Novel sartan compound as well as preparation method and application thereof

Abstract

The invention discloses a novel sartan compound as well as a preparation method and application thereof, and belongs to the technical field of medicine synthesis and application. Based on key sites of AT1R receptor protection myocardial remodeling discovered by the inventor in the earlier stage, a novel sartan compound shown as a formula I is designed and synthesized, and experimental results prove that the novel sartan compound can be used for treating hypertension and cardiovascular remodeling in cardiovascular diseases and has a relatively strong myocardial protection 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 drug for the treatment of hypertension and cardiovascular diseases. They work mainly 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 RAAS, which increases blood pressure by constricting blood vessels and promoting water and sodium retention. Sartans can inhibit the receptor binding of angiotensin II, thereby achieving the purpose of lowering blood pressure and improving cardiovascular function. Angiotensin II receptor (AT1R) is a member of the GPCR protein family. In the early stage, the inventor's research group discovered the key site of AT1R receptor protection of myocardial remodeling. The inventor designed and synthesized a new type of sartan based on its key site of action, in order to exert a stronger cardiovascular protective effect. Summary of the invention

[0003] One object of the present invention is to provide a sartan compound with a completely new structure, which has a good protective effect on cardiovascular system, can better protect target organs and prevent cardiovascular remodeling while lowering blood pressure. Another object of the present invention is to provide a method for preparing the sartan compound. Another object of the present invention is to provide the use of the sartan compound in preparing a drug for treating hypertension.

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

[0005] In a 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 1-6, such as 1, 2, 3, 4, 5, 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, and 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 as shown in 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 as shown in 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, 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] Wherein, the reaction solvent in step S1 is selected from one or a combination of two or more of acetonitrile, isopropanol, tert-butyl alcohol, ethylene glycol dimethyl ether, 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 a pharmaceutically acceptable excipient.

[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 of formula I, or its salt, ester, solvate, isomer, 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 drugs 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 key sites of AT1R receptors that protect myocardial remodeling discovered by the inventors in the early stage, the present invention designs and synthesizes a new type of sartan compounds, and verifies their protective effects on myocardial remodeling at the cellular level and animal level. The results show that the new sartan compounds provided by the present invention can be used to treat hypertension and cardiovascular remodeling in cardiovascular diseases, and have a stronger myocardial protective effect. Compared with other common clinical sartan compounds, the new sartan compounds provided by the present invention have a more significant inhibitory effect on myocardial remodeling during myocardial hypertrophy, and the compounds can be used to treat 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 stable cell line after drug treatment, B1 is a new sartan compound; OL is olmesartan; AII is angiotensin II.

[0044] Figure 2 Western blot detection results 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 new sartan compound 4, Hx is new sartan compound x; OL is olmesartan; AII is angiotensin II.

[0046] Figure 4 Gray value statistical result diagram 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 The cardiac morphology of mice under the 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 cardiac pressure overload model 10 days after administration. B1 is a new sartan compound; OL is olmesartan; Los is losartan; 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 thickness of the interventricular septum; LVID represents the left ventricular inner diameter; LVPW represents the thickness of the posterior ventricular wall; EF represents the ejection fraction; and FS represents the left ventricular fractional shortening.

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

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

[0052] Fig.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] Fig.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 after 30 days of administration. B1 is a new sartan compound; OL is olmesartan; Los is losartan; Val is valsartan.

[0054] Fig.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 technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only some embodiments of the present invention, not all. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work 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 compounds, including acid addition salts and base addition salts well known to those skilled in the art.

[0058] In the present invention, the term "solvate" refers to a physical combination of a compound of the present invention and one or more solvent molecules. The physical combination includes various degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate can be separated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" includes solution-phase and separable solvates, and representative solvates include ethanolates, methanolates, etc.

[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 can be substituted on more than one carbon atom. In this case, all geometric forms, including cis and trans, 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 pentyloxy.

[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] Wherein, the reaction solvent in step S1 is selected from one or a combination of two or more of acetonitrile, isopropanol, tert-butyl alcohol, ethylene glycol dimethyl ether, 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 embodiment:

[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 modeling)

[0169] A vector containing the wild-type AT1R nucleic acid sequence was transferred into HEK293T cells, and a stable cell line HEK293T-AT1R was selected by puromycin. Subsequently, the novel sartan compound (B1) prepared by the present invention and olmesartan (OL) were used to intervene in HEK293T-AT1R, respectively, at a drug concentration of 10 -6 M; 2 hours later, 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, western blot was used to detect the activity of AT1R downstream genes pERK1 / 2 ( Figure 1 ).

[0170] The results show 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 new sartan drugs on rat neonatal cardiomyocytes (mechanical stretch model)

[0172] Rat neonatal cardiomyocytes were cultured using 10 -6 M novel sartan compound (B1) and olmesartan (OL) intervention, PBS as control, after 2 hours of culture, mechanical stretching was performed for 15 minutes using a mechanical stretching instrument, the stretching amplitude was set to 0-15%, once per second, and cardiac waveform was used. The cell culture medium was discarded, and total protein was extracted using RIPA. After BCA quantification, western blot was used to detect the activity of AT1R downstream genes pERK1 / 2 ( Figure 2 ). The results show that compared with Olmesartan, the novel sartan compound prepared by the present invention has a stronger inhibitory effect on pERK1 / 2.

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

[0174] Primary cardiomyocytes were cultured, and the novel sartan compounds (H1-H3, B1, H5-H24) prepared by the present invention and olmesartan (OL) were used to intervene in the cells, respectively, at a drug concentration of 10 -7 M; 2 hours later, add 10 -6 M angiotensin II was treated for 10 min to simulate myocardial hypertrophy, and PBS was used as a control. A blank control was also set up. The samples were washed with pre-cooled PBS, and 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 band was calculated and statistically analyzed. The results are as follows Figure 4 As shown. Figure 4 The statistical results show that compared with Olmesartan, the expression of AT1R downstream gene pERK1 / 2 in cells treated with the novel sartan compound prepared by the present invention is lower, indicating that the novel sartan compound prepared by the present invention has a stronger inhibitory effect on ATR1. Inhibiting the activity of AT1R can not only lower blood pressure, but also inhibit myocardial remodeling. Therefore, the novel sartan compound prepared by the present invention is superior to 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 Myocardial Hypertrophy

[0177] Eight-week-old male C57 mice underwent aortic arch ligation (TAC). The new sartan compound was given 4 days after surgery. Olmesartan, valsartan and losartan were used as positive controls, and 2% DMSO alone was used as a negative control. The mice were divided into 6 groups, including sham operation group (Sham group), DMSO after TAC (Saline group), new sartan compound after TAC (B1 group), Olmesartan after TAC (Olm group), valsartan after TAC (Val group), and losartan after TAC (Los group), with 5 mice in each group. The dosage of the new sartan compound and Olmesartan was 5.4 mg / kg / day / mouse; the dosage of valsartan was 21.4 mg / kg / day / mouse; the dosage of losartan was 13.4 mg / kg / day / mouse. The samples were collected after 30 consecutive days of administration, with the first echocardiogram on the 10th day of administration and the second echocardiogram on the 30th day of administration. After sampling, the heart-to-body weight ratio of mice was measured, the heart morphology was observed, RNA and protein of heart tissue were extracted, and 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. Specifically, Figure 5 As shown, 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. And the results of HE and WGA staining prove 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 the figure, the cardiac ultrasound results on the 10th and 30th days of administration showed that the new sartan compound B1 had a more significant effect in slowing down the ejection fraction and delaying heart failure, indicating that the new 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 ( Fig.11 ), the expression of nppa and nppb in the group treated with the novel sartan compound B1 was lower, and the expression of AT1R downstream gene pERK1 / 2 was lower. The reduction in the expression of nppa and nppb can also prove that compound B1 has a cardioprotective effect. In addition, according to Fig.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, namely, 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). SD group and SHR group were intraperitoneally injected with 200 μl 10% DMSO every day; SHR+OL group and SHR+B1 group were intraperitoneally injected with 7.0 mg kg -1 ·day -1 The tail artery pressure was measured before injection, 1 week, 2 weeks and 4 weeks after injection of the compound. There were 5 rats in each group, and 15 repeated blood pressure measurements were performed on each rat each time, and 9 median values ​​were taken for statistical analysis. The method for preparing the SHR rat model in this experiment is a conventional technical means in the art.

[0188] The results are as follows Fig.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 aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned 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, ester, solvate or isomer thereof, in, X is present or absent. When X is present, 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, 6; Y is selected from or R3, R4, and R5 are independently selected from -H, -OH, C 1-5 Alkyl, C 1-5 Alkoxy.

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

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

4. The compound according to claim 1, or a salt, ester, solvate or isomer thereof, characterized in that: The compound is shown in formula IV: Among them, R 4a , R 5a Independently selected from -H, -CH3, -C2H5.

5. The compound according to claim 1, or a salt, ester, solvate or isomer thereof, characterized in that: The compound is shown in formula V: Among them, R 4b , R 5b Independently selected from -H, -OH, -CH3, -C2H5.

6. The compound according to any one of claims 1 to 5, or a salt, ester, solvate, or isomer thereof, wherein the compound has the following structural formula:

7. A method for preparing the compound represented by formula I, comprising the following steps: 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, part of the solvent is 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 definition of H2N-XY is as shown in claim 1.

8. A pharmaceutical composition comprising the compound represented by formula I, or a salt, ester, solvate or isomer thereof.

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

10. Use of the compound represented by formula I, or its salt, ester, solvate, isomer in at least one of the following: (a1) Use in the preparation of a medicament for preventing and / or treating hypertension; (a2) Use in the preparation of drugs for preventing and / or treating cardiovascular diseases caused by hypertension; (a3) Use in the preparation of a drug having a myocardial protective effect; (a4) Use in the preparation of a drug having an effect of inhibiting cardiovascular remodeling.

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