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CN108383838B - Amide derivative and application thereof in hypertension, hyperlipidemia and atherosclerosis - Google Patents

Amide derivative and application thereof in hypertension, hyperlipidemia and atherosclerosis Download PDF

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CN108383838B
CN108383838B CN201810279142.4A CN201810279142A CN108383838B CN 108383838 B CN108383838 B CN 108383838B CN 201810279142 A CN201810279142 A CN 201810279142A CN 108383838 B CN108383838 B CN 108383838B
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amino
dichloromethane
amide derivative
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pyrrolo
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许枞
党怀欣
刘丹阳
桑琦
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Zhejiang Pharmaceutical Garden Biotechnology Co.,Ltd.
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Abstract

The invention discloses an amide derivative, which has a structural general formula shown as a formula (I):
Figure 100004_DEST_PATH_IMAGE002
wherein R is1Selected from H, OH or CH3，R2Selected from H, OH or CH3，R3Selected from H, OH or CH3The amide derivative of the invention is angiotensin II mediated ApoE‑/‑The amide derivative has good biological activity in a mouse model, so that the amide derivative has positive significance in preventing and/or treating cardiovascular and cerebrovascular diseases, and can be further studied in the aspects of hypertension, hyperlipidemia and/or atherosclerosis.

Description

Amide derivative and application thereof in hypertension, hyperlipidemia and atherosclerosis
Technical Field
The invention relates to the fields of drug synthesis, pharmacological tests and drug development, in particular to an amide derivative and application thereof in hypertension, hyperlipidemia and atherosclerosis.
Background
Cardiovascular and cerebrovascular diseases are the general names of cardiovascular diseases and cerebrovascular diseases, and the diseases are caused by hypertension, smoking and drinking, diabetes, dyslipidemia, metabolic syndrome and the like, and are manifested as ischemic or hemorrhagic diseases of the brain, the heart and the tissues of the whole body. With the rapid development of social economy and the continuous improvement of the living standard of residents, the proportion of cardiovascular diseases in the death causes of the residents is continuously increased, and the health of the residents is more and more greatly influenced.
Atherosclerosis is the main cause of cardiovascular and cerebrovascular diseases, ApoE gene knockout (ApoE)-/-) Is a classical model of the Atherosclerosis (AS) of mice, and provides a reliable drug screening platform for the treatment of diseases.
Angiotensin II binds with angiotensin receptor, makes systemic arteriole, vein contract, blood pressure rise, and blood volume of blood of heart returned increase, can cause hypertrophy of human smooth muscle cell, and can increase expression of platelet-derived growth factor of mouse artery smooth muscle cell cultured in vitro, thereby stimulating hyperplasia of smooth muscle cell and directly stimulating angiogenesis. Therefore, Angiotensin Converting Enzyme Inhibitors (ACEIs) and angiotensin receptor Antagonists (ARBs) have important blood pressure lowering effects.
Disclosure of Invention
The invention aims to provide an amide derivative with a structural formula shown as a formula (I)
Figure 160336DEST_PATH_IMAGE001
Wherein R is1Selected from H, OH or CH3，R2Selected from H, OH or CH3，R3Selected from H, OH or CH3。
Further, R1Selected from H, R2Selected from H, R3Is selected from H;
or R1Selected from OH, R2Selected from H, R3Is selected from H;
or R1Selected from H, R2Selected from H, R3Is selected from CH3；
Or R1Selected from H, R2Selected from OH, R3Is selected from H;
or R1Is selected from CH3，R2Selected from H, R3Is selected from H.
Numbering Structure of the product Structural data
a
Figure 546318DEST_PATH_IMAGE002
 LC-MS(ESI, pos, ion) m/z: 357[M+H]
b
Figure 326055DEST_PATH_IMAGE003
 LC-MS(ESI, pos, ion) m/z: 373[M+H]
c
Figure 721264DEST_PATH_IMAGE004
 LC-MS(ESI, pos, ion) m/z: 371[M+H]
d
Figure 535636DEST_PATH_IMAGE005
 LC-MS(ESI, pos, ion) m/z: 373[M+H]
e
Figure 826940DEST_PATH_IMAGE006
 LC-MS(ESI, pos, ion) m/z: 371[M+H]
The numbers are consistent with those of the test compounds in the test examples.
Further, a salt of the compound represented by the formula (I) or a solvent compound thereof.
Another object of the present invention is to provide a synthetic route of the amide derivatives of formula (I)
Figure 93974DEST_PATH_IMAGE008
Wherein R is1Selected from H, OH or CH3，R2Selected from H, OH or CH3，R3Selected from H, OH or CH3。
Further, R1Selected from H, R2Selected from H, R3Is selected from H;
or R1Selected from OH, R2Selected from H, R3Is selected from H;
or R1Selected from H, R2Selected from H, R3Is selected from CH3；
Or R1Selected from H, R2Selected from OH, R3Is selected from H;
or R1Is selected from CH3，R2Selected from H, R3Is selected from H.
Further, the synthesis method of each step in the synthesis route is as follows:
(1) dissolving the compound 1 in a proper solvent, adding DMFDMA and a small amount of triethylamine, heating the system for reaction for about 4 hours, then cooling the system to 60 ℃, decompressing and transferring out half of the solvent, cooling the rest system to normal temperature, and directly using the rest system for the next reaction without treatment.
Adding methanol into the system, adding sodium ethoxide, then adding a Pd/C catalyst, introducing hydrogen, reacting at 30 ℃, and carrying out aftertreatment to obtain an intermediate product compound 3. It is important to emphasize that: the hydroxyl group of the compound 3 is remained in the subsequent reaction until the final product, and a series of compounds without the hydroxyl group are synthesized in the research process, but the pharmacological activity comparison shows that the activity of the compound without the hydroxyl group is far lower than that of the compound with the hydroxyl group.
(2) Dissolving the compound 3 in dichloromethane, adding a certain amount of triethylamine, controlling low temperature, dropwise adding 2-chloroacetyl chloride into the system, recovering to room temperature after dropwise adding, reacting at normal temperature for 10 hours, and performing post-treatment to obtain a compound 4.
(3) Dissolving tert-butyl (2-amino-2-methylpropyl) carbamate and potassium carbonate in DMF, adding the compound 4 in a nitrogen atmosphere, heating for reaction for a period of time, and carrying out post-treatment to obtain a compound 5.
(4) Dissolving the compound 5 in dichloromethane, adding trifluoroacetic acid, and carrying out post-treatment after the reaction is finished to obtain a compound 6.
(5) At normal temperature, the corresponding carboxylic acid derivative and pyridine are dissolved in dichloromethane, DCC is added, the mixture is stirred for a period of time, then the compound 6 is added, the system is stirred overnight, and the corresponding carboxylic acid derivative is obtained after post-treatment.
Further, the reaction solvent in the step (1) is one of DMF, DMAC and THF, preferably DMF.
Further, the heating reaction temperature of the step (1) is 70-120 ℃, preferably 95-100 ℃.
Further, the low-temperature dropping temperature in the step (2) is 5-15 ℃, preferably 10 ℃.
Further, the reaction temperature in the step (3) is 60 to 90 ℃, preferably 70 to 80 ℃.
The amide derivative of the invention is the ApoE mediated by angiotensin II-/-The amide derivative has good biological activity in a mouse model, so that the amide derivative has positive significance in preventing and/or treating cardiovascular and cerebrovascular diseases, and can be further studied in the aspects of hypertension, hyperlipidemia and/or atherosclerosis.
The invention also aims to provide application of the amide derivative shown in the formula (I) in preparing medicaments for preventing and/or treating cardiovascular and cerebrovascular diseases.
Further, the cardiovascular and cerebrovascular diseases refer to hypertension, hyperlipidemia and/or atherosclerosis.
The invention also aims to provide application of the amide derivative shown in the formula (I) in preparing a medicament for preventing and/or treating abdominal aortic aneurysm.
Furthermore, the amide derivatives shown in formula (I) have the application of treating hypertension, hyperlipidemia and/or atherosclerosis and preventing abdominal aortic aneurysm from happening.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
Detailed Description
Example 1: synthesis of N- (2- ((2- (5-hydroxy-1H-pyrrolo [3,2] pyridin-1-yl) -2-ethoxy) amino) -2-methylpropyl) furan-2-carboxamide
Figure 292874DEST_PATH_IMAGE009
(1) Synthesis of 5-hydroxy-1H-pyrrolo [3,2] pyridine
Figure 430594DEST_PATH_IMAGE011
6-methyl-5-nitro-2-hydroxypyridine (10mmol) is added into 50ml of DMF, N-diformylamide formal (12 mmol) is added after stirring and full dissolution, then 0.7 ml of triethylamine is added, the system is heated to 95-100 ℃, and the temperature is maintained for reaction for 4 hours. The reaction system is cooled to about 60 ℃, half of the solvent is transferred out under reduced pressure, and the rest system is cooled to about 25 ℃. The solution of intermediate 2 obtained was directly subjected to the next reaction without further treatment.
50ml of methanol was added to the system in the previous step, 0.82 g of sodium acetate was added thereto, and then 0.8 g of Pd/C was added thereto, hydrogen gas was introduced thereto, and the system was allowed to fill with hydrogen gas by displacement three times and reacted at 30 ℃ for 4 hours. Removing catalyst by membrane filtration, evaporating the filtrate at 45 deg.C under reduced pressure to remove solvent, dissolving with small amount of dichloromethane, and separating by flash column chromatography to obtain 1.15 g white crystal 5-hydroxy-1H-pyrrole [3, 2%]Pyridine in 86% yield.1H-NMR (400 MHz, CDCl3) :4.53(s, 1H), 6.54(d,1H), 7.01(d, 1H), 7.41(d, 1H), 7.78(s, 1H), 8.03(d, 1H).13C-NMR(75 MHz,CDCl3) : 107.65, 109.06, 119.77, 126.27, 128.68, 142.13, 151.75. LC-MS(ESI,pos, ion) m/z: 135 [M+H]。
(2) Synthesis of 2-chloro-1- (5-hydroxy-1H-pyrrolo [3,2] pyridine-1-yl) -ethanone
Figure 423958DEST_PATH_IMAGE012
Reacting 5-hydroxy-1H-pyrrole [3,2]Dissolving pyridine (10mmol) in 40 ml dichloromethane solution, adding triethylamine 10 ml, controlling temperature below 10 deg.C, dropwise adding 2-chloroacetyl chloride (12 mmol) dichloromethane solution into the system, recovering to room temperature after dropwise adding, stirring at room temperature for 10 hr, washing the reaction system with 50ml 5% sodium carbonate aqueous solution, and using anhydrous Na as organic phase2SO4Drying, evaporating solvent, and flash column chromatography to obtain 1.9 g light yellow 2-chloro-1- (5-hydroxy-1H-pyrrole [3,2]]And pyridin-1-yl) -ethanone solid in 90% yield.1H-NMR (400 MHz, CDCl3): 4.71(s, 2H), 6.45(d, 1H), 6.54(d, 1H), 8.09(d, 1H), 8.76(d, 1H).13C-NMR(75MHz, CDCl3) : 42.91, 110.55, 115.56, 122.25, 127.21, 130.14, 137.60, 154.06,163.78. LC-MS(ESI, pos, ion) m/z: 211[M+H]。
(3) Synthesis of tert-butyl- (2- ((2- (5-hydroxy-1H-pyrrolo [3,2] pyridin-1-yl) -2-ethoxy) amino) -2-methylpropyl) aminomethyl ester
Figure 178287DEST_PATH_IMAGE013
In a 200ml capacity glass flask equipped with a stirring device, a thermometer, a reflux condenser and a dropping funnel, tert-butyl (2-amino-2-methylpropyl) carbamate (10mmol), potassium carbonate (11mmol) and 12 ml of N, N-dimethylformamide were added under a nitrogen atmosphere. While stirring at room temperature, 2-chloro-1- (5-hydroxy-1H-pyrrolo [3,2] is added]And (3) pyridine-1-yl) ethanone (11mmol), and reacting the mixture at 70-80 ℃ for 3-4 hours. After completion of the reaction, the mixture was cooled to room temperature, and then 40 ml of toluene was added. After washing twice with water (50ml), the mixture was dried over magnesium sulfate. After filtration, the mixture was concentrated under reduced pressure. The resulting yellow oil was then purified by silica gel column chromatography (packing material: Wakogel C-200, eluent: hexane/ethyl acetate = 1/2 (volume ratio)). 3.4 g of off-white tert-butyl- (2- ((2- (5-hydroxy-1H-pyrrolo [3,2 ]) are obtained]And pyridine-1-yl) -2-ethoxy) amino) -2-methylpropyl) aminomethyl ester solid (94% yield), 99% purity (area percent by high performance liquid chromatography).1H-NMR (400 MHz, CDCl3) : 1.27(s, 6H), 1.41(s,9H), 1.82(s, 1H), 3.12(s, 1H), 3.50(s, 1H), 3.78(d, 2H), 4.14(s, 1H), 6.43(d,1H), 6.52(d, 1H), 8.00(d, 1H), 8.67(d, 1H).13C-NMR(75 MHz, CDCl3) : 25.66,28.33, 47.13, 47.35, 51.12, 80.89, 110.55, 115.56, 122.25, 127.21, 130.14,137.60, 154.06, 157.93, 168.18. LC-MS(ESI, pos, ion) m/z: 363[M+H]。
(4) Synthesis of 2- ((1-amino-2-methylpropan-2-yl) amino) -1- (5-hydroxy-1H-pyrrolo [3,2] pyrid-1-yl) ethanone
Figure 384141DEST_PATH_IMAGE014
Mixing tert-butyl- (2- ((2- (5-hydroxy-1H-pyrrole [3,2]]And pyridine-1-yl) -2-ethoxy) amino) -2-methylpropyl) aminomethyl (10mmol) is dissolved in 30 ml dichloromethane, trifluoroacetic acid (15 mmol) is added thereto, the system is stirred at 30 ℃ for 4 hours until TLC detection reaction is completed, washing is carried out twice with 10% aqueous sodium carbonate solution 20ml × 2, the organic phase is dried over anhydrous sodium sulfate, after filtration, the solvent is evaporated to dryness in vacuum to obtain 2.4 g of off-white 2- ((1-amino-2-methylpropanyl-2-yl) amino) -1- (5-hydroxy-1H-pyrrole [3, 2-yl) pyrrole]And pyridine-1-yl) ethanone crystal with a yield of 92%.1H-NMR (400 MHz, CDCl3) : 1.26(s, 6H), 1.85(s, 2H), 2.64(s, 2H), 2.84(s, 1H),3.73(s, 1H), 3.85(s, 1H), 6.42(d, 1H), 6.51(d, 1H), 7.98(t, 2H).13C-NMR(75MHz, CDCl3) : 24.37, 47.35, 48.29, 50.15, 110.55, 115.56, 122.25, 127.21,130.14, 137.6, 154.06, 168.18. LC-MS(ESI, pos, ion) m/z: 263[M+H]。
(5) Synthesis of N- (2- ((2- (5-hydroxy-1H-pyrrolo [3,2] pyridin-1-yl) -2-ethoxy) amino) -2-methylpropyl) furan-2-carboxamide
Figure 907526DEST_PATH_IMAGE015
At 25 ℃ and N2To a solution of 2-furancarboxylic acid (12 mmol) and pyridine (20 mmol) in 20mL of anhydrous dichloromethane under an atmosphere was added 1, 3-dicyclohexylcarbodiimide DCC (15 mmol). After 5 minutes, 2- ((1-amino-2-methylpropan-2-yl) amino) -1- (5-hydroxy-1H-pyrrolo [3, 2) was added]And pyridin-1-yl) ethanone (10mmol) and the mixture was stirred overnight. TLC (95: 5 dichloromethane: methanol with 2% ammonia) indicated that all starting material was consumed. The reaction was quenched with sodium bicarbonate and filtered through a plug of celite. The stopper was rinsed with dichloromethane and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with Na2SO4After drying, filtration and concentration in vacuo, 3.4 g of a light brown solid are obtained. The crude product is purified by flash chromatography using 2% to 8% MeOH: purification was performed with a stepwise gradient of dichloromethane and 2% ammonia to yield 3.2 g of N- (2- ((2- (5-hydroxy-1H-pyrrolo [3, 2-l)) as a white powder]And Biao PiPyridin-1-yl) -2-ethoxy) amino) -2-methylpropyl) furan-2-carboxamide in 90% yield.1H-NMR (400 MHz, CDCl3) : 1.27(s, 6H), 2.67(s, 1H), 3.17(s, 1H),3.31(s, 1H), 3.81(d, 2H), 6.14(s, 1H), 6.45(d, 1H), 6.57(m, 2H), 7.16(m, 2H),8.02(m, 2H).13C-NMR(75 MHz, CDCl3) : 25.66, 47.35, 47.36, 51.12, 110.55,110.96, 114.54, 115.56, 122.25, 127.21, 130.14, 137.6, 144.18, 144.73,154.06, 163.42, 168.18. LC-MS(ESI, pos, ion) m/z: 357[M+H]。
Example 2: synthesis of N- (2- ((2- (5-hydroxy-1H-pyrrolo [3,2] pyridin-1-yl) -2-ethoxy) amino) -2-methylpropyl) - (5-hydroxyfuran-2-yl) -carboxamide
Figure 806212DEST_PATH_IMAGE016
At 25 ℃ and N2To a solution of 5-hydroxyfuran-2-carboxylic acid (12 mmol) and pyridine (20 mmol) in 20mL of anhydrous dichloromethane under an atmosphere was added 1, 3-dicyclohexylcarbodiimide DCC (15 mmol). After 5 minutes, 2- ((1-amino-2-methylpropan-2-yl) amino) -1- (5-hydroxy-1H-pyrrolo [3, 2) was added]And pyridin-1-yl) ethanone (10mmol) and the mixture was stirred overnight. TLC (95: 5 dichloromethane: methanol with 2% ammonia) indicated that all starting material was consumed. The reaction was quenched with sodium bicarbonate and filtered through a plug of celite. The stopper was rinsed with dichloromethane and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with Na2SO4After drying, filtration and concentration in vacuo, 3.4 g of a light brown solid are obtained. The crude product is purified by flash chromatography using 2% to 8% MeOH: purification was performed with a stepwise gradient of dichloromethane and 2% ammonia to yield 3.3 g of N- (2- ((2- (5-hydroxy-1H-pyrrolo [3, 2) as a white powder]And pyridin-1-yl) -2-ethoxy) amino) -2-methylpropyl) - (5-hydroxyfuran-2-yl) -carboxamide in 89% yield. LC-MS (ESI, pos, ion) M/z 373[ M + H ]]。
Example 3: synthesis of N- (2- ((2- (5-hydroxy-1H-pyrrolo [3,2] pyridin-1-yl) -2-ethoxy) amino) -2-methylpropyl) - (3-methylfuran-2-yl) -carboxamide
Figure 47837DEST_PATH_IMAGE004
At 25 ℃ and N2To a solution of 3-methylfuran-2-carboxylic acid (12 mmol) and pyridine (20 mmol) in 20mL of anhydrous dichloromethane under an atmosphere was added 1, 3-dicyclohexylcarbodiimide DCC (15 mmol). After 5 minutes, 2- ((1-amino-2-methylpropan-2-yl) amino) -1- (5-hydroxy-1H-pyrrolo [3, 2) was added]And pyridin-1-yl) ethanone (10mmol) and the mixture was stirred overnight. TLC (95: 5 dichloromethane: methanol with 2% ammonia) indicated that all starting material was consumed. The reaction was quenched with sodium bicarbonate and filtered through a plug of celite. The stopper was rinsed with dichloromethane and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with Na2SO4After drying, filtration and concentration in vacuo, 3.4 g of a light brown solid are obtained. The crude product is purified by flash chromatography using 2% to 8% MeOH: purification was performed with a stepwise gradient of dichloromethane and 2% ammonia to yield 3.1 g of N- (2- ((2- (5-hydroxy-1H-pyrrolo [3, 2) -2) as a white powder]And pyridin-1-yl) -2-ethoxy) amino) -2-methylpropyl) - (3-methylfuran-2-yl) -carboxamide in 84% yield. LC-MS (ESI, pos, ion) M/z 371[ M + H ]]。
Example 4: synthesis of N- (2- ((2- (5-hydroxy-1H-pyrrolo [3,2] pyridin-1-yl) -2-ethoxy) amino) -2-methylpropyl) - (4-hydroxyfuran-2-yl) -carboxamide
Figure 791802DEST_PATH_IMAGE005
At 25 ℃ and N2To a solution of 4-hydroxyfuran-2-carboxylic acid (12 mmol) and pyridine (20 mmol) in 20mL of anhydrous dichloromethane under an atmosphere was added 1, 3-dicyclohexylcarbodiimide DCC (15 mmol). After 5 minutes, 2- ((1-amino-2-methylpropan-2-yl) amino) -1- (5-hydroxy-1H-pyrrolo [3, 2) was added]And pyridin-1-yl) ethanone (10mmol) and the mixture was stirred overnight. TLC (95: 5 dichloromethane: methanol with 2% ammonia) indicated that all starting material was consumed. The reaction was quenched with sodium bicarbonate and filtered through a plug of celite. The stopper is flushed with dichloromethaneThe aqueous layer was extracted with dichloromethane. The combined organic layers were washed with Na2SO4After drying, filtration and concentration in vacuo, 3.4 g of a light brown solid are obtained. The crude product is purified by flash chromatography using 2% to 8% MeOH: purification was performed with a stepwise gradient of dichloromethane and 2% ammonia to yield 3.2 g of N- (2- ((2- (5-hydroxy-1H-pyrrolo [3, 2-l)) as a white powder]And pyridin-1-yl) -2-ethoxy) amino) -2-methylpropyl) - (4-hydroxyfuran-2-yl) -carboxamide in 92% yield. LC-MS (ESI, pos, ion) M/z 373[ M + H ]]。
Example 5: synthesis of N- (2- ((2- (5-hydroxy-1H-pyrrolo [3,2] pyridin-1-yl) -2-ethoxy) amino) -2-methylpropyl) - (5-methylfuran-2-yl) -carboxamide
Figure 435273DEST_PATH_IMAGE006
At 25 ℃ and N2To a solution of 5-methylfuran-2-carboxylic acid (12 mmol) and pyridine (20 mmol) in 20mL of anhydrous dichloromethane under an atmosphere was added 1, 3-dicyclohexylcarbodiimide DCC (15 mmol). After 5 minutes, 2- ((1-amino-2-methylpropan-2-yl) amino) -1- (5-hydroxy-1H-pyrrolo [3, 2) was added]And pyridin-1-yl) ethanone (10mmol) and the mixture was stirred overnight. TLC (95: 5 dichloromethane: methanol with 2% ammonia) indicated that all starting material was consumed. The reaction was quenched with sodium bicarbonate and filtered through a plug of celite. The stopper was rinsed with dichloromethane and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with Na2SO4After drying, filtration and concentration in vacuo, 3.4 g of a light brown solid are obtained. The crude product is purified by flash chromatography using 2% to 8% MeOH: purification was performed with a stepwise gradient of dichloromethane and 2% ammonia to yield 3.3 g of N- (2- ((2- (5-hydroxy-1H-pyrrolo [3, 2) as a white powder]And pyridin-1-yl) -2-ethoxy) amino) -2-methylpropyl) - (5-methylfuran-2-yl) -carboxamide in 89% yield. LC-MS (ESI, pos, ion) M/z 371[ M + H ]]。
Test example:
ApoE from 16-week males-/-The mice are randomly divided into a control group and a plurality of experimental groups to be tested, and then are anesthetized by 0.1 percent sodium pentobarbital,a mini-pump (model 2004, Alzet, Cupertino, CA) was subcutaneously implanted with angiotensin II (Sigma) dissolved in physiological saline to allow administration at a dose of 1000ng/kg/min for four weeks. From the first day after operation, mice were gavaged daily at fixed points, and the test group was a test compound (10 mg/kg), and the control group was water at the same amount. The materials are taken 28 days after the intragastric administration. The mice were measured for blood pressure by the tail-cap method using a BP-89A sphygmomanometer and weighed. The blood lipid level of the mouse is measured by taking orbital blood and plasma of 6000 rpm, centrifuging for 10 minutes, taking supernatant. See table 1.
TABLE 1 treatment of angiotensin II mediated ApoE-/-Effect of mice
Figure 708123DEST_PATH_IMAGE017
As can be seen from the above table, the compounds prepared according to the present invention are directed to angiotensin II mediated ApoE-/-The blood pressure of the mice is reduced to different degrees, which shows that the compound prepared by the invention can reduce the blood pressure rise mediated by angiotensin II. In addition, the compound prepared by the invention can reduce the levels of cholesterol, triglyceride and low-density lipoprotein in the plasma of mice to different degrees, which indicates that the compound prepared by the invention has the function of regulating blood fat and can be used as an alternative medicine for reducing blood fat and/or atherosclerosis to carry out more intensive pharmacological research.
Mice were sacrificed, the abdominal aorta of the mice fixed and isolated. The occurrence of abdominal aortic aneurysm was counted and the results are shown in table 2:
TABLE 2 treatment of angiotensin II mediated ApoE-/-Effect of Abdominal aortic aneurysm development in mice
Figure 902956DEST_PATH_IMAGE018
Statistics of occurrence of abdominal aortic aneurysm of mice shows that one of 15 mice in the control group died due to rupture of abdominal aortic aneurysm during experiment, 6 mice in the rest 14 mice generated abdominal aortic aneurysm after 28 days of pump burying, death and generation of abdominal aortic aneurysm due to rupture of abdominal aortic aneurysm are combined and calculated, and occurrence rate of abdominal aortic aneurysm is obtained.
The table shows that the incidence rates of abdominal aortic aneurysms of mice in different test drug groups are reduced to different degrees, which shows that the compound prepared by the invention has positive significance in preventing and/or treating the abdominal aortic aneurysms, can effectively prevent the abdominal aortic aneurysms especially in the treatment of hypertension or hyperlipidemia, and provides a new research idea for research and development of hypertension and hyperlipidemia drugs.

Claims (3)

1. An amide derivative selected from compounds of the following structures:
Figure DEST_PATH_IMAGE002
。
2. the use of amide derivatives as claimed in claim 1 for the preparation of medicaments for the prevention and/or treatment of cardiovascular and cerebrovascular diseases.
3. Use according to claim 2, wherein the cardiovascular and cerebrovascular diseases are hypertension, hyperlipidemia and/or atherosclerosis.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070093492A1 (en) * 2004-03-09 2007-04-26 Weir-Torn Jiaang Pyrrolidine derivatives
CN101242833A (en) * 2005-09-01 2008-08-13 实验室富尼耶公司 Pyrrolopyridine derivatives and their use as PPAR receptor modulators

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Publication number Priority date Publication date Assignee Title
US20070093492A1 (en) * 2004-03-09 2007-04-26 Weir-Torn Jiaang Pyrrolidine derivatives
CN101242833A (en) * 2005-09-01 2008-08-13 实验室富尼耶公司 Pyrrolopyridine derivatives and their use as PPAR receptor modulators

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Title
Anagliptin, a DPP-4 Inhibitor, Suppresses Proliferation of Vascular Smooth Muscles and Monocyte Inflammatory Reaction and Attenuates Atherosclerosis in Male apo E-Deficient Mice;Nasib Ervinna et al.;《Endocrinology》;20130331;第153卷(第3期);第511-517页 *
新型降糖药DPP-4抑制剂研究进展;陈文文 等;《中国医院药学杂志》;20160331;第36卷(第6期);第1260-1270页 *

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