- Discovery of dronedarone and its analogues as NLRP3 inflammasome inhibitors with potent anti-inflammation activity
-
Inhibiting NLRP3 inflammasome activation is a prospective therapeutic strategy for uncontrolled inflammatory diseases. It is the first time that dronedarone, a multiply ion channel blocker, was identified as a NLRP3-inflammasome inhibitor with an IC50 value of 6.84 μM against IL-1β release. A series of novel 5-amide benzofuran derivatives were designed and synthesized as NLRP3-inflammasome inhibitors. Compound 8c showed slightly increased activity (IC50 = 3.85 μM) against IL-1β release. Notably, treatment with 8c could significantly inhibit NLRP3-mediated IL-1β release and ameliorate peritoneal inflammation in a mouse model of sepsis. Collectively, 8c is a promising lead compound for further chemical development as a NLRP3 inhibitor with anti-inflammation effects.
- Chen, Hao,Chen, Xiuhui,Sun, Ping,Wu, Dan,Yue, Hu,Pan, Jintao,Li, Xinxuan,Zhang, Cheng,Wu, Xinyi,Hua, Lei,Hu, Wenhui,Yang, Zhongjin
-
-
- Benzofuran compound and application thereof
-
The invention provides a benzofuran compound as shown in a formula (I) or pharmaceutically acceptable salt thereof, and application thereof. The compound can selectively inhibit activation of NLRP3 inflammasomes and inhibit maturation and secretion of inflammation activation signal molecules Caspase-1 and P20 and inflammatory cytokines IL-1beta, has a good prevention and treatment effect on NLRP3 inflammasome related diseases, and particularly has a remarkable prevention and treatment effect on peritonitis and gouty arthritis. Therefore, the compound can be used for preparing drugs for treating NLRP3 inflammasome-related diseases, such as anti-inflammatory drugs or auxiliary anti-inflammatory drugs.
- -
-
-
- Preparation method of key intermediate of dronedarone
-
The invention relates to a preparation method of a key intermediate of drug dronedarone for treating atrial fibrillation, and specifically relates to the 2-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran. According to the method provided by the invention, a series of reactions are performed by using inexpensive p-nitrophenol as a starting material to prepare the 2-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran, the process is smooth, the costs are lower, the yield is higher, the controllability is stronger, and the method is suitable for industrial production.
- -
-
-
- Efficient Syntheses of Diverse, Medicinally Relevant Targets Planned by Computer and Executed in the Laboratory
-
The Chematica program was used to autonomously design synthetic pathways to eight structurally diverse targets, including seven commercially valuable bioactive substances and one natural product. All of these computer-planned routes were successfully executed in the laboratory and offer significant yield improvements and cost savings over previous approaches, provide alternatives to patented routes, or produce targets that were not synthesized previously. Although computers have demonstrated the ability to challenge humans in various games of strategy, their use in the automated planning of organic syntheses remains unprecedented. As a result of the impact that such a tool could have on the synthetic community, the past half century has seen numerous attempts to create in silico chemical intelligence. However, there has not been a successful demonstration of a synthetic route designed by machine and then executed in the laboratory. Here, we describe an experiment where the software program Chematica designed syntheses leading to eight commercially valuable and/or medicinally relevant targets; in each case tested, Chematica significantly improved on previous approaches or identified efficient routes to targets for which previous synthetic attempts had failed. These results indicate that now and in the future, chemists can finally benefit from having an “in silico colleague” that constantly learns, never forgets, and will never retire. Multistep synthetic routes to eight structurally diverse and medicinally relevant targets were planned autonomously by the Chematica computer program, which combines expert chemical knowledge with network-search and artificial-intelligence algorithms. All of the proposed syntheses were successfully executed in the laboratory and offer substantial yield improvements and cost savings over previous approaches or provide the first documented route to a given target. These results provide the long-awaited validation of a computer program in practically relevant synthetic design.
- Klucznik, Tomasz,Mikulak-Klucznik, Barbara,McCormack, Michael P.,Lima, Heather,Szymku?, Sara,Bhowmick, Manishabrata,Molga, Karol,Zhou, Yubai,Rickershauser, Lindsey,Gajewska, Ewa P.,Toutchkine, Alexei,Dittwald, Piotr,Startek, Micha? P.,Kirkovits, Gregory J.,Roszak, Rafa?,Adamski, Ariel,Sieredzińska, Bianka,Mrksich, Milan,Trice, Sarah L.J.,Grzybowski, Bartosz A.
-
p. 522 - 532
(2018/03/21)
-
- Microwave-assisted synthesis of (2-butyl-5-nitrobenzo[b]furan-3-yl)-[4-(substituted ethynyl)phenyl]methanones
-
We report a new method for the efficient and rapid synthesis of (2-butyl-5-nitrobenzo[b]furan-3-yl)[4- (substituted ethynyl)phenyl]methanones using a Pd-Cu catalyzed microwave-assisted Sonogashira coupling reaction. In comparison to the conventional heating procedure, the time of synthesis and effort are significantly reduced in the present method, without side-product formation. Microwave irradiation considerably accelerated the formation of (2-butyl-5-nitrobenzo[b]furan-3-yl)[4-(substituted ethynyl)phenyl]methanone analogues.
- Parmar, Nilesh D.,Hadiyal, Sanjay D.,Kapupara, Vimal H.,Joshi, Hitendra S.
-
p. 143 - 153
(2018/10/26)
-
- Identification and characterization of potential impurities of dronedarone hydrochloride
-
Six potential process related impurities were detected during the impurity profile study of an antiarrhythmic drug substance, Dronedarone (1). Simple high performance liquid chromatography and liquid chromatography-mass spectrometry methods were used for the detection of these process impurities. Based on the synthesis and spectral data (MS, IR, 1H NMR, 13C NMR, and DEPT), the structures of these impurities were characterized a s 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butylbenzofuran (impurity I); N-(2-butyl-3-(4-(3-(dibutylamino)propoxy)-benzoyl)benzofuran-5-yl)-N- (methylsulfonyl)-methanesulfonamide (impurity II); N-(2-butyl-3-(4-(3- (dibutylamino)propoxy)benzoyl)benzofuran-5-yl)-1-chloromethanesulfonamide (impurity III); N-{2-propyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran-5-yl} - methanesulfonamide (impurity IV); N-(2-butyl-3-(4-(3-(dibutylamino)propoxy) benzoyl)benzofuran-5-yl)-formamide (impurity V); and (2-butyl-5-((3- (dibutylamino)propyl)amino)benzofuran-3-yl)(4-(3- (dibutylamino)propoxy)phenyl) methanone (impurity VI). The synthesis and characterization of these impurities are discussed in detail.
- Mahender,Saravanan,Sridhar,Chandrashekar,Kumar, L. Jaydeep,Jayashree,Bandichhor, Rakeshwar
-
p. 157 - 162
(2014/05/20)
-
- An improved and efficient process for the production of dronedarone hydrochloride, an antiarrhythmia drug
-
An improved, high-yielding, and efficient process for the production of dronedarone hydrochloride (1), a class III antiarrhythmia drug for the prevention of cardiac arrhythmias such as atrial fibrillation (AF) is described. The developed process avoids isolation of unstable intermediates at several stages by telescoping the steps upon individual optimization, thereby minimizing the turnaround time of the batch cycle and increasing the throughput. Potential impurities (byproducts) arise during the reaction at various stages, and carry-over impurities from starting materials were controlled selectively by designing reaction conditions and suitable workup procedures, resulting in an increased overall yield from 33% (as per processes reported in the literature) to 66%.
- Mali, Anil C.,Ippar, Sharad S.,Bodke, Mahendra B.,Patil, Nilesh S.,Mathad, Vijayavitthal T.
-
p. 863 - 868
(2013/07/28)
-
- An alternative approach to synthesis of 2-n-butyl-5-nitrobenzofuran derivative: A key starting material for dronedarone hydrochloride
-
A practical synthesis of (2-butyl-5-nitrobenzofuran-3-yl)(4-hydroxyphenyl) methanone, a key intermediate in the preparation of anti arrhythmic drug, is described. The commercially available 4-nitrophenol (3) is converted in five steps to 2-butyl-5-nitrobenzofuran (9) which upon Friedel-Crafts acylation with 4-methoxybenzoyl chloride followed by deprotection of methyl group gives (2). Indian Academy of Sciences.
- Gopal, P. Raja,Chandrashekar,Saravanan,Bhaskar, B. Vijaya,Somaiah, P. Veera
-
p. 1077 - 1085
(2013/03/13)
-
- PROCESSES FOR PREPARING DRONEDARONE AND ITS INTERMEDIATES
-
The invention relates to process for the preparation of benzofuran derivative and intermediates thereof. More particularly, it relates to processes for the preparation of dronedarone or pharmaceutically acceptable acid addition salts thereof in crystalline form. The invention also relates to pharmaceutical compositions that include the dronedarone hydrochloride in crystalline form substantially free from disulfonamide impurity.
- -
-
-
- PROCESS FOR PREPARING 2-ALKYL-3-AROYL-5-NITRO-BENZOFURANS
-
The present invention relates to a process for the preparation of a compound of formula wherein R1 is selected from C1-6-alkyl, C3-6-cycloalkyl and aralkyl, and wherein R2 at each occurrence independently is halogen or C1-6-alkyl, and m is an integer from 0 to 4, Q is selected from halogen, —NO2 and —NR3R4, wherein R3 and R4 are independently selected from hydrogen, C1-6-alkyl, C3-6-cycloalkyl, aryl, aralkyl, mesyl and tosyl, or wherein R3 and R4 together form a C4-6-alkylene group, Y at each occurrence is hydrogen or a hydroxy protection group W that can be hydrolytically cleaved under acidic conditions, and n is an integer from 1 to 3, and n is an integer from 1 to 3, with the proviso that n and m together are not greater than 5.
- -
-
-
- A Novel and efficient synthesis of dronedarone hydrochloride, an antiarrhythmic drug substance
-
A novel and efficient synthesis of dronedarone hydrochloride starting from 2-n-butyl-5-nitrobenzofuran by employing mild and selective reaction conditions is described. The synthetic approach is operationally simple and suitable for industrial application.
- Mohanarangam, Saravanan,Satyanarayana, Bollikonda,Elati, Chandrashekar R.,Vijayabhaskar, Bolugoddu,Reddy, Padi Pratap
-
p. 841 - 845
(2012/02/05)
-
- PROCESS FOR PREPARING 2-ALKYL-3-AROYL-5-NITRO-BENZOFURANS
-
The present invention relates to a process for the preparation of a compound of formula (I), wherein R1 is selected from C1-6-alkyl, C3-6-cycloalkyl and aralkyl, and wherein R2 at each occurrence independently is halogen or C1-6-alkyl, and m is an integer from 0 to 4, Q is selected from halogen, -NO2 and -NR3R4, wherein R3 and R4 are independently selected from hydrogen, C1-6-alkyl, C3-6-cycloalkyl, aryl, aralkyl, mesyl and tosyl, or wherein R3 and R4 together form a C4-6-alkylene group, Y at each occurrence is hydrogen or a hydroxy protection group W that can be hydrolytically cleaved under acidic conditions, and n is an integer from 1 to 3, and n is an integer from 1 to 3, with the proviso that n and m together are not greater than 5.
- -
-
Page/Page column 23
(2010/04/28)
-
- Process for preparing 2-Alkyl-3-aroyl-5-nitro-benzofurans
-
The present invention relates to a process for the preparation of a compound of formula wherein R1 is selected from C1-6-alkyl, C3-6-cycloalkyl and aralkyl, and wherein R2 at each occurrence independently is halogen or C1-6-alkyl, and m is an integer from 0 to 4, Q is selected from halogen, -NO2 and -NR3R4, wherein R3 and R4 are independently selected from hydrogen, C1-6-alkyl, C1-6-cycloalkyl, aryl, aralkyl, mesyl and tosyl, or wherein R3 and R4 together form a C4-6-alkylene group, Y at each occurrence is hydrogen or a hydroxy protection group W that can be hydrolytically cleaved under acidic conditions, and n is an integer from 1 to 3, and n is an integer from 1 to 3, with the proviso that n and m together are not greater than 5.
- -
-
Page/Page column 14
(2010/11/17)
-
- NEW PROCESS FOR PREPARING HYDROXYLAMINES AND MEDICAMENTS
-
There is provided a process for the preparation of a compound of formula (II), wherein R1, R2, R3 and R4 are as described in the description. Such compounds may, for example, be useful intermediates in the synthesis of drugs such as Dronedarone.
- -
-
Page/Page column 53
(2010/11/03)
-
- PROCESS FOR THE PRODUCTION OF DRONEDARONE INTERMEDIATES
-
A process for the production of Dronedarone intermediates of the formula (I), by acylation of 2-(2-hydroxy-5-nitrophenyl)-1-(4-methoxyphenyl)-ethanone, subsequent treatment of the ester with bases and a zeolite (alumosilicate) catalyst and optional subsequent demethylation. This process can be used for the production of Dronedarone.
- -
-
Page/Page column 20
(2010/12/26)
-
- NEW PROCESS FOR PREPARING DIKETONES AND MEDICAMENTS
-
There is provided a process for the preparation of a compound of formula (III), wherein X and Y are as described in the description. Such compounds may, for example, be useful intermediates in the synthesis of drugs such as Dronedarone. There is also provided a process for the preparation of a compound of formula (I).
- -
-
Page/Page column 42
(2010/04/27)
-
- PROCESS FOR PREPARING BENZOFURANS
-
There is provided a process for the preparation of a compound of formula (I), wherein R1, R2, R3, R4, X and Y are as described in the description. Such compounds may, for example, be useful intermediates in the synthesis of drugs such as Dronedarone.
- -
-
Page/Page column 39-40
(2009/05/29)
-
- Method for Acylation of an Aromatic Compound
-
A method for acylation of an aromatic compound, comprising reacting an aromatic compound and an acylating agent of the carboxylic acid type, in the presence of a Lewis acid and of a silylated reagent selected from the group consisting of halosilanes and halosiloxanes.
- -
-
Page/Page column 7-9
(2008/12/06)
-
- PROCESS FOR THE PREPERATION OF N-ALKYL-2(HYDROXY-4 BENZOYL)-3 BENZOFURANS AND ITS INTERMEDIATES THEREOF
-
Process for the preparation of a 2-(n-alkyl)-3-(4-hydroxybenzoyl)benzofuran of formula (I) in which R represents a linear or branched alkyl radical including from 1 to 5 carbon atoms and R1 represents a linear or branched alkyl radical including from 1 to 3 carbon atoms, a linear or branched alkoxy radical including from 1 to 3 carbon atoms, a halogen atom or a nitro radical, and intermediates.
- -
-
Page/Page column 11-12
(2008/06/13)
-
- Alkylaminoalkyl derivatives of benzofuran, benzothiophene, indole and indolizine, process for their preparation and compositions containing them
-
The subject of the invention is benzofuran, benzothiophene, indole or indolizine compounds of general formula: STR1 in which: Het represents one of the groups: STR2 in which T,T' and T"represent particularly a group: STR3 R and Ra, identical or different, represent X represent --O-- or --S-- Y represents a radical STR4 These compounds are useful as medecines particularly for the treatment of pathological syndroms of the cardio-vascular system.
- -
-
-