Quinolone-conjugated thiazoles, processes for their preparation and medical use

Abstract

The present application relates to quinolone conjugated thiazole compounds and its preparation method and medical application, belong to chemical synthesis technical field, quinolone conjugated thiazole compounds such as general formula I and II are shown, the compound has good inhibitory activity to gram-positive bacteria and gram-negative bacteria, has multi-target antibacterial potential, can be used for preparing antibacterial drugs, provides more efficient, safe candidate drug for clinical antibacterial treatment, helps to solve the increasingly serious drug resistance, stubborn pathogenic microorganism and new emerging harmful microorganism and other clinical treatment problems.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to quinolone-conjugated thiazole compounds, their preparation methods, and pharmaceutical applications. Background Technology

[0002] Synthetic quinolones are widely used in clinical treatment due to their good therapeutic effects, broad antibacterial spectrum, and suitable pharmacokinetic properties. Quinolones containing 3-carboxyl and 4-carbonyl groups interfere with DNA replication by acting on bacterial DNA gyrases or DNA topoisomerase IV, leading to bacterial death. However, due to the widespread and excessive clinical use of these drugs, most pathogens have developed significant resistance to traditional quinolone antibiotics, often accompanied by a series of side effects. Therefore, there is an urgent need to develop novel, highly effective, and low-toxicity antibacterial agents to overcome resistance. Structural modification at the 7-position of the quinolone skeleton has proven to be a promising strategy to circumvent bacterial resistance while maintaining inhibitory efficacy against resistant bacteria.

[0003] Thiazole compounds are an important class of aromatic heterocycles containing nitrogen and sulfur heteroatoms. Their electron-rich nature allows them to readily bind to biological macromolecules through non-covalent bonds such as hydrogen bonds, coordination bonds, electrostatic interactions, and hydrophobic interactions. They are widely found in clinical anti-infective drugs, such as sulfathiazole and cefixime, which have broad-spectrum antibacterial effects. Modifying the 7-position of the quinolone skeleton using alkenyl-bridged thiazoles and quinolones yields novel quinolone-conjugated thiazole compounds. The alkenyl group can expand the conjugated system of the molecule, enhancing its binding ability to DNA. The polar cyano group is considered a bioisostere of the carbonyl and carboxyl groups, and can engage in supramolecular interactions with various protein residues through various polar non-covalent interactions such as hydrogen bonds and cation-π interactions, affecting the normal function of DNA or enzymes. This approach holds promise for achieving multi-target binding and enhancing antibacterial activity, overcoming the increasingly serious problem of drug resistance. Summary of the Invention

[0004] In view of this, one objective of the present invention is to provide quinolone-conjugated thiazole compounds and their pharmaceutically acceptable salts; a second objective is to provide a method for preparing quinolone-conjugated thiazole compounds and their pharmaceutically acceptable salts; and a third objective is to provide the application of quinolone-conjugated thiazole compounds and their pharmaceutically acceptable salts in the preparation of antibacterial drugs, thereby providing more efficient and safe candidate drugs for clinical antimicrobial therapy, and helping to solve clinical treatment problems such as increasingly serious drug resistance and side effects of quinolone drugs, stubborn pathogenic microorganisms, and newly emerging harmful microorganisms.

[0005] To achieve the above objectives, the present invention provides the following technical solution:

[0006] 1. Quinolone-conjugated thiazole compounds and their pharmaceutically acceptable salts, with structures shown in general formulas I and II:

[0007]

[0008] In the formula:

[0009] m and n are integers from 0 to 17;

[0010] R 1 R 3 It can be hydrogen, alkyl, halogen, cyano, alkenyl, alkynyl, aryl, morpholine, pyridine, trifluoromethyl, hydroxyalkyl, carboxyl, ester, acyl, or mercapto;

[0011] R 2 R 4 It can be hydrogen, alkyl, cyano, nitro, halogen, phenyl, substituted phenyl or heterocyclic group;

[0012] Preferably, it is any one of the following compounds:

[0013]

[0014] Preferably, the pharmaceutically usable salt is a hydrochloride, nitrate, or acetate.

[0015] 2. The method for preparing the quinolone-conjugated thiazole compounds and their pharmaceutically acceptable salts is as follows: the compound shown in general formula III is added to a mixed solution of alkali and ethanol, and 2-aldehyde thiazole or 2-aldehyde benzothiazole is added, followed by a reaction in the solvent ethanol, thereby obtaining the quinolone-conjugated thiazole compounds shown in general formulas I and II.

[0016]

[0017] in:

[0018] n is an integer between 0 and 7;

[0019] R can be hydrogen, alkyl, alkenyl, alkynyl, morpholine, or aryl.

[0020] Preferably:

[0021] The base is piperidine, and the molar ratio of intermediate III, 2-aldehyde thiazole or 2-aldehyde benzothiazole and piperidine is 1:2:2. The reaction is carried out at 65-100°C for 8-12 hours.

[0022] 3. The application of the quinolone conjugated thiazole compounds and their pharmaceutically acceptable salts in the preparation of antibacterial drugs.

[0023] 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.

[0024] 4. Preparations containing the quinolone conjugated thiazole compounds and their pharmaceutically acceptable salts.

[0025] Preferably, the preparation is one of the following: tablets, capsules, granules, injections, powder for injection, eye drops, liniments, suppositories, ointments, or aerosols.

[0026] The beneficial effects of this invention are as follows: This invention provides quinolone-conjugated thiazole compounds, their preparation methods, and applications. Utilizing the principle of drug design and synthesis, this invention introduces alkyl, alkenyl, alkynyl, aryl, and heterocyclic groups at the 1-position of a quinolone and an alkenyl thiazole fragment at the 7-position, designing and synthesizing a series of quinolone-conjugated thiazole compounds. These compounds, after in vitro antimicrobial activity testing, were found to be effective against Gram-positive bacteria (methicillin-resistant Staphylococcus aureus, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus aureus ATCC 25923, Staphylococcus aureus ATCC 29213) and Gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Pseudomonas aeruginosa ATCC). 27853, Escherichia coli ATCC25922, and Acinetobacter baumannii all have good inhibitory activity and can be used to prepare antibacterial drugs, providing more efficient and safe candidate drugs for clinical antibacterial treatment. This will help solve increasingly serious clinical treatment problems such as drug resistance, stubborn pathogenic microorganisms, and newly emerging harmful microorganisms.

[0027] 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. Attached Figure Description

[0028] To make the objectives, technical solutions, and beneficial effects of this invention clearer, the following figures are provided for illustration:

[0029] Figure 1 The diagram shows the inhibitory effects of compounds I-2, norfloxacin, and ciprofloxacin on the development of drug resistance in Staphylococcus aureus and Klebsiella pneumoniae, respectively. Detailed Implementation

[0030] 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.

[0031] Example 1: Preparation of Intermediate III

[0032]

[0033] Intermediate III was prepared by referring to the method disclosed in the patent "Zhou Chenghe, Zhang Jing, Tan Yimin, Li Shurui, Cyanomethylquinolone compounds and their preparation methods and applications, Chinese Patent, Application No.: 202310173614.9, Application Date: February 27, 2023".

[0034] Example 2, Preparation of compound I-1:

[0035]

[0036] Intermediate III-1 (80 mg, 0.31 mmol), piperidine (52 mg, 0.61 mmol), and 2-aldehydethiazole (70 mg, 0.61 mmol) were added to a 50 mL round-bottom flask. Ethanol (20 mL) was used as the solvent, and the mixture was stirred at 80 °C for 18 hours. Thin-layer chromatography was used to monitor the reaction until completion. Product I-1 (88 mg, 0.25 mmol) was obtained by column chromatography with a yield of 80.6%. It was a yellow solid with a melting point >250 °C. 1 H NMR(600MHz,DMSO-d6)δ14.78(s,1H,COOH),9.09(s,1H,quinolone-2-H),8.36(s,1H,thiazole-2-CH),8.32(d,J=6.3Hz,1H,quinolone-8-H ), 8.25 (d, J = 3.0Hz, 1H, thiazole-4-H), 8.22 (d, J = 3.0Hz, 1H, thiazole-5-H), 8.18 (d, J = 10.7Hz, 1H, quinolone-5-H), 4.19 (s, 3H, CH3) ppm.

[0037] Example 3, Preparation of compound I-2:

[0038]

[0039] Intermediate III-2 (200 mg, 0.73 mmol), piperidine (124 mg, 1.46 mmol), and 2-aldehydethiazole (165 mg, 1.46 mmol) were added to a 50 mL round-bottom flask. Ethanol (20 mL) was used as the solvent, and the mixture was stirred at 80 °C for 12 hours. Thin-layer chromatography was used to monitor the reaction until completion. Product I-2 (252.0 mg, 0.68 mmol) was obtained by column chromatography with a yield of 93.6%. It was a yellow solid with a melting point >250 °C. 1 H NMR(600MHz,DMSO-d6)δ14.80(s,1H,COOH),9.12(s,1H,quinolone-2-H),8.38(d,J=6.0Hz,1H,quinolone-8-H),8.32(s,1H,thiazole-2-CH),8.29–8.24(m,1 H, thiazole-4-H), 8.24–8.20 (m, 1H, thiazole-5-H), 8.18 (d, J = 10.4Hz, 1H, quinolone-5-H), 4.70 (q, J = 7.2Hz, 2H, CH2CH3), 1.48 (t, J = 7.2Hz, 3H, CH2CH3) ppm.

[0040] Example 4, Preparation of compound I-3:

[0041]

[0042] Intermediate III-3 (100.0 mg, 0.35 mmol), piperidine (59 mg, 0.69 mmol), and 2-aldehydethiazole (78 mg, 0.69 mmol) were added to a 50 mL round-bottom flask. Ethanol (20 mL) was used as the solvent, and the mixture was stirred at 80 °C for 12 hours. Thin-layer chromatography was used to monitor the reaction until completion. Product I-3 (95 mg, 0.25 mmol) was obtained by column chromatography, with a yield of 71.4%. It is a yellow solid with a melting point of 216.2–217.5 °C. 1H NMR(600MHz,DMSO-d6)δ14.78(s,1H,COOH),9.10(s,1H,quinolone-2-H),8.36(d,J=6.1Hz ,1H,quinolone-8-H),8.29(s,1H,thiazole-2-CH),8.26(d,J=3.0Hz,1H,thiazole-4-H), 8.22(d,J=2.9Hz,1H,thiazole-5-H),8.16(d,J=10.4Hz,1H,quinolone-5-H),4.64(t,J=7 .1Hz,2H,CH2CH2CH3),1.93–1.86(m,2H,CH2CH2CH3),0.94(t,J=7.3Hz,3H,CH2CH2CH3)ppm.

[0043] Example 5, Preparation of compound I-4:

[0044]

[0045] Intermediate III-4 (100 mg, 0.33 mmol), piperidine (56 mg, 0.66 mmol), and 2-aldehydethiazole (75 mg, 0.66 mmol) were added to a 50 mL round-bottom flask. Ethanol (20 mL) was used as the solvent, and the mixture was stirred at 80 °C for 12 hours. Thin-layer chromatography was used to monitor the reaction until completion. Product I-4 (89 mg, 0.22 mmol) was obtained by column chromatography, with a yield of 67.7%. It was a yellow solid with a melting point of 237.9–238.8 °C. 1 H NMR(600MHz,DMSO-d6)δ14.80(s,1H,COOH),9.10(s,1H,quinolone-2-H),8.35(d,J=5.9Hz,1H,qui nolone-8-H),8.31(s,1H,thiazole-2-CH),8.26(d,J=3.0Hz,1H,thiazole-4-H),8.23(d,J=2.9Hz ,1H,thiazole-5-H),8.18(d,J=10.5Hz,1H,quinolone-5-H),4.67(t,J=7.1Hz,2H,CH2(CH2)2CH3) ,1.84(m,2H,CH2CH2CH2CH3),1.36(m,2H,CH2CH2CH2CH3),0.93(t,J=7.3Hz,3H,CH2(CH2)2CH3)ppm.

[0046] Example 6, Preparation of compound I-5:

[0047]

[0048] Intermediate III-5 (50 mg, 0.16 mmol), piperidine (27 mg, 0.32 mmol), and 2-aldehydethiazole (36 mg, 0.32 mmol) were added to a 50 mL round-bottom flask. Ethanol (20 mL) was used as the solvent, and the mixture was stirred at 80 °C for 12 hours. Thin-layer chromatography was used to monitor the reaction until completion. Product I-5 (45 mg, 0.11 mmol) was obtained by column chromatography, with a yield of 69.2%. It was a yellow solid with a melting point of 246.0–247.2 °C. 1 H NMR(600MHz,DMSO-d6)δ14.81(s,1H,COOH),9.11(s,1H,quinolone-2-H),8.35(d,J=6.2Hz,1H,quinol one-8-H),8.31(s,1H,thiazole-2-CH),8.27(d,J=3.2Hz,1H,thiazole-4-H),8.24(d,J=3.5Hz,1H,th iazole-5-H),8.20(d,J=10.4Hz,1H,quinolone-5-H),4.67(t,J=7.5Hz,2H,CH2(CH2)3CH3),1.87(m,2 H,CH2CH2(CH2)2CH3),1.40–1.29(m,4H,CH2CH2(CH2)2CH3),0.88(t,J=6.6Hz,3H,CH2(CH2)3CH3)ppm.

[0049] Example 7, Preparation of compound I-6:

[0050]

[0051] Compound III-6 (150 mg, 0.45 mmol), piperidine (77 mg, 0.91 mmol), and 2-aldehydethiazole (103 mg, 0.91 mmol) were added to a 50 mL round-bottom flask. Ethanol (20 mL) was used as the solvent, and the mixture was stirred at 80 °C for 12 hours. Thin-layer chromatography was used to monitor the reaction until completion. Product I-6 (175 mg, 0.41 mmol) was obtained by column chromatography with a yield of 90.6%. It was a yellow solid with a melting point >250 °C. 1H NMR(600MHz,DMSO-d6)δ14.81(s,1H,COOH),9.11(s,1H,quinolone-2-H),8.35(d,J=5.9Hz,1H,quinolone-8-H),8.31(s,1H ,thiazole-2-CH),8.26(d,J=2.9Hz,1H,thiazole-4-H),8.23(d,J=3.0Hz,1H,thiazole-5-H),8.20(d,J=10.5Hz,1H,quinol one-5-H),4.66(t,J=7.2Hz,2H,CH2(CH2)4CH3),1.85(m,2H,CH2CH2(CH2)3CH3),1.37–1.33(m,2H,CH2CH2CH2(CH2)2CH3),1 .30–1.28(m,2H,CH2(CH2)2CH2CH2CH3),1.25(m,J=15.2Hz,2H,CH2(CH2)3CH2CH3),0.85(t,J=6.8Hz,3H,CH2(CH2)4CH3)ppm.

[0052] Example 8, Preparation of compound I-7:

[0053]

[0054] Compound III-7 (90 mg, 0.25 mmol), piperidine (43 mg, 0.50 mmol), and 2-aldehydethiazole (57 mg, 0.50 mmol) were added to a 50 mL round-bottom flask. Ethanol (20 mL) was used as the solvent, and the mixture was stirred at 80 °C for 12 hours. Thin-layer chromatography was used to monitor the reaction until completion. Product I-7 (91 mg, 0.20 mmol) was obtained by column chromatography with a yield of 79.9%. It is a yellow solid with a melting point of 202.0–203.0 °C. 1H NMR(600MHz,DMSO,DMSO-d6)δ14.78(s,1H,COOH),9.10(s,1H,quinolone-2-H),8.33(d,J=5.8Hz,1H,quinolone-8-H),8. 30(s,1H,thiazole-2-CH),8.26(d,J=2.9Hz,1H,thiazole-4-H),8.23(d,J=2.9Hz,1H,thiazole-5-H),8.17(d,J=10.4Hz, 1H,quinolone-5-H),4.66(t,J=7.1Hz,2H,quinolone-1-CH2),1.88–1.83(m,2H,CH2CH2(CH2)5CH3),1.36–1.29(m,4H,CH 2CH2(CH2)2(CH2)3CH3),1.26–1.21(m,6H,CH2CH2(CH2)2(CH2)3CH3),0.82(t,J=6.8Hz,3H,CH2CH2(CH2)2(CH2)3CH3)ppm.

[0055] Example 9, Preparation of compound I-8:

[0056]

[0057] Compound III-8 (150 mg, 0.52 mmol), piperidine (89 mg, 1.05 mmol), and 2-aldehydethiazole (119 mg, 1.05 mmol) were added to a 50 mL round-bottom flask. Ethanol (20 mL) was used as the solvent, and the mixture was stirred at 80 °C for 12 hours. Thin-layer chromatography was used to monitor the reaction until completion. Product I-8 (125 mg, 0.33 mmol) was obtained by column chromatography, with a yield of 62.6%. It was a yellow solid with a melting point of 227.8–228.5 °C. 1H NMR(600MHz,DMSO-d6)δ14.71(s,1H,COOH),9.12(s,1H,quinolone-2-H),8.30(d,J=6.0Hz,1H ,quinolone-8-H),8.27(s,1H,thiazole-2-CH),8.25(d,J=2.9Hz,1H,thiazole-5-H),8.23(d, J=2.9Hz,1H,thiazole-4-H),8.17(d,J=10.6Hz,1H,quinolone-5-H),6.15(m,J=22.2,11.0,5. 3Hz, 1H, CH2CH=CH2), 5.35 (d, J=1.6Hz, 2H, CH2CH=CH2), 5.33 (d, J=16.5Hz, 2H, CH2CH=CH2) ppm.

[0058] Example 10, Preparation of compound I-9:

[0059]

[0060] Compound III-9 (100 mg, 0.32 mmol), piperidine (54 mg, 0.64 mmol), and 2-aldehydethiazole (72 mg, 0.64 mmol) were added to a 50 mL round-bottom flask. Ethanol (20 mL) was used as the solvent, and the mixture was stirred at 80 °C for 12 hours. Thin-layer chromatography was used to monitor the reaction until completion. Product I-9 (86 mg, 0.21 mmol) was obtained by column chromatography, with a yield of 66.0%. It was a yellow solid with a melting point of 242.1–243.0 °C. 1 H NMR(600MHz,DMSO-d6)δ14.76(s,1H,COOH),9.09(s,1H,quinolone-2-H),8.31(s,1H,thiazole-2-C H),8.26(d,J=2.9Hz,1H,thiazole-5-H),8.24(d,J=2.8Hz,1H,thiazole-4-H),8.20(d,J=5.9Hz,1H ,quinolone-8-H),8.18(d,J=10.7Hz,1H,quinolone-5-H),5.43(t,J=6.0Hz,1H,CH2CH=C(CH3)2),5 .27(d,J=6.4Hz,2H,CH2CH=C(CH3)2), 1.90(s,3H,CH2CH=C(CH3)2), 1.77(s,3H,CH2CH=C(CH3)2)ppm.

[0061] Example 11, Preparation of compound I-10:

[0062]

[0063] Compound III-10 (100 mg, 0.35 mmol), piperidine (60 mg, 0.70 mmol), and 2-aldehydethiazole (80 mg, 0.70 mmol) were added to a 50 mL round-bottom flask. Ethanol (20 mL) was used as the solvent, and the mixture was stirred at 80 °C for 12 hours. Thin-layer chromatography was used to monitor the reaction until completion. Product I-10 (95 mg, 0.25 mmol) was obtained by column chromatography, with a yield of 71.2%. It was a yellow solid with a melting point >250 °C. 1 H NMR (600MHz, DMSO-d6) δ14.55(s,1H,COOH),9.24(s,1H,quinolone-2-H),8.41(d,J=5.9Hz,1H,quinolone-8-H),8.32(s,1H,thiazole-2-CH),8.27(d,J=3.0Hz,1 H, thiazole-4-H), 8.25 (d, J = 2.9Hz, 1H, thiazole-5-H), 8.21 (d, J = 10.5Hz, 1H, quinolone-5-H), 5.60 (s, 2H, quinolone-1-CH2), 3.83 (s, 1H, propargyl-CH) ppm.

[0064] Example 12, Preparation of compound I-11:

[0065]

[0066] Compound III-11 (100 mg, 0.33 mmol), piperidine (57 mg, 0.67 mmol), and 2-aldehydethiazole (75 mg, 0.67 mmol) were added to a 50 mL round-bottom flask. Ethanol (20 mL) was used as the solvent, and the mixture was stirred at 80 °C for 12 hours. Thin-layer chromatography was used to monitor the reaction until completion. Product I-11 (90 mg, 0.23 mmol) was obtained by column chromatography, with a yield of 68.4%. It is a yellow solid with a melting point of 240.2–241.0 °C. 1H NMR(600MHz,DMSO-d6)δ14.63(s,1H,COOH),9.14(s,1H,quinolone-2-H),8.49(d,J=5.6Hz,1H,qui nolone-8-H),8.33(s,1H,thiazole-2-CH),8.26(s,1H,thiazole-4-H),8.23(s,1H,thiazole-5-H ),8.19(d,J=10.3Hz,1H,quinolone-5-H),4.55(d,J=7.0Hz,2H,quinolone-1-CH2),1.53(s,1H,cy clopropyl-CH), 0.62 (d, J = 7.0 Hz, 2H, cyclopropyl-CH2), 0.56–0.52 (m, 2H, cyclopropyl-CH2) ppm.

[0067] Example 13, Preparation of compound I-12:

[0068]

[0069] Compound III-12 (150 mg, 0.44 mmol), piperidine (75 mg, 0.88 mmol), and 2-aldehydethiazole (99 mg, 0.88 mmol) were added to a 50 mL round-bottom flask. Ethanol (20 mL) was used as the solvent, and the mixture was stirred at 80 °C for 12 hours. Thin-layer chromatography was used to monitor the reaction until completion. Product I-12 (180 mg, 0.41 mmol) was obtained by column chromatography with a yield of 93.9%. It was a yellow solid with a melting point >250 °C. 1H NMR(600MHz,DMSO-d6)δ14.79(s,1H,COOH),9.03(s,1H,quinolone-2-H),8.34(d,J=5.9Hz,1H,quinolone-8-H),8.28 (s,1H,thiazole-2-CH),8.26(d,J=3.0Hz,1H,thiazole-4-H),8.23(d,J=3.0Hz,1H,thiazole-5-H),8.18(d,J=10.5Hz ,1H,quinolone-5-H),4.54(d,J=7.3Hz,2H,quinolone-1-CH2),1.96–1.90(m,J=8.6,5.6Hz,1H,cyclohexane-1-H),1 .67–1.56(m,4H,cyclohexane-2,6-4H),1.15(m,4H,cyclohexane-3,5-4H),1.10–1.05(m,2H,cyclohexane-4-2H)ppm.

[0070] Example 14, Preparation of compound I-13:

[0071]

[0072] Compound III-13 (100 mg, 0.28 mmol), piperidine (47 mg, 0.56 mmol), and 2-aldehydethiazole (63 mg, 0.56 mmol) were added to a 50 mL round-bottom flask. Ethanol (20 mL) was used as the solvent, and the mixture was stirred at 80 °C for 12 hours. Thin-layer chromatography was used to monitor the reaction until completion. Product I-13 (98 mg, 0.22 mmol) was obtained by column chromatography, with a yield of 77.5%. It was a yellow solid with a melting point >250 °C. 1H NMR(600MHz,DMSO-d6)δ14.80(s,1H,COOH),8.97(s,1H,quinolone-2-H),8.42(d,J=5.6Hz,1H,quinolone-8- H),8.34(s,1H,thiazole-2-CH),8.26(d,J=2.8Hz,1H,thiazole-4-H),8.23(d,J=2.7Hz,1H,thiazole-5-H), 8.18(d,J=10.4Hz,1H,quinolone-5-H),4.77(t,J=5.6Hz,2H,quinolone-1-CH2),3.48(t,J=4.5Hz,4H,morph oline-2, 6-4H), 2.74 (t, J = 5.5 Hz, 2H, quinolone-1-CH2CH2), 2.46 (t, J = 4.6 Hz, 4H, morpholine-3, 5-4H) ppm.

[0073] Example 15, Preparation of compound I-14:

[0074]

[0075] Compound III-14 (40 mg, 0.12 mmol), piperidine (20 mg, 0.24 mmol), and 2-aldehydethiazole (27 mg, 0.24 mmol) were added to a 50 mL round-bottom flask. Ethanol (20 mL) was used as the solvent, and the mixture was stirred at 80 °C for 12 hours. Thin-layer chromatography was used to monitor the reaction until completion. Product I-14 (36 mg, 0.08 mmol) was obtained by column chromatography, with a yield of 70.2%. It was a yellow solid with a melting point >250 °C. 1H NMR(600MHz,DMSO-d6)δ14.68(s,1H,COOH),9.31(s,1H,quinolone-2-H),8.49(d,J=4.8Hz,1H,2-pyridine-3-H), 8.28(d,J=6.1Hz,1H,quinolone-8-H),8.24(d,J=2.9Hz,1H,thiazole-4-H),8.21(d,J=3.0Hz,1H,thiazole-5-H) ,8.17(d,J=10.5Hz,1H,quinolone-5-H),8.12(s,1H,thiazole-2-CH),7.86(t,J=7.8Hz,1H,2-pyridine-4-H),7. 63 (d, J = 7.9 Hz, 1H, 2-pyridine-6-H), 7.35 (t, J = 7.1 Hz, 1H, 2-pyridine-5-H), 6.08 (s, 2H, quinolone-1-CH2) ppm.

[0076] Example 16, Preparation of compound I-15:

[0077]

[0078] Compound III-15 (100 mg, 0.30 mmol), piperidine (50 mg, 0.59 mmol), and 2-aldehydethiazole (67 mg, 0.59 mmol) were added to a 50 mL round-bottom flask. Ethanol (20 mL) was used as the solvent, and the mixture was stirred at 80 °C for 12 hours. Thin-layer chromatography was used to monitor the reaction until completion. Product I-15 (105 mg, 0.24 mmol) was obtained by column chromatography, with a yield of 81.6%. It was a yellow solid with a melting point >250 °C. 1H NMR(600MHz,DMSO-d6)δ14.68(s,1H,COOH),9.31(s,1H,quinolone-2-H),8.28(d,J=5.9Hz,1H,qu inolone-8-H),8.25(d,J=2.9Hz,1H,thiazole-4-H),8.23(d,J=2.7Hz,1H,thiazole-5-H),8.19( d,J=10.6Hz,1H,quinolone-5-H),8.12(s,1H,thiazole-2-CH),7.39(s,2H,phenyl-2,6-2H),7.3 8(s,2H,phenyl-3,5-2H), 7.34(t,J=4.1Hz,1H,phenyl-4-H), 5.96(s,2H,quinolone-1-CH2)ppm.

[0079] Example 17, Preparation of compound I-16:

[0080]

[0081] Compound III-16 (50 mg, 0.14 mmol), piperidine (24 mg, 0.29 mmol), and 2-aldehydethiazole (32 mg, 0.29 mmol) were added to a 50 mL round-bottom flask. Ethanol (20 mL) was used as the solvent, and the mixture was stirred at 80 °C for 12 hours. Thin-layer chromatography was used to monitor the reaction until completion. Product I-16 (35 mg, 0.08 mmol) was obtained by column chromatography, with a yield of 55.1%. It was a yellow solid with a melting point >250 °C. 1 H NMR(600MHz,DMSO-d6)δ14.66(s,1H,COOH),9.27(s,1H,quinolone-2-H),8.30(d,J=5.3Hz,1H,quinolone -8-H),8.26(d,J=3.0Hz,1H,thiazole-4-H),8.23(d,J=2.7Hz,1H,thiazole-5-H),8.19(d,J=10.5Hz,1H, quinolone-5-H),8.13(s,1H,thiazole-2-CH),7.29(d,J=7.7Hz,2H,methylphenyl-2,6-2H),7.20(d,J=7 .7Hz,2H,methylphenyl-3,5-2H),5.90(s,2H,quinolone-1-CH2),2.28(s,3H,methylphenyl-4-CH3)ppm.

[0082] Example 18, Preparation of compound I-17:

[0083]

[0084] Compound III-17 (100 mg, 0.26 mmol), piperidine (45 mg, 0.52 mmol), and 2-aldehydethiazole (59 mg, 0.52 mmol) were added to a 50 mL round-bottom flask. Ethanol (20 mL) was used as the solvent, and the mixture was stirred at 80 °C for 12 hours. Thin-layer chromatography was used to monitor the reaction until completion. Product I-17 (118 mg, 0.25 mmol) was obtained by column chromatography with a yield of 94.4%. It was a yellow solid with a melting point >250 °C. 1 H NMR(600MHz,DMSO-d6)δ14.65(s,1H,COOH),9.38(s,1H,quinolone-2-H),8.23(d,J=3.0Hz ,1H,thiazole-4-H),8.22(d,J=8.5Hz,2H,nitrophenyl-2,6-2H),8.20(d,J=1.3Hz,2H,qu inolone-5-H, thiazole-5-H), 8.14 (d, J = 5.9Hz, 1H, quinolone-8-H), 8.11 (s, 1H, thiazole-2-CH), 7.61 (d, J = 8.6Hz, 2H, nitrophenyl-3, 5-2H), 6.13 (s, 2H, quinolone-1-CH2) ppm.

[0085] Example 19, Preparation of compound I-18:

[0086]

[0087] Compound III-18 (40 mg, 0.10 mmol), piperidine (17 mg, 0.20 mmol), and 2-aldehydethiazole (22 mg, 0.20 mmol) were added to a 50 mL round-bottom flask. Ethanol (20 mL) was used as the solvent, and the mixture was stirred at 80 °C for 12 hours. Thin-layer chromatography was used to monitor the reaction until completion. Product I-18 (41 mg, 0.08 mmol) was obtained by column chromatography, with a yield of 83.0%. It was a yellow solid with a melting point >250 °C. 1H NMR(600MHz,DMSO-d6)δ14.65(s,1H,COOH),9.33(s,1H,quinolone-2-H),8.25(s,1H,quinolone -5-H),8.20(m,J=14.2,9.5Hz,3H,thiazole-4-H,thiazole-5-H,thiazole-2-CH),8.13(s,1H,q uinolone-8-H),7.77(s,1H,3,4-dichlorophenyl-2-H),7.61(d,J=7.7Hz,1H,3,4-dichlorophe nyl-5-H), 7.33 (d, J = 8.4Hz, 1H, 3,4-dichlorophenyl-6-H), 5.94 (s, 2H, quinolone-1-CH2) ppm.

[0088] Example 20, Preparation of compound I-19:

[0089]

[0090] Compound III-19 (100 mg, 0.25 mmol), piperidine (42 mg, 0.49 mmol), and 2-aldehydethiazole (56 mg, 0.49 mmol) were added to a 50 mL round-bottom flask. Ethanol (20 mL) was used as the solvent, and the mixture was stirred at 80 °C for 12 hours. Thin-layer chromatography was used to monitor the reaction until completion. Product I-19 (74 mg, 0.15 mmol) was obtained by column chromatography, with a yield of 59.9%. It was a yellow solid with a melting point >250 °C. 1 H NMR(600MHz,DMSO-d6)δ14.61(s,1H,COOH),9.20(s,1H,quinolone-2-H),8.23(d,J=3.3Hz,1H,quinolone-8-H) ,8.22(d,J=2.8Hz,1H,thiazole-4-H),8.21(d,J=3.0Hz,1H,thiazole-5-H),8.19(s,1H,thiazole-2-CH),8.05( d,J=5.9Hz,1H,quinolone-5-H),7.76(d,J=1.8Hz,1H,2,4-dichlorophenyl-3-H),7.35(dd,J=8.4,1.7Hz,1H,2 ,4-dichlorophenyl-5-H), 7.05 (d, J = 8.4Hz, 1H, 2, 4-dichlorophenyl-6-H), 5.99 (s, 2H, quinolone-1-CH2) ppm.

[0091] Example 21, Preparation of compound I-20:

[0092]

[0093] Compound III-20 (50 mg, 0.13 mmol), piperidine (23 mg, 0.27 mmol), and 2-aldehydethiazole (30 mg, 0.27 mmol) were added to a 50 mL round-bottom flask. Ethanol (20 mL) was used as the solvent, and the mixture was stirred at 80 °C for 12 hours. Thin-layer chromatography was used to monitor the reaction until completion. Product I-20 (38 mg, 0.08 mmol) was obtained by column chromatography, with a yield of 60.5%. It was a yellow solid with a melting point >250 °C. 1 H NMR(600MHz,DMSO-d6)δ14.63(s,1H,COOH),9.26(s,1H,quinolone-2-H),8.27(d,J=6.3Hz,1H,quinol one-5-H),8.26(d,J=3.1Hz,1H,thiazole-4-H),8.24(d,J=2.9Hz,1H,thiazole-5-H),8.22(s,1H,thia zole-2-CH),8.20(s,1H,quinolone-8-H),7.47(m,1H,2,4-difluorophenyl-3-H),7.35(m,1H,2,4-di fluorophenyl-5-H),7.10–7.06(m,1H,2,4-difluorophenyl-6-H),6.00(s,2H,quinolone-1-CH2)ppm.

[0094] Example 22, Preparation of Compound II:

[0095]

[0096] Compound III-2 (200 mg, 0.73 mmol), piperidine (124 mg, 1.46 mmol), and 2-aldehyde benzothiazole (238 mg, 1.46 mmol) were added to a 50 mL round-bottom flask. Ethanol (20 mL) was used as the solvent, and the mixture was stirred at 80 °C for 12 hours. Thin-layer chromatography was used to monitor the reaction until completion. Product II (188 mg, 0.45 mmol) was obtained by column chromatography, yielding 61.4%; a yellow solid with a melting point >250 °C. 1H NMR(600MHz,DMSO-d6)δ14.80(s,1H,COOH),9.14(s,1H,quinolone-2-H),8.45(d,J=9.0Hz,2H,quinolone-5-H,thiazole-2-CH),8.33(d,J=7.8Hz,1H,quinolone-8-H),8.22( m,2H,benzothiazole-4,7-2H),7.70-7.67(m,1H,benzothiazole-5-H),7.65-7.62(m,1H,benzothiazole-6-H),4.72(q,J=7.1Hz,2H,CH2CH3),1.49(t,J=7.1Hz,CH2CH3)ppm.

[0097] Example 23: In vitro antimicrobial activity of quinolone-conjugated thiazole compounds

[0098] The serial dilution method according to the Clinical and Laboratory Standards Institute (CLSI) was used to test the quinolone conjugated thiazole compounds prepared in Examples 2–22 against Gram-positive bacteria (methicillin-resistant Staphylococcus aureus, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus aureus ATCC 25923, Staphylococcus aureus ATCC 29213) and Gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 29213). To determine the minimum inhibitory concentration (MIC, μg / mL) of the test compound (Acinetobacter baumannii 25922), the 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 and 2.

[0099] Table 1. In vitro anti-Gram-positive bacterial activity (MIC, μg / mL) of quinolone-conjugated thiazole compounds prepared in Examples 2–22

[0100]

[0101] As shown in Table 1, most of the compounds in this invention exhibit excellent inhibitory activity against the tested Gram-positive bacteria, particularly Staphylococcus aureus. Short-chain hydrocarbons showed relatively good inhibitory activity, and 1-ethyl-7-thiazolinone cyanoquinolone I-2 demonstrated excellent inhibitory activity against all tested Gram-positive bacteria (MIC = 0.25–0.5 μg / mL), with I-2 showing superior activity compared to all reference drugs.

[0102] Table 2. In vitro anti-Gram-negative bacterial activity (MIC, μg / mL) of quinolone-conjugated thiazole compounds prepared in Examples 2–22

[0103]

[0104] As shown in Table 2, most of the compounds in this invention exhibited excellent inhibitory activity against the tested Gram-negative bacteria, particularly Klebsiella pneumoniae and Acinetobacter baumannii. Similarly, short-chain hydrocarbons and simple cyclic hydrocarbons showed relatively good inhibitory activity, and 1-ethyl-7-thiazolinone cyanoquinolone I-2 demonstrated excellent inhibitory activity against all tested Gram-negative bacteria (MIC = 0.25–0.5 μg / mL), with I-2 exhibiting broader-spectrum antibacterial activity superior to all reference drugs.

[0105] Example 24 Pharmaceutical Uses of Quinolone-Conjugated Thiazole Compounds

[0106] Based on the above antimicrobial activity test results, the quinolone-conjugated thiazole compounds of the present invention exhibit excellent antibacterial activity and can be formulated into antibacterial drugs for clinical use. These drugs can be single-component formulations, such as those composed of a quinolone-conjugated thiazole compound of one structure and pharmaceutically acceptable excipients; or they can be compound formulations, such as those composed of a quinolone-conjugated thiazole compound of one structure, an existing antibacterial active ingredient (e.g., ciprofloxacin), and pharmaceutically acceptable excipients, or those composed of quinolone-conjugated thiazole compounds of different structures and pharmaceutically acceptable excipients. The formulation types include, but are not limited to, tablets, capsules, powders, granules, drop pills, injections, powder for injection, solutions, suspensions, emulsions, suppositories, ointments, gels, films, aerosols, transdermal patches, and various sustained-release, controlled-release, and nano-formulations.

[0107] 1. Preparation of Compound I-2 tablets

[0108] Prescription: 10g of compound I-2, 50g of corn starch, 187g of lactose, 3.0g of magnesium stearate, and an appropriate amount of 70% ethanol solution, to make 1000 tablets.

[0109] Preparation: Dry corn starch at 105℃ for 5 hours for later use; mix compound I-2 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.

[0110] 2. Preparation of Compound I-3 Capsules

[0111] Prescription: Compound I-3 25g, modified starch (120 mesh) 12.5g, microcrystalline cellulose (100 mesh) 7.5g, low-substituted hydroxypropyl cellulose (100 mesh) 2.5g, talc (100 mesh) 2.0g, sweetener 1.25g, orange flavoring 0.25g, coloring as needed, water as needed, to make 1000 capsules.

[0112] Preparation method: The prescribed amount of compound I-3 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 made into a soft mass 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.

[0113] 3. Preparation of Compound I-8 Granules

[0114] Prescription: Compound I-8 26g, dextrin 120g, sucrose 280g.

[0115] Preparation method: Mix compound I-8, dextrin, and sucrose evenly, wet granulate, dry at 60℃, and package to obtain the final product.

[0116] 4. Preparation of Compound I-2 Injection

[0117] Prescription: Compound I-2 10g, propylene glycol 500mL, water for injection 500mL, to prepare a total of 1000mL.

[0118] Preparation: Weigh compound I-2, 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.

[0119] 5. Preparation of Compound I-9 Powder for Injection

[0120] Preparation method: The aseptic powder of compound I-9 is dispensed under aseptic conditions to obtain the product.

[0121] 6. Preparation of Compound I-10 Eye Drops

[0122] Prescription: Compound I-10 3.78g, sodium chloride 0.9g, boric acid buffer solution as needed, distilled water to 1000mL.

[0123] Preparation: Weigh compound I-10 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.

[0124] 7. Preparation of Compound I-11 Liniment

[0125] Prescription: Compound I-11 4g, potassium soap 7.5g, camphor 5g, distilled water to 100mL.

[0126] Preparation: Dissolve camphor in a 95% (v / v) ethanol solution and set aside; liquefy potassium soap by heating and set aside; weigh compound I-11, 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.

[0127] 8. Preparation of Compound I-12 Suppositories

[0128] Prescription: Compound I-12 4g, gelatin 14g, glycerin 70g, distilled water to 100mL, 100 tablets (metric).

[0129] 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-12, stir well, pour into a vaginal suppository mold when it is almost solidified, cool and solidify to obtain the product.

[0130] 9. Preparation of Compound I-2 Ointment

[0131] Prescription: Compound I-2 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 to 100g.

[0132] Preparation: Cetyl 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-1-2 is added, stirred and cooled to obtain the final product.

[0133] 10. Preparation of Compound I-2 Aerosol

[0134] Prescription: Compound I-2 2.5g, Span20 3g, talc (100 mesh) 4g, trichlorofluoromethane added to appropriate amount.

[0135] Preparation method: Place compound I-2, Span20 and talc powder 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.

[0136] 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. Quinolone conjugated thiazoles and their pharmaceutically acceptable salts, characterized in that, The quinolone-conjugated thiazole compound and the pharmaceutically acceptable salt thereof are selected from I-1 to I-20 or II:

2. The quinolone-conjugated thiazole compound and the pharmaceutically acceptable salt thereof according to claim 1, wherein: The quinolone-conjugated thiazole compound is I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, II; The pharmaceutically acceptable salt is a hydrochloride, a nitrate or an acetate.

3. Use of the quinolone-conjugated thiazole compound and the pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 for the preparation of an antibacterial medicament.

4. Use according to claim 3, wherein: The bacteria are selected from Staphylococcus aureus, Enterococcus faecalis, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa or Acinetobacter baumannii.

5. Use 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, and the Pseudomonas aeruginosa is Pseudomonas aeruginosa ATCC 27853.

6. A preparation comprising the quinolone-conjugated thiazole compound and the pharmaceutically acceptable salt thereof according to any one of claims 1 to 2.

7. The formulation of claim 6, wherein, The preparation is one of a tablet, a capsule, a granule, an injection, a powder injection, an eye drop, a liniment, a suppository, an ointment or an aerosol.

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