- Method for preparing Fimasartan
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The invention discloses a method for preparing Fimasartan. The method comprises the steps that valeronitrile is used as a raw material to prepare pentanimidamide hydrochloride, then pentanimidamide hydrochloride and acetylsuccinic acid diethyl ester conduct a cyclization reaction and an amidation reaction to prepare 2-(2-normal-butyl-4-hydroxyl-6-methylpyrimidine-5-radical)-N,N-dimethylacetamide (intermediate II), the intermediate II is subjected to sulfo-carbonylation through a Lawesson's reagent to obtain 2-(2-normal-butyl-4-hydroxyl-6-methylpyrimidine-5-radical)-N,N-dimethylacetamide (intermediate III), the intermediate III is subjected to an N-alkylation reaction, radicals are protected through detritylation, and Fimasartan is prepared. The preparation method has the advantages of highreaction selectivity, high synthesis yield, high reaction efficiency and the like.
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Paragraph 0037; 0038
(2019/01/16)
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- Discovery of the bifunctional modulator of angiotensin II type 1 receptor (AT1R) and PPARγ derived from the AT1R antagonist, Fimasartan
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Inspired by the well-known PPARγ partial agonism of angiotensin II type 1 receptor (AT1R) antagonists exemplified by an antihypertensive drug, Telmisartan, efforts to identify compounds with the dual activities have been pursued in order to control the two major metabolic disorders, hypertension and hyperglycemia simultaneously. Lead compound 18 derived from the AT1R antagonist, Fimasartan, has successfully presented the possibility to control the medical conditions by a single molecule.
- Choung, Wonken,Jung, Hui Jin,Nam, Eun Hye,Yang, Deokmo,Yoo, Byoungwook,Choi, Hyukjoon,Lee, Bo Ram,Park, Min,Jang, Su Min,Lim, Jae Soo,Kim, Kyung-Hee,Chin, Jungwook,Jung, Kyungjin,Lee, Geumwoo,Kim, Seong Heon
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p. 3155 - 3160
(2018/09/11)
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- 'Green' synthesis of 2-substituted 6-hydroxy-[3H]-pyrimidin-4-ones and 4,6-dichloropyrimidines: Improved strategies and mechanistic study
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An improved route to 2-substituted 6-hydroxy-[3H]-pyrimidin-4-ones 4 and to 2-substituted 4,6-dichloropyrimidines 5 is reported. Without using highly toxic reactants, compounds 4 can be prepared conveniently in a one pot synthesis on a one mol scale with average yields up to 80%. 4,6-Dichloropyrimidines 5, which are usually prepared in small quantities, are synthesized with average yields of 80%, using up to 80g of starting material. The mechanism of the chlorination of 4 is investigated computationally for the first time. The results suggest that the chlorination with phosphoryl chloride occurs in an alternating phosphorylation-chlorination manner (pathway 1) which is preferred over a sequence which starts with two phosphorylations. The investigated 4,6-dichloropyrimidines described herein form strong complexes with dichlorophosphoric acid but weak complexes with hydrochloric acid (generated during workup). These latter complexes explain the necessity of using aqueous sodium carbonate during the working up. In order to prevent possible formation of pyrimidinium salts between intermediates or the final dichloropyrimidines and unreacted hydroxypyrimidone, the latter could be deactivated with a strong acid such as dichlorophosphoric acid, thus allowing chlorination but prohibiting salt formation. Because of its general applicability to all nitrogen heterocycle chlorinations with phosphoryl chloride, the proposed route to dichloropyrimidines without solvent or side products, using less toxic reactants, is of general synthetic interest.
- Opitz, Andreas,Sulger, Werner,Daltrozzo, Ewald,Koch, Rainer
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p. 814 - 824
(2015/05/20)
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- Synthesis and antihypertensive activity of pyrimidin-4(3H)-one derivatives as losartan analogue for new angiotensin II receptor type 1 (AT1) antagonists
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The discovery, in vitro and in vivo studies of the highly potent AT1 antagonist 12a (BR-A-657, Fimasartan) are presented. A series of pyrimidin-4(3H)-one derivatives as losartan analogue were synthesized and evaluated for a novel class of AT1 receptor antagonists. Among them, 12a containing thioamido moiety displayed both high in vitro functional antagonism and binding affinity [IC50 = 0.42 and 0.13 nM, respectively] and inhibited strongly in vivo AngII-induced pressor response in pithed rats with an ED50 of 0.018 mg/kg. Moreover, in vivo evaluation in furosemide-treated rat and conscious renal hypertensive rat models and the pharmacokinetic study showed that 12a is a highly potent and orally active AT1 selective antagonist having stronger in vivo potency than losartan.
- Kim, Tae Woo,Yoo, Byoung Wook,Lee, Joon Kwang,Kim, Ji Han,Lee, Kyung-Tae,Chi, Yong Ha,Lee, Jae Yeol
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scheme or table
p. 1649 - 1654
(2012/04/04)
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- Dihydropyrimidine derivatives
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Novel A-II receptor antagonists have the formula STR1 and its isomer STR2 wherein R 1, R 2, R 3, R 4, R 5, R 6, R 7 and R 8 are as defined herein.
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- Angiotensin II receptor blocking 2,3,6-substituted 5,6,7,8-tetrahydro-pyrido[4,3-D]pyrimidin-4(3H)-ones
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The invention provides novel 2,3,6-substituted 5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4 (3H)-ones of the formula STR1 wherein X, R and R 6 are described in the specification which have activity as angiotensin II (AII) antagonists.
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- N-SUBSTITUTED HETEROCYCLIC DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS IN WHICH THEY ARE PRESENT
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The invention relates to N-substituted heterocyclic derivatives and its salts. These derivatives have the formula (I) in which the substituents are as defined in the specification. Application: Angiotensin II antagonists
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