CN113735846A - Benzothiazole derivative and medical application thereof - Google Patents

Benzothiazole derivative and medical application thereof Download PDF

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CN113735846A
CN113735846A CN202111183788.0A CN202111183788A CN113735846A CN 113735846 A CN113735846 A CN 113735846A CN 202111183788 A CN202111183788 A CN 202111183788A CN 113735846 A CN113735846 A CN 113735846A
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benzothiazole
yloxy
piperidine
nmr
pcsk9
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李文燕
王丽
刘洪涛
洪斌
许艳妮
司书毅
李文雅
姜珊
冀凯
李玥
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Institute of Medicinal Biotechnology of CAMS
Hebei Normal University
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Institute of Medicinal Biotechnology of CAMS
Hebei Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

The invention discloses a benzothiazole derivative and medical application thereof. The invention provides a series of benzothiazole derivatives, and researches show that the series of benzothiazole derivatives can effectively inhibit the transcription level of PCSK9, so the derivatives have the prospect of being developed into PCSK9 inhibitor medicines and the prospect of being developed into medicines for treating diseases which are relieved by inhibiting the transcription level of PCSK 9.

Description

Benzothiazole derivative and medical application thereof
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a benzothiazole derivative and medical application thereof.
Background
Cardiovascular disease (CVD) is a global disease, and the number of deaths per year from cardiovascular disease is greater than that from any other cause, and is the first cause of death worldwide. Atherosclerosis (AS) is the major pathological basis of CVD. Low density lipoprotein cholesterol (LDL-C) plays an important role in the generation and development of AS by promoting the formation of foam cells and inflammatory reactions. Elevated serum LDL-C levels are a major risk factor for the development of cardiovascular disease. Epidemiological studies have demonstrated that lowering LDL-C reduces the risk of cardiovascular disease, with lower levels of LDL-C also reducing the incidence of cardiovascular events. Numerous clinical trials have demonstrated that there is no lower limit to lowering LDL-C, and lower levels of LDL-C may be more beneficial in high risk patients.
Low Density Lipoprotein (LDL) clearance mediated by the LDLR receptor is a major factor in determining LDL-C levels in circulation. LDLR on the cell surface can be combined with LDL in plasma to mediate the cellular uptake of LDL to transport the LDL to lysosome for degradation, while LDLR is recycled to the cell surface to continue playing the role of reducing LDL.
Proprotein convertase subtilisin type 9 (PCSK 9) is a liver secretory protein. PCSK9 can prevent LDLR circulation in hepatocytes by directly binding to LDLR, thereby elevating LDL-C levels. PCSK9 can also be secreted into blood, PCSK9 in blood can be combined with LDLR on cell surface specifically to form complex and transported to lysosome, so that LDLR is degraded at high speed, LDL-C can not enter liver to be metabolized, and LDL-C level is raised. Therefore, inhibition of PCSK9 can significantly reduce plasma LDL-C levels.
In 2003, researchers found two PCSK9 gene mutations, S127R and F216L, in two autosomal dominant forms of familial hypercholesterolemia, french families, which may lead to severe familial hypercholesterolemia. In 2005, researchers described two PCSK9 loss-of-function mutations, Y142X and C679X, which were more frequent in african american populations with LDL-C levels (100 ± 45) mg/dL, 28% less than normal (138 ± 42) mg/dL, and 88% less risk of coronary heart disease. This finding establishes a causal relationship between two relatively common "loss of function" mutations in PCSK9 and low plasma LDL-C levels.
Two FDA-approved human monoclonal antibodies are currently used in the clinic, AIirocumab and Evolcumab, respectively. The monoclonal antibody inhibits the interaction of PCSK9 with LDLR by neutralizing PCSK9, resulting in an increase in the number of LDLR and ultimately enhanced LDL uptake. In patients with hypercholesterolemia and dyslipidemia with non-familial cholesterol elevation, LDL levels can be significantly reduced by up to 60% when Alirocumab or evocumumab is used alone or monoclonal antibodies are used in combination with other lipid lowering drugs. In addition, PCSK9 siRNA medicine Inclisiran is also marketed in 2020, has significant curative effect, and as long-acting lipid-lowering medicine, Inclisiran only needs to be subcutaneously injected twice a year to effectively lower the level of low-density lipoprotein LDL-C in blood circulation, so as to achieve the effect of lowering blood fat. The PCSK9 monoclonal antibody and the siRNA medicament can reduce the incidence rate of cardiovascular events and liver dysfunction and reverse atherosclerotic plaques, but the cost caused by the preparation of the antibody and the siRNA is too high, so that the popularization of the antibody and the siRNA is limited.
Inhibition of PCSK9 expression by small molecule compounds has been extremely challenging. The research on small molecule PCSK9 inhibitors is increasing, and part of candidate compounds enter the phase I clinical research. Compared with monoclonal antibody medicines, the small molecular compound has the advantages of more medicine dosage form selectivity and lower treatment cost. Since the binding site of PCSK9 and LDLR lacks a drug action pocket and small-molecule compounds are difficult to bind, the reduction of plasma cholesterol level by inhibiting the expression of PCSK9 transcript level becomes a new direction for preventing and treating AS. Therefore, the search for the small molecular PCSK9 transcription inhibitor has important significance for preventing and treating hyperlipidemia and coronary heart disease and developing new lipid-lowering drugs.
Disclosure of Invention
The invention aims to provide a benzothiazole derivative and medical application thereof.
The above purpose of the invention is realized by the following technical scheme:
a benzothiazole derivative, the chemical structural formula of which is one of the following structural formulas:
Figure BDA0003298363960000021
Figure BDA0003298363960000031
the benzothiazole derivative is used for preparing a PCSK9 inhibitor medicine.
The benzothiazole derivative is used for preparing a medicament for treating diseases relieved by inhibiting the transcription level of PCSK 9.
Has the advantages that:
the invention provides a series of benzothiazole derivatives, and researches show that the series of benzothiazole derivatives can effectively inhibit the transcription level of PCSK9, so the derivatives have the prospect of being developed into PCSK9 inhibitor medicines and the prospect of being developed into medicines for treating diseases which are relieved by inhibiting the transcription level of PCSK 9.
Detailed Description
The following examples are given to illustrate the essence of the present invention, but not to limit the scope of the present invention.
EXAMPLE 12 preparation of Ethyl- { [1- (2, 6-dichlorobenzenesulfonyl) -piperidine ] -4-yloxy } benzothiazole-6-carboxylate
1.2-Chlorobenzothiazole-6-carboxylic acid ethyl ester
Anhydrous CuCl is added2Dissolving the mixture in 30mL of anhydrous acetonitrile, adding tert-butyl nitrite in ice bath, adding 2-aminobenzothiazole-6-ethyl formate into the reaction solution by three times, and monitoring the reaction progress by TLC. After completion of the reaction, acetonitrile was distilled off under reduced pressure, a 1N HCl aqueous solution was added to the reaction solution, water, ethyl acetate and a saturated salt water washing agent were added in this order, and the organic phase was washed with anhydrous MgSO4Drying, vacuum filtering, vacuum concentrating, and separating by column chromatography to obtain white solid with yield of 79.7%. The melting point was 134-135 ℃.1H NMR(400MHz,DMSO)δ8.82(d,J＝1.8Hz,1H),8.13-8.01(m,2H),4.39(q,J＝7.1Hz,2H),1.38(t,J＝7.1Hz,3H).13C NMR(101MHz,DMSO)δ165.54,157.38,153.80,136.53,127.98,127.62,124.87,122.87,61.62,14.66,14.58.ESI-MS,m/z:242.1[M+H]+,244.1[M+Na]+.
2.1- (2, 6-Dichlorobenzenesulfonyl) -4-hydroxypiperidine
4-hydroxypiperidine was dissolved in redistilled tetrahydrofuran, and 2, 6-dichlorobenzenesulfonyl chloride was added to the reaction flask in three portions, one hour apart, with pyridine being added at each end. Stirring at room temperature, and after 7h, the reaction is complete. The reaction solution was distilled under reduced pressure to remove the solvent, and water was added to the reaction flask to extract with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered under reduced pressure and concentrated to give a crude product as a yellow oily compound with a yield of 83%. The crude product is directly put into the next reaction without purification. ESI-MS, M/z 310.0[ M + H ]]+.
3.2- { [1- (2, 6-Dichlorobenzenesulfonyl) -piperidine ] -4-yloxy } benzothiazole-6-carboxylic acid ethyl ester
Dissolving 1- (2, 6-dichlorobenzenesulfonyl) -4-hydroxypiperidine in acetonitrile, adding Cs2CO3Heating to 50 ℃, stirring for 1h, adding 2-chlorobenzothiazole-6-ethyl formate, and stopping reaction after 5 h. The reaction solution was distilled under reduced pressure to remove the solvent, water was added thereto, and extraction was performed with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, concentrated by suction filtration under reduced pressure, and separated by column chromatography to give the subtitle compound 2- { [1- (2, 6-dichlorobenzenesulfonyl) -piperidine as a white powder]-4-yloxy } benzeneBenzothiazole-6-carboxylic acid ethyl ester, yield 51%. The melting point is 116-118 ℃.1H NMR(CDCl3,400MHz)δ8.36(d,J＝1.4Hz,1H),8.06(dd,J＝8.5,1.6Hz,1H),7.66(d,J＝8.5Hz,1H),7.48(d,J＝8.1Hz,2H),7.36-7.32(m,1H),5.45-5.43(m,1H),4.39(q,J＝7.1Hz,2H),3.67-3.61(m,2H),3.55-3.49(m,2H),2.22-2.17(m,2H),2.12-2.05(m,2H),1.41(t,J＝7.1Hz,3H).13C NMR(CDCl3,101MHz)δ174.29,166.31,152.92,135.85,135.35,132.00,131.87,127.82,126.06,123.58,123.42,120.57,76.71,61.32,42.58,30.47,14.59.ESI-MS,m/z:537.0[M+Na]+.
Example preparation of Ethyl 22- { [1- (2, 4-dichlorobenzenesulfonyl) -piperidine ] -4-yloxy } benzothiazole-6-carboxylate
The same procedures used in example 1 were repeated except for using 4-hydroxypiperidine and 2, 4-dichlorobenzenesulfonyl chloride as starting materials for the second step in the procedure for example 1 to prepare 2- { [1- (2, 4-dichlorobenzenesulfonyl) -piperidine, a subtitle compound]-4-yloxy } benzothiazole-6-carboxylic acid ethyl ester as a white powder solid in 45% yield. The melting point was 140 ℃ and 142 ℃.1H NMR(CDCl3,400MHz)δ8.36(d,J＝1.1Hz,1H),8.04(dd,J＝16.3,8.4Hz,2H),7.65(d,J＝8.5Hz,1H),7.56(d,J＝1.8Hz,1H),7.39(dd,J＝8.5,1.8Hz,1H),5.42(s,1H),4.39(q,J＝7.1Hz,2H),3.55-3.39(m,4H),2.20-2.04(m,4H),1.40(t,J＝7.1Hz,3H).13C NMR(CDCl3,101MHz)δ174.25,166.32,152.86,139.75,135.34,133.44,133.09,132.31,132.07,131.85,127.83,126.08,123.37,120.45,76.53,61.33,42.66,30.43,14.51.ESI-MS,m/z:537.0[M+Na]+.
Example preparation of Ethyl 32- { [1- (2, 3-dichlorobenzenesulfonyl) -piperidine ] -4-yloxy } benzothiazole-6-carboxylate
The subtitle compound 2- { [1- (2, 3-dichlorobenzenesulfonyl) -piperidine was prepared according to the procedure for the step of example 1 in the same manner as in example 1 except that the second-step starting materials were 4-hydroxypiperidine and 2, 3-dichlorobenzenesulfonyl chloride]-4-yloxy } benzothiazole-6-carboxylic acid ethyl ester in 42% yield as white powder solid. The melting point is 144-146 ℃. 1H NMR (cdcl3,400mhz) δ 8.36(d, J ═ 1.2Hz,1H),8.05(td, J ═ 8.2,1.5Hz,2H),7.70-7.65(m,2H),7.36(t, J ═ 8.0Hz,1H),5.45-5.42(m,1H),4.39 (H), 1H), and c(q,J＝7.1Hz,2H),3.60-3.42(m,4H),2.22-2.04(m,4H),1.40(t,J＝7.1Hz,3H).13C NMR(CDCl3,101MHz)δ174.28,166.33,152.84,139.03,136.17,134.74,134.60,131.84,130.90,130.45,127.83,126.09,123.37,120.63,76.60,61.33,42.70,30.51,14.63.ESI-MS,m/z:537.0[M+Na]+.
Example preparation of ethyl 42- { [1- (2-trifluoromethylbenzenesulfonyl) -piperidine ] -4-yloxy } benzothiazole-6-carboxylate
The subtitle compound 2- { [1- (2-trifluoromethylbenzenesulfonyl) -piperidine was prepared according to the procedure for the step of example 1 in the same manner as in example 1 except that the second step was carried out using 4-hydroxypiperidine and 2, trifluoromethylbenzenesulfonyl chloride]-4-yloxy } benzothiazole-6-carboxylic acid ethyl ester as a white powder solid in 47% yield. The melting point is 102-104 ℃.1H NMR(CDCl3,400MHz)δ8.36(d,J＝1.4Hz,1H),8.17-8.15(m,1H),8.05(dd,J＝8.5,1.6Hz,1H),7.93-7.91(m,1H),7.73-7.71(m,2H),7.65(d,J＝8.5Hz,1H),5.44-5.40(m,1H),4.39(q,J＝7.1Hz,2H),3.53-3.36(m,4H),2.21-2.04(m,4H),1.40(t,J＝7.1Hz,3H).13C NMR(CDCl3,101MHz)δ174.28,166.33,152.88,138.06,133.01,132.45,132.12,131.84,128.82,127.81,126.05,124.08,123.40,121.35,120.47,76.61,61.32,42.53,30.29,14.59.ESI-MS,m/z:537.0[M+Na]+.
Example preparation of Ethyl 52- { [1- (4-trifluoromethylbenzenesulfonyl) -piperidine ] -4-yloxy } benzothiazole-6-carboxylate
The subtitle compound 2- { [1- (4-trifluoromethylbenzenesulfonyl) -piperidine was prepared according to the procedure for the step of example 1 in the same manner as in example 1 except that the second step was carried out using 4-hydroxypiperidine and 4-trifluoromethylbenzenesulfonyl chloride as starting materials]-4-yloxy } benzothiazole-6-carboxylic acid ethyl ester as a white powder solid in 50% yield. The melting point was 152 ℃ and 154 ℃.1H NMR(CDCl3,400MHz)δ8.34(d,J＝1.4Hz,1H),8.04(dd,J＝8.5,1.6Hz,1H),7.92(d,J＝8.3Hz,2H),7.84(d,J＝8.3Hz,2H),7.62(d,J＝8.5Hz,1H),5.34-5.30(m,1H),4.38(q,J＝7.1Hz,2H),3.32-3.19(m,4H),2.23-2.09(m,4H),1.40(t,J＝7.1Hz,3H).13C NMR(CDCl3,101MHz)δ174.13,166.31,152.81,140.28,134.99,134.66,131.83,128.28,127.83,126.59,126.11,123.53,120.48,76.06,61.34,43.09,30.04,14.53.ESI-MS,m/z:537.0[M+Na]+.
Example preparation of ethyl 62- { [1- (3-fluorophenylsulfonyl) -piperidine ] -4-yloxy } benzothiazole-6-carboxylate
The subtitle compound 2- { [1- (3-fluorobenzenesulfonyl) -piperidine was prepared according to the procedure for example 1 except that the starting material for the second step was 4-hydroxypiperidine and 3-fluorobenzenesulfonyl chloride]-4-yloxy } benzothiazole-6-carboxylic acid ethyl ester as a white powder solid in 46% yield. The melting point was 124-126 ℃.1H NMR(CDCl3,400MHz)δ8.34(s,1H),8.06-8.03(m,1H),7.63(d,J＝8.5Hz,1H),7.60-7.53(m,2H),7.50(d,J＝8.0Hz,1H),7.35(t,J＝7.6Hz,1H),5.32-5.31(m,1H),4.38(q,J＝7.1Hz,2H),3.30-3.17(m,4H),2.23-2.08(m,4H),1.40(t,J＝7.1Hz,3H).13C NMR(CDCl3,101MHz)δ174.17,166.30,163.96,161.45,152.83,138.60,138.53,131.82,127.81,126.07,123.34,120.41,115.11,76.17,61.32,43.15,30.03,14.49.ESI-MS,m/z:486.6[M+Na]+.
Example preparation of ethyl 72- { [1- (2, 6-difluorobenzenesulfonyl) -piperidine ] -4-yloxy } benzothiazole-6-carboxylate
The same procedures used in example 1 were repeated except for using 4-hydroxypiperidine and 2, 6-difluorobenzenesulfonyl chloride as starting materials for the second step in accordance with the procedure for example 1 to give the subtitle compound 2- { [1- (2, 6-difluorobenzenesulfonyl) -piperidine]-4-yloxy } benzothiazole-6-carboxylic acid ethyl ester as a white powder solid in 41% yield. The melting point is 160-162 ℃.1H NMR(CDCl3,400MHz)δ1H NMR(400MHz,CDCl3)δ8.35(d,J＝1.2Hz,1H),8.05(dd,J＝8.5,1.4Hz,1H),7.64(d,J＝8.5Hz,1H),7.58-7.51(m,1H),7.06(t,J＝8.8Hz,2H),5.41-5.38(m,1H),4.38(q,J＝7.1Hz,2H),3.52-3.40(m,4H),2.24-2.09(m,4H),1.40(t,J＝7.1Hz,3H).13C NMR(CDCl3,101MHz)δ174.05,166.10,161.02,158.48,152.55,131.57,127.64,125.92,123.41,123.31,120.37,115.80,76.30,61.13,42.47,30.04,14.37.ESI-MS,m/z:505.1[M+Na]+.
Example preparation of ethyl 82- { [1- (2-trifluoromethoxybenzenesulfonyl) -piperidine ] -4-yloxy } benzothiazole-6-carboxylate
The subtitle compound 2- { [1- (2-trifluoromethoxybenzenesulfonyl) -piperidine was prepared according to the procedure for the step of example 1 in the same manner as in example 1 except that the second-step starting material was 4-hydroxypiperidine and 2-trifluoromethoxybenzenesulfonyl chloride]-4-yloxy } benzothiazole-6-carboxylic acid ethyl ester as a white powder solid in 45% yield. The melting point was 112-114 ℃.1H NMR(CDCl3,400MHz)δ8.35(d,J＝1.2Hz,1H),8.06-8.01(m,2H),7.65-7.62(m,2H),7.45-7.40(m,2H),5.40-5.37(m,1H),4.38(q,J＝7.1Hz,2H),3.51-3.30(m,4H),2.21-2.03(m,4H),1.40(t,J＝7.1Hz,3H).13C NMR(CDCl3,101MHz)δ174.27,166.33,152.91,146.36,134.75,132.02,131.85,131.01,127.80,126.03,123.40,121.72,120.46,119.13,76.64,61.31,42.72,30.46,14.58.ESI-MS,m/z:553.0[M+Na]+.
Example preparation of ethyl 92- { [1- (3-trifluoromethoxybenzenesulfonyl) -piperidine ] -4-yloxy } benzothiazole-6-carboxylate
The subtitle compound 2- { [1- (3-trifluoromethoxybenzenesulfonyl) -piperidine was prepared according to the procedure for the step of example 1 in the same manner as in example 1 except that the second-step starting material was 4-hydroxypiperidine and 3-trifluoromethoxybenzenesulfonyl chloride]-4-yloxy } benzothiazole-6-carboxylic acid ethyl ester as a white powder solid in 47% yield. The melting point is 100-102 ℃.1H NMR(CDCl3,400MHz)δ8.34(s,1H),8.04(dd,J＝8.5,1.2Hz,1H),7.73(d,J＝7.8Hz,1H),7.64-7.60(m,3H),7.49(d,J＝8.3Hz,1H),5.32-5.30(m,1H),4.38(q,J＝7.1Hz,2H),3.31-3.16(m,4H),2.23-2.06(m,4H),1.40(t,J＝7.1Hz,3H).13C NMR(CDCl3,101MHz)δ174.17,166.31,152.79,149.64,138.72,131.81,127.82,126.10,123.53,123.40,121.78,120.43,120.27,76.16,61.33,43.11,30.02,14.52.ESI-MS,m/z:553.0[M+Na]+.
Example preparation of sodium 102- { [1- (2, 6-Dichlorobenzenesulfonyl) -piperidine ] -4-yloxy } benzothiazole-6-carboxylate
Preparation of 2- { [1- (2, 6-Dichlorobenzenesulfonyl) -piperidine according to example 1]-4-yloxy } benzothiazole-6-carboxylic acid ethyl ester, dissolving the ester in tetrahydrofuran, adding10% NaOH aqueous solution and absolute ethyl alcohol. Stirring at room temperature, and after 2h, the reaction is complete. Concentrating the reaction solution by reduced pressure distillation, refrigerating the concentrated reaction solution in a refrigerating chamber, generating a large amount of white solid in a reaction bottle after 8h, filtering under reduced pressure, washing a filter cake by distilled water, and drying the filter cake in vacuum to obtain the subtitle compound 2- { [1- (2, 6-dichlorobenzenesulfonyl) -piperidine]-4-yloxy } benzothiazole-6-sodium formate as a white powder solid in 79% yield.1H NMR(DMSO-d6，400MHz)δ8.29(s,1H),7.91(dd,J＝8.3,1.2Hz,1H),7.70(d,J＝7.7Hz,2H),7.62-7.60(m,1H),7.51(d,J＝8.3Hz,1H),5.36-5.32(m,1H),3.60-3.56(m,2H),3.40-3.35(m,2H),2.18-2.14(m,2H),1.90-1.81(m,2H).13C NMR(DMSO-d6,101MHz)δ172.01,169.38,149.66,137.05,134.88,134.68,134.42,132.62,130.47,128.02,123.06,119.33,76.82,42.88,30.47.HRMS:C19H15Cl2N2NaO5S2 H for[M+Na]+,calculated 508.9775found 508.9748.
EXAMPLE 112 preparation of sodium- { [1- (2, 4-Dichlorobenzenesulfonyl) -piperidine ] -4-yloxy } benzothiazole-6-carboxylate
Following the procedure of example 10, step (b) with 2- { [1- (2, 4-dichlorobenzenesulfonyl) -piperidine]Starting from ethyl (4-yloxy) benzothiazole-6-carboxylate (example 2), the subtitle compound 2- { [1- (2, 4-dichlorobenzenesulfonyl) -piperidine was prepared]-4-yloxy } benzothiazole-6-sodium formate as a white powder solid in 82% yield.1H NMR(DMSO-d6，400MHz)δ8.26(d,J＝1.1Hz,1H),7.99(d,J＝8.6Hz,1H),7.95(d,J＝2.0Hz,1H),7.90(dd,J＝8.3,1.4Hz,1H),7.67(dd,J＝8.5,2.1Hz,1H),7.49(d,J＝8.3Hz,1H),5.32-5.28(m,1H),3.51-3.46(m,2H),3.30-3.24(m,2H),2.15-2.12(m,2H),1.88-1.82(m,2H).13C NMR(DMSO-d6,101MHz)δ172.05,169.60,149.72,138.96,136.82,135.23,133.23,132.71,132.38,132.17,130.47,128.42,127.95,123.18,123.04,119.46,119.25,76.88,43.04,30.39.HRMS:C19H15Cl2N2NaO5S2 H for[M+Na]+,calculated 508.9775found 508.9764.
Example preparation of Ethyl 122- { [1- (2, 3-dichlorobenzenesulfonyl) -piperidine ] -4-yloxy } benzothiazole-6-carboxylate
Following the procedure of example 10, step (b) with 2- { [1- (2, 3-dichlorobenzenesulfonyl) -piperidine]Starting from ethyl (4-yloxy) benzothiazole-6-carboxylate (example 3), the subtitle compound 2- { [1- (2, 3-dichlorobenzenesulfonyl) -piperidine was prepared]-4-yloxy } benzothiazole-6-sodium formate as a white powder solid in 91% yield.1H NMR(DMSO-d6，400MHz)δ8.28(s,1H),7.99(t,J＝6.9Hz,2H),7.91(d,J＝8.2Hz,1H),7.60(t,J＝8.0Hz,1H),7.50(d,J＝8.3Hz,1H),5.34-5.30(m,1H),3.55-3.51(m,2H),3.33-3.29(m,2H),2.16-2.13(m,2H),1.88-1.82(m,2H).13C NMR(DMSO-d6,101MHz)δ172.08,169.73,149.77,138.79,136.69,135.35,135.10,130.61,130.49,129.62,129.14,128.06,123.14,119.37,76.82,43.07,30.52.HRMS:C19H15Cl2N2NaO5S2H for[M+Na]+,calculated 508.9775found 508.9755.
Example 132- { [1- (2-trifluoromethylbenzenesulfonyl) -piperidine]Preparation of sodium (E) -4-yloxy } benzothiazole-6-carboxylate following the procedure of example 10, the procedure is followed, starting from 2- { [1- (2-trifluoromethylbenzenesulfonyl) -piperidine]Starting from ethyl (4-yloxy) benzothiazole-6-carboxylate (example 4), the subtitle compound 2- { [1- (2-trifluoromethylbenzenesulfonyl) -piperidine was prepared]-4-yloxy } benzothiazole-6-sodium formate as a white powder solid in 92% yield.1H NMR(DMSO-d6，400MHz)δ8.28(s,1H),8.10(d,J＝7.5Hz,1H),8.05(d,J＝7.6Hz,1H),7.96-7.88(m,3H),7.50(d,J＝8.3Hz,1H),5.34-5.30(m,1H),3.51-3.47(m,2H),3.32-3.26(m,2H),2.17-2.14(m,2H),1.92-1.84(m,2H).13C NMR(DMSO-d6,101MHz)δ172.09,169.64,149.76,137.75,136.72,134.02,131.49,130.48,129.14,128.05,126.81,126.49,124.47,123.12,121.75,119.36,76.78,43.10,30.42.HRMS:C20H16F3N2NaO5S2Na for[M-H]-,calculated485.0438 found 485.0438.
Example 142- { [1- (4-trifluoromethylbenzenesulfonyl) -piperidine]Preparation of sodium (E) -4-yloxy } benzothiazole-6-carboxylate according to the procedure of example 10Method with 2- { [1- (4-trifluoromethylbenzenesulfonyl) -piperidine]Starting from ethyl (4-yloxy) benzothiazole-6-carboxylate (example 5), the subtitle compound 2- { [1- (4-trifluoromethylbenzenesulfonyl) -piperidine was prepared]-4-yloxy } benzothiazole-6-sodium formate as a white powder solid in 89% yield.1H NMR(DMSO-d6，400MHz)δ8.28(d,J＝1.1Hz,1H),8.11(d,J＝7.3Hz,1H),8.06-8.04(m,1H),7.96-7.89(m,3H),7.51(d,J＝8.3Hz,1H),5.34-5.31(m,1H),3.51-3.46(m,2H),3.33-3.27(m,2H),2.19-2.14(m,2H),1.92-1.84(m,2H).13C NMR(DMSO-d6,101MHz)δ172.08,171.99,169.65,149.71,140.15,136.75,133.43,131.50,130.43,128.89,128.06,127.14,123.10,119.36,76.57,43.58,29.95.HRMS:C20H16F3N2NaO5S2Na for[M-H]-,calculated485.0438 found 485.0459.
Example preparation of sodium 152- { [1- (2-trifluoromethoxy-benzenesulfonyl) -piperidine ] -4-yloxy } benzothiazole-6-carboxylate
Following the procedure of example 10, step (b) with 2- { [1- (2-trifluoromethoxybenzenesulfonyl) -piperidine]Starting from ethyl (4-yloxy) benzothiazole-6-carboxylate (example 8), the subtitle compound 2- { [1- (2-trifluoromethoxybenzenesulfonyl) -piperidine is prepared]-4-yloxy } benzothiazole-6-sodium formate as a white powder solid in 84% yield.1H NMR(DMSO-d6，400MHz)δ8.27(d,J＝1.0Hz,1H),7.97(dd,J＝7.8,1.5Hz,1H),7.91-7.83(m,2H),7.64(dd,J＝15.4,7.7Hz,2H),7.49(d,J＝8.3Hz,1H),5.29-5.25(m,1H),3.41-3.37(m,2H),3.21-3.16(m,2H),2.17-2.13(m,2H),1.88-1.81(m,2H).13C NMR(DMSO-d6,101MHz)δ172.03,169.71,149.74,145.48,136.72,136.02,131.87,130.46,130.39,128.00,124.12,123.13,122.07,121.55,119.39,118.97,76.56,43.07,30.40.HRMS:C20H16F3N2NaO6S2H for[M-H]-,calculated 501.0407found501.0411.
Example 162 preparation of sodium- { [1- (3-trifluoromethoxy-benzenesulfonyl) -piperidine ] -4-yloxy } benzothiazole-6-carboxylate
A method according to the steps of example 10 to2- { [1- (3-trifluoromethoxybenzenesulfonyl) -piperidine]Starting from ethyl (4-yloxy) benzothiazole-6-carboxylate (example 9), the subtitle compound 2- { [1- (3-trifluoromethoxybenzenesulfonyl) -piperidine is prepared]-4-yloxy } benzothiazole-6-sodium formate as a white powder solid in 94% yield.1H NMR(DMSO-d6，400MHz)δ8.26(s,1H),7.90(d,J＝8.3Hz,1H),7.84(d,J＝5.1Hz,2H),7.85-7.80(m,3H),7.48(d,J＝8.3Hz,1H),5.22-5.18(m,1H),3.28-3.26(m,2H),3.03(t,J＝8.5Hz,2H),2.16-2.13(m,2H),1.92-1.83(m,2H).HRMS:C20H16F3N2NaO6S2H for[M-H]-,calculated 501.0407found 501.0426.
Example 17 pharmacological Activity test
1. Experimental Material
MEM medium and fetal bovine serum were purchased from Hyclone; g418 was purchased from Invitrogen, usa; luciferase assay kits (luciferase assay System) were purchased from Promega corporation.
2. Experimental methods
2.1 cell culture
Culturing human hepatoma cell strain HepG2 in MEM culture medium containing 10% fetal calf serum; PCSK9p-Luc HepG2 (human PCSK9 transcription inhibitor high-throughput screening cell model based on luciferase reporter system) is cultured in a medium containing 500 mug-mL-1G418 and 10% fetal bovine serum in MEM; all cells were in 5% CO2Adherent culture is carried out in an incubator at 37 ℃.
2.3 Activity screening
Taking PCSK9p-Luc HepG2 cells in logarithmic growth phase, and counting the number of the cells by about 5 multiplied by 105Perml was inoculated into 96-well clear-bottom plates and 100. mu.L of single cell suspension was added to each well. After the cells adhered to the wall for 6-8h, the original culture medium was removed and the cells were rinsed once with PBS. A5. mu.g/ml solution of each compound was added to each well, with two wells per compound concentration. After 18-24h, the medium was removed, washed gently with PBS, 25. mu.l of cell lysate was added to each well, and cells were lysed at 37 ℃ for 30-45 min. After the cells are completely lysed, 50 mul of firefly luciferase detection reagent is rapidly added into each hole, and the analysis white plate is immediately placed into an enzyme labeling instrument for detection.Calculating the inhibition rate of the sample to be tested on the activity of the PCSK9 promoter according to the following formula:
inhibition (%) - (% inhibition) (luciferase activity after addition of blank sample DMSO-luciferase activity after addition of compound)/luciferase activity after addition of blank sample DMSO × 100%.
3. Results of the experiment
Figure BDA0003298363960000101
Figure BDA0003298363960000111
The experimental results show that the benzothiazole derivative provided by the invention can effectively inhibit the transcription level of PCSK9, so that the benzothiazole derivative has a prospect of being developed into a PCSK9 inhibitor drug and a prospect of being developed into a drug for treating diseases relieved by inhibiting the transcription level of PCSK 9.
The above-described embodiments are intended to be illustrative of the nature of the invention, but those skilled in the art will recognize that the scope of the invention is not limited to the specific embodiments.

Claims (3)

1. A benzothiazole derivative characterized by having a chemical structural formula which is one of the following structural formulas:
Figure FDA0003298363950000011
Figure FDA0003298363950000021
2. use of the benzothiazole derivative of claim 1 for the manufacture of a PCSK9 inhibitor medicament.
3. Use of a benzothiazole derivative according to claim 1 for the manufacture of a medicament for the treatment of a disease ameliorated by the inhibition of the transcription level of PCSK 9.
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