- Development of Chiral Organosuperbase Catalysts Consisting of Two Different Organobase Functionalities
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In the field of chiral Br?nsted base catalysis, a new generation of chiral catalysts has been highly anticipated to overcome the intrinsic limitation of pronucleophiles that are applicable to the enantioselective reactions. Herein, we reveal conceptually new chiral Br?nsted base catalysts consisting of two different organobase functionalities, one of which functions as an organosuperbase and the other as the substrate recognition site. Their prominent activity, which stems from the distinctive cooperative function by the two organobases in a single catalyst molecule, was demonstrated in the unprecedented enantioselective direct Mannich-type reaction of α-phenylthioacetate as a less acidic pronucleophile. The present achievement would provide a new guiding principle for the design and development of chiral Br?nsted base catalysts and significantly broaden the utility of Br?nsted base catalysis in asymmetric organic synthesis.
- Kondoh, Azusa,Oishi, Masafumi,Terada, Masahiro,Tezuka, Hikaru
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supporting information
p. 7472 - 7477
(2020/03/19)
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- Staudinger/aza-Wittig reaction to access Nβ-protected amino alkyl isothiocyanates
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A unified approach to access Nβ-protected amino alkyl isothiocyanates using Nβ-protected amino alkyl azides through a general strategy of Staudinger/aza-Wittig reaction is described. The type of protocol used to access isothiocyanates depends on the availability of precursors and also, especially in the amino acid chemistry, on the behavior of other labile groups towards the reagents used in the protocols; fortunately, we were not concerned about both these factors as precursor-azides were prepared easily by standard protocols, and the present protocol can pave the way for accessing title compounds without affecting Boc, Cbz and Fmoc protecting groups, and benzyl and tertiary butyl groups in the side chains. The present strategy eliminates the need for the use of amines to obtain title compounds and thus, this method is step-economical; additional advantages include retention of chirality, convenient handling and easy purification. A few hitherto unreported compounds were also prepared, and all final compounds were completely characterized by IR, mass, optical rotation, and 1H and 13C NMR studies.
- Santhosh,Durgamma,Shekharappa,Sureshbabu, Vommina V.
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p. 4874 - 4880
(2018/07/15)
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- [3 + 3] Cycloaddition of azides with in situ formed azaoxyallyl cations to synthesize 1,2,3,4-Tetrazines
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A formal [3 + 3] cycloaddition reaction between azides and in situ formed azaoxyallyl cations has been realized. This reaction provided an efficient and practical pathway to synthesize 1,2,3,4-tetrazines in good yields under mild conditions. Biologically active molecules could also be well compatible, highlighting the potential value of this reaction.
- Xu, Xiaoying,Zhang, Kaifan,Li, Panpan,Yao, Hequan,Lin, Aijun
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p. 1781 - 1784
(2018/04/14)
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- pH-Controlled recognition of amino acids by urea derivatives of β-cyclodextrin
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Water soluble amphiphilic urea-substituted β-cyclodextrins were synthesized and applied as amino acid receptors. A great affinity towards nonpolar amino acids was observed, ranging from 2300 M?1 for alanine to 54?800 M?1 for tryptoph
- Stepniak, Pawel,Lainer, Bruno,Chmurski, Kazimierz,Jurczak, Janusz
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p. 15742 - 15746
(2017/03/22)
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- N a aminopeptidase inhibitor and its preparation method and application
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The invention discloses an aminopeptidase N inhibitor which has a chemical name of 2-((S)-3-(3-((S)-2-amino-3-phenylpropyl)urea)-2,6-dioxopiperidine-1-yl)-N-hydroxyacetamide hydrochloride and is a compound with a structural formula (I) described in the sp
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- HETEROARYL SUBSTITUTED AMINOPYRIDINE COMPOUNDS
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Disclosed are compounds of Formula (I) or salts thereof, wherein HET is a heteroaryl selected from pyrrolo[2,3 b]pyridinyl, pyrrolo[2,3 d]pyrimidinyl, pyrazolo[3,4 b]pyridinyl, pyrazolo[3,4 d]pyrimidinyl, imidazolo[4,5 b]pyridinyl, and imidazolo[4,5 d]pyrimidinyl, wherein said heteroaryl is attached to the pyridinyl group in the compound of Formula (I) by a nitrogen ring atom in said heteroaryl and wherein said heteroaryl is substituted with zero to 2 Rb; A is pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxadiazolyl or dihydroisoxazolyl, each substituted with zero or 1 Ra; and R3, Ra, and Rb are define herein. Also disclosed are methods of using such compounds as modulators of IRAK4, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing inflammatory and autoimmune diseases, or in the treatment of cancer.
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- METHODS FOR INHIBITING DRUG DEGRADATION
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Methods of inhibiting cytochrome P450 enzymes are provided that can be used for improving the treatment of diseases by preventing degradation of drugs or other molecules by cytochrome P450. Pharmaceutical compositions are provided that can act as boosters
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Paragraph 0249; 0251
(2015/11/02)
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- A rapid entry to amino acid derived diverse 3,4-dihydropyrazines and dihydro[1,2,3]triazolo[1,5-a]pyrazines through 1,3-dipolar cycloaddition
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An efficient, general and practical synthesis of diverse 3,4-dihydropyrazines, 6,7-dihydro-[1,2,3]triazolopyrazines and 7,8-dihydro-[1,2,3]triazolodiazepines through intramolecular 1,3-dipolar cycloaddition from amino acid derived common intermediates with high yields is described. Moreover, one-pot access to optically active 3-aryl substituted 6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazines in the palladium-copper co-catalytic system has also been achieved in this work. The easy substrate availability and operational simplicity make the process suitable for further exploration. This journal is the Partner Organisations 2014.
- Bera, Saurav,Panda, Gautam
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p. 3976 - 3985
(2014/06/09)
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- Clickable coumarins as fluorescent labels for amino acids
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Seven trifunctional conjugates of Fmoc-protected amino acids with alkynyloxy-substituted coumarins have been prepared and spectroscopically characterized. The coumarin core was either coupled to the α or side chain amino group. This design allows for the
- Mertens, Matthias D.,Gütschow, Michael
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p. 2191 - 2200
(2014/08/18)
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- Bifunctional iminophosphorane organocatalysts for enantioselective synthesis: Application to the ketimine nitro-Mannich reaction
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The design, synthesis, and development of a new class of modular, strongly basic, and tunable bifunctional Bronsted base/H-bond-donor organocatalysts are reported. These catalysts incorporate a triaryliminophosphorane as the Bronsted basic moiety and are readily synthesized via a last step Staudinger reaction of a chiral organoazide and a triarylphosphine. Their application to the first general enantioselective organocatalytic nitro-Mannich reaction of nitromethane to unactivated ketone-derived imines allows the enantioselective construction of β-nitroamines possessing a fully substituted carbon atom. The reaction is amenable to multigram scale-up, and the products are useful for the synthesis of enantiopure 1,2-diamine and α-amino acid derivatives.
- Nunez, Marta G.,Farley, Alistair J. M.,Dixon, Darren J.
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supporting information
p. 16348 - 16351
(2013/12/04)
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- Helix-forming propensity of aliphatic urea oligomers incorporating noncanonical residue substitution patterns
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Aliphatic N,N′-linked oligoureas are peptidomimetic foldamers that adopt a well-defined helical secondary structure stabilized by a collection of remote three-center H-bonds closing 12- and 14-membered pseudorings. Delineating the rules that govern helix formation depending on the nature of constituent units is of practical utility if one aims to utilize this helical fold to place side chains in a given arrangement and elaborate functional helices. In this work, we tested whether the helix geometry is compatible with alternative substitution patterns. The central -NH-CH(R)-CH2-NH-CO- residue in a model oligourea pentamer sequence was replaced by guest units bearing various substitution patterns [e.g., -NH-CH2-CH2-NH-CO-, -NH-CH2-CH(R)-NH-CO-, and -NH-CH(R1)-CH(R 2)-NH-CO-], levels of preorganization (cyclic vs acyclic residues), and stereochemistries, and the helix formation was systematically assessed. The extent of helix perturbation or stabilization was primarily monitored in solution by Fourier transform IR, NMR, and electronic circular dichroism spectroscopies. Our results indicate that although three new substitution patterns were accommodated in the 2.5-helix, the helical urea backbone in short oligomers is particularly sensitive to variations in the residue substitution pattern (position and stereochemistry). For example, the trans-1,2- diaminocyclohexane unit was experimentally found to break the helix nucleation, but the corresponding cis unit did not. Theoretical calculations helped to rationalize these results. The conformational preferences in this series of oligoureas were also studied at high resolution by X-ray structure analyses of a representative set of modified oligomers.
- Pendem, Nagendar,Douat, Celine,Claudon, Paul,Laguerre, Michel,Castano, Sabine,Desbat, Bernard,Cavagnat, Dominique,Ennifar, Eric,Kauffmann, Brice,Guichard, Gilles
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p. 4884 - 4892
(2013/05/09)
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- Syntheis of new chiral 5,6,7,8-tetrahydrotetrazolo[1,5-a]pyrazines from α-amino acid derivatives following "click" chemistry
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An efficient and practical synthesis of new chiral fused tetrazoles have been synthesized following [3+2] cycloaddition reaction starting from α-amino acid derivatives.
- Mohapatra, Debendra K.,Maity, Pradip K.,Ghorpade, Ravindra V.,Gurjar, Mukund K.
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scheme or table
p. 865 - 872
(2010/09/16)
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- HIV PROTEASE INHIBITOR AND CYTOCHROME P450 INHIBITOR COMBINATIONS
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Compositions and methods of treating viral infections are provided. More particularly, compositions including a combination of protease inhibitors and cytochrome p450 enzyme inhibitors are provided. Methods of using the compositions for treatment of disea
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Page/Page column 45
(2009/10/18)
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- Discovery of highly potent and selective inhibitors of neuronal nitric oxide synthase by fragment hopping
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Selective inhibition of neuronal nitric oxide synthase (nNOS) has been shown to prevent brain injury and is important for the treatment of various neurodegenerative disorders. This study shows that not only greater inhibitory potency and isozyme selectivity but more druglike properties can be achieved by fragment hopping. On the basis of the structure of lead molecule 6, fragment hopping effectively extracted the minimal pharmacophoric elements in the active site of nNOS for ligand hydrophobic and steric interactions and generated appropriate lipophilic fragments for lead optimization. More potent and selective inhibitors with better druglike properties were obtained within the design of 20 derivatives (compounds 7-26). Our structure - based inhibitor design for nNOS and SAR analysis reveal the robustness and efficiency of fragment hopping in lead discovery and structural optimization, which implicates a broad application of this approach to many other therapeutic targets for which known druglike small-molecule modulators are still limited.
- Ji, Haitao,Li, Huiying,Martásek, Pavel,Roman, Linda J.,Poulos, Thomas L.,Silverman, Richard B.
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experimental part
p. 779 - 797
(2009/12/07)
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- Synthesis and evaluation of inhibitors of cytochrome P450 3A (CYP3A) for pharmacokinetic enhancement of drugs
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The HIV protease inhibitor ritonavir (RTV) is also a potent inhibitor of the metabolizing enzyme cytochrome P450 3A (CYP3A) and is clinically useful in HIV therapy in its ability to enhance human plasma levels of other HIV protease inhibitors (PIs). A nov
- Flentge, Charles A.,Randolph, John T.,Huang, Peggy P.,Klein, Larry L.,Marsh, Kennan C.,Harlan, John E.,Kempf, Dale J.
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supporting information; experimental part
p. 5444 - 5448
(2010/05/02)
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- COMPOSITIONS AND METHODS FOR INHIBITING CYTOCHROME P450
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Methods of inhibiting cytochrome P450 enzymes are provided that can be used for improving the treatment of diseases by preventing degradation of drugs or other molecules by cytochrome P450. Pharmaceutical compositions are provided that can act as boosters
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Page/Page column 48
(2008/06/13)
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- Amino-substituted heterocycles, compositions thereof, and methods of treatment therewith
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Provided herein are Heterocyclic Compounds having the following structure: wherein R1, R2, X, Y and Z are as defined herein, compositions comprising an effective amount of a Heterocyclic Compound and methods for treating or preventing cancer, inflammatory conditions, immunological conditions, metabolic conditions and conditions treatable or preventable by inhibition of a kinase pathway comprising administering an effective amount of a Heterocyclic Compound to a patient in need thereof.
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Page/Page column 54
(2008/12/07)
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- Synthesis of new chiral 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazines from α-amino acid derivatives under mild conditions
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A practical and efficient regioselective synthesis of several new chiral 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazines is described from α-amino acid derivatives following intramolecular 'click' reaction as the key step. The method obviates product pu
- Mohapatra, Debendra K.,Maity, Pradip K.,Gonnade, Rajesh G.,Chorghade, Mukund S.,Gurjar, Mukund K.
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p. 1893 - 1896
(2008/03/13)
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- Discovery of isonicotinamide derived β-secretase inhibitors: In vivo reduction of β-amyloid
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β-Secretase inhibition offers an exciting opportunity for therapeutic intervention in the progression of Alzheimer's disease. A series of isonicotinamides derived from traditional aspartyl protease transition state isostere inhibitors has been optimized to yield low nanomolar inhibitors with sufficient penetration across the blood-brain barrier to demonstrate β-amyloid lowering in a murine model.
- Stanton, Matthew G.,Stauffer, Shaun R.,Gregro, Alison R.,Steinbeiser, Melissa,Nantermet, Philippe,Sankaranarayanan, Sethu,Price, Eric A.,Wu, Guoxin,Crouthamel, Ming-Chih,Ellis, Joan,Lai, Ming-Tain,Espeseth, Amy S.,Shi, Xiao-Ping,Jin, Lixia,Colussi, Dennis,Pietrak, Beth,Huang, Qian,Xu, Min,Simon, Adam J.,Graham, Samuel L.,Vacca, Joseph P.,Selnick, Harold
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p. 3431 - 3433
(2008/02/11)
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- GUANIDINE-THIOUREA COMPOUND AND PROCESS FOR PRODUCTION OF NITRO ALCOHOL USING THE SAME
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Disclosed are: a guanidine-thiourea compound which can realize the production of a desired nitro alcohol through Henry reaction at a high optical purity and a high yield with reduced environmental impact; and a process for producing a nitro alcohol using the compound. The guanidine-thiourea compound can be produced through relatively simple steps and can realize the production of a desired nitro alcohol at a high optical purity and a high yield.
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Page/Page column 85-87
(2010/11/25)
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- Discovery and SAR of isonicotinamide BACE-1 inhibitors that bind β-secretase in a N-terminal 10s-loop down conformation
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A series of low-molecular weight 2,6-diamino-isonicotinamide BACE-1 inhibitors containing an amine transition-state isostere were synthesized and shown to be highly potent in both enzymatic and cell-based assays. These inhibitors contain a trans-S,S-methyl cyclopropane P3 which bind BACE-1 in a 10s-loop down conformation giving rise to highly potent compounds with favorable molecular weight and moderate to high susceptibility to P-glycoprotein (P-gp) efflux.
- Stauffer, Shaun R.,Stanton, Matthew G.,Gregro, Alison R.,Steinbeiser, Melissa A.,Shaffer, Jennifer R.,Nantermet, Philippe G.,Barrow, James C.,Rittle, Kenneth E.,Collusi, Dennis,Espeseth, Amy S.,Lai, Ming-Tain,Pietrak, Beth L.,Holloway, M. Katharine,McGaughey, Georgia B.,Munshi, Sanjeev K.,Hochman, Jerome H.,Simon, Adam J.,Selnick, Harold G.,Graham, Samuel L.,Vacca, Joseph P.
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p. 1788 - 1792
(2008/02/02)
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- (INDAZOL-5-YL)-PYRAZINES AND (1,3-DIHYDRO-INDOL-2-ONE)-PYRAZINES FOR TREATING RHO KINASE-MEDIATED DISEASES AND CONDITIONS
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Methods for using (indazol-5-yl)-pyrazines and (1,3-dihydro-indol-2-one)-pyrazines are disclosed herein to treat rho kinase-mediated diseases or rho kinase-mediated conditions, including controlling intraocular pressure and treating glaucoma, are disclosed. Ophthalmic pharmaceutical compositions useful in the treatment of eye diseases such as glaucoma, and additionally useful for controlling intraocular pressure, the compositions comprising an effective amount of (indazol-5-yl)-pyrazines and (1,3-dihydro-indol-2-one)-pyrazines, are disclosed herein.
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Page/Page column 7
(2010/11/27)
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- Novel compounds that are useful for improving pharmacokinetics
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Novel compounds of formula 1 or a pharmaceutically acceptable salt thereof inhibit cytochrome P450 monooxygenase.
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Page/Page column 25
(2008/06/13)
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- The solid phase synthesis of oligoureas
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An efficient method for solid phase synthesis of oligoureas from readily prepared optically active azido 4-nitrophenyl carbamate monomers is described.
- Kim, Jong-Man,Bi, Yingzhi,Paikoff, Sari J.,Schultz, Peter G.
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p. 5305 - 5308
(2007/10/03)
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- Synthesis of C2-symmetric (S,S)-1,4-dibenzyl-DTPA and 1,4-meso-dibenzyl-DTPA via chiral diamines
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Novel routes to C2-symmetric (S,S)-1,4-dibenzyl-DTPA and 1,4-meso-dibenzyl-DTPA are described. The methodology utilizes readily available starting materials.
- Sajiki, Hironao,Ong, Karen Y.
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p. 14507 - 14514
(2007/10/03)
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- Inhibitors of acyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. 8. Incorporation of amide or amine functionalities into a series of disubstituted ureas and carbamates. Effects of ACAT inhibition in vitro and efficacy in vivo
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A series of disubstituted ureas containing amide or amine groups was prepared and evaluated for their ability to inhibit acyl-CoA:cholesterol O- acyl transferase in vitro and to lower plasma total cholesterol in a variety of cholesterol-fed rat models in vivo. The presence of polar or ionizable functionalities within this class of compounds may impart greater aqueous solubility to those compounds and thus allow improved transport to the enzyme location within the intestinal enterocyte. Compounds from this class exhibit good cholesterol lowering in a chronic cholesterol-fed rat model of hypercholesterolemia even when dosed in an aqueous vehicle. In general, the amine-containing compounds were more potent and efficacious than the amides in the acute rat model of hypercholesterolemia. Further structure-activity relationship studies showed that the preferred position of the amide/amine group was β to the urea moiety and not α, and that in this series, the presence of a secondary amine (or amide) proton is required for good in vitro potency. One of these compounds, 9n(-), lowered plasma total cholesterol (- 47%) and elevated high-density lipoprotein cholesterol (+256%) when dosed in an aqueous vehicle to rats with preestablished hypercholesterolemia.
- O'Brien,Sliskovic,Blankley,Roth,Wilson,Hamelehle,Krause,Stanfield
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p. 1810 - 1822
(2007/10/02)
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- Modified Amino Acids and Peptides. Part 2. A Convenient Conversion of Amino and Peptide Alcohols into Amines.
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A convenient general method for the conversion of N-protected amino and peptide alcohols into amines is described.The hydroxyl group of the alcohols was replaced by an azido group and a substituted amino group after activation through mesylation.Hydrogenation of the N-protected amino azides afforded optically active monoprotected diamines or free 1,2-diamines depending on the N-protecting group.Selective reduction of the azido group in the presence of a benzyloxycarbonyl group was performed in high yield using sodium borohydride in the presence of 10percent palladium on charcoal.
- Kokotos, George,Constantinou-Kokotou, Violetta
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p. 3117 - 3132
(2007/10/02)
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