- Discovery of Novel and Highly Selective Inhibitors of Calpain for the Treatment of Alzheimer's Disease: 2-(3-Phenyl-1H-pyrazol-1-yl)-nicotinamides
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Calpain overactivation has been implicated in a variety of pathological disorders including ischemia/reperfusion injury, cataract formation, and neurodegenerative diseases such as Alzheimer's disease (AD). Herein we describe our efforts leading to the ide
- Kling, Andreas,Jantos, Katja,Mack, Helmut,Hornberger, Wilfried,Drescher, Karla,Nimmrich, Volker,Relo, Ana,Wicke, Karsten,Hutchins, Charles W.,Lao, Yanbin,Marsh, Kennan,Moeller, Achim
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p. 7123 - 7138
(2017/09/07)
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- A rapid and efficient one-pot method for the reduction of N-protected α-amino acids to chiral α-amino aldehydes using CDI/DIBAL-H
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N-Protected amino acids can be easily converted into chiral α-amino aldehydes in a one-pot reaction by activation with CDI followed by reduction with DIBAL-H. This method delivers Boc-, Cbz- and Fmoc-protected amino aldehydes from proteinogenic amino acids in very good isolated yields and complete stereointegrity.
- Ivkovic, Jakov,Lembacher-Fadum, Christian,Breinbauer, Rolf
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p. 10456 - 10460
(2015/11/10)
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- Resolution and absolute configuration of some a-aminoacetals: En route to enantiopure N-protected a-aminoaldehydes
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The first successful resolution of rac-a-aminoacetals via diastereoisomeric salt formation with optically pure N-protected aminoacids is reported. The absolute configuration assignment of a-aminoacetal enantiomers is performed by an entirely non-racemizing chemical correlation method involving N-protection and a new efficient hydrolysis step followed by a reduction of the resulting N-protected a-aminoaldehyde intermediates. A racemization method of optically enriched a-aminoacetals is exemplified to allow valorisation of both enantiomers. Springer-Verlag 2011.
- Albalat-Serradeil, Muriel,Primazot, Geraldine,Wilhelm, Didier,Vallejos, Jean-Claude,Vanthuyne, Nicolas,Roussel, Christian
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scheme or table
p. 687 - 696
(2012/09/22)
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- Carbonylation of functionalized diamine diols to cyclic ureas: Application to derivatives of DMP 450
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Synthesis of the cyclic urea core structure of the HIV protease inhibitor DMP 450 has been achieved via W(CO)6/I2-catalyzed carbonylation of diamine intermediates. Carbonylations of related functionalized diamines to derivatives of the DMP 450 core structure were also examined. Selected diamine diol substrates could be converted to the cyclic urea core structure by catalytic carbonylation without protection of the diol functionality.
- Darko, Ampofo K.,Curran, F. Chris,Copin, Chloé,McElwee-White, Lisa
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experimental part
p. 3976 - 3983
(2011/06/25)
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- A novel and efficient synthesis of chiral C2-symmetric 1,4-diamines
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A novel and efficient method for synthesis of (R,R)- and (S,S)-C2-symmetric 1,4-diamines was established. The key steps are a combination of Pinacol Coupling and Corey-Winter olefination.
- Xu, Lianhong,Desai, Manoj C.,Liu, Hongtao
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scheme or table
p. 552 - 554
(2009/05/07)
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- PROCESS OF DEACETALISATION OF ALPHA AMINOACETALS
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The invention relates to a process for the preparation of N-protected α-aminoaldehydes by deacetalization of the acetal functional group of corresponding N-protected α-aminoacetals using formic acid.
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Page/Page column 23-24
(2008/12/08)
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- HYDROXYMORPHOLINONE DERIVATIVE AND MEDICINAL USE THEREOF
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A compound represented by the following formula (I) wherein R1 and R2 are each a lower alkyl group optionally having substituents, which has a calpain inhibitory activity, or a salt thereof is provided.
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- Novel 6-Hydroxy-3-morpholinones as cornea permeable calpain inhibitors
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A novel series of 6-hydroxy-3-morpholinones, in which the functional aldehyde and the hydroxy group of P2 site form a cyclic hemiacetal, was identified as calpain inhibitors. The placement of isobutyl group at the 2-position of the 3-morpholino
- Nakamura, Masayuki,Miyashita, Hiroyuki,Yamaguchi, Masazumi,Shirasaki, Yoshihisa,Nakamura, Yoshikuni,Inoue, Jun
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p. 5449 - 5460
(2007/10/03)
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- A novel concept in combinatorial chemistry in solution with the advantages of solid-phase synthesis: Formation of N-betaines by multicomponent domino reactions
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Advantages of solid-phase and liquid-phase synthesis are combined in a new concept of combinatorial chemistry: a domino sequence comprising Knoevenagel and hetero-Diels-Alder reactions, with subsequent hydrogenation starting from protected aminoaldehydes, 1.3-dicarbonyl compounds, and enol ethers leads to N-heterocycles of high diversity with a betaine structure, which are isolated in highly pure form by precipitation with diethyl ether (see scheme), Cbz = benzylocycarbonyl, Bn = benzyl.
- Tietze, Lutz F.
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p. 903 - 905
(2007/10/03)
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- A new one-pot method for the synthesis of α-siloxyamides from aldehydes or ketones and its application to the synthesis of (-)-bestatin
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(equation presented) A new one-pot method for the synthesis of α-siloxyamides is described. The three substrates, H-C(CN)2O-SiMe2t-Bu, aldehydes or ketones, and primary or secondary amines, are simply mixed in one portion in acetonitrile or ether; the α-siloxyamides are obtained within short peroids in excellent yields in many cases. As a demonstration of our method, the synthesis of (-)-bestatin was carried out.
- Nemoto, Hisao,Ma, Rujian,Suzuki, Ichiro,Shibuya, Masayuki
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p. 4245 - 4247
(2007/10/03)
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- New synthetic technology for efficient construction of α-hydroxy-β-amino amides via the passerini reaction
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The Passerini reaction of N-protected amino aldehydes, isonitriles, and TFA using pyridine-type bases proceeds under mild conditions and directly affords α-hydroxy-β-amino amide derivatives in moderate to high yields. These adducts are readily hydrolyzed to αhydroxy-β-amino carboxylic acids. Application of these key intermediates to concise syntheses of P1-α-ketoamide protease inhibitors is illustrated.
- Semple, J. Edward,Owens, Timothy D.,Nguyen, Khanh,Levy, Odile E.
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p. 2769 - 2772
(2007/10/03)
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- Solid-phase synthesis of C-terminal peptide aldehydes from amino acetals anchored to a backbone amide linker (BAL) handle
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Peptide aldehydes were synthesized, starting from amino acetals, by a Solid-phase backbone amide linker (BAL) strategy. (C) 2000 Elsevier Science Ltd.
- Guillaumie,Kappel,Kelly,Barany,Jensen
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p. 6131 - 6135
(2007/10/03)
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- Process for producing optically active cyanohydrins
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An optically active cyanohydrin represented by the following general formula (1): STR1 wherein each of R1 and R2 is a hydrogen atom or an amino-protecting group, and the configurations relating to the carbon atoms at the *2-position and *3-position are as
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- Urethane group directed reductive couplings mediated by SmI2
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The SmI2-induced ketone-olefm coupling reactions of a-(alkoxycarbonyl)amino ketones 1 and 3 with methyl, ethyl, isopropyl, and tert-buty] crotohate took place with high stereocontrol about the new chiral centers providing the j)V!-l,2-amino alcohol products, sys-trans-γ-lactones 1 and 4, in excellent yields. Apparently, the stereochemical course of these reductive couplings is stereocontrolled by chelation of the Sm(in) cations attached to the resulting ketyl radicals with the urethane groups. Stereoselectivity increased as the size of the alkyl group of the esters of crotonic acid increased. In particular, 2 and 4 were almost exclusively obtained when the SmI2-induced couplings of 1 and 3 were carried out with rc;7-butyl crotonate. Interestingly, the hydroxy group-directed couplings induced by SmI2 of the a-hydroxy ketone 11 with methyl, ethyl, and isopropyl crotonate proceeded with a complete reversal of diastereoselectivity, almost exclusively providing the syn-l,2-diol product, yn-c/s-y-lactone 12.
- Matsuda, Fuyuhiko,Kawatsura, Motoi,Dekura, Fumiko,Shirahama, Haruhisa
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p. 2371 - 2375
(2007/10/03)
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- Inhibitors of β-amyloid protein production
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This invention relates to compounds and pharmaceutical compositions, and methods for inhibiting or preventing the amyloid protein deposits in the brain which are associated with Alzheimer's disease and aged Down's syndrome patients. More particularly, it relates to the treatment of Alzheimer's disease.
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- A concise and stereoselective synthesis of threo-γ-hydroxy-L-β-lysine lactone
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A stereoselective synthesis of threo-γ-hydroxy-β-L-lysine lactone is reported. The threo-amino alcohol functionality is introduced by iodine-mediated cyclocarbamation of the electron poor allylamine 6. The D-phenylalanine was used as starting material as
- Misiti, Domenico,Zappia, Giovanni,Delle Monache, Giuliano Delle
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p. 235 - 238
(2007/10/03)
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- Stereoselective synthesis of 2-amino-1-hydroxy-3-phenylpropylphosphonic acid
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A highly stereoselective synthesis of 2-amino-1-hydroxy-3-phenylpropylphosphonic acid was achieved by simple addition of diethyl phosphite to enantiomeric N-blocked phenylalaninals. These compounds exhibit significant herbicidal activity.
- Zygmunt, Jan,Gancarz, Roman,Lejczak, Barbara,Wieczorek, Piotr,Kafarski, Pawel
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p. 2989 - 2992
(2007/10/03)
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- Preparation and structure-activity relationship of novel P1/P1'- substituted cyclic urea-based human immunodeficiency virus type-1 protease inhibitors
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A series of novel P1/P1'-substituted cyclic urea-based HIV-1 protease inhibitors was prepared. Three different synthetic schemes were used to assemble these compounds. The first approach uses amino acid-based starting materials and was originally used to prepare DMP 323. The other two approaches use L-tartaric acid or L-mannitol as the starting material. The required four contiguous R,S,S,R centers of the cyclic urea scaffold are introduced using substrate control methodology. Each approach has specific advantages based on the desired P1/P1' substituent. Designing analogs based on the enzyme's natural substrates provided compounds with reduced activity. Attempts at exploiting hydrogen bond sites in the S1/S1' pocket, suggested by molecular modeling studies, were not fruitful. Several analogs had better binding affinity compared to our initial leads. Modulating the compound's physical properties led to a 10-fold improvement in translation resulting in better overall antiviral activity.
- Nugiel,Jacobs,Worley,Patel,Kaltenbach III,Meyer,Jadhav,De Lucca,Smyser,Klabe,Bacheler,Rayner,Seitz
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p. 2156 - 2169
(2007/10/03)
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- Stereoselective synthesis of HIV-1 protease inhibitor, DMP 323
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DMP 323, a potent HIV-1 protease inhibitor, has been synthesized by an efficient stereoselective process, amenable to large scale preparations. The core C2 symmetric diol was synthesized by a stereoselective pinacol coupling of CBZ protected D-phenylalanine. Judicious selection of protecting groups allowed cyclic urea formation under mild conditions, enhanced the ease of bis-alkylation, and led te intermediates which were easily purified without chromatography. Additionally, a one-pot, high yield process was developed te prepare the alkylating agent, 4-[(triphenylmethoxy)methyl]benzyl chloride from 1,4-benzenedimethanol.
- Pierce,Pierce, Michael E.,Harris,Harris, Gregory D.,Islam,Islam, Qamrul,Radesca,Radesca, Lilian A.,Storace,Storace, Louis,Waltermire,Waltermire, Robert E.,Wat,Wat, Ed,Jadhav,Jadhav, Prabhakar K.,Emmett,Emmett, George C.
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p. 444 - 450
(2007/10/02)
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- Cyclic HIV protease inhibitors: Synthesis, conformational analysis, P2/P2' structure-activity relationship, and molecular recognition of cyclic ureas
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High-resolution X-ray structures of the complexes of HIV-1 protease (HIV-1PR) with peptidomimetic inhibitors reveal the presence of a structural water molecule which is hydrogen bonded to both the mobile flaps of the enzyme and the two carbonyls flanking
- Lam, Patrick Y. S.,Ru, Yu,Jadhav, Prabhakar K.,Aldrich, Paul E.,DeLucca, George V.,Eyermann, Charles J.,Chang, Chong-Hwan,Emmett, George,Holler, Edward R.,Daneker, Wayne F.,Li, Liangzhu,Confalone, Pat N.,McHugh, Robert J.,Han, Qi,Li, Renhua,Markwalder, Jay A.,Seitz, Steven P.,Sharpe, Thomas R.,Bacheler, Lee T.,Rayner, Marlene M.,Klabe, Ronald M.,Shum, Linyee,Winslow, Dean L.,Kornhauser, David M.,Jackson, David A.,Erickson-Viitanen, Susan,Hodge, C. Nicholas
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p. 3514 - 3525
(2007/10/03)
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- 1,4-DIAMINO-2,3-DIHYDROXYBUTANES
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There are provided novel 1,4 Diamine 2,3 Dihydroxybutanes useful as antiviral agents, pharmaceutical compositions containing them and processes for preparing such compounds.
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- Synthesis and Stereoselective Reactions of 2-(Pyrrol-1-yl)alkanals and 2-(pyrrol-1-yl)alkan-1-ones
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2-(2,5-Dimethylpyrrol-1-yl)alkanals, 2-(pyrrol-1-yl)alkanals, and 2-(2,5-dimethylpyrrol-1-yl)alkan-1-ones were prepared.The reactions of these compounds with Grignard and hydride reagents proceeded stereoselectively to give the corresponding 2-(pyrrol-1-yl)alcohols, which were converted into 2-aminoalcohols, such as norephedrine and ephedrine, by cleavage of the pyrrole ring.
- Kashima, Choji,Maruyama, Tatsuya,Fujioka, Yoko,Harada, Kazuo
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p. 1041 - 1046
(2007/10/02)
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- Asymmetric Carbon to Nitrogen Bond Formation Using Optically Active Allylic Selenides: A New General Method for the Synthesis of N-Protected Optically Active α-Amino Acids
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Optically active allylic selenides undergo oxidative sigmatropic rearrangement to afford optically active, protected allylic amines.The synthetic utility of this process is demonstrated by the synthesis of several N-protected D-α-amino acids in 78-84percent enantiomeric excess.
- Fitzner, Jeffrey N.,Shea, Regan G.,Fankhauser, John E.,Hopkins, Paul B.
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p. 417 - 419
(2007/10/02)
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- Approaches to the Synthesis of Cytochalasans. Part 3. Synthesis of a Substituted Tetrahydroisoindolinone Moiety Possessing the Same Relative Configuration as Proxiphomin
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The total synthesis of the tetrahydroisoindolinone moiety corresponding to proxiphomin (1) is described, bearing functional groups for the attachment of the macrocyclic ring.Knoevenagel-Cope condensation of racemic 2-(benzyloxycarbonylamino)-3-phenylpropa
- Schmidlin, Tibur,Zuercher, Werner,Tamm, Christoph
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p. 235 - 250
(2007/10/02)
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