CN112898193A - Indole aryl sulfone derivative and preparation method and application thereof - Google Patents
Indole aryl sulfone derivative and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides an indole aryl sulfone derivative and a preparation method and application thereof. The derivative has a structure shown in the following general formula I or II. The invention also relates to a preparation method of the derivatives and application of the derivatives as HIV inhibitors in preparing anti-AIDS drugs.
Description
Technical Field
The invention belongs to the technical field of organic synthesis and medical application, and particularly relates to preparation of indole aryl sulfone derivatives and application of the indole aryl sulfone derivatives in the field of anti-HIV-1 medicines.
Background
AIDS, also known as Acquired Immunodeficiency Syndrome (AIDS), is a serious infectious disease that severely threatens Human life and health, the major pathogen of which is Human Immunodeficiency Virus Type 1 (HIV-1). Due to the integrated nature and high variability of the HIV-1 genetic material, the treatment of HIV-1 infection has been a major problem in the global medical and health field since its first discovery in the eighties of the last century. The use of Highly Active Antiretroviral Therapy (HAART) with a combination of multiple anti-HIV-1 drugs in the nineties has greatly reduced the morbidity and mortality of aids, however, with the popularity of HAART, the problems of dose complexity, patient compliance, and drug interactions have become more prominent. Meanwhile, a large number of drug-resistant mutant strains are emerging continuously. Reverse Transcriptase (RT) plays a key role in the life cycle of HIV, and has a clear action mechanism and a clear protein structure. Among them, HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) have the advantages of high efficiency, low toxicity and strong specificity, thus making them important components of HAART therapy. However, because the amino acid residues of the NNRTIs binding sites are easy to mutate, the drugs are easy to generate drug resistance, and the clinical potency is rapidly reduced. Therefore, there is an urgent need to develop new inhibitors with higher potency and lower toxicity, chemical diversity and good resistance to drugs, especially other types of NNRTIs.
Indolylarylsulfones (IASs) are a class of highly potent NNRTIs and the anomeric compound is L-737, 126(a), which inhibit the replication of HIV-1 wild-type and mutant strains at nanomolar concentrations. The compound b obtained by introducing 3, 5-dimethyl to the 3-sulfonylbenzene of the compound a has remarkably improved activity on HIV-1 mutant strains (see figure 1). Further structural optimization gave compound c, whose crystal complex structure with RT indicated that the amide side chain at position 2 of the indole parent ring was located in the entry channel of the NNRTI binding pocket, consisting mainly of Leu100, Glu138 and Val179 (see figure 2). Therefore, the current modification and modification of IASs mainly focuses on the amide group at the 2-position of indole to form additional acting force with the surrounding key amino acids, thereby further improving and enhancing the anti-HIV-1 activity, physicochemical property and pharmacokinetic property of IASs.
In order to discover a new generation of anti-HIV-1 drugs, the invention discloses an indole aryl sulfone HIV-1 non-nucleoside reverse transcriptase inhibitor with a brand new structure, and no relevant report is found in the prior art.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides an indole aryl sulfone derivative and a preparation method thereof, and also provides an anti-HIV-1 activity screening result and application of the compound.
The technical scheme of the invention is as follows:
indole aryl sulfone derivatives
The invention relates to an indole aryl sulfone derivative, or pharmaceutically acceptable salt, ester or prodrug thereof, which has a structure shown in the following general formula I or II:
wherein the content of the first and second substances,
m＝1,2,3,4,5,6；
n＝0,1,2,3；
r is: H. cyclopropyl, benzene ring, substituted naphthalene ring, various substituted six-membered heterocyclic rings, various substituted five-membered heterocyclic rings, various substituted six-membered fused six-membered heterocyclic rings, various substituted five-membered fused five-membered heterocyclic rings, various substituted benzo five-membered heterocyclic rings or various substituted benzo six-membered heterocyclic rings and various hydrocarbon chain structures with different lengths; the substituent is selected from methyl, methoxy, nitro, cyano, amino, trifluoromethyl, halogen or methyl 1-thiobutyrate-2 formyl.
In accordance with a preferred aspect of the present invention,
m＝1,2,3,4,5；
n＝0,1,2；
r is: H. benzene rings, substituted benzene rings, and various hydrocarbon chain structures of different lengths; the substituent is selected from methyl, methoxy, nitro, cyano, amino, trifluoromethyl, halogen or methyl 1-thiobutyrate-2 formyl.
According to a further preferred embodiment of the present invention, the indole aryl sulfone derivative represented by the general formula I or II is one of the following compounds:
as used herein, "pharmaceutically acceptable salts" means salts of the compounds which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and lower animals without undue toxicity, irritation, and allergic response and the like, are commensurate with a reasonable benefit-to-risk ratio, are generally water or oil soluble or dispersible, and are effective for their intended use. Including pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts, which are contemplated herein and are compatible with the chemical nature of the compounds of formula I or II. A list of suitable salts is found on pages 1-19 of s.m. berge et al, j.pharm.sci.,1977, 66.
The term "prodrug" as used herein refers to pharmaceutically acceptable derivatives such that the resulting biotransformation product of the derivative is the active drug as defined for the compounds of formula I or II.
Preparation method of di-indole aryl sulfone derivatives
The preparation method of the indole aryl sulfone derivative comprises the steps of taking 5-chloro-1H-indole-2-ethyl formate 1 as a raw material, carrying out aromatic nucleophilic substitution reaction on the raw material and 3, 5-dimethyl benzenethiol, carrying out oxidation reaction on the raw material and m-chloroperoxybenzoic acid, hydrolyzing the raw material by lithium hydroxide to obtain an intermediate 4, carrying out condensation reaction on the intermediate 4 and corresponding substituted amine and deprotection reaction on the intermediate and trifluoroacetic acid to obtain target compounds 6a-6f, and carrying out condensation reaction on the target compounds 6a-6f and 2- ((butyryloxy) methyl) thio) benzoic acid to obtain target compounds 7a-7 f.
The synthetic route is as follows:
reagents and conditions: (i)3, 5-dimethylphenylthiol, 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt, acetonitrile, room temperature; (ii) meta-chloroperoxybenzoic acid, dichloromethane; (iii) lithium hydroxide, tetrahydrofuran and water in a ratio of 1:1 at 45 ℃; (iv) substituted amines, HATU, N-diisopropylethylamine, N-dimethylformamide; (v) trifluoroacetic acid, dichloromethane; (vi)2- ((butyryloxy) methyl) thio) benzoic acid, HATU, N-diisopropylethylamine, N-dimethylformamide.
Wherein m and n are as defined in formula I or II above.
The substituted amine is as follows: N-Boc-1, 2-ethylenediamine, N-Boc-1, 3-propylenediamine, N-Boc-1, 4-butylenediamine, N-Boc-1, 5-pentylenediamine, 4- (Boc-amino) aniline, 4- (Boc-amino) benzylamine.
The room temperature of the invention is 20-30 ℃.
The preparation method of the indole aryl sulfone derivative comprises the following specific steps:
(1) adding 5-chloro-1H-indole-2-carboxylic acid ethyl ester (1), 3, 5-dimethyl benzenethiol, 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt and solvent acetonitrile into a round-bottom flask, and stirring at room temperature for 6 hours; after the reaction is finished, evaporating the solvent of the reaction solution to dryness, adding dichloromethane and saturated sodium chloride solution for extraction, separating an organic phase, adding anhydrous magnesium sulfate for drying, filtering, concentrating the filtrate under reduced pressure, and separating and purifying the obtained crude product by silica gel column chromatography to obtain an intermediate 2;
(2) dissolving the intermediate 2 in dichloromethane, adding m-chloroperoxybenzoic acid under an ice bath condition, converting to room temperature after 30 minutes, and continuing to react for 4 hours; after the reaction is finished, transferring the reaction solution into a separating funnel, adding dichloromethane for dilution, washing for 3 times by using a saturated sodium bisulfite solution, then adding a saturated sodium chloride solution for washing for 1 time, adding anhydrous magnesium sulfate for drying, filtering, concentrating the filtrate under reduced pressure, and separating and purifying the obtained crude product by silica gel column chromatography to obtain an intermediate 3;
(3) dissolving the intermediate 3 in a tetrahydrofuran/water mixed solvent with the volume ratio of 1:1, adding lithium hydroxide, and stirring for 8 hours at 45 ℃; after the reaction is finished, evaporating most of the solvent under reduced pressure, then dropwise adding 1N diluted HCl solution, adjusting the pH to 3-4, generating white insoluble substances in the process, performing suction filtration, and drying a filter cake to obtain an intermediate 4;
(4) under the ice-bath condition, dissolving the intermediate 4 in N, N-dimethylformamide, adding N, N-diisopropylethylamine after 5 minutes, adding HATU after 5 minutes, stirring for 30 minutes, adding corresponding substituted amine, and transferring to room temperature for reaction; after the reaction is finished, adding a proper amount of water and ethyl acetate into the reaction liquid for extraction, combining organic phases, adding a saturated sodium chloride solution for washing, then drying with anhydrous sodium sulfate, filtering, concentrating, and finally obtaining an intermediate 5a-5f through column chromatography;
(5) dissolving the intermediates 5a-5f in dichloromethane, dropwise adding trifluoroacetic acid while stirring at room temperature, and reacting for 40 minutes; after the reaction is finished, evaporating most of reaction liquid under reduced pressure, adding saturated sodium bicarbonate solution to adjust the pH value to be neutral, separating out white solid in the process, and recrystallizing ethyl acetate to obtain target compounds 6a-6 f;
(6) adding 2- ((butyryloxy) methyl) thio) benzoic acid into N, N-dimethylformamide, sequentially adding HATU and N, N-diisopropylethylamine under the condition of ice bath and stirring, activating for 30 minutes, adding compounds 6a-6f, and transferring to room temperature; and after the reaction is finished, adding ethyl acetate and water for extraction, washing by using a saturated sodium chloride solution, adding anhydrous sodium sulfate for drying, filtering, concentrating the filtrate under reduced pressure, and performing silica gel column chromatography on the obtained crude product to obtain the target compounds 7a-7 f.
Application of tri-indole aryl sulfone derivatives
The invention discloses an anti-HIV-1 activity screening result of indole aryl sulfone derivatives and an application of the indole aryl sulfone derivatives as an HIV-1 inhibitor for the first time. Experiments prove that the indole aryl sulfone derivative can be used as an HIV-1 inhibitor for preparing anti-AIDS medicaments. The invention also provides application of the compound in preparing anti-HIV-1 medicines.
anti-HIV-1 Activity and toxicity test of the target Compound
The cellular anti-HIV-1 activity and toxicity test is carried out on the indole aryl sulfone derivatives synthesized according to the method, the anti-HIV-1 activity and toxicity data of the indole aryl sulfone derivatives are listed in Table 1, and the non-nucleoside reverse transcriptase marketed drug rilpivirine (TMC278) reported in the literature is taken as a positive control.
The indole aryl sulfone derivative newly synthesized by the invention has obvious anti-HIV-1 activity. For example, the activity of compounds 6a, 6b, 6c, 6e, 6f is particularly pronouncedWhich inhibit EC of HIV-1 wild strain50Values close to or comparable to TMC 278. Therefore, the indole aryl sulfone derivatives have further development value.
The indole aryl sulfone derivative can be used as an HIV-1 inhibitor. In particular to the application of the compound as an HIV-1 inhibitor in preparing anti-AIDS drugs.
An anti-HIV-1 pharmaceutical composition comprises the indole aryl sulfone derivatives and one or more pharmaceutically acceptable carriers or excipients.
The invention provides indole aryl sulfone derivatives and a preparation method thereof, and also provides a screening result of anti-HIV-1 activity of partial compounds and the first application of the partial compounds in the field of antivirus. Tests prove that the indole aryl sulfone derivatives can be used as HIV-1 inhibitors and have high application value. In particular to the application of the compound as an HIV-1 inhibitor in preparing anti-AIDS drugs.
Drawings
FIG. 1 is a structural diagram of compounds a-c;
FIG. 2 is a structural diagram of a complex crystal of compound c with HIV-1RT (PDB Code:2FR 2).
Detailed Description
The invention will be understood by the following examples, which are given by way of illustration and are not intended to limit the scope of the invention.
Example 1: preparation of intermediate 5-chloro-3- ((3, 5-dimethylphenyl) thio) -1H-indole-2-carboxylic acid ethyl ester (2)
Ethyl 5-chloro-1H-indole-2-carboxylate (1, 0.5g, 2.13mmol, 1eq.), 3, 5-dimethylphenylthiol (280 μ L, 2.13mmol, 1eq.), 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt (0.83g, 2.55mmol, 1.1eq.), acetonitrile (25mL) were added to a round-bottomed flask and stirred at room temperature for 6 hours; after the reaction is finished, evaporating the solvent of the reaction solution to dryness, adding dichloromethane (15mL) and saturated sodium chloride solution (50mL) for extraction, extracting the water phase with dichloromethane (15mL) for 2 times, combining organic phases, adding anhydrous magnesium sulfate for drying, filtering, concentrating the filtrate under reduced pressure, and separating and purifying the obtained crude product by silica gel column chromatography (eluent ethyl acetate: petroleum ether ═ 1:12) to obtain an intermediate 5-chloro-3- ((3, 5-dimethylphenyl) thio) -1H-indole-2-carboxylic acid ethyl ester (2), wherein the yield is as follows: 57%, white solid, melting point: 135 ℃ and 136 ℃.
Spectral data:
1H NMR(400MHz,DMSO-d6)δ12.55(s,1H,Indole-NH),7.56(d,J＝8.8Hz,1H,Indole-H),7.39(d,J＝2.0Hz,1H,Indole-H),7.34(dd,J＝8.7,2.1Hz,1H,Indole-H),6.77(s,1H,Ph-H),6.72(s,2H,Ph-H),4.33(q,J＝7.1Hz,2H,OCH2),2.14(s,6H,2×CH3),1.26(t,J＝7.1Hz,3H,CH3).ESI-MS:m/z 358.39(M-1)-.C19H18ClNO2S[359.07].
example 2: preparation of intermediate 5-chloro-3- ((3, 5-dimethylphenyl) sulfonyl) -1H-indole-2-carboxylic acid ethyl ester (3)
Intermediate 2(0.1g, 0.277mmol, 1eq.) was dissolved in 10mL of dichloromethane and placed in an ice bath with stirring, and m-chloroperoxybenzoic acid (0.143g, 0.831mmol, 3eq.) was slowly added to the reaction flask. After 30 minutes, removing the ice bath, and transferring the reaction to room temperature and stirring; after 4 hours, the reaction was completed, and 20mL of dichloromethane was added to dilute the reaction solution, a saturated sodium hydrogen sulfite solution was added to wash the reaction solution (10mL × 3), the organic phases were combined, a saturated sodium hydrogen carbonate solution was added to wash the reaction solution (10mL × 3), and finally a saturated sodium chloride solution was used to wash the reaction solution (10mL), the organic phase was separated, dried over anhydrous magnesium sulfate was added, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1:4) to obtain an intermediate, ethyl 5-chloro-3- ((3, 5-dimethylphenyl) sulfonyl) -1H-indole-2-carboxylate (3), yield: 72%, white solid, melting point: 210 ℃ and 211 ℃.
Spectral data:
1H NMR(400MHz,DMSO-d6)δ13.29(s,1H,NH),8.24(s,1H,Ph-H),7.68–7.59(m,3H,Ph-H),7.44(d,J＝8.8Hz,1H,Ph-H),7.28(s,1H,Ph-H),4.37(q,J＝6.9Hz,2H,CH2),2.33(s,6H,CH3×2),1.30(t,J＝6.9Hz,3H,CH3).ESI-MS:m/z 390.40(M-1)-.C19H18ClNO4S[391.06].
example 3: preparation of intermediate 5-chloro-3- ((3, 5-dimethylphenyl) sulfonyl) -1H-indole-2-carboxylic acid (4)
Dissolving intermediate 3(0.1g, 0.255mmol, 1eq.) in a mixed solvent of tetrahydrofuran/water (1:1, 10mL), adding lithium hydroxide (32mg, 0.765mmol, 3eq.) with stirring at room temperature, and stirring at 45 ℃ for 8 hours; after the reaction is finished, evaporating most of solvent under reduced pressure, then dropwise adding 1N diluted HCl solution, adjusting the pH to 3-4, generating white insoluble substances in the process, performing suction filtration, and drying a filter cake to obtain an intermediate 5-chloro-3- ((3, 5-dimethylphenyl) sulfonyl) -1H-indole-2-carboxylic acid (4), wherein the yield is as follows: 66%, white solid, melting point: decomposing at 270 ℃.
Spectral data:
1H NMR(400MHz,DMSO-d6)δ14.22(s,1H,COOH),13.10(s,1H,NH),8.21(s,1H,Ph-H),7.63(s,2H,Ph-H),7.56(d,J＝8.7Hz,1H,Ph-H),7.40(d,J＝8.8Hz,1H,Ph-H),7.26(s,1H,Ph-H),2.31(s,6H,CH3×2).ESI-MS:m/z 362.02(M-1)-.C17H14ClNO4S[363.03].
example 4: preparation of intermediates 5a-5f
Dissolving the intermediate 4(1eq.) in N, N-dimethylformamide (5mL) under ice bath conditions, stirring for 5 minutes, adding N, N-diisopropylethylamine (3eq.) and HATU (1.5eq.) after 5 minutes, stirring for 30 minutes, adding the corresponding substituted amine (1.2eq.) and transferring to room temperature for reaction; after the reaction is finished, adding a proper amount of water and ethyl acetate into the reaction liquid for extraction, combining organic phases, adding a saturated sodium chloride solution for washing, then drying with anhydrous sodium sulfate, filtering, concentrating, and finally obtaining the intermediate 5a-5f through column chromatography.
The substituted amine is prepared by reacting N-Boc-1, 2-ethylenediamine with the intermediate 4 to prepare (2- (5-chloro-3- ((3, 5-dimethylphenyl) sulfonyl) -1H-indole-2-formamido) ethyl carbamic acid tert-butyl ester (intermediate 5a), and the white solid is obtained by column chromatography (ethyl acetate: petroleum ether ═ 1:4), the yield is 84%, and the melting point is 181-.
Spectral data:
1H NMR(400MHz,DMSO-d6)δ12.97(s,1H,NH),9.01(t,J＝5.3Hz,1H,NH),8.01–7.88(m,1H,Ph-H),7.65(s,2H,Ph-H),7.55(d,J＝8.7Hz,1H,Ph-H),7.35(dd,J＝8.7,1.8Hz,1H,Ph-H),7.26(s,1H,Ph-H),6.85(t,J＝5.0Hz,1H,NH),3.40(q,J＝6.2Hz,2H,CH2),3.19(q,J＝5.5Hz,2H,CH2),2.32(s,6H,CH3×2),1.39(s,9H,CH3×3).ESI-MS:m/z 504.49(M-1)-.C24H28ClN3O5S[505.14].
the substituted amine is prepared by reacting N-Boc-1, 3-propane diamine with the intermediate 4 to prepare (3- (5-chloro-3- ((3, 5-dimethylphenyl) sulfonyl) -1H-indole-2-carboxamide) propyl tert-butyl carbamate (intermediate 5b), and the white solid is obtained by column chromatography (ethyl acetate: petroleum ether ═ 1:4), the yield is 76%, and the melting point is 170 and 172 ℃.
Spectral data:
1H NMR(400MHz,DMSO-d6)δ13.01(s,1H,NH),8.95(t,J＝5.4Hz,1H,NH),7.94(d,J＝1.7Hz,1H,Ph-H),7.71–7.62(m,2H,Ph-H),7.53(d,J＝8.8Hz,1H,Ph-H),7.34(dd,J＝8.8,2.0Hz,1H,Ph-H),7.26(s,1H,Ph-H),6.88(t,J＝5.3Hz,1H,NH),3.36–3.28(m,2H,CH2),3.06(q,J＝6.5Hz,2H,CH2),2.31(s,6H,CH3×2),1.71(p,J＝6.7Hz,2H,CH2),1.39(s,9H,CH3×3).ESI-MS:m/z 518.67(M-1)-.C25H30ClN3O5S[519.16].
the substituted amine is N-Boc-1, 4-butanediamine and the intermediate 4 to prepare tert-butyl (4- (5-chloro-3- ((3, 5-dimethylphenyl) sulfonyl) -1H-indole-2-carboxamide) butyl) carbamate (intermediate 5 c). Flash column chromatography (ethyl acetate: petroleum ether ═ 1:2), white solid, yield: 83%, melting point: 160 ℃ and 161 ℃.
Spectral data:
1H NMR(400MHz,DMSO-d6)δ13.00(s,1H,NH),8.95(t,J＝5.4Hz,1H,NH),7.94(d,J＝1.9Hz,1H,Ph-H),7.63(s,2H,Ph-H),7.53(d,J＝8.8Hz,1H,Ph-H),7.34(dd,J＝8.8,2.0Hz,1H,Ph-H),7.27(s,1H,Ph-H),6.83(t,J＝5.4Hz,1H,NH),2.98(q,J＝6.2Hz,2H,CH2),2.32(s,6H,CH3×2),1.71–1.42(m,6H,CH2×3),1.38(s,9H,CH3×3).
the substituted amine was N-Boc-1, 5-pentanediamine and intermediate 4 were reacted to give tert-butyl (5- (5-chloro-3- ((3, 5-dimethylphenyl) sulfonyl) -1H-indole-2-carboxamido) pentyl) carbamate (intermediate 5 d). Flash column chromatography (ethyl acetate: petroleum ether ═ 1:2), white solid, yield: 68%, melting point: 148 ℃ and 150 ℃.
Spectral data:
1H NMR(400MHz,DMSO-d6)δ13.00(s,1H,NH),8.95(t,J＝5.4Hz,1H,NH),7.94(d,J＝1.8Hz,1H,Ph-H),7.63(s,2H,Ph-H),7.53(d,J＝8.8Hz,1H,Ph-H),7.34(dd,J＝8.8,1.8Hz,1H,Ph-H),7.27(s,1H,Ph-H),6.79(t,J＝5.1Hz,1H,NH),3.38–3.34(m,2H,CH2),2.93(q,J＝6.4Hz,2H,CH2),2.32(s,6H,CH3×2),1.58(p,J＝7.1Hz,2H,CH2),1.51–1.38(m,4H,CH2×2),1.37(s,9H,CH3×3).
the substituted amine is prepared by reacting 4- (Boc-amino) aniline with the intermediate 4 to prepare (4- (5-chloro-3- ((3, 5-dimethylphenyl) sulfonyl) -1H-indole-2-carboxamide) phenyl tert-butyl carbamate (intermediate 5e), performing flash column chromatography (ethyl acetate: petroleum ether ═ 1:2), and performing white solid chromatography, wherein the yield is 75%, and the melting point is 228-.
Spectral data:
1H NMR(400MHz,DMSO-d6)δ13.19(s,1H,NH),10.82(s,1H,NH),9.38(s,1H,NH),7.93(d,J＝1.7Hz,1H,Ph-H),7.65(s,2H,Ph-H),7.62(d,J＝8.9Hz,2H,Ph-H),7.55(d,J＝8.8Hz,1H,Ph-H),7.49(d,J＝8.7Hz,2H,Ph-H),7.36(dd,J＝8.7,1.8Hz,1H,Ph-H),7.26(s,1H,Ph-H),2.30(s,6H,CH3×2),1.48(s,9H,CH3×3).
the substituted amine is selected from 4- (Boc-amino) benzylamine to react with the intermediate 4 to prepare tert-butyl (4- ((5-chloro-3- ((3, 5-dimethylphenyl) sulfonyl) -1H-indole-2-carboxamide) methyl) phenyl) carbamate (intermediate 5 f). Flash column chromatography (ethyl acetate: petroleum ether ═ 1:2), white solid, yield: 67%, melting point: 208 ℃ and 209 ℃.
Spectral data:
1H NMR(400MHz,DMSO-d6)δ13.06(s,1H,NH),9.39(t,J＝5.7Hz,1H,NH),9.35(s,1H,NH),7.94(d,J＝1.8Hz,1H,Ph-H),7.58(s,2H,Ph-H),7.54(d,J＝8.8Hz,1H,Ph-H),7.45(d,J＝8.3Hz,2H,Ph-H),7.36(d,J＝1.9Hz,1H,Ph-H),7.34(s,1H,Ph-H),7.32(s,1H,Ph-H),7.25(s,1H,Ph-H),4.51(d,J＝5.7Hz,2H,CH2),2.27(s,6H,CH3×2),1.47(s,9H,CH3×3).
example 5: preparation of target Compounds 6a-6f
Dissolving the intermediates 5a to 5f (1eq) in dichloromethane (10mL), adding trifluoroacetic acid (5eq) dropwise while stirring at room temperature, and reacting for 40 minutes; and (3) after the reaction is finished, evaporating most of reaction liquid under reduced pressure, adding saturated sodium bicarbonate solution to adjust the pH value to be neutral, separating out solid in the process, and recrystallizing ethyl acetate to obtain the target compound (6a-6 f).
The intermediate 5a is selected as the reactant to prepare the N- (2-aminoethyl) -5-chloro-3- ((3, 5-dimethylphenyl) sulfonyl) -1H-indole-2-carboxamide (6 a). White solid, yield: 80%, melting point: 211 ℃ and 212 ℃.
Spectral data:
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H,NH),7.92(s,1H,Ph-H),7.64(s,2H,Ph-H),7.46(d,J＝8.7Hz,1H,Ph-H),7.18(s,1H,Ph-H),7.13(d,J＝8.7Hz,1H,Ph-H),3.45–3.35(m,2H,CH2),3.17(s,2H,NH2),2.85(t,J＝6.1Hz,2H,CH2),2.29(s,6H,CH3×2).13C NMR(100MHz,DMSO-d6)δ162.49(C＝O),144.71,141.82,138.69,137.89,134.09,128.28,126.07,124.21,122.64,118.88,117.41,109.62,21.29.ESI-MS:m/z 406.49(M+1)+.C19H20ClN3O3S[405.09].
the intermediate 5b is selected as the reactant to prepare the N- (3-aminopropyl) -5-chloro-3- ((3, 5-dimethylphenyl) sulfonyl) -1H-indole-2-carboxamide (6 b). White solid, yield: 74%, melting point: 208-210 ℃.
Spectral data:
1H NMR(400MHz,DMSO-d6)δ8.48(s,1H,NH),7.87(s,1H,Ph-H),7.63(s,2H,Ph-H),7.40(d,J＝8.6Hz,1H,Ph-H),7.13(s,1H,Ph-H),6.99(d,J＝8.6Hz,1H,Ph-H),3.33(t,J＝5.6Hz,2H,CH2),2.83(t,J＝6.8Hz,2H,CH2),2.28(s,6H,CH3×2),1.74(p,J＝6.3Hz,2H,CH2).13C NMR(100MHz,DMSO-d6)δ164.46(C＝O),145.87,144.89,141.05,138.25,133.40,129.96,124.96,124.16,120.93,118.78,118.46,37.86,36.29,29.58,21.34.ESI-MS:m/z 420.60(M+1)+.C20H22ClN3O3S[419.11].
the intermediate 5c was used to prepare N- (4-aminobutyl) -5-chloro-3- ((3, 5-dimethylphenyl) sulfonyl) -1H-indole-2-carboxamide (6 c). White solid, yield: 69%, melting point: 202 ℃ and 204 ℃.
Spectral data:
1H NMR(400MHz,DMSO-d6)δ8.29(s,1H,NH),7.90(s,1H,Ph-H),7.61(s,2H,Ph-H),7.39(d,J＝8.5Hz,1H,Ph-H),7.12(s,1H,Ph-H),6.98(d,J＝8.6Hz,1H,Ph-H),3.35–3.19(m,2H,CH2),2.76(t,J＝6.3Hz,2H,CH2),2.28(s,6H,CH3×2),1.55(s,4H,CH2×2).ESI-MS:m/z434.81(M+1)+.C21H24ClN3O3S[433.12].
the intermediate 5d was used to prepare N- (5-aminopentyl) -5-chloro-3- ((3, 5-dimethylphenyl) sulfonyl) -1H-indole-2-carboxamide (6 d). White solid, yield: 80%, melting point: 166 ℃ and 168 ℃.
Spectral data:
1H NMR(400MHz,DMSO-d6)δ8.68–8.41(m,1H,NH),7.98–7.86(m,1H,Ph-H),7.62(s,2H,Ph-H),7.54–7.39(m,1H,Ph-H),7.25–7.01(m,2H,Ph-H),3.28(q,J＝6.6Hz,2H,CH2),3.01–2.66(m,2H,CH2),2.29(s,6H,CH3×2),1.65–1.25(m,6H,CH2×3).ESI-MS:m/z448.73(M+1)+.C22H26ClN3O3S[447.14].
the intermediate 5e is selected to prepare the N- (4-aminophenyl) -5-chloro-3- ((3, 5-dimethylphenyl) sulfonyl) -1H-indole-2-carboxamide (6 e). White solid, yield: 70%, melting point: 160 ℃ and 161 ℃.
Spectral data:
1H NMR(400MHz,DMSO-d6)δ13.21(s,1H,NH),10.92(s,1H,NH),7.93(s,1H,Ph-H),7.70(d,J＝8.1Hz,2H,Ph-H),7.66(s,2H,Ph-H),7.57(d,J＝8.6Hz,1H,Ph-H),7.37(d,J＝8.7Hz,1H,Ph-H),7.27(s,1H,Ph-H),7.15(d,J＝8.0Hz,2H,Ph-H),2.30(s,6H,CH3×2).ESI-MS:m/z 452.61(M-1)-,488.23(M+35)-.C23H20ClN3O3S[453.09].
the intermediate 5f is selected to prepare the N- (4-aminobenzyl) -5-chloro-3- ((3, 5-dimethylphenyl) sulfonyl) -1H-indole-2-carboxamide (6 f). White solid, yield: 69%, melting point: 243 and 246 ℃.
Spectral data:
1H NMR(400MHz,DMSO-d6)δ13.04(s,1H,NH),9.28(t,J＝4.5Hz,1H,NH),7.95(s,1H,Ph-H),7.60–7.50(m,3H,Ph-H),7.34(d,J＝8.7Hz,1H,Ph-H),7.25(s,1H,Ph-H),7.11(d,J＝7.5Hz,2H,Ph-H),6.59(d,J＝7.4Hz,2H,Ph-H),4.41(d,J＝5.1Hz,2H,CH2),2.28(s,6H,CH3×2).ESI-MS:m/z 490.27(M+23)+.C24H22ClN3O3S[467.11].
example 6: preparation of target Compounds 7a-7f
Adding 2- ((butyryloxy) methyl) thio) benzoic acid (1.2eq) into N, N-dimethylformamide (8mL), sequentially adding HATU (1.2eq) and N, N-diisopropylethylamine (2eq) under ice-bath stirring, activating for 30 minutes, adding a compound (6a-6f, 1eq), and transferring to room temperature; after the reaction is finished, adding ethyl acetate (15mL) and water (30mL) for extraction, washing by using a saturated sodium chloride solution, separating an organic phase, adding anhydrous sodium sulfate for drying, filtering, concentrating a filtrate under reduced pressure, and performing silica gel column chromatography on an obtained crude product to obtain the target compound (7a-7 f).
The reactant was selected from 6a to prepare methyl ((2- ((2- (5-chloro-3- ((3, 5-dimethylphenyl) sulfonyl) -1H-indole-2-carboxamide) ethyl) carbamoyl) phenyl) sulfanylbutyrate (7a) as a white solid in 65% yield and 178 ℃ melting point.
Spectral data:
1H NMR(400MHz,DMSO-d6)δ13.00(s,1H,NH),9.10(t,J＝5.2Hz,1H,NH),8.43(t,J＝5.3Hz,1H,NH),7.92(s,1H,Ph-H),7.64(s,2H,Ph-H),7.61–7.39(m,3H,Ph-H),7.34(d,J＝8.7Hz,1H,Ph-H),7.32–7.21(m,2H,Ph-H),5.45(s,2H,CH2),3.50(dt,J＝18.6,5.6Hz,4H,CH2×2),2.38–2.19(m,6H,CH3×2),1.54(h,J＝7.4Hz,2H,CH2),1.24(s,2H,CH2),0.86(t,J＝7.2Hz,3H,CH3).ESI-MS:m/z 664.61(M+23)+.C31H32ClN3O6S2[641.14].
the reactant was selected from 6b to prepare methyl ((2- ((3- (5-chloro-3- ((3, 5-dimethylphenyl) sulfonyl) -1H-indole-2-carboxamido) propyl) carbamoyl) phenyl) sulfanylbutyrate (7b) as a white solid in 61% yield, 146-.
Spectral data:
1H NMR(400MHz,DMSO-d6)δ13.01(s,1H,NH),8.99(t,J＝5.1Hz,1H,NH),8.43(t,J＝4.9Hz,1H,NH),7.93(s,1H,Ph-H),7.65(s,2H,Ph-H),7.59(d,J＝7.8Hz,1H,Ph-H),7.53(d,J＝8.7Hz,1H,Ph-H),7.49–7.43(m,2H,Ph-H),7.37–7.29(m,2H,Ph-H),7.26(s,1H,Ph-H),5.46(s,2H,CH2),3.44(q,J＝6.5,6.0Hz,2H,CH2),3.39–3.33(m,2H,CH2),2.33(s,2H,CH2),2.31(s,6H,CH3×2),1.92–1.76(m,2H,CH2),1.53(h,J＝7.7Hz,2H,CH2),0.86(t,J＝7.3Hz,3H,CH3).13C NMR(100MHz,DMSO-d6)δ172.73(C＝O),168.01(C＝O),159.85(C＝O),143.00,139.41,138.26,137.88,135.12,133.93,133.27,130.69,129.53,128.10,127.66,126.89,125.62,125.09,124.22,119.34,115.30,111.88,66.83,37.81,37.27,35.81,29.30,21.23,18.30,13.77.ESI-MS:m/z 690.35(M+35)-.C32H34ClN3O6S2[655.16].
the reactant was selected from 6c to prepare methyl ((2- ((4- (5-chloro-3- ((3, 5-dimethylphenyl) sulfonyl) -1H-indole-2-carboxamido) butyl) carbamoyl) phenyl) sulfanylbutyrate (7c) as a white solid in 59% yield, 160. ang. 161 ℃.
Spectral data:
1H NMR(400MHz,DMSO-d6)δ13.00(s,1H,NH),8.98(t,J＝4.6Hz,1H,NH),8.39(t,J＝4.9Hz,1H,NH),7.93(s,1H,Ph-H),7.64(s,2H,Ph-H),7.58(d,J＝7.8Hz,1H,Ph-H),7.53(d,J＝8.8Hz,1H,Ph-H),7.44(dd,J＝15.0,7.4Hz,2H,Ph-H),7.32(dd,J＝12.1,8.7Hz,2H,Ph-H),7.27(s,1H,Ph-H),5.45(s,2H,CH2),3.39(q,J＝5.5Hz,2H,CH2),3.27(q,J＝4.9Hz,2H,CH2),2.31(s,6H,CH3×2),2.29(s,2H,CH2),1.75–1.60(m,4H,CH2×2),1.53(h,J＝7.2Hz,2H,CH2),0.86(t,J＝7.3Hz,3H,CH3).ESI-MS:m/z 668.80(M-1)-,704.28(M+35)-.C33H36ClN3O6S2[669.17].
the reactant was selected to prepare methyl ((2- ((5- (5- (5-chloro-3- ((3, 5-dimethylphenyl) sulfonyl) -1H-indole-2-carboxamido) pentyl) carbamoyl) phenyl) sulfanylbutyrate (7d) from 6d as a white solid with a yield of 48% and a melting point of 167-.
Spectral data:
1H NMR(400MHz,DMSO-d6)δ13.00(s,1H,NH),8.97(t,J＝5.1Hz,1H,NH),8.35(t,J＝4.5Hz,1H,NH),7.93(s,1H,Ph-H),7.63(s,2H,Ph-H),7.58(d,J＝7.9Hz,1H,Ph-H),7.52(d,J＝8.7Hz,1H,Ph-H),7.43(dd,J＝17.2,7.9Hz,2H,Ph-H),7.32(dd,J＝14.8,8.1Hz,2H,Ph-H),7.27(s,1H,Ph-H),5.45(s,2H,CH2),3.41–3.34(m,2H,CH2),3.22(q,J＝4.7Hz,2H,CH2),2.32(s,6H,CH3×2),2.29(s,2H,CH2),1.70–1.38(m,8H,CH2×4),0.87(t,J＝7.3Hz,3H,CH3).ESI-MS:m/z 682.54(M-1)-,718.09(M+35)-.C34H38ClN3O6S2[683.19].
the reactant was selected from 6e to prepare methyl ((2- ((4- (5-chloro-3- ((3, 5-dimethylphenyl) sulfonyl) -1H-indole-2-carboxamide) phenyl) carbamoyl) phenyl) sulfanylbutyrate (7e) as a white solid in 61% yield, melting point 215-.
Spectral data:
1H NMR(400MHz,DMSO-d6)δ13.22(s,1H,NH),10.94(s,1H,NH),10.45(s,1H,NH),7.94(s,1H,Ph-H),7.74(q,J＝8.6Hz,4H,Ph-H),7.67(s,3H,Ph-H),7.56(dt,J＝14.4,8.5Hz,3H,Ph-H),7.40(dd,J＝20.9,7.9Hz,2H,Ph-H),7.27(s,1H,Ph-H),5.49(s,2H,CH2),2.31(s,8H,CH3×2+CH2),1.53(h,J＝6.3Hz,2H,CH2),0.87(t,J＝7.3Hz,3H,CH3).ESI-MS:m/z688.58(M-1)-,724.06(M+35)-.C35H32ClN3O6S2[689.14].
the reactant was selected from 6f to prepare methyl ((2- ((4- ((5-chloro-3- ((3, 5-dimethylphenyl) sulfonyl) -1H-indole-2-carboxamido) methyl) phenyl) carbamoyl) phenyl) thiobutyrate (7f) as a white solid with a yield of 65% and a melting point of 185-187 ℃.
Spectral data:
1H NMR(400MHz,DMSO-d6)δ13.07(s,1H,NH),10.40(s,1H,NH),9.44(t,J＝5.4Hz,1H,NH),7.95(s,1H,Ph-H),7.69(dd,J＝15.2,8.0Hz,3H,Ph-H),7.63–7.49(m,5H,Ph-H),7.42(d,J＝7.8Hz,3H,Ph-H),7.35(d,J＝8.7Hz,1H,Ph-H),7.26(s,1H,Ph-H),5.47(s,2H,CH2),4.56(d,J＝5.3Hz,2H,CH2),2.37–2.17(m,8H,CH3×2+CH2),1.52(h,J＝6.9Hz,2H,CH2),0.85(t,J＝7.3Hz,3H,CH3).ESI-MS:m/z 702.88(M-1)-,738.04(M+35)-.C36H34ClN3O6S2[703.16].
example 7: in vitro anti-HIV-1 Activity test experiment for target Compounds
The test principle is as follows:
the compound in vitro anti-HIV activity screening adopts an MTT method. MTT is known collectively as 3- (4, 5-dimethyl-2-thiazolyl) -2, 5-diphenyltetrazolium bromide (trade name: thiazole blue), and can be used to detect the survival and growth of cells. The detection principle is as follows: MTT can be combined with succinate dehydrogenase in living cells and reduced to blue-violet crystal formazan which is insoluble in water, and the MTT is deposited in the cells, but dead cells do not have the function. Formazan in cells can be dissolved by dimethyl sulfoxide, and the number of living cells can be indirectly reflected by detecting the absorbance (A) value at 590nm by using an enzyme labeling instrument. Within a certain range of cell number, MTT crystals are formed in an amount proportional to the cell number.
Because the HIV-infected MT-4 cells can be diseased within a certain period of time (5-7 days), a solution of a compound to be detected with a proper concentration is added into the suspension of the HIV-infected MT-4 cells, and after a period of culture (5-7 days), the activity of the MT-4 cells is measured by an MTT (methyl thiazolyl tetrazolium) analysis method, so that the concentration of a drug (EC) for protecting 50% of the cells from cytopathic diseases is obtained (the concentration of the drug is the same as that of the drug (EC)50) The anti-HIV activity of the target compound can be obtained. Simultaneously obtaining the concentration (CC) of the target compound which can cause 50 percent of cells not infected by HIV to generate pathological changes50)。
Test materials and methods:
(1)HIV-1(IIIB): supplied by the institute Rega research institute of medical institute, Washington, Belgium.
(2) MT-4 cells: supplied by Rega research institute of medical institute, luwen university, belgium.
(3) MTT: purchased from Sigma, usa.
(4) Sample treatment: the samples were dissolved in DMSO to give appropriate concentrations just before use and diluted 5-fold with double distilled water, 5 dilutions each.
(5) Positive control drug: rilpivirine (TMC 278).
(6) The test method comprises the following steps: diluting the sample, adding into suspension of HIV-infected MT-4 cell, determining cell activity by MTT colorimetric method after a period of time, recording absorbance (A) value at 590nm in microplate reader, and calculating EC50，CC50。
(7) MTT colorimetric method: after adding the sample solution for incubation for a period of time, 20. mu.L of MTT solution (5mg/mL) was added to each well, and after incubation for several hours, the staining solution was discarded, 150. mu.L of DMSO was added to each well, mixed well, and the absorbance (A) at 590nm was measured in a microplate reader.
The experimental method comprises the following steps:
50 μ L of 1X 10-containing solution was added to a 96-well cell culture plate4Adding 20 μ L of infected HIV-1 (III) into MT-4 cell culture mediumB) MT-4 cell suspension (100-fold CCID per ml)50) Or blank (toxicity assay) and then add different concentrations of test compound solution or positive control drug, 3 replicate wells per concentration. Followed by cellsAt 5% CO2The culture was carried out under an atmosphere of 37 ℃ for 5 days, 20. mu.L (5mg/mL) of MTT solution was added to each well, the culture was continued for 2 hours, DMSO was then added, the absorbance of the reaction solution at 540nm was measured using a microplate reader, and the cell proliferation rate P% at various concentrations of the compound was calculated. Both blank and drug controls and positive drug controls were run to calculate the concentration of compound required to protect 50% of the cells from HIV-induced cytopathic Effects (EC)50)。
The experimental results are as follows:
the synthesized indole aryl sulfone derivatives are subjected to cell-level anti-HIV-1 (III) according to the experimental methodB) The activity screening of (2) and the activity results are shown in Table 1. The positive control drug was rilpivirine (TMC 278).
TABLE 1 anti-HIV-1 (III) derivatives of indolylararylsulfonesB) Cell activity and cytotoxicity (MT-4 cells)
Non-selective antiviral Activity, CC50/EC50<5。
Fourth, conclusion
As can be seen from Table 1, the indole aryl sulfone derivatives are a series of non-nucleoside HIV-1 reverse transcriptase inhibitors with novel skeletons, show good activity of resisting HIV-1 wild strains, and have low cytotoxicity. Among them, the compounds 6a, 6b, 6c, 6e and 6f have outstanding activity, and the EC of the compounds on HIV-1 wild strains50The value is close to or equivalent to that of the marketed drug rilpivirine (TMC 278). Therefore, the indole aryl sulfone derivatives have further research and development values and can be used as lead compounds for resisting HIV-1.
Claims (7)
1. An indole aryl sulfone derivative, or a pharmaceutically acceptable salt, ester or prodrug thereof, has a structure shown as the following general formula I or II:
wherein the content of the first and second substances,
m＝1,2,3,4,5,6；
n＝0,1,2,3；
r is:
r is: H. cyclopropyl, benzene ring, substituted naphthalene ring, various substituted six-membered heterocyclic rings, various substituted five-membered heterocyclic rings, various substituted six-membered fused six-membered heterocyclic rings, various substituted five-membered fused five-membered heterocyclic rings, various substituted benzo five-membered heterocyclic rings or various substituted benzo six-membered heterocyclic rings and various hydrocarbon chain structures with different lengths; the substituent is selected from methyl, methoxy, nitro, cyano, amino, trifluoromethyl, halogen or methyl 1-thiobutyrate-2 formyl.
2. The indole aryl sulfone derivative of claim 1, wherein m is 1,2,3,4, 5; n is 0,1, 2;
r is: H. benzene rings, substituted benzene rings, and various hydrocarbon chain structures of different lengths; the substituent is selected from methyl, methoxy, nitro, cyano, amino, trifluoromethyl, halogen or methyl 1-thiobutyrate-2 formyl.
3. The indole aryl sulfone derivative of claim 1 or 2, wherein the compound is one of:
4. the process for preparing an indolylsulfone derivative as claimed in claim 1, which comprises the steps of: taking 5-chloro-1H-indole-2-ethyl formate 1 as a raw material, carrying out aromatic nucleophilic substitution reaction on the raw material and 3, 5-dimethyl benzenethiol, carrying out oxidation reaction on the raw material and m-chloroperoxybenzoic acid, hydrolyzing the raw material by lithium hydroxide to obtain an intermediate 4, carrying out condensation reaction on the intermediate 4 and corresponding substituted amine and deprotection reaction on the intermediate 4 and trifluoroacetic acid in sequence to obtain target compounds 6a to 6f, and carrying out condensation reaction on the target compounds 6a to 6f and 2- ((butyryloxy) methyl) thio) benzoic acid to obtain target compounds 7a to 7 f;
the synthetic route is as follows:
reagents and conditions: (i)3, 5-dimethylphenylthiol, 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt, acetonitrile, room temperature; (ii) meta-chloroperoxybenzoic acid, dichloromethane; (iii) lithium hydroxide, tetrahydrofuran and water in a ratio of 1:1 at 45 ℃; (iv) substituted amines, HATU, N-diisopropylethylamine, N-dimethylformamide; (v) trifluoroacetic acid, dichloromethane; (vi)2- ((butyryloxy) methyl) thio) benzoic acid, HATU, N-diisopropylethylamine, N-dimethylformamide;
wherein m and n are as described in general formula I or II above;
the substituted amine is as follows: N-Boc-1, 2-ethylenediamine, N-Boc-1, 3-propylenediamine, N-Boc-1, 4-butylenediamine, N-Boc-1, 5-pentylenediamine, 4- (Boc-amino) aniline, 4- (Boc-amino) benzylamine.
5. The preparation method of the indole aryl sulfone derivative as claimed in claim 4, which comprises the following steps:
(1) adding 5-chloro-1H-indole-2-carboxylic acid ethyl ester (1), 3, 5-dimethyl benzenethiol, 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt and solvent acetonitrile into a round-bottom flask, and stirring at room temperature for 6 hours; after the reaction is finished, evaporating the solvent of the reaction solution to dryness, adding dichloromethane and saturated sodium chloride solution for extraction, separating an organic phase, adding anhydrous magnesium sulfate for drying, filtering, concentrating the filtrate under reduced pressure, and separating and purifying the obtained crude product by silica gel column chromatography to obtain an intermediate 2;
(2) dissolving the intermediate 2 in dichloromethane, adding m-chloroperoxybenzoic acid under an ice bath condition, converting to room temperature after 30 minutes, and continuing to react for 4 hours; after the reaction is finished, transferring the reaction solution into a separating funnel, adding dichloromethane for dilution, washing for 3 times by using a saturated sodium bisulfite solution, then adding a saturated sodium chloride solution for washing for 1 time, adding anhydrous magnesium sulfate for drying, filtering, concentrating the filtrate under reduced pressure, and separating and purifying the obtained crude product by silica gel column chromatography to obtain an intermediate 3;
(3) dissolving the intermediate 3 in a tetrahydrofuran/water mixed solvent with the volume ratio of 1:1, adding lithium hydroxide, and stirring for 8 hours at 45 ℃; after the reaction is finished, evaporating most of the solvent under reduced pressure, then dropwise adding 1N diluted HCl solution, adjusting the pH to 3-4, generating white insoluble substances in the process, performing suction filtration, and drying a filter cake to obtain an intermediate 4;
(4) under the ice-bath condition, dissolving the intermediate 4 in N, N-dimethylformamide, adding N, N-diisopropylethylamine after 5 minutes, adding HATU after 5 minutes, stirring for 30 minutes, adding corresponding substituted amine, and transferring to room temperature for reaction; after the reaction is finished, adding a proper amount of water and ethyl acetate into the reaction liquid for extraction, combining organic phases, adding a saturated sodium chloride solution for washing, then drying with anhydrous sodium sulfate, filtering, concentrating, and finally obtaining an intermediate 5a-5f through column chromatography;
(5) dissolving the intermediates 5a-5f in dichloromethane, dropwise adding trifluoroacetic acid while stirring at room temperature, and reacting for 40 minutes; after the reaction is finished, evaporating most of reaction liquid under reduced pressure, adding saturated sodium bicarbonate solution to adjust the pH value to be neutral, separating out white solid in the process, and recrystallizing ethyl acetate to obtain target compounds 6a-6 f;
(6) adding 2- ((butyryloxy) methyl) thio) benzoic acid into N, N-dimethylformamide, sequentially adding HATU and N, N-diisopropylethylamine under the condition of ice bath and stirring, activating for 30 minutes, adding compounds 6a-6f, and transferring to room temperature; and after the reaction is finished, adding ethyl acetate and water for extraction, washing by using a saturated sodium chloride solution, adding anhydrous sodium sulfate for drying, filtering, concentrating the filtrate under reduced pressure, and performing silica gel column chromatography on the obtained crude product to obtain the target compounds 7a-7 f.
6. Use of indolearyl sulphone derivatives as claimed in any one of claims 1-3 in the preparation of a medicament for the treatment and prevention of aids.
7. An anti-HIV pharmaceutical composition comprising the indolylsulfone derivative of any one of claims 1-3 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.
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| WO1993005020A1 (en) * | 1991-09-06 | 1993-03-18 | Merck & Co., Inc. | Indoles as inhibitors of hiv reverse transcriptase |
| WO2004014364A1 (en) * | 2002-08-07 | 2004-02-19 | Idenix (Cayman) Limited | Substituted phenylindoles for the treatment of hiv |
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2021
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| WO1993005020A1 (en) * | 1991-09-06 | 1993-03-18 | Merck & Co., Inc. | Indoles as inhibitors of hiv reverse transcriptase |
| WO2004014364A1 (en) * | 2002-08-07 | 2004-02-19 | Idenix (Cayman) Limited | Substituted phenylindoles for the treatment of hiv |
| CN105968095A (en) * | 2016-05-10 | 2016-09-28 | 山东大学 | Indolylaryl-sulfone derivative, as well as preparation method and application thereof |
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| MARIANNA NALLI等: "New indolylarylsulfone non-nucleoside reverse transcriptase inhibitors show low nanomolar inhibition of single and double HIV-1 mutant strains", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
| VALERIA FAMIGLINI等: "New indolylarylsulfones as highly potent and broad spectrum HIV-1 non-nucleoside reverse transcriptase inhibitors", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 李文馨: "基于靶标结构的新型HIV-1非核苷类逆转录酶抑制剂的设计、合成及活性评价", 《山东大学硕士学位论文》 * |
| 高萍: "新型HIV-1整合酶/RNase H双靶点抑制剂及非核苷类逆转录酶抑制剂的设计、合成及活性研究", 《山东大学博士学位论文》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115260081A (en) * | 2022-08-17 | 2022-11-01 | 山东大学 | Sulfonamide indole aryl sulfone derivative and preparation method and application thereof |
| CN115260081B (en) * | 2022-08-17 | 2024-04-02 | 山东大学 | Sulfonamide indole aryl sulfone derivative and preparation method and application thereof |
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| CN112898193B (en) | 2022-08-05 |
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