Sartan compound, preparation method and application thereof

Abstract

The present invention discloses a novel sartan compound, its preparation method, and application, belonging to the field of drug synthesis and application technology. Based on the inventors' previous discovery of a key site in the AT1R receptor that protects myocardial remodeling, the present invention designed and synthesized a novel sartan compound represented by Formula I. Experimental results demonstrate that the novel sartan compound can be used to treat hypertension and cardiovascular remodeling in cardiovascular diseases, exhibiting a strong myocardial protective effect. #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the technical field of drug synthesis and application, and specifically relates to a novel sartan compound and a preparation method and application thereof. Background Art

[0002] Sartans are a commonly used class of drugs for the treatment of hypertension and cardiovascular diseases. They primarily work by blocking the effects of angiotensin II in the renin-angiotensin-aldosterone system (RAAS) on blood pressure and the cardiovascular system. Angiotensin II is an important component of the RAAS, and it raises blood pressure by constricting blood vessels and promoting sodium and water retention. Sartans can inhibit the binding of angiotensin II to receptors, thereby achieving the purpose of lowering blood pressure and improving cardiovascular function. The angiotensin II receptor (AT1R) is a member of the GPCR protein family. In the early stages, the inventor's research team discovered that the AT1R receptor is a key site for protecting myocardial remodeling. Based on its key site of action, the inventor designed and synthesized a new type of sartan drug in order to exert a stronger cardiovascular protective effect. Summary of the Invention

[0003] An object of the present invention is to provide a sartan compound of a novel structure, which exhibits excellent cardiovascular protective effects, lowering blood pressure while better protecting target organs and preventing cardiovascular remodeling. Another object of the present invention is to provide a method for preparing the sartan compound. A further object of the present invention is to provide the use of the sartan compound in the preparation of a drug for treating hypertension.

[0004] The present invention provides the following technical solutions:

[0005] In the first aspect, the present invention provides a compound represented by formula I, or a salt, ester, solvate, or isomer thereof,

[0006]

[0007] Wherein, X exists or does not exist. When X exists, X is selected from R1 and R2 are independently selected from -H, C 1-5 Alkyl, C 1-5 Alkoxy; n is an integer between 1 and 6, such as 1, 2, 3, 4, 5, or 6.

[0008] In a preferred embodiment of the present invention, said R1 and R2 are selected from -H.

[0009] Y is selected from or

[0010] R3, R4, R5 are independently selected from -H, -OH, C 1-5 Alkyl, C1-5 Alkoxy.

[0011] In some embodiments of the present invention, the compound is as shown in Formula II:

[0012]

[0013] Among them, R 3a Selected from -H, -CH3, -C2H5.

[0014] In some embodiments of the present invention, the compound is as shown in Formula III:

[0015]

[0016] Among them, R 3b Selected from -H, -CH3, -C2H5.

[0017] In some embodiments of the present invention, the compound is represented by Formula IV:

[0018]

[0019] Among them, R 4a 、R 5a Independently selected from -H, -CH3, -C2H5.

[0020] In some embodiments of the present invention, the compound is represented by Formula V:

[0021]

[0022] Among them, R 4b 、R 5b Independently selected from -H, -OH, -CH3, -C2H5.

[0023] In the most preferred embodiment, the present invention includes compounds of the following structural formula, or salts, esters, solvates, or isomers thereof:

[0024] In a second aspect, the present invention provides a method for preparing a compound represented by formula I, comprising the following steps:

[0025]

[0026] S1: using the compound represented by formula VI as the starting material, reacting with H2N-XY under microwave conditions or conventional heating conditions for 5 to 72 hours at a reaction temperature of 80 to 120°C;

[0027] S2: After the reaction is completed, part of the solvent and most of the residual reagents are evaporated under reduced pressure, and the residue is separated by column chromatography to obtain the target compound represented by formula I.

[0028] The reaction solvent in step S1 is selected from one or a combination of two or more of acetonitrile, isopropyl alcohol, tert-butyl alcohol, ethylene glycol dimethyl ether, and N,N-dimethylformamide. The definitions of X and Y in H2N-XY are as shown above.

[0029] In a third aspect, the present invention provides a pharmaceutical composition comprising a compound represented by Formula I, or a salt, ester, solvate, or isomer thereof.

[0030] Preferably, the pharmaceutical composition further comprises pharmaceutically acceptable excipients.

[0031] Preferably, the pharmaceutical composition further comprises other active ingredients, including but not limited to diuretics, calcium ion antagonists, and angiotensin converting enzyme inhibitors.

[0032] In a fourth aspect, the present invention provides a compound represented by formula I, or its salt, ester, solvate, or isomer, for use in at least one of the following:

[0033] (a1) Use in the preparation of a medicament for preventing and / or treating hypertension;

[0034] (a2) use in the preparation of a medicament for preventing and / or treating cardiovascular diseases caused by hypertension;

[0035] (a3) Use in the preparation of a drug having a myocardial protective effect;

[0036] (a4) Use in the preparation of a drug having an effect of inhibiting cardiovascular remodeling.

[0037] The cardiovascular diseases caused by hypertension described in the present invention include but are not limited to myocardial hypertrophy, coronary heart disease, stroke, myocardial infarction, peripheral arterial disease, heart failure, structural heart disease, and ischemic heart disease.

[0038] The heart failure includes heart failure with reduced ejection fraction and heart failure with preserved ejection fraction.

[0039] In a preferred embodiment of the present invention, the cardiovascular remodeling includes myocardial remodeling and vascular remodeling.

[0040] In a specific embodiment of the present invention, the compound represented by formula I, or its salt, ester, solvate, isomer can be used alone or in combination with other active ingredients.

[0041] The other active ingredients are selected from one or a combination of two or more of diuretics, calcium ion antagonists, and angiotensin converting enzyme inhibitors.

[0042] Based on the inventors' earlier discovery of a key site in the AT1R receptor that protects against myocardial remodeling, the present invention designed and synthesized a new class of sartan compounds, validating their protective effects on myocardial remodeling at both the cellular and animal levels. The results demonstrate that the novel sartan compounds provided by the present invention can be used to treat hypertension and cardiovascular remodeling in cardiovascular diseases, exhibiting a stronger myocardial protective effect. Compared with other clinically available sartan compounds, the novel sartan compounds provided by the present invention exhibit a more significant inhibitory effect on myocardial remodeling during myocardial hypertrophy, and are therefore useful in treating cardiovascular diseases caused by hypertension. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 Western blot detection results of pERK1 / 2 expression in HEK-293T-AT1R stably transfected cell lines after drug treatment. B1 is a new sartan compound; OL is olmesartan; AII is angiotensin II.

[0044] Figure 2 Western blot analysis of pERK1 / 2 expression in primary cardiomyocytes of neonatal rats after drug treatment. B1 is a new sartan compound; OL is olmesartan; MS is mechanical stretch.

[0045] Figure 3 Western blot detection results of pERK1 / 2 expression in primary cardiomyocytes after drug treatment. B1 is the new sartan compound 4, Hx is the new sartan compound x; OL is olmesartan; AII is angiotensin II.

[0046] Figure 4 Grayscale value statistical results based on western blot detection results, B1 is the new sartan compound 4, Hx is the new sartan compound x; OL is Olmesartan; AII is angiotensin II.

[0047] Figure 5 Heart morphology of mice under cardiac pressure overload model 30 days after administration. HE is hematoxylin-eosin staining; WGA is wheat germ agglutinin staining; B1 is a new sartan compound; OL is olmesartan; Los is losartan; Val is valsartan.

[0048] Figure 6 Cardiac ultrasound images of mice under a cardiac pressure overload model 10 days after administration. B1 is a new sartan compound; OL is olmesartan; Los is losartan; and Val is valsartan.

[0049] Figure 7Statistical results of cardiac ultrasound parameters in the mouse cardiac pressure overload model 10 days after administration: IVS represents the interventricular septum thickness; LVID represents the left ventricular internal diameter; LVPW represents the posterior ventricular wall thickness; EF represents the ejection fraction; and FS represents the left ventricular fractional shortening.

[0050] Figure 8 Cardiac ultrasound images of mice under a cardiac pressure overload model 30 days after administration. B1 is a new sartan compound; OL is olmesartan; Los is losartan; and Val is valsartan.

[0051] Figure 9 Statistical results of cardiac ultrasound parameters in the mouse cardiac pressure overload model 30 days after administration: IVS represents the interventricular septum thickness; LVID represents the left ventricular internal diameter; LVPW represents the posterior ventricular wall thickness; EF represents the ejection fraction; and FS represents the left ventricular fractional shortening.

[0052] Figure 10 Cardiac ultrasound and heart-to-body weight ratio in the cardiac pressure overload model of mice 30 days after administration. B1 is a new sartan compound; OL is olmesartan; Los is losartan; Val is valsartan.

[0053] Figure 11 The results of the detection of cardiac hypertrophy markers (nppa and nppb) and AT1R downstream activity (pERK / 2) in the mouse cardiac pressure overload model 30 days after administration. B1 is a new sartan compound; OL is olmesartan; Los is losartan; Val is valsartan.

[0054] Figure 12 The tail artery pressure of rats was measured after 1, 2, and 4 weeks of drug administration. B1 is a new sartan compound; OL is olmesartan. DETAILED DESCRIPTION

[0055] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention without making any creative efforts are within the scope of protection of the present invention.

[0056] Explanation of terms

[0057] In the present invention, the term "salt" refers to pharmaceutically acceptable salts of the compound, including acid addition salts and base addition salts well known to those skilled in the art.

[0058] As used herein, the term "solvate" refers to a physical association of a compound of the invention with one or more solvent molecules. This physical association includes varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, a solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" includes both solution-phase and isolatable solvates, representative solvates including ethanolates, methanolates, and the like.

[0059] In the present invention, the term "isomer" includes the presence of enantiomers, diastereomers and geometric isomers. Some compounds of the present invention have cycloalkyl groups that may be substituted on more than one carbon atom. In this case, all geometric forms, including cis and trans forms, and mixtures thereof, are within the scope of the present invention.

[0060] In the present invention, the term "C 1-5 The term "alkyl" includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and isopentyl.

[0061] In the present invention, the term "C 1-5 "Alkoxy" includes methoxy, ethoxy, propoxy, butoxy and pentoxy.

[0062] In the present invention, the term "pharmaceutically acceptable excipient" includes any solvent, solid excipient, diluent or other liquid excipient, etc., which is suitable for a specific target dosage form.

[0063] Preparation of novel sartan compounds

[0064] The synthetic route is as follows:

[0065]

[0066] S1: using the compound represented by formula VI as the starting material, reacting with H2N-XY under microwave conditions or conventional heating conditions for 5 to 72 hours at a reaction temperature of 80 to 120°C;

[0067] S2: After the reaction is completed, part of the solvent and most of the residual reagents are evaporated under reduced pressure, and the residue is separated by column chromatography to obtain the target compound represented by formula I.

[0068] The reaction solvent in step S1 is selected from one or a combination of two or more of acetonitrile, isopropyl alcohol, tert-butyl alcohol, ethylene glycol dimethyl ether, and N,N-dimethylformamide. The definitions of X and Y in H2N-XY are as shown above.

[0069] According to the above preparation method, the following compounds were prepared in the present invention:

[0070] Compound 1 (H1)

[0071] N-Hydroxy-1-(4-(2'-tetrazol-5-yl)phenylbenzyl)-2-propyl-4-(2-hydroxypropan-2-yl)imidazole-5-carboxamide

[0072]

[0073] Pale yellow solid, 1 H NMR (400MHz, DMSO-d6) δ9.82(s,1H),7.82-7.68(m,2H),7.57-7.53(m,2H),7.02(d,J=8Hz,2H),6.88(d,J=8 Hz,2H),6.21(s,1H),5.51(s,2H),2.49(m,2H),1.55-1.51(m,2H),1.51(s,6H),0.82(t,J=5Hz,3H).ESI-MS m / z 462.3[M+H] + .

[0074] Compound 2(H2)

[0075] N-Methoxy-1-(4-(2'-tetrazol-5-yl)phenylbenzyl)-2-propyl-4-(2-hydroxypropan-2-yl)imidazole-5-carboxamide

[0076]

[0077] Pale yellow solid, 1 H NMR (400MHz, DMSO-d6) δ9.55(s,1H),7.78-7.65(m,2H),7.55-7.51(m,2H),7.15(d,J=8Hz,2H),6.93(d,J=8Hz,2H ),6.18(s,1H),5.56(s,2H),3.52(s,3H),2.46(m,2H),1.54-1.51(m,2H),1.50(s,6H),0.87(t,J=5Hz,3H).ESI-MS m / z 476.2[M+H] + .

[0078] Compound 3(H3)

[0079] N-(2-Hydroxyethyl)-1-(4-(2'-tetrazol-5-yl)phenylbenzyl)-2-propyl-4-(2-hydroxypropan-2-yl)imidazole-5-carboxamide

[0080]

[0081] Pale yellow solid, 1H NMR (400MHz, DMSO-d6) δ9.65 (s, 1H), 7.72-7.65 (m, 2H), 7.57-7.53 (m, 2H), 7.05 (d, J = 8Hz, 2H), 6.98 (d, J = 8Hz, 2H), 6.25 (s,1H),5.61(s,2H),3.42(m,2H),3.22(m,2H),2.50(m,2H),1.54-1.51(m,2H),1.52(s,6H),0.88(t,J=5Hz,3H).ESI-MS m / z490.3[M+H] + .

[0082] Compound 4(B1)

[0083] N-(3-Hydroxypropyl)-1-(4-(2'-tetrazol-5-yl)phenylbenzyl)-2-propyl-4-(2-hydroxypropan-2-yl)imidazole-5-carboxamide

[0084]

[0085] Pale yellow solid, 1 H NMR (400MHz, DMSO-d6) δ9.64(s,1H),7.72-7.65(m,2H),7.57-7.53(m,2H),7.05(d,J=8Hz,2H),6.98(d,J=8Hz,2H),6.20(s,1H),5 .60(s,2H),3.45(t,J=5Hz,2H),3.29(m,2H),2.48(m,2H),1.63(m,2H),1.54-1.51(m,2H),1.53(s,6H),0.87(t,J=5Hz,3H).ESI-MS m / z 504.3[M+H] + .

[0086] Compound 5 (H5)

[0087] N-(4-Hydroxybutyl)-1-(4-(2'-tetrazol-5-yl)phenylbenzyl)-2-propyl-4-(2-hydroxypropan-2-yl)imidazole-5-carboxamide

[0088]

[0089] Pale yellow solid, 1H NMR (400MHz, DMSO-d6) δ9.67(s,1H),7.78-7.68(m,2H),7.59-7.55(m,2H),7.05(d,J=8Hz,2H),6.98(d,J=8Hz,2H),6.34(s,1H),5.63 (s,2H),3.36(t,J=5Hz,2H),3.29(m,2H),2.54(m,2H),1.70-1.54(m,4H),1.54-1.51(m,2H),1.50(s,6H),0.90(t,J=5Hz,3H).ESI-MS m / z 518.2[M+H] + .

[0090] Compound 6 (H6)

[0091] N-(5-Hydroxypentyl)-1-(4-(2'-tetrazol-5-yl)phenylbenzyl)-2-propyl-4-(2-hydroxypropan-2-yl)imidazole-5-carboxamide

[0092]

[0093] Pale yellow solid, 1 H NMR (400MHz, DMSO-d6) δ9.73(s,1H),7.72-7.65(m,2H),7.59-7.54(m,2H),7.25(d,J=8Hz,2H),6.99(d,J=8Hz,2H),6.25(s,1H),5.5 8(s,2H),3.43(t,J=5Hz,2H),3.33(m,2H),2.58(m,2H),1.68-156(m,4H),1.55-1.53(m,4H),1.51(s,6H),0.87(t,J=5Hz,3H).ESI-MS m / z 531.3[M+H] + .

[0094] Compound 7 (H7)

[0095] N-(2-Ethoxyethyl)-1-(4-(2'-tetrazol-5-yl)phenylbenzyl)-2-propyl-4-(2-hydroxypropan-2-yl)imidazole-5-carboxamide

[0096]

[0097] Pale yellow solid, 1H NMR (400MHz, DMSO-d6) δ9.12(s,1H),7.74-7.60(m,2H),7.55-7.50(m,2H),7.01(d,J=8Hz,2H),6.83(d,J=8Hz,2H),6.21(s,1H),5.60(s,2H) ,3.40(m,2H),3.31(q,J=4Hz,2H),3.22(m,2H),2.48(m,2H),1.62(t,J=4Hz,3H),1.54-1.51(m,2H),1.53(s,6H),0.87(t,J=5Hz,3H).ESI-MS m / z 518.3[M+H] + .

[0098] Compound 8 (H8)

[0099] N-(3-Ethoxypropyl)-1-(4-(2'-tetrazol-5-yl)phenylbenzyl)-2-propyl-4-(2-hydroxypropan-2-yl)imidazole-5-carboxamide

[0100]

[0101] Pale yellow solid, 1 H NMR (400MHz, DMSO-d6) δ9.14(s,1H),7.71-7.64(m,2H),7.55-7.50(m,2H),7.05(d,J=8Hz,2H),6.98(d,J=8Hz,2H),6.22(s,1H),5.63(s,2H),3.35 (m,2H),3.31(q,J=4Hz,2H),3.28(m,2H),2.50(m,2H),1.64(m,2H),1.58( t,J=4Hz,3H),1.54-1.51(m,2H),1.53(s,6H),0.90(t,J=5Hz,3H).ESI-MS m / z 532.2[M+H] + .

[0102] Compound 9 (H9)

[0103] N-(2-methoxyethyl)-1-(4-(2'-tetrazol-5-yl)phenylbenzyl)-2-propyl-4-(2-hydroxypropan-2-yl)imidazole-5-carboxamide

[0104]

[0105] Pale yellow solid, 1H NMR (400MHz, DMSO-d6) δ9.14(s,1H),7.72-7.63(m,2H),7.59-7.53(m,2H),7.08(d,J=8Hz,2H),6.99(d,J=8Hz,2H),6.21(s,1H ),5.60(s,2H),3.66(s,3H),3.50(m,2H),3.29(m,2H),2.49(m,2H),1.54-1.51(m,2H),1.54(s,6H),0.88(t,J=5Hz,3H).ESI-MS m / z 504.3[M+H] + .

[0106] Compound 10 (H10)

[0107] N-(3-methoxypropyl)-1-(4-(2'-tetrazol-5-yl)phenylbenzyl)-2-propyl-4-(2-hydroxypropan-2-yl)imidazole-5-carboxamide

[0108]

[0109] Pale yellow solid, 1 H NMR (400MHz, DMSO-d6) δ9.14(s,1H),7.74-7.63(m,2H),7.56-7.52(m,2H),7.08(d,J=8Hz,2H),6.97(d,J=8Hz,2H),6.25(s,1H),5.5 9(s,2H),3.68(s,3H),3.55m,2H),3.40(m,2H),2.48(m,2H),1.66(m,2H),1.54-1.51(m,2H),1.53(s,6H),0.89(t,J=5Hz,3H).ESI-MS m / z 518.3[M+H] + .

[0110] Compound 11 (H11)

[0111] N-amino-1-(4-(2'-tetrazol-5-yl)phenylbenzyl)-2-propyl-4-(2-hydroxypropan-2-yl)imidazole-5-carboxamide

[0112]

[0113] Pale yellow solid, 1H NMR (400MHz, DMSO-d6) δ9.64(s,1H),7.72-7.65(m,2H),7.57-7.53(m,2H),7.05(d,J=8Hz,2H),6.98(d,J=8 Hz,2H),6.45(s,1H),5.65(s,2H),2.48(m,2H),1.54-1.51(m,2H),1.53(s,6H),0.90(t,J=5Hz,3H).ESI-MS m / z 461.2[M+H] + .

[0114] Compound 12 (H12)

[0115] N-Methylamino-1-(4-(2'-tetrazol-5-yl)phenylbenzyl)-2-propyl-4-(2-hydroxypropan-2-yl)imidazole-5-carboxamide

[0116]

[0117] Pale yellow solid, 1 H NMR (400MHz, DMSO-d6) δ9.62(s,1H),7.74-7.65(m,2H),7.59-7.55(m,2H),7.09(d,J=8Hz,2H),7.03(d,J=8Hz,2H ),6.22(s,1H),5.63(s,2H),3.10(s,3H),2.49(m,2H),1.54-1.51(m,2H),1.55(s,6H),0.89(t,J=5Hz,3H).ESI-MS m / z 475.3[M+H] + .

[0118] Compound 13 (H13)

[0119] N-(2-aminoethyl)-1-(4-(2'-tetrazol-5-yl)phenylbenzyl)-2-propyl-4-(2-hydroxypropan-2-yl)imidazole-5-carboxamide

[0120]

[0121] Pale yellow solid, 1H NMR (400MHz, DMSO-d6) δ9.56 (s, 1H), 7.74-7.63 (m, 2H), 7.57-7.53 (m, 2H), 7.06 (d, J = 8Hz, 2H), 6.94 (d, J = 8Hz, 2H), 6.14 (s,1H),5.61(s,2H),3.29(m,2H),2.78(m,2H),2.50(m,2H),1.54-1.51(m,2H),1.52(s,6H),0.90(t,J=5Hz,3H).ESI-MS m / z489.3[M+H] + .

[0122] Compound 14 (H14)

[0123] N-(3-Aminopropyl)-1-(4-(2'-tetrazol-5-yl)phenylbenzyl)-2-propyl-4-(2-hydroxypropan-2-yl)imidazole-5-carboxamide

[0124]

[0125] Pale yellow solid, 1 H NMR (400MHz, DMSO-d6) δ9.64(s,1H),7.75-7.65(m,2H),7.57-7.53(m,2H),7.05(d,J=8Hz,2H),6.98(d,J=8Hz,2H),6.25(s,1H ),5.68(s,2H),3.10(m,2H),2.55(m,2H),2.49(m,2H),1.65(m,2H),1.55-1.51(m,2H),1.49(s,6H),0.88(t,J=5Hz,3H).ESI-MS m / z 503.3[M+H] + .

[0126] Compound 15 (H15)

[0127] N-(4-aminobutyl)-1-(4-(2'-tetrazol-5-yl)phenylbenzyl)-2-propyl-4-(2-hydroxypropan-2-yl)imidazole-5-carboxamide

[0128]

[0129] Pale yellow solid, 1H NMR (400MHz, DMSO-d6) δ9.66(s,1H),7.77-7.69(m,2H),7.56-7.52(m,2H),7.05(d,J=8Hz,2H),6.98(d,J=8Hz,2H),6.20(s,1H ),5.65(s,2H),3.20(m,2H),2.78(m,2H),2.48(m,2H),1.65(m,4H),1.56-1.51(m,2H),1.52(s,6H),0.87(t,J=5Hz,3H).ESI-MS m / z 517.2[M+H] + .

[0130] Compound 16 (H16)

[0131] N-(5-aminopentyl)-1-(4-(2'-tetrazol-5-yl)phenylbenzyl)-2-propyl-4-(2-hydroxypropan-2-yl)imidazole-5-carboxamide

[0132]

[0133] Pale yellow solid, 1 H NMR (400MHz, DMSO-d6) δ9.68(s,1H),7.73-7.63(m,2H),7.54-7.50(m,2H),7.07(d,J=8Hz,2H),6.99(d,J=8Hz,2H),6.28(s,1H),5 .62(s,2H),3.20(m,2H),2.93(m,2H),2.48(m,2H),1.61-1.70(m,6H),1.54-1.51(m,2H),1.53(s,6H),0.87(t,J=5Hz,3H).ESI-MS m / z 531.4[M+H] + .

[0134] Compound 17 (H17)

[0135] N-(2-Methylaminoethyl)-1-(4-(2'-tetrazol-5-yl)phenylbenzyl)-2-propyl-4-(2-hydroxypropan-2-yl)imidazole-5-carboxamide

[0136]

[0137] Pale yellow solid, 1H NMR (400MHz, DMSO-d6) δ9.65(s,1H),7.81-7.75(m,2H),7.58-7.55(m,2H),7.05(d,J=8Hz,2H),6.98(d,J=8Hz,2H),6.27(s,1H ),5.59(s,2H),3.35(m,2H),3.29(m,2H),2.96(s,3H),2.51(m,2H),1.54-1.51(m,2H),1.53(s,6H),0.87(t,J=5Hz,3H).ESI-MS m / z 503.3[M+H] + .

[0138] Compound 18 (H18)

[0139] N-(3-Methylaminopropyl)-1-(4-(2'-tetrazol-5-yl)phenylbenzyl)-2-propyl-4-(2-hydroxypropan-2-yl)imidazole-5-carboxamide

[0140]

[0141] Pale yellow solid, 1 H NMR (400MHz, DMSO-d6) δ9.68(s,1H),7.78-7.69(m,2H),7.59-7.55(m,2H),7.10(d,J=8Hz,2H),6.94(d,J=8Hz,2H),6.25(s,1H),5.63(s, 2H),3.35(t,J=5Hz,2H),3.19(m,2H),2.88(s,3H),2.51(m,2H),1.60(m,2H),1.54-1.51(m,2H),1.52(s,6H),0.91(t,J=5Hz,3H).ESI-MS m / z 517.3[M+H] + .

[0142] Compound 19 (H19)

[0143] N-(2-Dimethoxyaminoethyl)-1-(4-(2'-tetrazol-5-yl)phenylbenzyl)-2-propyl-4-(2-hydroxypropan-2-yl)imidazole-5-carboxamide

[0144]

[0145] Pale yellow solid, 1H NMR (400MHz, DMSO-d6) δ9.68(s,1H),7.73-7.63(m,2H),7.57-7.53(m,2H),7.08(d,J=8Hz,2H),6.96(d,J=8Hz,2H),6.24(s,1H ),5.61(s,2H),3.19(m,2H),3.15(m,2H),2.88(s,6H),2.52(m,2H),1.54-1.51(m,2H),1.53(s,6H),0.95(t,J=5Hz,3H).ESI-MS m / z 517.3[M+H] + .

[0146] Compound 20 (H20)

[0147] N-(3-Dimethylaminopropyl)-1-(4-(2'-tetrazol-5-yl)phenylbenzyl)-2-propyl-4-(2-hydroxypropan-2-yl)imidazole-5-carboxamide

[0148]

[0149] Pale yellow solid, 1 H NMR (400MHz, DMSO-d6) δ9.72(s,1H),7.75-7.68(m,2H),7.58-7.54(m,2H),7.07(d,J=8Hz,2H),6.99(d,J=8Hz,2H),6.28(s,1H),5.71 (s,2H),3.25(m,2H),3.14(m,2H),2.98(s,6H),2.54(m,2H),1.56(m,2H),1.55-1.51(m,2H),1.52(s,6H),0.85(t,J=5Hz,3H).ESI-MS m / z 531.3[M+H] + .

[0150] Compound 21 (H21)

[0151] N-(2-Ethylaminoethyl)-1-(4-(2'-tetrazol-5-yl)phenylbenzyl)-2-propyl-4-(2-hydroxypropan-2-yl)imidazole-5-carboxamide

[0152]

[0153] Pale yellow solid, 1H NMR (400MHz, DMSO-d6) δ9.69(s,1H),7.75-7.67(m,2H),7.57-7.53(m,2H),7.05(d,J=8Hz,2H),6.94(d,J=8Hz,2H),6.25(s,1H),5.68(s,2H) ,3.23(m,2H),3.11(m,2H),2.98(q,J=4Hz,2H),2.51(m,2H),1.58(t,J=4Hz,3H),1.54-1.51(m,2H),1.53(s,6H),0.92(t,J=5Hz,3H).ESI-MS m / z 517.3[M+H] + .

[0154] Compound 22 (H22)

[0155] N-(3-Ethylaminopropyl)-1-(4-(2'-tetrazol-5-yl)phenylbenzyl)-2-propyl-4-(2-hydroxypropan-2-yl)imidazole-5-carboxamide

[0156]

[0157] Pale yellow solid, 1 H NMR (400MHz, DMSO-d6) δ9.65(s,1H),7.70-7.62(m,2H),7.55-7.51(m,2H),7.03(d,J=8Hz,2H),6.91(d,J=8Hz,2H),6.19(s,1H),5.62(s,2H),3.31 (m,2H),3.12(m,2H),2.98(q,J=4Hz,2H),2.45(m,2H),1.60(m,2H),1.56( t,J=4Hz,3H),1.54-1.51(m,2H),1.51(s,6H),0.84(t,J=5Hz,3H).ESI-MS m / z 531.3[M+H] + .

[0158] Compound 23 (H23)

[0159] N-(2-Hydroxyaminoethyl)-1-(4-(2'-tetrazol-5-yl)phenylbenzyl)-2-propyl-4-(2-hydroxypropan-2-yl)imidazole-5-carboxamide

[0160]

[0161] Pale yellow solid, 1H NMR (400MHz, DMSO-d6) δ9.69 (s, 1H), 7.77-7.69 (m, 2H), 7.59-7.57 (m, 2H), 7.10 (d, J = 8Hz, 2H), 7.08 (d, J = 8Hz, 2H), 6.28 (s,1H),5.70(s,2H),3.31(m,2H),3.12(m,2H),2.55(m,2H),1.55-1.53(m,2H),1.53(s,6H),0.95(t,J=5Hz,3H).ESI-MS m / z505.4[M+H] + .

[0162] Compound 24(H24)

[0163] N-(3-Hydroxyaminopropyl)-1-(4-(2'-tetrazol-5-yl)phenylbenzyl)-2-propyl-4-(2-hydroxypropan-2-yl)imidazole-5-carboxamide

[0164]

[0165] Pale yellow solid, 1 H NMR (400MHz, DMSO-d6) δ9.70(s,1H),7.73-7.64(m,2H),7.55-7.52(m,2H),7.15(d,J=8Hz,2H),6.99(d,J=8Hz,2H),6.21(s,1H ),5.62(s,2H),3.31(m,2H),3.28(m,2H),2.50(m,2H),1.60(m,2H),1.54-1.51(m,2H),1.53(s,6H),0.87(t,J=5Hz,3H).ESI-MS m / z 519.3[M+H] + .

[0166] Study Results

[0167] 1. New sartan drugs inhibit myocardial remodeling in myocardial mast cells

[0168] 1.1 Effects of novel sartan drugs on ATIR-overexpressing HEK293T cells (AII model)

[0169] A vector containing the wild-type AT1R nucleic acid sequence was transferred into HEK293T cells, and the stable cell line HEK293T-AT1R was selected by puromycin. Subsequently, the novel sartan compound (B1) and olmesartan (OL) prepared by the present invention were used to intervene in HEK293T-AT1R, respectively, at a drug concentration of 10 -6 M; after 2 hours, add 10 -6M angiotensin II was used to simulate myocardial hypertrophy, and PBS was used as a control. After 15 minutes, the cell culture medium was discarded, and total protein was extracted using RIPA. After BCA quantification, the activity of AT1R downstream genes pERK1 / 2 ( Figure 1 ).

[0170] The results showed that compared with Olmesartan, the novel sartan compound B1 prepared by the present invention has a stronger inhibitory effect on pERK1 / 2, indicating that compared with Olmesartan, the novel sartan compound prepared by the present invention has a better effect of inhibiting ATR1. Those skilled in the art know that inhibiting the activity of AT1R can not only lower blood pressure, but also inhibit myocardial remodeling and protect the myocardium. Therefore, according to Figure 1 The results show that the novel sartan compound prepared by the present invention is superior to Olmesartan in both lowering blood pressure and inhibiting myocardial remodeling.

[0171] 1.2 Effects of novel sartan drugs on rat neonatal cardiomyocytes (mechanical stretch model)

[0172] Culture rat neonatal cardiomyocytes using 10 -6 M novel sartan compound (B1) and olmesartan (OL) intervention, PBS as a control, after 2 hours of culture, mechanical stretching was performed for 15 minutes using a mechanical stretcher, with the stretch amplitude set at 0-15%, once per second, and cardiac waveforms were used. The cell culture medium was discarded, and total protein was extracted using RIPA. After BCA quantification, the activity of AT1R downstream genes pERK1 / 2 ( Figure 2 The results showed that the novel sartan compound prepared by the present invention had a stronger inhibitory effect on pERK1 / 2 than olmesartan.

[0173] 1.3 Effects of novel sartan drugs on primary cardiomyocytes (AII model)

[0174] Primary cardiomyocytes were cultured and the novel sartan compounds (H1-H3, B1, H5-H24) and Olmesartan (OL) prepared by the present invention were used to intervene in the cells at a drug concentration of 10 -7 M; after 2 hours, add 10 -6 The cells were treated with angiotensin II for 10 min to simulate myocardial hypertrophy. PBS was used as a control and a blank control was set up. The cells were washed with pre-cooled PBS and the total protein was extracted using RIPA. After BCA quantification, the activity of AT1R downstream genes pERK1 / 2 ( Figure 3 and Figure 4 ).

[0175] Among them, the western blot results of compound 4 (B1), compound 5 (H5), compound 6 (H6), compound 12 (H12), compound 17 (H17), compound 18 (H18), compound 19 (H19), and compound 24 (H24) are as follows Figure 3 As shown. Figure 3 It can be seen that compared with Olmesartan, the above compounds have a stronger inhibitory effect on pERK1 / 2. According to the western blot results, the gray value of the bands was calculated and statistically analyzed. The results are as follows Figure 4 As shown. Figure 4 Statistical results show that compared to olmesartan, cells treated with the novel sartan compounds prepared by the present invention showed lower expression of pERK1 / 2, a downstream gene of AT1R, indicating that the novel sartan compounds prepared by the present invention have a stronger inhibitory effect on ATR1. Inhibiting AT1R activity not only lowers blood pressure but also inhibits myocardial remodeling. Therefore, the novel sartan compounds prepared by the present invention are more effective than olmesartan in both lowering blood pressure and inhibiting myocardial remodeling.

[0176] II. Novel sartans inhibit myocardial remodeling in a mouse model of pressure overload-induced cardiac hypertrophy

[0177] Eight-week-old male C57 mice underwent aortic arch ligation (TAC) and were treated with a novel sartan compound starting 4 days after surgery. Olmesartan, valsartan, and losartan served as positive controls, and 2% DMSO alone served as a negative control. The mice were divided into six groups: sham surgery (Sham group), DMSO after TAC (Saline group), novel sartan compound after TAC (B1 group), olmesartan after TAC (Olm group), valsartan after TAC (Val group), and losartan after TAC (Los group), with five mice in each group. The novel sartan compound and olmesartan were administered at a dose of 5.4 mg / kg / day per mouse; valsartan was administered at a dose of 21.4 mg / kg / day per mouse; and losartan was administered at a dose of 13.4 mg / kg / day per mouse. Cardiac echocardiography was performed on day 10 and day 30 of administration for 30 consecutive days. After sampling, the heart-to-body weight ratio of the mice was measured, the heart morphology was observed, and RNA and protein were extracted from the heart tissue. qRT-PCR was used to detect cardiac hypertrophy markers nppa and nppb. The primer sequences were as follows:

[0178] qRT_mm_nppa_F:5'-GCTTCTTCCTCGTCTTGGCCTT-3',(SEQ ID NO:1)

[0179] qRT_mm_nppa_R:5'-CCTGCTTCCTCAGTCTGCTCAC-3'; (SEQ ID NO: 2)

[0180] qRT_mm_nppb_F:5'-GCCTCACAAAAGAACACCCAA-3',(SEQ ID NO:3)

[0181] qRT_mm_nppb_R:5'-GGAAAGAGACCCAGGCAGAGT-3'; (SEQ ID NO:4)

[0182] Gapdh was used as an internal reference gene for calibration, and its primer sequences were:

[0183] qRT_gapdh_mm_F:5'-TGTGTCCGTCGTGGATCTGA-3',(SEQ ID NO:5)

[0184] qRT_gapdh_mm_R: 5'-TTGCTGTTGAAGTCGCAGGAG-3'. (SEQ ID NO:6)

[0185] Western blot was used to detect the downstream gene activity of AT1R pERK1 / 2 ( Figure 5-11 The results showed that compared with other sartan compounds, the novel sartan compound B1 prepared by the present invention has a stronger inhibitory effect on myocardial remodeling in animals. Figure 5 As shown in the figure, from a morphological point of view, compared with Olmesartan (OL), Losartan (Los) and Valsartan (Val), the heart treated with compound B1 is smaller in size, indicating that the novel sartan compound B1 prepared by the present invention can more significantly inhibit cardiac hypertrophy and myocardial remodeling. In addition, the results of HE and WGA staining show that the myocardial fibers of the heart treated with the novel sartan compound B1 are densely arranged, with no difference from the sham operation group, indicating that the novel sartan compound B1 prepared by the present invention has a myocardial protective effect. Figure 6-9 As shown in Figure 2, the cardiac ultrasound results on the 10th and 30th days after administration showed that the novel sartan compound B1 had a more significant effect in reducing ejection fraction and delaying heart failure, indicating that the novel sartan compound B1 prepared by the present invention has a preventive and delaying effect on cardiovascular diseases such as heart failure. This result can also be reflected in the heart failure markers nppa and nppb ( Figure 11 ), the expression of nppa and nppb in the new sartan compound B1 group was lower, and the expression of AT1R downstream gene pERK1 / 2 was lower. The reduction of nppa and nppb expression can also prove that compound B1 has a cardioprotective effect. In addition, according to Figure 10As shown, the new sartan compound B1 can significantly reduce the heart-to-body weight ratio, compound B1 can inhibit cardiac hypertrophy, prevent and treat myocardial hypertrophy, and inhibit the occurrence of myocardial remodeling.

[0186] 3. Novel Sartans Suppress Blood Pressure in the SHR Mouse Model

[0187] Twenty rats were randomly divided into four groups: blank control group (SD group), model control group (SHR group), model olmesartan administration group (SHR+OL), and model novel sartan compound administration group (SHR+B1). The SD group and the SHR group were intraperitoneally injected with 200 μl of 10% DMSO every day; the SHR+OL group and the SHR+B1 group were intraperitoneally injected with 7.0 mg·kg -1 day -1 The compound was injected, and tail artery pressure was measured before, 1 week after, 2 weeks after, and 4 weeks after injection. Each group consisted of 5 rats, and 15 replicates of blood pressure were measured per rat. Nine median values ​​were used for statistical analysis. The SHR rat model used in this experiment was prepared using conventional techniques in the art.

[0188] The results are as follows Figure 12 As shown, compared with the SHR group, the novel sartan compound B1 prepared by the present invention has a similar antihypertensive effect as Olmesartan.

[0189] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the above embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A compound represented by formula I or a salt thereof, （Ⅰ） in, X is present or absent. When X is present, X is selected from , R1 and R2 are independently selected from -H; n is an integer between 1 and 6; Y is selected from or ; R3 is selected from -H, C 1-5 Alkyl; R4, R5 are independently selected from -H, -OH, C 1-5 alkyl.

2. The compound or salt thereof according to claim 1, characterized in that The compound is shown in Formula II: （Ⅱ） Among them, R 3a Selected from -H, -CH3, -C2H5.

3. The compound or salt thereof according to claim 1, characterized in that The compound is shown in formula III: （Ⅲ） Among them, R 3b Selected from -H, -CH3, -C2H5.

4. The compound or salt thereof according to claim 1, characterized in that The compound is shown in Formula IV: （Ⅳ） Among them, R 4a 、R 5a Independently selected from -H, -CH3, -C2H5.

5. The compound or salt thereof according to claim 1, characterized in that The compound is shown in Formula V: （Ⅴ） Among them, R 4b 、R 5b Independently selected from -H, -OH, -CH3, -C2H5.

6. The compound or salt thereof according to claim 1, wherein the compound has the following structural formula: 。 7. A method for preparing the compound of formula I according to claim 1, comprising the steps of: （Ⅵ） （Ⅰ） S1: Using the compound represented by formula VI as the starting material, reacting with H2N-XY under microwave conditions or conventional heating conditions for 5 to 72 hours at a reaction temperature of 80 to 120°C; S2: After the reaction is completed, the solvent is partially evaporated under reduced pressure, and the residue is separated by column chromatography to obtain the target compound represented by Formula I; in, The reaction solvent is selected from one or a combination of two or more of acetonitrile, isopropanol, tert-butanol, ethylene glycol dimethyl ether, and N,N-dimethylformamide, and the definitions of X and Y in the H2N-XY are as shown in claim 1.

8. A pharmaceutical composition comprising the compound of formula I or a salt thereof according to claim 1.

9. The pharmaceutical composition according to claim 8, characterized in that The pharmaceutical composition also includes pharmaceutically acceptable excipients.

10. Use of the compound of formula I or a salt thereof according to claim 1 in at least one of the following: (a1) Use in the preparation of medicaments for preventing and / or treating hypertension; (a2) Use in the preparation of medicaments for preventing and / or treating cardiovascular diseases caused by hypertension; (a3) Use in the preparation of drugs with myocardial protective effects; (a4) Use in the preparation of drugs capable of inhibiting cardiovascular remodeling.

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