Quinolone indole compounds, methods of making and using the same

Abstract

This invention relates to a quinolone indole compound, its preparation method, and its application, as shown in general formula I. This type of compound has certain inhibitory activity against both Gram-positive and Gram-negative bacteria, and can be used to prepare antibacterial drugs. Moreover, the raw materials for preparation are simple, inexpensive, and readily available, which is of great significance for anti-infection applications.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis, and relates to quinolone indole compounds, as well as the preparation method and application of such compounds. Background Technology

[0002] Bacterial infections are the leading cause of most hospital-acquired infections, resulting in high morbidity and mortality rates annually and posing a serious threat to human health. Quinolones, as one of the most important first-line broad-spectrum synthetic antibiotics, have been widely used to treat infections caused by various microorganisms due to their strong antibacterial activity, low toxicity, and good pharmacokinetics. However, the long-term widespread use and even abuse of these drugs has led to serious drug resistance problems, posing a significant challenge to anti-infective therapy.

[0003] Indole alkaloids are widely distributed in nature, and the presence of nitrogen-containing heterocycles in their molecular structure endows these compounds with significant biological activity. Indole alkaloids exhibit antibacterial activity through various mechanisms, including inhibition of efflux pumps, biomembranes, DNA gyrases, and topoisomerase IV. Indoles play an important role in the development of novel antibacterial drugs, possessing a wide variety of structures and mechanisms.

[0004] To discover new quinolones with a broad antibacterial spectrum and the ability to overcome drug resistance, extensive research both domestically and internationally has focused on their structural modification in order to obtain more effective quinolone antibacterial drugs. Through skeleton migration and substitution, a new class of novel quinolone indole antibacterial agents has been designed using garafloxacin as a template. Summary of the Invention

[0005] In view of this, one objective of the present invention is to provide a quinolone indole compound and its pharmaceutically acceptable salt; a second objective of the present invention is to provide a method for preparing the quinolone indole compound and its pharmaceutically acceptable salt; and a third objective of the present invention is to provide the application of the aforementioned quinolone indole compound and its pharmaceutically acceptable salt in the preparation of antibacterial drugs. This will provide more highly effective and safe candidate drugs for clinical antimicrobial therapy, helping to solve increasingly serious clinical treatment problems such as drug resistance, persistent pathogenic microorganisms, and newly emerging harmful microorganisms.

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

[0007] 1. Quinolone indole compounds and their pharmaceutically acceptable salts, with structures shown in general formula I:

[0008]

[0009] In the formula,

[0010] R 1It can be alkyl, alkenyl, alkynyl, esteryl, cyano, acyl, carboxyl, aryl, cycloalkyl, or heterocyclic.

[0011] R 2 It can be hydroxyl, alkyl, acyl, hydrazine, cyanalkyl, hydroxyalkyl, alkenyl, aralkyl, alkynyl, etheralkyl, carboxylalkyl, esteralkyl, carbonylalkyl, heterocyclic alkyl, alkoxy, alkenyloxy, or aryloxy.

[0012] Preferred,

[0013] R 1 It can be ethyl, allyl, acyl, benzyl, or aromatic;

[0014] R 2 It can be hydroxyl, acyl, hydrazine, aryl, alkoxy, alkenoxy, or aryloxy.

[0015] Preferably, it is any one of the following compounds:

[0016]

[0017]

[0018] Preferably, the pharmaceutically usable salt is a trifluoroacetate or an acetate.

[0019] 2. A method for preparing quinolone indole compounds, the method being as follows:

[0020] a. Preparation of intermediate II: Intermediate II is obtained from the starting material 3,4-difluoroaniline through substitution, cyclization, N-ethylation and hydrolysis reactions;

[0021]

[0022] b. Preparation of intermediate III: Intermediate III is obtained by reacting intermediate II and 3-indolecarboxaldehyde in the presence of potassium carbonate.

[0023]

[0024] in:

[0025] R 1 It can be ethyl, alkenyl, acyl, or aromatic.

[0026] c. Preparation of quinolone indole compounds of general formula I: Intermediate III is reacted with an amine compound under acidic conditions to obtain the compound of general formula I.

[0027] d. Preparation of pharmaceutically acceptable salts of indolequinolone compounds represented by general formula I: Dissolve the indolequinolone compound represented by general formula I in an organic solvent, add a pharmaceutically acceptable acid and react until no precipitate is formed, thus obtaining the pharmaceutically acceptable salt of the indolequinolone compound represented by formula I.

[0028] Preferably,

[0029] In step a, the molar ratio of the starting materials 3,4-difluoroaniline and diethyl ethoxymethylene malonate in the substitution reaction is 1:1.1, and the reaction temperature is 130°C; the solvent used in the cyclization reaction is diphenyl ether, and the temperature is 250°C; the solvent used in the N-ethylation reaction is acetonitrile, the alkylating agent is iodoethane, and the temperature is 80°C.

[0030] In step b, the molar ratio of intermediate II and 3-indolecarboxaldehyde in potassium carbonate is 1:1 to 1.5:1 to 2, and the reaction is specifically carried out in DMSO as solvent at 80°C for 4–10 h.

[0031] In step c, the ratio of intermediate III, amine compound and acid is 1:1 to 1.5:0.1 to 2, and the acid is one of glacial acetic acid, p-toluenesulfonic acid or trifluoroacetic acid. The reaction is specifically carried out in ethanol or toluene as solvent at 80-120°C for 4 to 24 hours.

[0032] In step d, the organic solvent is at least one of chloroform, acetone, acetonitrile, N,N-dimethylformamide, or tetrahydrofuran; the pharmaceutically acceptable acid is trifluoroacetic acid or acetic acid.

[0033] 3. The application of the quinolone indole compounds and their pharmaceutically acceptable salts in bacterial drugs.

[0034] Preferably, the bacteria are one or more of the following: methicillin-resistant Staphylococcus aureus, Staphylococcus aureus, Staphylococcus aureus ATCC 25923, Staphylococcus aureus ATCC 29213, Staphylococcus aureus ATCC 12600, Staphylococcus aureus ATCC 6538, Staphylococcus aureus ATCC 26003, Staphylococcus aureus ATCC 26001, Enterococcus faecalis, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Pseudomonas aeruginosa ATCC 27853, Pseudomonas aeruginosa ATCC 15442, Pseudomonas aeruginosa ATCC 9027, Pseudomonas aeruginosa ATCC 27853(B)10104, Escherichia coli ATCC 25922, or Acinetobacter baumannii.

[0035] 4. Preparations containing the aforementioned quinolone indole compounds and their pharmaceutically acceptable salts.

[0036] Preferably, the preparation is one of the following: tablets, capsules, granules, injections, powder for injection, eye drops, liniments, suppositories, ointments, or aerosols.

[0037] The beneficial effects of this invention are as follows: This invention utilizes the principle of drug design and synthesis to synthesize a series of novel indolequinolone compounds through hybrid design of indolealdehyde and quinolones. These compounds, when tested for antimicrobial activity in vitro, showed resistance against Gram-positive bacteria (methicillin-resistant Staphylococcus aureus, Staphylococcus aureus, Staphylococcus aureus ATCC 25923, Staphylococcus aureus ATCC 29213, Staphylococcus aureus ATCC 12600, Staphylococcus aureus ATCC 6538, Staphylococcus aureus ATCC 26003, Staphylococcus aureus ATCC 26001, and Enterococcus faecalis) and Gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Pseudomonas aeruginosa ATCC 27853, Pseudomonas aeruginosa ATCC 15442, Pseudomonas aeruginosa ATCC 9027, and Pseudomonas aeruginosa ATCC 27853, Pseudomonas aeruginosa ATCC 15442 ... 27853(B)10104, Escherichia coli ATCC 25922, and Acinetobacter baumannii all exhibit certain inhibitory activity. They can be used to prepare antibacterial drugs, thus providing more efficient and safe candidate drugs for clinical antimicrobial therapy, and helping to solve increasingly serious clinical treatment problems such as drug resistance, persistent pathogenic microorganisms, and emerging harmful microorganisms. Detailed Implementation

[0038] 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.

[0039] Example 1, Preparation of Intermediate II:

[0040]

[0041] Intermediate II was prepared according to the reference “Sunduru, N.; Gupta, L.; Chauhan, K.; Mishra, NN; Shukla, PK; Chauhan, PMS Synthesis 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.”

[0042] Example 2, Preparation of Intermediate III:

[0043]

[0044] Intermediate II (1 eq.), 3-indolecarboxaldehyde (1.5 eq.) and potassium carbonate (1.5 eq.) were stirred in 50 mL of dimethyl sulfoxide at 80 °C for 5 hours, cooled and poured into ice water, washed with ethanol and dried to give intermediate III in 60.0–90.0% yield as a pale yellow solid.

[0045] Example 3, Preparation of compound I-1:

[0046]

[0047] Intermediate III-1 (70 mg), aniline (26 mg), and two drops of trifluoroacetic acid were reacted in 10 mL of toluene at 110 °C for 15 hours with stirring. Recrystallization from ethanol gave a yellow solid I-1 (39 mg), with a yield of 46.5%. Melting point: 257–259 °C. 1 H NMR(600MHz,DMSO-d6)δ14.89(1H),9.16(1H),8.85(1H),8.55(1H),8.51(1H),8.41(1H),8. 38(1H),7.46(1H),7.43(2H),7.40–7.37(2H),7.29(2H),7.23(1H),4.68(2H),1.46(3H)ppm.

[0048] Example 4, Preparation of compound I-2:

[0049]

[0050] Intermediate III-1 (70 mg), 2-chloroaniline (35 mg), and two drops of trifluoroacetic acid were reacted in 10 mL of toluene at 110 °C for 15 hours with stirring. Recrystallization from ethanol gave a yellow solid I-2 (55 mg), with a yield of 85.3%. Melting point: 270–272 °C. 1 H NMR(600MHz,DMSO-d6)δ14.88(1H),9.16(1H),8.82(1H),8.63(1H),8.52(1H),8.44(1H),8. 38(1H),7.55(1H),7.47(1H),7.41–7.39(2H),7.30(1H),7.23(1H),4.67(2H),1.47(3H)ppm.

[0051] Example 5, Preparation of compound I-3:

[0052]

[0053] Intermediate III-1 (70 mg), 3-chloroaniline (35 mg), and two drops of trifluoroacetic acid were reacted in 10 mL of toluene at 110 °C for 15 hours with stirring. Recrystallization from ethanol gave a yellow solid I-3 (40 mg), yield 44.3%. Melting point: >300 °C; 1 H NMR(600MHz,DMSO-d6)δ14.88(1H),9.16(1H),8.87(1H),8.58–8.47(2H),8.39 (2H),7.46(2H),7.42–7.37(2H),7.36(1H),7.27(2H),4.67(2H),1.47(3H)ppm.

[0054] Example 6, Preparation of compound I-4:

[0055]

[0056] Intermediate III-1 (70 mg), 4-chloroaniline (35 mg), and two drops of trifluoroacetic acid were reacted in 10 mL of toluene at 110 °C for 15 hours with stirring. Recrystallization from ethanol gave a yellow solid I-4 (61 mg), yield 67.6%. Melting point: 275–277 °C; 1 H NMR(600MHz,DMSO-d6)δ14.88(1H),9.16(1H),8.85(1H),8.54–8.52(1H),8.50(1H), 8.42(1H),8.37(1H),7.47(3H),7.40–7.36(2H),7.32(2H),4.67(2H),1.46(3H)ppm.

[0057] Example 7, Preparation of compound I-5:

[0058]

[0059] Intermediate III-1 (70 mg), 4-fluoroaniline (31 mg), and two drops of trifluoroacetic acid were reacted in 10 mL of toluene at 110 °C for 15 hours with stirring. Recrystallization from ethanol gave a yellow solid I-5 (60 mg), yield 68.6%. Melting point: 273–275 °C; 1 H NMR(600MHz,DMSO-d6)δ14.87(1H),9.16(1H),8.86(1H),8.55–8.53(1H),8.50(1H), 8.40(1H),8.37(1H),7.46(1H),7.39–7.34(4H),7.26(2H),4.68(2H),1.47(3H)ppm.

[0060] Example 8, Preparation of compound I-6:

[0061]

[0062] Intermediate III-1 (70 mg), 4-methoxyaniline (34 mg), and two drops of trifluoroacetic acid were reacted in 10 mL of toluene at 110 °C for 15 hours with stirring. Recrystallization from ethanol gave a yellow solid I-6 (56 mg), yield 62.6%. Melting point: 261–263 °C; 1 HNMR(600MHz,DMSO-d6)δ14.89(1H),9.15(1H),8.85(1H),8.56(1H),8.48(1H),8.37–8.34 (2H),7.46(1H),7.38–7.35(2H),7.31(2H),6.99(2H),4.67(2H),3.79(3H),1.46(3H)ppm.

[0063] Example 9, Preparation of compound I-7:

[0064]

[0065] Intermediate III-1 (70 mg), aminourea (21 mg), and two drops of acetic acid were reacted in 10 mL of ethanol at 80 °C for 15 hours with stirring. Recrystallization from ethanol gave a yellow solid I-7 (65 mg), with a yield of 80.7%. Melting point: >300 °C; 1H NMR(600MHz,DMSO-d6)δ14.89(1H),11.39(1H),9.14(1H),8.43(2H),8.41(1H),8.35(1H) ,8.26(1H),8.18(1H),7.57(1H),7.41(1H),7.35(1H),7.32(1H),4.67(2H),1.46(3H)ppm.

[0066] Example 10, Preparation of compound I-8:

[0067]

[0068] Intermediate III-1 (70 mg), carbazide (25 mg), and two drops of acetic acid were reacted in 10 mL of ethanol at 80 °C for 15 hours with stirring. Recrystallization from ethanol yielded a yellow solid I-8 (70 mg), with a yield of 84.0%. Melting point: 240–242 °C. 1 H NMR(600MHz,DMSO-d6)δ14.91(1H),11.39(1H),9.12(1H),8.43(2H),8.41(1H),8.35(1H),8.26( 1H),8.18(1H),7.57(1H),7.41(1H),7.35(1H),7.32(1H),4.67(2H),3.35(s,2H),1.46(3H)ppm. .

[0069] Example 11, Preparation of compound I-9:

[0070]

[0071] Intermediate III-1 (70 mg), thioaminourea (25 mg), and two drops of acetic acid were reacted in 10 mL of ethanol at 80 °C for 15 hours with stirring. Recrystallization from ethanol yielded a yellow solid I-9 (66 mg), with a yield of 80.0%. Melting point: 260–262 °C. 1 H NMR(600MHz,DMSO-d6)δ14.89(1H),11.38(1H),9.14(1H),8.43(2H),8.40(1H),8.35(1H) ,8.25(1H),8.17(1H),7.57(1H),7.41(1H),7.35(1H),7.32(1H),4.66(2H),1.45(3H)ppm.

[0072] Example 12, Preparation of compound I-10:

[0073]

[0074] Intermediate III-1 (70 mg), thiocarbazine (30 mg), and two drops of acetic acid were reacted in 10 mL of ethanol at 80 °C for 15 hours with stirring. Recrystallization from ethanol gave a yellow solid I-10 (60 mg), yield 70.0%. Melting point: 280–282 °C; 1 H NMR(400MHz,DMSO-d6)δ11.39(1H),9.32(1H),9.14(1H),8.50(1H),8.43(1H),8.39–8 .32(2H),8.25(1H),7.44–7.39(1H),7.34(3H),4.67(2H),3.34(s,2H),1.46(3H)ppm.

[0075] Example 13, Preparation of compound I-11:

[0076]

[0077] Intermediate III-1 (70 mg), phenylhydrazine hydrochloride (40 mg), and two drops of acetic acid were reacted in 10 mL of ethanol at 80 °C for 15 hours with stirring. Recrystallization from ethanol yielded a yellow solid I-11 (63 mg), with a yield of 73.0%. Melting point: 285–2827 °C; 1 H NMR(600MHz,DMSO-d6)δ14.93(1H),10.16(1H),9.14(1H),8.44(1H),8.40(1H),8.35(1H),8.20 (1H),8.05(1H),7.45(1H),7.37(2H),7.26(2H),7.10(2H),6.74(1H),4.67(2H),1.46(3H)ppm.

[0078] Example 14, Preparation of compound I-12:

[0079]

[0080] Intermediate III-1 (70 mg), 2-chlorophenylhydrazine hydrochloride (50 mg), and two drops of acetic acid were reacted in 10 mL of ethanol at 80 °C for 15 hours with stirring. Recrystallization from ethanol gave a yellow solid I-12 (75 mg), yield 80.6%. Melting point: 196–197 °C; 1H NMR(600MHz,DMSO-d6)δ14.90(1H),9.70(1H),9.12(1H),8.60(1H),8.41(2H),8.36–8.32(1H),8. 08(1H),7.60(1H),7.45(1H),7.40–7.36(2H),7.35–7.32(2H),6.79(1H),4.67(2H),1.47(3H)ppm.

[0081] Example 15, Preparation of compound I-13:

[0082]

[0083] Intermediate III-1 (70 mg), 3-chlorophenylhydrazine hydrochloride (50 mg), and two drops of acetic acid were reacted in 10 mL of ethanol at 80 °C for 15 hours with stirring. Recrystallization from ethanol gave a yellow solid I-13 (59 mg), yield 63.4%. Melting point: 240–242 °C; 1 H NMR(400MHz,DMSO-d6)δ14.91(1H),10.36(1H),9.12(1H),8.42–8.36(2H),8.32(1H),8.21(1H),8.07(1H),7 .46(1H),7.38(2H),7.26(2H),7.17(1H),7.07(1H),7.02(1H),6.74(1H),4.66(2H),2.30(1H),1.46(3H)ppm.

[0084] Example 16, Preparation of compound I-14:

[0085]

[0086] Intermediate III-1 (70 mg), 4-chlorophenylhydrazine hydrochloride (50 mg), and two drops of acetic acid were reacted in 10 mL of ethanol at 80 °C for 15 hours with stirring. Recrystallization from ethanol gave a yellow solid I-14 (73 mg), yield 78.5%. Melting point: 285–287 °C; 1H NMR (400MHz, DMSO-d6) δ14.92(s,1H),10.30(s,1H),9.13(s,1H),8.41(q,J=4.7,3.4Hz,2H),8.34(d,J=10.4Hz,1H),8.20(s,1H),8.07(s ,1H),7.47–7.43(m,1H),7.39–7.35(m,2H),7.29(d,J=8.3Hz,2H),7.08(d,J=8.3Hz,2H),4.67(q,J=7.1Hz,2H),1.46(t,J=7.0Hz,3H)ppm.

[0087] Example 17, Preparation of compound I-15:

[0088]

[0089] Intermediate III-1 (70 mg), 3,4-chlorophenylhydrazine hydrochloride (59 mg), and two drops of acetic acid were reacted in 10 mL of ethanol at 80 °C for 15 hours with stirring. Recrystallization from ethanol gave a yellow solid I-15 (70 mg), yield 70.4%. Melting point: 292–294 °C; 1 HNMR(600MHz,DMSO-d6)δ14.90(s,1H),10.45(s,1H),9.14(s,1H),8.42(s,1H),8.36(s,1H),8.34(s,1H),8.22(s,1H),8.11(s, 1H),7.46(s,1H),7.45(s,1H),7.38(q,J=6.3,5.8Hz,2H),7.21(s,1H),7.04(d,J=7.5Hz,1H),4.66(d,J=9.3Hz,2H),1.46(3H).

[0090] Example 18, Preparation of compound I-16:

[0091]

[0092] Intermediate III-1 (70 mg), 4-methylphenylhydrazine hydrochloride (44 mg), and two drops of acetic acid were reacted in 10 mL of ethanol at 80 °C for 15 hours with stirring. Recrystallization from ethanol gave a yellow solid I-16 (56 mg), yield 62.7%. Melting point: 285–286 °C; 1HNMR(600MHz,DMSO-d6)δ14.92(1H),10.01(1H),9.13(1H),8.42(1H),8.39(1H),8.34(1H),8.1 6(1H),8.01(1H),7.44(1H),7.36(2H),7.07(2H),6.99(2H),4.67(2H),2.23(3H),1.46(3H)ppm.

[0093] Example 19, Preparation of compound I-17:

[0094]

[0095] Intermediate III-1 (70 mg), 2,4-dimethylphenylhydrazine hydrochloride (48 mg), and two drops of acetic acid were reacted in 10 mL of ethanol at 80 °C for 15 hours with stirring. Recrystallization from ethanol gave a yellow solid I-17 (66 mg), yield 71.8%. Melting point: 270–272 °C; 1 H NMR(600MHz,DMSO-d6)δ14.93(1H),9.24(1H),9.13(1H),8.41(3H),8.35(1H),8.03 (1H),7.45(1H),7.36(3H),6.99(1H),6.89(1H),4.67(2H),2.21(6H),1.46(3H)ppm.

[0096] Example 20, Preparation of compound I-18:

[0097]

[0098] Intermediate III-1 (70 mg), 4-carboxyphenylhydrazine hydrochloride (52 mg), and two drops of acetic acid were reacted in 10 mL of ethanol at 80 °C for 15 hours with stirring. Recrystallization from ethanol gave a yellow solid I-18 (63 mg), yield 66.4%. Melting point: 290–292 °C; 1 HNMR(600MHz,DMSO-d6)δ14.92(1H),12.23(1H),10.67(1H),9.14(1H),8.43(2H),8.35(1H),8 .28(1H),8.13(1H),7.86(2H),7.46(1H),7.41–7.35(2H),7.12(2H),4.67(2H),1.46(3H)ppm.

[0099] Example 21, Preparation of compound I-19:

[0100]

[0101] Intermediate III-1 (70 mg), 4-nitrophenylhydrazine hydrochloride (53 mg), and two drops of acetic acid were reacted in 10 mL of ethanol at 80 °C for 15 hours with stirring. Recrystallization from ethanol gave a yellow solid I-19 (60 mg). Yield: 63.2%. Melting point: >300 °C; 1 H NMR (400MHz, DMSO-d6) δ14.91(s,1H),11.22(s,1H),9.14(s,1H),8.43(dd,J=10.2,6.6Hz,2H),8.36(d,J=11.4Hz,2H),8.21–8.15(m, 3H), 7.47 (dd, J = 5.9, 3.2Hz, 1H), 7.40 (dt, J = 6.1, 2.3Hz, 2H), 7.18 (d, J = 8.8Hz, 2H), 4.67 (q, J = 7.1Hz, 2H), 1.46 (t, J = 7.0Hz, 3H) ppm.

[0102] Example 22, Preparation of compound I-20:

[0103]

[0104] Intermediate III-1 (70 mg), hydroxylamine hydrochloride (19 mg), and two drops of acetic acid were reacted in 10 mL of ethanol at 80 °C for 15 hours with stirring. Recrystallization from ethanol yielded a yellow solid I-20 (56 mg), with a yield of 77.0%. Melting point: 280–282 °C to 300 °C. 1 H NMR(600MHz,DMSO-d6)δ14.91(1H),11.66(1H),9.14(1H),8.56(1H),8.46(1H) ,8.34(1H),8.07(1H),7.98(1H),7.43(1H),7.33(2H),4.67(2H),1.44(3H)ppm.

[0105] Example 23, Preparation of compound I-21:

[0106]

[0107] Intermediate III-1 (70 mg), O-methoxyamine hydrochloride (23 mg), and two drops of acetic acid were reacted in 10 mL of ethanol at 80 °C for 15 hours with stirring. Recrystallization from ethanol yielded a yellow solid I-21 (52 mg), with a yield of 69.0%. Melting point: 265–267 °C. 1H NMR(600MHz,DMSO-d6)δ14.89(1H),9.14(1H),8.46(1H),8.43(1H),8.35(1H),8.1 8(1H),8.11(1H),7.44(1H),7.36–7.31(2H,),4.66(2H),3.94(3H),1.45(3H)ppm.

[0108] Example 24, Preparation of compound I-22:

[0109]

[0110] Intermediate III-1 (70 mg), O-ethoxyamine hydrochloride (27 mg), and two drops of acetic acid were reacted in 10 mL of ethanol at 80 °C for 15 hours with stirring. Recrystallization from ethanol gave a yellow solid I-22 (58 mg), yield 74.4%. Melting point: 250–252 °C; 1 H NMR(600MHz,DMSO-d6)δ14.88(1H),9.14(1H),8.46(1H),8.42(1H),8.35(1H),8.18(1H ),8.09(1H),7.44(1H),7.35-7.32(2H),4.66(2H),4.21(2H),1.45(3H),1.31(3H)ppm.

[0111] Example 25, Preparation of compound I-23:

[0112]

[0113] Intermediate III-1 (70 mg), O-tert-butylhydroxylamine hydrochloride (35 mg), and two drops of acetic acid were reacted in 10 mL of ethanol at 80 °C for 15 hours with stirring. Recrystallization from ethanol gave a yellow solid I-23 (66 mg), yield 79.4%. Melting point: 270–272 °C; 1 HNMR(600MHz,DMSO-d6)δ14.88(1H),9.14(1H),8.40(2H),8.34(1H),8.22–8.17(1 H),8.05(1H),7.45–7.42(1H),7.36–7.32(2H),4.66(2H),1.45(3H),1.38(9H)ppm.

[0114] Example 26, Preparation of compound I-24:

[0115]

[0116] Intermediate III-1 (70 mg), O-allyl hydroxylamine hydrochloride (30 mg), and two drops of acetic acid were reacted in 10 mL of ethanol at 80 °C for 15 hours with stirring. Recrystallization from ethanol gave a yellow solid I-24 (58 mg), yield 72.3%. Melting point: 188–190 °C; 1 HNMR(600MHz,DMSO-d6)δ14.88(1H),9.14(1H),8.51(1H),8.43(1H),8.34(1H),8.16(1H),8.10(1H),7.44( 1H),7.36–7.31(2H),6.12-6.09(1H),5.39(1H),5.28–5.24(1H),4.70–4.67(2H),4.66(2H),1.45(3H)ppm.

[0117] Example 27, Preparation of compound I-25:

[0118]

[0119] Intermediate III-1 (70 mg), benzyloxyamine hydrochloride (44 mg), and two drops of acetic acid were reacted in 10 mL of ethanol at 80 °C for 15 hours with stirring. Recrystallization from ethanol gave a yellow solid I-25 (56 mg), yield 62.6%. Melting point: 135–136 °C; ¹H NMR (400 MHz, DMSO-d6) δ 14.88 (1H), 9.14 (1H), 8.52 (1H), 8.44 (1H), 8.35 (1H), 8.17–8.07 (2H), 7.49–7.39 (5H), 7.34 (5H), 5.30 (1H), 5.22 (1H), 4.65 (2H), 1.43 (3H) ppm.

[0120] Example 28, Preparation of compound I-26:

[0121]

[0122] Intermediate III-2 (70 mg), O-methoxyamine hydrochloride (22 mg), and two drops of acetic acid were reacted in 10 mL of ethanol at 80 °C for 15 hours with stirring. Recrystallization from ethanol gave a yellow solid I-26 (46 mg), yield 61.6%. Melting point: 208–210 °C; ¹H NMR (400 MHz, DMSO-d6) δ 14.82 (1H), 9.15 (1H), 8.46 (1H), 8.36–8.30 (2H), 8.19–8.16 (1H), 8.06 (1H), 7.42 (1H), 7.37–7.32 (2H), 6.12 (1H), 5.37 (1H), 5.33–5.24 (3H), 3.94 (3H) ppm.

[0123] Example 29, Preparation of compound I-27:

[0124]

[0125] Intermediate III-3 (70 mg), O-methoxyamine hydrochloride (22 mg), and two drops of acetic acid were reacted in 10 mL of ethanol at 80 °C for 15 hours with stirring. Recrystallization from ethanol gave a yellow solid I-27 (42 mg), yield 56.0%. Melting point: 285–287 °C; 1 H NMR(400MHz,DMSO-d6)δ14.76(1H),9.14(1H),8.45(1H),8.35(1H),8.18(z,1H),8.1 1(1H),8.07(1H),7.87(1H),7.67(1H),7.47(1H),7.35(2H),5.34(2H),3.94(3H)ppm.

[0126] Example 30, Preparation of compound I-28:

[0127]

[0128] Intermediate III-4 (70 mg), O-methoxyamine hydrochloride (20 mg), and two drops of acetic acid were reacted in 10 mL of ethanol at 80 °C for 15 hours with stirring. Recrystallization from ethanol gave a yellow solid I-28 (46 mg), yield 61.7%. Melting point: 280–282 °C; 1 H NMR(600MHz,DMSO-d6)δ14.94(1H),9.10(1H),8.67(1H),8.30(1H),8.26(1H),8.14(1H ),8.01(1H),7.61(1H),7.43(2H),7.32–7.27(4H),5.68(2H),4.72(2H),1.49(3H)ppm.

[0129] Example 31, Preparation of compound I-29:

[0130]

[0131] Intermediate III-5 (70 mg), O-methoxyamine hydrochloride (20 mg), and two drops of acetic acid were reacted in 10 mL of ethanol at 80 °C for 15 hours with stirring. Recrystallization from ethanol gave a yellow solid I-29 (40 mg), yield 53.6%. Melting point: 283–285 °C; 1H NMR(600MHz,DMSO-d6)δ14.80(1H),9.39(1H),8.42(1H),8.35(1H),8.30(1H),8.20(1H),8.12(1H ),8.02(1H),8.00(1H),7.45(2H),7.28–7.27(2H),6.61(1H),6.49(1H),5.95(2H),3.93(3H)ppm.

[0132] Example 32, Preparation of compound I-30:

[0133]

[0134] Intermediate III-6 (70 mg), O-methoxyamine hydrochloride (19 mg), and two drops of acetic acid were reacted in 10 mL of ethanol at 80 °C for 15 hours with stirring. Recrystallization from ethanol gave a yellow solid I-30 (55 mg), yield 73.9%. Melting point: 258–260 °C; 1 H NMR(600MHz,DMSO-d6)δ14.73(1H),9.33(1H),8.43(1H),8.35(1H),8.20(1H),8.14(1H),8.00(1H ),7.52–7.49(1H), δ7.33(1H),7.29(2H),7.25(2H),7.14(1H),6.77(1H),6.00(2H),3.93(3H)ppm.

[0135] Example 33, Preparation of compound I-31:

[0136]

[0137] Intermediate III-7 (70 mg), O-methoxyamine hydrochloride (19 mg), and two drops of acetic acid were reacted in 10 mL of ethanol at 80 °C for 15 hours with stirring. Recrystallization from ethanol gave a yellow solid I-31 (48 mg), yield 64.5%. Melting point: 250–252 °C; 1 H NMR(400MHz,DMSO-d6)δ14.79(1H),9.37(1H),8.42(1H),8.35(1H),8.14(2H),8.02(1H ),7.50–7.46(1H),7.30(2H),7.22(1H),7.08(2H),6.48(1H),5.95(2H),3.93(3H)ppm.

[0138] Example 34, Preparation of compound I-32:

[0139]

[0140] Intermediate III-8 (70 mg), O-methoxyamine hydrochloride (17 mg), and two drops of acetic acid were reacted in 10 mL of ethanol at 80 °C for 15 hours with stirring. Recrystallization from ethanol gave a yellow solid I-32 (50 mg), with a yield of 67.6%. Melting point: >300 °C; 1 H NMR(400MHz,DMSO-d6)δ14.78(1H),9.41(1H),8.42(1H),8.37(1H),8.13(2H),8.02(1H), 7.82(2H),7.49(2H),7.29(1H),6.95(1H),6.39(1H),6.07(2H),3.92(3H),3.34(3H)ppm.

[0141] Example 35, Preparation of compound I-33:

[0142]

[0143] Intermediate III-9 (70 mg), O-methoxyamine hydrochloride (19 mg), and two drops of acetic acid were reacted in 10 mL of ethanol at 80 °C for 15 hours with stirring. Recrystallization from ethanol gave a yellow solid I-33 (52 mg), yield 70.0%. Melting point: 259–261 °C; 1 H NMR(400MHz,DMSO-d6)δ14.82(1H),9.34(1H),8.43(1H),8.33(1H),8.23(1H),8.14(1H),8.02 (1H),7.30(1H),7.24(2H),7.11(1H),7.00(2H),6.65(1H),5.85(2H),3.93(3H),3.79(3H)ppm.

[0144] Example 36, Preparation of compound I-34:

[0145]

[0146] Intermediate III-10 (70 mg), O-methoxyamine hydrochloride (22 mg), and two drops of acetic acid were reacted in 10 mL of ethanol at 80 °C for 15 hours with stirring. Recrystallization from ethanol gave a yellow solid I-34 (50 mg), with a yield of 66.7%. Melting point: 209–211 °C; 1HNMR(600MHz,DMSO-d6)δ14.87(1H),9.12(1H),8.47(1H),8.42(1H),8.34(1H),8.19–8.16(1H) ,8.09(1H),7.43(1H),7.34(2H),4.62(2H),3.94(3H),1.82(2H),1.36–1.33(2H),0.91(3H)ppm.

[0147] Example 37, Preparation of compound I-35:

[0148]

[0149] Intermediate III-11 (70 mg), O-methoxyamine hydrochloride (20 mg), and two drops of acetic acid were reacted in 10 mL of ethanol at 80 °C for 15 hours with stirring. Recrystallization from ethanol gave a yellow solid I-35 (44 mg), yield 58.0%. Melting point: 188–190 °C; 1 HNMR(400MHz,DMSO-d6)δ14.87(1H),9.12(1H),8.46(1H),8.43(1H),8.34(1H),8.21–8.14(1H) ,8.10(1H),7.42(1H),7.33(2H),4.61(2H),3.94(3H),1.82(2H),1.35–1.22(8H),0.84(3H)ppm.

[0150] Example 38, Preparation of compound I-36:

[0151]

[0152] Intermediate III-12 (70 mg), O-methoxyamine hydrochloride (19 mg), and two drops of acetic acid were reacted in 10 mL of ethanol at 80 °C for 15 hours with stirring. Recrystallization from ethanol gave a yellow solid I-36 (40 mg), yield 53.6%. Melting point: 184–186 °C; 1 HNMR(400MHz,DMSO-d6)δ14.86(1H),9.12(1H),8.46(1H),8.41(1H),8.32(1H),8.18(1H),8. 09(1H),7.43(1H),7.33(2H),4.61(2H),3.94(3H),1.83(2H),1.32–1.19(10H),0.82(3H)ppm.

[0153] Example 39: Antimicrobial activity of quinolone indole compounds:

[0154] The quinolone indole compounds prepared in Examples 3–38 were examined using a 96-well microdilution method conforming to the Clinical Laboratory Standards Institute (CLSI) standards for clinical trials. The effects of these compounds on Gram-positive bacteria (methicillin-resistant Staphylococcus aureus, Staphylococcus aureus, Staphylococcus aureus ATCC 25923, Staphylococcus aureus ATCC 29213, Staphylococcus aureus ATCC 12600, Staphylococcus aureus ATCC 6538, Staphylococcus aureus ATCC 26003, Staphylococcus aureus ATCC 26001, and one or more of Enterococcus faecalis) and Gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Pseudomonas aeruginosa ATCC 27853, Pseudomonas aeruginosa ATCC 15442, Pseudomonas aeruginosa ATCC 9027, and Pseudomonas aeruginosa ATCC 27853, Pseudomonas aeruginosa ATCC 15442, Pseudomonas aeruginosa ATCC 9027, and Pseudomonas aeruginosa ATCC 27853, Pseudomonas aeruginosa ATCC 15442, Pseudomonas aeruginosa ATCC 15442, and Pseudomonas aeruginosa ATCC 15442). The minimum inhibitory concentration (MIC) of one or more of the following: 27853(B)10104, Escherichia coli ATCC 25922, and Acinetobacter baumannii was determined by dissolving the test compound in a small amount of dimethyl sulfoxide, diluting it with water to prepare a solution with a concentration of 1.28 mg / mL, and then diluting it with culture medium to 128 μg / mL. The solution was incubated at 35°C for 24–72 hours. After thoroughly mixing the culture plate on a shaker, the MIC was measured at a wavelength of 590 nm. The results are shown in Tables 1–4.

[0155] Table 1. Antibacterial activity (MIC, μg / mL) of quinolone indole compounds prepared in Examples 3–38

[0156]

[0157] Note: ND indicates no test was conducted.

[0158] As shown in Table 1, the compounds in this invention exhibit certain inhibitory effects on the tested Gram-positive bacteria. In particular, the quinolone indole compound I-21 modified with O-methoxyamine hydrochloride has excellent inhibitory activity against the tested Gram-positive bacteria. Except for Staphylococcus aureus ATCC 25923, its MIC value is 0.25 μg / mL, which is superior to the reference drug norfloxacin (0.5–64 μg / mL). Especially its antibacterial activity against Staphylococcus aureus ATCC 6538 is 256 times that of norfloxacin.

[0159] Table 2. Antibacterial activity (MIC, μg / mL) of quinolone indole compounds prepared in Examples 3–38

[0160]

[0161]

[0162] Note: ND indicates no test was conducted.

[0163] As shown in Table 2, the compounds in this invention exhibited certain inhibitory effects on the tested Gram-negative bacteria. In particular, the quinolone indole compound I-21, modified with O-methoxyamine hydrochloride, showed excellent inhibitory activity against *Klebsiella pneumoniae*, *Escherichia coli*, *Escherichia coli* ATCC 25922, *Pseudomonas aeruginosa*, and *Pseudomonas aeruginosa* 27853, with MIC values ​​of 0.25 μg / mL. This is significantly superior to the inhibitory activity of the reference drug norfloxacin against these bacteria (MIC values ​​of 2, 0.5, 2, 0.5, and 8 μg / mL, respectively). Especially noteworthy is its activity against *Pseudomonas aeruginosa* ATCC 27853, which is 32 times more potent than that of norfloxacin.

[0164] Example 40: Pharmaceutical uses of quinolone indole compounds:

[0165] Based on the above antimicrobial activity test results, the quinolone indole compounds of the present invention exhibit good 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 single-structure quinolone indole compound and pharmaceutically acceptable excipients; or they can be compound formulations, such as those composed of a single-structure quinolone indole compound, existing antibacterial active ingredients (e.g., sulfamethoxazole, fluconazole, fosfluconazole, itraconazole, etc.), and pharmaceutically acceptable excipients, or several quinolone indole compounds with 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.

[0166] 1. Preparation of Compound I-2 tablets

[0167] 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.

[0168] 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.

[0169] 2. Preparation of Compound I-3 Capsules

[0170] 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.

[0171] Preparation: The prescribed amount of compound I-3 is micronized and pulverized into an extremely fine powder, then mixed with the prescribed amounts of modified starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, talc, sweetener, orange flavoring 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 50 mg and contains 25 mg of active ingredient.

[0172] 3. Preparation of Compound I-7 Granules

[0173] Prescription: Compound I-7 26g, dextrin 120g, sucrose 280g.

[0174] Preparation method: Mix compound I-7, dextrin, and sucrose evenly, wet granulate, dry at 60℃, and package to obtain the final product.

[0175] 4. Preparation of Compound I-9 Injection

[0176] Prescription: Compound I-9 10g, propylene glycol 500mL, water for injection 500mL, to prepare a total of 1000mL.

[0177] Preparation: Weigh compound I-9, 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.

[0178] 5. Preparation of Compound I-17 Powder for Injection

[0179] Preparation method: The intermediate I-17 aseptic powder is dispensed under aseptic conditions to obtain the product.

[0180] 6. Preparation of Compound I-18 Eye Drops

[0181] Prescription: Compound I-18 3.78g, sodium chloride 0.9g, boric acid buffer solution as needed, distilled water to 1000mL.

[0182] Preparation: Weigh compound I-18 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 into containers, seal, and sterilize with flowing steam at 100°C for 1 hour to obtain the final product.

[0183] 7. Preparation of Compound I-21 Liniment

[0184] Prescription: Compound I-21 4g, potassium soap 7.5g, camphor 5g, distilled water to 100mL.

[0185] Preparation: Dissolve camphor in a 95% (v / v) ethanol solution and set aside; liquefy potassium soap by heating and set aside; weigh compound I-21, 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.

[0186] 8. Preparation of Compound I-30 Suppositories

[0187] Prescription: Compound I-30 4g, gelatin 14g, glycerin 70g, distilled water to 100mL, 100 tablets (metric).

[0188] 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-30, stir well, pour into a vaginal suppository mold when it is almost solidified, and cool and solidify to obtain the product.

[0189] 9. Preparation of Compound I-32 Ointment

[0190] Prescription: Compound I-32 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.

[0191] 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-32 is added, stirred and cooled to obtain the final product.

[0192] 10. Preparation formula of compound I-34 aerosol: 2.5g of compound I-34, 3g of Span20, 4g of talc (100 mesh), and appropriate amount of trichlorofluoromethane.

[0193] Preparation method: Place compound I-34, 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.

[0194] 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 indole compounds and their pharmaceutically acceptable salts, characterized in that, It is any one of the following compounds:

2. The quinolone indole compound and its pharmaceutically acceptable salt according to claim 1, characterized in that: The pharmaceutically usable salt is trifluoroacetic acid or acetate.

3. The use of the quinolone indole compounds and their pharmaceutically acceptable salts as described in any one of claims 1 to 2 in the preparation of antibacterial drugs.

4. The application according to claim 3, wherein the bacteria are selected from one or more of Staphylococcus aureus, Enterococcus faecalis, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, or Acinetobacter baumannii.

5. The application according to claim 4, characterized in that, The *Staphylococcus aureus* is methicillin-resistant *Staphylococcus aureus*, *Staphylococcus aureus* ATCC 25923, *Staphylococcus aureus* ATCC 29213, *Staphylococcus aureus* ATCC 12600, *Staphylococcus aureus* ATCC 6538, *Staphylococcus aureus* ATCC 26003, or *Staphylococcus aureus* ATCC 26001; the *Escherichia coli* is *Escherichia coli* ATCC 25922; and the *Pseudomonas aeruginosa* is *Pseudomonas aeruginosa* ATCC 27853, *Pseudomonas aeruginosa* ATCC 15442, *Pseudomonas aeruginosa* ATCC 9027, or *Pseudomonas aeruginosa* ATCC 27853(B)10104.

6. A formulation comprising the quinolone indole compound as described in any one of claims 1 to 2 and its pharmaceutically acceptable salt.

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.

Images