CN108358869A - A kind of N- benzothiazolyls benzsulfamide analog derivative, Preparation method and use - Google Patents

A kind of N- benzothiazolyls benzsulfamide analog derivative, Preparation method and use Download PDF

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CN108358869A
CN108358869A CN201810254965.1A CN201810254965A CN108358869A CN 108358869 A CN108358869 A CN 108358869A CN 201810254965 A CN201810254965 A CN 201810254965A CN 108358869 A CN108358869 A CN 108358869A
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benzothiazolyls
benzsulfamide
pharmaceutically acceptable
analog derivative
preparation
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CN108358869B (en
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李文燕
徐辰
高梦远
耿云鹤
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Hebei Normal University
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Hebei Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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 kind of N benzothiazolyls benzsulfamide analog derivative, Preparation method and uses.It is known that B races I types scavenger receptor (SR BI) plays key effect during the reverse cholesterol transport of HDL, the level of cholesterol in blood plasma is thus reduced, blood vessel damages caused by inhibiting the oxidation of LDL and reducing oxidation LDL.The present invention provides a series of N benzothiazolyl benzsulfamide analog derivatives that can raise SR BI expression, shown in chemical structure of general formula such as formula (I), wherein：R1Independently represent OCH3, F, H, Cl or NO2, substituent R1The position of substitution on A rings is 3,4,5 or 6；Substituent group NHR2It is o-, m- or p- position substitution on B rings.The prior art is not disclosed chemical constitution, preparation method and its pharmacological activity of N benzothiazolyls benzsulfamide analog derivative of the present invention.

Description

A kind of N- benzothiazolyls benzsulfamide analog derivative, Preparation method and use
Technical field
The invention belongs to pharmaceutical synthesis field, it is related to a kind of N- benzothiazolyls benzsulfamide analog derivative, preparation method And by activating the expression of B race I type scavenger receptors to play the medical usage of effect for reducing fat.
Background technology
Angiocardiopathy (CVD) is a global disease, is the first factor for leading to human death.Atherosclerosis (AS) it is systemic disease by rich fatty patch characterized by main artery wall is built up, is the main pathological basis of CVD.Largely Clinical epidemiological study confirms that the horizontal incidence with AS of low density lipoprotein cholesterol (LDL-C) is proportionate in blood plasma, And high-density lipoprotein cholesterol (HDL-C) is horizontal then negatively correlated with the incidence of AS.All from basis and clinical data Show that HDL-C has the function of that anti-AS occurs.The main mechanism that HDL-C plays study of anti-atherogenic effect is to participate in courage to consolidate Alcohol counter transport (RCT) process.HDL removes cholesterol excessive in peripheral tissues and blood, protects by promoting reverse cholesterol transport Blood vessel is protected, the formation of AS is prevented or improves established AS.In addition, HDL also by inhibit LDL oxidative modifications, increase NO synthesis, The performance such as stimulating endothelial cell synthesis of prostaglandins is anti-inflammatory, antithrombotic, mitigation inner skin cell function is not complete, inhibits vascular smooth muscle The functions such as hyperplasia, to delay the progress of AS.
B races I types scavenger receptor (SR-BI) is the currently the only HDL receptors determined on a molecular scale, it can be selective The absorption for mediating cholesteryl ester in cholesterol and HDL particles, plays an important role in the metabolism of HDL.SR-BI overexpressions can increase Cholesterol is flowed out from extrahepatic tissue cell, accelerates the intake of hepatic cholesterol, therefore can reduce atherosclerosis (AS) Occur.Due to the effect of its anti-AS, SR-BI is considered as the novel targets for treating angiocardiopathy.Improving the expression of SR-BI becomes Prevent and treat the extremely promising directions AS.Therefore, the upper adjustment of SR-BI gene expressions is improved, it would be possible to become and adjust HDL The reactive compound of receptor pathway provides new method for prevention and treatment AS.
Invention content
An object of the present disclosure is to provide a kind of N- benzothiazolyls benzsulfamide analog derivative；
The present invention second is designed to provide the preparation method of said derivative；
Third of the present invention is designed to provide the purposes that said derivative is used to prepare B races I type scavenger receptor activator；
The present invention the 4th is designed to provide the medical usage that said derivative is used to prepare fat-reducing medicament.
The above-mentioned purpose of the present invention is achieved by following technical solution：
A kind of N- benzothiazolyls benzsulfamide analog derivative, shown in chemical structure of general formula such as formula (I)：
Wherein：
R1Independent representative-OCH3,-F ,-H ,-Cl or-NO2；
R2Independently represent following substituent group：
Substituent R1The position of substitution on A rings is 3,4,5 or 6；
Substituent group NHR2It is o-, m- or p- position substitution on B rings.
The pharmaceutically acceptable salt or precursor compound of the N- benzothiazolyls benzsulfamide analog derivative.
The preparation method of above-mentioned N- benzothiazolyls benzsulfamide analog derivative, including：With R1Substituted aniline is starting Raw material, phenylthiourea corresponding with potassium rhodanide reaction generation, cyclization is at R under the catalysis of bromine1Substituted 2- amino benzo thiophenes Azoles, then reacted with the benzene sulfonyl chloride of o-, m- or p- position nitro substitution and generate R1Substituted N- benzothiazolyl nitrobenzene sulfonamides, Nitro is reduced to amino with zinc powder, finally and R2Halides are reacted to obtain the final product；Synthetic route is as follows：
A, b, c, d, e are represented reagent and condition as：A, potassium rhodanide, DMF, heat reflux；B, bromine, chloroform, heat reflux；c、 Pyridine, THF, room temperature；D, zinc, ammonium chloride, ethyl alcohol, water, room temperature；e、R2Cl, potassium carbonate, DMF；
R1Independent representative-OCH3,-F ,-H ,-Cl or-NO2；
R2Independently represent following substituent group：
Above-mentioned N- benzothiazolyls benzsulfamide analog derivative or its pharmaceutically acceptable salt or precursor compound are used for Prepare the purposes of B races I type scavenger receptor activator.
Above-mentioned N- benzothiazolyls benzsulfamide analog derivative or its pharmaceutically acceptable salt or precursor compound are used for Prepare the purposes of fat-reducing medicament.
Above-mentioned N- benzothiazolyls benzsulfamide analog derivative or its pharmaceutically acceptable salt or precursor compound are used for The purposes of the drug of disease caused by prevention hyperlipidemia is prepared, disease includes atherosclerosis, height caused by the hyperlipidemia Pionemia, nonalcoholic fatty liver.
A kind of pharmaceutical preparation for lipid-loweringing, containing above-mentioned N- benzothiazolyls benzsulfamide analog derivative or its pharmaceutically Acceptable salt or precursor compound also contain pharmaceutically acceptable carrier or excipient, and being made can pharmaceutically receive Dosage form.
Further, pharmaceutically acceptable carrier or excipient include one or more solids, semisolid or liquid Auxiliary material.
Further, the pharmaceutically acceptable dosage form include tablet, capsule, granule, injection, pill, Syrup, powder, paste.
N- benzothiazolyls benzsulfamide analog derivative provided by the invention can go up the expression of mediator SR-BI, can be used as SR-BI activator is prepared into fat-reducing medicament for preventing disease caused by hyperlipidemia.
Specific implementation mode
Essentiality content of the present invention is specifically introduced with reference to embodiment, but does not limit the protection model of the present invention with this It encloses.
Embodiment 1：The preparation of N- (6- chloro benzothiazole -2- bases) -4- ((cyanogen methyl) amino) benzsulfamide
1, to the preparation of chlorobenzene and thiocarbamide
Parachloroanilinum (10.00g, 78.37mmol) is added in 250mL three-necked bottles, being added with stirring 70.00mL chlorobenzenes makes Raw material is completely dissolved, and under the conditions of ice-water bath, is slowly added to concentrated hydrochloric acid (3.00mL, 43.10mmol), has a large amount of white solids to give birth to At.Reaction bulb is moved in oil bath pan, after being warming up to 70 DEG C, potassium rhodanide (8.40g, 86.20mmol) is added, reaction solution becomes Aubergine improves reaction temperature to 100 DEG C of back flow reactions, and thin-layer chromatography monitors reaction process.The reaction was complete after 6h, at this time instead Liquid is answered to be lilac and have solid precipitation.Reaction solution is cool but to room temperature, and decompression filters to obtain solid, is washed with a small amount of ether, washes 2 Time.Dry white solid 9.20g, yield 63.02%.Fusing point is 180.1-181.3 DEG C.1H-NMR(DMSO-d6, 500MHz)δ:7.36 (2H, d, J=9.00Hz), 7.46 (2H, d, J=9.00Hz), 9.75 (1H, s) .ESI-MS, m/z: 187.2[M+H]+.
2, the preparation of the chloro- 2- aminobenzothiazoles of 6-
Chlorine thiocarbamide (8.50g, 45.70mmol) will be added in 250mL eggplant-shape bottles, and the dissolving of 50.00mL chloroforms be added, 50 Flow back 20 minutes under the conditions of DEG C oil bath, place reaction liquid under the conditions of ice-water bath later, be slowly added dropwise bromine (2.58mL, 50.27mmol), stirring after five minutes, is transferred back in oil bath pan, is increased temperature and is continued to flow back to 70 DEG C, thin-layer chromatography monitoring reaction Process, the reaction was complete after 9h.There are solid precipitation, decompression to filter after being cooled to room temperature, ammonium hydroxide is slowly added dropwise in filtrate, adjusts pH value To neutrality, white precipitate generation is had, after five minutes, decompression filters for stirring, and washing solid 2 times is dried under vacuum to constant weight, obtains white Color solid 3.62g, yield 43.10%.1H-NMR(DMSO-d6, 500MHz) and δ:7.76 (2H, d, J=9.00Hz), 7.45 (2H, d, J=9.00Hz), 9.75 (1H, s) .ESI-MS, m/z:185.2[M+H]+.
3, the preparation of N- (6- chloro benzothiazole -2- bases) -4- nitrobenzene sulfanilamide (SN)
The chloro- 2- aminobenzothiazoles (5.00g, 27.00mmol) of 6- are added in 250mL eggplant-shape bottles, are added with stirring The tetrahydrofuran that 100.00mL steams again makes it completely dissolved.After five minutes, by pyridine (24.10mL, 298.91mmol) average mark It is slowly added in eggplant-shape bottle three times, per minor tick 4h.It is stirred ten minutes after pyridine is added every time, by 4-Nitrobenzenesulfonyl chloride (8.97g, 40.50mmol) is added in three times.Solid precipitation is had after a period of time, if solid, which was precipitated, at most needs to add weight The tetrahydrofuran of steaming reacts at room temperature 10h.After reaction, it removes reaction solution under reduced pressure THF, adds 100mL water in solid, be precipitated A large amount of meat pink solids, stirring are depressurized after 1 hour and are filtered, and washing filter cake 2 times obtains meat pink solid, weighs after dry, obtains thick Product 8.15g.With petroleum ether and ethyl acetate mixtures 5：1 carries out column chromatographic isolation and purification, finally obtains meat purple powder solid 6.33g, yield 63.53%.1H-NMR(DMSO-d6, 500MHz) and δ:7.26 (1H, dd, J=7.50Hz), 7.38 (1H, d, J= 8.00Hz), 7.40 (1H, d, J=7.50Hz), 7.41 (1H, t, J=8.00Hz), 7.76 (1H, s), 7.85 (1H, s), 8.25 (1H,s),13.35(1H,s).ESI-MS,m/z:370.2[M+H]+,392.4[M+Na]+.
4, the preparation of N- (6- chloro benzothiazole -2- bases) -4- aminobenzene sulfanilamide (SN)
N- (6- chloro benzothiazole -2- bases) -4- nitrobenzene sulfonamides (2.00g, 5.42mmol) are loaded on 100mL eggplant-shape bottles In, with water：Ethyl alcohol：Methanol=2：6：3 be solvent, after 15mL is added, is warming up to 60 DEG C, 20 minutes solid major parts of heating stirring Dissolving, reaction solution is cooled to room temperature, addition ammonium chloride (1.74g, 32.52mmol) stirring 10min, addition zinc powder (4.22g, 65.04mmol), the reaction was complete after 2 hours.It removes reaction solution under reduced pressure solvent, adds water, 50mL × 3 time are extracted with ethyl acetate, Merge organic phase, the washing of saturated common salt aqueous solution, anhydrous sodium sulfate is dried overnight.Next day evaporated under reduced pressure.It is solid to obtain yellow powder Body 0.96g, yield 52.44%.1H-NMR(DMSO-d6, 500MHz) and δ:5.96 (2H, s), 7.13 (1H, dd, J=7.50Hz), 7.25 (1H, d, J=8.00Hz), 7.36 (1H, d, J=7.50Hz), 7.40 (1H, t, J=8.00Hz), 7.68 (1H, s), 7.98(1H,s),8.23(1H,s),13.26(1H,s).ESI-MS,m/z:340.2[M+H]+,362.4[M+Na]+.
5, the preparation of N- (6- chloro benzothiazole -2- bases) -4- ((cyanogen methyl) amino) benzsulfamide
N- (6- chloro benzothiazole -2- bases) -4- aminobenzene sulfonamides (0.60g, 1.77mmol) are added to 50mL eggplant shapes In bottle, 1.00mLDMF is added, sodium hydride (0.14g, 3.54mmol) is slowly added under ice-water bath, chlorine is added after five minutes in stirring Acetonitrile (0.17mL, 2.65mmol) adds dry tube reaction 8h.By reaction solution plus water, adds ethyl acetate 30mL × 4 time, be associated with Machine phase, the washing of saturated common salt aqueous solution, anhydrous sodium sulfate are dried overnight.Next day evaporated under reduced pressure.With petroleum ether and ethyl acetate column Chromatography obtains pale yellow powder shape solid 0.27g, yield 40.37%.1H-NMR(DMSO-d6, 500MHz) and δ:5.35(2H, S), 6.03 (2H, s), 6.59 (2H, d, J=8.50Hz), 7.52 (2H, d, J=8.50Hz), 7.58 (1H, dd, J= 8.50Hz), 7.72 (1H, d, J=9.00Hz)13C-NMR(DMSO-d6,500MHz)δ:33.24,112.95,113.04, 113.76,115.16,123.40,125.72,126.25,127.93,128.40,128.61,129.10,135.16,153.62, 164.50.ESI-MS,m/z:379.5[M+H]+,401.2[M+Na]+.
Embodiment 2：The preparation of N- (6- chloro benzothiazole -2- bases) -4- (allyl amino)-benzsulfamide
It is prepared according to the method for 1 step of embodiment, starting material is：Parachloroanilinum, final step halogenating agent are 3- chlorine Propylene obtains subtitle compounds N- (6- chloro benzothiazole -2- bases) -4- (allyl amino)-benzsulfamide, is off-white color powder Last shape 0.21g, yield 40.28%.1H-NMR(DMSO-d6, 500MHz) and δ:4.77 (2H, d, J=5.00Hz), 4.97 (1H, d, J =17.00Hz), 5.13 (1H, d, J=10.50Hz), 5.78-5.86 (1H, m), 5.98 (2H, s), 6.57 (2H, d, J= 8.50Hz),7.47(1H,s),7.48(3H,s),8.01(1H,s).13C-NMR(DMSO-d6,500MHz)δ:15.44,47.13, 49.05,112.99,114.28,118.10,122.97,126.00,127.01,127.59,128.35,128.43,130.89, 136.31,153.30,164.40,173.42.ESI-MS,m/z:380.2[M+H]+,402.1[M+Na]+.
Embodiment 3：The preparation of (4- (N- (6- chloro benzothiazole -2- bases) acyl group) phenyl) glycine ethyl ester
It is prepared according to the method for 1 step of embodiment, starting material is：Parachloroanilinum, final step halogenating agent are chloroethene Acetoacetic ester obtains subtitle compounds (3- (N- (6- chloro benzothiazole -2- bases) acyl group) phenyl) glycine ethyl ester, is off-white color Powdered 0.36g, yield 42.31%.1H-NMR(DMSO-d6, 500MHz) and δ:1.10 (3H, t, J=7.00Hz), 4.04-4.08 (2H, m), 5.00 (2H, s), 5.98 (2H, s), 6.57 (2H, d, J=8.50Hz), 7.44 (2H, d, J=8.50Hz), 7.50 (1H, dd, J=8.75Hz), 7.60 (1H, d, J=9.00Hz), 8.02 (1H, s)13C-NMR(DMSO-d6,500MHz)δ: 14.12,46.72,61.03,109.59,112.98.114.03,123.26,125.69,127.63,128.10,128.61, 136.98,151.22,152.42,164.16,167.34,175.66.ESI-MS,m/z:426.3[M+H]+,448.1[M+Na]+.
Embodiment 4：The preparation of (4- (N- (6- chloro benzothiazole -2- bases) acyl group) phenyl) glycine
(4- (N- (6- chloro benzothiazole -2- bases) acyl group) phenyl) glycine ethyl ester (0.36g, 0.85mmol) is dissolved in first Alcohol：Tetrahydrofuran：Water is 1:1:In 1 mixed solvent 10mL, lithium hydroxide (0.24g, 10mmol) is added, reacts at room temperature 6h, Reaction solution concentrates, and ice water 10mL, 1N salt acid for adjusting pH value is added to 2, a large amount of white solids are precipitated, filter to obtain faint yellow solid, Dry, column chromatography for separation obtains white solid powder 0.28g, yield 76.32%.1H-NMR(DMSO-d6, 500MHz) and δ:3.80 (2H, s), 6.05 (2H, s), 6.52 (1H, d, J=7.50Hz), 7.24 (2H, d, J=8.00Hz), 7.36 (1H, s), 7.60 (1H, dd, J=8.25Hz), 8.01 (1H, s), 13.06 (1H, s)13C-NMR(DMSO-d6,500MHz)δ:46.58, 109.56,112.98,113.28,122.31,125.9,127.30,128.30,128.61,136.28,151.38,152.86, 164.21,167.43,174.23.ESI-MS,m/z:398.2[M+H]+,420.3[M+Na]+.
Embodiment 5：The preparation of N- (benzothiazole -2- bases) -4- ((cyanogen methyl) amino) benzsulfamide
It is prepared according to the method for 1 step of embodiment, starting material is：2- aminobenzothiazoles, final step halogenating agent For chloroacetonitrile, subtitle compounds N- (benzothiazole -2- bases) -4- ((cyanogen methyl) amino) benzsulfamide is obtained, is yellow powder Last shape solid 0.19g, yield 39.27%.1H-NMR(DMSO-d6, 500MHz) and δ:5.41(2H,s),5.58(2H,s),6.76 (1H, dd, J=8.25Hz), 7.00 (1H, d, J=7.50Hz), 7.10 (1H, s), 7.17 (1H, t, J=8.00Hz), 7.38 (1H, t, J=7.75Hz), 7.54 (1H, t, J=7.75Hz), 7.74 (1H, d, J=8.00Hz), 7.92 (1H, d, J= 7.50Hz).13C-NMR(DMSO-d6,500MHz)δ:32.79,110.58,112.33,112.77,114.85,117.72, 123.26,123.40,124.94,127.69,129.53,135.55,141.59,149.47,165.30.ESI-MS,m/z: 345.4[M+H]+,367.1[M+Na]+.
Embodiment 6：The preparation of N- (benzo and thiazol-2-yl) -4- (allyl amino)-benzsulfamide
It is prepared according to the method for 1 step of embodiment, starting material is：2- aminobenzothiazoles, final step halogenating agent For chlorallylene, subtitle compounds N- (benzo and thiazol-2-yl) -4- (allyl amino)-benzsulfamide is obtained, is yellow Pulverulent solids 0.23g, yield 40.03%.1H-NMR(DMSO-d6, 500MHz) and δ:3.59 (2H, d, J=6.50Hz), 5.03 (1H, d, J=10.00Hz), 5.13 (1H, d, J=17.00Hz), 5.78-5.88 (1H, m), 7.11 (1H, t, J= 7.50Hz), 7.16 (1H, t, J=7.50Hz), 7.25 (1H, d, J=8.00Hz), 7.28 (1H, d, J=7.50Hz) 7.43 (1H, d, J=7.50Hz), 7.51 (1H, d, J=8.00Hz), 7.60 (1H, d, J=8.00Hz), 7.71 (1H, d, J= 7.50Hz).13C-NMR(DMSO-d6,500MHz)δ:35.93,118.07,118.94,121.03,122.21,125.40, 125.55,125.93,127.06,130.07,130.83,133.68,137.34,151.72,155.10,173.51.ESI-MS, m/z:346.4[M+H]+,368.1[M+Na]+.
Embodiment 7：The preparation of (4- (N- (benzothiazole -2- bases) acyl group) phenyl) glycine ethyl ester
It is prepared according to the method for 1 step of embodiment, starting material is：2- aminobenzothiazoles, final step halogenating agent For ethyl chloroacetate, subtitle compounds (4- (N- (benzothiazole -2- bases) acyl group) phenyl) glycine ethyl ester is obtained, is yellowish Color pulverulent solids 0.24g, yield 41.36%.1H-NMR(DMSO-d6, 500MHz) and δ:1.12 (3H, t, J=7.00Hz), 4.05-4.09 (2H, m), 5.01 (2H, s), 5.96 (2H, s), 6.56 (2H, d, J=9.00Hz), 7.30 (1H, t, J= 8.00Hz), 7.45 (3H, d, J=8.50Hz), 7.57 (1H, d, J=8.00Hz), 7.85 (1H, d, J=7.50Hz)13C-NMR (DMSO-d6,500MHz)δ:14.35,46.28,61.87,112.62,112.93,123.35,123.68,124.50, 126.96,127.65,128.33,128.46,137.48,153.32,165.08,167.32,175.27.ESI-MS,m/z: 392.3[M+H]+,414.2[M+Na]+.
Embodiment 8：The preparation of (4- (N- (benzothiazole -2- bases) acyl group) phenyl) glycine
It is prepared according to the method for 4 step of embodiment, starting material is：(4- (N- (benzothiazole -2- bases) acyl group) phenyl) Glycine ethyl ester obtains subtitle compounds (4- (N- (benzothiazole -2- bases) acyl group) phenyl) glycine, is pale yellow powder Shape solid 0.21g, yield 63.21%.1H-NMR(DMSO-d6, 500MHz) and δ:5.02(2H,s),5.97(2H,s),6.43 (2H, d, J=7.50Hz), 7.28 (1H, t, J=7.50Hz), 7.43 (1H, t, J=8.00Hz), 7.46 (2H, d, J= 8.00Hz), 7.54 (1H, dd, J=8.00Hz), 7.89 (1H, dd, J=7.50Hz)13C-NMR(DMSO-d6,500MHz)δ: 46.31,112.30,112.78,123.05,123.47,124.16,126.88,127.31,128.02,128.43,137.31, 154.02,164.93,167.35,175.23.ESI-MS,m/z:364.3[M+H]+,386.5[M+Na]+.
Embodiment 9：N- (6- methoxybenzothiazole -2- bases) -4- (cyanogen methyl) amino)-benzsulfamide preparation
It is prepared according to the method for 1 step of embodiment, starting material is：6- methoxyl group -2- aminobenzothiazoles, final step Halogenating agent is chloroacetonitrile, obtains subtitle compounds N- (6- methoxybenzothiazole -2- bases) -4- (cyanogen methyl) amino)-benzene Sulfonamide is pale yellow powder shape solid 0.19g, yield 39.48%.1H-NMR(DMSO-d6, 500MHz) and δ:3.79(3H,s), 5.34 (2H, s), 5.99 (2H, s), 6.59 (2H, d, J=9.00Hz), 7.11 (1H, dd, J=8.75Hz), 7.52 (2H, d, J =8.50Hz), 7.55 (1H, s), 7.62 (1H, d, J=9.00Hz)13C-NMR(DMSO-d6,500MHz)δ:32.85, 55.96,108.05,110.57,112.75,113.11,114.85,114.86,117.63,124.54,129.27,129.50, 141.76,149.44,156.95,164.85.ESI-MS,m/z:375.1[M+H]+,397.1[M+Na]+.
Embodiment 10：The preparation of N- (6- methoxybenzothiazole -2- bases) -4- (allyl amino)-benzsulfamide
It is prepared according to the method for 1 step of embodiment, starting material is：6- methoxyl group -2- aminobenzothiazoles, final step Halogenating agent is chlorallylene, obtains subtitle compounds N- (6- methoxybenzothiazole -2- bases) -4- (allyl amino) - Benzsulfamide is pale yellow powder shape solid 0.23g, yield 40.66%.1H-NMR(DMSO-d6, 500MHz) and δ:3.77(3H, S), 4.75 (2H, d, J=4.00Hz), 4.97 (1H, d, J=17.00Hz), 5.13 (1H, d, J=10.50Hz), 5.78-5.86 (1H, m), 5.93 (2H, s), 6.57 (2H, d, J=8.50Hz), 7.02 (1H, dd, J=7.75Hz), 7.39 (1H, d, J= 8.50Hz), 7.47 (2H, d, J=8.50Hz), 7.50 (1H, s)13C-NMR(DMSO-d6,500MHz)δ:48.70,53.07, 102.08,108.08,110.67,112.39,115.28,116.39,119.30,127.49,129.86,131.47,135.27, 140.39,147.29,154.09,154.66.ESI-MS,m/z:376.2[M+H]+,398.4[M+Na]+.
Embodiment 11：The preparation of (4- (N- (6- methoxybenzothiazole -2- bases) acyl group) phenyl) glycine ethyl ester
It is prepared according to the method for 1 step of embodiment, starting material is：6- methoxyl group -2- aminobenzothiazoles, final step Halogenating agent is ethyl chloroacetate, obtains subtitle compounds (4- (N- (6- methoxybenzothiazole -2- bases) acyl group) phenyl) Glycine ethyl ester is pale yellow powder shape solid 0.25g, yield 39.83%.1H-NMR(DMSO-d6, 500MHz) and δ:1.11 (3H, t, J=7.25Hz), 3.78 (3H, s), 4.06 (2H, q), 4.97 (2H, s), 5.94 (2H, s), 6.56 (2H, d, J= 8.50Hz), 7.02 (1H, dd, J=8.50Hz), 7.45 (2H, d, J=9.00Hz), 7.48 (1H, d, J=9.00Hz), 7.51 (1H,s).13C-NMR(DMSO-d6,500MHz)δ:14.34,46.37,56.28,61.84,107.98,112.91,113.35, 114.69,124.88,127.22,128.28,131.32,149.24,153.21,156.82,164.67,167.32, 175.43.ESI-MS,m/z:422.3[M+H]+,444.1[M+Na]+.
Embodiment 12：The preparation of (4- (N- (6- methoxybenzothiazole -2- bases) acyl group) phenyl) glycine
It is prepared according to the method for 4 step of embodiment, starting material is：(4- (N- (6- methoxybenzothiazole -2- bases) acyls Base) phenyl) glycine ethyl ester, it is sweet to obtain subtitle compounds (4- (N- (6- methoxybenzothiazole -2- bases) acyl group) phenyl) Propylhomoserin is pale yellow powder shape solid 0.19g, yield 62.31%.1H-NMR(DMSO-d6, 500MHz) and δ:3.78(3H,s), 4.96 (2H, s), 6.02 (2H, s), 6.63 (2H, d, J=8.00Hz), 7.05 (1H, dd, J=7.50Hz), 7.39 (2H, d, J =8.00Hz), 7.46 (1H, d, J=8.00Hz), 7.50 (1H, s), 13.03 (1H, s)13C-NMR(DMSO-d6,500MHz) δ:46.12,56.21,107.02,112.78,113.21,114.30,123.55,127.63,128.13,130.11,148.56, 153.22,157.22,164.21,167.18,174.32.ESI-MS,m/z:394.1[M+H]+,416.3[M+Na]+.
Embodiment 13：N- (6- fluoro benzothiazole -2- bases) -4- (cyanogen methyl) amino)-benzsulfamide preparation
It is prepared according to the method for 1 step of embodiment, starting material is：6- fluorine 2- aminobenzothiazoles, final step are halogenated Reagent is chloroacetonitrile, obtains subtitle compounds N- (6- fluoro benzothiazole -2- bases) -4- (cyanogen methyl) amino)-benzsulfamide, For pale yellow powder shape solid 0.19g, yield 38.77%.1H-NMR(DMSO-d6, 500MHz) and δ:5.37(2H,s),6.03 (2H, s), 6.59 (2H, d, J=9.00Hz), 7.41 (1H, t, J=9.00Hz), 7.52 (2H, d, J=8.50Hz), 7.74 (1H, dd, J=9.00Hz), 7.86 (1H, dd, J=8.25Hz)13C-NMR(DMSO-d6,500MHz)δ:33.29,110.89, 111.12,113.03,113.75,115.23,115.39,126.31,128.58,132.72,153.61,157.66,158.47, 160.39,164.66.ESI-MS,m/z:363.2[M+H]+,385.1[M+Na]+.
Embodiment 14：The preparation of N- (6- fluoro benzothiazole -2- bases) -4- (allyl amino) benzsulfamide
It is prepared according to the method for 1 step of embodiment, starting material is：6- fluorine 2- aminobenzothiazoles, final step are halogenated Reagent is chlorallylene, obtains subtitle compounds N- (6- fluoro benzothiazole -2- bases) -4- (allyl amino) benzsulfamide, For pale yellow powder shape solid 0.22g, yield 39.59%.1H-NMR(DMSO-d6, 500MHz) and δ:4.78 (2H, d, J= 4.00Hz), 4.98 (1H, d, J=17.00Hz), 5.14 (1H, d, J=10.50Hz), 5.78-5.86 (1H, m), 5.97 (2H, S), 6.57 (2H, d, J=8.50Hz), 7.31 (1H, t, J=9.00Hz), 7.47 (3H, d, J=9.00Hz), 7.82 (1H, dd, J=8.50Hz)13C-NMR(DMSO-d6,500MHz)δ:35.04,108.01,108.22,113.37,113.56,117.53, 117.60,118.83,119.85,119.91,133.63,148.80,157.41,159.30,173.90.ESI-MS,m/z: 364.4[M+H]+,386.6[M+Na]+.
Embodiment 15：The preparation of (4- (N- (6- fluoro benzothiazole -2- bases) acyl group) phenyl) glycine ethyl ester
It is prepared according to the method for 1 step of embodiment, starting material is：6- fluorine 2- aminobenzothiazoles, final step are halogenated Reagent is ethyl chloroacetate, obtains subtitle compounds (4- (N- (6- fluoro benzothiazole -2- bases) acyl group) phenyl) glycine second Ester is pale yellow powder shape solid 0.31g, yield 40.23%.1H-NMR(DMSO-d6, 500MHz) and δ:1.16 (3H, t, J= 7.00Hz), 4.12 (2H, q), 5.06 (2H, s), 6.04 (2H, s), 6.62 (2H, d, J=8.00Hz), 7.38 (1H, t, J= 7.50Hz), 7.49 (2H, d, J=8.00Hz), 7.67 (1H, dd, J=8.00Hz), 7.98 (1H, dd, J=7.50Hz)13C- NMR(DMSO-d6,500MHz)δ:14.12,46.72,61.03,109.59,112.98.114.03,123.26,125.69, 127.63,128.10,128.61,136.98,151.22,152.42,164.16,167.34,175.66.ESI-MS,m/z: 410.1[M+H]+,432.3[M+Na]+.
Embodiment 16：The preparation of (4- (N- (6- fluoro benzothiazole -2- bases) acyl group) phenyl) glycine
It is prepared according to the method for 4 step of embodiment, starting material is：(4- (N- (6- fluoro benzothiazole -2- bases) acyl group) benzene Base) glycine ethyl ester, subtitle compounds (4- (N- (6- fluoro benzothiazole -2- bases) acyl group) phenyl) glycine is obtained, is light Yellow powdery solid 0.33g, yield 69.68%.1H-NMR(DMSO-d6, 500MHz) and δ:3.82(2H,s),6.12(2H, S), 6.73 (1H, s) 7.13 (2H, d, J=8.00Hz), 7.26 (1H, dd, J=8.50Hz), 7.68 (2H, d, J=7.50Hz), 7.93 (1H, dd, J=8.00Hz), 13.01 (1H, s)13C-NMR(DMSO-d6,500MHz)δ:46.30,109.23, 109.56,113.37,119.23,119.95,129.30,130.06,130.69,143.12,151.89,152.12,163.12, 167.05175.13.ESI-MS,m/z:382.1[M+H]+,404.3[M+Na]+.
Embodiment 17：The preparation of N- (benzothiazole -2- bases) -3- (allyl amino) benzsulfamide
It is prepared according to the method for 1 step of embodiment, starting material is：2- aminobenzothiazoles, final step halogenating agent For chlorallylene, subtitle compounds N- (benzothiazole -2- bases) -3- (allyl amino) benzsulfamide is obtained, is faint yellow Powdered 0.30g, yield 36.23%.1H-NMR(DMSO-d6, 500MHz) and δ:4.83 (2H, d, J=4.50Hz), 5.01 (1H, D, J=17.50Hz), 5.15 (1H, d, J=10.50Hz), 5.58 (1H, s), 5.81-5.89 (1H, m), 6.73 (1H, dd, J= 8.00Hz), 6.94 (1H, d, J=7.50Hz), 7.05 (1H, s), 7.13 (1H, t, J=8.00Hz), 7.31 (1H, t, J= 7.75Hz), 7.45 (1H, t, J=7.50Hz), 7.52 (1H, d, J=8.00Hz), 7.87 (1H, d, J=8.00Hz)13C-NMR (DMSO-d6,500MHz)δ:47.14,110.88,113.07,117.84,118.25,121.30,123.35,123.98, 124.71,127.76,129.80,130.95,137.11,142.55,149.75,165.75.ESI-MS,m/z:346.3[M+H ]+,368.2[M+Na]+.
Embodiment 18：N- (benzothiazole -2- bases) -3- ((cyanogen methyl) amino) benzsulfamide
It is prepared according to the method for 1 step of embodiment, starting material is：2- aminobenzothiazoles, final step halogenating agent For chloroacetonitrile, subtitle compounds N- (benzothiazole -2- bases) -3- ((cyanogen methyl) amino) benzsulfamide is obtained, is faint yellow Powdered 0.21g, yield 35.28%.1H-NMR(DMSO-d6, 500MHz) and δ:5.44(2H,s),5.62(2H,s),6.76(1H, Dd, J=7.75Hz), 6.99 (1H, d, J=8.00Hz), 7.10 (1H, s), 7.16 (1H, t, J=7.75Hz), 7.38 (1H, t, ), J=7.50Hz 7.54 (1H, t, J=8.00Hz), 7.76 (1H, d, J=8.00Hz), 7.92 (1H, d, J=8.00Hz)13C- NMR(DMSO-d6, 500MHz) and δ:32.79,110.58,112.33,112.77,114.85,117.72,123.26,123.40, 124.94,127.69,129.53,135.55,141.59,149.47,165.30.ESI-MS,m/z:345.1[M+H]+,367.3 [M+Na]+.
Embodiment 19：The preparation of N- (6- methoxybenzothiazole -2- bases) -3- (allyl amino) benzsulfamide
It is prepared according to the method for 1 step of embodiment, starting material is：6- methoxyl group -2- aminobenzothiazoles, final step Halogenating agent is chlorallylene, obtains subtitle compounds N- (6- methoxybenzothiazole -2- bases) -3- (allyl amino) benzene Sulfonamide is pale yellow powder shape 0.19g, yield 30.29%.1H-NMR(DMSO-d6, 500MHz) and δ:3.81(3H,s),4.61 (2H, d, J=5.00Hz), 5.17 (1H, d, J=10.00Hz), 5.27 (1H, d, J=17.00Hz), 5.75 (2H, s), 5.88- 5.95 (1H, m), 6.84 (1H, dd, J=8.00Hz), 6.96 (1H, d, J=8.00Hz), 7.02 (1H, dd, J=9.00Hz), 7.06 (1H, s), 7.22 (1H, t, J=8.00Hz), 7.58 (1H, s), 7.64 (1H, d, J=8.50Hz)13C-NMR(DMSO- d6, 500MHz) and δ:48.70,53.07,102.08,108.08,110.67,112.39,115.28,116.39,119.30, 127.49,129.86,131.47,135.27,140.39,147.29,154.09,154.66.ESI-MS,m/z:376.2[M+H ]+,398.1[M+Na]+.
Embodiment 20：The preparation of N- (benzothiazole -2- bases) -3- ((cyanogen methyl) amino) benzsulfamide
It is prepared according to the method for 1 step of embodiment, starting material is：6- methoxyl group -2- aminobenzothiazoles, final step Halogenating agent is chloroacetonitrile, obtains subtitle compounds N- (benzothiazole -2- bases) -3- ((cyanogen methyl) amino) benzsulfamide, For yellow powder 0.32g, yield 33.19%.1H-NMR(DMSO-d6, 500MHz) and δ:3.80(3H,s),5.40(2H,s), 5.61 (2H, s), 6.76 (1H, d, J=8.00Hz), 6.99 (1H, d, J=7.50Hz), 7.10 (1H, s), 7.22 (1H, t, J= 8.00Hz), 7.59 (1H, s), 7.69 (1H, d, J=9.00Hz)13C-NMR(DMSO-d6, 500MHz) and δ:32.85,55.96, 108.05,110.57,112.75,113.11,114.85,114.86,117.63,124.54,129.27,129.50,141.76, 149.44,156.95,164.85.ESI-MS,m/z:375.1[M+H]+,397.1[M+Na]+.
Embodiment 21：The preparation of N- (6- fluoro benzothiazole -2- bases) -3- (allyl amino) benzsulfamide
It is prepared according to the method for 1 step of embodiment, starting material is：6- fluorine 2- aminobenzothiazoles, final step are halogenated Reagent is chlorallylene, obtains subtitle compounds N- (6- fluoro benzothiazole -2- bases) -4- (allyl amino) benzsulfamide, For pale yellow powder shape solid 0.22g, yield 39.59%.1H-NMR(DMSO-d6, 500MHz) and δ:3.66(2H,s),5.09 (1H, d, J=10.00Hz), 5.25 (1H, d, J=16.50Hz), 5.79-5.88 (1H, m), 7.03 (1H, t, J=7.25Hz), 7.09 (1H, t, J=8.00Hz), 7.21 (1H, d, J=7.50Hz), 7.35 (1H, s), 7.47 (1H, dd, J=8.00Hz), 7.60 (1H, dd, J=7.50Hz)13C-NMR(DMSO-d6,500MHz)δ:35.06,108.10,108.56,113.28, 113.31,117.41,117.79,119.01,119.85,119.98,134.21,148.63,157.41,159.50, 174.20.ESI-MS,m/z:364.1[M+H]+,386.2[M+Na]+.
Embodiment 22：Effect example, the expression of mediator SR-BI in compound prepared by testing example 1-21
SR-BI is that first molecule and the well-defined HDL receptor of function, mankind SR-BI are also known as CLA- 1。
1, experiment material
1640 culture mediums of RPMI, MEM culture mediums and fetal calf serum are purchased from Hyclone；G418 is purchased from U.S. Invitrogen Company；Luciferase Assay Reagent box (LuciferaseAssay System) is purchased from Promega companies.
2, experimental method
2.1 cell culture
HepG 2 cell is incubated in the MEM culture mediums containing 10% fetal calf serum；CLA-1-LUC HepG2 is incubated at containing 500 μ gmL-1In the MEM culture mediums of G418 and 10% fetal calf serum；All cells are all in 5%CO2Culture 37 DEG C of adhere-wall cultures in case.
2.2 plasmid transfection
The method mediated using LipofectamineTM2000 (Invitrogen) will recombinate reporter plasmid pGL3- CLAP (regulatory sequences of CLA-1 containing someone [- 1055~-62bp, with the A of CLA1 gene start codons ATG be+ 1]-luciferase reporter gene) and pcDNA3 (containing neo genes) cotransfection enter HepG2 cells.Through 600 μ gmL-1At G418 Reason carries the cell clonal formation of G418 resistances after 14 days.A series of monoclonalization operations are carried out to the cell clone of formation, together When track its uciferase activity.The stabilization cell clone of high expressing luciferase and presentation normal cell-cycle is named as CLA-1p-LUC HepG2。
2.3 screening active ingredients
The CLA-1p-LUC HepG2 cells of logarithmic growth phase, with cell number about 5 × 105It is transparent that/mL is inoculated in 96 holes 100 μ L of single cell suspension are added per hole for bottom blank.By compound respectively with the RPMI-1640 cell culture mediums containing 5%FBS, MEM cell culture mediums containing 5%FBS are 100 μM a concentration of, 50 μM, 25 μM, 12.5 μM, 6.25 μM, 3.125 μM, 1.5625 μM, 0.78125 μM, 0.39 μM, 0.039 μM, 0.0039 μM, totally 11 concentration.6-8h is removed former after cell is adherent Culture medium, it is primary with PBS rinsing cells.It is separately added into advance with the good certain density compound of cell culture medium per hole 200 μ l of solution, each each concentration of compound set two multiple holes.Culture medium is removed after 18-24h, after gently being rinsed with PBS, often 25 μ l cell pyrolysis liquids, 37 DEG C of lytic cell 30-45min are added in hole.After cell completely cracking, 50 μ l fireflies are rapidly added per hole Analysis blank is put into microplate reader detects immediately by fireworm Luciferase Assay Reagent.Sample to be tested is calculated to fluorescein enzyme activity The rate of change of property, after uciferase activity/addition blank control sample (DMSO) after rate of change (%)=addition compound Uciferase activity × 100.Rate of change >=150% of sample to be tested is considered as positive findings using GraphPad mapping meters Calculate each reactive compound EC50。
3, experimental result
The results are shown in Table 1.By table 1 as it can be seen that compound prepared by embodiment 1-21 can significantly raise the table of CLA-1 It reaches.
Table 1 tests EC of the compound to CLA-1p-LUC HepG2 cell CLA-1 up-regulated expressions50Value
The above results show that N- benzothiazolyl benzsulfamide analog derivatives prepared by embodiment 1-21 are having for SR-BI Imitate activator.One skilled in the art will appreciate that SR-BI activator has effect for reducing fat, caused by can be used for preventing hyperlipidemia Disease, such as atherosclerosis, hyperlipidemia, nonalcoholic fatty liver.Therefore, the N- benzothiazolyls that prepared by embodiment 1-21 Benzsulfamide analog derivative can be used for being prepared into fat-reducing medicament for preventing atherosclerosis, hyperlipidemia, non-alcoholic Fatty liver etc..The fat-reducing medicament contain above-mentioned N- benzothiazolyls benzsulfamide analog derivative or its pharmaceutically acceptable salt or Precursor compound also contains pharmaceutically acceptable carrier or excipient, pharmaceutically acceptable dosage form is made；Pharmaceutically Acceptable carrier or excipient include one or more solids, semisolid or Auxiliary Liquid Material；Pharmaceutically acceptable agent Type includes tablet, capsule, granule, injection, pill, syrup, powder, paste.
The effect of above-described embodiment is specifically to introduce the essentiality content of the present invention, but those skilled in the art should know Protection scope of the present invention should not be confined to the specific embodiment by road.

Claims (9)

1. a kind of N- benzothiazolyls benzsulfamide analog derivative, which is characterized in that shown in chemical structure of general formula such as formula (I)：
Wherein：
R1Independent representative-OCH3,-F ,-H ,-Cl or-NO2；
R2Independently represent following substituent group：
Substituent R1The position of substitution on A rings is 3,4,5 or 6；
Substituent group NHR2It is o-, m- or p- position substitution on B rings.
2. the pharmaceutically acceptable salt or precursor chemical combination of N- benzothiazolyls benzsulfamide analog derivative described in claim 1 Object.
3. the preparation method of N- benzothiazolyls benzsulfamide analog derivative described in claim 1, it is characterised in that：With R1Substitution Aniline be starting material, with the corresponding phenylthiourea of potassium rhodanide reaction generation, cyclization is at R under the catalysis of bromine1Substitution 2- aminobenzothiazoles, then reacted with the benzene sulfonyl chloride of o-, m- or p- position nitro substitution and generate R1Substituted N- benzothiazolyls Nitro is reduced to amino by nitrobenzene sulfonamide with zinc powder, finally and R2Halides are reacted to obtain the final product；Synthetic route is as follows：
A, b, c, d, e are represented reagent and condition as：A, potassium rhodanide, DMF, heat reflux；B, bromine, chloroform, heat reflux；C, pyrrole Pyridine, THF, room temperature；D, zinc, ammonium chloride, ethyl alcohol, water, room temperature；e、R2Cl, potassium carbonate, DMF；
R1Independent representative-OCH3,-F ,-H ,-Cl or-NO2；
R2Independently represent following substituent group：
4. N- benzothiazolyls benzsulfamide analog derivative or its pharmaceutically acceptable salt or precursor chemical combination described in claim 1 Object is used to prepare the purposes of B races I type scavenger receptor activator.
5. N- benzothiazolyls benzsulfamide analog derivative or its pharmaceutically acceptable salt or precursor chemical combination described in claim 1 Object is used to prepare the purposes of fat-reducing medicament.
6. N- benzothiazolyls benzsulfamide analog derivative or its pharmaceutically acceptable salt or precursor chemical combination described in claim 1 Object is used to prepare the purposes of the drug of disease caused by prevention hyperlipidemia, and disease includes Atherosclerosis caused by the hyperlipidemia Change, hyperlipidemia, nonalcoholic fatty liver.
7. a kind of pharmaceutical preparation for lipid-loweringing, it is characterised in that：Contain N- benzothiazolyls benzene sulfonyl described in claim 1 Amine derivant or its pharmaceutically acceptable salt or precursor compound also contain pharmaceutically acceptable carrier or figuration Pharmaceutically acceptable dosage form is made in agent.
8. pharmaceutical preparation according to claim 7, it is characterised in that：The pharmaceutically acceptable carrier or excipient Including one or more solids, semisolid or Auxiliary Liquid Material.
9. pharmaceutical preparation according to claim 7, it is characterised in that：The pharmaceutically acceptable dosage form includes piece Agent, capsule, granule, injection, pill, syrup, powder, paste.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113121467A (en) * 2021-04-20 2021-07-16 河北师范大学 Benzothiazole derivative and medical application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1437588A (en) * 2000-05-22 2003-08-20 比奥维特罗姆股份公司 Inhibitors of 11-beta-hydroxy steroid dehydrogenase type l
WO2014063167A1 (en) * 2012-10-19 2014-04-24 The Broad Institute, Inc. Thiazole-based inhibitors of scavenger receptor bi
WO2014181287A1 (en) * 2013-05-09 2014-11-13 Piramal Enterprises Limited Heterocyclyl compounds and uses thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1437588A (en) * 2000-05-22 2003-08-20 比奥维特罗姆股份公司 Inhibitors of 11-beta-hydroxy steroid dehydrogenase type l
WO2014063167A1 (en) * 2012-10-19 2014-04-24 The Broad Institute, Inc. Thiazole-based inhibitors of scavenger receptor bi
WO2014181287A1 (en) * 2013-05-09 2014-11-13 Piramal Enterprises Limited Heterocyclyl compounds and uses thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
徐辰: "新型SR-BⅠ表达上调剂—苯并噻唑类衍生物的设计、合成及活性研究", 《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113121467A (en) * 2021-04-20 2021-07-16 河北师范大学 Benzothiazole derivative and medical application thereof

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