Epsilon-caprolactam compound containing guanidyl structural unit as well as preparation method and application of epsilon-caprolactam compound

Abstract

The invention belongs to the field of compound synthesis, and discloses an epsilon-caprolactam compound containing a guanidyl structural unit and preparation and application of the epsilon-caprolactam compound, the chemical structure of the epsilon-caprolactam compound is shown in the specification, and the epsilon-caprolactam compound containing the guanidyl structural unit has good anti-malarial activity and is expected to become a novel drug intermediate. The compound is used for preparing antimalarial drugs. The invention also discloses a preparation method of the epsilon-caprolactam compound containing the guanidyl structural unit. The preparation method of the epsilon-caprolactam compound containing the guanidyl structural unit has the advantages that the raw materials and the catalyst are cheap and easy to obtain; reaction conditions are mild, and operation is simple and convenient; and the method has the advantages of wide substrate universality, high yield for a series of epsilon-caprolactam products containing guanidyl structural units, and the like.

Description

Technical Field

[0001] This invention belongs to the field of compound synthesis, and specifically relates to an ε-caprolactam compound containing a guanidine group structural unit, its preparation method, and its application. Background Technology

[0002] Compounds containing guanidine groups constitute a class of important nitrogen-containing bioactive molecules with wide applications, serving as crucial building blocks in chemical and pharmaceutical processes [SHKim, D. Semenya, Eur. J. Med. Chem. 2021, 216, 113293.]. Studies have shown that compounds containing a guanidine core skeleton generally possess good biological and pharmaceutical activities. Examples include agmatine, a competitive inhibitor of nitric oxide synthase (NOS); trimethoprim, a broad-spectrum antibacterial agent; and proguanil, a drug used to treat or prevent Pneumocystis pneumonia, toxoplasmosis, malaria, and babesiosis.

[0003]

[0004] The ε-caprolactam structure is an important and advantageous backbone in medicinal chemistry, widely found in drug molecules [FI Saldívar-González, E. Lenci, A. Trabocchi, JLMedina-Franco, RSC Adv., 2019, 9, 27105]. Studies have shown that, in addition to significant antibiotic activity, drugs containing the ε-caprolactam structure also have potential therapeutic applications in various fields. The following three representative drugs all contain the ε-caprolactam structure.

[0005]

[0006] For example, the MMP3 inhibitor DB02090 can inhibit arthritis, cardiovascular disease, and tumors that may be caused by excessive activity of the MMP3 gene; prazepam is a widely used antidepressant; and the μ-opioid receptor agonist CHEMBL401142 can be used as a short-acting analgesic. These ε-caprolactam compounds have complex structures and good drug activity, and the synthesis of compounds containing the ε-caprolactam structure is extremely difficult.

[0007] In summary, analysis of compounds containing guanidine-containing structural units and ε-caprolactams suggests that combinations of these units may yield novel pharmaceutically active compounds, as they may inherit the structure and properties of both. Therefore, developing efficient and economical methods for synthesizing ε-caprolactam compounds containing guanidine-containing structural units holds significant potential pharmaceutical value and application prospects. Summary of the Invention

[0008] In order to overcome the shortcomings and deficiencies of the prior art, the primary objective of this invention is to provide an ε-caprolactam compound containing a guanidine structural unit.

[0009] Another object of the present invention is to provide a method for preparing the above-mentioned ε-caprolactam compound containing a guanidine group structural unit.

[0010] Another object of the present invention is to provide the application of the above-mentioned ε-caprolactam compounds containing guanidine structural units.

[0011] The objective of this invention is achieved through the following solution:

[0012] An ε-caprolactam compound containing a guanidine group structural unit has the general chemical structure shown in Formula I:

[0013]

[0014] Among them, Ar 1 Selected from any of the aryl groups; Ar 2 Selected from any of the aryl groups;

[0015] Preferably, the Ar 1 Selected from; one of naphthyl, phenyl, 3-methylphenyl, 4-ethylphenyl, 2,4-xylyl, 4-methoxyphenyl, 4-chlorophenyl, 3-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-cyanophenyl, 4-trifluoromethylphenyl; Ar 2 It is selected from one of naphthyl, phenyl, 3-methylphenyl, 4-ethylphenyl, 2,4-dimethylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 3-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-cyanophenyl, and 4-trifluoromethylphenyl.

[0016] Preferably, the ε-caprolactam compound containing a guanidine group structural unit has a chemical structure selected from one of the following structural formulas:

[0017]

[0018] A method for preparing the above-mentioned ε-caprolactam compound containing a guanidine structural unit includes the following steps: mixing the compound shown in Formula II, the compound shown in Formula III, and a solvent evenly, and stirring under sealed conditions at -50 to 100°C until the reaction is complete, and separating the compound shown in Formula I.

[0019]

[0020] Among them, Ar 1 Selected from any of the aryl groups; Ar 2 Selected from any aryl group;

[0021] The mechanism of the preparation method of the present invention is as follows, wherein H2O comes from air and moisture contained in the solvent:

[0022]

[0023] In the preparation method described above, water may be added as an additional raw material, wherein the amount of water used is 0.1-10 times the amount of the compound shown in Formula III, preferably 0.1-1 times.

[0024] In the preparation method described above, it is preferable to seal and stir the reaction at room temperature until the reaction is complete, wherein room temperature refers to 10-30℃.

[0025] The compound shown in Formula II is 1,8-diazabicyclo[5.4.0]undec-7-ene, which is commercially available.

[0026] The compound shown in Formula III is a carbodiimide compound, which can be synthesized according to the following literature method [HE Houck, KAMc Connell, CJ Klingler, AL Koenig, GK Himka, MB Larsen, ACS Macro Letters 2023, 12, 1112-1117.].

[0027] The amount of substance of the compound shown in Formula II is x times the amount of substance of the compound shown in Formula III, where x = 0.1 to 80, preferably 4 times.

[0028] The solvent is at least one selected from toluene, dichloromethane, isopropanol, tetrahydrofuran, 1,2-dichloroethane, chloroform, 1,1,2-trichloroethane, 1,1,2,2-tetrachloroethane, ethanol, diethyl ether, ethyl acetate, methanol, acetone, acetonitrile, DMF, and nitromethane.

[0029] The amount of solvent used is 0.1 mL to 50 mL per millimole (mmol) of the compound represented by Formula III.

[0030] The method for preparing ε-caprolactam compounds containing guanidine structural units described in this invention is a simple and efficient method for synthesizing ε-caprolactam compounds containing guanidine structural units; the raw materials of this method are readily available, the conditions are mild, and the substrates have broad applicability.

[0031] The above-mentioned ε-caprolactam compounds containing guanidine structural units are used in the preparation of antimalarial drugs.

[0032] Preferably, the malaria parasite is Plasmodium falciparum, and more preferably, it is the Plasmodium falciparum 3D7 strain.

[0033] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0034] The ε-caprolactam compounds containing guanidine structural units described in this invention represent a series of novel poly-ε-caprolactam compounds containing guanidine structural units. These ε-caprolactam compounds exhibit good antimalarial activity and are expected to become a new type of pharmaceutical intermediate. The preparation method of the ε-caprolactam compounds containing guanidine structural units described in this invention has the following advantages: the raw materials and catalysts are inexpensive and readily available; the reaction conditions are mild, and the operation is simple and convenient; the substrate has broad applicability, achieving high yields (≥56%) for a series of ε-caprolactam products containing guanidine structural units. Detailed Implementation

[0035] The present invention will be further described in detail below with reference to embodiments, but the implementation of the present invention is not limited thereto. Unless otherwise specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments used, unless otherwise specified, are all commercially available products.

[0036] Example 1

[0037] Synthesis of ε-caprolactam compounds containing guanidine structural units as shown in Formula I-1:

[0038]

[0039] In a 10 mL Shrek tube, 1,8-diazabicyclo[5.4.0]undec-7-ene II (77.0 mg, 0.4 mmol), dinaflavylcarbodiimide III-1 (29.4 mg, 0.1 mmol), and toluene (1.0 mL) were added sequentially. After sealing, the reaction solution was stirred at room temperature for 19 h. TLC analysis showed that the starting material had almost completely reacted, and the reaction was stopped. Column chromatography was performed after the reaction, with dichloromethane / methanol as eluent (15 / 1), yielding 34.3 mg of product I-1, a reddish-brown solid, with a yield of 74%.

[0040] Analytical data for ε-caprolactam compounds containing guanidine structural units, as shown in Formula I-1: 1H NMR (500MHz, CDCl3) δ1.58-1.64(m,7H),1.76-1.78(m,2H),2.43(d,J=7.5Hz,2H),3.24(d,J=5.5Hz,2H),3.37(t,J=7.0Hz,2H),3.4 4(t,J=7.0Hz,2H),5.03(s,1H),7.25(d,J=8.5Hz,2H),7.32(t,J=7.5Hz,2H),7.40(t,J=7.0Hz,2H),7.51(s,2H),7.71-7.75(m,6H); 13 C NMR (126MHz, CDCl3) δ176.08,148.61,134.31,129.92,128.96,127.44,126.86,126.03,12 4.05,123.30,118.18,49.43,45.42,38.69,36.98,29.76,28.39,27.83,23.23.Exactmass calcd for C 30 H 33 N4O[M+H] + :465.2649,Found:465.2647.

[0041] Example 2

[0042] Synthesis of ε-caprolactam compounds containing guanidine structural units as shown in Formula I-2:

[0043]

[0044] In a 10 mL Shrek tube, 1,8-diazabicyclo[5.4.0]undec-7-ene II (77.0 mg, 0.4 mmol), diphenylcarbodiimide III-2 (19.4 mg, 0.1 mmol), and toluene (1.0 mL) were added sequentially. After sealing, the reaction solution was stirred at room temperature for 16 h. TLC analysis showed that the starting material had almost completely reacted, and the reaction was stopped. Column chromatography was performed after the reaction, with dichloromethane / methanol as the eluent (15 / 1), yielding 29.1 mg of product I-2, a yellow oily liquid, with a yield of 80%.

[0045] Analytical data for ε-caprolactam compounds containing guanidine structural units, as shown in Formula I-2: 1H NMR (500MHz, CDCl3) δ1.60-1.66(m,5H),1.69-1.72(m,2H),1.74-1.80(m,2H),2.47-2.49(m,2H),3.31-3.33(m,4H),3.43(t,J= 6.5Hz,2H),4.77(s,1H),7.01(t,J=7.5Hz,2H),7.05(d,J=7.5Hz,4H),7.25-7.26(m,1H),7.26-7.27(m,2H),7.28-7.29(m,1H); 13 C NMR (126MHz, CDCl3) δ176.33,148.77,129.29,123.04,122.78,49.64,45.50,38.59,37.11,29.91,29.65,28.51,27.84,23.35.HRMS(ESI): Exact mass calcd for C 22 H 29 N4O[M+H] + :365.2336,Found:365.2342

[0046] Example 3

[0047] Synthesis of ε-caprolactam compounds containing guanidine structural units as shown in Formula I-3:

[0048]

[0049] In a 10 mL Shrek tube, 1,8-diazabicyclo[5.4.0]undec-7-ene II (77.0 mg, 0.4 mmol), di-(3-methylphenyl)carbodiimide III-3 (22.2 mg, 0.1 mmol), and toluene (1.0 mL) were added sequentially. After sealing, the reaction solution was stirred at room temperature for 19 h. TLC analysis showed that the starting material had almost completely reacted, and the reaction was stopped. Column chromatography was performed after the reaction, with dichloromethane / methanol = 15 / 1 as eluent, yielding 27.4 mg of product I-3 as a yellow solid, with a yield of 70%.

[0050] Analytical data for ε-caprolactam compounds containing guanidine structural units, as shown in Formula I-3: 1H NMR (500MHz, CDCl3) δ1.60-1.66(m,5H),1.68-1.71(m,2H),1.74-1.79(m,2H),2.30(s,6H),2.46-2.48(m,2H),3.3 0-3.32(m,4H),3.43(t,J=6.5Hz,2H),4.62(s,1H),6.82-6.85(m,5H),7.16(t,J=8.0Hz,2H),7.32(d,J=4.0Hz,1H); 13 CNMR(126MHz, CDCl3)δ176.10,148.40,141.26,139.07,129.04,128.27,127.19,126.80,12 3.59,119.79,64.83,49.59,45.59,38.39,37.07,29.87,28.50,27.81,23.31,21.32.Exact mass calcd for C 24 H 33 N4O[M+H] + :393.2649,Found:393.2652.

[0051] Example 4

[0052] Synthesis of ε-caprolactam compounds containing guanidine structural units as shown in Formula I-4:

[0053]

[0054] In a 10 mL Shrek tube, 1,8-diazabicyclo[5.4.0]undec-7-ene II (77.0 mg, 0.4 mmol), di-(4-ethylphenyl)carbodiimide III-4 (25.0 mg, 0.1 mmol), and toluene (1.0 mL) were added sequentially. After sealing, the reaction solution was stirred at room temperature for 19 h. TLC analysis showed that the starting material had basically reacted completely, and the reaction was stopped. Column chromatography was performed after the reaction, with dichloromethane / methanol = 15 / 1 as eluent, yielding 32.0 mg of product I-4, a yellow oily liquid, with a yield of 76%.

[0055] Analytical data for ε-caprolactam compounds containing guanidine structural units, as shown in Formula I-4: 1H NMR (500MHz, CDCl3) δ1.19(t,J=7.5Hz,6H),1.57-1.64(m,5H),1.65-1.69(m,2H),1.72-1.77(m,2H),2.44-2.46(m,2H),2 .57(q,J=7.5Hz,4H),3.28-3.30(m,2H),3.40(t,J=7.0Hz,4H),4.56(s,1H),6.95(d,J=8.0Hz,4H),7.09(d,J=8.0Hz,4H); 13 C NMR (126MHz, CDCl3) δ175.90,148.66,138.64,128.52,122.90,49.48,45.58,38.38,36.97,29.76,28.38,28.02,27.76,23.20,15.48.Exact mass calcd for C 26 H 37 N4O[M+H] + :421.2962,Found:421.2967.

[0056] Example 5

[0057] Synthesis of ε-caprolactam compounds containing guanidine structural units as shown in Formula I-5:

[0058]

[0059] In a 10 mL Shrek tube, 1,8-diazabicyclo[5.4.0]undec-7-ene II (77.0 mg, 0.4 mmol), di-(2,4-dimethylphenyl)carbodiimide III-5 (25.0 mg, 0.1 mmol), and toluene (1.0 mL) were added sequentially. After sealing, the reaction solution was stirred at room temperature for 19 h. TLC analysis showed that the starting material had basically reacted completely, and the reaction was stopped. Column chromatography was performed after the reaction, with dichloromethane / methanol = 15 / 1 as eluent, yielding 29.0 mg of product I-5, a yellow oily liquid, with a yield of 69%.

[0060] Analytical data for ε-caprolactam compounds containing guanidine structural units, as shown in Formula I-5: 1H NMR (500MHz, CDCl3) δ1.58-1.65(m,5H),1.66-1.70(m,2H),1.76-1.81(m,2H),2.17(s,6H),2.26(s ,6H),2.44-2.46(m,2H),3.29-3.32(m,4H),3.39(t,J=6.5Hz,2H),6.93-6.98(m,6H),7.28(s,1H); 13 C NMR (126MHz, CDCl3) δ175.65,147.92,127.93,127.19,126.69,126.55,49.47,45.64,38.14,36.95,29.75,28.41,27.86,23.21,20.61,17.70.Exact mass calcd forC 26 H 37 N4O[M+H] + :421.2962,Found:421.2961.

[0061] Example 6

[0062] Synthesis of ε-caprolactam compounds containing guanidine structural units as shown in Formula I-6:

[0063]

[0064] In a 10 mL Shrek tube, 1,8-diazabicyclo[5.4.0]undec-7-ene II (77.0 mg, 0.4 mmol), di-(4-methoxyphenyl)carbodiimide III-6 (25.4 mg, 0.1 mmol), and toluene (1.0 mL) were added sequentially. After sealing, the reaction solution was stirred at room temperature for 19 h. TLC analysis showed that the starting material had basically reacted completely, and the reaction was stopped. Column chromatography was performed after the reaction, with dichloromethane / methanol = 15 / 1 as eluent, yielding 27.1 mg of product I-6, a yellow oily liquid, with a yield of 64%.

[0065] Analytical data for ε-caprolactam compounds containing guanidine structural units, as shown in Formula I-6: 1 H NMR (500MHz, CDCl3) δ1.57-1.63(m,5H),1.65-1.74(m,4H),2.43-2.45(m,2H),3.25-3.29(m,4H) ),3.37(t,J=6.5Hz,2H),3.73(s,6H),4.68(s,1H),6.81(d,J=9.0Hz,4H),6.96(d,J=8.5Hz,4H); 13C NMR (126MHz, CDCl3) δ176.05,155.86,149.73,124.91,114.52,55.32,49.55,45.52,38.21,37.00,29.81,28.43,27.75,23.25.Exact mass calcd for C 24 H 33 N4O3[M+H] + :425.2547,Found:425.2541.

[0066] Example 7

[0067] Synthesis of ε-caprolactam compounds containing guanidine structural units as shown in Formula I-7:

[0068]

[0069] In a 10 mL Shrek tube, 1,8-diazabicyclo[5.4.0]undec-7-ene II (77.0 mg, 0.4 mmol), di-(4-chlorophenyl)carbodiimide III-7 (26.2 mg, 0.1 mmol), and toluene (1.0 mL) were added sequentially. After sealing, the reaction solution was stirred at room temperature for 16 h. TLC analysis showed that the starting material had basically reacted completely, and the reaction was stopped. Column chromatography was performed after the reaction, with dichloromethane / methanol = 15 / 1 as eluent, yielding 36.7 mg of product I-7, a yellow oily liquid, with a yield of 85%.

[0070] Analytical data for ε-caprolactam compounds containing guanidine structural units, as shown in Formula I-7: 1 H NMR (500MHz, CDCl3) δ1.60-1.66(m,5H),1.68-1.73(m,4H),2.47-2.49(m,2H),3.25(t,J=6.0Hz 2H),3.30-3.32(m,2H),3.42(t,J=6.5Hz,2H),4.93(s,1H),6.98(d,J=8.5Hz,4H),7.20(d,J=8.5Hz,4H); 13 C NMR (126MHz, CDCl3) δ180.29,177.10,151.15,139.53,129.12,128.75,123.1 3,49.69,45.05,39.84,37.08,29.80,28.19,24.30,23.31.HRMS(ESI):Exact masscalcd for C 22 H 27 Cl2N4O[M+H] +:433.1556,Found:433.1552.

[0071] Example 8

[0072] Synthesis of ε-caprolactam compounds containing guanidine structural units as shown in Formula I-8:

[0073]

[0074] In a 10 mL Shrek tube, 1,8-diazabicyclo[5.4.0]undec-7-ene II (77.0 mg, 0.4 mmol), di-(3-chlorophenyl)carbodiimide III-8 (26.2 mg, 0.1 mmol), and toluene (1.0 mL) were added sequentially. After sealing, the reaction solution was stirred at room temperature for 16 h. TLC analysis showed that the starting material had basically reacted completely, and the reaction was stopped. Column chromatography was performed after the reaction, using dichloromethane / methanol = 15 / 1 as eluent, to give 24.1 mg of product I-8, a yellow oily liquid, with a yield of 56%.

[0075] Analytical data for ε-caprolactam compounds containing guanidine structural units, as shown in Formula I-8: 1 H NMR (500MHz, CDCl3) δ1.56-1.63(m,5H),1.65-1.71(m,4H),2.44-2.46(m,2H),3.20(t,J=6.0Hz,2H),3.2 6-3.28(m,2H),3.39(t,J=6.0Hz,2H),4.98(s,1H),6.88-6.92(m,4H),7.03(s,2H),7.12(t,J=8.0Hz,2H); 13 C NMR (126MHz, CDCl3) δ176.38,148.36,134.32,129.94,122.13,121.82,119.95,49.44,45.07,38.80,36.93,29.72,28.29,27.75,23.19.Exact masscalcd for C 22 H 27 Cl2N4O[M+H] + :433.1556,Found:433.1553.

[0076] Example 9

[0077] Synthesis of ε-caprolactam compounds containing guanidine structural units as shown in Formula I-9:

[0078]

[0079] In a 10 mL Shrek tube, 1,8-diazabicyclo[5.4.0]undec-7-ene II (77.0 mg, 0.4 mmol), di-(4-bromophenyl)carbodiimide III-9 (34.9 mg, 0.1 mmol), and toluene (1.0 mL) were added sequentially. After sealing, the reaction solution was stirred at room temperature for 16 h. TLC analysis showed that the starting material had almost completely reacted, and the reaction was stopped. Column chromatography was performed after the reaction, with dichloromethane / methanol as eluent (15 / 1), yielding 41.6 mg of product I-9 as a yellow solid, with a yield of 80%.

[0080] Analytical data for ε-caprolactam compounds containing guanidine structural units, as shown in Formula I-9: 1 H NMR (500MHz, CDCl3) δ1.61-1.65(m,4H),1.64-1.72(m,5H),2.46-2.48(m,2H),3.22(t,J=6.0Hz,2H) ,3.28-3.30(m,2H),3.41(t,J=6.0Hz,2H),5.01(s,1H),6.92(d,J=8.5Hz,4H),7.33(d,J=8.5Hz,4H); 13 C NMR (126MHz, CDCl3) δ176.57,148.48,132.13,123.86,115.26,49.57,45.17,38.70,37.08,29.87,28.44,27.78,23.33.HRMS(ESI):Exact mass calcd forC 22 H 27 Br2N4O[M+H] + :521.0546,Found:521.0545.

[0081] Example 10

[0082] Synthesis of ε-caprolactam compounds containing guanidine structural units as shown in Formula I-10:

[0083]

[0084] In a 10 mL Shrek tube, 1,8-diazabicyclo[5.4.0]undec-7-ene II (77.0 mg, 0.4 mmol), di-(4-iodophenyl)carbodiimide III-10 (44.5 mg, 0.1 mmol), and toluene (1.0 mL) were added sequentially. After sealing, the reaction solution was stirred at room temperature for 16 h. TLC analysis showed that the starting material had basically reacted completely, and the reaction was stopped. Column chromatography was performed after the reaction, with dichloromethane / methanol = 15 / 1 as eluent, yielding 46.8 mg of product I-10, a yellow oily liquid, with a yield of 76%.

[0085] Analytical data for ε-caprolactam compounds containing guanidine structural units, as shown in Formula I-10: 1 H NMR (500MHz, CDCl3) δ1.59-1.63(m,5H),1.67-1.71(m,4H),2.45-2.47(m,2H),3.20(t,J=6.0Hz,2H) ,3.27-3.29(m,2H),3.39(t,J=6.0Hz,2H),5.88(s,1H),6.79(d,J=8.5Hz,4H),7.48(d,J=8.5Hz,4H); 13 C NMR (126MHz, CDCl3) δ180.25,176.54,148.89,143.35,137.91,123.95,85.69,49.50,45.08,39.03,36.97,29.75,28.30,27.80,23.22.Exact mass calcd forC 22 H 27 I₂N₄O[M+H] + :617.0269,Found:617.0264.

[0086] Example 11

[0087] Synthesis of ε-caprolactam compounds containing guanidine structural units as shown in Formula I-11:

[0088]

[0089] In a 10 mL Shrek tube, 1,8-diazabicyclo[5.4.0]undec-7-ene II (77.0 mg, 0.4 mmol), di-(4-cyanophenyl)carbodiimide III-11 (24.4 mg, 0.1 mmol), and toluene (1.0 mL) were added sequentially. After sealing, the reaction solution was stirred at room temperature for 16 h. TLC analysis showed that the starting material had almost completely reacted, and the reaction was stopped. Column chromatography was performed after the reaction, with dichloromethane / methanol as eluent (15 / 1), yielding 35.6 mg of product I-11, a yellow oily liquid, with a yield of 86%.

[0090] Analytical data for ε-caprolactam compounds containing guanidine structural units, as shown in Formula I-11: 1H NMR (500MHz, CDCl3) δ1.60-1.65(m,5H),1.71-1.74(m,3H),1.77-1.81(m,2H),2.46-2.48(m,2H),3.33-3.34(m,2H),3. 38(t,J=6.0Hz,2H),3.62(q,J=6.0Hz,1H),4.68(s,1H),7.30-7.35(m,1H),7.54-7.59(m,5H),7.95(s,1H),8.91(s,1H); 13 C NMR (126MHz, CDCl3) δ179.86,177.29,142.37,140.70,133.08,128.42,127.51,126.98, 122.27,118.85,107.23,65.07,49.78,45.37,41.07,36.96,29.74,28.25,23.21.Exact mass calcd for C 24 H 27 N6O[M+H] + :415.2241,Found:415.2248.

[0091] Example 12

[0092] Synthesis of ε-caprolactam compounds containing guanidine structural units as shown in Formula I-12:

[0093]

[0094] In a 10 mL Shrek tube, 1,8-diazabicyclo[5.4.0]undec-7-ene II (77.0 mg, 0.4 mmol), di-(4-trifluoromethylphenyl)carbodiimide III-12 (33.0 mg, 0.1 mmol), and toluene (1.0 mL) were added sequentially. After sealing, the reaction solution was stirred at room temperature for 16 h. TLC analysis showed that the starting material had basically reacted completely, and the reaction was stopped. Column chromatography was performed after the reaction, with dichloromethane / methanol = 15 / 1 as eluent, yielding 42.5 mg of product I-12, a yellow oily liquid, with a yield of 85%.

[0095] Analytical data for ε-caprolactam compounds containing guanidine structural units, as shown in Formula I-12: 1H NMR (500MHz, CDCl3) δ1.59-1.75 (m, 9H), 2.49-2.51 (m, 2H), 3.23 (t, J = 5.5Hz, 2H), 3.30-3. 32(m,2H),3.46(t,J=6.0Hz,2H),5.08(s,1H),7.15(d,J=6.5Hz,4H),7.46(d,J=8.5Hz,4H); 13 C NMR (126MHz, CDCl3) δ176.86, 148.43, 126.26 (q, J = 3.5Hz), 124.45 (q, J = 269.5Hz), 12 3.69(q,J=32.3Hz),120.99,49.55,44.98,39.27,37.05,29.79,28.32,27.88,23.28; 19 F NMR(471MHz,CDCl3)δ-61.68.Exact mass calcd for C 24 H 27 F6N4O[M+H] + :501.2084,Found:501.2079.

[0096] Example 13

[0097]

[0098] In a 10 mL Shrek tube, 1,8-diazabicyclo[5.4.0]undec-7-ene II (77.0 mg, 0.4 mmol), dinafylcarbodiimide III-1 (29.4 mg, 0.1 mmol), water (1.8 mg, 0.1 mmol), and toluene (1.0 mL) were added sequentially. After sealing, the reaction mixture was stirred at room temperature for 19 h. TLC analysis showed that the starting material had almost completely reacted, and the reaction was stopped. Column chromatography was performed after the reaction, with dichloromethane / methanol as eluent (15 / 1), yielding 10.8 mg of product I-1, a reddish-brown solid, with a yield of 23.4%.

[0099] Example 14

[0100] Antimalarial activity testing of ε-caprolactam compounds containing guanidine structural units:

[0101] Given that the ε-caprolactam compound containing the guanidinium structural unit that we synthesized possesses two important elements for drug development, we next tested the antibacterial activity of the compounds mentioned in the above examples. The background above introduces atovaquinone (Proguanil) as a potent, selective, and orally active inhibitor of the parasitic mitochondrial cytochrome bc1 complex. The compounds synthesized using the method of this invention have certain similarities to it; therefore, this example uses atovaquinone (Proguanil) as a reference to test the antimalarial activity of the compounds shown in Table 1 below. The specific implementation process is as follows: Plasmodium falciparum 3D7 strain was cultured in RPMI-1640 medium containing 25 mM HEPES, 50 mg / L 6-hydroxypurine, 2.1 g / L NaHCO3, and 0.5% bovine serum albumin, with the pH adjusted to 7.2. The Plasmodium falciparum 3D7 strain was a circumstellate stage Plasmodium 3D7, induced by 5% sorbitol treatment. A suspension of Plasmodium was prepared by mixing human erythrocytes with intact culture medium, resulting in a hematocrit of 2% and a Plasmodium infection rate of 0.5%. 90 μL of the Plasmodium suspension was added to each well of a 96-well plate, using RPMI-1640 medium containing 4% hematocrit and free of parasites as a control. A series of compounds (I-1–12) in DMSO solution were serially diluted to 100 μL in each well, with three replicates for each concentration, ranging from 0.1–1000 nM. The plates were incubated for 48 hours at 37°C. The antimalarial efficacy of the test compound against Plasmodium falciparum was then evaluated using the fluorescence-based SYBRgreen-I method: 100 μL of the incubated culture medium and 100 μL of SYBRgreen-I solution were transferred to 96-well plates. Simultaneously, 100 μL of RPMI-1640 medium (containing red blood cells, culture medium, and DMSO solution of the corresponding concentration of the compound) + 100 μL of SYBRgreen-I solution was also transferred to 96-well plates as blank wells. The plates were then incubated at room temperature in the dark for 2 hours. Fluorescence was measured using a multi-mode microplate reader with excitation wavelength of 485 nm and emission wavelength of 535 nm. Background fluorescence was subtracted from the blank wells, the drug inhibition rate was calculated, and the IC50 of the drug was fitted. 50 The curve compares the IC50 values ​​of the tested compounds. 50 Numerical values ​​were used to determine the antimalarial activity of the compound. The test results are as follows.

[0102] Table 1. Antitumor activity test data of atovaquinone (Proguanil) and the polycyclic ε-caprolactam compounds containing guanidine structural units described in Examples 1-12.

[0103]

[0104]

[0105]

[0106] The data in table a is the average of three tests; b IC 50 This indicates the concentration at which the tested compound produces half of its maximum inhibitory effect.

[0107] As can be seen from the data in Table 1, compounds I-1 to I-12 all possess antimalarial activity. Their inhibitory ability varies depending on the substituents in each compound. Compounds I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, and I-11 show slightly weaker inhibitory effects against Plasmodium 3D7 than atovaquinone (Proguanil), while compound I-12 shows stronger inhibitory effects against Plasmodium 3D7 than atovaquinone (Proguanil). Overall, the activity test data in Table 1 indicate that the ε-caprolactam compounds containing guanidine structural units described in this invention possess antimalarial activity, and the activities of compounds with different substitutions vary to some extent. These compounds are expected to be developed into a new type of antimalarial drug.

[0108] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. An ε-caprolactam compound containing a guanidine group structural unit, characterized in that... Its general chemical structure is shown in Formula I: Among them, Ar 1 Selected from any of the aryl groups; Ar 2 Selected from any aryl group.

2. The ε-caprolactam compound containing a guanidine group structural unit according to claim 1, characterized in that: The Ar 1 Selected from one of naphthyl, phenyl, 3-methylphenyl, 4-ethylphenyl, 2,4-xylyl, 4-methoxyphenyl, 4-chlorophenyl, 3-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-cyanophenyl, and 4-trifluoromethylphenyl; Ar 2 It is selected from one of naphthyl, phenyl, 3-methylphenyl, 4-ethylphenyl, 2,4-dimethylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 3-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-cyanophenyl, and 4-trifluoromethylphenyl.

3. The ε-caprolactam compound containing a guanidine group structural unit according to claim 1, characterized in that... Its chemical structure is selected from one of the following structural formulas:

4. The ε-caprolactam compound containing a guanidine group structural unit according to claim 1, characterized in that... Its chemical structure is shown below:

5. A method for preparing an ε-caprolactam compound containing a guanidine group structural unit according to any one of claims 1-4, characterized in that... Includes the following steps: The compound shown in Formula II, the compound shown in Formula III, and the solvent were mixed evenly, and the mixture was sealed and stirred at -50 to 100°C until the reaction was complete, and the compound shown in Formula I was separated. The compound represented by Formula II is 1,8-diazabicyclo[5.4.0]undec-7-ene, and the structural formulas of the compounds represented by Formula III and Formula I are shown below: Among them, Ar 1 Selected from any of the aryl groups; Ar 2 Selected from any aryl group.

6. The method for preparing the ε-caprolactam compound containing a guanidine group structural unit according to claim 5, characterized in that: The amount of the 1,8-diazabicyclo[5.4.0]undec-7-ene is x times the amount of the compound shown in Formula III, where x = 0.1 to 80; The solvent is at least one selected from toluene, dichloromethane, isopropanol, tetrahydrofuran, 1,2-dichloroethane, chloroform, 1,1,2-trichloroethane, 1,1,2,2-tetrachloroethane, ethanol, diethyl ether, ethyl acetate, methanol, acetone, acetonitrile, DMF, and nitromethane.

7. The method for preparing the ε-caprolactam compound containing a guanidine group structural unit according to claim 5, characterized in that: The preparation method further includes the addition of water as a raw material, wherein the amount of water used is 0.1-10 times the amount of the compound shown in Formula III.

8. The use of the ε-caprolactam compound containing a guanidine group structural unit according to any one of claims 1-4 in the preparation of antimalarial parasite drugs.

9. The use of the ε-caprolactam compound containing a guanidine group structural unit according to claim 8 in the preparation of antimalarial parasite drugs, characterized in that... The malaria parasite mentioned is Plasmodium falciparum.

10. The use of the ε-caprolactam compound containing a guanidine group structural unit according to claim 8 in the preparation of antimalarial parasite drugs, characterized in that... The malaria parasite mentioned is the Plasmodium falciparum 3D7 strain.

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