- TETRAHYDROPYRAZOLO-PYRAZINYL-DIHYDROIMIDAZOLONE OR TETRAHYDROPYRAZOLO-PYRIDINYL-DIHYDROIMIDAZOLONE COMPOUNDS AND METHODS OF USING SAME
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The application relates to a compound of Formula (I) : or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, which modulates the activity of GLP-1 receptor, a pharmaceutical composition comprising a compound of Formula (I), and a method of treating or preventing a disease in which GLP-1 receptor plays a role.
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Paragraph 00636
(2022/02/05)
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- Metal-Free Stereoselective Synthesis of (E)- And (Z)-N-Monosubstituted β-Aminoacrylates via Condensation Reactions of Carbamates
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N-monosubstituted β-aminoacrylates are building blocks, which have been used in the preparation of amino acids and pharmaceuticals. Two efficient, stereoselective methods of preparation, via acid- or base-promoted condensation reactions of carbamates, are described. The base-promoted reaction is E-selective, while acid catalysis can, through the choice of solvent, selectively form E or Z. The acid-catalyzed E-selective process proceeds through a crystallization obviating the need for chromatographic purification.
- Pollack, Scott R.,Dion, Amélie
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p. 11748 - 11762
(2021/09/07)
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- Development of the large-scale synthesis of tetrahydropyran glycine, a precursor to the HCV NS5A inhibitor BMS-986097
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An efficient large-scale synthesis of acid 1, a penultimate precursor to the HCV NS5A inhibitor BMS-986097, along with the final API step are described. Three routes were devised for the synthesis of 1 at the various stages of the program. The third generation route, the one that proved scalable and is the main subject of this paper, features a one-step Michael addition of t-butyl 2-((diphenylmethylene)amino)acetate (24) to (E)-benzyl 4-(1-hydroxycyclopropyl)but-2-enoate (28) followed by cyclization and chiral separation to form 27c, the core skeleton of cap piece 1. The epimerization and chiral resolution of 27c followed by further synthetic manipulations involving the carbamate formation, lactone reduction and cyclization, afforded cyclopropyl pyran 1. A detailed study of diphenylmethane deprotection via acid hydrolysis as well as a key lactone to tetrahydropyran conversion, in order to avoid a side reaction that afforded an alternative cyclization product, are discussed. This synthesis was applied to the preparation of more than 100 g of the final API BMS-986097 for toxicology studies.
- Mathur, Arvind,Wang, Bei,Smith, Daniel,Li, Jianqing,Pawluczyk, Joseph,Sun, Jung-Hui,Wong, Michael Kwok,Krishnananthan, Subramaniam,Wu, Dauh-Rurng,Sun, Dawn,Li, Peng,Yip, Shiuhang,Chen, Bang-Chi,Baran, Phil S.,Chen, Qi,Lopez, Omar D.,Yong, Zhong,Bender, John A.,Nguyen, Van N.,Romine, Jeffrey L.,St Laurent, Denis R.,Wang, Gan,Kadow, John F.,Meanwell, Nicholas A.,Belema, Makonen,Zhao, Rulin
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p. 10376 - 10387
(2018/05/31)
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- Synthesis of functionalized γ-lactone via Sakurai exo -cyclization/rearrangement of 3,3-bis(silyl) enol ester with a tethered acetal
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An efficient synthesis of functionalized γ-lactones has been developed involving Sakurai exo-cyclization/rearrangement of 3,3-bis(silyl) enol esters with a tethered acetal. While the steric and electronic effects of geminal bis(silane) favor the desired Sakurai pathway, the methoxy species formed in the deprotection step also facilitates both cyclization and rearrangement. The synthetic value of this approach has been demonstrated by efficiently transforming the E-vinylsilane into enyne and the γ-lactone moiety into multisubstituted THF.
- Yin, Zhiping,Liu, Zengjin,Huang, Zhenggang,Chu, Yang,Chu, Zhiwen,Hu, Jia,Gao, Lu,Song, Zhenlei
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supporting information
p. 1553 - 1556
(2015/03/30)
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- HEPATITIS C VIRUS INHIBITORS
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The present disclosure relates to compounds, compositions and methods for the treatment of Hepatitis C virus (HCV) infection. Also disclosed are pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment of HCV infection.
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Page/Page column 49
(2014/05/24)
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- Bronsted acid mediated cyclization of enaminones. Rapid and efficient access to the tetracyclic framework of the strychnos alkaloids
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The development of an efficient diastereoselective method that permits rapid construction of the tetracyclic core 17 of the Strychnos-Aspidosperma alkaloids is described. Enaminone 16, synthesized in high yield, has been cyclized under the influence of a Bronsted acid to provide the core tetracyclic framework 17 of the Strychnos alkaloids in optically active form or alternatively to the β-ketoester tetrahydro-β-carboline (THBC) unit 18, by varying the equivalents of acid and the molar concentration. Attempts to utilize 18 to form the C(7)-C(16) bond of the akuammiline related alkaloids represented by strictamine (22), using metal-carbenoid chemistry, are also described.
- Edwankar, Rahul V.,Edwankar, Chitra R.,Namjoshi, Ojas A.,Deschamps, Jeffrey R.,Cook, James M.
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supporting information; experimental part
p. 181 - 188
(2012/05/19)
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- HEPATITIS C VIRUS INHIBITORS
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The present disclosure relates to compounds, compositions and methods for the treatment of Hepatitis C virus (HCV) infection of following Fomula (I). Also disclosed are pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment of HCV infection.
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Page/Page column 49
(2012/12/13)
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- NOVEL HETEROCYCLYL COMPOUNDS
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The invention is concerned with novel heterocyclyl compounds of formula (I): wherein A, X, R3, R4, R5, R6, R7, R8, R9, R10, m, n and p are as defined in the description and in the claims, as well as physiologically acceptable salts thereof. These compounds are antagonists of CCR2 receptor, CCR5 receptor and/or CCR3 receptor and may be used as medicaments.
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Page/Page column 48
(2010/02/17)
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- Highly stereoselective hydrogenations-as key-steps in the total synthesis of statins
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Statins are inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG-CoA reductase) and became the standard of care for treatment of hypercholesterolemia because of their efficacy, safety, and long-term benefits. They are administered as diaste
- Andrushko, Natalia,Andrushko, Vasyl,Tararov, Vitali,Korostylev, Andrei,Koenig, Gerd,Boerner, Armin
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scheme or table
p. 534 - 541
(2010/08/20)
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- CARBOXAMIDE COMPOUNDS AND THEIR USE AS ANTAGONISTS OF THE CHEMOKINE CCR2 RECEPTOR
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Chemokine receptor antagonists, in particular, compounds of Formula (I) that act as antagonists of the chemokine CCR2 receptor, including pharmaceutical compositions and uses thereof to treat or prevent diseases associated with monocyte accumulation, lymphocyte accumulation or leukocyte accumulation are described; wherein (B/A) is an optionally substituted fused aromatic or partially aromatic bicyclic ring containing at least one nitrogen atom.
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Page/Page column 65-66
(2009/07/17)
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- Rational design of inhibitors of VirA-VirG two-component signal transduction
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VirA-VirG two-component system regulates the vir (virulence) operon in response to specific host factors (xenognosins) in the plant pathogen Agrobacterium tumefaciens. Using whole cell assays, stable inhibitors inspired by the labile natural benzoxazinone inhibitor HDMBOA are developed. It is found that aromatic aldehydes represent a minimal structural unit for activity. In particular, 3-hydroxy-4,6-dimethoxy-3H-isobenzofuran-1-one (HDI) was found to have the highest activity, making it the most potent developed inhibitor of virulence gene expression in Agrobacterium.
- Maresh, Justin,Zhang, Jin,Tzeng, Yih-Ling,Goodman, Nora A.,Lynn, David G.
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p. 3281 - 3286
(2008/02/08)
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- Aryl-and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
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The compounds of the present invention are represented by the following aryl- and heteroaryl-substituted tetrahydrobenzazepine and dihydrobenzazapine derivatives having formulae I(A-E) and formula (II): where the carbon atom designated * is in the R or S configuration, and the substituents X and R1-R9 are as defined herein.
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Page/Page column 58; 81; 82; 83; 84-85; 86; 88; 89; 91; 94; 95; 97
(2008/06/13)
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- Structural features in the seven-membered vs. Fourteen-membered ring cyclization of hydroxyamido ketals derived from β-amino alcohols
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Hydroxyamido ketals 1 and 3-12, prepared from β-amino alcohols, are obtained either as a single form with a trans (1 and 3-8) or cis (9) conformation in the R = H series or as two cis and trans rotamers in the R ≠ H series (10-12). - The cyclization of these compounds was studied under acidic conditions (PTSA) and over a well defined range of concentrations (c = 0.1-0.2 M). While cis amide 9 and mixtures of cis and trans rotamers 10-12 resulted practically exclusively in the formation of seven-membered ring lactams 22-25, trans compounds 1 and 3-8 afforded fourteen-membered ring bislactams 2, 13-18, the formation of which involves a dimerization. Macrocycles were obtained as three diastereomers in the chiral series 2, 13-16 and as two isomers in the achiral series 17 and 18. Nineteen macrocyclic bislactams have thus been synthesized.
- Valade, Anne-Gaelle,Dugat, Denise,Jeminet, Georges,Royer, Jacques,Husson, Henri-Philippe
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p. 2041 - 2053
(2007/10/03)
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- Carbostyril compounds connected via an oxyalkyl group with a piperidine ring and having pharmaceutical utility
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Carbostyril derivatives of Formula I: STR1 wherein: m is 0, 1, or 2; n is 0, 1, or 2; R1 is hydrogen or lower alkyl; R2 is hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy, aralkoxy, or acyloxy; R3 is hydrogen, halogen, lower alkyl, or lower alkoxy; R4 is hydrogen, hydroxy, lower alkyl, acyloxy, provided that when R4 is hydroxy or acyloxy, m and n are both 1; R5 is hydrogen or lower alkyl; and R6 is alkyl, hydroxyalkyl, alkoxyalkyl, or (dialkylamino)alkyl; and the pharmaceutically acceptable acid addition salts and N-oxides (at the carbostyril nitrogen) thereof, and compositions containing them, are useful in treating cardiovascular diseases, particularly arrhythmias. Methods of preparing intermediates, the compounds, their formulations and methods of treatment therewith are also disclosed.
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- New photochemical approaches to the synthesis of chromones
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Irradiation of the p-methoxyphenyl and p-methylphenyl esters of 2-butynoic, propynoic, 3-(ethylenedioxy)butanoic, 3,3-dimethoxypropanoic and 3-oxobutanoic acids (1-3) affords the corresponding photo-Fries products 4-6. Compound 5a is converted in part into the acetophenone 7a, by way of a Norrish type II photo-reaction, while compound 6a is reluctant to undergo this process, in spite of the fact that it also possess γ-carbonyl hydrogen atoms. From the preparative point of view, the photorearrangement of the esters 1a-d and 2a,c-d is exploitable, while that of 3a proceeds with a lower yield. The differences found in the photochemical behaviour of 2a and 3a show the sharp influence of the acetal group on the course of the reaction. Compounds 4-6 are representative model compounds valuable as direct chromone precursors; in fact, they can be readily cyclized to the chromones 10 under basic or acidic conditions.
- Alvaro, Mercedes,Garcia, Hermenegildo,Iborra, Sara,A. Miranda, Miguel,Primo, Jaime
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p. 143 - 148
(2007/10/02)
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