- Syntheses of SGLT2 inhibitors by Ni- And Pd-catalyzed fukuyama coupling reactions
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Nickel- and palladium-catalyzed Fukuyama coupling reactions of a D-gluconolactone-derived thioester with arylzinc reagents at ambient temperature provided the corresponding multifunctional aryl ketones in high yield. Ligand screening for the nickel-catalyzed Fukuyama coupling reactions indicated that 1,2- bis(dicyclohexylphosphino)ethane (dCype) served as a superior supporting ligand to improve the product yield. In addition, Pd/C was a practical alternative that enabled ligand-free Fukuyama coupling reactions and was efficiently applied to the key C-C bond-forming step to prepare canagliflozin and dapagliflozin, which are diabetic SGLT2 inhibitors of current interest.
- Kato, Daiki,Mashima, Kazushi,Nagae, Haruki,Seki, Masahiko,Talode, Jalindar,Tsurugi, Hayato
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Read Online
- Tetra-n-propylammonium tetra-oxoruthenate(VII): A reagent of choice for the oxidation of diversely protected glycopyranoses and glycofuranoses to lactones
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2,3,4,6-Tetra-O-benzyl-D-glucopyranose, 2,3,5-tri-O-allyl-D-ribofuranose, 2,3,5-tri-O-allyl- and -tri-O-benzyl-D-arabinofuranose, and 2-deoxy-3,5-di- O-allyl-D-erythro-pentofuranose were oxidized to their corresponding lactones 6-10 by dimethyl sulfoxide activated by oxalyl chloride, pyridinium dichromate in the presence of molecular sieves and acetic acid, and tetra-n- propylammonium tetra-oxoruthenate(VII) using 4-methylmorpholine N-oxide as co-oxidant. With the latter reagent, analytically pure lactones were obtained in 83-98% yield. A multistep preparation of 3,4,6-tri-O-benzyl-2-deoxy-D- arabino-hexono-1,5-lactone (14) from 3,4,6-tri-O-benzyl-1,5-anhydro-2-deoxy- D-arabino-hex-1-enitol (65% overall yield) is described. 2,3,4,6-Tetra-O-benzyl-D-glucopyranose, 2,3,5-tri-O-allyl-D-ribofuranose, 2,3,5-tri-O-allyl- and -tri-O-benzyl-D-arabinofuranose, and 2-deoxy-3,5-di-O-allyl-D-erythro-pentofuranose were oxidized to their corresponding lactones 6-10 by dimethyl sulfoxide activated by oxalyl chloride, pyridinium dichromate in the presence of molecular sieves and acetic acid, and tetra-n-propylammonium tetra-oxoruthenate(VII) using 4-methylmorpholine N-oxide as co-oxidant. With the latter reagent, analytically pure lactones were obtained in 83-98% yield. A multistep preparation of 3,4,6-tri-O-benzyl-2-deoxy-D-arabino-hexono-1,5-lactone (14) from 3,4,6-tri-O-benzyl-1,5-anhydro-2-deoxy-D-arabino-hex-1-enitol (65% overall yield) is described.
- Benhaddou,Czernecki,Farid,Ville,Xie,Zegar
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Read Online
- Glucopyranosyl derivative and application thereof
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The present invention relates to glucopyranosyl derivative and uses thereof. Specifically, the invention relates to a glucopyranosyl derivative used as a sodium-dependent glucose transporter 1(SGLT1)inhibitor and a pharmaceutically acceptable salt or stereoisomer thereof, and further relates to a pharmaceutical composition containing the derivative. The invention also relates to application of thecompound and the pharmaceutical composition thereof in preparation of drugs for treating diabetes and diabetes-related diseases.
- -
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Paragraph 0260; 0272-0274
(2021/01/24)
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- Synthesis method of voglibose
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The invention provides a synthesis method of voglibose, and solves the technical problems that in an existing synthesis method of voglibose, raw materials are difficult to obtain, high in price, large in investment, low in yield and not suitable for industrial production. The synthesis method comprises the steps: synthesizing a compound V by taking glucose monohydrate and sodium acetate as raw materials through eleven reaction steps; and preparing a compound VIII from the compound V through an addition reaction, a ring-opening reaction and an aldol condensation reaction, and thus obtaining voglibose through amination reduction of the compound VIII. The synthesis method of voglibose can be widely applied to the technical field of voglibose synthesis methods.
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Paragraph 0060- 0061; 0075-0077
(2021/08/07)
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- Method for continuously synthesizing benzyl-substituted glucolactone by adopting microchannel reaction device
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The invention discloses a method for continuously synthesizing benzyl-substituted glucolactone by adopting a microchannel reaction device. The method comprises the following steps: taking methyl-alpha-D-mannopyranoside as an initial raw material, preparing the methyl-alpha-D-mannopyranoside into an old organic solvent solution, and reacting the old organic solvent solution with an organic solvent solution of benzyl chloride in a first microreactor to generate methyl glucose with hydroxyl protected by benzyl; reacting a homogeneous solution formed by mixing a reaction solution of benzyl-substituted gluconic acid and a small amount of hydrochloric acid solution in a second microreactor for demethylation to generate hydroxyl benzyl-substituted glucose; and finally, reacting the reaction solution with an aqueous solution of hydrogen peroxide and sodium hydroxide and an organic solvent solution of tetramethylpiperidine nitrogen oxide in a third microreactor to generate the high-purity hypoglycemic drug Dapagliflozin intermediate benzyl substituted glucolactone. The method disclosed by the invention is higher in heat and mass transfer efficiency and easier to industrially amplify, the initial materials are simple, cheap and easily available, the process is simple, the obtained intermediate is high in purity and high in yield, the production cost can be effectively reduced, and the method is suitable for industrial production.
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Page/Page column 0043; 0046; 0047; 0051; 0052-0053; 0056-0057; 0061
(2021/06/21)
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- Synthetic method of SGLT2 inhibitor intermediate
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The invention discloses a synthesis method of an SGLT2 inhibitor intermediate, which comprises the following steps: S1, oxidation: dissolving a compound I, adding into an oxidation system, carrying out liquid-liquid separation, and collecting an organic phase A to obtain a compound II; S2, dealkylation: adding the compound II into a dealkylation system to obtain a reaction solution, and performing liquid-liquid separation to obtain a compound III; S3, iodination: adding the compound III into an iodination system, performing liquid-liquid separation, and collecting an organic phase B to obtain a compound IV; S4, reduction: dissolving the compound IV, adding the dissolved compound IV into a reduction system, carrying out liquid-liquid separation, and collecting an organic phase C to obtain a target product V; the synthesis method has few synthesis steps, and the process is simple and easy to operate; expensive and dangerous compounds are not used in the synthesis process, and no safety risk exists; the total yield reaches 60 percent or higher; the method uses commercially available starting materials, is low in cost, ensures good reproducibility of a synthetic route, and is a process suitable for large-scale industrial production.
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Paragraph 0063; 0064
(2021/04/14)
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- GLUCOPYRANOSYL DERIVATIVE AND USE THEREOF
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The present invention relates to a glucopyranosyl derivative and a use thereof. In particular, the present invention relates to a glucopyranosyl derivative that is used as an inhibitor of sodium-dependent glucose transporters (SGLTs), particularly being used as an inhibitor of sodium-dependent glucose transporter-1 (SGLT1), and a pharmaceutically acceptable salt or stereoisomer thereof, further relating to a pharmaceutical composition containing the derivative. The present invention further relates to a use of the compound and a pharmaceutical composition thereof in the preparation of a drug for treating diabetes and diabetes-related diseases.
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Paragraph 0242; 0263-0264
(2020/12/16)
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- Glucose-based spiro-oxathiazoles as: In vivo anti-hyperglycemic agents through glycogen phosphorylase inhibition
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The design of glycogen phosphorylase (GP) inhibitors targeting the catalytic site of the enzyme is a promising strategy for a better control of hyperglycaemia in the context of type 2 diabetes. Glucopyranosylidene-spiro-heterocycles have been demonstrated as potent GP inhibitors, and more specifically spiro-oxathiazoles. A new synthetic route has now been elaborated through 1,3-dipolar cycloaddition of an aryl nitrile oxide to a glucono-thionolactone affording in one step the spiro-oxathiazole moiety. The thionolactone was obtained from the thermal rearrangement of a thiosulfinate precursor according to Fairbanks' protocols, although with a revisited outcome and also rationalised with DFT calculations. The 2-naphthyl substituted glucose-based spiro-oxathiazole 5h, identified as one of the most potent GP inhibitors (Ki = 160 nM against RMGPb) could be produced on the gram-scale from this strategy. Further evaluation in vitro using rat and human hepatocytes demonstrated that compound 5h is a anti-hyperglycaemic drug candidates performing slightly better than DAB used as a positive control. Investigation in Zucker fa/fa rat model in acute and subchronic assays further confirmed the potency of compound 5h since it lowered blood glucose levels by ~36% at 30 mg kg-1 and ~43% at 60 mg kg-1. The present study is one of the few in vivo investigations for glucose-based GP inhibitors and provides data in animal models for such drug candidates.
- Azay-Milhau, Jacqueline,Balzarin, Sophie,Czifrák, Katalin,Demontrond, Fanny,Docsa, Tibor,Duret, Cédric,Gergely, Pál,Goyard, David,Kónya, Bálint,Larini, Paolo,Leroy, Jérémy,Maurel, Patrick,Petit, Pierre,Praly, Jean-Pierre,Somsák, László,Tournier, Michel,Tousch, Didier,Vidal, Sébastien
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p. 931 - 940
(2020/02/15)
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- Sodium sugar-translocator 2 inhibitor, its preparation and its pharmaceutical composition and use thereof
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The invention discloses an inhibitor for sodium-glucose co-transporter 2 (SGLT2), a preparation method and a pharmaceutical composition thereof, and application of the inhibitor and the pharmaceutical composition. Specifically, the invention discloses the SGLT2 inhibitor with a general formula (I) as described in the specification and pharmaceutically acceptable salts thereof, preparation process of the SGLT2 inhibitor, the pharmaceutical composition containing the inhibitor with the general formula (I) as described in the specification, and application of the inhibitor and the pharmaceutical composition in antidiabetic aspects.
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Paragraph 0201; 0202; 0205
(2019/07/16)
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- Highly stereoselective synthesis of aryl/heteroaryl-: C -nucleosides via the merger of photoredox and nickel catalysis
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A photoredox/nickel dual-catalyzed decarboxylative cross-coupling reaction of anomeric ribosyl/deoxyribosyl acids with aryl/heteroaryl bromides has been developed. The reaction proceeds smoothly under visible-light irradiation and features the using of cost-effective and easily handled catalysts and starting materials, which allows the highly stereoselective synthesis of diverse aryl/heteroaryl-C-nucleosides in moderate to high yields.
- Ma, Yingying,Liu, Shihui,Xi, Yifan,Li, Hongrui,Yang, Kai,Cheng, Zhihao,Wang, Wei,Zhang, Yongqiang
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p. 14657 - 14660
(2019/12/11)
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- GLUCOPYRANOSYL DERIVATIVE AND USE THEREOF
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Provided are a glucopyranosyl derivative as a sodium-dependent glucose transporters inhibitor, especially as a SGLT1 inhibitor, a pharmaceutically acceptable salt or a stereoisomer thereof, a pharmaceutical composition thereof, and the uses of the compound and pharmaceutical composition thereof in the preparation of drugs for the treatment of diabetes and diabetes-related diseases.
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Paragraph 00253
(2019/08/12)
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- ANTI-EGFR ANTIBODY DRUG CONJUGATES
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The invention relates to anti-Epidermal Growth Factor Receptor (EGFR) antibody drug conjugates (ADCs) which inhibit Bcl-xL, including compositions and methods of using said ADCs.
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Paragraph 1116
(2019/06/07)
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- Fluorine-Directed Glycosylation Enables the Stereocontrolled Synthesis of Selective SGLT2 Inhibitors for Type II Diabetes
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Inhibition of the sodium-glucose co-transporters (SGLT1 and SGLT2) is a validated strategy to address the increasing prevalence of type II diabetes mellitus. However, achieving selective inhibition of human SGLT1 or SGLT2 remains challenging. Orally available small molecule drugs based on the d-glucose core of the natural product Gliflozin have proven to be clinically effective in this regard, effectively impeding glucose reabsorption. Herein, we disclose the influence of molecular editing with fluorine at the C2 position of the pyranose ring of Phlorizin analogues Remogliflozin Etabonate and Dapagliflozin (Farxiga) to concurrently direct β-selective glycosylation, as is required for biological efficacy, and enhance aspects of the physicochemical profile. Given the abundance of glycosylated pharmaceuticals in diabetes therapy that contain a β-configured d-glucose nucleus, it is envisaged that this strategy may prove to be expansive.
- Sadurní, Anna,Kehr, Gerald,Ahlqvist, Marie,Wernevik, Johan,Sj?gren, Helena Peilot,Kankkonen, Cecilia,Knerr, Laurent,Gilmour, Ryan
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supporting information
p. 2832 - 2836
(2017/12/26)
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- PROCESS FOR THE PREPARATION OF DAPAGLIFLOZIN
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The present invention discloses a novel process for the preparation of Dapagliflozin (S)-propylene glycol hydrate of Formula II. (Formula II)
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Page/Page column 14; 15
(2018/08/26)
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- ANTI-CD98 ANTIBODIES AND ANTIBODY DRUG CONJUGATES
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The invention relates to anti-CD98 antibodies and antibody drug conjugates (ADCs), including compositions and methods of using said antibodies and ADCs.
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Page/Page column 475
(2018/01/15)
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- ANTI-EGFR ANTIBODY DRUG CONJUGATES
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The invention relates to anti-Epidermal Growth Factor Receptor (EGFR) antibody drug conjugates (ADCs) which inhibit Bcl-xL, including compositions and methods of using said ADCs.
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Page/Page column 423; 424
(2018/01/15)
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- ANTI-CD98 ANTIBODIES AND ANTIBODY DRUG CONJUGATES
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The invention relates to anti-CD98 antibodies and antibody drug conjugates (ADCs), including compositions and methods of using said antibodies and ADCs.
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Page/Page column 622-623
(2018/01/17)
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- A puerarin morphine preparation method
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The invention discloses a preparation method for puerarin morphine. The preparation method comprises the following steps: (1) the synthesis of puerarin, to be specific, 1) preparing a compound 2 by taking a compound 1 as a raw material; 2) modifying the compound 2 to prepare a compound 3; 3) removing hydroxide radicals of the compound 3 to prepare a compound 4; 4) enabling the compound 4 to react with p-methoxyphenylacetyl chloride to prepare a compound 5; 5) reducing the compound 5 into a compound 6 through boron tribromide; 6) synthesizing the puerarin by taking the compound 6 as a raw material; (2) the synthesis of puerarin morphine. Through the use of the puerarin morphine, the dosage of morphine is reduced, the addiction and tolerance of the morphine are reduced, side effects of the morphine in the aspects of the respiratory system, cardiovascular system and central nervous system are effectively slowed down, and the puerarin morphine can be used for pain treatment as a substitute for morphine.
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Paragraph 0023; 0028
(2017/08/25)
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- ANTI-CD98 ANTIBODIES AND ANTIBODY DRUG CONJUGATES
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The invention relates to anti-CD98 antibodies and antibody drug conjugates (ADCs), including compositions and methods of using said antibodies and ADCs.
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Page/Page column 356
(2018/01/15)
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- ANTI-B7-H3 ANTIBODIES AND ANTIBODY DRUG CONJUGATES
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The invention relates to B7 homology 3 protein (B7-H3) antibodies and antibody drug conjugates (ADCs), including compositions and methods of using said antibodies and ADCs.
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Paragraph 2084
(2018/01/13)
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- Total synthesis of N-butyl-1-deoxynojirimycin
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N-Butyl-1-deoxynojirimycin (NB-DNJ) derived from imino sugar deoxynojirimycin (DNJ) has been approved for the treatment of Gaucher’s disease. Herein, a facile and efficient synthetic procedure for NB-DNJ has been described. Comparing to the methods reported previously,methanesulfonyl group was used as a leaving group for easy displacement upon attack by the imine in the sugar ring, leading to a high yield during the introduction of the n-butyl group. Thismethod can serve as an excellent protocol for the synthesis of DNJ derivatives with a variety of N-alkyl substituents and for large-scale production.
- Wang, Jiajia,Zhao, Yunyan,Zhao, Wei,Wang, Peng,Li, Jing
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p. 445 - 454
(2017/08/23)
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- Total Synthesis of (+)-Vicenin-2
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The bis-C-glucosyl flavonoid vicenin-2 (1) has been synthesized by exploiting bis-C-glycosylation of 1,3,5-trifluorobenzene and aromatic nucleophilic substitution to transform fluorine atoms to oxygen functions in excellent yield.
- Ho, Thanh C.,Kamimura, Haruki,Ohmori, Ken,Suzuki, Keisuke
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supporting information
p. 4488 - 4490
(2016/09/28)
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- Improved synthesis of the C-glucuronide/glycoside of 4-hydroxybenzylretinone (4-HBR)
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Improvements in the synthesis of carbon-linked glucuronide/ glucoside conjugates of cancer chemopreventive retinoids have been achieved starting with 2,3,4,6-tetra-Obenzyl- D-glucopyranose. The revised approach demonstrates better yields, eliminates the use of an expensive, carcinogenic protecting group reagent, and avoids much painstaking chromatography. The new approach should allow synthesis of larger quantities of the agents for detailed animal and mechanistic studies.
- Cavanaugh, Kathryn R.,Narayanasamy, Sureshbabu,Walker, Joel R.,Clagett-Dame, Margaret,Curley, Robert W.
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p. 249 - 260
(2016/10/22)
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- Synthesis of Unprecedented Sulfonylated Phosphono-exo-Glycals Designed as Inhibitors of the Three Mycobacterial Galactofuranose Processing Enzymes
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This study reports a new methodology to synthesize exo-glycals bearing both a sulfone and a phosphonate. This synthetic strategy provides a way to generate exo-glycals displaying two electron-withdrawing groups and was applied to eight different carbohydrates from the furanose and pyranose series. The Z/E configurations of these tetrasubstituted enol ethers could be ascertained using NMR spectroscopic techniques. Deprotection of an exo-glycal followed by an UMP (uridine monophosphate) coupling generated two new UDP (uridine diphosphate)-galactofuranose analogues. These two Z/E isomers were evaluated as inhibitors of UGM, GlfT1, and GlfT2, the three mycobacterial galactofuranose processing enzymes. Molecule 46-(E) is the first characterized inhibitor of GlfT1 reported to date and was also found to efficiently inhibit UGM in a reversible manner. Interestingly, GlfT2 showed a better affinity for the (Z) isomer. The three enzymes studied in the present work are not only interesting because, mechanistically, they are still the topic of intense investigations, but also because they constitute very important targets for the development of novel antimycobacterial agents.
- Frédéric, Christophe J.-M.,Tikad, Abdellatif,Fu, Jian,Pan, Weidong,Zheng, Ruixiang B.,Koizumi, Akihiko,Xue, Xiaochao,Lowary, Todd L.,Vincent, Stéphane P.
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supporting information
p. 15913 - 15920
(2016/10/25)
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- BCL-XL Inhibitory Compounds and Antibody Drug Conjugates Including the Same
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Small molecule Bcl-xL inhibitors and Antibody Drug Conjugates (ADCs) comprising small molecule Bcl-xL inhibitors are disclosed herein. The Bcl-xL inhibitors and ADCs of the disclosure are useful for, among other things, inhibiting anti-apoptotic Bcl-xL proteins as a therapeutic approach towards the treatment of diseases that involve a dysregulated apoptosis pathway.
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Paragraph 1047
(2016/06/28)
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- BCL XL INHIBITORY COMPOUNDS HAVING LOW CELL PERMEABILITY AND ANTIBODY DRUG CONJUGATES INCLUDING THE SAME
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The present disclosure concerns Bcl-xL inhibitors having low cell permeability, antibody drug conjugates (ADCs) comprising the inhibitors, synthons useful for synthesizing the ADCs, compositions comprising the inhibitors or ADCs, and various methods of using the inhibitors and ADCs.
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Paragraph 0001105
(2016/07/05)
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- C-Aryl glucoside SGLT2 inhibitors containing a biphenyl motif as potential anti-diabetic agents
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A series of highly active C-aryl glucoside SGLT2 inhibitors containing a biphenyl motif were designed and synthesized for biological evaluation. Among the compounds tested, compound 16l demonstrated high inhibitory activity against SGLT2 (IC50 = 1.9 nM) with an excellent pharmacokinetic profile. Further study indicated that the in vivo efficacy of compound 16l was comparable to that of dapagliflozin, suggesting that further development would be worthwhile.
- Ding, Yuyang,Mao, Liufeng,Xu, Dengfeng,Xie, Hui,Yang, Ling,Xu, Hongjiang,Geng, Wenjun,Gao, Yong,Xia, Chunguang,Zhang, Xiquan,Meng, Qingyi,Wu, Donghai,Zhao, Junling,Hu, Wenhui
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supporting information
p. 2744 - 2748
(2015/06/08)
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- Iodine monochloride (ICl) as a highly efficient, green oxidant for the oxidation of alcohols to corresponding carbonyl compounds
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Iodine monochloride (ICl) was discovered to be a highly efficient, green oxidant, which can oxidize aldose hemiacetals, diarylmethanols, arylalkylmethanols, anddialkylmethanols to the corresponding aldose lactones, diarylmethanones, arylalkylmethanones, and dialkylmethanones, respectively, in high yields. ICl as a green, metal-free oxidant is characterized by mild reaction condition, short reaction time, good yield, and broad scope.
- Wei, Peng,Zhang, Datong,Gao, Zhigang,Cai, Wenqing,Xu, Weiren,Tang, Lida,Zhao, Guilong
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supporting information
p. 1457 - 1470
(2015/05/20)
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- Commercial route research and development for SGLT2 inhibitor candidate ertugliflozin
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A practical synthesis of SGLT2 inhibitor candidate ertugliflozin (1) has been developed for potential commercial application. The highly telescoped process involves only three intermediate isolations over a 12-step sequence. The dioxabicyclo[ 3.2.1]octane motif is prepared from commercially available 2,3,4,6-tetra-O-benzyl-D-glucose, with nucleophilic hydroxymethylation of a 5-ketogluconamide intermediate as a key step. The aglycone moiety is introduced via aryl anion addition to a methylpiperazine amide. High chemical purity of the API is assured through isolation of the crystalline penultimate intermediate, tetraacetate 39. A cocrystalline complex of the amorphous solid 1 with L-pyroglutamic acid has been prepared in order to improve the physical properties for manufacture and to ensure robust API quality.
- Bowles, Paul,Brenek, Steven J.,Caron, Stephane,Do, Nga M.,Drexler, Michele T.,Duan, Shengquan,Dube, Pascal,Hansen, Eric C.,Jones, Brian P.,Jones, Kris N.,Ljubicic, Tomislav A.,Makowski, Teresa W.,Mustakis, Jason,Nelson, Jade D.,Olivier, Mark,Peng, Zhihui,Perfect, Hahdi H.,Place, David W.,Ragan, John A.,Salisbury, John J.,Stanchina, Corey L.,Vanderplas, Brian C.,Webster, Mark E.,Weekly, R. Matt
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- Synthesis of C-spiro-glycoconjugates from sugar lactones via zinc mediated Barbier reaction
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Anomeric gem-diallylation, mono-β-crotylation and mono-β- propargylation of sugar 1,5 and 1,4 lactones have been achieved under Barbier reaction conditions using Zn powder and a catalytic amount of TMSCl as an activator. Ring closing olefin metathesis of the synthesized gem-diallyl derivatives furnished C-spiro cyclopentene glycosides. Finally, the cyclopentene rings were converted into carbohydrate based tricyclic morpholine fused triazole glycoconjugates as potential SGLT2 inhibitors.
- Lambu, Mallikharjuna Rao,Hussain, Altaf,Sharma, Deepak K.,Yousuf, Syed Khalid,Singh, Baldev,Tripathi, Anil. K.,Mukherjee, Debaraj
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p. 11023 - 11028
(2014/03/21)
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- GEM-DIFLUORINATED C-GLYCOSIDE COMPOUNDS AS ANTI-CANCER AGENTS
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The present document describes a synthesis of a class of gem-difluorinated C-glycoside compounds derived from podophyllotoxin, which may be used, but not exclusively, in oncology for the treatment of cancer. More particularly, the podophyllotoxin gem-difluorinated C-glycoconjugated derivatives display improved conformational and chemical stability, and improved cytotoxicity exhibited against drug-resistant cancer cell lines.
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Paragraph 00131; 00132; 00133
(2014/07/23)
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- Sugar-derived cyclic imines: One-pot synthesis and direct functionalization
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A simple method for the synthesis of sugar-derived imines by a Schwartz's reagent reduction of easily available sugar lactams has been described. A direct addition of nucleophiles to the generated in situ cyclic imines and subsequent deprotection of hydroxyl function allows to convert sugar lactams in polyhydroxylated pyrrolidines and piperidines.
- Szcze?niak, Piotr,Stecko, Sebastian,Staszewska-Krajewska, Olga,Furman, Bart?omiej
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p. 1880 - 1888
(2014/03/21)
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- Oxidation of alcohols to aldehydes or ketones with 1-acetoxy-1,2- benziodoxole-3(1H)-one derivatives
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Various benzylic and aliphatic alcohols were smoothly oxidized to the corresponding aromatic aldehydes and ketones as well as aliphatic ketones by treatment with 1-acetoxy-5-nitro-1,2-benziodoxole-3(1H)-one (ANBX), 1-acetoxy-5-bromo-1,2-benziodoxole-3(1H)-one (ABBX), 1-acetoxy-5-chloro-1,2- benziodoxole-3(1H)-one (ACBX), and 1-acetoxy-5-fluoro-1,2-benziodoxole-3(1H)-one (AFBX). These new tri-valent iodine compounds were prepared from 5-substituted 2-iodobenzoic acids and meta-chloroperoxybenzoic acid (m-CPBA). ANBX and ABBX were the most effective reagents for this oxidation of alcohols, and this present reaction is very attractive because of the ease of product isolation and the reusability of the reagents.
- Iinuma, Masataka,Moriyama, Katsuhiko,Togo, Hideo
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p. 772 - 780
(2014/03/21)
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- Oxidation of Alcohols to Aldehydes or Ketones with 1-Acetoxy-1,2-benziodoxole-3(1H)-one Derivatives
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Various benzylic and aliphatic alcohols were smoothly oxidized to the corresponding aromatic aldehydes and ketones as well as aliphatic ketones by treatment with 1-acetoxy-5-nitro-1,2-benziodoxole-3(1H)-one (ANBX), 1-acetoxy-5-bromo-1,2-benziodoxole-3(1H)-one (ABBX), 1-acetoxy-5-chloro-1,2-benziodoxole-3(1H)-one (ACBX), and 1-acetoxy-5-fluoro-1,2-benziodoxole-3(1H)-one (AFBX). These new trivalent iodine compounds were prepared from 5-substituted 2-iodobenzoic acids and meta-chloroperoxybenzoic acid (m-CPBA). ANBX and ABBX were the most effective reagents for this oxidation of alcohols, and this present reaction is very attractive because of the ease of product isolation and the reusability of the reagents.
- Iinuma, Masataka,Moriyama, Katsuhiko,Togo, Hideo
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p. 772 - 780
(2015/10/05)
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- Synthesis of polyhydroxylated quinolizidine and indolizidine scaffolds from sugar-derived lactams via a one-pot reduction/Mannich/Michael sequence
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A direct approach to the synthesis of indolizidine and quinolizidine scaffolds of iminosugars is described. The presented strategy is based on a one-pot sugar lactam reduction with Schwartz's reagent followed by a diastereoselective Mannich/Michael tandem reaction of the resulting sugar imine with Danishefsky's diene. The stereochemical course of the investigated reaction has been explained in detail. The obtained bicyclic products are attractive building blocks for the synthesis of various naturally occurring polyhydroxylated alkaloids and their derivatives.
- Szczesniak, Piotr,Stecko, Sebastian,Maziarz, Elzbieta,Staszewska-Krajewska, Olga,Furman, Bartlomiej
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p. 10487 - 10503
(2015/02/19)
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- Various oxidative reactions with novel ion-supported (diacetoxyiodo) benzenes
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The oxidation of secondary alcohols and primary alcohols with two novel ion-supported (diacetoxyiodo)benzenes (IS-DIBs) A and B in the presence of a catalytic amount of 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO) in dichloromethane at room temperature proceeded efficiently to provide the corresponding ketones and aldehydes, respectively, in good yields. The oxidative reaction of N,N-diisopropylbenzylamines with those IS-DIBs was also carried out to generate the corresponding aromatic aldehydes in good yields. In addition, the Hofmann rearrangement of primary amides in methanol under basic conditions and the oxidative 1,2-rearrangement of propiophenones in trimethyl orthoformate under acidic conditions with those IS-DIBs provided the corresponding methyl carbamates and methyl 2-arylpropanoates, respectively, in good yields. Moreover, treatment of acetophenones with those IS-DIBs in the presence of trifluoromethanesulfonic acid in acetonitrile generated the corresponding 5-aryl-2-methyloxazoles in good yields. In those five reactions, the desired products were obtained in good yields with high purity by simple extraction of the reaction mixture with diethyl ether and subsequent removal of the solvent from the extract. Moreover, ion-supported iodobenzenes, which were the co-products derived from IS-DIBs in the present oxidative reactions, were recovered in good yields and could be re-oxidized to IS-DIBs A and B for reuse in the same oxidative reactions.
- Iinuma, Masataka,Moriyama, Katsuhiko,Togo, Hideo
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p. 2961 - 2970
(2013/04/10)
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- MAGNETIC LABELING OF BACTERIA
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The present invention provides novel methods of magnetically labeling a bacterial cell by contacting the call with an affinity ligand and subsequently contacting the cell with a magnetic agent, where the affinity ligand and magnetic agent include bioorthogonally reactive groups that can react with each other to form a covalent bond. Compounds, compositions, kits and applications of the method are also described.
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Page/Page column 59
(2014/01/08)
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- Facile oxidation of alcohols to aldehydes or ketones with 1-acetoxy-5-nitro-1,2-benziodoxole-3(1 H)-one
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Various benzylic alcohols and aliphatic secondary alcohols were smoothly oxidized to the corresponding aromatic aldehydes, aromatic ketones, and aliphatic ketones, respectively, with the novel 1-acetoxy-5-nitro-1,2- benziodoxole-3(1H)-one (ANBX) alone, a trivalent iodine prepared from the oxidation of 2-iodo-5-nitrobenzoic acid with MCPBA. The present reaction is the first effective method for the oxidation of alcohols with a trivalent iodine alone under mild reaction conditions. Georg Thieme Verlag Stuttgart New York.
- Iinuma, Masataka,Moriyama, Katsuhiko,Togo, Hideo
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p. 1707 - 1711
(2013/09/02)
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- Facile synthesis of 1,2,3-triazole analogs of SGLT2 inhibitors by 'click chemistry'
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Novel analogs of SGLT2 inhibitors containing the 1,2,3-triazole motif were designed and synthesized for urinary glucose excretion evaluation. The C-glucosides with triazole aglycone can be easily constructed by click chemistry. Most of the synthesized compounds increased urinary glucose excretion and demonstrated inhibition of glucose transport.
- Li, Lan-Tao,Zhou, Li-Fei,Li, Yan-Jun,Huang, Juan,Liu, Rui-Hua,Wang, Bin,Wang, Peng
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supporting information; experimental part
p. 642 - 644
(2012/03/11)
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- Synthesis of protected sugar-amino acid hybrid molecules as platform for further derivatization
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The sugar-amino acid hybrid molecules with appropriate protecting groups were synthesized from sugar-derived lactones and ester of amino acids in five high yielding steps. The C-5 of the resultant hybrid molecule, upon selective deprotection, can be further derivatized to afford the linear depsipeptide.
- Liu, Han,Li, Xuechen
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supporting information
p. 6957 - 6960
(2013/01/15)
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- FAMILY OF ARYL, HETEROARYL, O-ARYL AND O-HETEROARYL CARBASUGARS
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The present invention relates to a compound of the following formula (I): as well as its process of preparation, pharmaceutical and cosmetics composition comprising it and use thereof, notably as an inhibitor of the sodium-dependent glucose co-transporter, such as SGLTl, SGLT2 and SGLT3, in particular in the treatment or prevention of diabetes, and more particularly type-II diabetes, diabetes-related complications, such as arthritis of the lower extremities, cardiac infarction, renal insufficiency, neuropathy or blindness, hyperglycemia, hyperinsulinemia, obesity, hypertriglyceridemia, X syndrome and arteriosclerosis, as well as for its use as an anticancer, anti-infective, anti-viral, anti-thrombotic or anti- inflammatory drug, or for lightening, bleaching, depigmenting the skin, removing blemishes from the skin, particularly age spots and freckles, or preventing pigmentation of the skin.
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Page/Page column 47-48
(2012/12/13)
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- Efficient Swern oxidation and Corey-Kim oxidation with ion-supported methyl sulfoxides and methyl sulfides
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The Swern oxidation of various benzylic and allylic alcohols, primary alcohols, and secondary alcohols with two ion-supported methyl sulfoxides A-1 (C6) and B-1 (C10), and oxalyl chloride in the presence of triethylamine in dichloromethane, followed by simple diethyl ether extraction of the reaction mixture, gave the corresponding aldehydes and ketones, respectively, in good yields with high purity. Similarly, the Corey-Kim oxidation of various benzylic and allylic alcohols, primary alcohols, and secondary alcohols with two ion-supported methyl sulfides A-2 (C6) and B-2 (C10), and N-chlorosuccinimide in the presence of triethylamine in dichloromethane, followed by simple diethyl ether extraction of the reaction mixture, furnished the corresponding aldehydes and ketones, respectively, in good yields with high purity. Both reactions did not produce any unpleasant odor at all. In the Swern oxidation, ion-supported methyl sulfides were recovered in high yields and could be re-oxidized to produce ion-supported methyl sulfoxides A-1 (C6) and B-1 (C10), for reuse in the same oxidation. In the Corey-Kim oxidation, ion-supported methyl sulfides A-2 (C6) and B-2 (C10) were recovered in high yields and could be also reused for the same oxidation.
- Tsuchiya, Daisuke,Tabata, Masayuki,Moriyama, Katsuhiko,Togo, Hideo
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experimental part
p. 6849 - 6855
(2012/08/28)
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- A practical stereoselective synthesis and novel cocrystallizations of an amphiphatic SGLT-2 inhibitor
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A practical synthesis of the SGLT-2 inhibitor β-C-aryl-d-glucoside (1) has been developed. The route employed 2,3,4,6-tetra-O-trimethlysilyl-d- glucano-1,5-lactone as the key chiral building block, prepared efficiently from the commercially available, inexpensive raw materials, d-gluconolactone and trimethylsilyl chloride. The salient step in the synthesis is the Lewis acid-mediated stereoselective reduction of a methyl C-aryl peracetylated glycoside using a silyl hydride to set the stereochemistry of the crucial anomeric chiral center. Several novel cocrystalline complexes of 1 with l-phenylalanine and l-proline were discovered. Single-crystal structures of these complexes and several synthetic intermediates have been determined. The l-phenylalanine complex was developed and used to purify and isolate the API. All steps were implemented at multikilogram scale.
- Deshpande, Prashant P.,Singh, Janak,Pullockaran, Annie,Kissick, Thomas,Ellsworth, Bruce A.,Gougoutas, Jack Z.,Dimarco, John,Fakes, Michael,Reyes, Mayra,Lai, Chiajen,Lobinger, Hidegard,Denzel, Theo,Ermann, Peter,Crispino, Gerard,Randazzo, Michael,Gao, Zenrong,Randazzo, Renee,Lindrud, Mark,Rosso, Victor,Buono, Frederic,Doubleday, Wendel W.,Leung, Simon,Richberg, Pricilla,Hughes, David,Washburn, William N.,Meng, Wei,Volk, Kevin J.,Mueller, Richard H.
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scheme or table
p. 577 - 585
(2012/08/07)
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- Total synthesis of indole-3-acetonitrile-4-methoxy-2-C-β-d- glucopyranoside. Proposal for structural revision of the natural product
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Indole-3-acetonitrile-4-methoxy-2-C-β-d-glucopyranoside (1), a novel C-glycoside from Isatis indigotica with important cytotoxic activity, has been prepared in ten steps from ethynyl-β-C-glycoside 3 and 2-iodo-3-nitrophenyl acetate 6. Key steps in the synthesis include a Sonogashira coupling and a CuI-mediated indole formation. NMR spectroscopic data for synthetic 1 differs from that reported for the natural product. A revised structure for the natural product, containing an alternate carbohydrate substituent, is proposed. The Royal Society of Chemistry 2012.
- Yepremyan, Akop,Minehan, Thomas G.
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supporting information; experimental part
p. 5194 - 5196
(2012/08/08)
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- Structure-activity relationships in a series of C2-substituted gluco-configured tetrahydroimidazopyridines as β-glucosidase inhibitors
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Inhibition of glycoside hydrolases has widespread application in treatment of diabetes, viral infections, lysosomal storage diseases and cancers. Gluco-configured tetrahydroimidazopyridines are the most potent β-glucosidase inhibitors reported to date. Using transition state mimic strategy, a series of C2-substituted gluco-configured tetrahydroimidazopyridines were designed and synthesized. Compounds 3 (Ki = 0.64 nM) and 5 (Ki = 0.58 nM) showed stronger inhibitory potency against β-glucosidase. Maestro 9.1 was used to study the structure-activity relationships by docking the compounds into the β-glucosidase active sites. Crown Copyright
- Li, Tiehai,Guo, Lina,Zhang, Yan,Wang, Jiajia,Zhang, Zhenxing,Li, Jing,Zhang, Wenpeng,Lin, Jianping,Zhao, Wei,Wang, Peng George
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experimental part
p. 2136 - 2144
(2011/05/06)
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- Highly efficient synthesis of ketoheptoses
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A reliable, facile, high overall yielding and diastereoselective synthesis of ketoheptoses was developed and applied for preparation of the two most diabetogenic ketoheptoses as well as in a modified version for the synthesis of kamusol.
- Waschke, Daniel,Thimm, Julian,Thiem, Joachim
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supporting information; experimental part
p. 3628 - 3631
(2011/09/15)
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- Synthesis of pyridazine and thiazole analogs as SGLT2 inhibitors
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With anticipation of the improvement in biological aspects in our SGLT2 program, novel pyridazinyl and thiazolyl analogs were designed and efficiently synthesized. The installation of the pyridazine ring at the anomeric carbon of d-glucopyranose was carried out in a stereoselective fashion. On the other hand, a series of thiazolyl analogs was also synthesized through a coupling reaction between perbenzyl gluconolactone 9 and 2-lithiothiazole. Biological activities of the compounds thus prepared were evaluated by the in vitro SGLT2 inhibition assay. Considering assay results, the novel benzylpyridazinyl and benzylthiazolyl analogs, disclosed in this article, could be a quick reference to prospective SGLT2 inhibitors useful for pharmacotherapy.
- Lee, Jinhwa,Kang, Suk Youn,Song, Kwang-Seop,Lee, Junwon,Lee, Sung-Han
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experimental part
p. 6069 - 6079
(2010/09/17)
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- Novel C-aryl glucoside SGLT2 inhibitors as potential antidiabetic agents: 1,3,4-Thiadiazolylmethylphenyl glucoside congeners
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Novel C-aryl glucoside SGLT2 inhibitors containing 1,3,4-thiadiazole moieties were designed and synthesized. Among the compounds tested, biaryl-type compounds containing pyrazine 59, 2-furan 61, and 3-thiophene 71 showed the best in vitro inhibitory activities to date (IC50 = 3.51-7.03 nM) against SGLT2. A selected compound 61, demonstrated reasonable blood glucose-lowering effects, indicating that the information obtained from the SAR studies in this 1,3,4-thiadiazolylmethylphenyl glucoside series might help to design more active SGLT2 inhibitors that are structurally related.
- Lee, Junwon,Lee, Sung-Han,Seo, Hee Jeong,Son, Eun-Jung,Lee, Suk Ho,Jung, Myung Eun,Lee, MinWoo,Han, Ho-Kyun,Kim, Jeongmin,Kang, Jahyo,Lee, Jinhwa
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experimental part
p. 2178 - 2194
(2010/06/12)
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- NOVEL C-ARYL GLUCOSIDE SGLT2 INHIBITORS AND PHARMACEUTICAL COMPOSITION COMPRISING SAME
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A novel C-aryl glucoside compound, or a pharmaceutically acceptable salt or a prodrug thereof having an inhibitory activity against sodium-dependent glucose cotransporter 2 (SGLT2) being present in the intestine and kidney; and a pharmaceutical composition comprising the same as an active ingredient, which is useful for preventing or treating metabolic disorders, particularly, diabetes, are provided.
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Page/Page column 50
(2010/12/31)
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- NOVEL GEM-DIFLUORINATED C-GLYCOSIDE COMPOUNDS DERIVED FROM PODOPHYLLOTOXIN, THEIR PREPARATION AND THEIR APPLICATIONS
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The invention relates to a gem-difluoride glycoconjugated compound with formula (I): where R represents II or a benzyl, acetyl, benzoyl alkyl group, R1 and R2 may be identical or different and represent H or an alkyl, benzyl, benzoyl, acetyl, pivaloyl, trialkylsilyl, tertiobutyldiphenylsilyl protective group or an acetal group of the CR′R′ type, where R′ and R′ may be identical or different and represent H or an alkyl, aryl, benzyl or thiophene group, R3 represents H or an alkyl, benzyl, benzoyl, acetyl, pivaloyl, trialkylsilyl or tertiobutyldiphenylsilyl protective group, R4 represents OR″, NGR′GR′, N3, or a phthalimide, where R″ represents H or an alkyl, benzyl, benzoyl, acetyl, pivaloyl, trialkylsilyl or tertiobutyldiphenylsilyl protective group, GR′ and GR′ may be identical or different and represent II or an alkyl, benzyl, benzoyl, acetyl, alkyloxycarbonyl, allyloxycarbonyl or benzyloxycarbonyl group, R5 represents a free or protected hydroxyl group or a halogen, R6 represents H or an alkyl, acetyl, benzyl, PO3H or PO3Na group. It is applicable to the preparation of compounds that can be used particularly for the treatment of cancer.
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Page/Page column 10
(2009/12/28)
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- SPIROHETEROCYCLIC GLYCOSIDES AND METHODS OF USE
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Provided are compounds having an inhibitory effect on sodium-dependent glucose cotransporter SGLT. The invention also provides pharmaceutical compositions, methods of preparing the compounds, synthetic intermediates, and methods of using the compounds, independently or in combination with other therapeutic agents, for treating diseases and conditions which are affected by SGLT inhibition.
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Page/Page column 51
(2008/12/07)
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