152628-03-0Relevant articles and documents
Design, synthesis and evaluation of novel angiotensin II receptor 1 antagonists with antihypertensive activities
Bao, Xiao-Lu,Zhu, Wei-Bo,Shan, Tian-Li,Wu, Zhuo,Zhang, Rui-Jing,Liao, Ping-Yong,Zheng, Mei-Zhen,Tang, He-Sheng,Yan, Yi-Jia,Chen, Zhi-Long
, p. 26401 - 26410 (2017)
A series of novel angiotensin II receptor 1 antagonists (1a-f, 2a-f) were designed, synthesized and evaluated. Radioligand binding assays showed that all these prepared compounds displayed nanomolar affinity for angiotensin II type 1 receptor, among which compound 1f was more affinitive than telmisartan at the same order of magnitude with an IC50 value of 1.13 ± 1.68 nM. The antihypertensive effects showed that all these compounds could decrease blood pressure in a dose dependent manner on spontaneously hypertensive rats. And compound 2-(4-((2-butyl-4-methyl-6-(oxazolo[4,5-b]pyridine-2-yl)benzimidazole-1-yl)methyl)-1H-indol-1-yl) benzoic acid (1f), showed efficient and long-lasting effects in reducing blood pressure, with a maximal response lowered 55.98 ± 4.74 mmHg at 10 mg kg-1 and 35.82 ± 6.20 mmHg at 5 mg kg-1, the antihypertensive effect of it lasted beyond 24 h which was better than telmisartan. In the single-dose pharmacokinetic experiments, compound 1f was absorbed efficiently and metabolized smoothly in Wistar rats. The values of Cmax, Tmax, AUC0-72, MRT0-72 and T1/2 were 17.92 ± 10.85 ng mL-1, 2.60 ± 3.05 h, 252.85 ± 144.59 ng mL-1 h, 18.75 ± 0.43 h and 17.16 ± 4.24 h respectively. Compound 1f was distributed into tissues rapidly and extensively after oral administration and the level of it was the highest in the liver, followed by in the kidney, and the lowest in brain. The acute toxicity assays in ICR rats of 1f showed that it had low acute toxicity with an LD50 value of 1459.89 mg kg-1. These encouraging results make 1f an efficient, long-acting and safe antihypertensive drug candidate and deserving of further investigation.
Preparation method of benzimidazole compound
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Paragraph 0033-0035, (2021/04/10)
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of a benzimidazole compound. The benzimidazole compound is prepared by taking a halogenated benzoic acid amine compound as a reaction raw material through azidation reaction and cyclization reaction. The benzimidazole compound with high yield and high purity can be obtained, and the method is suitable for industrial production.
Design, Synthesis, and Biological Evaluation of 6-Benzoxazole Benzimidazole Derivatives with Antihypertension Activities
Wu, Zhuo,Bao, Xiao-Lu,Zhu, Wei-Bo,Wang, Yan-Hui,Phuong Anh, Nguyen Thi,Wu, Xiao-Feng,Yan, Yi-Jia,Chen, Zhi-Long
supporting information, p. 40 - 43 (2019/01/14)
A series of new angiotensin II receptor 1 antagonists were prepared. They displayed nanomolar affinity to AT1 receptor and could decrease blood pressure efficiently in spontaneously hypertensive rats. Among them, compounds 1b and 2b could reduce the blood pressure with more or equal potency compared to Losartan. So, compounds 1b and 2b could be considered as potential antihypertension drug candidates.
Design, synthesis and biological evaluation of AT1 receptor blockers derived from 6-substituted aminocarbonyl benzimidazoles
Wu, Zhuo,Anh, Nguyen Thi Phuong,Yan, Yi-Jia,Xia, Ming-Bao,Wang, Yan-Hui,Qiu, Yan,Chen, Zhi-Long
, (2019/08/01)
A series of new 6-substituted aminocarbonyl benzimidazole derivatives with 1, 4-disubsituted or 1, 5-disubsituted indole moiety and benzoic acid moiety were designed, synthesized and pharmacologically evaluated. Most of the synthesized compounds could bind to the AT1 receptor and decrease blood pressure significantly. Notably, 2e and 1h could obviously decrease MBP in a dose dependent manner. The maximal response lowered 57.9 ± 2.3 mmHg (2e) and 57.6 ± 1.9 mmHg (1h) of MBP at 10 mg/kg after oral administration, and the antihypertensive effect lasted beyond 24 h, which performed better than Losartan (Fig. 1). These results indicate that 2e and 1h are effective and long-lasting anti-hypertension drug candidates and deserve further investigation for therapeutic application.
Preparation method of telmisartan intermediate
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Paragraph 0021; 0029; 0031; 0032; 0034; 0035; 0037; 0038, (2019/02/21)
The invention relates to a preparation method of a telmisartan intermediate, namely 2-n-propyl-4-methyl-6-Benzimidazolecarboxylic acid. The preparation method of the 2-n-propyl-4-methyl-6-Benzimidazolecarboxylic acid comprises the following steps: firstly, ethanol hydrochloride acts with butyronitrile and anhydrous hydrogen chloride within the range of 0-35 DEG C; the mixture obtained in the firststep reacts with 3-methyl-4-aminobenzoic acid and ice vinegar within the range of pH 5.0-11.0 at the controlled temperature of 10-40 DEG C, and an intermediate shown in the formula II is obtained; and then the intermediate shown in the formula II reacts with a sodium hypochlorite solution, and the 2-n-propyl-4-methyl-6-Benzimidazolecarboxylic acid is obtained. The intermediate preparation processis suitable for industrial production, and meanwhile the product quality is improved.
Synthetic method of 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid
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Paragraph 0050; 0051; 0017; 0030; 0031, (2017/09/13)
The invention relates to a synthetic method of 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid. The synthetic method comprises the following steps: through nitric acid/concentrated sulfuric acid nitrification reaction of 3,5-dimethylnitrobenzene, generating an intermediate product II, namely 3,5-dimethyl-1,2-dinitrobenzene; performing Pd/C catalytic hydrogenation reaction on the intermediate product II in an ethanol solution to obtain an intermediate product III, namely 3,5-dimethyl-1,2-phenylenediamine; enabling the intermediate product III to react with N-butyric acid in a polyphosphoric acid solution to obtain an intermediate product IV, namely 2-n-propyl-4,6-dimethylbenzimidazole; performing cobalt salt air liquid-phase oxidation reaction on the intermediate product IV in an acetic acid solution to obtain a product V, namely the 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid. The synthetic method provided by the invention has the benefits that the operation is simple, raw materials are easy to obtain, a used solvent can be recycled, the product content can reach 95 percent or above, the yield is up to 73.2 percent, the pollution is less, and the suitability for industrial production is realized.
A method for synthesizing intermediate telmisartan
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, (2018/01/11)
The invention provides a totally novel synthetic method for the telmisartan intermediate 7-methyl-2-propyl-(1H)-benzimidazole-5-carboxylic acid. The synthetic method provided by the invention overcomes the defects of a lot of reaction steps and low total yield of synthetic processes for 7-methyl-2-propyl-(1H)-benzimidazole-5-carboxylic acid reported in literature and prepares the intermediate from 2-methyl-4-aminobenzoic acid, i.e., a compound 10, through three actions. Reduction of steps in the synthetic method enables product quality and yield to be substantially improved, production cost to be reduced, technological operation to be simplified and adverse influence on the environment to be substantially reduced.
N-Phenyl indole derivatives as AT1 antagonists with anti-hypertension activities: Design, synthesis and biological evaluation
Zhu, Weibo,Bao, Xiaolu,Ren, He,Da, Yajing,Wu, Dan,Li, Fuming,Yan, Yijia,Wang, Li,Chen, Zhilong
, p. 161 - 178 (2016/04/05)
The design, synthesis, in vitro and in vivo evaluation of 6-substituted benzimidazole with 1, 4-disubsituted or 1, 5-disubsituted indole derivatives as novel angiotensin II receptor antagonists are outlined. Radioligand binding assays showed that several 6-substituted benzimidazole derivatives displayed high affinities binding to the angiotensin II type 1 receptor at the same order of magnitude to telmisartan. The biological evaluation on spontaneously hypertensive rats showed that 2-[4-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazole-1-yl]methyl]-1H-indol-1-yl]benzoic acid, 1c, could cause significant decrease on MBP in a dose dependent manner. Its maximal response lowered 53 mmHg of MBP at 5 mg/kg and 64 mmHg of MBP at 10 mg/kg after oral administration, and the significant antihypertensive effect lasted beyond 24 h, which was better than both losartan and telmisartan. A study designed to determine acute toxicity showed that 1c had low acute toxicity with no significant changes in the weight and no obvious untoward reactions. The encouraging results make 1c an effective and durable anti-hypertension drug candidate and deserve further investigation for therapeutic application.
AN IMPROVED PROCESS FOR THE PREPARATION OF TELMISARTAN
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Page/Page column 17, (2012/03/26)
Methyl-4-(butyramido)-3-methyl-5-nitrobenzoate is treated with sulphur containing reducing agent to give methyl-4-methyl-2-propyl-lH-benzimidazole-6-carboxylate, which is further hydrolyzed to the corresponding acid, 2-n-propyl-4-methyl-6- carboxy benzimidazole. The critical intermediate l,4'-dimethyl-2'-propyl-lH,3'H- 2,6'-bisbenzimidazol (DMPBB) is prepared by treating the above acid with N- mehtyl-o-phenylenediamine dihydrochloride under acidic conditions. Reaction of 4'-halomethylbiphenyl-2-carboxylic acid alkyl ester with DMPBB in presence of base to give Telmisartan ester which is further converted to Telmisartan of Formula (I).
TRICYCLIC COMPOUND
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Page/Page column 83-84, (2011/06/23)
Provided is a tricyclic compound having a PPAR γ agonist activity, which is represented by the general formula (I) wherein Z represents a single bond or the like, Y represents a hydrogen atom, lower alkyl optionally having substituent(s) or the like, X represents a hydrogen atom or the like, A represents aryl or the like, B and C are the same or different and each represents an aromatic carbocycle or the like, R4 - R9 are the same or different and each represents hydrogen or the like, V represents a single bond or the like, R10 and R11 are the same or different and each represents hydrogen or the like, or a pharmaceutically acceptable salt thereof or the like:
