CN114920676B - Compound for treating respiratory system diseases and preparation method and application thereof - Google Patents

Compound for treating respiratory system diseases and preparation method and application thereof Download PDF

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CN114920676B
CN114920676B CN202210635451.7A CN202210635451A CN114920676B CN 114920676 B CN114920676 B CN 114920676B CN 202210635451 A CN202210635451 A CN 202210635451A CN 114920676 B CN114920676 B CN 114920676B
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CN114920676A (en
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石万棋
杨鸿均
更尕桑毛
卢宝兆
姚茂玲
陈科
尹爽
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Sichuan Guokang Pharmaceutical Co Ltd
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Abstract

The invention provides a compound for treating respiratory diseases, a preparation method and application thereof, and belongs to the field of pharmacy. The structure of the compound is shown as a formula I. The compound can effectively inhibit MUC5AC secretion, in particular to compounds 7e, 7f, 7g, 7h and 7j, and the inhibition effect is even better than that of positive control Fudosteine. The compound can be used for preparing medicines for inhibiting MUC5AC secretion, and has wide application prospects in preparing medicines for preventing and/or treating respiratory diseases such as chronic obstructive pulmonary diseases and the like.

Description

Compound for treating respiratory system diseases and preparation method and application thereof
Technical Field
The invention belongs to the field of pharmacy, and in particular relates to a compound for treating respiratory diseases, a preparation method and application thereof.
Background
Respiratory mucus secretion is an important innate immune response that protects the respiratory mucosal surfaces from external pathogens (bacteria, viruses and fungi) and irritation. Mucin 5AC (mucin 5AC, MUC5 AC) is an important mucin in respiratory tract mucus, and various factors such as infection, inflammatory factors, environmental pollutants and the like can realize the regulation and control of the expression of MUC5AC at multiple levels such as transcription, post-transcription, epigenetic and the like. However, the hypersecretion and overproduction of respiratory mucus can in turn cause a variety of respiratory diseases such as chronic obstructive pulmonary disease (COPD for short), bronchial asthma, chronic asthmatic bronchitis, bronchiectasis, tuberculosis, pneumoconiosis, atypical mycobacteriosis, pneumonia, diffuse bronchitis, etc. Inhibition of excessive secretion of respiratory mucus is an important strategy for the treatment of respiratory diseases with high secretion of respiratory mucus.
COPD is a representative pulmonary disease characterized by bronchiolitis obliterans and emphysema (destruction of the lung parenchyma), which continuously inhibits and shuts off lung tissue airflow, ultimately leading to patient death. Chronic obstructive pulmonary disease can be caused by various causes of cigarette smoke, dust, chemicals, air pollution, bacterial infection, and the like. It was found that the expression of MUC5AC is regulated by TNF- α, a major cytokine responsible for COPD, and that MUC5AC expression is significantly increased in COPD patients. MUC5AC is an important targeting factor for treating COPD, so that the development of drugs capable of effectively inhibiting excessive secretion of COPD is of great significance for clinically treating respiratory diseases such as COPD.
Fudosteine is a novel expectorant, is an L-cysteine derivative and is widely used for clinically eliminating phlegm of respiratory diseases such as COPD and the like. According to literature reports (J.Utility in China, volume 37, 8, and pages 751-753), fudosteine can reduce MUC5AC in sputum of COPD patients, and the action mechanism is probably that Fudosteine inhibits cup cell metaplasia and ERK1/2 and p38MAPK signal pathway activation caused by ROS through antioxidation, and finally down regulates gene expression of MCU5 AC. However, the effect of Fudosteine on inhibiting MCU5AC secretion has yet to be further improved.
Disclosure of Invention
The invention aims to provide a novel compound for inhibiting MCU5AC secretion, and a preparation method and application of the compound.
The present invention provides compounds of formula I, pharmaceutically acceptable salts thereof, stereoisomers thereof:
wherein R is a 、R b Each independently selected from hydrogen, C 1-6 Alkyl, unsubstituted or substituted by R c The substituted following groups: l (L) 1 R d The method comprises the steps of carrying out a first treatment on the surface of the Or R is a 、R b Connected in a ring, the ring being unsubstituted or R e Substituted 5-6 membered saturated heterocyclic group;
R c selected from C 1-6 Alkyl, C 1-6 Alkoxy, halogen;
L 1 selected from none or C 1-3 An alkylene group;
R d selected from 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclyl, 5-6 membered aryl, 5-6 membered heteroaryl, fused ring alkyl, and fused ring group;
R e selected from C 1-6 Alkyl, C 1-6 Alkoxy, halogen.
Further, the structure of the compound is shown as a formula II:
wherein Y is selected from O, S, CH 2 。
Further, the structure of the compound is shown in a formula III:
wherein R is a Selected from C 1-3 Alkyl, R b Selected from C 1-3 An alkyl group.
Further, the structure of the compound is shown as a formula IV:
wherein R is c1 Selected from hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, halogen.
Further, the structure of the compound is shown as a formula V:
wherein R is c2 Selected from C 1-3 An alkyl group.
Further, the compound is one of the following compounds:
the invention also provides a preparation method of the compound, which comprises the following steps:
(a) Reacting the compound I-1 with benzyl alcohol and thionyl chloride to obtain a compound I-2;
(b) Reacting the compound I-2 with an amino protecting reagent to obtain a compound I-3;
(c) Reacting the compound I-3 with methylsulfonyl chloride to obtain a compound I-4;
(d) Compound I-4Reacting to obtain a compound I-5;
(e) Reacting the compound I-5 with a deprotection reagent to obtain a compound I-6;
(f) Reacting the compound I-6 with a palladium-carbon catalyst in a hydrogen atmosphere to obtain a compound shown in a formula I;
wherein the method comprises the steps of，R a 、R b As described above, R x Is an amino protecting group.
The invention also provides a medicament for inhibiting MCU5AC secretion, which is a preparation prepared by taking the compound, pharmaceutically acceptable salt thereof and stereoisomer thereof as active ingredients and adding pharmaceutically acceptable auxiliary materials.
The invention also provides application of the compound, pharmaceutically acceptable salts thereof and stereoisomers thereof in preparing medicines for inhibiting MCU5AC secretion.
Further, the drug for inhibiting the secretion of MCU5AC is a drug for preventing and/or treating respiratory diseases.
Further, the respiratory disease is chronic obstructive pulmonary disease, bronchial asthma, chronic asthmatic bronchitis, bronchiectasis, tuberculosis, pneumoconiosis, atypical mycobacteriosis, pneumonia, diffuse bronchitis, lung cancer.
Definition of terms used in connection with the present invention: unless otherwise indicated, the initial definitions provided for groups or terms herein apply to the groups or terms throughout the specification; for terms not specifically defined herein, the meanings that one skilled in the art can impart based on the disclosure and the context.
The minimum and maximum values of the carbon atom content of the hydrocarbon groups are indicated by a prefix, e.g. prefix C a～b Alkyl means any alkyl group containing from "a" to "b" carbon atoms. For example, C 1-6 Alkyl refers to straight or branched chain alkyl groups containing 1 to 6 carbon atoms.
"aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, such as phenyl and naphthyl. The aryl ring may be fused to other cyclic groups (including saturated and unsaturated rings) but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, while the point of attachment to the parent must be at a carbon atom on the ring with a conjugated pi-electron system. Aryl groups may be substituted or unsubstituted.
"heteroaryl" refers to a heteroaromatic group containing one to more heteroatoms. Heteroatoms as referred to herein include oxygen, sulfur and nitrogen. Such as furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring. Heteroaryl groups may be optionally substituted or unsubstituted.
"fused ring alkyl" refers to a polycyclic cycloalkyl group in which two rings share two adjacent carbon atoms.
"heterofused ring group" refers to a polycyclic heterocyclic group having two rings sharing two adjacent carbon or heteroatom.
Halogen is fluorine, chlorine, bromine or iodine.
Experimental results show that the compound can effectively inhibit MUC5AC secretion of NCI-H292 cell model induced by TNF-alpha, and particularly the inhibition effect of the compound 7e, 7f, 7g, 7H and 7j is even better than that of positive control Fudosteine. The compound can be used for preparing medicines for inhibiting MUC5AC secretion, and has wide application prospects in preparing medicines for preventing and/or treating respiratory diseases such as COPD and the like.
The preparation method of the compound is simple, low in cost and controllable in conditions, and is suitable for industrial production.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Detailed Description
The raw materials and equipment used in the invention are all known products and are obtained by purchasing commercial products.
Compounds 7a to 7n according to the present invention were synthesized, respectively, according to the following synthetic routes.
The following is a synthetic method of the intermediate product.
Synthesis of Compound 2
Benzyl alcohol (43.00 ml,413mmol,15 eq.) is added to a three-necked round bottom flask under the protection of argon, cooled to-10 ℃, thionyl chloride (6.00 ml,82.60mmol,3 eq.) is slowly added dropwise to the reaction system at-10 ℃, the temperature of the reaction system is controlled to be not more than 0 ℃, fudosteine (5.00 g,27.90mmol,1 eq.) is added after the dropwise addition, the temperature is slowly increased to 60 ℃ and reflux is carried out, and the reaction is carried out for 2h. Excess thionyl chloride was distilled off under reduced pressure to give a yellow oily liquid. The yellow oily liquid was purified by column chromatography (dichloromethane: methanol=100:1) to give yellow oily substance 2 in a yield of 51%. 1 H NMR(400MHz,CDCl 3 )δ7.39–7.30(m,5H),5.16(d,J＝4.1Hz,2H),3.70(d,J＝7.1Hz,1H),3.53(t,J＝6.1Hz,2H),2.87(ddd,J＝20.6,13.4,5.8Hz,2H),2.62(t,J＝7.2Hz,2H),1.86(s,2H). 13 C NMR(101MHz,CDCl 3 )δ173.40(s),135.31(s),128.70–128.30(m),67.09(s),54.70(s),36.31(s),32.59(s),29.83(s).
Synthesis of Compound 3
Compound 2 (5.00 g,18.6mmol,1 eq.) was taken in dichloromethane and placed in a three-necked round bottom flask at below 0deg.C and triethylamine (5.15 mL, 372mmol,2 eq.) was slowly added dropwise. After the completion of the addition, boc anhydride (6.49 g, 29.7 mmol) was added. The ice bath was removed and stirred at room temperature until the reaction was complete by TLC. The reaction solution was washed three times with saturated sodium carbonate solution and saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether: ethyl acetate=5:1) to give compound 3 in 50% yield. 1 H NMR(400MHz,CDCl 3 )δ7.61–7.06(m,5H),5.17(q,J＝12.2Hz,2H),4.56(dd,J＝13.2,5.5Hz,1H),3.74–3.55(m,2H),2.93(ddd,J＝19.8,13.9,5.4Hz,2H),2.68–2.50(m,2H),1.74(tq,J＝14.2,7.2Hz,2H),1.42(s,9H).
Synthesis of Compound 4
Compound 3 (6.00 g,16.3mmol,1 eq.) was dissolved in dichloromethane under argon protection, placed in a three-necked round bottom flask at 0 ℃, triethylamine (11.33 ml,81mmol,5 eq.) was slowly added dropwise, and after the addition, methylsulfonyl chloride (5.00 ml,65mmol,4 eq.) was slowly added dropwise, the reaction was stirred at 25 ℃ for 2.5 hours at room temperature, and the reaction was complete by TLC method. The sulfonate was filtered off, dissolved in methylene chloride, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and finally purified by column chromatography on silica gel (petroleum ether: ethyl acetate=5:1) to give 4g of the compound in 99% yield. 1 H NMR(400MHz,CDCl 3 )δ7.45–7.27(m,5H),5.26–5.11(m,2H),4.54(t,J＝16.7Hz,1H),4.34–4.15(m,2H),3.08–2.85(m,5H),2.70–2.48(m,2H),2.03–1.85(m,2H),1.43(s,9H).
Synthesis of Compound 5a
4 (0.50 g,1.10 mmol), potassium carbonate (0.36 g,2.60 mmol), piperonylethylamine (0.75 mL,5.60 mmol) was dissolved in acetonitrile and added to a three-necked round bottom flask, stirred at 80℃under reflux until the TLC detection reaction was complete. Separation and purification by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =3:1) gave 5a as a yellow oil in 94% yield. 1 H NMR(400MHz,CDCl 3 )δ7.45–7.25(m,5H),6.73–6.62(m,3H),5.90(d,J＝5.6Hz,3H),5.22–5.06(m,2H),3.73–3.58(m,1H),2.97–2.38(m,12H),1.70(td,J＝14.5,7.3Hz,2H). 13 C NMR(101MHz,CDCl 3 )δ173.4,147.9,146.6,135.3,130.4,128.7,128.3,121.7,109.0,108.5,101.0,67.1,54.7,49.6,46.4,36.3,32.6,29.8,25.9.
Synthesis of Compound 5b
4 (0.50 g,1.10 mmol), potassium carbonate (0.36 g,2.60 mmol), furanmethanamine (0.50 mL,5.60 mmol) were dissolved in acetonitrile and added to a three-necked round bottom flask, stirred at 80℃under reflux until the TLC detection reaction was complete. The yellow oily substance 5b is obtained by separation and purification through a silica gel chromatographic column (petroleum ether: ethyl acetate (v/v) =3:1), and the yield is 67%. 1 H NMR(400MHz,CDCl 3 )δ7.47–7.18(m,6H),6.33–6.25(m,1H),6.14(d,J＝3.0Hz,1H),5.16(d,J＝8.7Hz,2H),4.65–4.47(m,1H),3.73(s,2H),2.94(d,J＝4.8Hz,2H),2.63(t,J＝6.1Hz,2H),2.52(t,J＝7.2Hz,2H),1.68(dt,J＝14.4,7.2Hz,2H),1.42(s,9H). 13 C NMR(101MHz,CDCl 3 )δ171.1,155.3,153.8,141.8,135.2,128.7–128.3,110.2,106.9,80.1,67.4,53.6,47.4,46.0,34.5,30.5,29.5,28.4.
Synthesis of Compound 5c
4 (0.50 g,1.10 mmol), potassium carbonate (0.36 g,2.60 mmol) and N-methylpiperazine (0.62 mL,5.60 mmol) were dissolved in acetonitrile and added to a three-necked round bottom flask, and stirred at 80℃under reflux until the TLC detection reaction was complete. The yellow oily substance 5c is obtained by separation and purification through a silica gel chromatographic column (petroleum ether: ethyl acetate (v/v) =3:1), and the yield is 71%. 1 H NMR(400MHz,CDCl 3 )δ7.43–7.17(m,5H),5.14(q,J＝12.3Hz,2H),4.53(d,J＝6.4Hz,1H),2.90(d,J＝17.7Hz,2H),2.66–2.07(m,15H),1.71–1.61(m,2H),1.40(s,9H). 13 C NMR(101MHz,CDCl 3 )δ171.0,155.2,135.2,128.8–128.2,80.1,67.4,57.1,55.1,53.5,53.2,46.1,34.6,30.6,28.4,26.8.
Synthesis of Compound 5d
4 (0.50 g,1.10 mmol), potassium carbonate (0.36 g,2.60 mmol) and cyclohexylmethylamine (0.64 mL,5.60 mmol) were dissolved in acetonitrile and added to a three-necked round bottom flask, and stirred at 80℃under reflux until the TLC detection reaction was complete. The mixture was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =3:1) to give a yellow oil 5d in 75% yield. 1 H NMR(400MHz,CDCl 3 )δ7.57–7.12(m,5H),5.17(q,J＝12.3Hz,2H),4.55(s,1H),2.95(s,2H),2.58(dt,J＝48.9,7.0Hz,4H),2.37(t,J＝10.3Hz,1H),1.84(d,J＝11.5Hz,2H),1.78–1.62(m,4H),1.57–1.31(m,9H),1.29–0.92(m,6H). 13 C NMR(101MHz,CDCl 3 )δ171.1,135.3,128.8–128.1,67.5,56.9,53.6,45.7,34.64,33.1,30.8,30.3,28.4,26.3,25.2.
Synthesis of Compound 5e
4 (0.50 g,1.10 mmol), potassium carbonate (0.36 g,2.60 mmol), morpholine (0.49 mL,5.60 mmol) were dissolved in acetonitrile and added to a three-necked round bottom flask and stirred at 80℃under reflux until the TLC detection reaction was complete. The yellow oily matter 5e is obtained through separation and purification by a silica gel chromatographic column (petroleum ether: ethyl acetate (v/v) =3:1), and the yield is 58%. 1 H NMR(400MHz,CDCl 3 )δ7.42–7.20(m,5H),5.15(q,J＝12.3Hz,2H),4.52(s,1H),3.75(s,4H),2.94(s,2H),2.65–2.32(m,8H),1.84–1.71(m,2H),1.41(s,9H).
Synthesis of Compound 5f
4 (0.50 g,1.10 mmol), potassium carbonate (0.36 g,2.60 mmol), piperidine (0.55 mL,5.60 mmol) were dissolved in acetonitrile and added to a three-necked round bottom flask, and stirred at 80℃under reflux until the TLC detection reaction was complete. The yellow oily matter 5f is obtained through separation and purification by a silica gel chromatographic column (petroleum ether: ethyl acetate (v/v) =3:1), and the yield is 58%. The yield thereof was found to be 66%. 1 H NMR(400MHz,CDCl 3 )δ7.45–7.23(m,5H),5.26–5.07(m,2H),4.55(d,J＝6.1Hz,1H),2.97(t,J＝15.9Hz,2H),2.56–2.18(m,8H),1.74–1.64(m,2H),1.59–1.35(m,15H).
Synthesis of Compound 5g
4 (0.50 g,1.10 mmol), potassium carbonate (0.36 g,2.60 mmol), diethylamine (0.58 mL,5.60 mmol) were dissolved in acetonitrile and added to a three-necked round bottom flask, stirred at 80℃under reflux until the TLC detection reaction was complete. The mixture was separated and purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =3:1) to obtain 5g of a yellow oil with a yield of 58%. The yield thereof was found to be 66%. The yield thereof was found to be 88%. 1 H NMR(400MHz,CDCl 3 )δ7.30(d,J＝32.7Hz,5H),5.17(q,J＝12.4Hz,2H),4.56(s,1H),2.96(s,2H),2.60–2.20(m,8H),1.63(t,J＝14.1Hz,2H),1.52–1.28(m,9H),1.11–0.68(m,6H).
Synthesis of Compound 5h
4 (0.50 g,1.10 mmol), potassium carbonate (0.36 g,2.60 mmol), cyclopropylamine (0.55 mL,5.60 mmol) was dissolved in acetonitrile and added to a three-necked round bottom flask, stirred at 80℃under reflux until the TLC detection reaction was complete. The yellow oily matter is obtained through separation and purification by a silica gel chromatographic column (petroleum ether: ethyl acetate (v/v) =3:1) for 5h, and the yield is 58%. The yield thereof was found to be 66%. The yield thereof was found to be 53%. 1 H NMR(400MHz,CDCl 3 )δ7.52–7.21(m,5H),5.16(q,J＝12.3Hz,2H),4.54(s,1H),2.91(t,J＝16.4Hz,2H),2.70(t,J＝6.9Hz,2H),2.53(dot,J＝14.3,6.9Hz,2H),2.06(dd,J＝6.1,2.5Hz,1H),1.68(dt,J＝14.0,7.0Hz,2H),1.46(d,J＝30.4Hz,9H),0.55–0.22(m,4H).
Synthesis of Compound 5i
4 (0.50 g,1.10 mmol), potassium carbonate (0.36 g,2.60 mmol), KI (0.56 g,3.40 mmol), p-toluidine (0.60 g,5.60 mmol) were dissolved in acetonitrile and added to a three-necked roundThe bottom flask was stirred at 80℃under reflux until the TLC detection was complete. The compound 5i was isolated and purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =3:1) to give a yellow solid with 73% yield. 1 H NMR(400MHz,CDCl 3 )δ7.31(d,J＝38.5Hz,5H),6.99(d,J＝8.0Hz,2H),6.54(d,J＝8.0Hz,2H),5.19(q,J＝12.2Hz,2H),4.58(s,1H),3.19(dt,J＝13.3,6.8Hz,2H),3.04–2.88(m,2H),2.67–2.48(m,2H),2.24(s,3H),1.90–1.74(m,2H),1.45(s,9H).
Synthesis of Compound 5j
4 (0.50 g,1.10 mmol), potassium carbonate (0.36 g,2.60 mmol), KI (0.56 g,3.40 mmol), p-methoxyaniline (0.69 g,5.60 mmol) were dissolved in acetonitrile and added to a three-necked round bottom flask, and stirred under reflux at 80℃until the TLC detection reaction was complete. The yellow oily matter 5j is obtained through separation and purification by a silica gel chromatographic column (petroleum ether: ethyl acetate (v/v) =3:1), and the yield is 68%. 1 H NMR(400MHz,CDcl 3 )δ7.31(d,J＝36.7Hz,5H),6.84–6.48(m,4H),5.18(q,J＝12.3Hz,2H),4.58(s,1H),3.74(s,3H),3.14(dd,J＝16.9,10.3Hz,2H),3.04–2.89(m,2H),2.68–2.50(m,2H),1.89–1.74(m,2H),1.36(d,J＝63.6Hz,9H).
Synthesis of Compound 5k
4 (0.50 g,1.10 mmol), potassium carbonate (0.36 g,2.60 mmol), KI (0.56 g,3.40 mmol), thiophene methylamine (0.57 mL,5.60 mmol) were dissolved in acetonitrile and added to a three-necked round bottom flask, and stirred under reflux at 80℃until the TLC detection reaction was complete. The yellow oily matter is separated and purified by a silica gel chromatographic column (petroleum ether: ethyl acetate (v/v) =3:1) to obtain yellow oily matter 5k, and the yield is 77%. 1 H NMR(400MHz,CDCl 3 )δ7.30(d,J＝35.3Hz,5H),7.19(d,J＝4.2Hz,1H),6.91(dd,J＝18.6,11.4Hz,2H),5.18(q,J＝12.2Hz,2H),4.63–4.48(m,1H),3.95(s,2H),2.96(s,2H),2.76–2.47(m,4H),1.77–1.64(m,2H),1.44(s,9H).
Synthesis of Compound 5l
4 (0.50 g,1.10 mmol), potassium carbonate (0.36 g,2.60 mmol), KI (0.56 g,3.40 mmol), n-butylamine (0.55 mL,5.60 mmol) were dissolved in acetonitrile and added to a three-necked round bottom flask, stirred at 80℃under reflux until the TLC detection reaction was complete. Separation and purification by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =3:1) gave 5l of yellow oil in 74% yield. 1 H NMR(400MHz,CDCl 3 )δ7.30(d,J＝34.2Hz,4H),5.17(q,J＝12.3Hz,2H),4.56(s,1H),2.95(s,2H),2.70–2.44(m,6H),1.70(dd,J＝13.8,6.8Hz,2H),1.43(s,9H),1.34–1.22(m,2H),0.99–0.77(m,3H).
Synthesis of Compound 5m
4 (0.50 g,1.10 mmol), potassium carbonate (0.36 g,2.60 mmol), KI (0.56 g,3.40 mmol), naphthylamine (0.72 mL,5.60 mmol) were dissolved in acetonitrile and added to a three necked round bottom flask, and stirred under reflux at 80℃until the TLC detection reaction was complete. The yellow oily matter is separated and purified by a silica gel chromatographic column (petroleum ether: ethyl acetate (v/v) =3:1) to obtain yellow oily matter with the yield of 5m being 66%. 1 H NMR(400MHz,CDCl 3 )δ7.83(dd,J＝18.3,7.9Hz,3H),7.52–7.21(m,8H),6.60(d,J＝7.4Hz,1H),5.19(dd,J＝24.6,12.2Hz,2H),4.64(s,1H),3.38(dd,J＝17.4,11.2Hz,2H),3.01(dt,J＝13.3,7.6Hz,2H),2.76–2.58(m,2H),1.98(dd,J＝12.9,6.4Hz,2H),1.54(d,J＝62.3Hz,9H).
Synthesis of Compound 5n
4 (0.50 g,1.10 mmol), potassium carbonate (0.36 g,2.60 mmol), KI (0.56 g,3.40 mmol), parachloroaniline (0.50 mL,5.60 mmol) were dissolved in acetonitrile and added to a three-necked round bottom flask, stirred at 80℃under reflux until the TLC detection reaction was complete. The yellow oily matter 5n is obtained through separation and purification by a silica gel chromatographic column (petroleum ether: ethyl acetate (v/v) =3:1), and the yield is 60%. 1 H NMR(400MHz,CDCl 3 )δ7.35(s,5H),7.10(d,J＝8.6Hz,2H),6.51(d,J＝8.6Hz,2H),5.18(q,J＝12.1Hz,2H),4.57(s,1H),3.15(t,J＝6.5Hz,2H),3.04–2.87(m,2H),2.57(d,J＝3.8Hz,2H),1.80(dd,J＝12.2,6.2Hz,2H),1.44(s,9H).
Synthesis of Compound 6a
Compound 5a (0.61 g,1.20 mmol) was dissolved in dichloromethane and added to a three-necked round bottom flask and placed under zero degree stirring, trifluoroacetic acid (5.00 ml,65.2 mmol) was added dropwise to the reaction system, stirring at room temperature until the TLC detection reaction was complete, concentrating the reaction solution under reduced pressure, adding ethyl acetate (30 ml) for dissolution, washing with saturated sodium bicarbonate (3X 15 ml), drying the organic layer with anhydrous sodium sulfate, concentrating under reduced pressure to give yellow oily substance 6a in 80% yield. 13 C NMR(101MHz,CDCl 3 )δ173.40,147.90,146.58,135.31,130.42,128.70–128.30,121.70,109.02,108.51,101.02,67.09,54.70,49.60,46.41,36.31,32.59,29.83,25.85.
Synthesis of Compound 6b
Compound 5b (0.60 g,1.34 mmol) was dissolved in dichloromethane and added to a three-necked round bottom flask and placed under zero degree stirring, trifluoroacetic acid (5.00 ml,65.2 mmol) was added dropwise to the reaction system, stirring at room temperature until the reaction was complete by TLC, concentrating the reaction solution under reduced pressure, adding ethyl acetate (30 ml) for dissolution, washing with saturated sodium bicarbonate (3 x 15 ml), drying the organic layer with anhydrous sodium sulfate, concentrating under reduced pressure to give yellow oily substance 6b in 89% yield, 1 H NMR(400MHz,DMSO)δ7.52(s,1H),7.36(d,J＝5.1Hz,4H),6.28(d,J＝55.4Hz,2H),5.11(s,2H),3.70–3.51(m,3H),2.72(td,J＝13.2,6.7Hz,6H),1.60(dt,J＝13.6,6.7Hz,2H). 13 C NMR(101MHz,CDCl 3 )δ173.9,153.8,141.8,135.4,128.8–128.3,110.1,106.9,66.9,54.4,47.7,46.1,37.3,30.4,29.8.
synthesis of Compound 6c
Compound 5c (0.60 g,1.33 mmol) was dissolved in dichloromethane and added to a three-necked round bottom flask and placed under zero degree stirring, trifluoroacetic acid (5.00 ml,65.2 mmol) was added dropwise to the reaction system, stirring at room temperature until the reaction was complete by TLC, concentrating the reaction solution under reduced pressure, adding ethyl acetate (30 ml) for dissolution, washing with saturated sodium bicarbonate (3 x 15 ml), drying the organic layer with anhydrous sodium sulfate, concentrating under reduced pressure to give yellow oily substance 6c in 90% yield, 1 H NMR(400MHz,CDCl 3 )δ7.52–7.14(m,5H),5.28–5.02(m,2H),3.73–3.56(m,1H),3.00–2.16(m,17H),1.77–1.62(m,2H). 13 C NMR(101MHz,CDCl 3 )δ173.9,135.5,128.7–128.2(m),66.9,57.0,55.0,54.3,53.0,45.9,37.3,30.5,26.9.
synthesis of Compound 6d
Dissolving compound 5d (0.60 g,1.37 mmol) in dichloromethane, adding into a three-necked round bottom flask, stirring at zero degree, dropwise adding trifluoroacetic acid (5.00 ml,65.2 mmol) into the reaction system, stirring at room temperature until TLC detection reaction is complete, concentrating the reaction solution under reduced pressure, adding ethyl acetate (30 ml) for dissolving, washing with saturated sodium bicarbonate (3×15 ml), drying the organic layer with anhydrous sodium sulfate, concentrating under reduced pressure to obtain yellow oily substance 6d with a yield of 95%, 1 H NMR(400MHz,CDCl 3 )δ7.57–7.12(m,5H),5.17(q,J＝12.3Hz,2H),4.55(s,1H),2.95(s,2H),2.58(dt,J＝48.9,7.0Hz,4H),2.37(t,J＝10.3Hz,1H),1.84(d,J＝11.5Hz,2H),1.78–1.62(m,4H),1.29–0.92(m,6H).
synthesis of Compound 6e
Compound 5e (0.60 g,1.41 mmol) was dissolved in dichloromethane and added to a three-necked round bottom flask and placed under zero degree stirring, trifluoroacetic acid (5.00 ml,65.2 mmol) was added dropwise to the reaction system, stirring at room temperature until the reaction was complete by TLC, concentrating the reaction solution under reduced pressure, adding ethyl acetate (30 ml) for dissolution, washing with saturated sodium bicarbonate (3 x 15 ml), drying the organic layer with anhydrous sodium sulfate, concentrating under reduced pressure to give yellow oily substance 6e in 91% yield, 1 H NMR(400MHz,CDCl 3 )δ7.42–7.20(m,5H),5.15(q,J＝12.3Hz,2H),4.52(s,1H),3.75(s,4H),2.94(s,2H),2.65–2.32(m,8H),1.84–1.71(m,2H).
synthesis of Compound 6f
Dissolving compound 5f (0.60 g,1.42 mmol) in dichloromethane, adding into a three-necked round bottom flask, stirring at zero degree, dropwise adding trifluoroacetic acid (5.00 ml,65.2 mmol) into the reaction system, stirring at room temperature until TLC detection reaction is complete, concentrating the reaction solution under reduced pressure, adding ethyl acetate (30 ml) for dissolving, washing with saturated sodium bicarbonate (3×15 ml), drying the organic layer with anhydrous sodium sulfate, concentrating under reduced pressure to obtain yellow oily substance 6f with yield of 85%, 1 H NMR(400MHz,CDCl 3 )δ7.45–7.23(m,5H),5.26–5.07(m,2H),4.55(d,J＝6.1Hz,1H),2.97(t,J＝15.9Hz,2H),2.56–2.18(m,8H),1.74–1.64(m,2H),1.59–1.35(m,6H).
synthesis of Compound 6g
5g (0.60 g,1.46 mmol) of the compound is dissolved in methylene chloride, a three-necked round bottom flask is added, stirring is carried out at zero degree, trifluoroacetic acid (5.00 ml,65.2 mmol) is added dropwise to the reaction system, stirring is carried out at room temperature until TLC detection reaction is complete, the reaction solution is concentrated under reduced pressure, ethyl acetate (30 ml) is added for dissolution, saturated sodium bicarbonate (3X 15 ml) is used for washing, an organic layer is dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain yellow oily substance 6g, yield 91%, 1 H NMR(400MHz,CDCl 3 )δ7.30(d,J＝32.7Hz,5H),5.17(q,J＝12.4Hz,2H),4.56(s,1H),2.96(s,2H),2.60–2.20(m,8H),1.63(t,J＝14.1Hz,2H),1.11–0.68(m,6H).
synthesis of Compound 6h
Dissolving compound 5h (0.60 g,1.47 mmol) in dichloromethane, adding into a three-necked round bottom flask, stirring at zero degree, dropwise adding trifluoroacetic acid (5.00 ml,65.2 mmol) into the reaction system, stirring at room temperature until TLC detection reaction is complete, concentrating the reaction solution under reduced pressure, adding ethyl acetate (30 ml) for dissolving, washing with saturated sodium bicarbonate (3×15 ml), drying the organic layer with anhydrous sodium sulfate, concentrating under reduced pressure to obtain yellow oily substance 6h with a yield of 94%, 1 H NMR(400MHz,cdcl 3 )δ7.52–7.21(m,5H),5.16(q,J＝12.3Hz,2H),4.54(s,1H),2.91(t,J＝16.4Hz,2H),2.70(t,J＝6.9Hz,2H),2.53(dt,J＝14.3,6.9Hz,2H),2.06(dd,J＝6.1,2.5Hz,1H),1.68(dt,J＝14.0,7.0Hz,2H),0.55–0.22(m,4H).
synthesis of Compound 6i
Dissolving compound 5i (0.60 g,1.31 mmol) in dichloromethane, adding into a three-necked round bottom flask, stirring at zero degree, dropwise adding trifluoroacetic acid (5.00 ml,65.2 mmol) into the reaction system, stirring at room temperature until TLC detection reaction is complete, concentrating the reaction solution under reduced pressure, adding ethyl acetate (30 ml) for dissolving, washing with saturated sodium bicarbonate (3×15 ml), drying the organic layer with anhydrous sodium sulfate, concentrating under reduced pressure to obtain yellow oily substance 6i with yield of 90%, 1 H NMR(400MHz,CDCl 3 )δ7.31(d,J＝38.5Hz,5H),6.99(d,J＝8.0Hz,2H),6.54(d,J＝8.0Hz,2H),5.19(q,J＝12.2Hz,2H),4.58(s,1H),3.19(dt,J＝13.3,6.8Hz,2H),3.04–2.88(m,2H),2.67–2.48(m,2H),2.24(s,3H),1.90–1.74(m,2H).
synthesis of Compound 6j
Dissolving compound 5j (0.60 g,1.27 mmol) in dichloromethane, adding into a three-necked round bottom flask, stirring at zero degree, dropwise adding trifluoroacetic acid (5.00 ml,65.2 mmol) into the reaction system, stirring at room temperature until TLC detection reaction is complete, concentrating the reaction solution under reduced pressure, adding ethyl acetate (30 ml) for dissolving, washing with saturated sodium bicarbonate (3×15 ml), drying the organic layer with anhydrous sodium sulfate, concentrating under reduced pressure to obtain yellow oily substance 6j with yield of 89%, 1 H NMR(400MHz,cdcl 3 )δ7.31(d,J＝36.7Hz,5H),6.84–6.48(m,4H),5.18(q,J＝12.3Hz,2H),4.58(s,1H),3.74(s,3H),3.14(dd,J＝16.9,10.3Hz,2H),3.04–2.89(m,2H),2.68–2.50(m,2H),1.89–1.74(m,2H),
synthesis of Compound 6k
Dissolving compound 5k (0.60 g,1.29 mmol) in dichloromethane, adding into a three-necked round bottom flask, stirring at zero degree, dropwise adding trifluoroacetic acid (5.00 ml,65.2 mmol) into the reaction system, stirring at room temperature until TLC detection reaction is complete, concentrating the reaction solution under reduced pressure, adding ethyl acetate (30 ml) for dissolving, washing with saturated sodium bicarbonate (3×15 ml), drying the organic layer with anhydrous sodium sulfate, concentrating under reduced pressure to obtain yellow oily substance 6k with yield of 89%, 1 H NMR(400MHz,cdcl 3 )δ7.30(d,J＝35.3Hz,5H),7.19(d,J＝4.2Hz,1H),6.91(dd,J＝18.6,11.4Hz,2H),5.18(q,J＝12.2Hz,2H),4.63–4.48(m,1H),3.95(s,2H),2.96(s,2H),2.76–2.47(m,4H),1.77–1.64(m,2H).
synthesis of Compound 6l
5l (0.60 g,1.41 mmol) of the compound is dissolved in methylene chloride, a three-necked round bottom flask is added, stirring is carried out at zero degree, trifluoroacetic acid (5.00 ml,65.2 mmol) is added dropwise to the reaction system, stirring is carried out at room temperature until TLC detection reaction is complete, the reaction solution is concentrated under reduced pressure, ethyl acetate (30 ml) is added for dissolution, saturated sodium bicarbonate (3X 15 ml) is used for washing, an organic layer is dried by anhydrous sodium sulfate, and concentrated under reduced pressure to obtain yellow oily substance 6l with the yield of 87%, 1 H NMR(400MHz,cdcl 3 )δ7.30(d,J＝34.2Hz,4H),5.17(q,J＝12.3Hz,2H),4.56(s,1H),2.95(s,2H),2.70–2.44(m,6H),1.70(dd,J＝13.8,6.8Hz,2H),1.34–1.22(m,2H),0.99–0.77(m,3H).
synthesis of Compound 6m
Dissolving compound 5m (0.60 g,1.21 mmol) in dichloromethane, adding into a three-necked round bottom flask, stirring at zero degree, dropwise adding trifluoroacetic acid (5.00 ml,65.2 mmol) into the reaction system, stirring at room temperature until TLC detection reaction is complete, concentrating the reaction solution under reduced pressure, adding ethyl acetate (30 ml) for dissolving, washing with saturated sodium bicarbonate (3×15 ml), drying the organic layer with anhydrous sodium sulfate, concentrating under reduced pressure to obtain yellow oily substance 6m with yield of 89%, 1 H NMR(400MHz,cdcl 3 )δ7.83(dd,J＝18.3,7.9Hz,3H),7.52–7.21(m,8H),6.60(d,J＝7.4Hz,1H),5.19(dd,J＝24.6,12.2Hz,2H),4.64(s,1H),3.38(dd,J＝17.4,11.2Hz,2H),3.01(dt,J＝13.3,7.6Hz,2H),2.76–2.58(m,2H),1.98(dd,J＝12.9,6.4Hz,2H).
synthesis of Compound 6n
Dissolving compound 5n (0.60 g,1.25 mmol) in dichloromethane, adding into a three-necked round bottom flask, stirring at zero degree, dropwise adding trifluoroacetic acid (5.00 ml,65.2 mmol) into the reaction system, stirring at room temperature until TLC detection reaction is complete, concentrating the reaction solution under reduced pressure, adding ethyl acetate (30 ml) for dissolving, washing with saturated sodium bicarbonate (3×15 ml), drying the organic layer with anhydrous sodium sulfate, concentrating under reduced pressure to obtain yellow oily substance 6n with yield of 85%, 1 H NMR(400MHz,CDCl 3 )δ7.35(s,5H),7.10(d,J＝8.6Hz,2H),6.51(d,J＝8.6Hz,2H),5.18(q,J＝12.1Hz,2H),4.57(s,1H),3.15(t,J＝6.5Hz,2H),3.04–2.87(m,2H),2.57(d,J＝3.8Hz,2H),1.80(dd,J＝12.2,6.2Hz,2H),1.44(s,9H).
the following is a method for synthesizing the target compounds 7a to 7n.
Example 1: synthesis of Compound 7a
Adding a compound 6a (0.5 g) and 10% palladium carbon (0.66 g) into a three-necked round bottom flask, using double exhaust pipes to replace air in the reaction flask, enabling the system to be in argon atmosphere, using hydrogen to replace the reaction flask for three times, adding methanol to introduce a hydrogen balloon, stirring at 35 ℃, reacting the reaction system in the hydrogen environment for 72 hours, detecting the reaction completely by TLC, filtering to remove palladium carbon, distilling the filtrate under reduced pressure to obtain colorless crystalline solid, and separating and purifying the colorless crystalline solid by a silica gel chromatographic column (dichloromethane: methanol (v/v) =20:1) to obtain the compound 7a with the yield of 66%. 1 H NMR(400MHz,DMSO)δ6.78(d,J＝4.8Hz,2H),6.63(d,J＝7.8Hz,1H),5.93(s,2H),3.55(d,J＝42.6Hz,4H),3.05–2.53(m,12H),1.67–1.52(m,2H). 13 C NMR(101MHz,DMSO)δ174.60,147.15,145.35,133.96,121.39,109.03,108.06,100.62,54.48,51.60,50.92,47.69,36.34,35.15,29.54,29.12.HRMS(ESI)calcd for C 16 H 24 N 2 O 4 S[M+H] + 341.1530,found 341.1589.
Example 2: synthesis of Compound 7b
Compound 6b (0.5 g) and 10% palladium on carbon (0.66 g) were charged into a three-necked round bottom flask, the air in the flask was replaced with a double vent, the system was placed under an argon atmosphere, and the mixture was replaced three times with hydrogen gasAdding methanol into the mixture, introducing a hydrogen balloon, stirring the mixture at 35 ℃, reacting the reaction system for 72 hours in a hydrogen environment, detecting the reaction completely by TLC, filtering to remove palladium carbon, distilling the filtrate under reduced pressure to obtain colorless crystalline solid, separating and purifying the colorless crystalline solid by a silica gel chromatographic column (dichloromethane: methanol (v/v) =20:1) to obtain a compound 7b with the yield of 49%, 1 H NMR(400MHz,DMSO)δ7.52(s,1H),6.28(d,J＝55.4Hz,2H),3.82–3.55(m,4H),3.61(s,2H),2.72(td,J＝13.2,6.7Hz,6H),1.60(dot,J＝13.6,6.7Hz,2H). 13 C NMR(101MHz,DMSO)δ173.97,153.84,141.80,110.13,106.91,66.98,54.36,47.73,46.13,37.27,30.44,29.77.HRMS(ESI)calcd for C 12 H 21 N 2 O 3 S[M+H] + 273.1267,found 273.1251.
example 3: synthesis of Compound 7c
Adding a compound 6c (0.5 g) and 10% palladium carbon (0.66 g) into a three-necked round bottom flask, using double-exhaust pipes to replace air in the reaction flask, enabling the system to be in argon atmosphere, using hydrogen to replace the system for three times, adding methanol to introduce a hydrogen balloon, stirring at 35 ℃, reacting the reaction system in the hydrogen environment for 72 hours, detecting the reaction completely by TLC, filtering to remove palladium carbon, distilling the filtrate under reduced pressure to obtain colorless crystalline solid, separating and purifying the colorless crystalline solid by a silica gel chromatographic column (dichloromethane: methanol (v/v) =20:1) to obtain the compound 7c with the yield of 52%, 1 H NMR(400MHz,CD 3 OD)δ3.74(s,3H),3.69(t,J＝6.0Hz,1H),2.97–2.43(m,12H),2.37(s,3H),1.83–1.75(m,2H). 13 C NMR(101MHz,CD 3 OD)δ175.29,57.81,55.31,54.89,53.25,52.76,45.60,37.23,30.99,27.34.HRMS(ESI)calcd for C 12 H 26 N 3 O 2 S[M+H] + 276.1740,found 276.1738.
example 4: synthesis of Compound 7d
Adding 6d (0.5 g) of compound and 10% palladium carbon (0.66 g) into a three-necked round bottom flask, replacing air in the reaction flask with double-exhaust pipes to enable the system to be in argon atmosphere, replacing the system with hydrogen for three times, adding methanol, introducing a hydrogen balloon, stirring at 35 ℃, reacting the reaction system in the hydrogen environment for 72 hours, detecting the reaction completely by TLC, filtering to remove palladium carbon, distilling the filtrate under reduced pressure to obtain colorless crystalline solid, and purifying the colorless crystalline solid by a silica gel chromatographic column(dichloromethane: methanol (v/v) =20:1) to obtain compound 7d with a yield of 55%, 1 H NMR(400MHz,CD 3 OD)δ3.73(dd,J＝10.6,3.0Hz,4H),3.16–2.79(m,5H),2.67(t,J＝6.8Hz,2H),2.12(s,2H),1.93(dd,J＝23.8,16.4Hz,4H),1.30(ddd,J＝33.0,20.5,10.8Hz,6H). 13 C NMR(101MHz,CD 3 OD)δδ174.56,57.06,54.31,53.55,43.09,39.17,35.44,33.35,29.00,28.76,28.62,26.02,25.78,24.84,24.69,24.29,24.06.HRMS(ESI)calcd for C 13 H 27 N 2 O 2 S[M+H] + 275.1788,found 275.1786.
example 5: synthesis of Compound 7e
Adding a compound 6e (0.5 g) and 10% palladium carbon (0.66 g) into a three-necked round bottom flask, replacing air in the reaction flask by using a double-exhaust pipe, enabling the system to be in argon atmosphere, replacing the reaction flask by using hydrogen for three times, adding methanol, introducing a hydrogen balloon, stirring at 35 ℃, reacting the reaction system in the hydrogen environment for 72 hours, detecting the reaction completely by TLC, filtering to remove palladium carbon, distilling the filtrate under reduced pressure to obtain a colorless crystalline solid, and separating and purifying the colorless crystalline solid by using a silica gel chromatographic column (dichloromethane: methanol (v/v) =20:1) to obtain the compound 7e, wherein the yield is 75%, and m.p.80-81 ℃. 1 H NMR(400MHz,CDCl 3 )δ3.74(s,3H),3.65(t,J＝6.0Hz,1H)3.55(s,4H),2.94(s,2H),2.65–2.32(m,8H),1.84–1.71(m,2H). 13 C NMR(101MHz,CDCl 3 )δ170.98,70.19,67.43,66.15,60.19,34.58,30.31,28.36,25.55.HRMS(ESI)calcd for C 11 H 23 N 2 O 3 S[M+H] + 263.1424,found 263.1420.
Example 6: synthesis of Compound 7f
Adding a compound 6f (0.5 g) and 10% palladium carbon (0.66 g) into a three-necked round bottom flask, using double exhaust pipes to replace air in the reaction flask, enabling the system to be in argon atmosphere, using hydrogen to replace the system for three times, adding methanol to introduce a hydrogen balloon, stirring at 35 ℃, reacting the reaction system in the hydrogen environment for 72 hours, detecting the reaction completely by TLC, filtering to remove palladium carbon, distilling the filtrate under reduced pressure to obtain colorless crystalline solid, separating and purifying the colorless crystalline solid by a silica gel chromatographic column (dichloromethane: methanol (v/v) =20:1) to obtain the compound 7f with the yield of 47%, 1 H NMR(400MHz,CDCl 3 )δ3.69(s,3H),3.60(dd,J＝7.3,4.7Hz,1H),2.87(dd,J＝13.5,4.6Hz,1H),2.71(dd,J＝13.5,7.5Hz,1H),2.51(t,J＝7.3Hz,2H),2.31(t,J＝7.2Hz,6H),1.77–1.67(m,2H),1.57–1.47(m,4H),1.37(s,2H). 13 C NMR(101MHz,CDCl 3 )δ174.56,58.03,54.61,54.19,52.24,37.36,30.66,26.95,25.95,24.43.HRMS(ESI)calcd for C 11 H 23 N 2 O 3 S[M+H] + 261.1631,found 261.1634.
example 7: synthesis of Compound 7g
Adding 6g (0.5 g) of compound and 10% palladium carbon (0.66 g) into a three-necked round bottom flask, using double-exhaust pipes to replace air in the reaction flask, enabling the system to be in argon atmosphere, using hydrogen to replace the system for three times, adding methanol to introduce a hydrogen balloon, stirring at 35 ℃, reacting the reaction system in the hydrogen environment for 72 hours, detecting the reaction completely by TLC, filtering to remove palladium carbon, distilling the filtrate under reduced pressure to obtain colorless crystalline solid, separating and purifying the colorless crystalline solid by a silica gel chromatographic column (dichloromethane: methanol (v/v) =20:1) to obtain 7g of compound with the yield of 67%, 1 H NMR(400MHz,CD 3 OD)δ3.83–3.58(m,4H),2.87(ddd,J＝20.1,13.6,6.0Hz,2H),2.64(dq,J＝27.7,7.0Hz,8H),1.79(dt,J＝14.7,7.2Hz,2H),1.11(t,J＝7.2Hz,6H). 13 C NMR(101MHz,CD 3 OD)δ175.44,54.98,52.65,52.29,47.93,37.47,31.09,26.73,10.97.HRMS(ESI)calcd for C 11 H 25 N 2 O 2 S[M+H] + 249.1631,found 249.1634.
example 8: synthesis of Compound 7h
Adding 6h (0.5 g) of a compound and 10% palladium carbon (0.66 g) into a three-necked round bottom flask, using double-exhaust pipes to replace air in the reaction flask, enabling the system to be in argon atmosphere, using hydrogen to replace the system for three times, adding methanol to introduce a hydrogen balloon, stirring at 35 ℃, reacting the reaction system in the hydrogen environment for 72 hours, detecting the reaction completely by TLC, filtering to remove palladium carbon, distilling the filtrate under reduced pressure to obtain colorless crystalline solid, separating and purifying the colorless crystalline solid by a silica gel chromatographic column (dichloromethane: methanol (v/v) =20:1) to obtain the compound 7h with the yield of 54%, 1 H NMR(400MHz,CD 3 OD)δ3.74(s,3H),3.65(t,J＝6.0Hz,1H),2.95–2.49(m,6H),2.15(ddd,J＝10.4,6.9,3.7Hz,1H),1.83–1.73(m,2H),0.58–0.27(m,4H). 13 C NMR(101MHz,CD 3 OD)δ175.49,54.94,52.63,37.44,31.15,30.17,5.98.HRMS(ESI)calcd for C 10 H 21 N 2 O 2 S[M+H] + 233.1318,found 233.1316.
example 9: synthesis of Compound 7i
Adding a compound 6i (0.5 g) and 10% palladium carbon (0.66 g) into a three-necked round bottom flask, replacing air in the reaction flask by using a double-exhaust pipe, enabling the system to be in argon atmosphere, replacing the reaction flask by using hydrogen for three times, adding methanol, introducing a hydrogen balloon, stirring at 35 ℃, reacting the reaction system in the hydrogen environment for 72 hours, detecting the reaction completely by TLC, filtering to remove palladium carbon, distilling the filtrate under reduced pressure to obtain a colorless crystalline solid, and separating and purifying the colorless crystalline solid by using a silica gel chromatographic column (dichloromethane: methanol (v/v) =20:1) to obtain the compound 7i, wherein the yield is 69%, and m.p.57-59 ℃. 1 H NMR(400MHz,CDCL 3 )δ6.98(d,J＝8.2Hz,2H),6.54(d,J＝8.2Hz,2H),3.88–3.50(m,4H),3.31–3.11(m,2H),3.01–2.56(m,4H),2.23(s,3H),1.94–1.80(m,2H). 13 C NMR(101MHz,CDCl 3 )δ174.52,145.87,129.79,126.61,113.01,54.22,52.31,42.99,37.30,30.24,29.19,20.42.HRMS(ESI)calcd for C 14 H 23 N 2 O 2 S[M+H] + 283.1475,found 283.1473.
Example 10: synthesis of Compound 7j
Adding a compound 6j (0.5 g) and 10% palladium carbon (0.66 g) into a three-necked round bottom flask, replacing air in the reaction flask by using a double-exhaust pipe, enabling the system to be in argon atmosphere, replacing the reaction flask by using hydrogen for three times, adding methanol, introducing a hydrogen balloon, stirring at 35 ℃, reacting the reaction system in the hydrogen environment for 72 hours, detecting the reaction completely by TLC, filtering to remove palladium carbon, distilling the filtrate under reduced pressure to obtain a colorless crystalline solid, and separating and purifying the colorless crystalline solid by using a silica gel chromatographic column (dichloromethane: methanol (v/v) =20:1) to obtain the compound 7j, wherein the yield is 70%, and m.p.59-61 ℃. 1 H NMR(400MHz,CDCl 3 )δ6.67(dd,J＝77.4,8.7Hz,4H),3.79–3.56(m,7H),3.26–3.06(m,2H),3.01–2.69(m,2H),2.73–2.55(m,2H),2.32(s,3H),1.86(p,J＝6.8Hz,2H). 13 C NMR(101MHz,CDCl 3 )δ174.52,152.17,142.37,114.97,114.19,55.87,54.23,52.33,43.66,37.28,30.27,29.25.HRMS(ESI)calcd for C 14 H 23 N 2 O 3 S[M+H] + 299.1424,found 299.1425.
EXAMPLE 11 Synthesis of Compound 7k
Adding 6k (0.5 g) of compound and 10% palladium carbon (0.66 g) into a three-necked round bottom flask, using double-exhaust pipes to replace air in the reaction flask, enabling the system to be in argon atmosphere, using hydrogen to replace the system for three times, adding methanol to introduce a hydrogen balloon, stirring at 35 ℃, reacting the reaction system in the hydrogen environment for 72 hours, detecting the reaction completely by TLC, filtering to remove palladium carbon, distilling the filtrate under reduced pressure to obtain colorless crystalline solid, separating and purifying the colorless crystalline solid by a silica gel chromatographic column (dichloromethane: methanol (v/v) =20:1) to obtain 7k of compound with the yield of 72%, 1 H NMR(400MHz,CDCl 3 )δ7.19(d,J＝4.8Hz,1H),6.98–6.85(m,2H),3.97(s,2H),3.82–3.55(m,4H),2.82(ddd,J＝23.4,13.4,5.3Hz,4H),2.60(t,J＝7.1Hz,2H),1.76(dd,J＝13.8,6.8Hz,2H). 13 C NMR(101MHz,CDCl 3 )δ174.50,143.88,126.62,124.91,124.38,109.99,54.14,52.23,48.26,47.64,37.25,30.33,29.70.HRMS(ESI)calcd for C 12 H 21 N 2 O 2 S 2 [M+H] + 289.1039,found 289.1039.
EXAMPLE 12 Synthesis of Compound 7l
Adding 6l (0.5 g) of compound and 10% palladium carbon (0.66 g) into a three-necked round bottom flask, using double-exhaust pipes to replace air in the reaction flask, enabling the system to be in argon atmosphere, using hydrogen to replace the system for three times, adding methanol to introduce hydrogen balloon, stirring at 35 ℃, reacting the reaction system in the hydrogen environment for 72 hours, detecting the reaction completely by TLC, filtering to remove palladium carbon, decompressing and distilling the filtrate to obtain colorless crystalline solid, separating and purifying the colorless crystalline solid by a silica gel chromatographic column (dichloromethane: methanol (v/v) =20:1) to obtain 7l of compound with the yield of 65%, 1 H NMR(400MHz,CDCl 3 )δ3.72(s,4H),3.19–2.43(m,8H),2.09–1.88(m,2H),1.64(dd,J＝14.7,7.3Hz,2H),1.36(dd,J＝14.6,7.3Hz,2H),0.90(t,J＝7.2Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ173.87,172.33,162.31,145.89,118.13,115.52,115.22,113.13,54.36,52.46,47.87,46.33,36.17,29.64,27.95,25.47,19.90,13.51.HRMS(ESI)calcd for C 11 H 25 N 2 O 2 S[M+H] + 249.1631,found 249.1629.
EXAMPLE 13 Synthesis of Compound 7m
Adding 6m (0.5 g) of compound and 10% palladium carbon (0.66 g) into a three-necked round bottom flask, using double-exhaust pipes to replace air in the reaction flask, enabling the system to be in argon atmosphere, using hydrogen to replace the system for three times, adding methanol to introduce hydrogen balloon, stirring at 35 ℃, reacting the reaction system in the hydrogen environment for 72 hours, detecting the reaction completely by TLC, filtering to remove palladium carbon, decompressing and distilling the filtrate to obtain colorless crystalline solid, separating and purifying the colorless crystalline solid by a silica gel chromatographic column (dichloromethane: methanol (v/v) =20:1) to obtain the compound 7m with the yield of 59%, 1 H NMR(400MHz,CDCl 3 )δ7.80(t,J＝9.0Hz,2H),7.54–7.14(m,4H),6.61(d,J＝7.4Hz,1H),3.85–3.56(m,4H),3.40(t,J＝6.2Hz,2H),3.05–2.62(m,4H),2.04(dd,J＝12.6,6.6Hz,2H). 13 C NMR(101MHz,CDCl 3 )δ174.43,143.29,134.34,128.68,126.64,125.75,124.71,123.44,119.94,117.36,104.26,54.20,52.33,42.94,37.24,30.45,29.74,28.82.HRMS(ESI)calcd for C 17 H 23 N 2 O 2 S[M+H] + 319.1475,found 319.1473.
EXAMPLE 14 Synthesis of Compound 7n
Adding 6n (0.5 g) of compound and 10% palladium carbon (0.66 g) into a three-necked round bottom flask, using double-exhaust pipes to replace air in the reaction flask, enabling the system to be in argon atmosphere, using hydrogen to replace the system for three times, adding methanol to introduce hydrogen balloon, stirring at 35 ℃, reacting the reaction system in the hydrogen environment for 72 hours, detecting the reaction completely by TLC, filtering to remove palladium carbon, decompressing and distilling the filtrate to obtain colorless crystalline solid, separating and purifying the colorless crystalline solid by a silica gel chromatographic column (dichloromethane: methanol (v/v) =20:1) to obtain 7n of compound with the yield of 66%, 1 H NMR(400MHz,CDCl 3 )δ7.09(d,J＝8.8Hz,2H),6.51(d,J＝8.8Hz,2H),3.93–3.58(m,4H),3.31–3.12(m,2H),2.84(ddd,J＝20.6,13.5,6.0Hz,2H),2.69–2.56(m,2H),1.92–1.79(m,2H). 13 C NMR(101MHz,CDCl 3 )δ174.53,146.72,121.87,113.85,54.28,52.37,42.70,37.30,30.20,28.93.HRMS(ESI)calcd for C 13 H 20 ClN 2 O 2 S[M+H] + 303.0929,found 303.0927.
the following experiments prove the beneficial effects of the invention.
Experimental example 1: test Compounds for their ability to inhibit MUC5AC secretion
This experimental example uses TNF-alpha to stimulate NCI-292H cells and a model of COPD cells was constructed to test the ability of each compound to inhibit MUC5AC secretion.
1. Cell origin
NCI-H292 cells were purchased from Shanghai reputation biotechnology limited and STR assays were performed to confirm the presence of pathogens in compliance with NCI-H292 cell characteristics.
Establishment of TNF-alpha-induced NCI-H292 cell model
(1) NCI-H292 cells were raised and cultured according to 2X 10 4 Well plates/Kong Dianru 96 well plates.
(2) After the cells are stably attached, adding the medicine to be detected into each cell hole according to an experimental plan, and incubating for 2 hours.
(3) TNF- α was spotted into each cell well to give a final concentration of 20ng/mL.
(4) The cell culture plates were placed in a cell incubator and incubated for 24 hours.
(5) MUC5AC concentration in cell supernatants was detected using a MUC5AC kit.
3. Medicine dissolving and adding method
Ultrapure grade DMSO was used as compound mother liquor. The compound concentrations were 0.5, 1.0, 3.0, 9.0, 20.0mg/mL, and the final concentration of DMSO was 0.5%, 1.0%, 3.0%, 0.9%, 2.0%.
ELISA method for detecting MUC5AC in cell supernatant
(1) 100. Mu.L of each cell culture plate supernatant was spotted into the corresponding position of ELISA plate, and 10. Mu.L of 10 Xsample dilution was added to each well and incubated at 4℃for 24 hours.
(2) The ELISA plate was washed 5 times with wash solution.
(3) HRP conjugated secondary antibody was added to each well and incubated for 30 min at room temperature.
(4) The ELISA plate was washed 5 times with wash solution.
(5) ELISA developer is added and developed for 5-15 minutes.
(6) Adding a stop solution.
(7) And reading data by using an enzyme label instrument.
5. Statistical analysis
Statistical analysis was performed using PRISM 5.0 and Origin8.5 software. Results are expressed as mean.+ -. Standard deviation, with two sets of data being statistically analyzed using Student's-test and multiple sets of data being statistically analyzed using One-way ANOVA. * (P < 0.05) or (P < 0.01) is considered to have significant differences.
6. Results
The recombinant TNF-alpha is used for stimulating NCI-292 cells to successfully construct an extracellular secretion model of MUC5 AC. Calculation of IC for inhibiting MUC5AC secretion of each Compound based on test results 50 Values, results are shown in table 1.
TABLE 1 results of Compounds' ability to inhibit MUC5AC secretion test
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It can be seen that the compounds of the present invention are effective in inhibiting MUC5AC secretion in TNF- α -induced NCI-H292 cell model, especially compounds 7e, 7f, 7g, 7H, 7j, which are even better than the positive control Fudosteine.
The experimental result shows that the compound can be used for preparing the medicine for inhibiting MUC5AC secretion, and has wide application prospect in preparing medicines for preventing and/or treating respiratory diseases such as COPD and the like.
In summary, the invention provides a compound for inhibiting MCU5AC secretion and pharmaceutical application thereof. The compound can effectively inhibit MUC5AC secretion, in particular to compounds 7e, 7f, 7g, 7h and 7j, and the inhibition effect is even better than that of positive control Fudosteine. The compound can be used for preparing medicines for inhibiting MUC5AC secretion, and has wide application prospects in preparing medicines for preventing and/or treating respiratory diseases such as chronic obstructive pulmonary diseases and the like.

Claims (10)

1. A compound, a pharmaceutically acceptable salt thereof, characterized in that: the structure of the compound is shown as a formula II:
wherein Y is selected from O, S, CH 2 。
2. A compound, a pharmaceutically acceptable salt thereof, characterized in that: the structure of the compound is shown in a formula III:
wherein R is a’ Selected from C 1-3 Alkyl, R b’ Selected from C 1-3 An alkyl group.
3. A compound, a pharmaceutically acceptable salt thereof, characterized in that: the structure of the compound is shown in a formula IV:
wherein R is c1 Selected from hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, halogen.
4. A compound, a pharmaceutically acceptable salt thereof, characterized in that: the structure of the compound is shown as a formula V:
wherein R is c2 Selected from C 1-3 An alkyl group.
5. A compound, a pharmaceutically acceptable salt thereof, characterized in that: the compound is one of the following compounds:
6. the preparation method of the compound shown in the formula I is characterized by comprising the following steps: the method comprises the following steps:
(a) Reacting the compound I-1 with benzyl alcohol and thionyl chloride to obtain a compound I-2;
(b) Reacting the compound I-2 with an amino protecting reagent to obtain a compound I-3;
(c) Reacting the compound I-3 with methylsulfonyl chloride to obtain a compound I-4;
(d) Compound I-4Reacting to obtain a compound I-5;
(e) Reacting the compound I-5 with a deprotection reagent to obtain a compound I-6;
(f) Reacting the compound I-6 with a palladium-carbon catalyst in a hydrogen atmosphere to obtain a compound shown in a formula I; wherein,is-> Y is as defined in claim 1, R a’ And R is b’ As described in claim 2, R c1 As described in claim 3, R c2 As claimed in claim 4; r is R x Is an amino protecting group.
7. A medicament for inhibiting the secretion of MCU5AC, characterized in that: a preparation comprising the compound according to any one of claims 1 to 5, a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable adjuvant.
8. Use of a compound according to any one of claims 1-5, a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting MCU5AC secretion.
9. Use according to claim 8, characterized in that: the medicament for inhibiting the secretion of MCU5AC is a medicament for preventing and/or treating respiratory diseases.
10. Use according to claim 9, characterized in that: the respiratory diseases are chronic obstructive pulmonary disease, bronchial asthma, chronic asthmatic bronchitis, bronchiectasis, pulmonary tuberculosis, pneumoconiosis, atypical mycobacteriosis, pneumonia, diffuse bronchitis, and lung cancer.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4512979A (en) * 1981-03-23 1985-04-23 Merck & Co., Inc. Dipeptides containing thialysine and related amino acids as antihypertensives
US4826814A (en) * 1986-05-09 1989-05-02 Dainippon Pharmaceutical Co., Ltd. Tripeptide derivatives
CN1376143A (en) * 1999-07-26 2002-10-23 东丽株式会社 Carboxylic acid derivatives and adhesion molecule inhibitors containing the same as the active ingredient
CN108752250A (en) * 2018-04-23 2018-11-06 浙江国邦药业有限公司 A kind of synthetic method of high-purity Fudosteine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4512979A (en) * 1981-03-23 1985-04-23 Merck & Co., Inc. Dipeptides containing thialysine and related amino acids as antihypertensives
US4826814A (en) * 1986-05-09 1989-05-02 Dainippon Pharmaceutical Co., Ltd. Tripeptide derivatives
CN1376143A (en) * 1999-07-26 2002-10-23 东丽株式会社 Carboxylic acid derivatives and adhesion molecule inhibitors containing the same as the active ingredient
CN108752250A (en) * 2018-04-23 2018-11-06 浙江国邦药业有限公司 A kind of synthetic method of high-purity Fudosteine

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
"Hydroxyl-Tolerated Polymerization of N-Phenoxycarbonyl α-Amino Acids: A Simple Way to Polypeptides Bearing Hydroxyl Groups";Zhening Yang et al.;《JOURNAL OF POLYMER SCIENCE, PART A: POLYMER CHEMISTRY》;第57卷;第907-916页 *
"Impact of the Molecular Environment on Thiol−Ene Coupling For Biofunctionalization and Conjugation";Burcu Colak et al.;《Bioconjugate Chemistry》;第27卷;第2111−2123页 *
"福多司坦对慢性阻塞性肺疾病急性加重期患者痰液黏蛋白5AC研究";魏华生 等;《中国实用内科杂志》;第37卷(第8期);第751-753页 *
"福多司坦对肺癌细胞黏蛋白MUC1 和MUC5AC 的抑制作用研究";王乙妃 等;《中国现代应用药学》;第39卷(第7期);第868-877页 *

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