Heterocyclic sulfonamide / sulfonate derivative as well as preparation method and application thereof

Abstract

The invention discloses a heterocyclic sulfamide / sulfonate derivative and preparation and application thereof in the field of organic chemistry, the chemical structural general formula III of the heterocyclic sulfamide / sulfonate derivative is # imgabs0 #, and X is O or NH; r is one of a thiazole ring, an isoxazole ring, a quinoline ring, a coumarin ring, a benzothiadiazole ring and a benzofuran ring. The heterocyclic sulfamide / sulfonate derivative has remarkable antibacterial activity, and can be used for preparing a medicine for treating S.aureus, E.coli and MRSA (Methicillin Resistant Staphylococcus Aureus) infectious diseases. And meanwhile, the antibacterial agent can also be combined with other antibacterial active substances for use.

Description

Technical Field

[0001] The invention belongs to the field of organic chemistry, and specifically relates to a heterocyclic sulfonamide / sulfonate derivative and a preparation method and application thereof. Background Art

[0002] The extensive use of antimicrobial drugs has led to bacterial resistance and even the emergence of super bacteria, which has seriously affected the efficacy of antimicrobial drugs. The emergence of multi-drug resistant and super-resistant bacteria has seriously threatened human health and caused many infectious diseases to be unable to be completely cured clinically. Therefore, it is of great significance to develop novel antimicrobial drugs to address these worrying issues. Summary of the invention

[0003] The present invention aims to address the shortcomings of currently used antibiotics and provide a series of heterocyclic sulfonamide / sulfonate derivatives that can replace antibiotics in clinical medicine.

[0004] A heterocyclic sulfonamide / sulfonate derivative in this scheme has a chemical structure shown in Formula III:

[0005] Wherein, X is O or NH; R is one of a thiazole ring, an isoxazole ring, a quinoline ring, a coumarin ring, a benzothiadiazole ring, and a benzofuran ring.

[0006] Further, the compounds include IIIb, IIId, IIIe, IIIf, IIIg, IIIh, IIIj, IIIl, IIIm, IIIn, IIIo, and IIIp, and their structural formulas are as follows:

[0007]

[0008]

[0009] The heterocyclic sulfonamide / sulfonate derivatives of the present invention can be used as the sole active ingredient of an antibacterial drug or in combination with other antibacterial drugs or antibacterial active ingredients to prepare antibacterial drugs or drug compositions.

[0010] The heterocyclic sulfonamide / sulfonate derivative is used in preparing antibacterial drugs for bacterial infectious diseases.

[0011] Among them, the IIId, IIIe, IIIf, IIIg, IIIh, IIIl, IIIm, IIIn, IIIo, and IIIp have significant activity in resisting Staphylococcus aureus infection and can be used in the preparation of anti-Staphylococcus aureus drugs.

[0012] The IIIb, IIId, IIIe, IIIf, IIIg, IIIh, IIIj, IIIl, IIIm, IIIn, IIIo and IIIp have significant activity in resisting Escherichia coli infection and can be used in the preparation of anti-Escherichia coli drugs.

[0013] The IIId, IIIg, IIIh, IIIl, IIIn, IIIo and IIIp have significant activity in resisting methicillin-resistant Staphylococcus aureus infection and can be used in the preparation of anti-methicillin-resistant Staphylococcus aureus drugs.

[0014] The synthetic route of the heterocyclic sulfonamide / sulfonate derivatives of the present invention is as follows:

[0015]

[0016] Specifically, the preparation of the heterocyclic sulfonamide / sulfonate derivative comprises the following steps:

[0017] Preparation of intermediate I: 3-fluoro-4-morpholinoaniline, NaHCO3, acetone and distilled water are taken, benzyl chloroformate is slowly added dropwise at 0-5°C, the reaction is completed at 0-50°C, the acetone solvent is concentrated, filtered, washed, dried and added to the reaction bottle together with tetrahydrofuran, tert-butoxide lithium is added in multiple times at 0-5°C to react, (R)-epichlorohydrin is slowly added dropwise, the reaction is completed at 0-50°C, the solvent is concentrated, ice water is added and stirred, pH is adjusted to 7-8 with NH4Cl, extracted with ethyl acetate, the organic phases are combined, washed with saturated NaCl solution, dried with anhydrous Na2SO4, filtered, the solvent is concentrated, and silica gel column chromatography (V 乙酸乙酯 :V 石油醚 =1:3) separation and purification to obtain milky white crystals, add the milky white crystals, sodium acetate and 3mL dimethyl sulfoxide to the reaction bottle in sequence, react at 60-120°C, add ice water, stir, precipitate crystals, filter and dry to obtain a white solid, add the white solid, distilled water, acetone and Na2CO3 to the reaction bottle in sequence, react at 10-50°C, concentrate the solvent, extract with ethyl acetate, combine the organic phases, wash with saturated NaCl solution, dry with anhydrous Na2SO4, filter, concentrate the solvent, and use silica gel column chromatography (V 乙酸乙酯 :V 石油醚 =1:3) separation and purification to obtain intermediate I;

[0018] Preparation of intermediate II: 3-fluoro-4-morpholinoaniline, lithium trifluoromethanesulfonate, (R)-epichlorohydrin and isopropanol were added to a reaction flask in sequence, the reaction was completed at 20-60°C, the solvent was concentrated, ethyl acetate was added to dissolve, and then washed with saturated Na2CO3 solution and saturated NaCl solution respectively, dried over anhydrous Na2SO4, filtered, and the solvent was concentrated to obtain a yellow oil. The yellow oil, CaO and 2-methyltetrahydrofuran were added to the reaction flask, methyl chloroformate was slowly added at 0-5°C, the reaction was completed at 0-50°C, filtered, washed with saturated NaHCO3 solution and saturated NaCl solution in sequence, dried over anhydrous Na2SO4, filtered, the solvent was concentrated, and silica gel column chromatography (V 乙酸乙酯 :V石油醚 =1:3) separation and purification to obtain a light yellow oily substance, add the light yellow oily substance, ammonia water and methanol into a reaction bottle, react at 0-50°C until complete, concentrate the solvent, add dichloromethane, wash with saturated NaCl solution, dry with anhydrous Na2SO4, concentrate the solvent, and recrystallize to obtain intermediate II;

[0019] Preparation of compound III: Take intermediate I or intermediate II, sulfonyl chloride, anhydrous dichloromethane and triethylamine into a reaction tube in sequence, react at 20-40°C, track with thin layer chromatography, and after the reaction is completed, concentrate the solvent, separate and purify by silica gel column chromatography to obtain compound III. DETAILED DESCRIPTION

[0020] The present invention is further described below in conjunction with embodiments, but the present invention is not limited to the following embodiments. It can be foreseen that those skilled in the art may make various changes in the implementation in combination with the prior art.

[0021] The heterocyclic sulfonamide / sulfonate derivative shown in the general structural formula III of the present invention, Wherein, X is O or NH; R is one of a thiazole ring, an isoxazole ring, a quinoline ring, a coumarin ring, a benzothiadiazole ring, and a benzofuran ring.

[0022] This application cites the specific compounds shown in Table 1:

[0023] Table 1

[0024]

[0025]

[0026]

[0027] The preparation route of the heterocyclic sulfonamide / sulfonate derivative is as follows:

[0028]

[0029] The following is a detailed description of the preparation process using some compounds as examples:

[0030] Example 1: Preparation of Compound IIIg

[0031] Add 2.45 g (12.5 mmol) of 3-fluoro-4-morpholinoaniline, 1.26 g (15 mmol) of NaHCO3, 15 mL of acetone and 5 mL of distilled water into a 50 mL reaction bottle, slowly add 2.39 mL (17.5 mmol) of benzyl chloroformate dropwise at 0-5 °C, react at 30 °C, concentrate the solvent acetone, filter, wash and dry, and use the solid directly in the next reaction. Take 1.98g (6mmol) of the product from the previous step and 50mL of tetrahydrofuran and add them to a 100mL reaction bottle. Add 0.96g (12mmol) of lithium tert-butoxide in three portions at 0-5°C, stir to dissolve it, then slowly dropwise add 1.13mL (14.4mmol) (R)-epichlorohydrin, react at 30°C. After completion, concentrate the solvent, add 50mL of ice water and stir, adjust the pH to 7-8 with NH4Cl, extract with ethyl acetate, combine the organic phases, wash with saturated NaCl solution, dry with anhydrous Na2SO4, filter, concentrate the solvent, and perform silica gel column chromatography (V 乙酸乙酯 :V 石油醚 =1:3) separation and purification to obtain milky white crystals for the next reaction. In a 25mL reaction bottle, 0.21g (0.67mmol) of the milky white crystals obtained in the previous step, 0.08g (1mmol) of sodium acetate and 3mL of dimethyl sulfoxide (DMSO) were added in sequence, and the reaction was carried out at 100°C. After completion, 50mL of ice water was added, stirred, crystals were precipitated, filtered, and dried to obtain a white solid, which was directly used in the next reaction. In a 50mL reaction bottle, 0.62g (0.18mmol) of the white solid described in the previous step, 5mL of distilled water, 10mL of acetone and 0.14g (1.25mmol) of Na2CO3 were added in sequence, and the reaction was carried out at 30°C. After completion, the solvent was concentrated, extracted with ethyl acetate, the organic phases were combined, washed with saturated NaCl solution, dried with anhydrous Na2SO4, filtered, the solvent was concentrated, and silica gel column chromatography (V 乙酸乙酯 :V 石油醚 =1:1) to separate and purify to obtain a white solid, namely intermediate Ⅰ.

[0032] 0.45 mmol of intermediate I, 0.36 mmol of quinoline-8-sulfonyl chloride, 15 mL of anhydrous dichloromethane and 0.32 mL (7.5 mmol) of triethylamine were weighed into a 50 mL reaction tube and reacted at 20°C. TLC was used for tracking. After the reaction was completed, the solvent was concentrated and the silica gel column chromatography (V 石油醚 :V 乙酸乙酯 =3:1) to separate and purify to obtain compound IIIg.

[0033] Example 2: Preparation of Compound IIIn

[0034] In a 50 mL reaction bottle, 4.9 g (25 mmol) of 3-fluoro-4-morpholinoaniline, 3.9 g (25 mmol) of lithium trifluoromethanesulfonate, 2.30 g (30 mmol) (R)-epichlorohydrin and 25 mL of isopropanol were added in sequence and reacted at 20°C. After completion, the solvent was concentrated, 20 mL of ethyl acetate was added to dissolve, and then washed with saturated Na2CO3 solution and saturated NaCl solution respectively, dried over anhydrous Na2SO4, filtered, and the solvent was concentrated to obtain a yellow oil, which was directly used in the next step. Take 5.6g (19.6mmol) of the product from the previous step, 2.24g (40mmol) of CaO and 40mL of 2-methyltetrahydrofuran and add them into a 100mL reaction bottle, slowly add 2.1g (22mmol) of methyl chloroformate at 0-5°C, react at 10°C, filter, wash with saturated NaHCO3 solution and saturated NaCl solution in turn, dry with anhydrous Na2SO4, filter, concentrate the solvent, and use silica gel column chromatography (V 乙酸乙酯 :V 石油醚 =1:3) to separate and purify, and obtain a light yellow oily substance for the next reaction. Add 3.0 g (8.6 mmol) of the light yellow oily substance obtained in the previous step, 6 mL of ammonia water and 10 mL of methanol into a 50 mL reaction bottle, and react at 10°C. After completion, concentrate the solvent, add 20 mL of dichloromethane, wash with saturated NaCl solution, dry with anhydrous Na2SO4, concentrate the solvent, and recrystallize to obtain a white solid, namely Intermediate II.

[0035] 0.45 mmol of intermediate II, 0.36 mmol of benzo(1,2,5)thiazole-4-sulfonyl chloride, 15 mL of anhydrous dichloromethane and 0.32 mL (7.5 mmol) of triethylamine were weighed into a 50 mL reaction tube and reacted at 40 °C with thin layer chromatography. After the reaction was completed, the solvent was concentrated and the mixture was purified by silica gel column chromatography (V 石油醚 :V 乙酸乙酯 =3:1) to separate and purify to obtain compound IIIn.

[0036] Example 3: Preparation of Compound IIIo

[0037] In a 50 mL reaction bottle, 4.9 g (25 mmol) of 3-fluoro-4-morpholinoaniline, 3.9 g (25 mmol) of lithium trifluoromethanesulfonate, 2.30 g (30 mmol) (R)-epichlorohydrin and 25 mL of isopropanol were added in sequence and reacted at 25 °C. After completion, the solvent was concentrated, 20 mL of ethyl acetate was added to dissolve, and then washed with saturated Na2CO3 solution and saturated NaCl solution respectively, dried over anhydrous Na2SO4, filtered, and the solvent was concentrated to obtain a yellow oil, which was directly used in the next step. Take 5.6g (19.6mmol) of the product from the previous step, 2.24g (40mmol) of CaO and 40mL of 2-methyltetrahydrofuran and add them into a 100mL reaction bottle, slowly add 2.1g (22mmol) of methyl chloroformate at 0-5°C, react at 25°C, filter, wash with saturated NaHCO3 solution and saturated NaCl solution in turn, dry with anhydrous Na2SO4, filter, concentrate the solvent, and use silica gel column chromatography (V 乙酸乙酯 :V 石油醚 =1:3) to separate and purify, and obtain a light yellow oily substance for the next reaction. Add 3.0g (8.6mmol) of the light yellow oily substance obtained in the previous step, 6mL of ammonia water and 10mL of methanol into a 50mL reaction bottle, and react at 25°C. After completion, concentrate the solvent, add 20mL of dichloromethane, wash with saturated NaCl solution, dry with anhydrous Na2SO4, concentrate the solvent, and recrystallize to obtain a white solid, namely Intermediate II.

[0038] 0.45 mmol of intermediate II, 0.36 mmol of quinoline-8-sulfonyl chloride, 15 mL of anhydrous dichloromethane and 0.32 mL (7.5 mmol) of triethylamine were weighed into a 50 mL reaction tube and reacted at 30 °C with thin layer chromatography. After the reaction was completed, the solvent was concentrated and the silica gel column chromatography (V 石油醚 :V 乙酸乙酯 =3:1) to separate and purify to obtain compound IIIo.

[0039] Example 4: Preparation of Compound IIIp

[0040] In a 50 mL reaction bottle, 4.9 g (25 mmol) of 3-fluoro-4-morpholinoaniline, 3.9 g (25 mmol) of lithium trifluoromethanesulfonate, 2.30 g (30 mmol) (R)-epichlorohydrin and 25 mL of isopropanol were added in sequence and reacted at 20°C. After completion, the solvent was concentrated, 20 mL of ethyl acetate was added to dissolve, and then washed with saturated Na2CO3 solution and saturated NaCl solution respectively, dried over anhydrous Na2SO4, filtered, and the solvent was concentrated to obtain a yellow oil, which was directly used in the next step. Take 5.6 g (19.6 mmol) of the product from the previous step, 2.24 g (40 mmol) of CaO and 40 mL of 2-methyltetrahydrofuran and add them into a 100 mL reaction bottle, slowly add 2.1 g (22 mmol) of methyl chloroformate at 0-5 ° C, react at 20 ° C, filter, wash with saturated NaHCO3 solution and saturated NaCl solution in turn, dry with anhydrous Na2SO4, filter, concentrate the solvent, and use silica gel column chromatography (V 乙酸乙酯 :V 石油醚 =1:3) to separate and purify, and obtain a light yellow oily substance for the next reaction. Add 3.0g (8.6mmol) of the light yellow oily substance obtained in the previous step, 6mL of ammonia water and 10mL of methanol into a 50mL reaction bottle, and react at 20°C. After completion, concentrate the solvent, add 20mL of dichloromethane, wash with saturated NaCl solution, dry with anhydrous Na2SO4, concentrate the solvent, and recrystallize to obtain a white solid, namely Intermediate II.

[0041] Finally, 0.45 mmol II, 0.36 mmol coumarin-6-sulfonyl chloride, 15 mL anhydrous dichloromethane and 0.32 mL (7.5 mmol) triethylamine were weighed into a 50 mL reaction tube and reacted at 40 °C with thin layer chromatography. After the reaction was completed, the solvent was concentrated and the silica gel column chromatography (V 石油醚 :V 乙酸乙酯 =3:1) to separate and purify to obtain compound IIIp.

[0042] Antimicrobial activity test of the present invention:

[0043] Using oxacillin as the control drug, the microdilution method was used to determine the activity of the compound of formula III against Staphylococcus aureus (S.

[0044] aureus), Escherichia coli (E. coli) and methicillin-resistant Staphylococcus aureus (MRSA), and the data are shown in Table 2.

[0045] Table 2

[0046]

[0047]

[0048] It can be clearly seen from the above experimental results that the compounds of general formula III to be protected by the present invention have potential antibacterial activity. The antibacterial activity of some compounds against Escherichia coli (E.coli) is better than or equivalent to that of the control drug oxacillin, such as compounds IIIf, IIIg, IIIn, IIIo and IIIp; the inhibitory effect of some compounds on Staphylococcus aureus (S.aureus) is close to that of the control drug oxacillin, such as compounds IIIo and IIIp; most compounds are better than oxacillin in activity against methicillin-resistant Staphylococcus aureus (MRSA), such as compounds IIIn, IIIo and IIIp, which have significant anti-MRSA activity, far better than the control drug. This type of compound exhibits excellent antibacterial activity, and has good activity against Gram-positive bacteria, resistant bacteria and Gram-negative bacteria, and has a certain broad spectrum of antibacterial activity. Its potential antibacterial activity can be used to treat infectious diseases of S.aureus, E.coli and MRSA. At the same time, it can also be used in combination with other antibacterial active substances.

Claims

1. A heterocyclic sulfonamide / sulfonate derivative, characterized in that: Its chemical structure is shown in formula III: Wherein, X is O or NH; R is one of a thiazole ring, an isoxazole ring, a quinoline ring, a coumarin ring, a benzothiadiazole ring, and a benzofuran ring.

2. A heterocyclic sulfonamide / sulfonate derivative according to claim 1, characterized in that: The compounds include IIIb, IIId, IIIe, IIIf, IIIg, IIIh, IIIj, IIIl, IIIm, IIIn, IIIo, and IIIp, and their structural formulas are as follows:

3. A drug, characterized in that: The heterocyclic sulfonamide / sulfonate derivative according to claim 1 is included, wherein the heterocyclic sulfonamide / sulfonate derivative is used as the sole active ingredient or is combined with an antibacterial drug or an antibacterial active ingredient.

4. Use of a heterocyclic sulfonamide / sulfonate derivative according to claim 1 in the preparation of antibacterial drugs for bacterial infectious diseases.

5. Use of IIId, IIIe, IIIf, IIIg, IIIh, IIIl, IIIm, IIIn, IIIo, and IIIp according to claim 2 in the preparation of drugs for treating and / or preventing Staphylococcus aureus infectious diseases.

6. Use of IIIb, IIId, IIIe, IIIf, IIIg, IIIh, IIIj, IIIl, IIIm, IIIn, IIIo, and IIIp according to claim 2 in the preparation of drugs for treating and / or preventing Escherichia coli infectious diseases.

7. Use of IIId, IIIg, IIIh, IIIl, IIIn, IIIo and IIIp according to claim 2 in the preparation of drugs for treating and / or preventing methicillin-resistant Staphylococcus aureus infectious diseases.

8. The method for preparing a heterocyclic sulfonamide / sulfonate derivative according to claim 1, characterized in that: The relevant chemical reactions of the heterocyclic sulfonamide / sulfonate derivatives are as follows:

9. The method for preparing a heterocyclic sulfonamide / sulfonate derivative according to claim 8, characterized in that: The following steps are involved: Preparation of intermediate I: Take 3-fluoro-4-morpholinoaniline, NaHCO3, acetone and distilled water, slowly add benzyl chloroformate dropwise at 0-5°C, complete the reaction at 0-50°C, concentrate the solvent acetone, filter, wash, dry and add it into the reaction bottle together with tetrahydrofuran, add lithium tert-butoxide in multiple times at 0-5°C to react, then slowly add (R)-epichlorohydrin dropwise, complete the reaction at 0-50°C, concentrate the solvent, add ice water to stir, adjust the pH to 7-8 with NH4Cl, extract with ethyl acetate, combine the organic phases, wash with saturated NaCl solution, dry with anhydrous Na2SO4, filter , concentrate the solvent, separate and purify by silica gel column chromatography to obtain milky white crystals, add the milky white crystals, sodium acetate and dimethyl sulfoxide to the reaction bottle in sequence, react at 60-120°C, add ice water, stir, precipitate crystals, filter and dry to obtain a white solid, add the white solid, distilled water, acetone and Na2CO3 to the reaction bottle in sequence, react at 10-50°C, concentrate the solvent, extract with ethyl acetate, combine the organic phases, wash with saturated NaCl solution, dry with anhydrous Na2SO4, filter, concentrate the solvent, separate and purify by silica gel column chromatography to obtain intermediate Ⅰ; Preparation of intermediate II: 3-fluoro-4-morpholinylaniline, lithium trifluoromethanesulfonate, (R)-epichlorohydrin and isopropanol were added to a reaction flask in sequence, the reaction was completed at 20-60°C, the solvent was concentrated, ethyl acetate was added to dissolve, and then washed with saturated Na2CO3 solution and saturated NaCl solution respectively, dried over anhydrous Na2SO4, filtered, and the solvent was concentrated to obtain a yellow oily substance. The yellow oily substance, CaO and 2-methyltetrahydrofuran were added to a reaction flask, methyl chloroformate was slowly added at 0-5°C, the reaction was completed at 0-50°C, filtered, washed with saturated NaHCO3 solution and saturated NaCl solution in sequence, dried over anhydrous Na2SO4, filtered, and the solvent was concentrated. The light yellow oily substance was separated and purified by silica gel column chromatography to obtain a light yellow oily substance. The light yellow oily substance, ammonia water and methanol were added to a reaction flask, the reaction was completed at 0-50°C, the solvent was concentrated, dichloromethane was added, washed with saturated NaCl solution, dried over anhydrous Na2SO4, the solvent was concentrated, and recrystallized to obtain intermediate II. Preparation of compound III: Take intermediate I or intermediate II, sulfonyl chloride, anhydrous dichloromethane and triethylamine into a reaction tube in sequence, react at 20-40°C, track with thin layer chromatography, and after the reaction is completed, concentrate the solvent, separate and purify by silica gel column chromatography to obtain compound III.

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