Process for the preparation of cyanoethylene bridged quinolone imidazoles and their analogs and medical use thereof

Abstract

This invention relates to the preparation method and pharmaceutical application of cyanide-bridged quinolone imidazoles and their analogues, belonging to the field of chemical synthesis technology. The cyanide-bridged quinolone imidazoles and their analogues are shown in general formulas I-III. These compounds exhibit inhibitory activity against one or more Gram-positive bacteria, Gram-negative bacteria, and fungi, and can be used to prepare antibacterial and / or antifungal drugs. This offers the potential to provide more safe, efficient, and diverse candidate drugs for clinical antimicrobial therapy, helping to address increasingly serious clinical treatment problems such as drug resistance, persistent pathogenic microorganisms, and emerging harmful microorganisms. The raw materials used in their preparation are simple, inexpensive, and readily available, with high synthetic yields, making them significant for anti-infective applications.

Description

Technical Field

[0001] This invention belongs to the field of applied technology, specifically relating to the preparation method and pharmaceutical application of cyanide-bridged quinolone imidazoles and their analogues. Background Technology

[0002] Quinolone drugs play a vital role in clinical anti-infective therapy due to their broad antibacterial spectrum, strong antibacterial activity, good pharmacokinetic properties, and good tolerability. Since their introduction, quinolone antibiotics have undergone four generations of development. However, due to their widespread clinical use, bacteria have developed significant resistance to these drugs, and clinical resistance is very common, severely weakening their antibacterial efficacy. Structural modification of quinolones, particularly at the C-7 position, is a crucial strategy for addressing the increasingly serious problem of drug resistance.

[0003] Cyanoethylene fragments, possessing a polar cyano group and a flexible conjugated alkenyl group, are found in many clinical drugs. Studies have shown that introducing the cyano group into small molecule drugs can improve drug metabolic stability, enhance pharmacokinetic properties, and increase drug bioavailability by blocking readily metabolizable sites. The alkenyl group increases the size of the molecular conjugation system, enhancing DNA intercalation capability. Cyanoethylene fragments obtained after cyano substitution can enhance the binding affinity between ligands and target proteins and the selectivity for other target proteins through hydrogen bonding, dipole interactions, and π-π stacking.

[0004] Electron-rich imidazoles are an important class of nitrogen-containing five-membered heterocycles that readily interact with various enzymes and receptors in organisms through a variety of weak interactions, making them widely used in the construction of novel antimicrobial drugs. Recent studies have found that organically binding imidazoles to different functional fragments may enhance biological activity, enabling multi-site supramolecular binding and overcoming increasingly serious drug resistance. Therefore, structural modification of the C-7 position of quinolones using imidazole cyanide is a promising research topic, potentially leading to the development of a series of novel antibacterial drugs with low toxicity, high activity, and broad spectrum, providing new candidate molecules for clinical anti-infective therapy. Summary of the Invention

[0005] In view of this, one objective of the present invention is to provide pharmaceutically acceptable salts of cyanide-bridged quinolone imidazoles and their analogues; a second objective is to provide a method for preparing pharmaceutically acceptable salts of cyanide-bridged quinolone imidazoles and their analogues; and a third objective is to provide the use of pharmaceutically acceptable salts of cyanide-bridged quinolone imidazoles and their analogues in the preparation of antibacterial and / or antifungal drugs.

[0006] To achieve the above objectives, the present invention provides the following technical solution:

[0007] 1. Cyanoethylene-bridged quinolone imidazoles and their analogues, with structures shown in general formulas I-III:

[0008]

[0009] In the formula:

[0010] R is hydrogen, alkyl, cyanalkyl, hydroxyalkyl, alkenylalkyl, aralkyl, alkynylalkyl, etheralkyl, carboxylalkyl, esteralkyl, carbonylalkyl, or heterocyclic alkyl;

[0011] R 1 R 3 R 5 It is hydrogen, alkyl, unsaturated alkyl, heteroatom-substituted alkyl, benzyl, or substituted benzyl;

[0012] R 2 R 4 R 6 It can be hydrogen, alkyl, cyano or halogen.

[0013] 2. The cyanide-bridged quinolone imidazoles and their analogues, characterized in that,

[0014] R is an ethyl group;

[0015] R 1 R 2 R 5 R 6 It is hydrogen;

[0016] R 3 It is hydrogen, alkyl, unsaturated alkyl, heteroatom-substituted alkyl, benzyl, or substituted benzyl;

[0017] R 4 It can be a hydrogen, n-butyl, or chlorine atom.

[0018] The selection site is any one of the following compounds:

[0019]

[0020] Preferably, the pharmaceutically usable salt is a sodium salt, potassium salt, hydrochloride, nitrate, or acetate.

[0021] 3. The method for preparing the cyanide-bridged quinolone imidazoles and their analogues is as follows:

[0022] a. Preparation of intermediate IV: 2-Butyl-5-chloro-1H-imidazol-4-carboxaldehyde was dissolved in acetonitrile and reacted with a halogenated compound in the presence of potassium carbonate to obtain intermediate IV.

[0023]

[0024] in:

[0025] R1 It can be alkyl, alkenyl, alkynyl, cyano, fluoroalkyl, heterocyclic, or aryl;

[0026] b. Preparation of cyanide-bridged quinolone imidazoles and their analogues as shown in general formulas I-III: Compound V is reacted with commercially available imidazole aldehydes or intermediate IV in a condensation reaction using piperidine as a catalyst and ethanol as a solvent to obtain cyanide-bridged quinolone imidazoles and their analogues as shown in general formulas I-III.

[0027]

[0028] Preferably,

[0029] In step a, the molar ratio of 2-butyl-5-chloro-1H-imidazol-4-carboxaldehyde, the halogenated compound, and potassium carbonate is 1:1.5:2, the reaction solvent is acetonitrile, and the temperature is 50-80℃.

[0030] In step b, the molar ratio of compound V to aldehyde compound is 1:1.5, and the reaction temperature is 40-90℃.

[0031] 4. The use of the cyanide-bridged quinolone imidazoles and their analogues in the preparation of antibacterial and / or antifungal drugs.

[0032] Preferably, the bacteria are one or more of the following: methicillin-resistant Staphylococcus aureus, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus aureus ATCC 25923, Staphylococcus aureus ATCC 29213, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922, or Acinetobacter baumannii; and the fungus is one or more of the following: Candida albicans, Candida tropicalis, Aspergillus fumigatus, Candida albicans ATCC 90023, or Candida parapsilosis ATCC 22019.

[0033] 5. Preparations containing pharmaceutically acceptable salts of cyanide-bridged quinolone imidazoles and their analogues.

[0034] Preferably, the preparation is one of the following: tablets, capsules, granules, injections, powder for injection, eye drops, liniments, suppositories, ointments, or aerosols.

[0035] The beneficial effects of this invention are as follows: This invention provides a method for preparing and applying cyanide-bridged quinolone imidazoles and their analogues. By bridging with cyanide fragments to increase the conjugated system, the effects of introducing different active fragments on antibacterial activity are explored. A series of cyanide-bridged quinolone imidazoles and their analogues have been designed and synthesized. These compounds, after in vitro antimicrobial activity testing, showed inhibitory activity against Gram-positive bacteria (methicillin-resistant Staphylococcus aureus, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus aureus ATCC 25923, Staphylococcus aureus ATCC 29213), Gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922, Acinetobacter baumannii), and fungi (Candida albicans, Candida tropicalis, Aspergillus fumigatus, Candida albicans ATCC 90023, Candida parapsilosis ATCC 22019). They can be used to prepare antibacterial and / or antifungal drugs, thus providing more efficient and safe candidate drugs for clinical antimicrobial therapy. This will help address increasingly serious clinical treatment problems such as drug resistance, persistent pathogenic microorganisms, and emerging harmful microorganisms. The raw materials used in their preparation are simple, inexpensive, and readily available, making them significant for anti-infective applications.

[0036] Other advantages, objectives, and features of the invention will be set forth in part in the description which follows, and in part will be apparent to those skilled in the art from the following examination, or may be learned from practice of the invention. The objectives and other advantages of the invention can be realized and obtained through the following description. Detailed Implementation

[0037] The following specific examples illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention.

[0038] Experimental Example 1: Preparation of Intermediate IV

[0039]

[0040] Intermediate IV was prepared using the method disclosed in the reference “Wang, J.; Ansari, MF; Lin, JM; Zhou, CH Design and synthesis of sulfanilamide aminophosphonates as novel antibacterial agents towards Escherichia coli. Chin. J. Chem. 2021, 39, 2251-2263.”

[0041] Experimental Example 2: Preparation of Intermediate V

[0042]

[0043] References "[1] Sunduru, N.; Gupta, L.; Chauhan, K.; Mishra, NN; Shukla, PK; Chauhan, PMSSynthesis and antibacterial evaluation of novel 8-fluoronorfloxacin derivatives as potential probes for methicillin and vancomycin-resistant Staphylococcus aureus.Eur.J.Med.Chem.2011,46,1232-1244.[2]Valery,NC;Nataliya,NM;Fedor,VA;Svetlana,KK;Emiliya,VN;Marina,AE;Mikhail,IK;Marionella,AKSynthesis and antimycobacterial evaluation of new(2-oxo-2H-chromen-3-yl)substituted Intermediate V was prepared by the method described in "fluoroquinolones. J. Fluorine Chem. 2018, 208, 15-23."

[0044] Example 3: Preparation of Compound I

[0045]

[0046] Intermediate V (200 mg, 0.73 mmol) was added to a clean 50 mL round-bottom flask, and ethanol (20 mL) was added as a solvent. Piperidine (10 mg, 0.12 mmol) was added dropwise, and the mixture was stirred at room temperature for half an hour. 2-Imidazole carboxaldehyde (70 mg, 0.88 mmol) was added, and the mixture was heated to 80 °C under nitrogen protection. Thin-layer chromatography was used to monitor the reaction until completion. After cooling to room temperature, the mixture was poured into ice water, and then filtered, recrystallized, and dried to obtain compound I (142 mg), with a yield of 55.3%; yellow solid; melting point: >250 °C. 1 H NMR(600MHz,DMSO-d6)δ14.93(s,1H),13.07(s,1H),9.11(s,1H),8.28(d,J=10.0Hz,1H),8.1 6(d,J=4.8Hz,1H),7.67(s,1H),7.45(s,2H),4.67(q,J=6.8Hz,2H),1.47(t,J=7.1Hz,3H)ppm.

[0047] Example 4: Preparation of Compound II-1

[0048]

[0049] Intermediate V (200 mg, 0.73 mmol) was added to a clean 50 mL round-bottom flask, and ethanol (20 mL) was added as a solvent. Piperidine (10 mg, 0.12 mmol) was added dropwise, and the mixture was stirred at room temperature for half an hour. 4-Imidazole carboxaldehyde (70 mg, 0.88 mmol) was added, and the mixture was heated to 80 °C under nitrogen protection. Thin-layer chromatography was used to monitor the reaction until completion. The mixture was cooled to room temperature, poured into ice water, and then filtered, recrystallized, and dried to obtain compound II-1 (240 mg), with a yield of 93.5%; yellow solid; melting point: >250 °C. 1 H NMR(600MHz,DMSO-d6)δ14.90(s,1H),12.76(s,1H),9.09(s,1H),8.21(d,J=6.2Hz,1H),8.13 (d,J=10.7Hz,1H),7.97(s,2H),7.88(s,1H),4.69(q,J=7.0Hz,2H),1.47(t,J=7.1Hz,3H)ppm.

[0050] Example 5: Preparation of Compound II-2-1

[0051]

[0052] Intermediate V (200 mg, 0.73 mmol) was added to a clean 50 mL round-bottom flask, and ethanol (20 mL) was added as a solvent. Piperidine (10 mg, 0.12 mmol) was added dropwise, and the mixture was stirred at room temperature for half an hour. 2-Butyl-4-chloro-1H-imidazolium-5-carboxaldehyde (163 mg, 0.88 mmol) was added, and the mixture was heated to 80 °C under nitrogen protection. Thin-layer chromatography was used to monitor the reaction until completion. After cooling to room temperature, the mixture was poured into ice water, and then filtered, recrystallized, and dried to obtain compound II-2-1 (282 mg), with a yield of 87.4%; yellow solid; melting point: >250 °C. 1 H NMR (600MHz, DMSO-d6) δ14.56(s,1H),9.18(s,1H),8.87(d,J=5.7Hz,1H),8.47(d,J=10.4Hz,1H),8.07(s,1H),4.70(q,J= 7.0Hz,2H),3.31-3.28(t,J=7.1Hz,2H),1.88(m,2H),1.59–1.55(m,2H),1.54(t,J=7.3Hz,3H),1.01(t,J=7.4Hz,3H)ppm.

[0053] Example 6: Preparation of Compound II-2-2

[0054]

[0055] Intermediate V (200 mg, 0.73 mmol) was added to a clean 50 mL round-bottom flask, and ethanol (20 mL) was added as a solvent. Piperidine (10 mg, 0.12 mmol) was added dropwise, and the mixture was stirred at room temperature for half an hour. 2-Butyl-4-chloro-1-ethyl-1H-imidazolium-5-carboxaldehyde (188 mg, 0.88 mmol) was added, and the mixture was heated to 80 °C under nitrogen protection. Thin-layer chromatography was used to monitor the reaction until completion. After cooling to room temperature, the mixture was poured into ice water, and then filtered, recrystallized, and dried to obtain compound II-2-2 (188 mg), with a yield of 54.9%; yellow solid; melting point: >250 °C. 1H NMR (600MHz, DMSO-d6) δ14.61(s,1H),8.75(s,1H),8.66(d,J=5.7Hz,1H),8.28(d,J=10.5Hz,1H),7.77(s,1H),4.45(q,J=6.9Hz,2H),4.25(q ,J=7.1Hz,2H),3.15(t,J=7.1Hz,2H),1.86–1.79(m,2H),1.54(m,2H),1.48(t,J=7.1Hz,3H),1.33(t,J=7.1Hz,3H),1.00(t,J=7.3Hz,3H)ppm.

[0056] Example 7: Preparation of Compound II-2-3

[0057]

[0058] Intermediate V (200 mg, 0.73 mmol) was added to a clean 50 mL round-bottom flask, and ethanol (20 mL) was added as a solvent. Piperidine (10 mg, 0.12 mmol) was added dropwise, and the mixture was stirred at room temperature for half an hour. 2-Butyl-4-chloro-1-propyl-1H-imidazolium-5-carboxaldehyde (200 mg, 0.88 mmol) was added, and the mixture was heated to 80 °C under nitrogen protection. Thin-layer chromatography was used to monitor the reaction until completion. After cooling to room temperature, the mixture was poured into ice water, and then filtered, recrystallized, and dried to obtain compound II-2-3 (225 mg), with a yield of 63.7%; yellow solid; melting point: >250 °C. 1 H NMR (600MHz, DMSO-d6) δ14.79(s,1H),9.10(s,1H),8.21(d,J=5.4Hz,1H),8.14(d,J=10.4Hz,1H),7.86(s,1H),4.69(q,J=7.1Hz,2H),4.05(t,J= 6.6Hz,2H),2.73(t,J=7.5Hz,2H),1.70(m,2H),1.65(m,2H),1.47(t,J=7 .0Hz,3H),1.40(m,2H),0.93(t,J=7.3Hz,3H),0.86(t,J=7.3Hz,3H)ppm.

[0059] Example 8: Preparation of Compound II-2-4

[0060]

[0061] Intermediate V (200 mg, 0.73 mmol) was added to a clean 50 mL round-bottom flask, and ethanol (20 mL) was added as a solvent. Piperidine (10 mg, 0.12 mmol) was added dropwise, and the mixture was stirred at room temperature for half an hour. 2-Butyl-4-chloro-1-hexyl-1H-imidazolium-5-carboxaldehyde (200 mg, 0.88 mmol) was added, and the mixture was heated to 80 °C under nitrogen protection. Thin-layer chromatography was used to monitor the reaction until completion. After cooling to room temperature, the mixture was poured into ice water, and then filtered, recrystallized, and dried to obtain compound II-2-4 (290 mg), with a yield of 75.6%; yellow solid; melting point: 208.1-208.6 °C. 1 H NMR (600MHz, DMSO-d6) δ14.81 (s, 1H), 9.11 (s, 1H), 8.21 (d, J = 5.7Hz, 1H), 8. 16(d,J=10.5Hz,1H),7.86(s,1H),4.69(q,J=6.9Hz,2H),4.07(t,J=6.9Hz,2H ),2.73(t,J=7.5Hz,2H),1.71–1.66(m,2H),1.61(m,2H),1.46(t,J=7.0Hz,3H ), 1.39 (n, 2H), 1.23 (s, 6H), 0.93 (t, J = 7.3Hz, 3H), 0.80 (t, J = 6.2Hz, 3H) ppm.

[0062] Example 9: Preparation of Compound II-2-5

[0063]

[0064] Intermediate V (200 mg, 0.73 mmol) was added to a clean 50 mL round-bottom flask, and ethanol (20 mL) was added as a solvent. Piperidine (10 mg, 0.12 mmol) was added dropwise, and the mixture was stirred at room temperature for half an hour. 2-Butyl-4-chloro-1-(cyclopropylmethyl)-1H-imidazolium-5-carboxaldehyde (211 mg, 0.88 mmol) was added, and the mixture was heated to 80 °C under nitrogen protection. Thin-layer chromatography was used to monitor the reaction until completion. After cooling to room temperature, the mixture was poured into ice water, and then filtered, recrystallized, and dried to obtain compound II-2-5 (279 mg), with a yield of 77.2%; yellow solid; melting point: >250 °C. 1H NMR (600MHz, DMSO-d6) δ14.84 (s, 1H), 9.12 (s, 1H), 8.21 (d, J = 5.8Hz, 1H), 8. 18(d,J=10.5Hz,1H),7.88(s,1H),4.69(q,J=7.2Hz,2H),4.00(d,J=6.7Hz,2 H),2.75(t,J=7.6Hz,2H),1.73–1.67(m,2H),1.46(t,J=7.0Hz,3H),1.39(m, 2H), 0.93 (t, J = 7.3Hz, 3H), 0.51 (d, J = 7.2Hz, 2H), 0.31 (d, J = 4.4Hz, 2H) ppm.

[0065] Example 10: Preparation of Compound II-2-6

[0066]

[0067] Intermediate V (200 mg, 0.73 mmol) was added to a clean 50 mL round-bottom flask, and ethanol (20 mL) was added as a solvent. Piperidine (10 mg, 0.12 mmol) was added dropwise, and the mixture was stirred at room temperature for half an hour. 2-Butyl-4-chloro-1-(cyclohexylmethyl)-1H-imidazolium-5-carboxaldehyde (248 mg, 0.88 mmol) was added, and the mixture was heated to 80 °C under nitrogen protection. Thin-layer chromatography was used to monitor the reaction until completion. After cooling to room temperature, the mixture was poured into ice water, and then filtered, recrystallized, and dried to obtain compound II-2-6 (293 mg), with a yield of 74.5%; yellow solid; melting point: 235.5-236.3 °C. 1 H NMR (600MHz, CDCl3) δ14.42(s,1H),8.80(s,1H),8.27(d,J=5.5Hz,1H),7.98(d,J=10. 5Hz,1H),7.72(s,1H),4.48(q,J=7.2Hz,2H),3.76(d,J=7.1Hz,2H),2.71–2.67(m,2H), 1.82(m,2H),1.79–1.75(m,2H),1.68(s,2H),1.67(d,J=7.3Hz,4H),1.64(s,1H),1.49 –1.42(m,2H),1.20(t,J=7.2Hz,3H),1.00(d,J=10.3Hz,2H),0.98(d,J=7.3Hz,3H)ppm.

[0068] Example 11: Preparation of Compound II-2-7

[0069]

[0070] Intermediate V (200 mg, 0.73 mmol) was added to a clean 50 mL round-bottom flask, and ethanol (20 mL) was added as a solvent. Piperidine (10 mg, 0.12 mmol) was added dropwise, and the mixture was stirred at room temperature for half an hour. 1-Allyl-2-butyl-4-chloro-1H-imidazolium-5-carboxaldehyde (198 mg, 0.88 mmol) was added, and the mixture was heated to 80 °C under nitrogen protection. Thin-layer chromatography was used to monitor the reaction until completion. After cooling to room temperature, the mixture was poured into ice water, and then filtered, recrystallized, and dried to obtain compound II-2-7 (111 mg), with a yield of 31.6%; yellow solid; melting point: 213.5-214.2 °C. 1 H NMR (600MHz, CDCl3) δ14.42(s,1H),9.26(s,1H),8.64(s,1H),8.02(s,1H),7.93(s,1H),6.09(m,1H),5.49(m,1H),5.32(m,1H),4.89(d ,J=5.7Hz,2H),4.41(q,J=7.2Hz,2H),3.47(t,J=7.8Hz,2H),2.05(m,2H),1.69(m,2H),1.66(t,J=7.1Hz,3H),1.03(t,J=7.4Hz,3H)ppm.

[0071] Example 12, Preparation of Compound II-2-8

[0072]

[0073] Intermediate V (200 mg, 0.73 mmol) was added to a clean 50 mL round-bottom flask, and ethanol (20 mL) was added as a solvent. Piperidine (10 mg, 0.12 mmol) was added dropwise, and the mixture was stirred at room temperature for half an hour. 2-Butyl-4-chloro-1-(prop-2-yn-1-yl)-1H-imidazol-5-carboxaldehyde (197 mg, 0.88 mmol) was added, and the mixture was heated to 80 °C under nitrogen protection. Thin-layer chromatography was used to monitor the reaction until completion. After cooling to room temperature, the mixture was poured into ice water, and then filtered, recrystallized, and dried to obtain compound II-2-8 (260 mg), with a yield of 74.1%; yellow solid; melting point: >250 °C; 1H NMR (600MHz, DMSO-d6) δ8.85(s,1H),8.77(s,1H),8.34(s,1H),7.87(s,1H),4.89(d,J=1.8Hz,2H),4.48(q,J=7.2Hz ,2H),3.59(s,1H),3.27(t,J=7.8Hz,2H),1.85(m,2H),1.56(m,2H),1.49(t,J=7.1Hz,3H),1.00(t,J=7.3Hz,3H)ppm.

[0074] Example 13: Preparation of Compound II-2-9

[0075]

[0076] Intermediate V (200 mg, 0.73 mmol) was added to a clean 50 mL round-bottom flask, and ethanol (20 mL) was added as a solvent. Piperidine (10 mg, 0.12 mmol) was added dropwise, and the mixture was stirred at room temperature for half an hour. 2-(2-butyl-4-chloro-5-formyl-1H-imidazol-1-yl)acetonitrile (198 mg, 0.88 mmol) was added, and the mixture was heated to 80 °C under nitrogen protection. Thin-layer chromatography was used to monitor the reaction until completion. After cooling to room temperature, the mixture was poured into ice water, and then filtered, recrystallized, and dried to obtain compound II-2-9 (273 mg), with a yield of 77.6%; yellow solid; melting point: >250 °C; 1 H NMR (600MHz, DMSO-d6) δ14.99(s,1H),9.12(s,1H),8.21(d,J=5.5Hz,1H),8.14(d,J=9.2Hz,1H),7.68(s,1H),6.33(s,2H) ,4.69(q,J=7.1Hz,2H),3.18(t,J=7.5Hz,2H),1.75(m,2H),1.44(t,J=6.9Hz,3H),1.40(m,2H),0.94(t,J=7.3Hz,3H)ppm.

[0077] Example 14: Preparation of Compound II-2-10

[0078]

[0079] Intermediate V (200 mg, 0.73 mmol) was added to a clean 50 mL round-bottom flask, and ethanol (20 mL) was added as a solvent. Piperidine (10 mg, 0.12 mmol) was added dropwise, and the mixture was stirred at room temperature for half an hour. 2-Butyl-4-chloro-1-(2-fluoroethyl)-1H-imidazolium-5-carboxaldehyde (204 mg, 0.88 mmol) was added, and the mixture was heated to 80 °C under nitrogen protection. Thin-layer chromatography was used to monitor the reaction until completion. After cooling to room temperature, the mixture was poured into ice water, and then filtered, recrystallized, and dried to obtain compound II-2-10 (127 mg), with a yield of 35.7%; yellow solid; melting point: 244.4-245.3 °C. 1 H NMR (600MHz, CDCl3) δ14.41(s,1H),9.24(s,1H),8.65(s,1H),8.03(d,J=10.4Hz,1H),7.92(s,1H),4.78(m,2H),4.63(m,2H ), 4.43 (q, J = 7.1Hz, 2H), 3.46 (t, J = 7.3Hz, 2H), 2.03 (m, 2H), 1.68 (m, 2H), 1.62 (t, J = 7.1Hz, 3H), 1.03 (t, J = 7.3Hz, 3H) ppm.

[0080] Example 15: Preparation of Compound II-2-11

[0081]

[0082] Intermediate V (200 mg, 0.73 mmol) was added to a clean 50 mL round-bottom flask, and ethanol (20 mL) was added as a solvent. Piperidine (10 mg, 0.12 mmol) was added dropwise, and the mixture was stirred at room temperature for half an hour. 2-Butyl-4-chloro-1-(3-morpholinoethyl)-1H-imidazol-5-carboxaldehyde (262 mg, 0.88 mmol) was added, and the mixture was heated to 80 °C under nitrogen protection. Thin-layer chromatography was used to monitor the reaction until completion. After cooling to room temperature, the mixture was poured into ice water, and then filtered, recrystallized, and dried to obtain compound II-2-11 (331 mg), with a yield of 81.6%; yellow solid; melting point: 202.5-203.4 °C. 1H NMR(600MHz,DMSO-d6)δ14.82(s,1H),9.11(s,1H),8.19(d,J=7.3Hz,1H), 8.17(s,1H),7.91(s,1H),4.68(q,J=6.8Hz,2H),4.18(s,2H),3.47(s,4H) ,2.75(t,J=7.3Hz,2H),2.53(s,2H),2.36(s,4H),1.74–1.68(m,2H),1.46 (t,J=6.3Hz,3H), 1.40(dt,J=14.1,7.1Hz,2H), 0.94(t,J=7.1Hz,3H)ppm.

[0083] Example 16: Preparation of Compound II-2-12

[0084]

[0085] Intermediate V (200 mg, 0.73 mmol) was added to a clean 50 mL round-bottom flask, and ethanol (20 mL) was added as a solvent. Piperidine (10 mg, 0.12 mmol) was added dropwise, and the mixture was stirred at room temperature for half an hour. 2-Butyl-4-chloro-1-(3-morpholinopropyl)-1H-imidazol-5-carboxaldehyde (267 mg, 0.88 mmol) was added, and the mixture was heated to 80 °C under nitrogen protection. Thin-layer chromatography was used to monitor the reaction until completion. After cooling to room temperature, the mixture was poured into ice water, and then filtered, recrystallized, and dried to obtain compound II-2-12 (371 mg), with a yield of 89.4%; yellow solid; melting point: 207.8-208.4 °C. 1 H NMR (600MHz, CDCl3) δ14.41(s,1H),8.81(s,1H),8.27(d,J=5.4Hz),7.97(d,J=10.3Hz,1H),7.76(s,1H),4.45(q,J=7.2Hz,2H),4.05(s,2H),3. 63(s,4H),2.73(m,2H),2.46(s,2H),2.38(s,4H),2.32(s,2H),1.88(s, 2H),1.79(d,J=5.6Hz,2H),1.45(t,J=6.7Hz,3H),1.00–0.97(m,3H)ppm.

[0086] Example 17: Preparation of Compound II-2-13

[0087]

[0088] Intermediate V (200 mg, 0.73 mmol) was added to a clean 50 mL round-bottom flask, and ethanol (20 mL) was added as a solvent. Piperidine (10 mg, 0.12 mmol) was added dropwise, and the mixture was stirred at room temperature for half an hour. 2-Butyl-4-chloro-1-(2-fluorobenzyl)-1H-imidazol-5-carboxaldehyde (258 mg, 0.88 mmol) was added, and the mixture was heated to 80 °C under nitrogen protection. Thin-layer chromatography was used to monitor the reaction until completion. After cooling to room temperature, the mixture was poured into ice water, and then filtered, recrystallized, and dried to obtain compound II-2-13 (367 mg), with a yield of 91.4%; yellow solid; melting point: 223.5-224.2 °C. 1 H NMR(600MHz,DMSO-d6)δ14.80(s,1H),9.10(s,1H),8.13(d,J=10.5Hz,1H),8.08( d,J=5.9Hz,1H),7.83(s,1H),7.38(m,1H),7.25–7.21(m,1H),7.17(t,J=7.5Hz,1H ),6.96(t,J=7.4Hz,1H),5.46(s,2H),4.65(q,J=7.0Hz,2H),2.73(t,J=7.5Hz,2H) ,1.61–1.55(m,2H),1.42(t,J=7.1Hz,3H),1.32(m,2H),0.85(t,J=7.3Hz,3H)ppm.

[0089] Example 18: Preparation of Compound II-2-14

[0090]

[0091] Intermediate V (200 mg, 0.73 mmol) was added to a clean 50 mL round-bottom flask, and ethanol (20 mL) was added as a solvent. Piperidine (10 mg, 0.12 mmol) was added dropwise, and the mixture was stirred at room temperature for half an hour. 2-Butyl-4-chloro-1-(4-fluorobenzyl)-1H-imidazol-5-carboxaldehyde (258 mg, 0.88 mmol) was added, and the mixture was heated to 80 °C under nitrogen protection. Thin-layer chromatography was used to monitor the reaction until completion. After cooling to room temperature, the mixture was poured into ice water, and then filtered, recrystallized, and dried to obtain compound II-2-14 (326 mg), with a yield of 81.1%; yellow solid; melting point: 248.5-249.4 °C. 1H NMR(600MHz,DMSO-d6)δ14.80(s,1H),9.10(s,1H),8.13(d,J=10.5Hz,1H), 8.08(d,J=6.0Hz,1H),7.76(s,1H),7.19(t,J=8.8Hz,2H),7.12(dd,J=8.3, 5.6Hz,2H),5.39(s,2H),4.65(q,J=7.0Hz,2H),2.72(t,J=7.6Hz,2H),1.61 –1.56(m,2H),1.41(t,J=7.1Hz,3H),1.32(m,2H),0.86(t,J=7.4Hz,3H)ppm.

[0092] Example 19: Preparation of Compound II-2-15

[0093]

[0094] Intermediate V (200 mg, 0.73 mmol) was added to a clean 50 mL round-bottom flask, and ethanol (20 mL) was added as a solvent. Piperidine (10 mg, 0.12 mmol) was added dropwise, and the mixture was stirred at room temperature for half an hour. 2-Butyl-4-chloro-1-(4-chlorobenzyl)-1H-imidazolium-5-carboxaldehyde (272 mg, 0.88 mmol) was added, and the mixture was heated to 80 °C under nitrogen protection. Thin-layer chromatography was used to monitor the reaction until completion. After cooling to room temperature, the mixture was poured into ice water, and then filtered, recrystallized, and dried to obtain compound II-2-15 (355 mg), with a yield of 85.7%; yellow solid; melting point: >250 °C; 1 H NMR (600MHz, DMSO-d6) δ14.78(s,1H),9.09(s,1H),8.12(d,J=10.1,1H,),8.09(d,J=5.9Hz,1H),7.77(s,1H),7.42(d,J=7.3Hz,2H),7.09(d,J=7.7 Hz,2H),5.43(s,2H),4.66(q,J=7.1Hz,2H),2.71(t,J=7.5Hz,2H),1.62–1 .57(m,2H),1.41(t,J=6.9Hz,3H),1.32(m,2H),0.86(t,J=7.3Hz,3H)ppm.

[0095] Example 20: Preparation of Compound II-2-16

[0096]

[0097] Intermediate V (200 mg, 0.73 mmol) was added to a clean 50 mL round-bottom flask, and ethanol (20 mL) was added as a solvent. Piperidine (10 mg, 0.12 mmol) was added dropwise, and the mixture was stirred at room temperature for half an hour. 2-Butyl-4-chloro-1-(2,4-difluorobenzyl)-1H-imidazolium-5-carboxaldehyde (266 mg, 0.88 mmol) was added, and the mixture was heated to 80 °C under nitrogen protection. Thin-layer chromatography was used to monitor the reaction until completion. After cooling to room temperature, the mixture was poured into ice water, and then filtered, recrystallized, and dried to obtain compound II-2-16 (326 mg), with a yield of 78.5%; green solid; melting point: 237.2-237.9 °C. 1 H NMR (600MHz, CDCl3) δ14.57(s,1H),8.77(s,1H),8.22(d,J=11.7Hz,1H),8.01( d,J=6.0Hz,1H),7.77(s,1H),6.94–6.89(m,1H),6.89–6.86(m,1H),6.82(dd,J =14.6,8.2Hz,1H),5.20(s,2H),4.47(q,J=7.1Hz,2H),2.68(t,J=7.6Hz,2H),1 .80(m,2H),1.65(t,J=7.2Hz,3H),1.49–1.43(m,2H),0.94(t,J=7.4Hz,3H)ppm.

[0098] Example 21: Preparation of compound II-2-17

[0099]

[0100] Intermediate V (200 mg, 0.73 mmol) was added to a clean 50 mL round-bottom flask, and ethanol (20 mL) was added as a solvent. Piperidine (10 mg, 0.12 mmol) was added dropwise, and the mixture was stirred at room temperature for half an hour. 2-Butyl-4-chloro-1-(2,4-dichlorobenzyl)-1H-imidazolium-5-carboxaldehyde (302 mg, 0.88 mmol) was added, and the mixture was heated to 80 °C under nitrogen protection. Thin-layer chromatography was used to monitor the reaction until completion. After cooling to room temperature, the mixture was poured into ice water, and then filtered, recrystallized, and dried to obtain compound II-2-17 (317 mg), with a yield of 72.3%; yellow solid; melting point: >250 °C; 1H NMR(600MHz,DMSO-d6)δ14.78(s,1H),9.10(s,1H),8.12(d,J=10.5Hz,1H),8.06( d,J=5.9Hz,1H),7.72(s,1H),7.69(d,J=1.9Hz,1H),7.41(dd,J=8.3,1.7Hz,1H), 6.72(d,J=8.4Hz,1H),5.44(s,2H),4.64(q,J=7.0Hz,2H),2.67(t,J=7.5Hz,2H), 1.61–1.55(m,2H),1.40(t,J=7.1Hz,3H),1.31(m,2H),0.85(t,J=7.3Hz,3H)ppm.

[0101] Example 22, Preparation of Compound III

[0102]

[0103] Intermediate V (200 mg, 0.73 mmol) was added to a clean 50 mL round-bottom flask, and ethanol (20 mL) was added as a solvent. Piperidine (10 mg, 0.12 mmol) was added dropwise, and the mixture was stirred at room temperature for half an hour. Benzo[d]imidazole-2-carboxaldehyde (128 mg, 0.88 mmol) was added, and the mixture was heated to 80 °C under nitrogen protection. Thin-layer chromatography was used to monitor the reaction until completion. After cooling to room temperature, the mixture was poured into ice water, and then filtered, recrystallized, and dried to obtain compound III (170 mg), with a yield of 57.8%; yellow solid; melting point: >250 °C. 1 H NMR (600MHz, DMSO-d6) δ14.84(s,1H),13.12(s,1H),9.15(s,1H),8.23(d,J=8.9Hz,1H),7.91( s,1H),7.79(s,2H),7.69(s,1H),7.34(s,2H),4.67(q,J=7.0Hz,2H),1.52(t,J=7.1Hz,3H)ppm.

[0104] Example 23: In vitro antimicrobial activity of cyanide-bridged quinolone imidazoles and their analogues

[0105] The 96-well microdilution method, conforming to the Clinical and Laboratory Standards Institute (CLSI) standards, was used to detect the effects of cyanide-bridged quinolones and their analogues prepared in Examples 3-22 on Gram-positive bacteria (methicillin-resistant Staphylococcus aureus, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus aureus ATCC 29213, Staphylococcus aureus ATCC 25923), Gram-negative bacteria (Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922, Acinetobacter baumannii), and fungi (Candida albicans, Aspergillus fumigatus, Candida tropicalis, Candida albicans ATCC 90023, Candida parapsilosis ...). To determine the minimum inhibitory concentration (MIC) of the test compound (22019), the test compound was dissolved in a small amount of dimethyl sulfoxide and then diluted to 512 μg / mL with culture medium. After continuous dilution, the compound was inoculated with microorganisms and cultured at 37°C for 24 hours. The culture plate was then thoroughly shaken on a shaker, and the MIC was measured at a wavelength of 600 nm and read visually. The results are shown in Tables 1–3.

[0106] Table 1. In vitro anti-Gram-positive bacterial activity data (MIC, μg / mL) of cyanide-bridged quinolone imidazoles and their analogues I-III

[0107]

[0108]

[0109] As shown in Table 1, most of the compounds I-III prepared in this invention can effectively inhibit the growth of the tested bacterial species and have a broad antibacterial spectrum. Most compounds show antibacterial activity superior to the reference drugs. In particular, compound I has good antibacterial activity against all tested Gram-positive bacteria, with a MIC value range of 0.5 μg / mL, and its activity is superior to that of the reference drugs norfloxacin and ciprofloxacin.

[0110] Table 2. In vitro anti-Gram-negative bacterial activity data (MIC, μg / mL) of cyanide-bridged quinolone imidazoles and their analogues I-III

[0111]

[0112] As shown in Table 2, most of the compounds I-III prepared in this invention can effectively inhibit the growth of the tested bacterial species and have a broad antibacterial spectrum. Most compounds show antibacterial activity superior to the reference drug. In particular, compound II-2-1 has good antibacterial activity against all tested Gram-negative bacteria, with MIC values ​​ranging from 0.5 to 1 μg / mL, and its inhibitory activity against most Gram-negative bacteria is superior to that of the reference drug norfloxacin.

[0113] Table 3. In vitro antifungal activity data (MIC, μg / mL) of cyanide-bridged quinolone imidazoles and their analogues I-III

[0114]

[0115]

[0116] As shown in Table 3, compounds I-III prepared in this invention exhibited certain inhibitory effects against the tested fungi. Compounds II-2-3 and II-2-9 both showed high antifungal activity against the tested fungi, with MIC values ​​of 0.5 μg / mL for both. Most of the compounds showed stronger antifungal activity than the reference drug fluconazole.

[0117] Example 24: Pharmaceutical Uses of Cyanoethylene-Bridged Quinolones and Imidazoles and Their Analogs

[0118] Based on the above antimicrobial activity test results, the cyanide-bridged quinolone imidazoles and their analogues of the present invention exhibit good antibacterial and antifungal activities and can be formulated into antibacterial and antifungal drugs for clinical use. These drugs can be single-component formulations, for example, made from a single-structure cyanide-bridged quinolone imidazole and its analogue with pharmaceutically acceptable excipients; or they can be compound formulations, for example, made from a single-structure cyanide-bridged quinolone imidazole and its analogue with existing antibacterial and antifungal active ingredients (such as norfloxacin, ciprofloxacin, clindamycin, quinolone mexazole, fluconazole, itraconazole, etc.) and pharmaceutically acceptable excipients, or made from several cyanide-bridged quinolone imidazoles and their analogues with different structures and pharmaceutically acceptable excipients. The formulation types include, but are not limited to, tablets, capsules, powders, granules, drop pills, injections, powder injections, solutions, suspensions, emulsions, suppositories, ointments, gels, films, aerosols, transdermal patches, and various sustained-release, controlled-release, and nano-formulations.

[0119] 1. Preparation of Compound I tablets

[0120] Prescription: Compound I 10g, lactose 187g, corn starch 50g, magnesium stearate 3g, and an appropriate amount of 70% ethanol solution, to make 1000 tablets.

[0121] Preparation: Dry corn starch at 105℃ for 5 hours for later use; mix compound I-1 with lactose and corn starch evenly, prepare a soft mass with 70% ethanol solution, sieve to make wet granules, add magnesium stearate, compress into tablets to obtain the product; each tablet weighs 250mg and contains 10mg of active ingredient.

[0122] 2. Preparation of Compound I Capsules

[0123] Prescription: Compound I 25g, modified starch (120 mesh) 12.5g, microcrystalline cellulose (100 mesh) 7.5g, low-substituted hydroxypropyl cellulose (100 mesh) 2.5g, talc (100 mesh) 2g, sweetener 1.25g, orange flavoring 0.25g, coloring as needed, water as needed, to make 1000 capsules.

[0124] Preparation method: The prescribed amount of compound I is micronized and pulverized into an extremely fine powder, and then mixed with the prescribed amounts of modified starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, talc, sweetener, orange flavor and coloring. The mixture is then softened with water, granulated through a 12-14 mesh sieve, dried at 40-50℃, sieved and granulated, and filled into empty capsules to obtain the product; each capsule weighs 50mg and contains 25mg of active ingredient.

[0125] 3. Preparation of Compound I Granules

[0126] Prescription: Compound I 26g, dextrin 120g, sucrose 280g.

[0127] Preparation method: Mix compound I, dextrin and sucrose evenly, wet granulate, dry at 60℃, and package to obtain the final product.

[0128] 4. Preparation of Compound I Injection

[0129] Prescription: Compound I 10g, propylene glycol 500mL, water for injection 500mL, to prepare a total of 1000mL.

[0130] Preparation: Weigh compound I, add propylene glycol and water for injection, stir to dissolve, then add 1g of activated carbon, stir thoroughly and let stand for 15 minutes, filter with a 5μm titanium rod to remove carbon, then filter with microporous membranes with pore sizes of 0.45μm and 0.22μm in sequence, and finally fill into 10mL ampoules and sterilize with flowing steam at 100℃ for 45 minutes to obtain the product.

[0131] 5. Preparation of Compound I Powder for Injection

[0132] Preparation method: Compound I is prepared by aseptically dispensing the aseptic powder under aseptic conditions.

[0133] 6. Preparation of Compound I eye drops

[0134] Prescription: Compound I 3.78g, sodium chloride 0.9g, boric acid buffer solution as needed, distilled water to 1000mL.

[0135] Preparation: Weigh compound I and sodium chloride and add them to 500 mL of distilled water. After complete dissolution, adjust the pH to 6.5 with boric acid buffer solution, add distilled water to 1000 mL, stir well, filter through a microporous membrane, fill, seal, and sterilize with flowing steam at 100°C for 1 hour to obtain the product.

[0136] 7. Preparation of Compound I Liniment

[0137] Prescription: Compound I 4g, potassium soap 7.5g, camphor 5g, distilled water to 100mL.

[0138] Preparation: Dissolve camphor in a 95% (v / v) ethanol solution and set aside; liquefy potassium soap by heating and set aside; weigh compound I, add potassium soap solution and camphor ethanol solution while stirring continuously, then gradually add distilled water, and after complete emulsification, add distilled water to the total volume to obtain the final product.

[0139] 8. Preparation of Compound I Suppositories

[0140] Prescription: Compound I 4g, gelatin 14g, glycerin 70g, distilled water to 100mL, make 100 pieces.

[0141] Preparation: Weigh gelatin and glycerin, add distilled water to 100mL, heat in a water bath at 60℃ until melted into a paste, add compound I, stir well, pour into a vaginal suppository mold when it is almost solidified, cool and solidify to obtain the product.

[0142] 9. Preparation of Compound I Ointment

[0143] Prescription: Compound I 0.5-2g, cetyl alcohol 6-8g, white petrolatum 8-10g, liquid paraffin 8-19g, monoglyceride 2-5g, polyoxyethylene (40) stearate 2-5g, glycerin 5-10g, ethylparaben 0.1g, distilled water 100g.

[0144] Preparation: Hexadecyl alcohol, white petrolatum, liquid paraffin, monoglyceride and polyoxyethylene (40) stearate are heated and completely melted, then mixed and kept at 80°C to prepare the oil phase. Ethylparaben is added to glycerol and distilled water and heated to 85°C to dissolve. The oil phase is then added while stirring continuously. After emulsification, compound I is added, stirred and cooled to obtain the final product.

[0145] 10. Preparation of Compound II-2-3 and Fluconazole Compound Powder for Injection

[0146] Prescription: Compound II-2-3 50g, fluconazole 50g, sodium benzoate 1g, made into 100 bottles.

[0147] Preparation: Take the prescribed amounts of compound II-2-3, fluconazole, and sodium benzoate, mix them thoroughly under sterile conditions, and dispense into 100 bottles.

[0148] 11. Preparation of Compound I Aerosol

[0149] Prescription: Compound I 2.5g, Span20 3g, talc (100 mesh) 4g, trichlorofluoromethane added to appropriate amount.

[0150] Preparation method: Place compound I, Span20 and talc powder (100 mesh) in a vacuum drying oven and dry for several hours. Cool to room temperature in a desiccator and pulverize into fine powder using an air jet mill. Mix well according to the prescription amount, pour into a sealed container, and add trichlorofluoromethane to the specified amount to obtain the final product.

[0151] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A cyanide-bridged quinolone imidazole compound and its analogues and pharmaceutically acceptable salts, characterized in that, The cyanide-bridged quinolone imidazole compounds and their analogues are selected from I, II-1, II-2-1 to II-2-16 or III:

2. The cyanide-bridged quinolone imidazole compound and its analogues as described in claim 1, characterized in that, The pharmaceutically acceptable salt is a sodium salt, potassium salt, hydrochloride, nitrate, or acetate.

3. The use of the cyanide-bridged quinolone imidazole compounds and their analogues as described in any one of claims 1 to 2 in the preparation of antibacterial or antifungal drugs.

4. The application as described in claim 3, characterized in that, The bacteria are selected from Staphylococcus aureus, Enterococcus faecalis, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, or Acinetobacter baumannii; the fungi are selected from Candida albicans, Candida tropicalis, Aspergillus fumigatus, or Candida parapsilosis ATCC 22019.

5. The application according to claim 4, characterized in that, The *Staphylococcus aureus* is methicillin-resistant *Staphylococcus aureus*, *Staphylococcus aureus* ATCC 25923, or *Staphylococcus aureus* ATCC 29213; the *Escherichia coli* is *Escherichia coli* ATCC 25922; the *Pseudomonas aeruginosa* is *Pseudomonas aeruginosa* ATCC 27853; and the *Candida albicans* is *Candida albicans* ATCC 90023.

6. A pharmaceutically acceptable salt comprising a cyanide-bridged quinolone imidazole compound or its analogue as described in any one of claims 1 to 2.

7. The formulation according to claim 6, characterized in that, The preparation is one of the following: tablets, capsules, granules, injections, powder for injection, eye drops, liniments, suppositories, ointments, or aerosols.

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