- A highly efficient way to recycle inactive stereoisomers of Bedaquiline into two previous intermediates via base-catalyzed Csp3Csp3 bond cleavage
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Abstract Bedaquiline is a new medicine for pulmonary multi-drug resistant tuberculosis (MDR-TB), which is a pure enantiomer with two chiral centers. The current industrial preparation process requires the separation of active Bedaquiline from a mixture of four isomers. Obviously, direct dispose of the other three undesired stereoisomers will cause significant waste and increase the unnecessary cost of production. Here, we developed an efficient, facile and scalable process for recycling the inactive stereoisomers of Bedaquiline. All these inactive stereoisomers could be recycled by their conversion to two important intermediates in the Bedaquiline synthesis via a base-catalyzed Csp3Csp3 bond cleavage of a benzyl alcohol intermediate. And the precise conditions and mechanism of the base-catalyzed cleavage reaction were discussed.
- Kong, De-Long,Huang, Ye,Ren, Lai-Yang,Feng, Wen-Hua
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Read Online
- Design, synthesis and biological evaluation of novel triaryldimethylaminobutan-2-ol derivatives against Mycobacterium tuberculosis
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Bedaquiline (TMC207), a typical diarylquinoline anti-tuberculosis drug, has been approved by FDA to specifically treat MDR-TB. Herein we describe design, synthesis, and in vitro biological evaluation against Mycobacterium tuberculosis of a series of triaryldimethylaminobutan-2-ol derivatives obtaining from the structural modification of TMC207. Compounds 23, 25, 28, 32, 39 and 43 provided superior anti-mycobacterial activity than positive control PC01 which shows the same configuration and contains TMC207. Compounds 16, 20, 29, 34, 37, 45 and 47 exhibited the similar activity to positive control PC01. Most importantly, the series of compounds showed excellent activity against XDR-Mtb. The result of acute toxicity suggested that this class of triaryldimethylaminobutan-2-ol derivatives should be graded as low. Further SAR analysis indicates that a large steric bulk of triaryl and 7-Br, 3-OCH3 on 1-naphthyl are critical.
- Cao, Ruiyuan,Fan, Shiyong,Li, Song,Liu, Ping,Lu, Yu,Wang, Bin,Wang, Xiaokui,Zhong, Wu
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- SMALL MOLECULE CMKLR1 ANTAGONISTS IN INFLAMMATORY DISEASE
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α-NETA analogs are provided for the treatment of inflammatory disease.
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Paragraph 0199; 0230; 0232
(2020/12/01)
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- New 1-(2-chloroquinolin-3-yl)-4-dimethylamino-2-(naphthalen-1-yl)-1-phenylbutan-2-ols with antituberculosis activity
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New 4-dimethylamino-2-(naphthalen-1-yl)-1-phenyl-1-(quinolin-3-yl)butan-2-ols with antituberculosis activity were synthesized. (1R*,2S*)-1-(6-Bromo-2-chloroquinolin-3-yl)-4-dimethylamino-2-(naphthalen-1-yl)-1-phenylbutan-2-ol hydrocitrate exhibiting high
- Omel’kov,Fedorov,Stepanov
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p. 1908 - 1918
(2019/10/22)
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- 6-Cyano Analogues of Bedaquiline as Less Lipophilic and Potentially Safer Diarylquinolines for Tuberculosis
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Bedaquiline (1) is a new drug for tuberculosis and the first of the diarylquinoline class. It demonstrates excellent efficacy against TB but induces phospholipidosis at high doses, has a long terminal elimination half-life (due to its high lipophilicity), and exhibits potent hERG channel inhibition, resulting in clinical QTc interval prolongation. A number of structural ring A analogues of bedaquiline have been prepared and evaluated for their anti-M.tb activity (MIC90), with a view to their possible application as less lipophilic second generation compounds. It was previously observed that a range of 6-substituted analogues of 1 demonstrated a positive correlation between potency (MIC90) toward M.tb and drug lipophilicity. Contrary to this trend, we discovered, by virtue of a clogP/M.tb score, that a 6-cyano (CN) substituent provides a substantial reduction in lipophilicity with only modest effects on MIC values, suggesting this substituent as a useful tool in the search for effective and safer analogues of 1.
- Tong, Amy S. T.,Choi, Peter J.,Blaser, Adrian,Sutherland, Hamish S.,Tsang, Sophia K. Y.,Guillemont, Jerome,Motte, Magali,Cooper, Christopher B.,Andries, Koen,Van Den Broeck, Walter,Franzblau, Scott G.,Upton, Anna M.,Denny, William A.,Palmer, Brian D.,Conole, Daniel
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supporting information
p. 1019 - 1024
(2017/10/18)
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- PYRIDINE DERIVATIVES AND APPLICATION OF ANTI-MACOBACTERIUM THEREOF
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The present invention provides a series of pyridine derivatives and their preparation method and application thereof. The series of pyridine derivatives can be applied to treating mycobacterium-related diseases, especially to treatments of fatal mycobacterium-related diseases. The fatal diseases may be related to mycobacterium tuberculosis, mycobacterium bovis, mycobacterium avium, and mycobacterium marinum.
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Paragraph 0342; 0343
(2016/10/08)
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- AROMATIC BUTAN-2-OL COMPOUNDS, PREPARATION METHODS AND USES THEREOF
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The present invention relates to aromatic butan-2-ol compounds and preparation methods and uses thereof. Specifically, the present invention relates to the compound of Formula I, or an optical isomer, racemate, diastereomer, pharmaceutically acceptable salt or solvate thereof: wherein each of the substituents have the definitions as given in the specification. The present invention further relates to a pharmaceutical composition containing the compound, and the use of the compound in manufacture of a medicament for the treatment and/or prophylaxis of a disease or disorder caused by tubercle bacillus infection. The compound of Formula I of the present invention has advantages in treatment and/or prophylaxis of a disease or disorder caused by tubercle bacillus infection.
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Paragraph 0065; 0066
(2013/04/10)
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- NEW QUINOLINE DERIVATIVES, A METHOD FOR THE PRODUCTION AND THE USE THEREOF FOR TREATING MICROBACTERIAL INFECTIONS AND A PHARMACEUTICAL COMPOSITION BASED ON SAID DERIVATIVES
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The invention relates to the new derivatives of the quinoline, their stereoisomers or mixtures in any proportion, pharmaceutically acceptable acidic or basic additive salts, including solvates that have the mycobacterial activity, to the process of their
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Page/Page column 7
(2011/10/13)
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- Synthesis and pharmacological evaluation of 3-aryl-3-azolylpropan-1-amines as selective triple serotonin/norepinephrine/dopamine reuptake inhibitors
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A series of 3-aryl-3-azolylpropan-1-amines was prepared and screened for its capability of inhibiting monoamine reuptake. Analogs with nanomolar potency, good human in vitro microsomal stability, and low drug-drug interaction potential were described. In
- Lee, Ki-Ho,Park, Chun-Eung,Min, Kyung-Hyun,Shin, Yong-Je,Chung, Coo-Min,Kim, Hui-Ho,Yoon, Hae-Jeoung,Won-Kim,Ryu, Eun-Ju,Shin, Yu-Jin,Nam, Hyun-Sik,Cho, Jeong-Woo,Lee, Hee-Yoon
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scheme or table
p. 5567 - 5571
(2010/12/29)
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- PROCESS FOR PREPARING (ALPHA S, BETA R)-6-BROMO-ALPHA-[2-(DIMETHYLAMINO)ETHYL]-2-METHOXY-ALPHA-1-NAPHTHALENYL-BETA-PHENYL-3-QUINOLINEETHANOL
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The present invention relates to a process for isolating (αS, βR)-6-bromo-α-[2-(dimethylamino)ethyl]-2-methoxy-α-1-naphthalenyl-β-phenyl-3-quino lineethano l from a mixture of stereoisomeric forms of 6-bromo-α-[2-(dimethylamino)ethyl]-2-methoxy-α-1-naphthalenyl-β-phenyl-3-quino lineethano l by optical resolution with chiral 4-hydroxydinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin 4-oxide or a derivative thereof, in particular (11bR)-4-hydroxydinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin 4-oxide, as resolution agent.
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Page/Page column 20
(2010/11/25)
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