),4.13(d,J =3.2Hz,2H),3.80(d,J=5.2Hz,2H),3.76–3.64(m,4H),3.41–3.24(m,2H),2.98–2.73(m,3H),2.60(dd, J=15.4,8.4Hz,1H),2.45(dd,J=9.9,3.7Hz,6H),2.33(dd,J=7.2,2.4Hz,1H),2.30–2.25(m,1H),2.13–2.00 (m,2H),1.98(d,J=2.6Hz,1H),1.75–1.64(m,3H),1.47–1.37(m,1H),1.31(s,3H),1.23(s,3H), 1.11(s,3H),1.03(s,3H). ¹³ C NMR(75MHz,CDCl ₃ )δ207.43,171.17,166.78,142.64,140.45,119.71,109.20,82.39,78.05,77.83,66.47(2C),65.02, 60.79, 60.22, 56.37, 53.17(2C), 52.60, 52.04, 50.49, 48.30, 38.91, 37.90, 37.13, 36.00, 33.12, 29.45, 25.16, 22.98, 21.89, 20.68, 15.40.HR-ESIMS.3 m/z7 M+H] ⁺ (calcd for C ₃₃ H ₄₇ N ₂ O ₉ :615.3276).

Example 16

Preparation of Compound I-16

Using limonin (1) and N,N-dimethylpropylamine as raw materials, the operation was the same as that of I-11, and the crude product was purified by column chromatography (dichloroalkane:methanol=100:1) to obtain a white solid (I- 16) 0.51g, yield 66%, mp 114-116°C. IR(KBr)υ(cm ^-1 ):3629,3650,3422,2965,2865,2776,2362,1715,1712,1654,1542,1507,1466,1389,1367,1344,1285,1265,1164,1112 ,1009,1007,957,917,898,875,823,802,764,734,711,602,586,526. ¹ H NMR (300MHz, CDCl ₃ )δ7.43–7.38(m,2H),7.14(brs,1H),6.35(s,1H),5.43,4s,13() s,2H),3.81–3.75(m,2H),3.39–3.28(m,2H),2.92–2.79(m,2H),2.70–2.55(m,2H),2.50–2.39(m,3H), 2.33(dd,J＝6.6,1.7Hz,2H),2.28(s,6H),2.10-2.05(m,1H),2.00–1.95(m,1H),1.78–1.63(m,3H),1.31( s,3H),1.23(s,3H),1.11(s,3H),1.03(s,3H). ¹³ C NMR(75MHz,CDCl ₃ )δ207.50,171.17,166.78,142.61,140.45,119.72,109.21,82.42 ,77.90,65.04,60.82,60.17,58.09,56.97,52.61,52.05,50.50,48.33,44.91(2C),38.87,37.67,37.14,36.02,33.13,29.42,26.23,22.97,21.4.88,1HR- ESIMS m/z573.3180[M+H] ⁺ (calcd for C ₃₁ H ₄₈ N ₂ O ₅ ,573.3170).

Example 17

Preparation of Compound II-1

Compound 2

Add limonin (4g, 9mmol), hydroiodic acid (70mL) and glacial acetic acid (70mL) into a 250mL three-necked bottle, react at 60°C, follow TLC until the reaction is complete, and slowly pour 400mL of saturated sodium sulfite into the reaction solution after cooling solution, extracted three times with dichloromethane (150mL×3), combined the organic layers, washed twice with saturated sodium bicarbonate solution (200mL×2), washed twice with saturated brine (200mL×2), anhydrous sulfuric acid Sodium dry. Filter and distill off the solvent under reduced pressure. The crude product was recrystallized from acetonitrile and water to obtain 2.7 g of white or light yellow crystal (2), yield 70%, mp>250°C. ¹ H NMR (CDCl ₃ , 500MHz), δ(ppm): 7.50(s, 1H), 7.45(s, 1H), 6.85(s, 1H), 6.42(d, J=0.95Hz, 1H), 5.01( s, 1H), 4.63 (dd, J ₁ =56.0Hz, J ₂ =13.1Hz, 2H), 4.11 (brs, 1H), 2.98 (dd, J ₁ =16.9Hz, J ₂ =3.6Hz, 1H), 2.82 (t, J = 16.0Hz, 1H), 2.65 (dd, J ₁ = 16.9Hz, J ₂ = 1.95Hz, 1H), 2.61 (dd, J ₁ = 16.1Hz, J ₂ = 3.8Hz, 1H), 2.54(q,J=7.4Hz,1H),2.31(dd, _J1 =15.8Hz, _J2 =3.7Hz,1H),2.13–2.03(m,1H),1.91-1.81(m,1H),1.65 –1.54(m,1H),1.61–1.58(m,1H),1.42(s,3H),1.31(s,3H),1.26(s,3H),1.20(s,3H).MS(ESI(- )70V)m/z 455.2[M+H] ⁺ .

Compound II-1

Compound 2 (1 g, 2.20 mmol) and acetonitrile (30 mL) were added to a 100 mL three-necked flask, and ammonia water (20 mL) was added dropwise in an ice bath. After dropping, remove the ice bath and react at room temperature for 4h. TLC detected that the reaction was complete, and part of the solvent was distilled off under reduced pressure. Add 100 mL of water to the residue, adjust the pH to acidic with 5% dilute hydrochloric acid, extract the aqueous layer three times with dichloromethane (80 mL×3), combine the organic layers, wash with saturated brine three times (100 mL×3), and dry over anhydrous sodium sulfate . Filter and distill off the solvent under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol=100:1) to obtain 0.32 g of white solid (II-1), yield 31%, 160°C (decomposition). IR(KBr,υcm ^-1 ): 3453, 3359, 3195, 2971, 2934, 2885, 1710, 1661, 1506, 1465, 1383, 1289, 1155, 1044, 1016, 877, 808, 767, 730, 608, 571 ^.1 H NMR(500MHz,CDCl ₃ ),δ(ppm):7.49(s,1H),7.42(s,1H),6.61(s,1H),6.48(s,1H),6.40(s,1H) ,5.38(s,1H),5.30(s,2H),5.02(s,1H),4.22(d,J=11.2Hz,1H),3.91(t,J=10.4Hz,2H),2.92(d, J=37.2Hz, 1H), 2.79(d, J=15.9Hz, 1H), 2.65(ddd, J ₁ ＝33.7Hz, J ₂ ＝19.2Hz, J ₃ ＝10.9Hz, 3H), 2.49(ddd, J ₁ = 19.4Hz, J ₂ = 15.4Hz, J ₃ = 6.2Hz, 2H), 2.18(dd, J ₁ = 15.2Hz, J ₂ = 5.7Hz, 1H), 1.86(d, J = 8.4Hz, 1H) ,1.65(s,3H),1.28(s,3H),1.24(s,3H),1.12(s,3H). ¹³ C NMR(75MHz,CDCl ₃ )δ208.77,173.92,168.29,143.00,141.37,120.00, 114.95,109.93,82.60,81.46,79.24,64.66,59.76,58.30,51.31,49.61,44.60,39.11,37.36,30.24,26.63,26.54,23.92,21.17,18.95.HR-ESIMS m/z27 ] ⁺ (calcd for C ₂₆ H ₃₄ NO ₇ ,472.233).

Example 18

Preparation of Compound II-2

Using compound 2 and methylamine aqueous solution as raw materials, the operation was the same as II-1, and the crude product was purified by column chromatography (dichloromethane:methanol=100:1) to obtain 0.56 g of white solid (II-2), with a yield of 52% , 150°C (decomposition). IR(KBr,υcm ^-1 ):3392,3115,2943,1711,1643,1555,1502,1381,1281,1157,1045,1007,874,797,694,597. ¹ H NMR(500MHz,CDCl ₃ ),δ(ppm): 7.48(s,1H),7.42(s,1H),6.59(s,1H),6.57(brs,1H),6.39(s,1H),5.30(s,1H),5.01(s,1H),4.17 (d,J=11.4Hz,1H),3.89(d,J=11.7Hz,1H),3.86(s,1H),2.80(d,J=4.7Hz,3H),2.77(s,1H),2.70 –2.59(m,3H), 2.47(dd, J ₁ =18.0Hz, J ₂ =5.6Hz, 1H), 2.41(dd, J ₁ =12.7Hz, J ₂ =6.9Hz, 1H), 2.14(dd, J ₁ =15.3Hz, J ₂ =5.6Hz,1H),1.90–1.82(m,1H),1.65(s,3H),1.63–1.56(m,1H),1.40–1.35(m,1H),1.27 (s,3H),1.23(s,3H),1.10(s,3H). ¹³ C NMR(75MHz,DMSO),δ(ppm):210.37,170.81,169.83,164.81,143.20,141.71,120.20,113.60, 110.29, 81.68, 81.30, 77.73, 58.47, 56.62, 50.81, 47.79, 43.03, 38.31, 38.07, 37.47, 29.81, 26.09, 25.95, 25.50, 24.02, 20.49, 17.80. ] ⁺ (calcd for C ₂₇ H ₃₆ NO ₇ ,486.2486).

Example 19

Preparation of Compound II-3

Using compound 2 and ethylamine aqueous solution as raw materials, the operation was the same as II-1, and the crude product was purified by column chromatography (dichloromethane:methanol=100:1) to obtain 0.58 g of white solid (II-3), with a yield of 53% , 146°C (decomposition). IR(KBr,υcm ^-1 ):3374,3126,2979,2879,1725,1634,1546,1454,1269,1242,1163,1004,871,800,700,606. ¹ H NMR(500MHz,CDCl ₃ ),δ(ppm): 7.48(s,1H),7.41(t,J=1.6Hz,1H),6.60(s,1H),6.43(brs,1H),6.39(s,1H),5.30(s,1H),5.02(s ,1H),4.17(d,J=11.5Hz,1H),3.89(d,J=11.6Hz,1H),3.84(dd,J ₁ =8.4Hz,J ₂ =2.2Hz,1H),3.34–3.24 (m,2H),2.76(dd,J ₁ =15.5Hz,J ₂ =2.9Hz,1H),2.74–2.60(m,3H),2.47(dd,J ₁ =18.0Hz,J ₂ =5.6Hz, 1H), 2.41(dd, J ₁ ＝12.8Hz, J ₂ ＝6.9Hz, 1H), 2.13(dd, J ₁ ＝15.8Hz, J ₂ ＝5.7Hz, 1H), 1.91–1.83(m, 1H), 1.66(s,3H),1.63–1.57(m,1H),1.42–1.35(m,1H),1.27(s,3H),1.24(s,3H),1.41(t,J＝7.3Hz,3H) ,1.11(s,3H). ¹³ C NMR(75MHz,DMSO),δ(ppm):210.39,170.04,169.86,164.81,143.20,141.72,120.20,113.59,110.29,81.65,81.30,77.68,58.49,56.64, 50.81,47.79,43.01,38.28,38.07,37.49,33.29,29.78,26.09,25.94,24.02,20.50,17.79,14.67. HR-ESIMS m/z500.2635[M+H] ⁺ (calcd for C ₂₈ H ₃₈ NO _7,500.2643 ).

Example 20

Preparation of Compound II-4

Compound 2 (1g, 2.20mmol), benzylamine (1.41g, 13.20mmol) and acetonitrile (30mL) were added into a 100mL three-necked flask, and refluxed for 24 hours. TLC detected that the reaction was complete, and part of the solvent was distilled off under reduced pressure. Add 100 mL of water to the residue, adjust the pH to acidic with 5% dilute hydrochloric acid, extract the aqueous layer three times with dichloromethane (80 mL×3), combine the organic layers, wash with saturated brine three times (100 mL×3), and dry over anhydrous sodium sulfate . Filter and distill off the solvent under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol=100:1) to obtain 0.62 g of white solid (II-4), yield 75%, 218°C (decomposition). IR(KBr,υcm ^-1 ):3473,3432,3146,3110,2967,2926,2889,1697,1542,1453,1379,1289,1167,1118,1044,1020,869,734,697,608. ¹ H NMR (500MHz, CDCl ₃ ),δ(ppm):7.48(s,1H),7.42(t,J＝1.7Hz,1H),7.32–7.26(m,4H),6.74(brs,1H),6.60(s,1H), 6.39(d, J＝1.1Hz, 1H), 5.29(s, 1H), 5.01(s, 1H), 4.50–4.42(m, 2H), 4.14(dd, J ₁ ＝11.5Hz, J ₂ ＝4.0Hz ,1H),3.89–3.86(m,2H),2.81(dd,J ₁ =15.2Hz,J ₂ =2.7Hz,1H),2.72–2.58(m,3H),2.51–2.44(m,3H), 1.92–1.84(m,1H),1.65(s,3H),1.61–1.57(m,2H),1.41–1.36(m,1H),1.24(s,3H),1.22(s,3H),1.04( s,3H) ^.13C NMR(75MHz,DMSO),δ(ppm):210.36,170.59,169.86,164.83,143.20,141.72,139.64,128.03,126.94,126.50,120.21,113.64,110.30,81.371,87 , ^{58.49,56.66,50.81,47.96,42.96,41.83,38.53,38.09,37.50,29.80,26.11,25.91,24.05,20.45,17.85} _{. 40} NO ₇ , 562.2799).

Example 21

Preparation of Compound II-5

Using compound 2 and p-fluorobenzylamine as raw materials, the operation was the same as that of II-4, and the crude product was purified by column chromatography (dichloromethane:formazine=100:1) to obtain 1.07 g of white solid (II-5), with a yield of 84 %, 212°C (decomposition). IR(KBr,υcm ^-1 ):3493,3432,3151,3110,2975,2930,2893,1710,1612,1546,1502,1383,1297,1151,1048,877,816,571. ¹ H NMR(500MHz,CDCl ₃ ) ,δ(ppm):7.48(s,1H),7.42(s,1H),7.31–7.21(m,2H),7.00(t,J＝8.6Hz,2H),6.78(t,J＝5.6Hz, 1H),6.59(s,1H),6.39(s,1H),5.01(s,1H),4.48–4.35(m,2H),4.16(d,J＝11.5Hz,1H),3.88(d,J ＝11.1Hz, 2H), 2.87–2.78(m, 1H), 2.65(ddd, J ₁ ＝25.3Hz, J ₂ ＝19.2Hz, J ₃ ＝8.3Hz, 4H), 2.52–2.40(m, 2H), 2.15(dd, J ₁ ＝15.3Hz, J ₂ ＝5.7Hz, 1H), 1.88(dt, J ₁ ＝17.5Hz, J ₂ ＝8.1Hz, 1H), 1.65(s, 3H), 1.59(dd,J ₁ ＝15.8Hz, J ₂ ＝7.0Hz, 1H), 1.39(dd, J ₁ ＝15.1Hz, J ₂ ＝9.3Hz, 1H), 1.23(s, 3H), 1.21(s, 3H), 1.04(s ,3H). ¹³ C NMR (126MHz, CDCl ₃ ), δ (ppm): 208.75, 171.44, 168.39, 165.34, 163.12, 161.16, 143.00, 141.37, 134.01, 129.24, 129.18, 120.02, 115.579, 110.3 ,82.60,81.68,79.12,59.65,58.29,51.35,49.65,44.65,42.86,39.48,38.84,37.33,30.18,26.64,26.56,23.86,21.17,18.97 ^. (calcd for C ₃₃ H ₃₉ FNO ₇ , 580.2705).

Example 22

Preparation of compound II-6

Using compound 2 and p-methoxybenzylamine as raw materials, the operation was the same as in II-4, and the crude product was purified by column chromatography (dichloromethane:methanol=100:1) to obtain 1.03 g of white solid (II-6). Rate 79%, 214°C (decomposition). IR(KBr,υcm ^-1 ):3538,3355,3151,2967,2922,2885,1702,1669,1612,1538,1465,1383,1061,881,812,604,522. ¹ H NMR(500MHz,CDCl ₃ ),δ(ppm ):7.47(s,1H),7.41(t,J=1.6Hz,1H),7.20(d,J=8.6Hz,2H),6.85(d,J=8.7Hz,2H),6.81(t,J =5.4Hz,1H),6.58(s,1H),6.39(d,J=0.9Hz,1H),5.00(s,1H),4.45–4.28(m,2H),4.19–4.12(m,1H) ,3.86(dd,J ₁ =14.0Hz,J ₂ =5.3Hz,2H),3.79(s,3H),2.97(s,1H),2.80(dd,J ₁ =15.4Hz,J ₂ =2.2Hz, 1H), 2.66(ddd, J ₁ =23.8Hz, J ₂ =16.7Hz, J ₃ =12.2Hz, 3H), 2.51–2.37(m, 2H), 2.13(dd, J ₁ =15.3Hz, J ₂ = 5.7Hz, 1H), 1.86(td, J ₁ =17.3Hz, J ₂ =8.3Hz, 1H), 1.64(s, 3H), 1.58(dt, J ₁ =14.2Hz, J ₂ =9.7Hz, 1H) ,1.42–1.33(m,1H),1.23(s,3H),1.20(s,3H),1.04(s,3H). ¹³ C NMR(75MHz,DMSO),δ(ppm):210.36,170.43,169.85 ,164.82,158.03,143.19,141.71,131.54,128.25,120.21,113.64,113.45,110.28,81.86,81.32,77.69,58.48,56.68,54.99,50.82,47.94,43.00,41.31,38.53,38.09,37.50,29.80,26.11 ,25.95,24.04,20.48,17.84. HR-ESIMS m/z592.2922[M+H] ⁺ (calcd for C ₃₄ H ₄₂ NO ₉ ,592.2905).

Example 23

Preparation of Compound II-7

Using compound 2 and phenethylamine as raw materials, the operation was the same as in II-4, and the crude product was purified by column chromatography (dichloromethane:methanol=100:1) to obtain 0.74 g of white solid (II-7), with a yield of 58% , 126°C (decomposition). IR(KBr,υcm ^-1 ):3363,2938,2879,1716,1655,1546,1493,1449,1375,1275,1246,1163,1045,1028,1010,877,704,606. ¹ H NMR(500MHz,CDCl ₃ ) ,δ(ppm):7.48(s,1H),7.42(s,1H),7.30(t,J=7.2Hz,2H),7.22(t,J=8.4Hz,3H),6.59(s,2H) ,6.39(s,1H),5.01(s,1H),4.13(d,J=8.0Hz,1H),3.86(d,J=11.7Hz,1H),3.75(d,J=8.7Hz,1H) ,3.63–3.44(m,2H),2.82(dd,J ₁ =12.5Hz,J ₂ =6.4Hz,2H),2.74(d,J=13.7Hz,2H),2.69–2.54(m,3H), 2.47(dd, J ₁ =17.9Hz, J ₂ =5.6Hz, 1H), 2.40(dd, J ₁ =12.5Hz, J ₂ =6.8Hz, 1H), 2.08(dd, J ₁ =15.2Hz, J ₂ ＝5.7Hz,1H),1.90–1.77(m,1H),1.64(s,4H),1.62–1.53(m,1H),1.43–1.34(m,1H),1.24(s,3H),1.12( s,3H),1.04(s,3H). ¹³ C NMR(75MHz,DMSO),δ(ppm):210.37,170.42,169.84,164.82,143.21,141.72,139.57,128.65,128.21,125.97,120.21,113.62, 110.29,81.71,81.30,77.72,58.47,56.63,50.81,47.84,43.02,40.24,38.38,38.08,37.46,34.98,29.80,26.09,25.94,24.02,20.49,17.86 H] ⁺ (calcd for C ₃₄ H ₄₂ NO ₇ ,576.2956).

Example 24

Preparation of Compound II-8

Using compound 2 and p-fluorophenethylamine as raw materials, the operation was the same as that of II-4, and the crude product was subjected to column chromatography (dichloromethane:methanol=100:1) to obtain 0.98 g of white solid (II-8). The yield was 75%, 122°C (decomposition). IR(KBr,υcm ^-1 ):3371,2971,2926,2885,1722,1667,1538,1502,1461,1379,1281,1216,1550,1048,877,693,612. ¹ HNMR(500MHz,CDCl ₃ ),δ( ppm): 7.48(s, 1H), 7.42(t, J=1.7Hz, 1H), 7.17(dd, J ₁ =8.6Hz, J ₂ =5.4Hz, 2H), 6.98(t, J=8.7Hz, 2H), 6.59(s, 1H), 6.50(t, J=5.7Hz, 1H), 6.39(d, J=1.1Hz, 1H), 5.01(s, 1H), 4.15(d, J=11.3Hz, 1H), 3.87(d, J=11.5Hz, 1H), 3.78(d, J=7.7Hz, 1H), 3.58–3.44(m, 2H), 2.85–2.77(m, 2H), 2.74(dd,J ₁ = 15.5Hz, _J2 = 2.4Hz, 1H), 2.69–2.54(m, 3H), _2.48 (dd, J1 = 18.0Hz, _J2 = 5.7Hz, 2H), 2.41(dd, _J1 = 12.8 Hz, _J2 = 6.8Hz, 1H), 2.11 (dd, _J1 = 15.3Hz, _J2 = 5.8Hz, 1H), 1.85 (ddd, _J1 = 17.2Hz, _J2 = 14.4Hz, _J3 = 9.2 Hz, 1H), 1.64(s, 3H), 1.63–1.54(m, 2H), 1.39(dd, J ₁ = 15.2Hz, J ₂ = 9.8Hz, 1H), 1.23(s, 3H), 1.16(s ,3H),1.05(s,3H). ¹³ C NMR(75MHz,DMSO),δ(ppm):222.39,210.36,170.44,169.83,164.82,143.21,141.71,135.68,130.48,130.38,120.20,114.96,114. ,113.62,110.28,81.72,81.30,77.72,58.46,56.59,50.80,47.84,43.02,40.19,38.39,38.07,37.45,34.03,29.79,26.09,25.94,24.02,20.417,17 2861[M+H] ⁺ (calcd for C ₃₄ H ₄₁ FNO ₇ ,594.2862).

Example 25

Preparation of Compound II-9

Using compound 2 and m-methoxyphenethylamine as raw materials, the operation was the same as II-4, and the crude product was purified by column chromatography (dichloromethane:methanol=100:1) to obtain 1.08 g of white solid (II-9), Yield 81%, 104°C (decomposition). IR(KBr,υcm ^-1 ):3367,3138,2967,2934,2885,1722,1648,1596,1257,1163,1032,873,771,693,604. ¹ H NMR(300MHz,CDCl ₃ ),δ(ppm):7.48( s,1H),7.42(s,1H),7.22(t,J＝7.8Hz,1H),6.88–6.72(m,3H),6.67(s,1H),6.59(s,1H),6.39(s ,1H),5.01(s,1H),4.14(d,J=11.0Hz,1H),3.86(d,J=11.1Hz,1H),3.78(s,4H),3.53(qd,J ₁ =14.3 Hz, J ₂ ＝7.6Hz, 2H), 2.68(ddd, J ₁ ＝23.3Hz, J ₂ ＝20.1Hz, J ₃ ＝7.0Hz, 6H), 2.52–2.34(m, 2H), 2.08(dd,J ₁ = 15.7Hz, J ₂ = 5.7Hz, 1H), 1.93–1.73(m, 2H), 1.64(s, 3H), 1.39(d, J = 10.9Hz, 1H), 1.24(s, 3H), 1.11 (s,3H),1.03(s,3H). ¹³ C NMR(75MHz,DMSO),δ(ppm):210.38,170.39,169.84,164.82,159.21,143.21,141.72,141.11,129.20,120.89,120.21,114.25 ,113.62,111.41,110.29,81.65,81.31,77.73,58.47,56.64,54.82,50.81,47.84,43.04,38.36,38.07,37.47,35.01,29.75,26.08,25.95,23.408,27 z 606.3059[M+H] ⁺ (calcd for C ₃₅ H ₄₄ NO ₈ ,606.3061).

Example 26

Preparation of Compound II-10

Using compound 2 and 3,4-dimethoxyphenethylamine as raw materials, the operation was the same as in II-4, and the crude product was purified by column chromatography (dichloromethane:methanol=100:1) to obtain a white solid (II-10 ) 1.11g, yield 79%, 118°C (decomposition). IR(KBr,υcm ^-1 ):3367,3122,2967,2938,2828,1718,1653,1514,1457,1383,1269,1167,1032,877,804,767,600. ¹ H NMR(500MHz,CDCl ₃ ),δ(ppm ):7.48(s,1H),7.41(d,J＝1.5Hz,1H),6.82–6.70(m,3H),6.60(s,1H),6.47(brs,1H),6.39(s,1H) ,5.01(s,1H),4.15(d,J=11.4Hz,1H),3.88(d,J=4.7Hz,1H),3.86(s,3H),3.85(s,3H),3.80(d, J＝7.5Hz, 1H), 3.52(dd, J ₁ ＝12.8Hz, J ₂ ＝6.8Hz, 2H), 2.82–2.70(m, 3H), 2.68–2.52(m, 3H), 2.50–2.39(m ,2H),2.11(dd,J ₁ =15.3Hz,J ₂ =5.7Hz,1H),1.91–1.81(m,1H),1.64(s,3H),1.58(d,J=16.9Hz,2H) , 1.39 (dd, J ₁ =14.4Hz, J ₂ =9.9Hz, 1H), 1.23 (s, 3H), 1.15 (s, 3H), 1.04 (s, 3H). ¹³ C NMR (75MHz, DMSO), δ(ppm):210.37,170.32,169.83,164.81,148.56,147.15,143.21,141.72,131.96,120.43,120.20,114.50,113.61,112.48,111.80,110.29,81.62,81.31,77.72,58.49,56.64,55.46,55.34 ,50.81,47.83,43.04,38.07,37.46,34.58,29.77,26.09,25.94,24.00,20.49,17.81. HR-ESIMS m/z 636.3155[M+H] ⁺ (calcd for C ₃₆ H ₄₆ NO ₉ ,636.3167) .

Example 27

Preparation of Compound II-11

Add compound 2 (1g, 2.2mmol), tetrahydrofuran (20mL), N,N-dimethylethylenediamine (1.1ml, 10mmol) into a 100mL three-necked flask, _N2 protection, reflux reaction, TLC tracking monitoring to the reaction Completely, the solvent was evaporated to dryness under reduced pressure. Add 50ml of water to the residue, adjust the pH to acidic with 0.5% dilute hydrochloric acid, extract three times with dichloromethane (60ml×3), combine the organic layers, wash with saturated brine three times (80mL×3), and dry over anhydrous sodium sulfate. After filtration, the solvent was evaporated to dryness under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol=100:1) to obtain 0.35 g of white solid (II-11), yield 29%, 150°C (expansion). IR(cm ^-1 ):3408.42,2971.39,2877.70,2771.82,1718.92,1647,1544.96,1503.82,1461.24,1381.10,1278.30,1250.37,1192.64,1162.71,1122.97,1040.86,1011.24,951.03,875.02,802.82,770.23,696.35 ,602.78,579.43. ¹ H NMR (500MHz,CDCl ₃ )δ7.48(s,1H),7.41(s,1H),7.00(s,1H),6.60(s,1H),6.39(s,1H) ,5.02(s,1H),4.20(d,J＝11.5Hz,1H),3.90–3.84(m,2H),3.44–3.37(m,1H),3.33–3.26(m,1H),2.82–2.77 (m,1H),2.70–2.66(m,1H),2.67–2.63(m,1H),2.63–2.60(m,1H),2.47–2.41(m,3H),2.26(s,6H),2.17 –2.16(m,1H),1.91–1.83(m,2H),1.66(s,3H),1.43(s,1H),1.41–1.36(m,1H),1.31–1.27(m,1H),1.26 (s,3H),1.24(s,3H),1.11(s,3H). ¹³ C NMR(75MHz,CDCl ₃ )δ208.83,171.33,168.28,165.03,142.49,140.86,119.53,114.17,109.49,82.09,81.10 ,78.41,58.83,57.69,57.35,50.90,48.96,44.44(2C),44.04,38.61,38.33,36.98,36.10,29.68,26.19,25.99,23.47,20.68,18.38.H-ESIMSm/z 5143. ] ⁺ (calcd for C ₃₀ H ₄₃ N ₂ O ₇ ,543.3065)

Example 28

Preparation of Compound II-12

Using compound 2 and N,N-diethylethylenediamine as raw materials, the operation was the same as II-11, and the crude product was purified by column chromatography (dichloromethane:methanol=100:1) to obtain a light yellow solid (II-12 ) 0.43g, yield 34%, 162°C (expansion). IR(cm ^-1 ): 3389.08, 2970.63, 2828.09, 1717.42, 1647.82, 1541.33, 1464.38, 1381.23, 1280.17, 1249.05, 1163.73, 1043.68, 1010.10, 8675.31, 803.39,

¹ H NMR (500MHz, CDCl ₃ )δ7.48(s,1H),7.41(s,1H),7.00(brs,1H),6.60(s,1H),6.39(s,1H),5.01(s, 1H),4.21-4.17(m,1H),3.98–3.88(m,2H),3.44–3.27(m,2H),2.84–2.75(m,1H),2.68–2.64(m,1H),2.63– 2.58(m,1H),2.51(s,1H),2.45(d,J=5.6Hz,2H),2.36–2.18(m,6H),2.13(d,J=5.7Hz,2H),1.88–1.83 ¹³ C NMR (75MHz,CDCl ₃ )δ208.78,171.33,168.23,165.01,142.48,140.85,119.54,114.21,109.48,82.08,81.16,78.48,58.88,57.74,50.95,48.90,46.17(2C),44.11,38.78,38.33,36.96 ,36.31,29.80,29.62,29.18,26.09,23.46,20.66,18.37,10.70(2C).

HR-ESIMS m/z571.3378[M+H] ⁺ (calcd for C ₃₂ H ₄₇ N ₂ O ₇ ,571.3383).

Example 29

Preparation of Compound II-13

Using compound 2 and N-(2-aminoethyl)piperidine as raw materials, the operation was the same as in II-11, and the crude product was purified by column chromatography (dichloromethane:methanol=100:1) to obtain a light yellow solid (II- 13) 0.48g, yield 37%, 180°C (decomposition). IR(cm ^-1 ): 3422.96, 2938.06, 1718.13, 1655.12, 1640.54, 1383.32, 1279.82 ^, 1251.79, 1161.37, 1011.15, 874.98, 602.00, 579.15. 7.48(s,1H),7.41(s,1H),6.59(s,1H),6.39(s,1H),5.02(s,1H),4.22(d,J=11.2Hz,1H),4.03–3.93 (m,1H),3.87(d,J＝11.9Hz,1H),3.58–3.40(m,2H),3.11–3.02(m,2H),2.83–2.69(m,6H),2.66(s,1H ),2.61(s,1H),2.54–2.40(m,2H),2.21–2.10(m,1H),1.83–1.74(m,3H),1.66(s,2H),1.62–1.49(m,3H ),1.43–1.33(m,5H),1.24(s,6H),1.10(s,3H). ¹³ C NMR(75MHz,CDCl3)δ208.86,171.36,168.31,164.95,142.43,140.85,119.57,114.18,109.52 ,82.10,81.15,78.24,58.86,57.76,56.95,53.77,50.92,48.83,45.37,44.02,38.57,38.35,37.01,34.73,29.84,26.20,26.04,23.86,13.48,20.6 -ESIMSm/z583.3368[M+H] ⁺ (calcd for C ₃₃ H ₄₇ N ₂ O ₇ ,583.3378).

Example 30

Preparation of Compound II-14

Using compound 2 and N-(2-aminoethyl)morpholine as raw materials, the operation was the same as that of compound II-11, and the crude product was purified by column chromatography (dichloromethane:methanol=100:1) to obtain a light yellow solid (II -14) 0.41g, yield 32%, 185°C (decomposition). IR(cm ^-1 ):3411.13,2963.63,1716.83,1648.24,1541.74,1458.21,1381.14,1279.18,1249.12,1163.89,1117.37,1044.32,1010.13,912.72,875.15,803.57,769.98,696.44,603.25. ¹ H NMR(500MHz ,CDCl ₃ )δ7.48(s,1H),7.41(s,1H),6.96(brs,1H),6.60(s,1H),6.39(s,1H),5.02(s,1H),4.20( s,1H),3.95–3.85(m,2H),3.75–3.70(m,4H),3.49–3.43m,1H),3.40–3.31(m,1H),2.84–2.77(m,2H),2.71 –2.60(m,3H),2.60–2.49(m,6H),2.45–2.40(m,1H),2.20–2.12(m,1H),1.94–1.79(m,3H),1.66(s,3H) ,1.27(s,3H),1.24(s,3H),1.12(s,3H). ¹³ C NMR(75MHz,CDCl ₃ )δ208.59,171.19,168.04,164.96,142.53,140.87,119.50,114.25,109.46,82.09 ,81.11,78.56,66.29(2C),58.91,57.65,56.84,52.88(2C),50.84,49.05,44.11,38.50,38.11,36.90,35.23,29.94,26.12,25.98,23.53,20.629.SIMHRE m/z585.3173[M+H] ⁺ (calcd for C ₃₂ H ₄₅ N ₂ O ₈ ,585.3098).

Example 31

Preparation of Compound II-15

Using compound 2 and N-(3-aminopropyl)morpholine as raw materials, the operation was the same as in II-11, and the crude product was purified by column chromatography (dichloromethane:methanol=100:1) to obtain a light yellow solid (II- 15) 0.43g, yield 33%, 210°C (decomposition). IR(cm ^-1 ):3411.23,2963.34,2814.26,1716.56,1654.23,1544.46,1503.12,1458.87,1381.17,1277.24,1251.32,1163.94,1116.94,1011.64,875.09,860.72,802.58,770.51,695.96,602.88,580.44. ¹ H NMR (300MHz, CDCl3) δ7.48(s,1H),7.42(s,1H),7.21–7.10(m,1H),6.60(s,1H),6.39(s,1H),5.02(s, 1H), 4.16(d, J=11.4Hz, 1H), 3.93–3.82(m, 2H), 3.77–3.67(m, 4H), 3.37–3.28(m, 2H), 3.14(s, 1H), 2.76 –2.70(m,1H),2.68–2.56(m,3H),2.53–2.39(m,8H),2.19–2.10(m,1H),1.89–1.82(m,1H),1.74–1.69(m, 2H),1.66(s,3H),1.42–1.32(m,2H),1.30–1.19(m,6H),1.09(s,3H). ¹³ C NMR(75MHz,CDCl ₃ )δ208.74,171.03,168.32, 165.09,142.52,140.85,119.49,114.18,109.47,82.09,81.18,78.45,66.46(2C),58.90,57.71,56.43,53.14(2C),50.87,48.89,44.08,38.912,363.9 26.17,25.99,25.13,23.52,20.67,18.34. HR-ESIMS m/z599.3326[M+H] ⁺ (calcd for C ₃₃ H ₄₇ N ₂ O ₈ ,599.3327).

Claims (10)

1. Compounds of general formula I or II: Where R represents: H, C ₁ ~ C ₆ alkyl, R ¹ represents: H, C ₁ ~ C ₆ alkyl; R ² represents: H, F, Cl, Br, CH ₃ , OCH ₃ , NH ₂ , NHCOCH ₃ , CONH ₂ , CN or NO ₂ , and R ² is monosubstituted or double substituted; X stands for: CH ₂ , NH, NCH ₃ or O; m=2 or 3; n=1 or 2. 2. The compound of claim 1, wherein R represents CH ₃ , CH ₂ C ₆ H ₅ , CH ₂ CH ₂ C ₆ H ₅ , 3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein R represents 4. the preparation method of general formula I compound among the claim 1, comprises: Wherein the definition of R is the same as claim 1. 5. The preparation method of claim 4, wherein R-NH ₂ is selected from corresponding aliphatic amines or substituted anilines, and the reaction solvent is selected from acetonitrile or tetrahydrofuran. 6. the preparation method of general formula II compound in claim 1, comprising: Wherein the definition of R is the same as claim 1. 7. The preparation method of claim 6, wherein R-NH ₂ is selected from corresponding aliphatic amines or substituted anilines, and the reaction solvent is selected from acetonitrile or tetrahydrofuran. 8. A pharmaceutical combination comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 9. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of an anti-inflammatory drug. 10. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of an analgesic.