CN105669519B - Benzazole compounds, preparation method and its application as drug-resistance bacteria medicine - Google Patents

Abstract

Provided are an indole compound of the following general formula and its salt, a preparation method, the corresponding medical application of the compound and its salt, and medicines and disinfectants containing the compound and its salt. A large number of experiments have proved that the compounds and their salts have good effects on MRSA (drug-resistant Staphylococcus aureus), MDR K.Pneumonia (drug-resistant Klebsiella pneumoniae), and MDR A.Baumanii (drug-resistant Acinetobacter baumannii). antibacterial and bactericidal activity. Wherein, X is methylene, carbonyl or sulfonyl; R1 is fluorine, chlorine, bromine, methoxyl, nitro or hydrogen; R2 is methoxyl, (p-methoxyl)phenyl, (p-trifluorooxy base) phenyl, (p-trifluoro)phenyl, (m-methoxyl)phenyl, (m-trifluorooxy)phenyl, (p-fluorom-chloro)phenyl or hydrogen; HA is an inorganic acid or moiety Strongly acidic organic acid, preferably hydrochloric acid or hydrobromic acid.

Description

Indole compound, preparation method and application thereof as anti-drug-resistant bacteria drug

technical field

The invention relates to the field of chemical and medical application of compounds, in particular to an indole compound containing indole, aminoguanidine or hydrazonone and a salt thereof, a preparation method and a medical application as an anti-drug-resistant bacteria drug.

Background technique

In recent years, with the continuous development and marketing and clinical application of various antibiotics, especially under the requirements of some medical institutions, medical personnel and patients based on the rapid elimination of infected patients, the abnormal use of large doses and excessive doses of antibiotics has become more and more serious. These phenomena have led to the rapid development and evolution of drug-resistant bacteria against antibacterial agents: the emergence of methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive Staphylococcus aureus (MSSA) have given clinical antibacterial and anti-infective The treatment brought new problems.

However, infection by pathogenic microorganisms such as bacteria has always been one of the important diseases threatening human health. Due to the wide antibacterial spectrum, strong antibacterial activity and wide clinical application of fluoroquinolones, in recent years, the phenomenon of bacterial resistance to fluoroquinolones has become increasingly serious, and the spread of drug-resistant bacteria has forced medical researchers to study and medical staff urgently need to develop And the application of new drugs to overcome this increasingly serious problem of drug resistance. Among them, Staphylococcus aureus is one of the most common bacteria that cause iatrogenic and medical device infections: for example, the emerging drug-resistant mutant strains such as MRSA are extremely resistant to existing antibacterial drugs; Acinetobacter mannensis is a typical iatrogenic or opportunistic pathogen. Klebsiella pneumoniae can cause diseases such as pneumonia and meningitis; Acinetobacter burbaumannii can cause bacteremia, urinary tract infection, secondary Meningitis, surgical site infection, and ventilator-associated pneumonia.

Due to the emergence of the above-mentioned drug-resistant bacteria, the routine infectious diseases that have been controlled to a certain extent have become increasingly serious, and have attracted serious attention from clinical and microbiologists. The current slow progress in the development of new drugs and the inability of existing drugs to treat drug-resistant bacteria further exacerbate the above problems. The development of drug molecules with new structures against drug-resistant bacteria is a breakthrough to solve this problem.

Contents of the invention

The present invention is proposed in order to solve the above problems, and it provides an indole compound and its salt, a preparation method and the corresponding medical use of the compound and its salt, as well as the medicine and disinfectant containing the compound and its salt agent. The inventor has proved through a large number of experiments that this class of compounds and salts thereof have the effect on MRSA (drug-resistant Staphylococcus aureus), MDRK.Pneumonia (drug-resistant Klebsiella pneumoniae), MDR A.Baumanii (drug-resistant Acinetobacter baumannii) Good bacteriostatic and bactericidal activity.

A kind of indole compound provided by the invention has the general chemical structure formula as follows:

in,

X is methylene, carbonyl or sulfonyl;

R1 is fluorine, chlorine, bromine, methoxyl, nitro or hydrogen;

R2 is methoxyl, (p-methoxyl) phenyl, (p-trifluorooxy) phenyl, (p-trifluoro) phenyl, (m-methoxyl) phenyl, (m-trifluorooxy) Phenyl, (p-fluoro-m-chloro)phenyl or hydrogen.

Indole compounds provided by the present invention, in order to obtain better antibacterial and bactericidal effects, R wherein R is preferably p _- chloro, p-bromo, p-fluoro, p-methoxyl, p-nitrobenzyl, m-methoxyl, m-nitro.

Indole compounds provided by the present invention, in order to obtain better antibacterial and bactericidal effects, R wherein R2 is preferably ₅ -methoxyacyl, 6-methoxyacyl, 5-(p-methoxyacyl) phenyl, 5 -(p-trifluorooxy)phenyl, 5-(p-trifluoro)phenyl, 5-(m-methoxyl)phenyl, 5-(m-trifluorooxy)phenyl, 5-(p-fluoro m-chloro)phenyl.

The indole compounds provided by the present invention, their corresponding X, R ₁ , R ₂ and compound numbers are shown in Table 1 and Table 2 below.

Table 1 Compounds of general formula I

Above-mentioned general formula I indole compound name is:

Compound 1: 2-[(1-p-chlorobenzyl-5-methoxycarbonyl-3-indole)methylene]aminoguanidine;

Compound 2: 2-[(1-p-fluorobenzyl-5-methoxycarbonyl-3-indole)methylene]aminoguanidine;

Compound 3: 2-[(1-p-methoxycarbonylbenzyl-5-methoxycarbonyl-3-indole)methylene]aminoguanidine;

Compound 4: 2-[(1-m-methoxycarbonylbenzyl-5-methoxycarbonyl-3-indole)methylene]aminoguanidine;

Compound 5: 2-[(1-p-nitrobenzyl-5-methoxycarbonyl-3-indole)methylene]aminoguanidine;

Compound 6: 2-[(1-m-nitrobenzyl-5-methoxycarbonyl-3-indole)methylene]aminoguanidine;

Compound 7: 2-[(1-p-chlorobenzyl-6-methoxycarbonyl-3-indole)methylene]aminoguanidine;

Compound 8: 2-[(1-p-fluorobenzyl-6-methoxycarbonyl-3-indole)methylene]aminoguanidine;

Compound 9: 2-[(1-p-methoxycarbonylbenzyl-6-methoxycarbonyl-3-indole)methylene]aminoguanidine;

Compound 10: 2-[(1-m-methoxycarbonylbenzyl-6-methoxycarbonyl-3-indole)methylene]aminoguanidine;

Compound 11: 2-[(1-p-nitrobenzyl-6-methoxycarbonyl-3-indole)methylene]aminoguanidine;

Compound 12: 2-[(1-m-nitrobenzyl-6-methoxycarbonyl-3-indole)methylene]aminoguanidine;

Compound 13: 2-[(1-benzoyl-5-methoxycarbonyl-3-indole)methylene]aminoguanidine;

Compound 14: 2-[(1-benzoyl-6-methoxycarbonyl-3-indole)methylene]aminoguanidine;

Compound 15: 2-[(1-Benzenesulfonyl-5-(4-methoxycarbonylphenyl)-3-indole)methylene]aminoguanidine;

Compound 16: 2-[(1-Benzenesulfonyl-5-(3-methoxycarbonylphenyl)-3-indole)methylene]aminoguanidine;

Compound 17: 2-[(1-benzenesulfonyl-5-(4-trifluoromethoxyphenyl)-3-indole)methylene]aminoguanidine;

Compound 18: 2-[(1-benzenesulfonyl-5-(3-trifluoromethoxyphenyl)-3-indole)methylene]aminoguanidine;

Compound 19: 2-[(1-benzenesulfonyl-5-(4-trifluoromethylphenyl)-3-indole)methylene]aminoguanidine;

Compound 20: 2-[(1-Benzenesulfonyl-5-(4-fluoro-3-chlorophenyl)-3-indole)methylene]aminoguanidine.

Table 2 Compounds of general formula II

Above-mentioned general formula II indole compound name is:

Compound 21: 1-p-chlorobenzyl-5-methoxycarbonyl-3-indolecarbaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazinone;

Compound 22: 1-p-fluorobenzyl-5-methoxycarbonyl-3-indolecarbaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazinone;

Compound 23: 1-p-methoxycarbonylbenzyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazinone;

Compound 24: 1-m-methoxycarbonylbenzyl-5-methoxycarbonyl-3-indolecarbaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazinone;

Compound 25: 1-p-nitrobenzyl-5-methoxycarbonyl-3-indolecarbaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazinone;

Compound 26: 1-m-nitrobenzyl-5-methoxycarbonyl-3-indolecarbaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazinone;

Compound 27: 1-p-chlorobenzyl-6-methoxycarbonyl-3-indolecarbaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazinone;

Compound 28: 1-p-fluorobenzyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazinone;

Compound 29: 1-p-methoxycarbonylbenzyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazinone;

Compound 30: 1-m-methoxycarbonylbenzyl-6-methoxycarbonyl-3-indolecarbaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazinone;

Compound 31: 1-p-nitrobenzyl-6-methoxycarbonyl-3-indolecarbaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazinone;

Compound 32: 1-m-nitrobenzyl-6-methoxycarbonyl-3-indolecarbaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazinone;

Compound 33: 1-benzoyl-5-methoxycarbonyl-3-indolecarbaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazinone;

Compound 34: 1-benzoyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazinone;

Compound 35: 1-benzenesulfonyl-5-(4-methoxycarbonylphenyl)-3-indolecarboxaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazinone;

Compound 36: 1-benzenesulfonyl-5-(3-methoxycarbonylphenyl)-3-indolecarboxaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazinone;

Compound 37: 1-benzenesulfonyl-5-(4-trifluoromethoxyphenyl)-3-indolecarbaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazinone;

Compound 38: 1-benzenesulfonyl-5-(3-trifluoromethoxyphenyl)-3-indolecarbaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazinone;

Compound 39: 1-benzenesulfonyl-5-(4-trifluoromethylphenyl)-3-indolecarbaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazinone;

Compound 40: 1-Benzenesulfonyl-5-(4-fluoro-3-chlorophenyl)-3-indolecarbaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazinone.

The present invention also provides a kind of salt of indole compound, it is characterized in that:

The salt is the salt (III, IV) obtained by reacting any one of the above-mentioned indole compounds with an inorganic acid or an organic acid, and its structure is shown as:

Among them, HA is an inorganic acid or some organic acids with strong acidity;

And the definition of X, R ₁ , R ₂ is the same as that mentioned above:

X is methylene, carbonyl or sulfonyl;

R1 is fluorine, chlorine, bromine, methoxyl, nitro or hydrogen;

R2 is methoxyl, (p-methoxyl) phenyl, (p-trifluorooxy) phenyl, (p-trifluoro) phenyl, (m-methoxyl) phenyl, (m-trifluorooxy) Phenyl, (p-fluoro-m-chloro)phenyl or hydrogen.

Further in order to obtain better bacteriostasis and bactericidal effect, wherein R is preferably p _- chloro, p-bromo, p-fluoro, p-methoxyl, p-nitrobenzyl, m-methoxyl, m-nitrogen base.

Further in order to obtain better bacteriostasis and bactericidal effect, wherein R2 is preferably ₅ -methoxyacyl, 6-methoxyacyl, 5-(p-methoxyacyl) phenyl, 5-(p-trifluorooxy ) phenyl, 5-(p-trifluoro)phenyl, 5-(m-methoxyl)phenyl, 5-(m-trifluorooxy)phenyl, 5-(p-fluorom-chloro)phenyl.

Further, for the preparation process and use effect, the inorganic acid is any one of sulfuric acid, phosphoric acid, hydrochloric acid, and hydrobromic acid, and the organic acid is sulfonic acid.

The salts of indole compounds provided by the present invention are preferably hydrochloride or hydrogen bromide salts, and their corresponding X, R ₁ , R ₂ and compound numbers are shown in Table 3 and Table 4 below.

Table 3 Compounds of general formula III

The salt name of above-mentioned general formula III indole compound is:

Compound 41: 2-[(1-p-chlorobenzyl-5-methoxycarbonyl-3-indole)methylene]aminoguanidine hydrochloride;

Compound 42: 2-[(1-p-fluorobenzyl-5-methoxycarbonyl-3-indole)methylene]aminoguanidine hydrochloride;

Compound 43: 2-[(1-p-methoxycarbonylbenzyl-5-methoxycarbonyl-3-indole)methylene]aminoguanidine hydrochloride;

Compound 44: 2-[(1-m-methoxycarbonylbenzyl-5-methoxycarbonyl-3-indole)methylene]aminoguanidine hydrochloride;

Compound 45: 2-[(1-p-nitrobenzyl-5-methoxycarbonyl-3-indole)methylene]aminoguanidine hydrochloride;

Compound 46: 2-[(1-m-nitrobenzyl-5-methoxycarbonyl-3-indole)methylene]aminoguanidine hydrochloride;

Compound 47: 2-[(1-p-chlorobenzyl-6-methoxycarbonyl-3-indole)methylene]aminoguanidine hydrochloride;

Compound 48: 2-[(1-p-fluorobenzyl-6-methoxycarbonyl-3-indole)methylene]aminoguanidine hydrochloride;

Compound 49: 2-[(1-p-methoxycarbonylbenzyl-6-methoxycarbonyl-3-indole)methylene]aminoguanidine hydrochloride;

Compound 50: 2-[(1-m-methoxycarbonylbenzyl-6-methoxycarbonyl-3-indole)methylene]aminoguanidine hydrochloride;

Compound 51: 2-[(1-p-nitrobenzyl-6-methoxycarbonyl-3-indole)methylene]aminoguanidine hydrochloride;

Compound 52: 2-[(1-m-nitrobenzyl-6-methoxycarbonyl-3-indole)methylene]aminoguanidine hydrochloride;

Compound 53: 2-[(1-benzoyl-5-methoxycarbonyl-3-indole)methylene]aminoguanidine hydrochloride;

Compound 54: 2-[(1-benzoyl-6-methoxycarbonyl-3-indole)methylene]aminoguanidine hydrochloride;

Compound 55: 2-[(1-Benzenesulfonyl-5-(4-methoxycarbonylphenyl)-3-indole)methylene]aminoguanidine hydrochloride;

Compound 56: 2-[(1-Benzenesulfonyl-5-(3-methoxycarbonylphenyl)-3-indole)methylene]aminoguanidine hydrochloride;

Compound 57: 2-[(1-Benzenesulfonyl-5-(4-trifluoromethoxyphenyl)-3-indole)methylene]aminoguanidine hydrochloride;

Compound 58: 2-[(1-Benzenesulfonyl-5-(3-trifluoromethoxyphenyl)-3-indole)methylene]aminoguanidine hydrochloride;

Compound 59: 2-[(1-Benzenesulfonyl-5-(4-trifluoromethylphenyl)-3-indole)methylene]aminoguanidine hydrochloride;

Compound 60: 2-[(1-Benzenesulfonyl-5-(4-fluoro-3-chlorophenyl)-3-indole)methylene]aminoguanidine hydrochloride.

Table 4 General formula IV compound

The salt name of above-mentioned general formula IV indole compound is:

Compound 61: 1-p-chlorobenzyl-5-methoxycarbonyl-3-indolecarbaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazonone hydrogen bromide;

Compound 62: 1-p-fluorobenzyl-5-methoxycarbonyl-3-indolecarbaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazonone hydrogen bromide;

Compound 63: 1-p-methoxycarbonylbenzyl-5-methoxycarbonyl-3-indolecarbaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazonone hydrogen bromide;

Compound 64: 1-m-methoxycarbonylbenzyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazonone hydrogen bromide;

Compound 65: 1-p-nitrobenzyl-5-methoxycarbonyl-3-indolecarbaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazonone hydrogen bromide;

Compound 66: 1-m-nitrobenzyl-5-methoxycarbonyl-3-indolecarbaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazonone hydrogen bromide;

Compound 67: 1-p-chlorobenzyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazonone hydrogen bromide;

Compound 68: 1-p-fluorobenzyl-6-methoxycarbonyl-3-indolecarbaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazonone hydrogen bromide;

Compound 69: 1-p-methoxycarbonylbenzyl-6-methoxycarbonyl-3-indolecarbaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazonone hydrogen bromide;

Compound 70: 1-m-methoxycarbonylbenzyl-6-methoxycarbonyl-3-indolecarbaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazonone hydrogen bromide;

Compound 71: 1-p-nitrobenzyl-6-methoxycarbonyl-3-indolecarbaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazonone hydrogen bromide;

Compound 72: 1-m-nitrobenzyl-6-methoxycarbonyl-3-indolecarbaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazonone hydrogen bromide;

Compound 73: 1-benzoyl-5-methoxycarbonyl-3-indolecarbaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazonone hydrogen bromide;

Compound 74: 1-benzoyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazonone hydrogen bromide;

Compound 75: 1-Benzenesulfonyl-5-(4-methoxycarbonylphenyl)-3-indolecarboxaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazonone hydrogen bromide;

Compound 76: 1-Benzenesulfonyl-5-(3-methoxycarbonylphenyl)-3-indolecarboxaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazonone hydrogen bromide;

Compound 77: 1-Benzenesulfonyl-5-(4-trifluoromethoxyphenyl)-3-indolecarbaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazonohydrobromide Salt;

Compound 78: 1-Benzenesulfonyl-5-(3-trifluoromethoxyphenyl)-3-indolecarboxaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazonohydrobromide Salt;

Compound 79: 1-Benzenesulfonyl-5-(4-trifluoromethylphenyl)-3-indolecarbaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazonone hydrogen bromide salt ;

Compound 80: 1-Benzenesulfonyl-5-(4-fluoro-3-chlorophenyl)-3-indolecarboxaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazonohydrobromide Salt.

The present invention also provides an anti-drug-resistant bacteria pharmaceutical composition, characterized in that:

Wherein, the pharmaceutical composition contains the above-mentioned general formula I, II indole compound or the salt of the above-mentioned general formula III, IV indole compound and pharmaceutically acceptable auxiliary materials, the auxiliary materials include excipients, diluents, stabilizers and Flavoring agents, etc., are mixed according to conventional methods of pharmacy, and made into solid dosage forms such as tablets, capsules, granules, and powders, and liquid dosage forms such as syrups and oral liquids.

The doses of compounds I, II and their salts III and IV vary with the age, gender, and condition of patients. Generally, the dosage for adults can be 0.01-5000 mg/day, preferably 1-1000 mg/day, more preferably 5-500 mg/day.

The present invention also provides a kind of disinfectant, is used for disinfecting and sterilizing medical equipment or staff, it is characterized in that:

Wherein, the pharmaceutical composition contains the above-mentioned indole compound of general formula I, II or the salt of the above-mentioned indole compound of general formula III, IV and an appropriate solvent, such as water, ethanol or a mixed solvent thereof.

The concentration of compounds I, II and their salts III and IV in the disinfectant is related to the requirements of disinfection and sterilization. Generally, the disinfection of surgical instruments is a mass concentration of 0.05%-2.0%, preferably 0.1%-1.0%, more preferably 0.5% %-1.0%.

Application of the above general formula I, II indole compound or the salt of the above general formula III, IV indole compound in the preparation of anti-drug-resistant fungal drugs.

The method for preparing the salt of the indole compound of above-mentioned formula (III, IV) is characterized in that comprising will have the compound of general formula (V) and general formula (VI) to mix reaction in dry anhydrous polar solvent namely Obtain the salt of the indole compound of formula (III, IV); And the salt of the indole compound of formula (III, IV) can obtain the indole compound of formula (I, II) by adding alkali

in,

X, R ₁ , R ₂ , and HA have the same meanings as above;

That is, when X in the general formula (V) is different,

When X is a methylene group, the intermediate 1-(3- or 4-substituted benzyl)-3-formyl-5 (or 6)-methoxycarbonylindole (3) is prepared, and the reaction scheme is as follows:

When X is a carboxyl group, the intermediate 1-benzoyl-3-formyl-5 (or 6)-methoxycarbonylindole (4) is prepared, and the reaction scheme is as follows:

When X is a sulfonyl group, the intermediate 1-benzenesulfonyl-3-formyl-5-(3- or 4-substituted phenyl)indole (8) is prepared, and the reaction scheme is as follows:

Obtain above-mentioned intermediate 3,4,8 (being general formula V) after it is respectively reacted with the compound of general formula (VI) to obtain the compound in general formula (III, I)

Alkalinization Use NaOH solution for alkalization until the pH is above 10;

Compounds in general formula (IV, II) can be obtained in the same way.

The method for preparing the above-mentioned indole compound of formula (I, II) and the salt of the above-mentioned indole compound of formula (III, IV), wherein, the polar solvent is preferably methanol, ethanol, acetonitrile, N, Any one of N-dimethylformamide or its mixed solvent.

The method for preparing the above-mentioned indole compound of formula (I, II) and the salt of the above-mentioned indole compound of formula (III, IV), wherein the temperature of the mixing reaction is preferably room temperature or reflux temperature.

Pharmacological experiments of the compounds of the present invention

(1) Experimental manipulation

The 96-well microplate method was used to measure the antibacterial activity in vitro to obtain the minimum inhibitory concentration (MIC), and the blood plate coating method was used to determine the minimum bactericidal concentration (MBC).

(1) Experimental strains

In this experiment, the following four common human pathogenic strains were selected as test objects:

Staphylococcus aureus, drug-resistant Staphylococcus aureus, drug-resistant Klebsiella pneumoniae, drug-resistant Acinetobacter baumannii

(2) Experimental method: Determination of antibacterial activity of compounds in vitro

Cultivation of strains: A single colony grown on a trypticase soybean broth (TSB) plate was selected and inoculated in liquid TSB at 37°C, 200rpm. Cultivated for 18 hours to obtain a strain culture for subsequent determination of antibacterial activity.

The antibacterial activity assay method is: use a sterile 96-well plate to assay the antibacterial activity of the compound. For the initial screening of all strains, each compound was screened in parallel with 3 wells at a concentration of 100 μg/ml to obtain the initial antibacterial activity. The compounds with antibacterial activity at the concentration of 100 μg/ml were selected to further determine the minimum inhibitory concentration (MIC). Drugs diluted with 2-fold concentration medium (Tryptone Soy Broth, TSB) were added to each well respectively. Each positive compound obtained by synthesis was made into an initial solution of appropriate concentration, diluted with medium (2×) to double the concentration of each compound used, each positive compound had 12 gradients, 200 μl was added to each well of a 96-well plate, and each positive The final compound concentrations were: 100.0, 50.0, 25.0, 12.5, 6.3, 3.1, 1.6, 0.8, 0.4, 0.2, 0.1 and 0.05 μg/ml. The final concentrations of the 12 gradients of the control drug levofloxacin were: 64.0, 32.0, 16.0, 8.0, 4.0, 2.0, 1.0, 0.5, 0.25, 0.125, 0.063, 0.031 and 0.016 μg/ml. Then add a kind of bacteria S.aureus (ATCC 29213), MRSA, MDR K.pneumoniae and MDR A.baumanii, and measure the MIC of each bacterium for each compound. Inoculate 100 μl per well, the amount of bacteria per well is about 1×10 ⁵ cfu, and the final volume of each well is 200 μl. Each plate is equipped with 2 growth positive control wells without antibacterial drugs and 2 growth negative control wells with distilled water instead of medium. After the 96-well plate is covered, the surrounding area is sealed with scotch tape, and placed in a humid box at 37°C. nourish. The absorbance at 600nm at different time points of each well was measured with a microplate reader, and the time points were selected as 0, 24h and 48h, respectively. After 48 hours, the wells in which a clear difference was observed between the positive growth control well and the negative growth control well were spread on the blood agar plate, and 1% DMSO was used as a control. Thereby, the bactericidal situation of the drug is determined, and the minimum bactericidal concentration (MBC) is obtained.

(2) Experimental results

The results of the in vitro antibacterial test are shown in Table 5.

The minimum concentration of target compounds in vitro (MIC, unit μg/mL) in Table 5.

table 5

Note: S.aureus: Staphylococcus aureus; MRSA: drug-resistant Staphylococcus aureus; MDR K.pneumonia: drug-resistant Klebsiella pneumoniae; MDR A.baumanii: drug-resistant Acinetobacter baumannii; levofloxacin: levofloxacin; Vancomycin: vancomycin; -: no experiment was performed

Table 6 is a comparison of the minimum concentration values of antibacterial and bactericidal in vitro for some compounds (MIC and MBC, unit μg/mL).

Table 6

Note: MRSA: drug-resistant Staphylococcus aureus; MDR K.pneumonia: drug-resistant Klebsiella pneumoniae; MDRA.baumanii: drug-resistant Acinetobacter baumannii; Vancomycin: vancomycin; >: greater than or equal to 100 μg/ml ;-: No experiment performed

Invention function and effect

As can be seen from Tables 5 and 6, the salt (hydrochloride, hydrogen bromide) of the novel indole compounds of the present invention has good activity against drug-resistant bacteria, wherein compounds 41, 47, 55, 56, 57, 58, 61, 68, 75, 77, 78, 79 have much better in vitro antibacterial activity against drug-resistant bacteria than levofloxacin, especially compounds 41, 47, 61 are also effective against drug-resistant Klebsiella pneumoniae and drug-resistant Baumannii Bacillus also has superior antibacterial activity. Therefore, the compounds of the present invention and their salts can be used to prepare medicines against drug-resistant Staphylococcus aureus and other drug-resistant bacteria and disinfectants for medical appliances.

detailed description

In order to make the technical means, creative features, goals and effects of the present invention easy to understand, the following examples describe the compounds of the present invention, the preparation of compound salts, their medicinal uses and pharmaceutical dosage forms in detail.

Embodiment 1 general formula III, the preparation of I compound

Preparation of intermediate 1-(3- or 4-substituted benzyl)-3-formyl-5(or 6)-methoxycarbonylindole 3 in general formula V

Preparation of 3-formyl-5(or 6)-methoxycarbonylindole (2)

5 (or 6)-methoxycarbonylindole (1) reacts with phosphorus oxychloride (POCl ₃ ) under the condition of dry N, N-dimethyl sulfoxide to generate 3-formyl- 5(or 6)-methoxycarbonylindole (2)

Preparation of 3-formyl-5 (or 6)-methoxycarbonylindole (2) manipulation example

Preparation of 3-formyl-5-methoxycarbonylindole

Under nitrogen protection, 5.00 g (28.57 mmol) of methyl indole-5-carboxylate was added to 20 mL of ultra-dry DMF, cooled to 0°C, and then 3.62 mL (38.86 mol) of phosphorus oxychloride was slowly added dropwise. After reacting at 0°C for 10 min, react at room temperature for 3 h. After cooling the reaction liquid to 0°C, add 60 mL of water to quench the reaction, then adjust the pH of the reaction liquid to 10 with 2M NaOH aqueous solution, continue stirring for 5 min, then heat to 70°C for 30 min. The reaction solution was cooled to room temperature, filtered under reduced pressure, and the filter cake was washed with water and methanol respectively to obtain a pale pink solid with a yield of 89%, mp231.4-233.0°C; ¹ H-NMR (400MHz, DMSO): 12.44 (brs, 1H, NH), 9.98 (s, 1H, CHO), 8.77 (d, J = 1.2, 1H, Ar-H), 8.44 (s, 1H, Ar-H), 7.88 (dd, J ₁ =8.4, J ₂ = 1.6, 1H, Ar-H), 7.61 (d, J = 8.8, 1H, Ar-H), 3.87 (s, 3H, CH ₃ ); ES-MS 204.1 (M+H) ⁺ .

3-formyl-5 (or 6)-methoxycarbonylindole (2) reacts with substituted benzyl bromide in the presence of sodium hydride to generate (3)

Preparation of 1-(3- or 4-substituted benzyl)-3-formyl-5(or 6)-methoxycarbonylindole (3) manipulation example

Preparation of 1-p-chlorobenzyl-3-formyl-5-methoxycarbonylindole

Under nitrogen protection, 0.50 g (2.46 mmol) of 3-formyl-5-methoxycarbonylindole was added to 8 mL of ultra-dry DMSO, then 0.11 g (2.71 mmol) of sodium hydride was added, and the reaction was carried out at room temperature for 1 h. 0.56 g (2.71 mmol) of p-chlorobenzyl bromide was added to the reaction liquid, and reacted at room temperature for 10 h. After the reaction, 20 mL of saturated ammonium chloride solution was added to the reaction solution, and extracted with dichloromethane (150 mL×3), the organic layer was washed with saturated aqueous sodium chloride solution and water, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to obtain The crude product was subjected to column chromatography with dichloromethane as the eluent to obtain 0.42g of white solid, the yield was 52%, mp160.2-160.7°C; ¹ H-NMR (400MHz, CDCl ₃ ): 10.06(s, 1H , CHO), 9.03 (s, 1H, Ar-H), 8.02 (dd, J ₁ =8.4, J ₂ =1.6, 1H, Ar-H), 7.78 (s, 1H, Ar-H), 7.35 (d , J=8.4, 2H, Ar-H), 7.33 (d, J=8.4, 1H, Ar-H), 7.10-7.12 (d, J=8.4, 2H, Ar-H), 5.37 (s, 2H, CH ₂ ), 3.95 (s, 3H, CH ₃ ); ES-MS 328.1 (M+H) ⁺ .

In the same way, intermediate 3 with different R1 and R2 substituents can be prepared:

When preparing 1-p-fluorobenzyl-3-formyl-5-methoxycarbonylindole, 3-formyl-5-methoxycarbonylindole and p-fluorobenzyl bromide are used as raw materials, and the method is the same as above. The yield is 96%, mp 153.3-153.9°C; ¹ H-NMR (400MHz, CDCl ₃ ): 10.05(s, 1H, CHO), 9.02(s, 1H, Ar-H), 8.03(dd, J ₁ =8.8, J ₂ =1.6, 1H, Ar-H), 7.77 (s, 1H, Ar-H), 7.35 (d, J=8.4, 1H, Ar-H), 7.17 (dd, J ₁ =8.8, J ₂ =5.2, 2H, Ar-H), 7.06(t, J=8.8, 2H, Ar-H), 5.36(s, 2H, CH ₂ ), 3.94(s, 3H, CH ₃ ); ES-MS312 .1(M+H) ⁺ .

When preparing 1-p-methoxycarbonylbenzyl-3-formyl-5-methoxycarbonylindole, 3-formyl-5-methoxycarbonylindole and p-methoxycarbonylbenzyl bromide are used as raw materials, and the method is the same as above. The yield is 92%, mp203.6-204.0°C; ¹ H-NMR (400MHz, CDCl ₃ ): δ10.06 (s, 1H, CHO), 9.03 (d, J=1.2, 1H, Ar-H), 8.03 (d, J = 8.4, 2H, Ar-H), 8.00 (dd, J ₁ = 8.8, J ₂ = 1.6, 1H, Ar-H), 7.81 (s, 1H, Ar-H), 7.30 (d , J=8.8, 1H, Ar-H), 7.21(d, J=8.4, 2H, Ar-H), 5.46(s, 2H, CH ₂ ), 3.94(s, 3H, CH ₃ ), 3.91(s , 3H, CH ₃ ); ES-MS 352.1 (M+H) ⁺ .

When preparing 1-m-methoxycarbonylbenzyl-3-formyl-5-methoxycarbonylindole, 3-formyl-5-methoxycarbonylindole and m-methoxycarbonylbenzyl bromide are used as raw materials, and the method is the same as above. The yield is 91%, mp 148.6-149.3°C; ¹ H-NMR (400MHz, CDCl ₃ ): 10.06 (s, 1H, CHO), 9.03 (d, J=1.2, 1H, Ar-H), 8.02( dd, J ₁ =8.8, J ₂ =1.2, 2H, Ar-H), 7.94(s, 1H, Ar-H), 7.80(s, 1H, Ar-H), 7.44(t, J=8.0, 1H , Ar-H), 7.34 (d, J=8.8, 1H, Ar-H), 7.31 (d, J=8.0, 1H, Ar-H), 5.44 (s, 2H, CH ₂ ), 3.94 (s, 3H, CH ₃ ), 3.91 (s, 3H, CH ₃ ); ES-MS 352.1 (M+H) ⁺ .

When preparing 1-p-nitrobenzyl-3-formyl-5-methoxycarbonylindole, 3-formyl-5-methoxycarbonylindole and p-nitrobenzyl bromide are used as raw materials, and the method is the same as above. Yield: 86%, mp219.2-219.6°C; ¹ H-NMR (400MHz, DMSO): 10.01(s, 1H, CHO), 8.80(d, J=1.2, 1H, Ar-H), 8.66(s , 1H, Ar-H), 8.21 (d, J=8.8, 2H, Ar-H), 7.88 (dd, J ₁ =8.4, J ₂ =1.6, 1H, Ar-H), 7.69 (d, J= 8.4, 1H, Ar-H), 7.51 (d, J = 8.8, 2H, Ar-H), 5.79 (s, 2H, CH ₂ ), 3.87 (s, 3H, CH ₃ ); ES-MS 339.1 (M +H) ⁺ .

When preparing 1-m-nitrobenzyl-3-formyl-5-methoxycarbonylindole, 3-formyl-5-methoxycarbonylindole and m-nitrobenzyl bromide are used as raw materials, and the method is the same as above. The yield is 71%, mp 190.9-193.9°C; ¹ H-NMR (400MHz, CDCl ₃ ): 10.09(s, 1H, CHO), 9.04(s, 1H, Ar-H), 8.21(d, J= 8.4, 1H, Ar-H), 8.11 (s, 1H, Ar-H), 8.03 (dd, J ₁ =8.8, J ₂ =1.6, 1H, Ar-H), 7.85 (s, 1H, Ar-H ), 7.55 (t, J=8.0, 1H, Ar-H), 7.41 (d, J=8.0, 1H, Ar-H), 7.30 (d, J=8.8Hz, 1H, Ar-H), 5.52 ( s, 2H, CH ₂ ), 3.95 (s, 3H, CH ₃ ); ES-MS 339.1 (M+H) ⁺ .

When preparing 1-p-chlorobenzyl-3-formyl-6-methoxycarbonylindole, 3-formyl-6-methoxycarbonylindole and p-chlorobenzyl bromide are used as raw materials, and the method is the same as above. The yield is 64%, mp 153.1-154.2°C; ¹ H-NMR (400MHz, CDCl ₃ ): 10.03 (s, 1H, CHO), 8.36 (d, J=8.0, 1H, Ar-H), 8.09( s, 1H, Ar-H), 8.02 (dd, J ₁ =8.4, J ₂ =1.6, 1H, Ar-H), 7.82 (s, 1H, Ar-H), 7.35 (d, J = 8.4, 2H , Ar-H), 7.12-7.14 (d, J=8.4, 2H, Ar-H), 5.40 (s, 2H, CH ₂ ), 3.94 (s, 3H, CH ₃ ); ES-MS328.1 (M +H) ⁺ .

When preparing 1-p-fluorobenzyl-3-formyl-6-methoxycarbonylindole, 3-formyl-6-methoxycarbonylindole and p-fluorobenzyl bromide are used as raw materials, and the method is the same as above. The yield is 56%, mp 155.6-155.7°C; ¹ H-NMR (400MHz, CDCl ₃ ): 10.03 (s, 1H, CHO), 8.35 (d, J=8.4, 1H, Ar-H), 8.11( s, 1H, Ar-H), 8.01 (dd, J ₁ =8.4, J ₂ =1.6, 1H, Ar-H), 7.81 (s, 1H, Ar-H), 7.20 (dd, J ₁ =8.8, J ₂ =5.2, 2H, Ar-H), 7.07 (t, J = 8.4, 2H, Ar-H), 5.40 (s, 2H, CH ₂ ), 3.94 (s, 3H, CH ₃ ); ES-MS 312.1(M+H) ⁺ .

When preparing 1-p-methoxycarbonylbenzyl-3-formyl-6-methoxycarbonylindole, 3-formyl-6-methoxycarbonylindole and p-methoxycarbonylbenzyl bromide are used as raw materials, and the method is the same as above. The yield is 58%, mp 169.9-171.1°C; ¹ H-NMR (400MHz, CDCl ₃ ): 10.05(s, 1H, CHO), 8.37(d, J=8.0, 1H, Ar-H), 8.07( s, 1H, Ar-H), 8.03 (d, J=8.4, 2H, Ar-H), 8.01-8.03 (dd, J ₁ =8.4, J ₂ =1.2, 1H, Ar-H), 7.85 (s , 1H, Ar-H), 7.23(d, J=8.4Hz, 2H, Ar-H), 5.50(s, 2H, CH ₂ ), 3.93(s, 3H, CH ₃ ), 3.91(s, 3H, CH ₃ ); ES-MS 352.1 (M+H) ⁺ .

When preparing 1-m-methoxycarbonylbenzyl-3-formyl-6-methoxycarbonylindole, 3-formyl-6-methoxycarbonylindole and m-methoxycarbonylbenzyl bromide are used as raw materials, and the method is the same as above. The yield is 56%, mp 141.2-141.7°C; ¹ H-NMR (400MHz, CDCl ₃ ): 10.03 (s, 1H, CHO), 8.36 (d, J=8.0, 1H, Ar-H), 8.10( s, 1H, Ar-H), 8.02 (d, J = 8.0, 1H, Ar-H), 8.01 (dd, J ₁ = 8.0, J ₂ = 1.6, 1H, Ar-H), 7.94 (s, 1H , Ar-H), 7.84(s, 1H, Ar-H), 7.45(t, J=7.6, 1H, Ar-H), 7.34(d, J=7.6, 1H, Ar-H), 5.47(s , 2H, CH ₂ ), 3.93 (s, 3H, CH ₃ ), 3.91 (s, 3H, CH ₃ ); ES-MS 352.1 (M+H) ⁺ .

When preparing 1-p-nitrobenzyl-3-formyl-6-methoxycarbonylindole, 3-formyl-6-methoxycarbonylindole and p-nitrobenzyl bromide are used as raw materials, and the method is the same as above. The yield is 80%, mp 184.5-184.9°C; ¹ H-NMR (400MHz, CDCl ₃ ): 10.08 (s, 1H, CHO), 8.39 (d, J=8.0, 1H, Ar-H), 8.22( d, J=8.8, 2H, Ar-H), 8.02-8.04 (m, 2H, Ar-H), 7.89 (s, 1H, Ar-H), 7.30 (d, J=8.8, 2H, Ar-H ), 5.56 (s, 2H, CH ₂ ), 3.93 (s, 3H, CH ₃ ); ES-MS 339.1 (M+H) ⁺ .

When preparing 1-m-nitrobenzyl-3-formyl-6-methoxycarbonylindole, 3-formyl-6-methoxycarbonylindole and m-nitrobenzyl bromide are used as raw materials, and the method is the same as above. The yield is 70%, mp 153.8-155.3°C; ¹ H-NMR (400MHz, CDCl ₃ ): 10.07 (s, 1H, CHO), 8.38 (d, J=8.4, 1H, Ar-H), 8.21( dd, J ₁ =8.4, J ₂ =1.2, 1H, Ar-H), 8.10 (s, 1H, Ar-H), 8.05 (s, 1H, Ar-H), 8.03 (dd, J ₁ =8.4, J ₂ =1.2, 1H, Ar-H), 7.89(s, 1H, Ar-H), 7.55(t, J=8.0, 1H, Ar-H), 7.42-7.44(d, J=8.0, 1H, Ar-H), 5.55 (s, 2H, CH ₂ ), 3.93 (s, 3H, CH ₃ ); ES-MS 339.1 (M+H) ⁺ .

Preparation of intermediate 1-benzoyl-3-formyl-5 (or 6)-methoxycarbonylindole in general formula V, i.e. intermediate 4

3-formyl-5 (or 6)-methoxycarbonylindole (2) reacts with benzoyl chloride in the presence of sodium hydride in DMF to generate 1-benzoyl-3-formyl-5 (or 6)- Methoxycarbonylindole (4)

Preparation of 1-benzoyl-3-formyl-5 (or 6)-methoxycarbonylindole (4) manipulation example

Preparation of 1-benzoyl-3-formyl-5-methoxycarbonylindole

Under the protection of argon, add 0.10 g (0.49 mmol) of 3-formyl-5-methoxycarbonylindole into 2 mL of ultra-dry DMF, and add 0.02 g (0.54 mmol) of sodium hydride after cooling to 0° C. Reaction 1h. Then the reaction solution was cooled to 0°C, 0.07 mL (0.54 mmol) of benzoyl chloride was added dropwise, and the reaction was carried out at room temperature overnight. After the reaction, the reaction solution was poured into 100 mL of water and left to stand, and the crude product was obtained by suction filtration under reduced pressure. After column chromatography, the eluent was ethyl acetate:petroleum ether=1:8 (V:V), and a white solid 0.11 g, the yield is 71%. mp172.7-173.3°C; ¹ H-NMR (400MHz, CDCl ₃ ): 10.10(s, 1H, CHO), 9.00(d, J=1.2, 1H, Ar-H), 8.35(d, J=8.8, 1H, Ar-H), 8.18 (dd, J ₁ =8.8, J ₂ =1.6, 1H, Ar-H), 8.03 (s, 1H, Ar-H), 7.81-7.79 (m, 2H, Ar-H ), 7.71 (t, J=7.6, 1H, Ar-H), 7.61 (t, J=7.6, 2H, Ar-H), 3.98 (s, 3H, CH ₃ ); ES-MS 308.1 (M+H ) ⁺ .

In the same way, intermediate 4 with different R1 and R2 substituents can be prepared:

When preparing 1-benzoyl-3-formyl-6-methoxycarbonylindole, 3-formyl-6-methoxycarbonylindole is used as raw material, and the method is the same as above. The yield is 66%, mp 176.1-176.4°C; ¹ H-NMR (400MHz, CDCl ₃ ): 10.09 (s, 1H, CHO), 9.00 (s, 1H, Ar-H), 8.38 (d, J= 8.0, 1H, Ar-H), 8.15 (dd, J ₁ =8.4, J ₂ =1.2, 1H, Ar-H), 8.08 (s, 1H, Ar-H), 7.81-7.79 (m, 2H, Ar -H), 7.73 (t, J=7.6, 1H, Ar-H), 7.62 (t, J=7.6, 2H, Ar-H), 3.97 (s, 3H, CH ₃ ); ES-MS 308.1 (M +H) ⁺ .

Preparation of intermediate 1-benzenesulfonyl-3-formyl-5-(3- or 4-substituted phenyl) indole in general formula V, i.e. intermediate (8)

Preparation of 3-formyl-5-bromoindole (6)

The Vilsmeier-Hack reaction of 5-bromoindole (5) with phosphorus oxychloride (POCl ₃ ) in dry N,N-dimethylsulfoxide produces 3-formyl-5-bromoindole (6 )

Preparation of 3-formyl-5-bromoindole (6) manipulation example

Under nitrogen protection, 5.00 g (25.5 mmol) of 5-bromoindole was added to ultra-dry DMF (20 ml), cooled to 0° C., and then 3.22 ml (34.68 mol) of phosphorus oxychloride was slowly added dropwise. After reacting at 0°C for 10 min, turn to room temperature and react for 3 h. After cooling the reaction liquid to 0°C, add water (100ml) to quench the reaction, then adjust the pH of the reaction liquid to 8-9 with 2M NaOH aqueous solution, continue stirring for 5 min, then heat to 70°C for 30 min. The reaction solution was cooled to room temperature, and suction-filtered under reduced pressure to obtain a filter cake. After drying, 5.19 g of a white solid was obtained, with a yield of 99%. mp203.5-204.3°C; ¹ H-NMR (400MHz, DMSO): 12.28(s, 1H, NH), 9.93(s, 1H, CHO), 8.35(s, 1H, Ar-H), 8.21(d, J=2.0, 1H, Ar-H), 7.49 (d, J=8.4, 1H, Ar-H), 7.43 (dd, J ₁ =8.8, J ₂ =2.0, 1H, Ar-H); ES-MS 225.1(M+H) ⁺ .

Preparation of 1-benzenesulfonyl-3-formyl-5-bromoindole (7)

3-formyl-5-bromoindole (6) reacts with benzenesulfonyl chloride under the action of sodium hydride to generate 1-benzenesulfonyl-3-formyl-5-bromoindole (7)

Preparation of 1-benzenesulfonyl-3-formyl-5-bromoindole (7) manipulation example

Under the protection of nitrogen, 2.00 g (8.8807 mmol) of 3-formyl-5-methoxycarbonylindole was added to 15 ml of ultra-dry DMSO, and then 0.392 g (9.7706 mmol) of sodium hydride was added to react at room temperature for 1 h. 1.883 g (10.664 mmol) of benzenesulfonyl chloride was added to the reaction liquid, and reacted at room temperature for 18 h. After the reaction, 100ml of saturated ammonium chloride solution was added to the reaction solution, and extracted with dichloromethane (200ml×3), the organic layer was washed with saturated aqueous sodium chloride solution and water, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to obtain The crude product was recrystallized from acetone/n-hexane to obtain 2.675 g of white solid with a yield of 83%. mp235.2-239.3°C; ¹ H-NMR (400MHz, DMSO): 10.06(s, 1H, CHO), 8.96(s, 1H, Ar-H), 8.22(d, J=2.0, 1H, Ar-H ), 8.14-8.12 (m, 2H, Ar-H), 7.95 (d, J=8.8, 1H, Ar-H), 7.81-7.77 (m, 1H, Ar-H), 7.69-7.65 (m, 2H , Ar-H), 7.62 (dd, J ₁ =8.8, J ₂ =2.0, 1H, Ar-H); ES-MS 365.2 (M+H) ⁺ .

Preparation of 1-benzenesulfonyl-3-formyl-5-(3- or 4-substituted phenyl) indole as intermediate (8)

1-Benzenesulfonyl-3-formyl-5-bromoindole (7) and substituted phenylboronic acid in [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd( dppf)Cl ₂ ) catalyzed by Suzuki reaction to generate 1-benzenesulfonyl-3-formyl-5-(3- or 4-substituted phenyl)indole (8)

Preparation of 1-benzenesulfonyl-3-formyl-5-(3- or 4-substituted phenyl) indole (8) manipulation example

Preparation of 1-benzenesulfonyl-3-formyl-5-p-methoxycarbonylphenylindole

Add 0.5g (1.37mmol) of 1-benzenesulfonyl-3-formyl-5-bromoindole to 10mlTHF and 10ml water, then add 0.28g (2.055mmol) of potassium carbonate and 0.24g of p-methoxycarbonylphenylboronic acid (1.64mmol), 1,1′-bis(di-tert-butylphosphino)ferrocenedichloropalladium 8.9mg (0.0137mmol), heated to 60°C and stirred for 8h. After the reaction was completed, it was extracted with ethyl acetate (100ml×3), dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to obtain a crude product. After column chromatography, the eluent was ethyl acetate/petroleum ether to obtain 0.62 g of a white solid. The rate is 86%. mp166.5-166.8°C; ¹ H-NMR (400MHz, CDCl ₃ ): 10.13 (s, 1H, CHO), 8.52 (d, J=2.0, 1H, Ar-H), 8.27 (s, 1H, Ar- H), 8.11 (d, J=8.4, 2H, Ar-H), 8.04 (d, J=8.8, 1H, Ar-H), 8.02-7.99 (m, 2H, Ar-H), 7.70-7.63 ( m, 4H, Ar-H), 7.57-7.53 (m, 2H, Ar-H), 3.94 (s, 3H, OCH ₃ ); ES-MS 420.5 (M+H) ⁺ .

In the same way, intermediates 8 with different R1 and R2 substituents can be prepared:

The preparation of 1-benzenesulfonyl-3-formyl-5-m-methoxycarbonylphenylindole is to use 1-benzenesulfonyl-3-formyl-5-bromoindole as raw material, the method is the same as above, and the yield is 53 %. mp186.8-187.1°C; 1H NMR (400MHz, CDCl ₃ ): 10.13 (s, 1H, CHO), 8.50 (d, J=1.6, 1H, Ar-H), 8.28-8.27 (m, 2H, Ar- H), 8.05-7.99 (m, 4H, Ar-H), 7.83-7.80 (m, 1H, Ar-H), 7.69 (dd, J ₁ =8.8, J ₂ =2.0, 1H, Ar-H), 7.66-7.63 (m, 1H, Ar-H), 7.57-7.50 (m, 3H, Ar-H), 3.95 (s, 3H, OCH ₃ ); ES-MS 420.5 (M+H) ⁺ .

The preparation of 1-benzenesulfonyl-3-formyl-5-p-trifluorooxyphenylindole is to use 1-benzenesulfonyl-3-formyl-5-bromoindole as raw material, the method is the same as above, and the yield is 89 %. mp180.4-181.3°C; 1H NMR (400MHz, DMSO): 10.12 (s, 1H, CHO), 8.98 (s, 1H, Ar-H), 8.34 (d, J=1.6, 1H, Ar-H), 8.18-8.16 (m, 2H, Ar-H), 8.07 (d, J=8.8, 1H, Ar-H), 7.80-7.75 (m, 2H, Ar-H), 7.69-7.65 (m, 3H, Ar -H), 7.61-7.57 (m, 2H, Ar-H), 7.37 (d, J=8.4, 1H, Ar-H); ES-MS 446.4 (M+H) ⁺ .

The preparation of 1-benzenesulfonyl-3-formyl-5-m-trifluorooxyphenylindole is to use 1-benzenesulfonyl-3-formyl-5-bromoindole as raw material, the method is the same as above, and the yield is 74 %. mp150.4-151.0℃; 1H-NMR (400MHz, DMSO): δ10.12(s, 1H, CHO), 8.98(s, 1H, Ar-H), 8.33(d, J=1.6, 1H, Ar- H), 8.18-8.16 (m, 2H, Ar-H), 8.07 (d, J=8.8, 1H, Ar-H), 7.78-7.74 (m, 4H, Ar-H), 7.70-7.66 (m, 2H, Ar-H), 7.45 (d, J=8.0, 2H, Ar-H); ES-MS 446.4 (M+H) ⁺ .

The preparation of 1-benzenesulfonyl-3-formyl-5-p-trifluorophenylindole is to use 1-benzenesulfonyl-3-formyl-5-bromoindole as raw material, the method is the same as above, and the yield is 67% . mp216.5-216.8°C; ¹ H-NMR (400MHz, CDCl ₃ ): 10.13 (s, 1H, CHO), 8.50 (d, J=1.6, 1H, Ar-H), 8.28 (s, 1H, Ar- H), 8.05(d, J=8.8, 1H, Ar-H), 8.03-8.00(m, 2H, Ar-H), 7.74-7.68(m, 4H, Ar-H), 7.68-7.63(m, 2H, Ar-H), 7.58-7.53 (m, 2H, Ar-H); ES-MS 430.4 (M+H) ⁺ .

The preparation of 1-benzenesulfonyl-3-formyl-5-p-fluorom-chlorophenylindole is to use 1-benzenesulfonyl-3-formyl-5-bromoindole as raw material, the method is the same as above, and the yield is 83 %. mp171.1-171.6°C; 1H NMR (400MHz, CDCl ₃ ): δ10.12(s, 1H, CHO), 8.41(d, J=1.6, 1H, Ar-H), 8.27(s, 1H, Ar- H), 8.03-7.99 (m, 3H, Ar-H), 7.67-7.62 (m, 2H, Ar-H), 7.58-7.53 (m, 3H, Ar-H), 7.46 (ddd, J ₁ =8.6 , J ₂ =4.4, J ₃ =2.41H, Ar-H), 7.21 (t, J=8.6, 1H, Ar-H); ES-MS 414.9 (M+H) ⁺ .

After preparing the above-mentioned intermediates 3, 4, and 8, they can react with the salts in the general formula VI respectively

Preparation of target compound III

Intermediate (3) or (4) or (8) reacts with aminoguanidine hydrochloride VI at room temperature in dry methanol to generate target compound III

Preparation of 2-[(1-p-chlorobenzyl-5-methoxycarbonyl-3-indole) methylene]aminoguanidine hydrochloride (compound 41 in Table 7) manipulation example

Add 0.20 g (0.61 mmol) of 1-p-chlorobenzyl-3-formyl-5-methoxycarbonylindole to 5 mL of anhydrous methanol, then add 0.07 g (0.61 mmol) of aminoguanidine hydrochloride, and After adjusting the pH of the reaction solution to 3-4 with concentrated hydrochloric acid at room temperature, react at room temperature for 80 min. After the reaction was completed, ether was added to the reaction liquid and the solid precipitated out. The filter cake was filtered under reduced pressure, and the filter cake was washed with ether to obtain 0.22 g of a milky white solid with a yield of 87%. The experimental data of compound 41 and other compounds 42-60 are shown in Table 7.

Compounds 42-52 in Table 7 were prepared using intermediate (3) as raw material, and the method was the same as above.

Compounds 53 and 54 in Table 7 were prepared using intermediate (4) as raw material, and the method was the same as above.

Compounds 55-60 in Table 7 were prepared using intermediate (8) as raw material, and the method was the same as above.

Preparation of target compound I

Dissolve or suspend 0.5-1.0 g powder of the obtained target compound (III) in 5%-10% ice-cold NaOH solution, then add dichloromethane DCM solvent of 1 times the volume of NaOH solution and stir vigorously for 10-30 minutes to When the pH value of the upper aqueous phase solution was above 10 (granular NaOH solids could be added appropriately), the mixture was left to stand and separated, and the organic phase was extracted with 0.5 times the amount of DCM solvent, and concentrated to dryness under reduced pressure at a temperature of 30 degrees Celsius to obtain the target compound I.

Table 7 shows the R1, R2 and X group combination, yield and H NMR spectrum data of the target compound III, see Attached Table 7.

In the same way, such manipulation only changes aminoguanidine hydrochloride into sulfate, phosphate, hydrobromide or sulfonate, and the same reaction solvent is ethanol, acetonitrile, N,N-dimethylformamide DMF or The mixed solvent can obtain the corresponding sulfate, phosphate, hydrobromide or sulfonate of the corresponding target compound III.

Beneficial actions and effects of the present embodiment

The synthesis method of target compounds I and III provided in this example has simple steps, reaction at room temperature or under reflux conditions, separation by filtration, easy purification, high yield, easy manipulation, and is suitable for future industrial production.

Embodiment two general formula IV, the preparation of II compound

Preparation of target compound IV

Intermediate (3) or (4) or (8) respectively reacts with 4,5-dihydroimidazole-2-hydrazine hydrogen bromide VI in dry methanol to reflux the target compound IV;

Preparation of 1-p-chlorobenzyl-5-methoxycarbonyl-3-indolecarbaldehyde, (4,5-dihydro-1H-imidazol-2-yl)hydrazonone hydrogen bromide salt (compound 61 in Table 8) manipulation instance

0.05 g (0.15 mmol) of 1-p-chlorobenzyl-3-formyl-6-methoxycarbonylindole was added to 2 mL of anhydrous methanol, and then 4,5-dihydroimidazole-2-hydrazine was brominated 0.03 g (0.15 mmol) of hydrogen was added to the reaction solution, and heated to 75°C for reaction. After the reaction, the reaction solution was cooled to room temperature, and diethyl ether was added to stand still to precipitate a solid, which was filtered under reduced pressure, and the filter cake was washed with diethyl ether to obtain 0.07 g of a milky white solid, with a yield of 87%. The experimental data of compound 61 and other compounds 62-80 are shown in Table 8.

Compounds 62-72 in Table 8 were prepared using intermediate (3) as raw material, and the method was the same as above.

Compounds 73 and 74 in Table 8 were prepared using intermediate (4) as raw material, and the method was the same as above.

Compounds 75-80 in Table 8 were prepared using intermediate (8) as raw material, and the method was the same as above.

Preparation of Target Compound II

Dissolve or suspend 0.5-1.0 g powder of the obtained target compound IV in 5%-10% ice-cold NaOH solution, then add dichloromethane DCM solvent of 1 times the volume of NaOH solution and stir vigorously for 10-30 minutes to the upper layer When the pH value of the aqueous phase solution was above 10 (granular NaOH solids could be added appropriately), the mixture was left to stand and separated, and the organic phase was extracted with 0.5 times the amount of DCM solvent, and concentrated to dryness under reduced pressure at a temperature of 30 degrees Celsius to obtain the target compound II.

Table 8 shows the combination of R1, R2 and X group of the target compound IV, the yield and 1H NMR spectrum data are shown in attached table 8.

In the same way, such manipulation only changes aminoguanidine hydrochloride into sulfate, phosphate, hydrobromide or sulfonate, and the same reaction solvent is ethanol, acetonitrile, N,N-dimethylformamide DMF or The mixed solvent can obtain the corresponding sulfate, phosphate, hydrobromide or sulfonate of the corresponding target compound IV.

Beneficial actions and effects of the present embodiment

The synthesis method of the target compounds II and IV provided in this example has simple steps, reacts at room temperature or under reflux conditions, and has high yields. The products are easy to extract, purify, and manipulate, and are suitable for future industrial production.

Embodiment 3 Preparation of sterile powder injection of compound of the present invention

1. Prescription:

Prescription 1:

Any one of 250g in compound III or IV (based on compound)

A total of 1000 sticks were prepared

Prescription 2:

Any one of compound III or IV 500g (based on compound)

A total of 1000 sticks were prepared

Prescription 3:

Any one of compound III or IV 1000g (calculated as compound)

A total of 1000 sticks were prepared

Prescription 4:

Any one of compound III or IV 2000g (based on compound)

A total of 1000 sticks were prepared

2. Preparation process:

(1) Aseptically process the antibiotic glass bottles, rubber stoppers, etc. used for the preparation;

(2) Weigh the raw materials according to the prescription (feeding after conversion), put the sterile powder in the filling machine for subpackaging, and check the loading at any time;

(3) Stoppering, capping, full inspection of finished products, packaging and storage.

Embodiment 4 Preparation of sterile freeze-dried powder injection of the compound of the present invention

1. Prescription:

Prescription 1:

2. Preparation process:

(1) The container is prepared, and the antibiotic vials, rubber stoppers, etc. used for the preparation are aseptically processed;

(2) Prepare the solution, weigh the raw materials according to the prescription (feeding after conversion), use 500-800ml water for injection to stir and dissolve in the container, and use 10% hydrochloric acid to adjust the solubility and pH value;

(3) Filter until half stoppered, filter the above-mentioned solution, subpackage, and half stopper;

(4) Freeze-drying, stoppering, capping, full inspection of finished products, packaging and storage.

Embodiment five The preparation of compound tablet of the present invention

1. Prescription:

Prescription 1:

Prescription 2:

2. Preparation process:

(1) Crushing the raw materials through a 100-mesh sieve, and passing the rest of the auxiliary materials through a 100-mesh sieve respectively, for subsequent use;

(2) Weigh raw materials and auxiliary materials according to the prescription quantity;

(3) dissolving hypromellose in water to make a 2% aqueous solution for subsequent use;

(4) Mix any one of compound I or II or III or IV of the present invention or B, pregelatinized starch, low-substituted hydroxypropyl cellulose, and microcrystalline cellulose evenly, add an appropriate amount of 2% HPMC aqueous solution, and stir evenly , made into a suitable soft material;

(5) cross 20 mesh sieves to make granules;

(6) The particles are dried at 60°C;

(7) Add magnesium stearate, micropowder silica gel and carboxymethyl starch sodium to the dried granules, pass through a 18-mesh sieve for granulation, and mix well;

(8) Sampling and testing of semi-finished products;

(9) Press the tablet according to the weight determined by the test;

(10) Full inspection of finished products, packaging and storage.

Embodiment 6 The preparation of compound disinfectant of the present invention

Dissolve the above-mentioned compound I or II or III or IV in a mixed solvent of ethanol and water to prepare a solution with a concentration of 0.5%-1.0%, and add appropriate preservatives and stabilizers (ethylene glycol, mannitol, etc.) .

Beneficial actions and effects of the present embodiment

The disinfectants of the target compounds I, II, III, and IV provided in this example are easy to produce and can be widely used in the disinfection and sterilization of surgical instruments in hospitals.

appendix

Table 7 R1 of target compound III, R2 and X group collocation, yield, melting point, NMR spectrum and mass spectrum data

Table 8 R1 of target compound IV, R2 and X group collocation, yield, melting point, NMR spectrum and mass spectrum data

Claims (10)

1. An indole compound has a chemical structure general formula as follows:

wherein,

x is methylene, carbonyl or sulfonyl;

R₁is fluorine, chlorine, bromine, methoxyacyl, nitro or hydrogen;

R₂is methoxyacyl, (p-methoxyacyl) phenyl, (p-methoxyacyl)Trifluorooxy) phenyl, (p-trifluorooxy) phenyl, (m-methoxyacyl) phenyl, (m-trifluorooxy) phenyl, (p-fluoro-m-chloro) phenyl or hydrogen.

2. The indole compound of claim 1, wherein:

wherein R is₁Is p-chloro, p-bromo, p-fluoro, p-methoxyacyl, p-nitro, m-methoxyacyl, m-nitro.

3. The indole compound of claim 1, wherein:

wherein R is₂5-methoxyacyl, 6-methoxyacyl, 5- (p-methoxyacyl) phenyl, 5- (p-trifluoroxy) phenyl, 5- (p-trifluoro-phenyl), 5- (m-methoxyacyl) phenyl, 5- (m-trifluoro-oxy) phenyl, 5- (p-fluoro-m-chloro) phenyl.

4. The indole compound of claim 1, wherein:

the compound is selected from:

2- [ (1-p-chlorobenzyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine;

2- [ (1-p-fluorophenylmethyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine;

2- [ (1-p-methoxycarbonylbenzyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine;

2- [ (1-m-methoxycarbonylbenzyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine;

2- [ (1-p-nitrobenzyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine;

2- [ (1-m-nitrobenzyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine;

2- [ (1-p-chlorobenzyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine;

2- [ (1-p-fluorophenylmethyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine;

2- [ (1-p-methoxycarbonylbenzyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine;

2- [ (1-m-methoxycarbonylbenzyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine;

2- [ (1-p-nitrobenzyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine;

2- [ (1-m-nitrobenzyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine;

2- [ (1-benzoyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine;

2- [ (1-benzoyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine;

2- [ (1-benzenesulfonyl-5- (4-methoxycarbonylphenyl) -3-indole) methylene ] aminoguanidine;

2- [ (1-benzenesulfonyl-5- (3-methoxycarbonylphenyl) -3-indole) methylene ] aminoguanidine;

2- [ (1-benzenesulfonyl-5- (4-trifluoromethoxyphenyl) -3-indole) methylene ] aminoguanidine;

2- [ (1-benzenesulfonyl-5- (3-trifluoromethoxyphenyl) -3-indole) methylene ] aminoguanidine;

2- [ (1-benzenesulfonyl-5- (4-trifluoromethylphenyl) -3-indole) methylene ] aminoguanidine;

2- [ (1-benzenesulfonyl-5- (4-fluoro-3-chlorophenyl) -3-indole) methylene ] aminoguanidine;

1-p-chlorobenzyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;

1-p-fluorobenzyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;

1-p-methoxycarbonylbenzyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;

1-m-methoxycarbonylbenzyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;

1-p-nitrobenzyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;

1-m-nitrobenzyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;

1-p-chlorobenzyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;

1-p-fluorobenzyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;

1-p-methoxycarbonylbenzyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;

1-m-methoxycarbonylbenzyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;

1-p-nitrobenzyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;

1-m-nitrobenzyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;

1-benzoyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone;

1-benzoyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone;

1-benzenesulfonyl-5- (4-methoxycarbonylphenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;

1-benzenesulfonyl-5- (3-methoxycarbonylphenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;

1-benzenesulfonyl-5- (4-trifluoromethoxyphenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;

1-benzenesulfonyl-5- (3-trifluoromethoxyphenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;

1-benzenesulfonyl-5- (4-trifluoromethylphenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;

1-benzenesulfonyl-5- (4-fluoro-3-chlorophenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone.

5. A salt of an indole compound characterized by:

the salts are salts (III, IV) obtained by reacting the indole compound of any one of claims 1 to 4 with an inorganic or organic acid, and the structures of the salts are shown as follows:

wherein,

x is methylene, carbonyl or sulfonyl;

R₁is fluorine, chlorine, bromine, methoxyacyl, nitro or hydrogen;

R₂is methoxyacyl, (p-methoxyacyl) phenyl, (p-trifluoroxy) phenyl, (m-methoxyacyl) phenyl, (m-trifluoroxy) phenyl, (p-fluoro-m-chloro) phenyl or hydrogen;

HA is an inorganic acid or an organic acid with strong partial acidity.

6. The salt of an indole compound of claim 5, wherein:

wherein, the inorganic acid is any one of sulfuric acid, phosphoric acid, hydrochloric acid and hydrobromic acid, and the organic acid is sulfonic acid.

7. The salt of an indole compound of claim 5, wherein:

selected from:

2- [ (1-p-chlorobenzyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;

2- [ (1-p-fluorophenylmethyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;

2- [ (1-p-methoxycarbonylbenzyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;

2- [ (1-m-methoxycarbonylbenzyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;

2- [ (1-p-nitrobenzyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;

2- [ (1-m-nitrobenzyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;

2- [ (1-p-chlorobenzyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;

2- [ (1-p-fluorophenylmethyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;

2- [ (1-p-methoxycarbonylbenzyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;

2- [ (1-m-methoxycarbonylbenzyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;

2- [ (1-p-nitrobenzyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;

2- [ (1-m-nitrobenzyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;

2- [ (1-benzoyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;

2- [ (1-benzoyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;

2- [ (1-benzenesulfonyl-5- (4-methoxycarbonylphenyl) -3-indole) methylene ] aminoguanidine hydrochloride;

2- [ (1-benzenesulfonyl-5- (3-methoxycarbonylphenyl) -3-indole) methylene ] aminoguanidine hydrochloride;

2- [ (1-benzenesulfonyl-5- (4-trifluoromethoxyphenyl) -3-indole) methylene ] aminoguanidine hydrochloride;

2- [ (1-benzenesulfonyl-5- (3-trifluoromethoxyphenyl) -3-indole) methylene ] aminoguanidine hydrochloride;

2- [ (1-benzenesulfonyl-5- (4-trifluoromethylphenyl) -3-indole) methylene ] aminoguanidine hydrochloride;

2- [ (1-benzenesulfonyl-5- (4-fluoro-3-chlorophenyl) -3-indole) methylene ] aminoguanidine hydrochloride;

1-p-chlorobenzyl-5-methoxycarbonyl-3-indolylal, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;

1-p-fluorobenzyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;

1-p-methoxycarbonylbenzyl-5-methoxycarbonyl-3-indolylal, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;

1-m-methoxycarbonylbenzyl-5-methoxycarbonyl-3-indolylal, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;

1-p-nitrobenzyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazonone hydrogen bromide;

1-m-nitrobenzyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazonone hydrogen bromide;

1-p-chlorobenzyl-6-methoxycarbonyl-3-indolylal, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;

1-p-fluorobenzyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;

1-p-methoxycarbonylbenzyl-6-methoxycarbonyl-3-indolylal, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;

1-m-methoxycarbonylbenzyl-6-methoxycarbonyl-3-indolylal, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;

1-p-nitrobenzyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazonone hydrogen bromide;

1-m-nitrobenzyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazonone hydrogen bromide;

1-benzoyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;

1-benzoyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;

1-benzenesulfonyl-5- (4-methoxycarbonylphenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;

1-benzenesulfonyl-5- (3-methoxycarbonylphenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;

1-benzenesulfonyl-5- (4-trifluoromethoxyphenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;

1-benzenesulfonyl-5- (3-trifluoromethoxyphenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;

1-benzenesulfonyl-5- (4-trifluoromethylphenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazonone hydrogen bromide;

1-benzenesulfonyl-5- (4-fluoro-3-chlorophenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazonone hydrogen bromide.

8. A process for the preparation of a salt of an indole of formula (iii, iv) as defined in any one of claims 5 to 7 and an indole of formula (I, II) as defined in any one of claims 1 to 4, which comprises reacting a compound of formula (v) with a compound of formula (vi) in a dry, anhydrous polar solvent to obtain a salt of an indole of formula (iii, iv); the indole compound of the formula (I, II) can be obtained by alkalifying the salt of the indole compound of the formula (III, IV) with alkali,

wherein,

x is methylene, carbonyl or sulfonyl;

R₁is fluorine, chlorine, bromine, methoxyacyl, nitro or hydrogen;

R₂is methoxyacyl, (p-methoxyacyl) phenyl, (p-trifluoroxy) phenyl, (m-methoxyacyl) phenyl, (m-trifluoroxy) phenyl, (p-fluoro-m-chloro) phenyl or hydrogen;

HA is an inorganic acid or an organic acid with strong partial acidity.

9. The process according to claim 8 for the preparation of the salts of indoles of formula (iii, iv) as claimed in any one of claims 5-7 and indoles of formula (I, II) as claimed in any one of claims 1-4, characterized in that:

wherein the polar solvent is any one or a mixed solvent of methanol, ethanol, acetonitrile and N, N-dimethylformamide,

the temperature of the mixing reaction is room temperature or reflux temperature.

10. An anti-drug-resistant bacteria pharmaceutical composition or disinfectant, characterized in that:

wherein the pharmaceutical composition or disinfectant comprises the indole compound according to any one of claims 1 to 4 or the salt of the indole compound according to any one of claims 5 to 7.