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

Abstract

The invention discloses an N-benzothiazolylbenzenesulfonamide derivative, a preparation method and an application. It is known that scavenger receptor type I of group B (SR‑BI) plays a key role in the reverse cholesterol transport of HDL, thereby reducing the level of cholesterol in plasma, inhibiting the oxidation of LDL and reducing the vascular damage caused by oxidized LDL. . _The present invention provides a series of N-benzothiazolylbenzenesulfonamide derivatives that can up-regulate the expression of SR-BI _. , -H, -Cl or -NO ₂ , the substitution position of the substituent R ₁ on the A ring is 3, 4, 5 or 6; the substituent NHR ₂ is the ortho, meta or para substitution on the B ring. The prior art has not disclosed the chemical structure, preparation method and pharmacological activity of the N-benzothiazolylbenzenesulfonamide derivatives of the present invention.

Description

A kind of N-benzothiazolylbenzenesulfonamide derivatives, preparation method and application

technical field

The invention belongs to the field of drug synthesis, and relates to an N-benzothiazolylbenzenesulfonamide derivative, a preparation method and a medical application for lowering blood lipid by activating the expression of type I scavenger receptors of group B.

Background technique

Cardiovascular disease (CVD) is a global disease and the number one cause of human death. Atherosclerosis (AS) is a systemic disease characterized by the accumulation of fatty plaques in the walls of large arteries, and is the main pathological basis of CVD. A large number of clinical epidemiological studies have confirmed that the level of low-density lipoprotein cholesterol (LDL-C) in plasma is positively correlated with the incidence of AS, while the level of high-density lipoprotein cholesterol (HDL-C) is negatively correlated with the incidence of AS. . Both basic and clinical data show that HDL-C has anti-AS effect. The main mechanism for HDL-C to exert its anti-atherosclerotic effect is to participate in the reverse cholesterol transport (RCT) process. HDL removes excessive cholesterol in peripheral tissues and blood by promoting cholesterol reverse transport, protects blood vessels, prevents the formation of AS or improves the formed AS. In addition, HDL also exerts anti-inflammatory, antithrombotic, alleviating endothelial cell dysfunction, and inhibiting vascular smooth muscle cell proliferation by inhibiting LDL oxidative modification, increasing NO synthesis, and stimulating endothelial cells to synthesize prostaglandins, etc., thereby delaying the progression of AS.

Family B type I scavenger receptor (SR-BI) is the only HDL receptor identified at the molecular level, it can selectively mediate the absorption of cholesterol and cholesteryl esters in HDL particles, and plays an important role in the metabolism of HDL . Overexpression of SR-BI can increase cholesterol efflux from extrahepatic tissue cells and accelerate hepatic cholesterol uptake, thus reducing the occurrence of atherosclerosis (AS). Due to its anti-AS effect, SR-BI is considered as a new target for the treatment of cardiovascular diseases. Improving the expression of SR-BI has become a very promising direction for the prevention and treatment of AS. Therefore, the up-regulator that increases the expression of SR-BI gene may become an active compound that regulates the HDL receptor pathway, providing a new method for the prevention and treatment of AS.

Contents of the invention

The first object of the present invention is to provide a kind of N-benzothiazolylbenzenesulfonamide derivatives;

The second object of the present invention is to provide a preparation method for the above-mentioned derivatives;

The third object of the present invention is to provide the use of the above-mentioned derivatives for the preparation of B group I type scavenger receptor activators;

The fourth object of the present invention is to provide the medical use of the above-mentioned derivatives for the preparation of lipid-lowering drugs.

Above-mentioned purpose of the present invention is achieved by following technical scheme:

A kind of N-benzothiazolylbenzenesulfonamide derivatives, the general chemical structure formula is as shown in formula (I):

in:

R ₁ independently represents -OCH ₃ , -F, -H, -Cl or -NO ₂ ;

R _{independently} represents the following substituents:

The substitution position of substituent R ₁ on ring A is 3, 4, 5 or 6;

The substituent NHR ₂ is ortho-, inter- or para-substituted on the B ring.

A pharmaceutically acceptable salt or precursor compound of the N-benzothiazolylbenzenesulfonamide derivative.

The preparation method of above-mentioned N-benzothiazolyl benzene sulfonamide derivatives comprises: with _R substituted aniline as starting raw material, reacts with potassium thiocyanate to generate corresponding phenylthiourea, under the catalysis of bromine, cyclic Synthesis of 2-aminobenzothiazole substituted by R ₁ , and then reacting with benzenesulfonyl chloride substituted by o-, m- or p-position nitro to generate N-benzothiazolyl nitrobenzenesulfonamide substituted by R ₁ , and nitrobenzene sulfonamide substituted by zinc powder It is reduced to amino, and finally reacted with _R2 halide to get final product; the synthetic route is as follows:

The reagents and conditions represented by a, b, c, d, and e are: a, potassium thiocyanate, DMF, heat reflux; b, bromine, chloroform, heat reflux; c, pyridine, THF, normal temperature; d, zinc, chlorine Ammonium chloride, ethanol, water, room temperature; e, R ₂ Cl, potassium carbonate, DMF;

R ₁ independently represents -OCH ₃ , -F, -H, -Cl or -NO ₂ ;

R _{independently} represents the following substituents:

Use of the above-mentioned N-benzothiazolylbenzenesulfonamide derivatives or pharmaceutically acceptable salts or precursor compounds for preparing B group I type scavenger receptor activators.

Use of the above-mentioned N-benzothiazolylbenzenesulfonamide derivatives or pharmaceutically acceptable salts or precursor compounds for the preparation of lipid-lowering drugs.

Use of the above-mentioned N-benzothiazolylbenzenesulfonamide derivatives or pharmaceutically acceptable salts or precursor compounds thereof for the preparation of drugs for preventing and treating diseases caused by hyperlipidemia, and the diseases caused by hyperlipidemia include atherosclerosis Cirrhosis, hyperlipidemia, non-alcoholic fatty liver.

A pharmaceutical preparation for lipid-lowering, which contains the above-mentioned N-benzothiazolylbenzenesulfonamide derivatives or pharmaceutically acceptable salts or precursor compounds thereof, and also contains pharmaceutically acceptable carriers or excipients, Made into a pharmaceutically acceptable dosage form.

Further, the pharmaceutically acceptable carrier or excipient includes one or more solid, semi-solid or liquid excipients.

Further, the pharmaceutically acceptable dosage forms include tablets, capsules, granules, injections, pills, syrups, powders, and ointments.

The N-benzothiazolylbenzenesulfonamide derivatives provided by the invention can up-regulate the expression of human SR-BI, and can be used as SR-BI activators to prepare lipid-lowering drugs for preventing and treating diseases caused by hyperlipidemia.

Detailed ways

The substantive content of the present invention will be described in detail below in conjunction with the embodiments, but the protection scope of the present invention is not limited thereto.

Embodiment 1: the preparation of N-(6-chlorobenzothiazol-2-yl)-4-((cyanomethyl)amino)benzenesulfonamide

1. Preparation of p-chlorobenzothiourea

Add p-chloroaniline (10.00g, 78.37mmol) into a 250mL three-necked flask, add 70.00mL of chlorobenzene under stirring to completely dissolve the raw material, and slowly add concentrated hydrochloric acid (3.00mL, 43.10mmol) under ice-water bath conditions, a large amount of white Solids are formed. Move the reaction bottle to an oil bath, heat up to 70°C, add potassium thiocyanate (8.40g, 86.20mmol), the reaction solution turns purple, raise the reaction temperature to 100°C for reflux reaction, and monitor by thin layer chromatography reaction process. After 6 hours, the reaction was complete. At this time, the reaction solution was light purple and solids were precipitated. The reaction solution was cooled to room temperature, filtered under reduced pressure to obtain a solid, washed with a small amount of ether and washed twice with water. After drying, 9.20 g of white solid was obtained, and the yield was 63.02%. The melting point is 180.1-181.3°C. ¹ H-NMR (DMSO-d ₆ , 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, Preparation of 6-chloro-2-aminobenzothiazole

Add p-chlorothiourea (8.50g, 45.70mmol) into a 250mL eggplant-shaped bottle, add 50.00mL of chloroform to dissolve, reflux for 20 minutes under the condition of 50°C oil bath, then place the reaction solution under the condition of ice-water bath, slowly drop Bromine (2.58mL, 50.27mmol), after stirring for 5 minutes, transferred back to the oil bath, raised the temperature to 70°C and continued to reflux. The reaction progress was monitored by TLC, and the reaction was complete after 9 hours. After cooling to room temperature, a solid precipitates, filter under reduced pressure, slowly add ammonia water dropwise to the filtrate, adjust the pH value to neutral, a white precipitate will form, stir for 5 minutes, filter under reduced pressure, wash the solid twice with water, and dry in vacuum To constant weight, 3.62 g of white solid was obtained with a yield of 43.10%. ¹ H-NMR (DMSO-d ₆ , 500MHz) 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. Preparation of N-(6-chlorobenzothiazol-2-yl)-4-nitrobenzenesulfonamide

Add 6-chloro-2-aminobenzothiazole (5.00 g, 27.00 mmol) into a 250 mL eggplant-shaped flask, and add 100.00 mL redistilled tetrahydrofuran under stirring to dissolve it completely. Five minutes later, pyridine (24.10 mL, 298.91 mmol) was slowly added into the eggplant-shaped flask in three equal portions with an interval of 4 h between each time. Stir for ten minutes after each addition of pyridine, and add p-nitrobenzenesulfonyl chloride (8.97 g, 40.50 mmol) three times. After a period of time, solids will be precipitated. If too much solids are precipitated, it is necessary to add redistilled tetrahydrofuran and react at room temperature for 10 hours. After the reaction was completed, THF was evaporated from the reaction solution under reduced pressure, and 100 mL of water was added to the solid, and a large amount of flesh-pink solid was precipitated. After stirring for 1 hour, the filter cake was filtered under reduced pressure, and the filter cake was washed with water twice to obtain a flesh-pink solid, which was weighed after drying. 8.15 g of crude product were obtained. A 5:1 mixture of petroleum ether and ethyl acetate was used for separation and purification by column chromatography to finally obtain 6.33 g of a flesh-pink powder solid with a yield of 63.53%. ¹ H-NMR (DMSO-d ₆ , 500MHz) 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. Preparation of N-(6-chlorobenzothiazol-2-yl)-4-aminobenzenesulfonamide

Put N-(6-chlorobenzothiazol-2-yl)-4-nitrobenzenesulfonamide (2.00g, 5.42mmol) in a 100mL eggplant-shaped bottle with water:ethanol:methanol=2:6:3 As a solvent, after adding 15mL, heat up to 60°C, heat and stir for 20 minutes to dissolve most of the solids, cool the reaction solution to room temperature, add ammonium chloride (1.74g, 32.52mmol) and stir for 10min, add zinc powder (4.22g, 65.04 mmol), the reaction was complete after 2 hours. The reaction solution was evaporated to remove the solvent under reduced pressure, water was added, and 50 mL of ethyl acetate was extracted three times. The organic phases were combined, washed with saturated saline solution, and dried overnight over anhydrous sodium sulfate. The next day, it was evaporated to dryness under reduced pressure. 0.96 g of a yellow powder solid was obtained, with a yield of 52.44%. ¹ H-NMR (DMSO-d ₆ , 500MHz) 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. Preparation of N-(6-chlorobenzothiazol-2-yl)-4-((cyanomethyl)amino)benzenesulfonamide

N-(6-chlorobenzothiazol-2-yl)-4-aminobenzenesulfonamide (0.60g, 1.77mmol) was added to a 50mL eggplant-shaped flask, 1.00mL DMF was added, and sodium hydride (0.14 g, 3.54mmol), after stirring for five minutes, chloroacetonitrile (0.17mL, 2.65mmol) was added, and a drying tube was added to react for 8h. Add water to the reaction solution, add 30 mL of ethyl acetate x 4 times, combine the organic phases, wash with saturated saline solution, and dry over anhydrous sodium sulfate overnight. The next day, it was evaporated to dryness under reduced pressure. It was separated by petroleum ether and ethyl acetate column chromatography to obtain 0.27 g of light yellow powdery solid with a yield of 40.37%. ¹ H-NMR (DMSO-d ₆ , 500MHz) 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). ¹³ C-NMR(DMSO-d ₆ ,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] ⁺ .

Example 2: Preparation of N-(6-chlorobenzothiazol-2-yl)-4-(allylamino)-benzenesulfonamide

Prepared according to the method of Example 1 step, the starting material is: p-chloroaniline, and the halogenating reagent in the last step is 3-chloropropene to obtain the subtitle compound N-(6-chlorobenzothiazol-2-yl)-4-( Allylamino)-benzenesulfonamide, off-white powder 0.21g, yield 40.28%. ¹ H-NMR (DMSO-d ₆ , 500MHz) δ: 4.77 (2H, d, J = 5.00Hz), 4.97 (1H, d, J = 17.00Hz), 5.13 (1H, d, J = 10.50Hz), ¹³ C-NMR(DMSO-d ₆ ,500MHz)δ:15.44,47.13,49.05,112.99,114.28,118.10,122.97,126.00,127.01,127.59,128.35,128.43,130.89,136.31,153.3240,174 ESIMS. ,m/z:380.2[M+H] ⁺ ,402.1[M+Na] ⁺ .

Embodiment 3: Preparation of (4-(N-(6-chlorobenzothiazol-2-yl) acyl) phenyl) glycine ethyl ester

Prepared according to the method of Example 1 step, the starting material is: p-chloroaniline, and the halogenating reagent in the last step is ethyl chloroacetate to obtain the subtitle compound (3-(N-(6-chlorobenzothiazol-2-yl) Acyl)phenyl)glycine ethyl ester, off-white powder 0.36g, yield 42.31%. ¹ H-NMR (DMSO-d ₆ , 500MHz) 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). ¹³ C-NMR (DMSO-d ₆ , 500MHz) δ: 14.12, 46.72, 61.03, 109.59, 112.98. 175.66.ESI-MS, m/z: 426.3[M+H] ⁺ ,448.1[M+Na] ⁺ .

Example 4: Preparation of (4-(N-(6-chlorobenzothiazol-2-yl)acyl)phenyl)glycine

Dissolve (4-(N-(6-chlorobenzothiazol-2-yl)acyl)phenyl)glycine ethyl ester (0.36g, 0.85mmol) in a mixed solvent of methanol: tetrahydrofuran: water at 1:1:1 Add lithium hydroxide (0.24g, 10mmol) to 10mL, react at room temperature for 6h, concentrate the reaction solution, add 10mL of ice water, adjust the pH value to 2 with 1N hydrochloric acid, a large amount of white solid precipitates, and obtain a light yellow solid by suction filtration, dry, column Chromatographic separation gave 0.28 g of white solid powder with a yield of 76.32%. ¹ H-NMR (DMSO-d ₆ , 500MHz) 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). ¹³ C-NMR(DMSO-d ₆ ,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[ ] ⁺ .

Embodiment 5: Preparation of N-(benzothiazol-2-yl)-4-((cyanomethyl)amino)benzenesulfonamide

Prepared according to the method of Example 1 step, the starting material is: 2-aminobenzothiazole, and the halogenating reagent in the last step is chloroacetonitrile to obtain the subtitle compound N-(benzothiazol-2-yl)-4-((cyano Methyl)amino)benzenesulfonamide, 0.19 g of yellow powdery solid, yield 39.27%. ¹ H-NMR (DMSO-d ₆ , 500MHz) 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). ¹³ C-NMR (DMSO-d ₆ , 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: Preparation of N-(benzothiazol-2-yl)-4-(allylamino)-benzenesulfonamide

Prepared according to the method in Example 1, the starting material is: 2-aminobenzothiazole, and the halogenating reagent in the last step is 3-chloropropene to obtain the subtitle compound N-(benzothiazol-2-yl)-4- (Allylamino)-benzenesulfonamide, 0.23 g of yellow powdery solid, yield 40.03%. ¹ H-NMR (DMSO-d ₆ , 500MHz) 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=8.00Hz),7.71(1H,d,J=8.00Hz) 7.50Hz). ¹³ C-NMR (DMSO-d ₆ , 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, 137.30, 151.12 ESI-MS, m/z:346.4[M+H] ⁺ ,368.1[M+Na] ⁺ .

Example 7: Preparation of (4-(N-(benzothiazol-2-yl)acyl)phenyl)glycine ethyl ester

Prepared according to the method of Example 1 step, the starting material is: 2-aminobenzothiazole, and the halogenating reagent in the last step is ethyl chloroacetate to obtain the subtitle compound (4-(N-(benzothiazol-2-yl) Acyl)phenyl)glycine ethyl ester, 0.24 g of light yellow powdery solid, yield 41.36%. 1H-NMR (DMSO-d ₆ , 500MHz) 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). ¹³ C-NMR (DMSO-d ₆ , 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, 137.42, 153. 165.08, 167.32, 175.27.ESI-MS, m/z: 392.3[M+H] ⁺ ,414.2[M+Na] ⁺ .

Example 8: Preparation of (4-(N-(benzothiazol-2-yl)acyl)phenyl)glycine

Prepared according to the method of Example 4 steps, the starting material is: (4-(N-(benzothiazol-2-yl)acyl)phenyl)glycine ethyl ester to obtain the subtitle compound (4-(N-(benzothiazol-2-yl)acyl)ethyl glycine Thiazol-2-yl)acyl)phenyl)glycine, 0.21 g of light yellow powdery solid, yield 63.21%. ¹ H-NMR (DMSO-d ₆ , 500MHz) 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). ¹³ C-NMR (DMSO-d ₆ , 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. z:364.3[M+H] ⁺ ,386.5[M+Na] ⁺ .

Example 9: Preparation of N-(6-methoxybenzothiazol-2-yl)-4-(cyanomethyl)amino)-benzenesulfonamide

Prepared according to the method in Example 1, the starting material is: 6-methoxy-2-aminobenzothiazole, and the halogenating reagent in the last step is chloroacetonitrile to obtain the subtitle compound N-(6-methoxybenzothiazole -2-yl)-4-(cyanomethyl)amino)-benzenesulfonamide, 0.19 g of light yellow powdery solid, yield 39.48%. ¹ H-NMR (DMSO-d ₆ , 500MHz) 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). ¹³ C-NMR (DMSO-d ₆ , 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: ⁺ ,397.1[M+Na] ⁺ .

Example 10: Preparation of N-(6-methoxybenzothiazol-2-yl)-4-(allylamino)-benzenesulfonamide

Prepared according to the method of Example 1, the starting material is: 6-methoxy-2-aminobenzothiazole, and the halogenating reagent in the last step is 3-chloropropene to obtain the subtitle compound N-(6-methoxybenzene Andthiazol-2-yl)-4-(allylamino)-benzenesulfonamide, 0.23 g of light yellow powdery solid, yield 40.66%. ¹ H-NMR (DMSO-d ₆ , 500MHz) 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). ¹³ C-NMR(DMSO-d ₆ ,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] ⁺ .

Example 11: Preparation of (4-(N-(6-methoxybenzothiazol-2-yl)acyl)phenyl)glycine ethyl ester

Prepared according to the method of Example 1 step, the starting material is: 6-methoxy-2-aminobenzothiazole, and the halogenating reagent in the last step is ethyl chloroacetate to obtain the subtitle compound (4-(N-(6- Methoxybenzothiazol-2-yl)acyl)phenyl)glycine ethyl ester, 0.25 g of light yellow powdery solid, yield 39.83%. ¹ H-NMR (DMSO-d ₆ , 500MHz) 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). ¹³ C-NMR(DMSO-d ₆ ,500MHz)δ:14.34,46.37,56.28,61.84,107.98,112.91,113.35,114.69,124.88,127.22,128.28,131.32,149.221,15 ,156.82,164.67,167.32,175.43.ESI-MS,m/z:422.3[M+H] ⁺ ,444.1[M+Na] ⁺ .

Example 12: Preparation of (4-(N-(6-methoxybenzothiazol-2-yl)acyl)phenyl)glycine

Prepared according to the method of Example 4 steps, the starting material is: (4-(N-(6-methoxybenzothiazol-2-yl)acyl)phenyl)glycine ethyl ester to obtain the subtitle compound (4-( N-(6-methoxybenzothiazol-2-yl)acyl)phenyl)glycine, 0.19 g of light yellow powdery solid, yield 62.31%. ¹ H-NMR (DMSO-d ₆ , 500MHz) 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). ¹³ C- NMR(DMSO-d ₆ ,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.z/ESI-MS,174.32 :394.1[M+H] ⁺ ,416.3[M+Na] ⁺ .

Example 13: Preparation of N-(6-fluorobenzothiazol-2-yl)-4-(cyanomethyl)amino)-benzenesulfonamide

Prepared according to the method in Example 1, the starting material is: 6-fluoro 2-aminobenzothiazole, and the halogenating reagent in the last step is chloroacetonitrile to obtain the subtitle compound N-(6-fluorobenzothiazol-2-yl) -4-(cyanomethyl)amino)-benzenesulfonamide, 0.19 g of light yellow powdery solid, yield 38.77%. ¹ H-NMR (DMSO-d ₆ , 500MHz) 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). ¹³ C-NMR (DMSO-d ₆ , 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 ^[ ,385. M+Na] ⁺ .

Example 14: Preparation of N-(6-fluorobenzothiazol-2-yl)-4-(allylamino)benzenesulfonamide

Prepared according to the method in Example 1, the starting material is: 6-fluoro 2-aminobenzothiazole, and the halogenating reagent in the last step is 3-chloropropene to obtain the subtitle compound N-(6-fluorobenzothiazole-2- base)-4-(allylamino)benzenesulfonamide, 0.22 g of light yellow powdery solid, yield 39.59%. ¹ H-NMR (DMSO-d ₆ , 500MHz) 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). ¹³ C-NMR (DMSO-d ₆ , 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] ⁺ .

Example 15: Preparation of (4-(N-(6-fluorobenzothiazol-2-yl)acyl)phenyl)glycine ethyl ester

Prepared according to the method of Example 1 step, the starting material is: 6-fluoro 2-aminobenzothiazole, and the halogenating reagent in the last step is ethyl chloroacetate to obtain the subtitle compound (4-(N-(6-fluorobenzothiazole) Thiazol-2-yl)acyl)phenyl)glycine ethyl ester, 0.31 g of light yellow powdery solid, yield 40.23%. ¹ H-NMR (DMSO-d ₆ , 500MHz) 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). ¹³ C-NMR(DMSO-d ₆ ,500MHz)δ:14.12,46.72,61.03,109.59,112.98.114.03,123.26,125.69,127.63,128.10,128.61,136.968,151.412,154. ,167.34,175.66.ESI-MS,m/z:410.1[M+H] ⁺ ,432.3[M+Na] ⁺ .

Example 16: Preparation of (4-(N-(6-fluorobenzothiazol-2-yl)acyl)phenyl)glycine

Prepared according to the method of Example 4 steps, the starting material is: (4-(N-(6-fluorobenzothiazol-2-yl) acyl) phenyl) glycine ethyl ester to obtain the subtitle compound (4-(N- (6-Fluorobenzothiazol-2-yl)acyl)phenyl)glycine, 0.33 g of light yellow powdery solid, yield 69.68%. ¹ H-NMR (DMSO-d ₆ , 500MHz) 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). ¹³ C-NMR (DMSO-d ₆ , 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 ^: 382.3,404. [M+Na] ⁺ .

Example 17: Preparation of N-(benzothiazol-2-yl)-3-(allylamino)benzenesulfonamide

Prepared according to the method of Example 1 step, the starting material is: 2-aminobenzothiazole, and the halogenating reagent in the last step is 3-chloropropene to obtain the subtitle compound N-(benzothiazol-2-yl)-3-( Allylamino)benzenesulfonamide, 0.30 g of light yellow powder, yield 36.23%. ¹ H-NMR (DMSO-d ₆ , 500MHz) 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). ¹³ C-NMR (DMSO-d ₆ , 500MHz) δ: 47.14, 110.88, 113.07, 117.84, 118.25, 121.30, 123.35, 123.98, 124.71, 127.76, 129.80, 130.9575, 137.59.15, 142 ,165.75.ESI-MS,m/z:346.3[M+H] ⁺ ,368.2[M+Na] ⁺ .

Example 18: N-(Benzothiazol-2-yl)-3-((cyanomethyl)amino)benzenesulfonamide

Prepared according to the method of Example 1 step, the starting material is: 2-aminobenzothiazole, and the halogenating reagent in the last step is chloroacetonitrile to obtain the subtitle compound N-(benzothiazol-2-yl)-3-((cyano Methyl)amino)benzenesulfonamide, 0.21 g of light yellow powder, yield 35.28%. ¹ H-NMR (DMSO-d ₆ , 500MHz) 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). ¹³ C-NMR (DMSO-d ₆ , 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:345.1[M+H] ⁺ ,367.3[M+Na] ⁺ .

Example 19: Preparation of N-(6-methoxybenzothiazol-2-yl)-3-(allylamino)benzenesulfonamide

Prepared according to the method of Example 1, the starting material is: 6-methoxy-2-aminobenzothiazole, and the halogenating reagent in the last step is 3-chloropropene to obtain the subtitle compound N-(6-methoxybenzene (Thiazol-2-yl)-3-(allylamino)benzenesulfonamide, 0.19 g of light yellow powder, yield 30.29%. ¹ H-NMR (DMSO-d ₆ , 500MHz) 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). ¹³ C- NMR (DMSO-d ₆ , 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 /z:376.2[M+H] ⁺ ,398.1[M+Na] ⁺ .

Example 20: Preparation of N-(benzothiazol-2-yl)-3-((cyanomethyl)amino)benzenesulfonamide

Prepared according to the method in Example 1, the starting material is: 6-methoxy-2-aminobenzothiazole, and the halogenating reagent in the last step is chloroacetonitrile to obtain the subtitle compound N-(benzothiazol-2-yl) -3-((cyanomethyl)amino)benzenesulfonamide, 0.32 g of yellow powder, yield 33.19%. ¹ H-NMR (DMSO-d ₆ , 500MHz) 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). ¹³ C- NMR (DMSO-d ₆ , 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 :375.1[M+H] ⁺ ,397.1[M+Na] ⁺ .

Example 21: Preparation of N-(6-fluorobenzothiazol-2-yl)-3-(allylamino)benzenesulfonamide

Prepared according to the method in Example 1, the starting material is: 6-fluoro 2-aminobenzothiazole, and the halogenating reagent in the last step is 3-chloropropene to obtain the subtitle compound N-(6-fluorobenzothiazole-2- base)-4-(allylamino)benzenesulfonamide, 0.22 g of light yellow powdery solid, yield 39.59%. ¹ H-NMR (DMSO-d ₆ , 500MHz) 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). ¹³ C-NMR(DMSO-d ₆ ,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] ⁺ .

Example 22: Effect example, test the compound prepared in Example 1-21 to up-regulate the expression of human SR-BI

SR-BI is the first molecularly and functionally well-defined high-density lipoprotein receptor, and human SR-BI is also known as CLA-1.

1. Experimental materials

RPMI 1640 medium, MEM medium and fetal bovine serum were purchased from Hyclone; G418 was purchased from Invitrogen, USA; and the luciferase assay kit (Luciferase Assay System) was purchased from Promega.

2. Experimental method

2.1 Cell culture

Human liver cancer cell line HepG2 cells were cultured in MEM medium containing 10% fetal bovine serum; CLA-1-LUCHepG2 were cultured in MEM medium containing 500 μg·mL ^-1 G418 and 10% fetal bovine serum; all cells were in Adherent culture was carried out at 37°C in a 5% CO ₂ incubator.

2.2 Plasmid transfection

Using the method mediated by LipofectamineTM2000 (Invitrogen), the recombinant reporter gene plasmid pGL3-CLAP (containing the upstream regulatory sequence of the human CLA-1 gene [-1055 ~ -62bp, with the A of the CLA1 gene start codon ATG as +1]- luciferase reporter gene) and pcDNA3 (containing the neo gene) were co-transfected into HepG2 cells. After being treated with 600μg·mL ^-1 G418 for 14 days, G418-resistant cell clones formed. Perform a series of monoclonalization operations on the formed cell clones while tracking their luciferase activity. The stable cell clone with high luciferase expression and normal cell cycle was named CLA-1p-LUC HepG2.

2.3 Activity Screening

CLA-1p-LUC HepG2 cells in the logarithmic growth phase were inoculated on a 96-well transparent bottom white plate at a cell number of about 5×10 ⁵ /mL, and 100 μL of single cell suspension was added to each well. The compounds were diluted with RPMI-1640 cell culture medium containing 5% FBS and MEM cell culture medium containing 5% FBS at concentrations of 100 μM, 50 μM, 25 μM, 12.5 μM, 6.25 μM, 3.125 μM, 1.5625 μM, 0.78125 μM, 0.39 μM, 0.039μM, 0.0039μM, 11 concentrations in total. 6-8h after the cells adhered to the wall, the original medium was removed, and the cells were rinsed once with PBS. Add 200μl of a compound solution of a certain concentration diluted with cell culture medium to each well, and set up two replicate wells for each concentration of each compound. After 18-24 hours, the culture medium was removed, and after gently rinsing with PBS, 25 μl of cell lysate was added to each well, and the cells were lysed at 37°C for 30-45 minutes. After the cells were completely lysed, quickly add 50 μl firefly luciferase detection reagent to each well, and immediately put the analysis white plate into a microplate reader for detection. Calculate the change rate of the luciferase activity of the test sample, change rate (%)=luciferase activity after adding the compound/luciferase activity after adding the blank control sample (DMSO)×100. A test sample with a change rate ≥ 150% is considered a positive result. Use GraphPad to calculate the EC ₅₀ of each active compound.

3. Experimental results

The results are shown in Table 1. It can be seen from Table 1 that the compounds prepared in Examples 1-21 can significantly up-regulate the expression of CLA-1.

Table 1 _EC50 values of test compounds on CLA-1p-LUC HepG2 cell CLA-1 up-regulated expression

The above results show that the N-benzothiazolylbenzenesulfonamide derivatives prepared in Examples 1-21 are effective activators of SR-BI. Those skilled in the art know that SR-BI activators have a lipid-lowering effect and can be used to prevent and treat diseases caused by hyperlipidemia, such as atherosclerosis, hyperlipidemia, and non-alcoholic fatty liver. Therefore, the N-benzothiazolylbenzenesulfonamide derivatives prepared in Examples 1-21 can be used to prepare lipid-lowering drugs for the prevention and treatment of atherosclerosis, hyperlipidemia, and non-alcoholic fatty liver. The lipid-lowering drug contains the above-mentioned N-benzothiazolylbenzenesulfonamide derivatives or pharmaceutically acceptable salts or precursor compounds thereof, and also contains pharmaceutically acceptable carriers or excipients, and is made into pharmaceutically acceptable dosage forms; pharmaceutically acceptable carriers or excipients include one or more solid, semi-solid or liquid excipients; pharmaceutically acceptable dosage forms include tablets, capsules, granules, injections, pills, syrups, Powder, ointment.

The purpose of the above embodiments is to specifically introduce the substantive content of the present invention, but those skilled in the art should know that the protection scope of the present invention should not be limited to the specific embodiments.

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.