cas 878672-00-5, RDEA 594 | Articles data

Articles about 878672-00-5Total 32 be found

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Characterization of stereoselective metabolism, inhibitory effect on uric acid uptake transporters, and pharmacokinetics of lesinurad atropisomers
Lesinurad [Zurampic; 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)], a selective inhibitor of uric acid reabsorption transporters approved for the treatment of gout, is a racemate of two atropisomers. The objective of this investigation was to evaluate the stereoselectivity of metabolism, the inhibitory potency on kidney uric acid reabsorption transporters (URAT1 and OAT4), and the clinical pharmacokinetics of the lesinurad atropisomers. Incubations with human liver microsomes (HLM), recombinant CYP2C9, and recombinant CYP3A4 were carried out to characterize the stereoselective formation of three metabolites: M3 (hydroxyl-ation), M4 (a dihydrodiol metabolite), and M6 (S-dealkylation). The formation of M3 in HLM with atropisomer 1 was approximately twice as much as that with atropisomer 2, whereas formation of M4 with atropisomer 1 was 8- to 12-fold greater than that with atropisomer 2. There were no significant differences in the plasma protein binding among lesinurad and the atropisomers. Following oral administration of 400 mg lesinurad once daily for 14 days to healthy human volunteers, the systemic exposure (Cmax at steady state and area under the concentration-time curve from time zero to the time of dosing interval) of atropisomer 1 was approximately 30% lower than that of atropisomer 2, whereas renal clearance was similar. In vitro cell-based assays using HEK293 stable cells expressing URAT1 and OAT4 demonstrated that atropisomer 2 was approximately 4-fold more potent against URAT1 than atropisomer 1 and equally active against OAT4. In conclusion, lesinurad atropisomers showed stereoselectivity in clinical pharmacokinetics, metabolism, and inhibitory potency against URAT1.
Yang, Chun,Zhou, Dongmei,Shen, Zancong,Wilson, David M.,Renner, Matthew,Miner, Jeffrey N.,Girardet, Jean-Luc,Lee, Caroline A.
p. 104 - 113
(2019)
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RESOLUTION METHOD FOR AXIS CHIRAL ENANTIOMERS OF LESINURAD
A resolution method of axial chiral enantiomers of lesinurad (2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid) adopts inexpensive and readily available quinoline natural products and derivatives thereof, such as quinine, cinchonine, quinidine or cinconidine as resolving agents to react with lesinurad racemate in an organic solvent to form a salt, and the salt is dissociated by acidification so as to obtain optically pure (R)- or (S)-2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid. The method can give axial chiral enantiomer of lesinurad in R configuration with a chiral purity ee of up to 100% and a total yield of 90% or more. The obtained axial chiral enantiomer of lesinurad in S configuration can reach a chiral purity ee of up to 99.9% and a total yield of 80% or more.
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(2021/02/26)

Method for purifying Lesinurad impurity
The invention relates to a method for purifying a Lesinurad impurity. The purification route is shown in the specification. The method is simple and safe in operation, good in yield, high in product purity, good in economic effect and suitable for industrial production.
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(2020/07/12)

Synthesis of lesinurad via a multicomponent reaction with isocyanides and disulfides
An efficient synthesis of Lesinurad a selective uric acid reabsorption (URAT1) inhibitor, is described in this article. The route to synthesis of Lesinurad avoids the use of thiophosgene and the formation of thiols. The key reaction in this synthesis is construction of the 1,2,4-Triazole ring in 72percent yield. The title product is obtained in 45percent yield over 5 steps.
Li, Yaoqi,Sun, Zhihua
supporting information

(2020/07/21)

Refining method of Lesinured
The invention relates to a refining method of Lesinured. The method comprises the following steps: adding a Lesinured crude product into a solvent which is heated to boil, heating to dissolve, addingactivated carbon, filtering, dropwise adding n-hexane, slowly cooling to 35-45 DEG C, crystallizing for 1-2 h, slowly cooling to 0-10 DEG C, crystallizing for 2-3 h, filtering, and drying under reduced pressure to obtain a high-purity finished product. Compared with the prior art, the method provided by the invention has the advantages of good refining effect, common solvent used in the refining process, simple industrial operation, and high yield and purity of the refined target product, and is suitable for industrial mass production.
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Paragraph 0032-0033

(2020/06/05)

Novel Human Urate Transporter 1 Inhibitors as Hypouricemic Drug Candidates with Favorable Druggability
Lesinurad, a human urate transporter 1 (URAT1) inhibitor approved as a medication for the treatment of hyperuricemia associated with gout in 2015, can cause liver and renal toxicity. Here, we modified all three structural components of lesinurad by applying scaffold hopping, bioisosterism, and substituent-decorating strategies. In a mouse model of acute hyperuricemia, 21 of the synthesized compounds showed increased serum uric acid (SUA)-reducing activity; SUA was about 4-fold lower in animals treated with 44, 54, and 83 compared with lesinurad or benzbromarone. In the URAT1 inhibition assay, 44 was over 8-fold more potent than lesinurad (IC50: 1.57 μM vs 13.21 μM). Notably, 83 also displayed potent inhibitory activity (IC50 = 31.73 μM) against GLUT9. Furthermore, we also preliminarily explored the effect of chirality on the potency of the promising derivatives 44 and 54. Compounds 44, 54, and 83 showed favorable drug-like pharmacokinetics and appear to be promising candidates for the treatment of hyperuricemia and gout.
Zhao, Tong,Meng, Qing,Sun, Zhuosen,Chen, Yanyu,Ai, Wei,Zhao, Zean,Kang, Dongwei,Dong, Yue,Liang, Ruipeng,Wu, Ting,Pang, Jianxin,Liu, Xinyong,Zhan, Peng
p. 10829 - 10854
(2020/11/09)

Method for preparing
The reaction of the intermediate, with 1 - bromo - 4 4-cyclopropylnaphthalene and S - (5 - oxo - 4444185-dihydro - 111111111, 2, 4-triazole - 3 3-yl) thiocarboxylic acid ester to obtain the intermediate 3, greatly improves the route efficiency 4, and reduces the process cost 5, and also reduces the production S - of the finished product. The method, is suitable for amplifying and producing; products . The reaction yield is high, obtained by the reaction of the intermediates, through; alkylation reaction with sodium chlorfenac to obtain a Retnatid product according to the present invention as shown in Table, The present invention discloses a method, for producing a. rasid product.
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Paragraph 0051-0053

(2020/03/25)

In Situ Activation of Disulfides for Multicomponent Reactions with Isocyanides and a Broad Range of Nucleophiles
Activation of disulfides with N-halogen succinimide in the presence of TEMPO allows insertion reaction by an isocyanide, the product of which can further accept a wide range of nucleophiles for the generation of isothioureas and related molecular moieties. This new procedure overcomes previous methods that accept essentially only aryl amines as the third nucleophilic component. The diverse nucleophiles usable in our new protocol make this approach a general method for de novo synthesis of many S-containing heterocycles.
Lei, Xiaofang,Wang, Yuanyuan,Fan, Erkang,Sun, Zhihua
supporting information
p. 1484 - 1487
(2019/02/26)

Preparation method of Lesinurad
The invention discloses a preparation method of Lesinurad, and belongs to the technical field of chemical drug synthesis. A compound of the formula Les-03 in the description is prepared from compoundsshown in formulas Les-01 and Les-02 as raw materials, a compound of the formula Les-04 is added, and a compound of the formula Les-05 is prepared. The compound of the Les-05 has high selectivity during coupling, so that the purity of a reaction product is high, post-treatment is facilitated, and quality of an obtained final product is controllable; the compound in Les-07 is prepared from the compound in Les-05 and the compound in Les-06 by Suzuki coupling reaction, the Suzuki coupling reaction has high reliability and good repeatability, and finally Lesinurad is obtained through protecting group removal. The preparation method has the advantages of short process route, high yield and low cost; adopted reagents are non-toxic or low-toxic conventional reagents, and are basically harmless tooperators and basically pollution-free to the environment; the whole process is simple and convenient to operate, the process stability is good, the quality of the obtained final product is controllable and stable, and the method is suitable for commercial production.
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Paragraph 0064-0066; 0080-0082; 0096-0098

(2018/05/16)

Preparation method of Roxadustat
The invention discloses a preparation method of Roxadustat. The chemical name of Roxadustat is 2-[[5-bromo-4-(4-cyclopropyl-1-naphthalene)-4H-1,2,4-triazole-3-yl] sulfo] acetic acid. The molecular formula is C17H14BrN3O2S. The preparation process is concise, raw materials are easily available and the preparation process is economical and environmentally friendly, industrialization is achieved favorably, the economical technical development of bulk pharmaceutical chemicals of Roxadustat can be promoted, the production cost is lowered, the yield is high, the environmental pollution is slight, and the method is suitable for large-scaled production.
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Paragraph 0011; 0012; 0013

(2018/04/28)

Identification of an Unexpected Impurity in a New Improved Synthesis of Lesinurad
An unexpected phenomenon concerning an otherwise common impurity of lesinurad has been observed in the context of synthetic process development. A new industrial process was designed as a chlorine-free process, but the critical chlorinated impurity 10 was surprisingly detected in the isolated product. Because of the structural similarity of the impurity and the product, no efficient separation of 10 by conventional methods (e.g., crystallization) was discovered. The formation of the impurity was explained by a chlorine impurity in a commercial brominating agent. This communication also describes control of the critical impurity.
Halama, Ale?,Stach, Jan,Rádl, Stanislav,Benediktová, Kristyna
p. 1861 - 1867
(2019/01/04)

Processes for the Preparation of Lesinurad and Intermediates Thereof
The present invention provides processes for the preparation of Lesinurad (1), as well as intermediates useful in the preparation thereof. In particular, the processes of the invention utilize novel intermediate compounds of Formulas (3) and (11), which provide improvements over the known processes for the preparation of Lesinurad (1).
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Paragraph 0230-0231

(2018/10/04)

Preparing method of Lesinurad impurities
The invention belongs to the technical field of medicines, and relates to a preparing method of Lesinurad impurities. The preparing method includes the following steps of firstly, making 5-bromo-4-(4-cyclopropyl naphthalene-1-yl)-4H-1,2,4-triazolyl-3-thiol as the initial raw material have a substitution reaction with 2,2-methyl dibromoacetate(ethyl ester and other esters); secondly, making the obtained product have a hydrolysis reaction with a water solution of lithium hydrate to obtain 2-bromo-2-((5-bromo-4-(4-cyclopropyl naphthalene-1-yl)-4H-1,2,4-triazolyl-3-yl)sulfo)acetic acid.
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(2018/06/28)

Preparation method for Lesinurd and intermediate of Lesinurd
The invention provides a preparation method for Lesinurd and an intermediate of Lesinurd. A compound (IV) is reacted with a compound (V) under an alkali action in a solvent to prepare a compound (III). The compound (III) is reacted with a brominated reagent under a suitable catalyst to obtain a compound (II). The compound (II) is hydrolyzed under base catalysis in the solvent to obtain salt of a compound (I), then crystals are acidized by using an acidizing reagent to obtain a crude product of the compound (I). The crude product of the compound (I) is recrystallized to obtain a quality productof the compound (I) which is a qualified product. The invention further discloses structural formulae and preparation methods of the compound (III) and the compound (II). The Lesinurd disclosed by the invention is simple and convenient in post-processing, less in waste gas, waste water and waste residues and beneficial to industrial production.
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(2018/04/03)

NOVEL CRYSTALLINE FORMS OF LESINURAD
The present invention provides novel crystalline forms of Lesinurad, pharmaceutical compositions comprising these crystalline forms, and their use in the treatment of hyperuricemia associated with gout. Specific crystalline forms provided by the present invention include Lesinurad Forms APO-I, a hemi- methanolate, APO-II, a hemi-ethanolate, and APO-III, a co-crystal of Lesinurad and nicotinamide.
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Paragraph 0032; 0066

(2018/05/27)

Preparation method of lesinurad
The invention discloses a preparation method of lesinurad. The method comprises: allowing 1-cyclopropylnaphthalene-4-yl isorhodanate and acethydrazide to undergo an addition reaction, allowing the obtained 4-acetyl-1-(4-cyclopropylnaphthalene-1-yl) thiosemicarbazide to undergo a cyclization reaction in the function of an alkali reagent, allowing the obtained 4-(4-cyclopropylnaphthalene-1-yl)-5-methyl-4H-1,2,3-triazole-3-mercaptan and methyl chloroacetate (or methyl bromoacetate) to undergo a condensation reaction, allowing the obtained 2-{[4-(4-cyclopropylnaphthalene-1-yl)-5-methyl-4H-1,2,4-triazole-3-yl]sulfo} methyl acetate to undergo an oxidation reaction, allowing the obtained 5-[(methoxycarbonyl)methylthio]-4-(4-cyclopropylnaphthalene-1-yl)-4H-1,2,4-triazole-3-carboxylic acid undergo a bromination reaction, and carrying out an esterolysis reaction to obtain lesinurad. The method is reasonable and simple in technical route, simplified in operation and low in cost. The method is green and eco-friendly and suitable for industrial production.
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(2017/08/29)

Resolving method of medicine lesinurad axial chiral enantiomer
The invention discloses a resolving method of a medicine lesinurad axial chiral enantiomer. An alkamine derivative with optical activity is used as a resolving agent and reacts with a lesinurad racemic body in an organic solvent to form salts; the salts are dissociated to obtain (R)- or (S)-2-(5-bromo-4-(4-cyclopropylnaphthalene-1-yl-4H-1,2,4-triazole-3-sulfenyl)acetic acid with optical activity is obtained. By the method, an S configuration axial chiral enantiomer and an R configuration axial chiral enantiomer with the optical activity ee reaching 93 percent or higher can be obtained.
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(2017/09/08)

Discovery and Assessment of Atropisomers of (±)-Lesinurad
(+)- and (?)-Lesinurad were isolated as atropisomers from racemic lesinurad for the first time. No interconversion was observed between the two atropisomers under various conditions tested. The two atropisomers showed significant differences in hURAT1 highly expressed HEK293 cell-based inhibition assays, monkey pharmacokinetic studies, and in vitro human recombinant CYP2C9 stability studies. It was speculated that (+)-lesinurad might offer a better hyperuricemia/gout therapy than (?)-lesinurad or the racemate.
Wang, Jianfei,Zeng, Wenqin,Li, Shaohua,Shen, Liang,Gu, Zhengxian,Zhang, Yang,Li, Jian,Chen, Shuhui,Jia, Xiangbo
p. 299 - 303
(2017/03/17)

Synthetic method of Lesinurad
The invention relates to a synthetic method of Lesinurad. The method comprises the following steps: carrying out a nucleophilic addition reaction on an initial raw material 1-cyclopropylnaphthalene-4-yl-isorhodanate (compound 7) and methyl hydrazinocarboxylate to generate a compound 6, cyclizing the compound 6 under the action of sodium hydroxide to generate a compound 5, carrying out a condensation reaction on the compound 5 and a compound 4 to remove one molecule of halogen hydride in order to generate a compound 3, brominating the compound 3 to generate a compound 2, and hydrolyzing the compound 2 under the action of an alkali to obtain the target product Lesinurad. The preparation method is simple and easy; the compound 2 is prepared through carrying out the nucleophilic addition reaction on the hydroxyl group of the compound 3 by an introduced bromine atom, so generation of an alpha-bromocarboxylic acid impurity in the target product is avoided; the purity of the reaction product is high and reaches 99.5% or above; side reactions are few, so the yield of the target product is high and reaches 96%; and most raw materials used in the whole preparation process are nontoxic, so industrial production of the target product is conveniently realized.
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(2017/07/21)

Modulators of a uric acid preparation method and its intermediate
The invention relates to a purification method of a compound as shown in the formula (I). The purification method comprises the steps of (1) reacting the low-purity compound as shown in the formula (I) with organic amine of a compound as shown in the form
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Paragraph 0091; 0092; 0093; 0094; 0095; 0096

(2017/04/12)

A LESINURAD, FREE FORM / LESINURAD ETHYL ESTER CO-CRYSTAL
The present disclosure relates to a co-crystal comprising 2-[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylsulfanyl]acetic acid (lesinurad, free form) and ethyl-2-[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylsulfanyl]acetate (lesinurad ethyl ester). The present disclosure also generally relates to the use of a lesinurad, free form / lesinurad ethyl ester co-crystal for the preparation of amorphous lesinurad.
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Page/Page column 18

(2017/03/28)

Preparing method of triazole thioglycolic acid compound for curing metabolic arthritis
The invention discloses a preparing method of a triazole thioglycolic acid compound for curing metabolic arthritis. According to the method, compound II and compound III are utilized as initial materials and are generated into intermediate compound IV through Suzuki reaction; then nucleophilic substitution happens between the intermediate compound IV and 1,1minute-thiocarbonyl polypyridobisinudazole to generate intermediate compound V; the compound V generates intermediate compound VI through cyclization reaction, and then nucleophilic substitution happens between the compound VI and methyl chloroacetate to generate intermediate compound VII; the intermediate compound VII generates intermediate compound VIII through bromination reaction; and a target product 2-((5-bromine-4-(4-cyclopropyl naphthalene-1-yl)-4H-1,2,4-triazole-3-yl)sulfenyl) acetic acid (I) is generated through hydrolysis reaction. The preparing method is high in selectivity and simple to operate and avoids poisonous reagents and rigorous reacting conditions. Compared with an original synthetic method, the reacting time of the preparing method is shortened, the energy consumption is reduced, and the reaction yield is improved.
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Paragraph 0075; 0076; 0077

(2016/10/09)

Optically pure thioacetic compound
The invention belongs to the field of pharmacy and relates to an optically pure thioacetic compound and application thereof to medicine. The optically pure thioacetic compound comprises levorotatory 2-(5-bromo-4-(4-cyclopropyl-naphthalene-1-base)-4H-1,2,4-triazole-3-based sulfenyl) acetic acid and dextral 2-(5-bromo-4-(4-cyclopropyl-naphthalene-1-base)-4H-1,2,4-triazole-3-based sulfenyl) acetic acid.
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Paragraph 0045; 0046; 0047

(2016/12/26)

Axial chiral isomers and preparation method and pharmaceutical application thereof
The invention discloses two axial chiral isomers, available medicinal salts thereof, a preparation method thereof, and pharmaceutical application of the two axial chiral isomers or medicinal compositions thereof.
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Paragraph 0132; 0133; 0134; 0135

(2016/10/10)

Axially chiral enantiomers of drug Lesinurad
The invention discloses an axially chiral R-enantiomer and an axially chiral S-enantiomer of the drug Lesinurad. The axially chiral R-enantiomer shows excellent URAT1 inhibition effect, overcomes the problems that a high dosage of Lesinurad racemate leads to renal toxicity and a low dosage Lesinurad racemate cannot produce additional drug effect, and can be applied to treatment or prevention of symptoms of abnormal tissue uric acid levels.
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(2016/10/08)

AMORPHOUS AND AMORPHOUS SOLID DISPERSION OF LESINURAD AND THEIR PREPARATION
The present invention provides amorphous form of lesinurad, amorphous solid dispersion of lesinurad and processes for preparation thereof. The present invention also provides a pharmaceutical composition comprising amorphous or amorphous solid dispersion of lesinurad and one or more pharmaceutically acceptable excipient or carrier.
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Page/Page column 13

(2017/01/02)

THIO-1,2,4-TRIAZOLE DERIVATIVES AND METHOD FOR PREPARING THE SAME
Provided is a process for preparing a compound shown as formula (I), comprising a step of contacting a compound shown as formula (II) or a salt thereof with a brominating agent, wherein R1is OR2 or NR3R4; R2 is C1-C6 alkyl or phenyl; each R3, R4 is independently H, C1-C6 alkyl or cycloalkyl, wherein C1-C6 alkyl, cycloalkyl, or phenyl is optionally further substituted by F, Cl, Br, CH3 or CF3. A process for preparing a compound shown as formula (II), a process for preparing a compound shown as formula (V), a process for preparing a compound shown as formula (III), and an intermediate compound as shown as formula (IIa) or formula (Ib) are also provided.
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Paragraph 077-078

(2015/01/09)

MANUFACTURE OF 2- (5- BROMO-4 (-CYCLOPROPYLNAPHTHALEN-1-YL) -4H-1,2,4-TRIAZOL-3-YLTHIO) ACETIC ACID
Described herein are certain processes for the synthesis of compounds of Formula (I):
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Paragraph 0340-0344

(2014/01/18)

POLYMORPHIC FORMS OF 2-(5-BROMO-4-(4-CYCLOPROPYLNAPHTHALEN-1-YL)-4H-1,2,4-TRIAZOL-3-YLTHIO)ACETIC ACID AND USES THEREOF
Crystalline polymorph forms of 2-(5-bromo-4-(4-cyclopropyl naphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid are described. Pharmaceutical compositions and the uses of such compounds, compound forms, and compositions for the treatment of a variety of diseases and conditions are also presented.
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Page/Page column 12

(2012/07/14)

POLYMORPHIC, CRYSTALLINE AND MESOPHASE FORMS OF SODIUM 2-(5-BROMO-4-(4-CYCLOPROPYLNAPHTHALEN-1-YL)-4H-1,2,4-TRIAZOL-3-YLTHIO)ACETATE, AND USES THEREOF
Crystalline polymorphs and solid mesophase forms of sodium 2-(5-bromo-4- (4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-ylthio)acetate are described. In addition, pharmaceutical compositions and uses of such compositions for the treatment of a variety of diseases and conditions are provided.
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Page/Page column 38-39

(2011/08/03)

NOVEL COMPOUNDS AND COMPOSITIONS AND METHODS OF USE
Described herein are compounds useful in the modulation of blood uric, acid levels, formulations containing them and methods of using them. In some embodiments, the compounds described herein are used in the treatment or prevention of disorders relafed to aberrant levels of uric acid
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Page/Page column 91

(2009/07/03)

S-TRIAZOLYL α-MERCAPTOACETANILDES AS INHIBITORS OF HIV REVERSE TRANSCRIPTASE
A series of S-triazolyl α-mercaptoacetanilides having general structure (1) are provided, where Q is CO2H, CONR2, SO3H, or SO2NR2. The compounds inhibit several variants of the reverse transcriptase of HIV, and are useful in the treatment of HIV infections.
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Page/Page column 24

(2010/10/20)