Biphenylsulfonamides as dual angiotensin and endothelin receptor antagonists

Abstract

The application discloses a chemical structural formula of a biphenyl sulfonamide compound of a bis-benzimidazole, and also discloses application of the compound in preparation of a pharmaceutically acceptable salt or solvate, application of the compound and the pharmaceutically acceptable salt or solvate in preparation of a medicine for treating endothelin-dependent or angiotensin II-dependent diseases. Meanwhile, the biphenyl sulfonamide compound of the bis-benzimidazole can also be used in combination by changing substituted functional groups. The biphenyl sulfonamide compound of the bis-benzimidazole, the prepared pharmaceutically acceptable salt or solvate and the medicine prepared by the compound have pharmacological activities, and have pharmacological effects in animals including human beings, and are particularly useful in treatment or prevention of IgA nephropathy, focal segmental glomerulosclerosis, nephrotic syndrome, chronic kidney disease, diabetic nephropathy, hypertension, coronary heart disease and myocardial infarction.

Description

Technical Field

[0001] This invention relates to biphenylsulfonamide compounds that are dual antagonists of angiotensin and endothelin receptors, to the use of such compounds in the preparation of pharmaceutically acceptable salts or solvates, and to pharmaceutical compositions containing such compounds. Background Technology

[0002] Currently, first-line drugs for treating IgA nephropathy mainly include angiotensin-converting enzyme inhibitors (ACEIs) (such as captopril, benazepril, and ramipril) and angiotensin II receptor blockers (ARBs) (such as irbesartan). Other drug categories include glucocorticoids (such as budesonide), anticancer drugs (such as cyclophosphamide), and immunosuppressants (cyclosporine A and mycophenolate mofetil). Existing treatments are either not sufficiently effective or have significant side effects. Therefore, there is a substantial unmet clinical need in this area. Summary of the Invention

[0003] The purpose of this invention is to provide a biphenylsulfonamide drug of benzimidazole and its application in order to address the above-mentioned problems.

[0004] The technical solution to achieve this objective is:

[0005] A biphenylsulfonamide drug based on benzimidazole, the compound having the chemical structure shown in Formula I:

[0006]

[0007] In Formula I, R1 represents a hydrogen atom, a C1-C5 alkyl group, a C5-C7 cycloalkyl group, or a halogenated C1-C5 alkyl group.

[0008] The biphenylsulfonamide of bisbenzimidazole shown in Formula I above can also be used in combination. When used in combination, R1 is selected from at least two functional groups selected from hydrogen atom, C1-C5 alkyl, C5-C7 cycloalkyl or halogenated C1-C5 alkyl, but not limited to two.

[0009] The compounds represented by Formula I include, but are not limited to, any of the following structures:

[0010]

[0011]

[0012] This invention also relates to another biphenylsulfonamide drug of bisbenzimidazole, the compound having the chemical structure shown in Formula II:

[0013]

[0014] In Formula II, R2 represents a hydrogen atom, a C1-C5 alkyl group, a C5-C7 cycloalkyl group, or a halogenated C1-C5 alkyl group.

[0015] The biphenylsulfonamide of bisbenzimidazole shown in Formula II above can also be used in combination. When used in combination, R2 is selected from at least two functional groups selected from hydrogen atom, C1-C5 alkyl, C5-C7 cycloalkyl or halogenated C1-C5 alkyl, but not limited to two.

[0016] The compounds represented by Formula II include, but are not limited to, any of the following structures:

[0017]

[0018] The biphenylsulfonamides of bisbenzimidazole described in Formulas I and II of the present invention can also be used for the preparation of pharmaceutically acceptable salts or solvates.

[0019] Biphenylsulfonamide of bisbenzimidazole as shown in Formula I and its pharmaceutically acceptable salts or solvates, and biphenylsulfonamide of bisbenzimidazole as shown in Formula II and its pharmaceutically acceptable salts or solvates can be used to treat endothelin-dependent or angiotensin II-dependent diseases.

[0020] Therefore, the present invention also relates to:

[0021] 1) The use of biphenylsulfonamide of bisbenzimidazole as shown in Formula I in the preparation of drugs for treating endothelin-dependent or angiotensin II-dependent diseases.

[0022] 2) The use of salts or solvates prepared by formula I in the preparation of drugs for treating endothelin-dependent or angiotensin II-dependent diseases.

[0023] 3) The use of biphenylsulfonamide of bisbenzimidazole as shown in Formula II in the preparation of drugs for treating endothelin-dependent or angiotensin II-dependent diseases.

[0024] 4) The use of salts or solvates prepared by formula II in the preparation of drugs for treating endothelin-dependent or angiotensin II-dependent diseases.

[0025] In human use, compounds I and II of this invention can be taken alone, but are usually taken in combination with a drug-acceptable carrier, the choice of which depends on the designed route of administration and standard pharmaceutical practice. For example, oral administration can be in tablets containing excipients such as starch or lactose, taken orally or sublingually, or in capsules or oval capsules alone or in combination with excipients, or in granules, solutions, or suspensions containing flavoring agents or coloring agents.

[0026] The beneficial effects of the present invention are: the biphenylsulfonamide compounds I and II of the present invention, which are benzimidazoles, have pharmacological activity and have pharmacological effects in animals, including humans. In particular, these compounds are useful in the treatment or prevention of IgA nephropathy, focal segmental glomerulosclerosis, nephrotic syndrome, chronic kidney disease, diabetic nephropathy, hypertension, coronary heart disease and myocardial infarction.

[0027] The compounds of the present invention can be prepared using the following embodiments. Solvents, temperatures, pressures, and other reaction conditions can be selected by those skilled in the art. The starting materials for synthesizing the compounds of the present invention, such as "1-1", "1-5", "1-8", and "1-11", are commercially available or readily prepared by those skilled in the art, and their preparation methods can be found in the paper published by Uwe J. Ries et al. in the Journal of Medicinal Chemistry, 1993, 36(25):4040-4051. The starting materials for synthesizing the compounds of the present invention, such as "1-2" and "2-1", are commercially available or readily prepared by those skilled in the art, and their preparation methods can be found in the paper published by Natesan Murugesan et al. in the Journal of Medicinal Chemistry, 2005, 48(1):171-179.

[0028] The in vitro activity test of the compounds of the present invention was performed by the method described in the Chinese Journal of Pharmacology, 2008, 24(11): 1422-6. Detailed Implementation

[0029] The invention will now be described in further detail with reference to specific embodiments. It should be understood that the embodiments of the present invention are for illustrative purposes only and are not intended to limit the invention. Various substitutions and modifications made based on ordinary technical knowledge and common practices in the art without departing from the technical concept of the present invention should be included within the scope of the present invention.

[0030] Example 1

[0031] Preparation of N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)-4'-((1,2',7'-trimethyl-1H,3'H-[2,5'-bisbenzo[d]imidazol]-3'-yl)methyl)-[1,1'-biphenyl]-2-sulfonamide

[0032]

[0033]

[0034] (i) Preparation of N-(4,5-dimethylisoxazo-3-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)-4'-((1,2',7'-trimethyl-1H,3'H-[2,5'-bisbenzo[d]imidazol]-3'-yl)methyl)-[1,1'-biphenyl]-2-sulfonamide

[0035] Take a 250mL three-necked flask that has been dried in an oven, and then add a device equipped with a mechanical stirrer, nitrogen protection, and a thermometer. Add 1',2,4-trimethyl-6-(benzimidazol-2-yl)benzimidazole (compound "1-1") (11.0g, 40mmol), add DMF (60mL), stir to dissolve, and cool in an ice-salt bath at -5℃ to 0℃. Add NaH (3.2g, 60% in mineral oil, 80mmol). The resulting mixture was stirred at -5°C to 0°C for 30 minutes. Then, a solution of 18.8 g (35.9 mmol) of 4'-(bromomethyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)[1,1'-biphenyl]-2-sulfonamide (compound "1-2")) in 75 mL of DMF was added dropwise over 10 minutes. After the addition was complete, the mixture was stirred for another 20 minutes in an ice-salt bath. The ice-salt bath was then removed and replaced with a water bath at 20°C to 25°C, and the mixture was stirred for another 5 hours. TLC was used to determine if the reaction was complete. The reaction mixture was then poured uniformly into a mixture of EtOAc and purified water. The mixture was transferred to a separatory funnel, and the organic layer was washed with purified water and saturated brine. The organic phase was dried over MgSO4, filtered, and the filtrate was concentrated. The concentrate was separated by silica gel column chromatography using hexane:EtOAc = 1:1 as the solvent, yielding a gel-like N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)-4'-((1,2',7'-trimethyl-1H,3'H-[2,5'-bisbenzo[d]imidazole]-3'-yl)methyl)-[1,1'-biphenyl]-2-sulfonamide (compound "1-3") (21.2 g, 29.5 mmol, yield 82.2%).

[0036] 1 H NMR (500MHz, CDCI3): δ=1.08(s,3H), 1.92(s,3H), 2.23(s,3H), 2.50(s,3H), 2.62(s,3H), 3. 31(s,3H), 3.47(m,2H), 3.94(s,3H), 4.56(s / m,2H), 4.60-4.84(m,4H), 7.26-8.01(m,13H).

[0037] MS: m / e = 719 (ESI + mode)

[0038] (ii) Preparation of N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-4'-((1,2',7'-trimethyl-1H,3'H-[2,5'-bisbenzo[d]imidazol]-3'-yl)methyl)-[1,1'-biphenyl]-2-sulfonamide (molecular weight 674.27)

[0039] Compound "1-3" (5.4 g, 7.5 mmol) was weighed and dissolved in 95% EtOH (90 mL). 6N HCl (75 mL) was added, and the resulting solution was heated under reflux for 2 hours. TLC was used to determine the complete reaction of the starting materials. The reaction mixture was then concentrated, and the pH was adjusted to pH 8 using a saturated sodium bicarbonate solution. The reaction solution was then re-acidified to pH 5 with glacial acetic acid, and the mixture was extracted with EtOAc. The combined organic extracts were washed with purified water and saturated brine. The organic phase was dried over MgSO4, filtered, and the filtrate was concentrated. The concentrate was separated by silica gel chromatography using a 1:4 hexane / EtOAc ratio to obtain compound "1-4" as a white, foamy solid (4.4 g, 87.0%).

[0040] 1 H NMR (500MHz, CDCI3): δ=1.07(s,3H), 1.93(s,3H), 2.22(s,3H), 2.52(s,3H), 2 .62(s,3H), 3.47(m,2H), 3.94(s,3H), 4.60-4.84(m,4H), 7.24-8.02(m,13H).

[0041] MS: m / e = 675 (ESI + mode)

[0042] Elemental analysis results: C, 67.55; H, 5.76; N, 12.51; C 38 H 38 Theoretical values ​​for N6O4S: C, 67.63; H, 5.68; N, 12.45.

[0043] Example 2

[0044] Preparation of N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-4'-((2'-ethyl-1,7'-dimethyl-1H,3'H-[2,5'-bisbenzo[d]imidazol]-3'-yl)methyl)-[1,1'-biphenyl]-2-sulfonamide

[0045]

[0046] (i) Preparation of N-(4,5-dimethylisoxazo-3-yl)-2'-(ethoxymethyl)-4'-((2'-ethyl-1,7'-dimethyl-1H,3'-[2,5'-bisbenzo[d]imidazol]-3'-yl)methyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide

[0047] Take a 250mL three-necked flask that has been dried in an oven, and then add a device equipped with a mechanical stirrer, nitrogen protection, and a thermometer. Add 11.6g (40mmol) of 2-ethyl-4-methyl-6-(1'-methylbenzimidazol-2-yl)benzimidazole (compound "1-5"), add 60mL of DMF, stir to dissolve, and cool in an ice-salt bath at -5℃ to 0℃. Add 3.2g (60% in mineral oil, 80mmol) of NaH. The resulting mixture was stirred at -5°C to 0°C for 30 minutes. Then, a solution of 18.8 g (35.9 mmol) of 4'-(bromomethyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)[1,1'-biphenyl]-2-sulfonamide (compound "1-2")) in 75 mL of DMF was added dropwise over 10 minutes. After the addition was complete, the mixture was stirred for another 20 minutes in an ice-salt bath. The ice-salt bath was then removed and replaced with a water bath at 20°C to 25°C, and the mixture was stirred for another 5 hours. TLC was used to determine if the reaction was complete. The reaction mixture was then poured uniformly into a mixture of EtOAc and purified water. The mixture was transferred to a separatory funnel, and the organic layer was washed with purified water and saturated brine. The organic phase was dried over MgSO4, filtered, and the filtrate was concentrated. The concentrate was separated by silica gel column chromatography using hexane:EtOAc = 1:1 as the solvent, yielding a gel-like N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-4'-((2'-ethyl-1,7'-dimethyl-1H,3'H-[2,5'-bisbenzo[d]imidazole]-3'-yl)methyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (compound "1-6") (22.6 g, 29.5 mmol, yield 85.9%).

[0048] 1 H NMR (500MHz, CDCI3): δ=1.06(s,3H),1.27(t,3H),1.92(s,3H),2.23(s,3H),2.60(s,3H),2.78(m ,2H), 3.31(s,3H),3.46(m,2H),3.92(s,3H),4.56(s,2H), 4.60-4.84(m,4H), 7.26-8.00(m,13H).

[0049] MS: m / e = 733 (ESI + mode)

[0050] (ii) Preparation of N-(4,5-dimethylisoxazo-3-yl)-2'-(ethoxymethyl)-4'-((2'-ethyl-1,7'-dimethyl-1H,3'H-[2,5'-bisbenzo[d]imidazol]-3'-yl)methyl)-[1,1'-biphenyl]-2-sulfonamide

[0051] Compound "1-6" (5.5 g, 7.5 mmol) was weighed and dissolved in 95% EtOH (90 mL). 6N HCl (75 mL) was added, and the resulting solution was heated under reflux for 2 hours. The reaction mixture was then concentrated by TLC, and the pH was adjusted to pH 8 using a saturated sodium bicarbonate solution. The reaction solution was then re-acidified to pH 5 with glacial acetic acid, and the mixture was extracted with EtOAc. The combined organic extracts were washed with purified water and saturated brine, and the organic phase was dried over MgSO4. After drying, the system was filtered, and the filtrate was concentrated. The concentrate was separated by silica gel chromatography using a 1:4 hexane / EtOAc ratio to obtain "compound 1-4" as a white, foamy solid (4.2 g, 81.3%).

[0052] 1 H NMR (500MHz, CDCI3): δ=1.07(s,3H), 1.25(t,3H), 1.92(s,3H), 2.23(s,3H), 2.62(s ,3H), 2.78(m,2H), 3.47(m,2H), 3.94(s,3H), 4.60-4.84(m,4H), 7.26-8.01(m,13H).

[0053] MS: m / e = 689 (ESI + mode)

[0054] Elemental analysis results: C, 68.11; H, 5.86; N, 12.31. 39 H 40 Theoretical values ​​for N6O4S: C, 68.00; H, 5.85; N, 12.20.

[0055] Example 3

[0056] Preparation of 4'-((1,7'-dimethyl-2'-propyl-1H,3'H-[2,5'-bisbenzo[d]imidazolium]-3'-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide

[0057]

[0058]

[0059] (i) Preparation of 4'-((1,7'-dimethyl-2'-propyl-1H,3'H-[2,5'-bisbenzo[d]imidazol]-3'-yl)methyl)-N-(4,5-dimethylisoxazo-3-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide

[0060] Take a 250mL three-necked flask that has been dried in an oven, and then add a device equipped with a mechanical stirrer, nitrogen protection, and a thermometer. Add 12.2g (40mmol) of 2-n-propyl-4-methyl-6-(1'-methylbenzimidazol-2-yl)benzimidazole (compound "1-8"), add 60mL of DMF, stir to dissolve, and cool in an ice-salt bath at -5℃ to 0℃. Add 3.2g (60% in mineral oil, 80mmol) of NaH. The resulting mixture was stirred at -5°C to 0°C for 30 minutes. Then, a solution of 18.8 g (35.9 mmol) of 4'-(bromomethyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)[1,1'-biphenyl]-2-sulfonamide (compound "1-2")) in 75 mL of DMF was added dropwise over 10 minutes. After the addition was complete, the mixture was stirred for another 20 minutes in an ice-salt bath. The ice-salt bath was then removed and replaced with a water bath at 20°C to 25°C, and the mixture was stirred for another 5 hours. TLC was used to determine if the reaction was complete. The reaction mixture was then poured uniformly into a mixture of EtOAc and purified water. The mixture was transferred to a separatory funnel, and the organic layer was washed with purified water and saturated brine. The organic phase was dried over MgSO4, filtered, and the filtrate was concentrated. The concentrate was separated by silica gel column chromatography using hexane:EtOAc = 1:1 as the solvent, yielding a gel-like 4'-((1,7'-dimethyl-2'-propyl-1H,3'H-[2,5'-bisbenzo[d]imidazole]-3'-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (“Compounds 1-9”) (22.5 g, 30.1 mmol, yield 83.9%).

[0061] 1H NMR (500MHz, CDCI3): δ=0.91(t,3H), 1.07(s,3H), 1.68(m,2H), 1.93(s,3H), 2.24(s,3H), 2.63(s,3H), 2 .84(t,2H), 3.31(s,3H), 3.47(m,2H), 3.93(s,3H), 4.56(s,2H), 4.60-4.84(m,4H), 7.29-8.04(m,13H).

[0062] MS: m / e = 747 (ESI + mode)

[0063] (ii) Preparation of 4'-((1,7'-dimethyl-2'-propyl-1H,3'H-[2,5'-bisbenzo[d]imidazolium]-3'-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (ExactMass: 702.30)

[0064] Compound "1-9" (5.6 g, 7.5 mmol) was weighed and dissolved in 95% EtOH (90 mL). 6N HCl (75 mL) was added, and the resulting solution was heated under reflux for 2 hours. TLC was used to determine the complete reaction of the starting materials. The reaction mixture was then concentrated, and the pH was adjusted to pH 8 using a saturated sodium bicarbonate solution. The reaction solution was then re-acidified to pH 5 with glacial acetic acid, and the mixture was extracted with EtOAc. The combined organic extracts were washed with purified water and saturated brine. The organic phase was dried over MgSO4, filtered, and the filtrate was concentrated. The concentrate was separated by silica gel chromatography using a 1:5 hexane / EtOAc ratio to obtain compound "1-10" as a white, foamy solid (4.0 g, 75.9%).

[0065] 1 H NMR (500MHz, CDCI3): δ = 0.89 (t, 3H), 1.06 (s, 3H), 1.67 (m, 2H), 1.92 (s, 3H), 2.23 (s, 3H), 2 .60(s,3H),2.83(t,2H),3.47(m,2H),3.94(s,3H),4.60-4.84(m,4H),7.26-8.01(m,13H).

[0066] MS: m / e = 703 (ESI + mode)

[0067] Elemental analysis results: C, 68.13; H, 5.97; N, 11.85. 39 H 40Theoretical values ​​for N6O4S: C, 68.35; H, 6.02; N, 11.96.

[0068] Example 4

[0069] Preparation of 4'-((2'-butyl-1,7'-dimethyl-1H,3'H-[2,5'-bisbenzo[d]imidazolium]-3'-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide

[0070]

[0071] (i) Preparation of 4'-((2'-butyl-1,7'-dimethyl-1H,3'H-[2,5'-bisbenzo[d]imidazol]-3'-yl)methyl)-N-(4,5-dimethylisoxazo-3-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide

[0072] Take a 250mL three-necked flask that has been dried in an oven, and then add a device equipped with a mechanical stirrer, nitrogen protection, and a thermometer. Add 12.7g (40mmol) of 2-butyl-4-methyl-6-(1'-methylbenzimidazol-2-yl)benzimidazole (compound "1-11"), add 60mL of DMF, stir to dissolve, and cool in an ice-salt bath at -5℃ to 0℃. Add 3.2g (60% in mineral oil, 80mmol) of NaH. The resulting mixture was stirred at -5°C to 0°C for 30 minutes. Then, a solution of 18.8 g (35.9 mmol) of 4'-(bromomethyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)[1,1'-biphenyl]-2-sulfonamide (compound "1-2")) in 75 mL of DMF was added dropwise over 10 minutes. After the addition was complete, the mixture was stirred for another 20 minutes in an ice-salt bath. The ice-salt bath was then removed and replaced with a water bath at 20°C to 25°C, and the mixture was stirred for another 5 hours. TLC was used to determine if the reaction was complete. The reaction mixture was then poured uniformly into a mixture of EtOAc and purified water. The mixture was transferred to a separatory funnel, and the organic layer was washed with purified water and saturated brine. The organic phase was dried over MgSO4, filtered, and the filtrate was concentrated. The concentrate was separated by silica gel column chromatography using hexane:EtOAc = 1:1 as the solvent, yielding a gel-like compound 4'-((1,7'-dimethyl-2'-butyl-1H,3'H-[2,5'-bisbenzo[d]imidazole]-3'-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (compound "1-12") (23.2 g, 30.5 mmol, yield 84.9%).

[0073] 1 H NMR (500MHz, CDCI3): δ=0.90(t,3H),1.37(m,2H),1.60(m,2H),2.82(t,2H),2.62(s,3H),3.94(s,3H),7.30-7.52(m,4H),7.80(d, 2H),4.60-4.84(m,4H),1.07(s,3H),3.47(m,2H),7.26-8.01(m,7H),3.31(s,3H,MOM),4.56(m,2H,MOM),1.92(s,3H),2.23(s,3H).

[0074] MS: m / e = 761 (ESI + mode).

[0075] (ii) Preparation of 4'-((2'-butyl-1,7'-dimethyl-1H,3'H-[2,5'-bisbenzo[d]imidazol]-3'-yl)methyl)-N-(4,5-dimethylisoxazo-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide

[0076] Compound "1-12" (5.7 g, 7.5 mmol) was weighed and dissolved in 95% EtOH (90 mL). 6N HCl (75 mL) was added, and the resulting solution was heated under reflux for 2 hours. The reaction mixture was then concentrated by TLC, and the pH was adjusted to pH 8 using a saturated sodium bicarbonate solution. The reaction solution was then re-acidified to pH 5 with glacial acetic acid, and the mixture was extracted with EtOAc. The combined organic extracts were washed with purified water and saturated brine, and the organic phase was dried over MgSO4. After drying, the system was filtered, and the filtrate was concentrated. The concentrate was separated by silica gel chromatography using a 1:5 hexane / EtOAc ratio to obtain "1-13" as a white, foamy solid (4.2 g, 78.1%).

[0077] 1 H NMR (500MHz, CDCI3): δ=0.91(t,3H), 1.07(s,3H), 1.36(m,2H), 1.62(m,2H), 1.92(s,3H), 2.23(s ,3H), 2.64(s,3H),2.82(t,2H), 3.47(m,2H), 3.94(s,3H), 4.60-4.84(m,4H), 7.25-8.02(m,13H).

[0078] MS: m / e = 717 (ESI + mode)

[0079] Elemental analysis results: C, 68.81; H, 6.09; N, 11.64. 39 H 40 Theoretical values ​​for N6O4S: C, 68.69; H, 6.19; N, 11.72.

[0080] Example 5

[0081] Preparation of 4'-((1,7'-dimethyl-2'-propyl-1H,3'H-[2,5'-bisbenzo[d]imidazolium]-3'-yl)methyl)-N-(3,4-dimethylisoxazol-5-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide

[0082]

[0083]

[0084] (i) Preparation of 4'-((1,7'-dimethyl-2'-propyl-1H,3'H-[2,5'-bisbenzo[d]imidazol]-3'-yl)methyl)-N-(3,4-dimethylisoxazo-5-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide

[0085] Take a 250mL three-necked flask that has been dried in an oven, and then add a device equipped with a mechanical stirrer, nitrogen protection, and a thermometer. Add 12.2g (40mmol) of 2-n-propyl-4-methyl-6-(1'-methylbenzimidazol-2-yl)benzimidazole (compounds 1-8), add 60mL of DMF, stir to dissolve, and cool in an ice-salt bath at -5℃ to 0℃. Add 3.2g (60% in mineral oil, 80mmol) of NaH. The resulting mixture was stirred at -5°C to 0°C for 30 minutes. Then, a solution of 18.8 g (35.9 mmol) of 4'-(bromomethyl)-N-(3,4-dimethylisoxazol-5-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)[1,1'-biphenyl]-2-sulfonamide (compound 2-1) in 75 mL of DMF was added dropwise over 10 minutes. After the addition was complete, the mixture was stirred for another 20 minutes in an ice-salt bath. The ice-salt bath was then removed and replaced with a water bath at 20°C to 25°C, and the mixture was stirred for another 5 hours. TLC was used to confirm the reaction was complete. The reaction mixture was then poured into a mixture of EtOAc and purified water at a uniform rate. The mixture was transferred to a separatory funnel, and the organic layer was washed with purified water and saturated brine. The organic phase was dried over MgSO4, filtered, and the filtrate was concentrated. The concentrate was separated by silica gel column chromatography using hexane:EtOAc = 1:1 as the solvent, yielding a gel-like compound 4'-((1,7'-dimethyl-2'-propyl-1H,3'H-[2,5'-bisbenzo[d]imidazole]-3'-yl)methyl)-N-(3,4-dimethylisoxazol-5-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (compound 2-2) (23.2 g, 31.1 mmol, yield 86.6%).

[0086] 1H NMR (500MHz, CDCI3): δ=0.90(t,3H),1.05(s,3H),1.67(m,2H),1.88(s,3H),2.15(s,3H),2.62(s,3H),2.83(t,2H),3.3 3(s,3H), 3.47(m,2H), 3.94(s,3H), 4.56(s,2H), 4.60-4.85(m,4H), 7.30-7.52(m,4H), 7.80(d,2H), 7.26-8.05(m,13H)

[0087] MS: m / e = 747 (ESI + mode)

[0088] (ii) 4'-((1,7'-dimethyl-2'-propyl-1H,3'H-[2,5'-bisbenzo[d]imidazol]-3'-yl)methyl)-N-(3,4-dimethylisoxazo-5-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide

[0089] Compound "2-2" (5.6 g, 7.5 mmol) was weighed and dissolved in 95% EtOH (90 mL). 6N HCl (75 mL) was added, and the resulting solution was heated under reflux for 2 hours. TLC was used to determine the complete reaction of the starting materials. The reaction mixture was then concentrated, and the pH was adjusted to pH 8 using a saturated sodium bicarbonate solution. The reaction solution was then re-acidified to pH 5 with glacial acetic acid, and the mixture was extracted with EtOAc. The combined organic extracts were washed with purified water and saturated brine. The organic phase was dried over MgSO4, filtered, and the filtrate was concentrated. The concentrate was separated by silica gel chromatography using a 1:5 hexane / EtOAc ratio to give compound "2-3" as a white, foamy solid (4.2 g, 79.7%).

[0090] 1 H NMR (500MHz, CDCI3): δ = 0.92 (t, 3H), 1.07 (s, 3H), 1.63 (m, 2H), 1.88 (s, 3H), 2.13 (s, 3H), 2 .62(s,3H),2.83(t,2H),3.47(m,2H),3.92(s,3H),4.60-4.84(m,4H),7.26-8.05(m,13H).

[0091] MS: m / e = 703 (ESI + mode)

[0092] Elemental analysis results: C, 68.38; H, 6.08; N, 12.08. C 39 H 40Theoretical values ​​for N6O4S: C, 68.35; H, 6.02; N, 11.96.

[0093] Example 6

[0094] Preparation of 4'-((2'-butyl-1,7'-dimethyl-1H,3'H-[2,5'-bisbenzo[d]imidazol]-3'-yl)methyl)-N-(3,4-dimethylisoxazol-5-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide;

[0095]

[0096] (i) Preparation of 4'-((2'-butyl-1,7'-dimethyl-1H,3'H-[2,5'-bisbenzo[d]imidazol]-3'-yl)methyl)-N-(3,4-dimethylisoxazo-5-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide;

[0097] Take a 250mL three-necked flask that has been dried in an oven, and then add a device equipped with a mechanical stirrer, nitrogen protection, and a thermometer. Add 12.7g (40mmol) of 2-butyl-4-methyl-6-(1'-methylbenzimidazol-2-yl)benzimidazole (compound "1-11"), add 60mL of DMF, stir to dissolve, and cool in an ice-salt bath at -5℃ to 0℃. Add 3.2g (60% in mineral oil, 80mmol) of NaH. The resulting mixture was stirred at -5°C to 0°C for 30 minutes. Then, a solution of 18.8 g (35.9 mmol) of 4'-(bromomethyl)-N-(3,4-dimethylisoxazol-5-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)[1,1'-biphenyl]-2-sulfonamide (compound "2-1")) in 75 mL of DMF was added dropwise over 10 minutes. After the addition was complete, the mixture was stirred for another 20 minutes in an ice-salt bath. The ice-salt bath was then removed and replaced with a water bath at 20°C to 25°C, and the mixture was stirred for another 5 hours. TLC was used to determine if the reaction was complete. The reaction mixture was then poured into a mixture of EtOAc and purified water at a uniform rate. The mixture was transferred to a separatory funnel, and the organic layer was washed with purified water and saturated brine. The organic phase was dried over MgSO4, filtered, and the filtrate was concentrated. The concentrate was separated by silica gel column chromatography using hexane:EtOAc = 1:1 as the solvent, yielding a gel-like compound 4'-((1,7'-dimethyl-2'-butyl-1H,3'H-[2,5'-bisbenzo[d]imidazole]-3'-yl)methyl)-N-(3,4-dimethylisoxazo-5-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (compound "2-4") (21.9 g, 28.8 mmol, yield 80.2%).

[0098] 1 H NMR (500MHz, CDCI3): δ=0.91(t,3H),1.07(s,3H),1.38(m,2H),1.60(m,2H),1.90(s,3H),2.15(s,3H),2.62(s ,3H),2.85(t,2H),3.31(s,3H),3.47(m,2H),3.94(s,3H),4.56(s,2H),4.60-4.84(m,4H),7.26-8.01(m,13H).

[0099] MS: m / e = 761 (ESI + mode)

[0100] (ii) Preparation of 4'-((2'-butyl-1,7'-dimethyl-1H,3'H-[2,5'-bisbenzo[d]imidazol]-3'-yl)methyl)-N-(3,4-dimethylisoxazol-5-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide;

[0101] Weigh out 5.7 g (7.5 mmol) of compound "2-4" and dissolve it in 90 mL of 95% EtOH. Add 75 mL of 6 N HCl and heat the resulting solution under reflux for 2 hours. TLC was used to determine the complete reaction of the starting materials. The reaction mixture was then concentrated, and the pH was adjusted to pH 8 by adding a saturated sodium bicarbonate solution. The reaction solution was then re-acidified to pH 5 with glacial acetic acid, and the mixture was extracted with EtOAc. The combined organic extracts were washed with purified water and saturated brine. The organic phase was dried over MgSO4, filtered, and the filtrate was concentrated. The concentrate was separated by silica gel chromatography using a 1:5 hexane / EtOAc ratio to obtain compound "2-5" as a white, foamy solid (4.4 g, 81.8%).

[0102] 1 H NMR (500MHz, CDCI3): δ = 0.90 (t, 3H), 1.07 (s, 3H), 1.37 (m, 2H), 1.61 (m, 2H), 1.93 (s, 3H), 2.14 (s ,3H),2.60(s,3H),2.84(t,2H),3.50(m,2H),3.94(s,3H),4.60-4.84(m,4H),7.28-8.02(m,13H).

[0103] MS: m / e = 717 (ESI + mode)

[0104] Elemental analysis results: C, 68.82; H, 6.13; N, 11.87. C 39 H 40 Theoretical values ​​for N6O4S: C, 68.69; H, 6.19; N, 11.72.

[0105] Example 7 Compounds on AT1 and ET A Evaluation of receptor inhibitory activity

[0106] Isolated rat aortic ring experiment: Male rats were decapitated and their thoracic aortas were placed in a bath containing 10 ml of Krebs-Henseleit. The temperature was kept constant at 37°C. One end of the specimen was fixed, and the other end was connected to a computer via a tension transducer. The preload was maintained at 1.2–1.5 g. A mixture of 95% O2 and 5% CO2 was continuously introduced. The liquid was changed every 15 minutes, and the experiment was conducted after equilibration for 60 minutes.

[0107] (1) First add a final concentration of 10 nmol·L to the bath. -1 Ang II or 10 nmol·L -1 ET-1, add to a final concentration of 1 μmol·L⁻¹ when the vasoconstriction reaches maximum tension. -1 The test compound was used to observe changes in vascular tension over 20 minutes.

[0108] (2) First add a final concentration of 1 μmol·L to the bath. -1 The test compound was treated with incrementally increasing concentrations of Ang II or ET-1 (0.05–50 nmol·L⁻¹) after 10 min. -1 ), observe the changes in the dose-response curve of Ang II or ET-1 in the aortic ring.

[0109] Based on this experimental model, AT1 and ET were compared. A Compounds with high receptor affinity were screened, and the screening results for each compound are shown in Table 1 below.

[0110] Telmisartan, an AT1 receptor antagonist approved by the US FDA in 1998, was used as a control in our AT1 and ET comparisons. A The results of the evaluation of receptor inhibitory activity are shown in Table 1.

[0111] Table 1. Biphenylsulfonamide compounds of bisbenzimidazole and their effects on AT1 and ET. A Results of receptor inhibitory activity

[0112]

[0113] We evaluated the activity of the designed biphenylsulfonamide compounds of benzimidazole and telmisartan, and tested their AT1 receptor antagonism. As shown in Table 1, compounds "1-7", "1-10", "1-13", "2-3", and "2-5" have similar potency to telmisartan. However, their AT1 receptor antagonism is not as strong. A The receptor antagonism test results in Table 1 show that compounds “1-7”, “1-10”, “1-13”, “2-3”, and “2-5” have much higher activity than telmisartan.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that, The structural formula of the compound is:

2. The use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating endothelin-dependent or angiotensin II-dependent diseases.

Images