104872-04-0Relevant articles and documents
A stereoselective synthesis of (-)-tetrahydrolipstatin
Ghosh, Arun K.,Liu, Chunfeng
, p. 1743 - 1744 (1999)
A stereoselective synthesis of (-)-tetrahydrolipstatin has been accomplished utilizing olefin metathesis of an acrylate ester as the key step.
Total Synthesis of Tetrahydrolipstatin, Its Derivatives, and Evaluation of Their Ability to Potentiate Multiple Antibiotic Classes against Mycobacterium Species
Khan, Saniya S.,Landgraf, Alexander D.,Ronning, Donald R.,Sucheck, Steven J.,Sudasinghe, Thanuja D.
, (2021/09/27)
Tetrahydrolipstatin (THL, 1a) has been shown to inhibit both mammalian and bacterial α/β hydrolases. In the case of bacterial systems, THL is a known inhibitor of several Mycobacterium tuberculosis hydrolases involved in mycomembrane biosynthesis. Herein we report a highly efficient eight-step asymmetric synthesis of THL using a route that allows modification of the THL α-chain substituent to afford compounds 1a through 1e. The key transformation in the synthesis was use of a (TPP)CrCl/Co2(CO)8-catalyzed regioselective and stereospecific carbonylation on an advanced epoxide intermediate to yield a trans-β-lactone. These compounds are modest inhibitors of Ag85A and Ag85C, two α/β hydrolases of M. tuberculosis involved in the biosynthesis of the mycomembrane. Among these compounds, 10d showed the highest inhibitory effect on Ag85A (34 ± 22 μM) and Ag85C (66 ± 8 μM), and its X-ray structure was solved in complex with Ag85C to 2.5 ? resolution. In contrast, compound 1e exhibited the best-in-class MICs of 50 μM (25 μg/mL) and 16 μM (8.4 μg/mL) against M. smegmatis and M. tuberculosis H37Ra, respectively, using a microtiter assay plate. Combination of 1e with 13 well-established antibiotics synergistically enhanced the potency of few of these antibiotics in M. smegmatis and M. tuberculosis H37Ra. Compound 1e applied at concentrations 4-fold lower than its MIC enhanced the MIC of the synergistic antibiotic by 2-256-fold. In addition to observing synergy with first-line drugs, rifamycin and isoniazid, the MIC of vancomycin against M. tuberculosis H37Ra was 65 μg/mL; however, the MIC was lowered to 0.25 μg/mL in the presence of 2.1 μg/mL 1e demonstrating the potential of targeting mycobacterial hydrolases involved in mycomembrane and peptidoglycan biosynthesis.
COMPOUNDS FOR THE REDUCING LIPOTOXIC DAMAGE
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Page/Page column 4, (2019/01/30)
Provided herein are novel lipase inhibitors and methods for using the same to treat inflammation, multisystem organ failure, necrotic pancreatic acinar cell death, acute pancreatitis, sepsis (e.g., culture negative sepsis), burns, and acne. For example, provided herein are two novel lipase inhibitors useful in the methods described herein: (I) (II) or a pharmaceutically acceptable salt thereof.
Stereochemical Structure Activity Relationship Studies (S-SAR) of Tetrahydrolipstatin
Liu, Xiaofan,Wang, Yanping,Duclos, Richard I.,O'Doherty, George A.
supporting information, p. 274 - 278 (2018/03/21)
Tetrahydrolipstatin (THL), its enantiomer, and an additional six diastereomers were evaluated as inhibitors of the hydrolysis of p-nitrophenyl butyrate by porcine pancreatic lipase. IC50s were found for all eight stereoisomers ranging from a low of 4.0 nM for THL to a high of 930 nM for the diastereomer with the inverted stereocenters at the 2,3,2′-positions. While the enantiomer of THL was also significantly less active (77 nM) the remaining five stereoisomers retained significant inhibitory activities (IC50s = 8.0 to 20 nM). All eight compounds were also evaluated against three human cancer cell lines (human breast cancers MCF-7 and MDA-MB-231, human large-cell lung carcinoma H460). No appreciable cytotoxicity was observed for THL and its seven diastereomers, as their IC50s in a MTT cytotoxicity assay were all greater than 3 orders of magnitude of camptothecin.
Weight-reducing medicine orlistat synthesis method
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Paragraph 0018; 0019; 0020; 0021; 0022; 0023; 0024-0036, (2017/08/28)
The invention discloses a weight-reducing medicine orlistat synthesis method. The synthesis method includes that in existence of (R,R)-(-)-N,N'-bis(3,5-ditert-butyl-salicylidene)-1,2-cyclohexyl diamine cobalt, lipstatin and sodium borohydride are subjected to reduction reaction under catalysis of cuprous chloride to obtain orlistat. The orlistat synthesis method is quick in reaction, and reaction yield is increased effectively. By adoption of (R,R)-(-)-N,N'-bis(3,5-ditert-butyl-salicylidene)-1,2-cyclohexyl diamine cobalt as a stabilizer of a reducing agent, low side reaction quantity, easiness in product purification and suitableness for industrial expanded production are realized.
Method for preparing weight-reducing medicine orlistat
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Paragraph 0009; 0020; 0021; 0022; 0223; 0024; 0025-0037, (2017/08/28)
The invention discloses a method for preparing a weight-reducing medicine orlistat. The method comprises the following steps of using lipstatin as a starting raw material, and under the catalysis of pentacarbonyl iron, making the lipstatin generate reduction reaction with a hydrazine hydrate to obtain the orlistat. The method for preparing the orlistat, which is provided by the invention, is mild in reaction condition and simple to operate; the reaction yield is effectively improved; the hydrazine hydrate is adopted as a reducing agent and a hydrogen source; reaction by-products are few; the after treatment is simple.
Total synthesis of tetrahydrolipstatin and stereoisomers via a highly regio- and diastereoselective carbonylation of epoxyhomoallylic alcohols
Mulzer, Michael,Tiegs, Brandon J.,Wang, Yanping,Coates, Geoffrey W.,O'Doherty, George A.
, p. 10814 - 10820 (2014/08/18)
A concise enantioselective synthesis of tetrahydrolipstatin (THL) and seven stereoisomers has been achieved. The synthesis of THL was accomplished in 10 steps and 31% overall yield from an achiral ynone. Key to the success of the approach is the use of a bimetallic [Lewis acid]+[Co(CO)4]- catalyst for a late-stage regioselective carbonylation of an enantiomerically pure cis-epoxide to a trans-β-lactone. The success of this route to THL and its stereoisomers also demonstrated the practicality of the carbonylation catalyst for complex molecule synthesis as well as its functional group compatibility.
MNBA-mediated β-lactone formation: Mechanistic studies and application for the asymmetric total synthesis of tetrahydrolipstatin
Shiina, Isamu,Umezaki, Yuma,Kuroda, Nobutaka,Iizumi, Takashi,Nagai, Shunsuke,Katoh, Takashi
, p. 4885 - 4901 (2012/07/30)
Various β-lactones were prepared from β-hydroxycarboxylic acids by intramolecular dehydration condensation using MNBA, an effective coupling reagent, along with a nucleophilic catalyst. The transition state that provides the desired 4-membered ring model system is disclosed by density functional theory (DFT) calculations, and the structural features of the transition form are discussed. This method was successfully applied to the asymmetric total synthesis of tetrahydrolipstatin (THL), an antiobestic drug used in clinical treatment to inhibit the activity of pancreatic lipase.
Use of orlistat for the anti-parasitic treatment of a parasitic disease
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, (2011/12/14)
The present invention relates to the field of medicine, parasitology and microbiology and more particularly to the use of Orlistat as a therapeutic agent for preventing, treating or eliminating a protozoal and parasitic disease in an animal including a human.
PROCESS FOR THE PREPARATION OF ORLISTAT
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Page/Page column 2, (2010/08/03)
The present invention provides a process for preparing orlistat from amino orlistat using Pivaloyl Formic Anhydride (PFA) as an alkanoylating agent.
