- A convenient synthesis of N-methoxy-N-methylamides from carboxylic acids
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Carboxylic acids can be converted to their corresponding N-methoxy-N-methylamides in high yields using 2-chloro-1-methylpyridinium iodide as the coupling agent. The reaction proceeds without racemization when chiral carboxylic acids are used as the starting material.
- Sibi,Stessman,Schultz,Christensen,Lu,Marvin
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- Practical one-pot double functionalizations of proline
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Solubilization of proline as the triethylammonium salt allows N-protection (as the Boc, Cbz or Moc derivative) and subsequent esterification or amidation of the carboxy terminus to be performed in an efficient one-pot fashion. Based on this concept, highly practical protocols were developed to prepare a series of proline derivatives (including Pro-Ser dipetides, Weinreb amides and N-protected proline esters), which are important intermediates, for instance, for the synthesis of proline-derived peptides, chiral reagents and catalysts for asymmetric synthesis. Georg Thieme Verlag Stuttgart - New York.
- Huy, Peter,Schmalz, Hans-Guenther
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- β-fluorinated proline derivatives: Potential transition state inhibitors for proline selective serine dipeptidases
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Three new types of β-fluorinated proline derivatives were synthesized as potential transition state inhibitors for proline selective serine dipeptidases. The fluorophosponate derived from protected proline was tested as a Wadsworth-Horner-Emmons reagent for the synthesis of fluoro-olefin-containing pseudodipeptides.
- Van Der Veken, Pieter,Senten, Kristel,Kertèsz, István,Haemers, Achiel,Augustyns, Koen
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- 1,2,3-Triazole Stabilized Neurotensin-Based Radiopeptidomimetics for Improved Tumor Targeting
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Neurotensin (NT) is a regulatory peptide with nanomolar affinity toward NT receptors, which are overexpressed by different clinically relevant tumors. Its binding sequence, NT(8-13), represents a promising vector for the development of peptidic radiotracers for tumor imaging and therapy. The main drawback of the peptide is its short biological half-life due to rapid proteolysis in vivo. Herein, we present an innovative strategy for the stabilization of peptides using nonhydrolizable 1,4-disubstituted, 1,2,3-triazoles as amide bond surrogates. A triazole scan?of the peptide sequence yielded novel NT(8-13) analogues with enhanced stability, retained receptor affinity, and improved tumor targeting properties in vivo. The synthesis of libraries of triazole-based peptidomimetics was achieved efficiently on solid support by a combination of Fmoc-peptide chemistry, diazo transfer reactions, and the Cu(I)-catalyzed alkyne azide cycloaddition (CuAAC) employing methods that are fully compatible with standard solid phase peptide synthesis (SPPS) chemistry. Thus, the amide-to-triazole substitution strategy may represent a general methodology for the metabolic stabilization of biologically active peptides.
- Mascarin, Alba,Valverde, Ibai E.,Vomstein, Sandra,Mindt, Thomas L.
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- An expedient conversion of α-amino acids into Weinreb amides using COMU As a coupling agent
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The use of COMU, as a non-hazardous partner, in the coupling of N-protected α-amino acids to N-methoxy-N-methylamine to afford the corresponding Weinreb amides is discussed. From a practical point of view the reaction can be monitored visually by virtue of the colour change associated with the conversion of substrates (yellow) into the products (orange). As the by-products of the reaction are conveniently water-soluble the products are isolated relatively pure and with minimal racemisation. These factors coupled with the short reaction time make this a very useful procedure.
- Tyrrell, Elizabeth,Brawn, Peter,Carew, Mark,Greenwood, Iain
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- In search of constrained FTY720 and phytosphingosine analogs as dual acting anticancer agents targeting metabolic and epigenetic pathways
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A series of compounds containing pyrrolidine and pyrrolizidine cores with appended hydrophobic substituents were prepared as constrained analogs of FTY720 and phytosphingosine. The effect of these compounds on the viability of cancer cells, on downregulation of the nutrient transport systems, and on their ability to cause vacuolation was studied. An attempt to inhibit HDACs with some phosphate esters of our analogs was thwarted by our failure to reproduce the reported inhibitory action of FTY720-phosphate.
- Garsi, Jean-Baptiste,Sernissi, Lorenzo,Vece, Vito,Hanessian, Stephen,McCracken, Alison N.,Simitian, Grigor,Edinger, Aimee L.
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- Efficient Analysis of 2-Acetyl-1-pyrroline in Foods Using a Novel Derivatization Strategy and LC-MS/MS
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2-Acetyl-1-pyrroline (2-AP) is a key odorant in many foods, such as aromatic rice and wheat bread, with a very low odor threshold of 0.05 μg/L in water. The small molecule with a popcornlike, roasty odor is generated biologically or by Strecker degradation within the Maillard-reaction cascades during thermal food processing with methylglyoxal and 1-pyrroline as the main direct precursors. Numerous gas-chromatographic methods for the analysis of 2-AP have been published, but the reactivity of the compound leads to discrimination or degradation during sample workup. We developed a novel derivatization method for 2-AP with o-phenylenediamine followed by HPLC-MS/MS analysis of the resulting stable quinoxaline. The precision (7%), repeatability (14%), recovery (92%), linearity (0.79-500 μg/kg), limit of detection (LOD, 0.26 μg/kg), and limit of quantitation (LOQ, 0.79 μg/kg) were validated for rice matrix and were excellent as compared with those of methods published before. With the novel method, 2-AP levels in typical foods like aromatic rice (131 μg/kg), wheat bread (18 μg/kg), brown bread (18 μg/kg), rye bread (18 μg/kg), and popcorn (38 μg/kg) were determined.
- Jost, Tobias,Heymann, Thomas,Glomb, Marcus A.
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- A convenient method for the conversion of hindered carboxylic acids to N-methoxy-N-methyl (Weinreb) amides
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The conversion of sterically hindered carboxylic acids to N-methoxy-N-methyl amides can be efficiently carried out with 1.1 equiv of methanesulfonyl chloride, 3 equiv of triethylamine, and 1.1 equiv of N-methoxy-N-methylamine. Yields for this process rang
- Woo, Jacqueline C. S.,Fenster, Erik,Dake, Gregory R.
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- An intramolecular Tsuji-Trost reaction based approach to the synthesis of 6-methylene indolizidines
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Herein we describe the efficient stereoselective preparation of C8 substituted indolizidines bearing a 6-methylene group, from the chiral pool starting material l-proline. This synthesis, employing a Tsuji-Trost reaction as the key step, represents a potentially, efficient route to pumiliotoxin natural product epimers. Crown Copyright
- Martin, Romy E.,Polomska, Marta E.,Byrne, Lindsay T.,Stewart, Scott G.
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- Synthesis and activity of 3-pyridylamine ligands at central nicotinic receptors
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A series of thirty 2-(3-pyridylaminomethyl)azetidine, pyrrolidine and piperidine analogues as nicotinic acetylcholine receptor (nAChR) ligands was explored. In general, pyrrolidinyl and many azetidinyl compounds were found to bind with enhanced affinity relative to the piperidines. In the three series, the parallel structural changes (stereochemistry, N-methylation and/or chloro substitution) do not consistently lead to parallel shifts in affinity. The more active compounds (K(i) affinity values ranging from 8.9 to 90 nM) were about as analgesic as nicotine in a tail-flick assay in mice after subcutaneous injections. (C) 2000 Editions scientifiques et medicales Elsevier SAS.
- Balboni, Gianfranco,Marastoni, Mauro,Merighi, Stefania,Borea, Pier Andrea,Tomatis, Roberto
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- Convenient Synthesis of Alternatively Bridged Tryptophan Ketopiperazines and Their Activities against Trypanosomatid Parasites
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There is an urgent need for the development of new treatments against trypanosomatid parasites; the causative agents of some of the most debilitating diseases in the developing world. This work targets an interesting 6-5-6-6 fused carboline scaffold, accessing a range of substituted derivatives through stereospecific intramolecular Pictet–Spengler condensation. Modification of the cyclisation conditions allowed retention of the carbamate protecting group and gave insight into the reaction mechanism. Compounds’ bioactivities were measured against T. brucei, T. cruzi, L. major and HeLa cells. We have identified promising pan-trypanocidal lead compounds based on the core scaffold, and highlight key SAR trends which will be useful for the future development of these compounds as potent trypanocidal agents.
- Cockram, Peter E.,Turner, Callum A.,Slawin, Alexandra M. Z.,Smith, Terry K.
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supporting information
(2022/01/11)
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- Formal Fluorinative Ring Opening of 2-Benzoylpyrrolidines Utilizing [1,2]-Phospha-Brook Rearrangement for Synthesis of 2-Aryl-3-fluoropiperidines
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A ring expansion of 2-benzoylpyrrolidines, which involves the formal fluorinative ring opening utilizing the [1,2]-phospha-Brook rearrangement under Br?nsted base catalysis and a subsequent intramolecular reductive amination, was developed. The operationally simple three-step protocol provides an efficient access to 2-aryl-3-fluoropiperidines. The methodology was further applied to the syntheses of azepanes and tetrahydroquinolines.
- Kondoh, Azusa,Ojima, Rihaku,Terada, Masahiro
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supporting information
p. 7894 - 7899
(2021/10/20)
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- Macrocyclic compound serving as ALK and ROS regulators
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The invention belongs to the field of medicinal chemistry, and relates to a macrocyclic compound serving as an ALK and ROS regulators, in particular to a compound as shown in a formula I or pharmaceutically acceptable salt thereof, a preparation method, a
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Paragraph 0309-0312
(2021/05/19)
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- Diastereoselective Synthesis of Nonplanar 3-Amino-1,2,4-oxadiazine Scaffold: Structure Revision of Alchornedine
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Herein, we report the diastereoselective synthesis of a 3-amino-1,2,4-oxadiazine (AOXD) scaffold. The presence of a N-O bond in the ring prevents the planar geometry of the aromatic system and induces a strong decrease in the basicity of the guanidine moiety. While DIBAL-H appeared to be the most efficient reducing agent because it exhibited high diastereoselectivity, we observed various behaviors of the Mitsunobu reaction on the resulting β-aminoalcohol, leading to either inversion or retention of the configuration depending on the steric hindrance in the vicinity of the hydroxy group. The physicochemical properties (pKa and log D) and hepatic stability of several AOXD derivatives were experimentally determined and found that the AOXD scaffold possesses promising properties for drug development. Moreover, we synthesized alchornedine, the only natural product with the AOXD scaffold. Based on a comparison of the analytical data, we found that the reported structure of alchornedine was incorrect and hypothesized a new one.
- Bihel, Frédéric,Bricard, Jacques,Garnier, Delphine,Gizzi, Patrick,Leloire, Maeva,Mohr, Julie,Schmitt, Martine,Schneider, Séverine,Tang, Shuang-Qi
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p. 15347 - 15359
(2020/11/30)
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- SYNTHETIC CYTOTOXIC MOLECULES, DRUGS, METHODS OF THEIR SYNTHESIS AND METHODS OF TREATMENT
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Small molecules compounds and methods of their synthesis are provided. Formulations and medicaments are also provided that are directed to the treatment of disease, such as, for example, neoplasms, cancers, and other diseases. Therapeutics are also provided containing a therapeutically effective dose of one or more small molecule compounds, present either as pharmaceutically effective salt or in pure form, including, but not limited to, formulations for oral, intravenous, or intramuscular administration.
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Paragraph 0052; 0170
(2020/01/08)
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- Pyrazolo[3,4-c]pyridine-7-amine derivative, and preparation method and application thereof
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The invention discloses a pyrazolo[3,4-c]pyridine-7 amine derivative, and a preparation method and an application thereof, and provides a compound represented by formula I, and a pharmaceutically acceptable salt, a polymorph, a hydrate, a solvate, an acti
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Paragraph 0067-0074
(2019/10/05)
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- Aromatic cycloamines derivative and application in multi-target antidepressant medicine
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The invention discloses an aromatic cycloamines derivative and an application in multi-target antidepressant medicine. The aromatic cycloamines derivative has inhibitory activity on 5-HT reuptake, NEreuptake and DA reuptake, is a novel compound of a 5-HT/
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Paragraph 0079; 0080; 0088; 0089
(2019/11/29)
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- PROCESS FOR THE PREPARATION OF CHIRAL PYROLLIDINE-2-YL- METHANOL DERIVATIVES
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The invention relates to a novel process for the preparation of a chiral pyrollidine-2-yl-methanol derivative or a salt thereof of the formula (I), wherein R1 is aryl or heteroaryl and both aryl or heteroaryl are optionally substituted by C1-4-alkyl, halo-C1-4-alkyl, C1-4-alkoxy or halogen. The synthesis proceeds through an intermediate Weinreb amide, which is reacted with a Grignard reagent and hydrogenated. The chiral pyrollidine-2-yl-methanol derivatives of the formula (I) are versatile building blocks in the synthesis of pharmacologically active compounds, such as for the stereospecific synthesis of oligonucleotides carrying chiral phosphonate moieties.
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Page/Page column 12-13
(2018/09/26)
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- COMPOUNDS, COMPOSITIONS AND METHODS FOR SYNTHESIS
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The present disclosure, among other things, provides technologies for synthesis, including reagents and methods for stereoselective synthesis. In some embodiments, the present disclosure provides compounds useful as chiral auxiliaries. In some embodiments, the present disclosure provides reagents and methods for oligonucleotide synthesis. In some embodiments, the present disclosure provides reagents and methods for chirally controlled preparation of oligonucleotides. In some embodiments, technologies of the present disclosure are particularly useful for constructing challenging internucleotidic linkages, providing high yields and stereoselectivity.
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Paragraph 00577; 00579; 00581; 00582; 00614; 00615; 00616
(2019/01/10)
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- Series of Alkynyl-Substituted Thienopyrimidines as Inhibitors of Protozoan Parasite Proliferation
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Discovery of new chemotherapeutic lead agents can be accelerated by optimizing chemotypes proven to be effective in other diseases to act against parasites. One such medicinal chemistry campaign has focused on optimizing the anilinoquinazoline drug lapatinib (1) and the alkynyl thieno[3,2-d]pyrimidine hit GW837016X (NEU-391, 3) into leads for antitrypanosome drugs. We now report the structure-activity relationship studies of 3 and its analogs against Trypanosoma brucei, which causes human African trypanosomiasis (HAT). The series was also tested against Trypanosoma cruzi, Leishmania major, and Plasmodium falciparum. In each case, potent antiparasitic hits with acceptable toxicity margins over mammalian HepG2 and NIH3T3 cell lines were identified. In a mouse model of HAT, 3 extended life of treated mice by 50%, compared to untreated controls. At the cellular level, 3 inhibited mitosis and cytokinesis in T. brucei. Thus, the alkynylthieno[3,2-d]pyrimidine chemotype is an advanced hit worthy of further optimization as a potential chemotherapeutic agent for HAT.
- Woodring, Jennifer L.,Behera, Ranjan,Sharma, Amrita,Wiedeman, Justin,Patel, Gautam,Singh, Baljinder,Guyett, Paul,Amata, Emanuele,Erath, Jessey,Roncal, Norma,Penn, Erica,Leed, Susan E.,Rodriguez, Ana,Sciotti, Richard J.,Mensa-Wilmot, Kojo,Pollastri, Michael P.
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supporting information
p. 996 - 1001
(2018/09/21)
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- Cationic Chiral Fluorinated Oxazaborolidines. More Potent, Second-Generation Catalysts for Highly Enantioselective Cycloaddition Reactions
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The coordination of chiral ligands to Lewis acid metal derivatives, a useful strategy for enantioselective, electrophilic catalysis, generally leads to a lower level of catalytic activity than that of the original uncomplexed compound. Activation by furth
- Mahender Reddy, Karla,Bhimireddy, Eswar,Thirupathi, Barla,Breitler, Simon,Yu, Shunming,Corey
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p. 2443 - 2453
(2016/03/08)
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- Gold-catalyzed synthesis of enantioenriched furfurylamines from amino acids
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Abstract A convenient gold-catalyzed asymmetric synthesis of polysubstituted furfurylamines starting from amino acids has been achieved. The cyclization proceeded under mild conditions and generally provided the furan or iodofuran derivatives in good to e
- Guieu, Benjamin,Le Roch, Myriam,David, Michèle,Gouault, Nicolas
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p. 868 - 875
(2015/08/18)
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- Total synthesis of (+)-antofine and (-)-cryptopleurine
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The tylophorine alkaloid anticancer compounds antofine and cryptopleurine have been synthesized in optically active form. Both syntheses use optically pure α-amino acids as the starting materials, require only seven steps from known 2-ethynylpyrrolidine or 2-ethynylpiperidine derivatives, and are free of protecting groups. The key steps include an alkyne hydration and a chromium-carbene-complex-based net [5 + 5]-cycloaddition step. The alkyne hydration was accompanied by racemization of the β-amino ketone product under most of the conditions examined, and minimization of this side-reaction was achieved through careful pH control and choice of metal additive. The final ring closure involved a Bischler-Napieralski reaction using a carbamate (antofine) or urea (cryptopleurine) precursor. Single enantiomers of the tylophorine alkaloids antofine and cryptopleurine have been prepared by using a short synthesis that involves regioselective alkyne hydration of a chiral propargylic amide, Fischer carbene complex mediated net [5+5] cycloaddition, and urea-based Friedel-Crafts acylation as key steps. Copyright
- Ying, Weijiang,Herndon, James W.
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supporting information
p. 3112 - 3122
(2013/06/26)
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- Rh2(II)-catalyzed selective aminomethylene migration from styryl azides
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Rh2(II)-Carboxylate complexes were discovered to promote the selective migration of aminomethylenes in β,β-disubstituted styryl azides to form 2,3-disubstituted indoles. Mechanistic data are also presented that suggest that the migration occurs stepwise before diffusion of the iminium ion.
- Kong, Chen,Jana, Navendu,Driver, Tom G.
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supporting information
p. 824 - 827
(2013/03/29)
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- Efficient synthesis of N-protected amino/peptide Weinreb amides from T3P and DBU
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The reaction of Nα-protected amino/peptide acid with N,O-dimethylhydroxylamine hydrochloride in the presence of T3P and DBU to obtain enantiomerically pure Nα-protected amino/peptidyl Weinreb amides in high yields has been described. Fmoc-Ala-Weinreb amide 2a is obtained as single crystal, and its structure was determined through X-ray crystallography.
- Sharnabai,Nagendra,Vishwanatha,Sureshbabu, Vommina V.
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p. 478 - 482
(2013/02/23)
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- A facile approach to the synthesis of securinega alkaloids: stereoselective total synthesis of (-)-allonorsecurinine
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A concise stereoselective total synthesis of alkaloid (-)-allonorsecurinine is described utilizing classical reactions such as Grignard, Aldol and Horner-Wittig reactions as the key steps.
- Sathish Reddy, Alugubelli,Srihari, Pabbaraja
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supporting information
p. 5926 - 5928,3
(2020/07/31)
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- Synthesis of α, β-unsaturated γ-amino esters with unprecedented high (E)-stereoselectivity and their conformational analysis in peptides
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Mild, efficient and racemization-free synthesis of N-protected α, β-unsaturated γ-amino esters with unprecedented high E- stereoselectivity is described. This method is found to be compatible with Boc-, Fmoc- and other side chain protecting groups. The crystal conformations of the vinylogous γ-amino esters in monomers and in homo- and mixed dipeptides are studied. Further, the vinylogous homo-dipeptide showed a β-sheet conformation, while mixed α- and α,β-unsaturated γ-hybrid dipeptide adapted an irregular structure in single crystals.
- Mali, Sachitanand M.,Bandyopadhyay, Anupam,Jadhav, Sandip V.,Kumar, Mothukuri Ganesh,Gopi, Hosahudya N.
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supporting information; experimental part
p. 6566 - 6574
(2011/11/05)
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- Conversion of α-amino acids into bioactive o-aminoalkyl resorcylates and related dihydroxyisoindolinones
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The synthesis of biologically active o-aminoalkyl resorcylates and related dihydroxyisoindolinones from functionalized α-amino acids without the use of phenolic protection is described. The key aminoalkyl-diketo-dioxinone intermediates were prepared utilizing a crossed Claisen condensation reaction in the presence of diethylzinc. The aromatic unit was constructed via late stage cyclization and aromatization, and subsequent modification provided the novel resorcylates which showed activity against a selection of receptors and kinases, including 5-HT and CDK.
- Patel, Bhavesh H.,Mason, Andrew M.,Patel, Hetal,Coombes, R. Charles,Ali, Simak,Barrett, Anthony G. M.
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experimental part
p. 6209 - 6217
(2011/10/02)
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- Arylation of α-chiral ketones by palladium-catalyzed cross-coupling reactions of tosylhydrazones with aryl halides
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(Figure Presented) Papa was a rollin' ketone: Arylation of ketones with preservation of the chirality in configurationally unstable α-chiral ketones has been achieved by the palladium-catalyzed cross-coupling reaction between tosylhydrazones and aryl halides (see scheme; Boc=tert-butoxycarbonyl, Ts=4-toluenesulfonyl). The regioselectivity in the β-hydride elimination step is key for the retention of configuration.
- Barluenga, Jose,Escribano, Maria,Aznar, Fernando,Valde, Carlos
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supporting information; experimental part
p. 6856 - 6859
(2010/12/19)
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- The design of potent and selective inhibitors of DPP-4: Optimization of ADME properties by amide replacements
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For a series of β-homophenylalanine based inhibitors of dipeptidyl peptidase IV ADME properties were improved by the incorporation of amide replacements. These efforts led to a novel series of potent and selective inhibitors of DPP-4 that exhibit an attractive pharmacokinetic profile and show excellent efficacy in an animal model of diabetes.
- Nordhoff, Sonja,Bulat, Stephan,Cerezo-Galvez, Silvia,Hill, Oliver,Hoffmann-Enger, Barbara,Lopez-Canet, Meritxell,Rosenbaum, Claudia,Rummey, Christian,Thiemann, Meinolf,Matassa, Victor G.,Edwards, Paul J.,Feurer, Achim
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scheme or table
p. 6340 - 6345
(2010/06/11)
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- HETEROCYCLODIAZEPINE CANNABINOID RECEPTOR MODULATORS FOR TREATMENT OF DISEASE
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The present invention relates to compounds and methods useful as modulators of CB2 for the treatment or prevention of disease states including, but not limited to pain, autoimmune disease, malabsorption syndrome, pulmonary disease, osteoporosis, muscle spasm in cancer, neuromuscular disorder, and atherosclerosis progression.
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Page/Page column 50
(2009/04/24)
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- Cis-trans proline isomerization effects on collagen triple-helix stability are limited
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We investigated the effect of restricting cis-trans proline isomerization on collagen triplehelix stability. The Pro residues at the Xaa and Yaa positions of an (Xaa-Yaa-Gly) triplet were replaced by a Pro-trans-Pro alkene isostere in the host-guest pepti
- Dai, Nan,Etzkorn, Felicia A.
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supporting information; experimental part
p. 13728 - 13732
(2010/01/06)
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- NOVEL COMPOUNDS
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The invention provides compounds of general formula (I) or a pharmaceutically acceptable salt, polymorph or solvate thereof, including all tautomers and stereoisomers thereof, wherein K, W, X; Y and Z are described throughout the description and claims. T
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Page/Page column 45; 46
(2009/03/07)
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- S-6-METH0XY-2- (2- (3- (PYRIMID-2-YL) IS0XAZ0L-5-YL) PYRROLIDIN-1-YL) -4- (5-METHYL-IH-PYRAZOL-S-YLAMINO) PYRIMIDINE AND POLYMORPHIC FORMS THEREOF AS MODULATORS OF THE INSULIN-LIKE GROWTH
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There is provided novel pyrimidine derivatives of formula (I) or pharmaceutically acceptable salsts thereof, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
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Page/Page column 39-40
(2008/12/04)
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- GLYCINE TRANSPORTER INHIBITOR
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The present invention provides a compound represented by the following formula or a pharmaceutically acceptable salt of the compound or a hydrate of the compound or the salt, which is useful for the prevention or treatment of diseases such as schizophreni
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Page/Page column 54
(2010/11/30)
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- Synthesis, SAR, and X-ray structure of novel potent DPPIV inhibitors: Oxadiazolyl ketones
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Synthesis of a novel series of DPPIV inhibitors with 1,2,4- and 1,3,4-oxadiazolyl ketone derivatives and its structure-activity relationships are discussed. Compound 18h showed good inhibitory activity against DPPIV and favorable pharmacokinetic properties. In vivo pharmacodynamic efficacy and co-crystal structure of compound 18h with DPPIV is also described.
- Koo, Ki Dong,Kim, Min Jung,Kim, Sungsub,Kim, Kyoung-Hee,Hong, Sang Yong,Hur, Gwong-Cheung,Yim, Hyeon Joo,Kim, Geun Tae,Han, Hee Oon,Kwon, O Hwan,Kwon, Tae Sik,Koh, Jong Sung,Lee, Chang-Seok
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p. 4167 - 4172
(2008/02/09)
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- Structure reassignment and synthesis of jenamidines A1/A 2, synthesis of (+)-NP25302, and formal synthesis of SB-311009 analogues
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The proposed structures of jenamidines A, B, and C (1-3) were revised to jenamidines A1/A2, B1/B2, and C (8-10). Jenamidines A1/A2 (8) were synthesized from activated proline derivative 43 by conversion to 26 in two steps and 50% overall yield. Acylation of 26 with acid chloride 38d gave 39d, which was deprotected with TFA and then mild base to give 8 in 45% yield from 26. (-)-trans-2,5- Dimethylproline ethyl ester (49) was prepared by the enantioselective Michael reaction of ethyl 2-nitropropionate (51) and methyl vinyl ketone (50) using modified dihydroquinine 60 as the catalyst. Further elaboration converted 49 to natural (+)-NP25302 (12). A Wittig reaction of proline NCA (76) with ylide 79 gave 72 as a 9/1 E/Z mixture in 27% yield, completing a one-step formal synthesis of SB-311009 analogues.
- Duvall, Jeremy R.,Wu, Fanghui,Snider, Barry B.
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p. 8579 - 8590
(2007/10/03)
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- β-isocupreidine-catalyzed Baylis-Hillman reaction of chiral N-Boc-α-amino aldehydes
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β-Isocupreidine (β-ICD)-catalyzed Baylis-Hillman reaction of chiral N-Boc-α-amino aldehydes and 1,1,1,3,3,3-hexafluoroisopropyl acrylate (HFIPA) takes place without racemization and exhibits the match-mismatch relationship between the substrate and the catalyst. In the case of acyclic amino aldehydes, α,-substrates show excellent syn selectivity and high reactivity in contrast to L-substrates. On the other hand, in the case of cyclic amino aldehydes, D-substrates rather than L-substrates show excellent anti selectivity and high reactivity.
- Nakano, Ayako,Takahashi, Keisuke,Ishihara, Jun,Hatakeyama, Susumi
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p. 5357 - 5360
(2007/10/03)
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- PROLINE BIS-AMIDE OREXIN RECEPTOR ANTAGONISTS
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The present invention is directed to proline bis-amide compounds which are antagonists of orexin receptors, and which are useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which orexin receptors are involved.
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Page/Page column 39-40
(2008/06/13)
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- PROLINE DERIVATIVE AS HEME OXYGENASE INDUCER OR INDUCTION PROMOTER
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PROBLEM TO BE SOLVED: To provide a new heme oxygenase inducer or induction promoter. SOLUTION: A proline derivative is expressed by general formula (1) [R1 is a 1-4C lower alkyl, a 1-4C lower alkylamino, phenyl which may be substituted, a heteroaromatic r
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Page/Page column 10
(2010/02/15)
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- COLLAGEN MIMICS
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Novel peptidomimetics are provided, which mimic collagen. Molecular structures of interest include for imparting the collagen-mimicking property are each of: Gly- Ψ[(E)-CH=C]-Xaa-Yaa; Gly-Xaa-Ψ[(E)CH=C]-Yaa; Gly-Xaa-Yaa-Ψ[(E)CH=CH]; Gly- Ψ[(E)CH=C]-Xaa-Ψ[(E)CH=C]-Yaa; Gly-Xaa-Ψ(E)CH=C]-Yaa-Ψ[(E)CH=CH]; Gly-Ψ[(E)CH=C]-Xaa-Yaa-Ψ[(E)CH=CH] and Gly-Ψ[(E)CH=C]-Xaa-Ψ[(E)CH=C]-Yaa-Ψ[(E)CH=CH]. Xaa and Yaa each means a natural amino acid, Hyp or Flp. Amide bonds may be altered to create collagen mimics. Preferably a tripeptide polymer comprising at least about 60 (Gly-Pro-Hyp) repeating units and having molecular weight of at least about 40,000 is synthesized as a long, collagen-like material. The new synthetic collagen-like materials may have better resistance to degradation, better mechanical strength and/or better ability to fold than natural collagen.
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Page/Page column 14
(2010/02/14)
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- Preparation of Weinreb amides using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4- methylmorpholinium chloride (DMT-MM)
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Weinreb amides were successfully prepared from the corresponding carboxylic acids using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) in the solvents, methanol, isopropyl alcohol, and acetonitrile, which can solubilize DMT-MM
- Hioki, Kazuhito,Kobayashi, Hiroko,Ohkihara, Rumi,Tani, Shohei,Kunishima, Munetaka
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p. 470 - 472
(2007/10/03)
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- HISTAMINE H3 RECEPTOR LIGANDS
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Compounds of formula (I) (and pharmaceutically acceptable salts thereof) are histamine H3 receptor ligands. A in the formula represents (CH2)m, m being from 1 to 3; B is (CH2)n, n being from 1 to 3; x is from 0 to 2; Ris C1 to C10 hydrocarbyl, in which up to 2 carbon atoms may be replaced by O, S or N; and up to 2 hydrogen atoms may be replaced by halogen; Ris H or C1 to C15 hydrocarbyl, in which up to 3 carbon atoms may be replaced by O, S or N, and up to 3 hydrogen atoms may be replaced by halogen; Ris absent when -Y-Z-R2 is attached to W, or is H or C1 to C7 hydrocarbyl when -Y-Z-Ris not attached to W; W is nitrogen; X is -CH2-, -O- or -NR-, Rbeing H or C1 to C3 alkyl; Y replaces a hydrogen atom on any of A, B, W and X, and is C2 to C10 alkylene, in which one non-terminal carbon atom may be replaced by O; and Z is (II), (III), (IV), (V), (VI), or (VII) wherein R, Rand Rare independently H or C1 to C15 hydrocarbyl, in which up to 3 carbon atoms may be replaced by O or N, and up to 3 hydrogen atoms may be replaced by halogen, and Q is H or methyl, or Q is linked to Ror Rto form a five-membered ring or Q is linked to Rto form a six-membered ring
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- [Bis(2-methoxyethyl)amino]sulfur Trifluoride, the Deoxo-Fluor Reagent: Application toward One-Flask Transformations of Carboxylic Acids to Amides
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The use of the Deoxo-Fluor reagent is a versatile method for acyl fluoride generation and subsequent one-flask amide coupling. It provides mild conditions and facile purification of the desired products in good to excellent yields. We have explored the utility of this reagent for the one-flask conversion of acids to amides and Weinreb amides and as a peptide-coupling reagent.
- White, Jonathan M.,Tunoori, Ashok Rao,Turunen, Brandon J.,Georg, Gunda I.
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p. 2573 - 2576
(2007/10/03)
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- Synthesis of optically active N-protected α-aminoketones and α-amino alcohols
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A series of optically active N-protected α-aminoketones were synthesized via the Grignard reaction of the Weinreb amides of the N-tert-butoxycarbonyl amino acids. Reduction of the α-aminoketones by sodium borohydride resulted in the corresponding 1,2-amino alcohols.
- Zhou, Zheng Hong,Tang, Yi Long,Li, Kang Ying,Liu, Bing,Tang, Chu Chi
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p. 603 - 606
(2007/10/03)
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- Total synthesis and conformational studies of ceratospongamide, a bioactive cyclic heptapeptide from marine origin
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The first total synthesis of cis,cis-ceratospongamide (cyclo[L-Pro-L-Ile-Me-oxazoline-L-Phe-L-Pro-thiazole-L-Phe-]) was accomplished and confirmed by X-ray crystal analysis. The heating of cis,cis-ceratospongamide in DMSO converted it not to the trans,trans isomer but to the trans,trans-[D-allo-Ile]-ceratospongamide, which was confirmed by total synthesis. Its solution conformation was constructed by the dynamic simulated annealing method using ROE cross peaks, revealing a rounded and flat ring structure which is in contrast with the slim and tight structure of cis,cis isomer. The results shows that the trans,trans-[D-allo-Ile] isomer is the main thermal product of cis,cis-ceratospongamide.
- Yokokawa, Fumiaki,Sameshima, Hirofumi,In, Yasuko,Minoura, Katsuhiko,Ishida, Toshimasa,Shioiri, Takayuki
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p. 8127 - 8143
(2007/10/03)
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- Oxazaborolidines as functional monomers: Ketone reduction using polymer-supported Corey, Bakshi, and Shibata catalysts
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The first two polymer-supported versions of the Corey, Bakshi, and Shibata (CBS) catalyst have been prepared. Functional monomers based structurally upon the original B-methylated catalyst have been used to prepare catalytic polymers containing the CBS moiety bound both in a pendant fashion and in the form of a cross-link. Enantioselective reductions of two prochiral ketones have been carried out using the original catalyst in the solution phase as well as the two solid-state systems. While the pendant-bound system shows reduced stereoselectivity, the cross-linked version affords enantioselectivities almost identical to those of the solution-phase model.
- Price, Michael D.,Sui, Jennifer K.,Kurth, Mark J.,Schore, Neil E.
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p. 8086 - 8089
(2007/10/03)
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- Synthesis of new chiral peptide nucleic acid (PNA) monomers
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We have synthesised a series of new chiral type I peptide nucleic acid monomers in total yields of 36-53%, derived from Val, Ile, Ser(Bzl), Pro, and Trp, employing convenient procedure.
- Falkiewicz,Wisniowski,Kolodziejczyk,Wisniewski
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p. 1393 - 1397
(2007/10/03)
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- Discovery and initial structure-activity relationships of trisubstituted ureas as thrombin receptor (PAR-1) antagonists
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Thrombin is the most potent agonist of platelet activation, and its effects are predominantly mediated by platelet thrombin receptors. Therefore, antagonists of the thrombin receptor have potential utility for the treatment of thrombotic disorders. Screening of combinatorial libraries revealed 2 to be a potent antagonist of the thrombin receptor. Modifications of this structure produced 11k, which inhibits thrombin receptor stimulated secretion and aggregation of platelets.
- Barrow, James C,Nantermet, Philippe G,Selnick, Harold G,Glass, Kristen L,Ngo, Phung L,Young, Mary Beth,Pellicore, Janetta M,Breslin, Michael J,Hutchinson, John H,Freidinger, Roger M,Condra, Cindra,Karczewski, Jerzy,Bednar, Rodney A,Gaul, Stanley L,Stern, Andrew,Gould, Robert,Connolly, Thomas M
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p. 2691 - 2696
(2007/10/03)
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- Total synthesis of cis,cis-ceratospongamide, a bioactive thiazole-containing cyclic peptide from marine origin
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The first total synthesis of cis,cis-ceratospongamide (1a), isolated from marine source, was accomplished via thiazole synthesis using CMD methodology, DEPC-mediated peptide coupling, macrolactamization, and cyclodehydration. Comparison of the cyclization sites and coupling reagents in the macrolactamization step was also investigated.
- Yokokawa,Sameshima,Shioiri
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p. 986 - 988
(2007/10/03)
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- A one-flask synthesis of weinreb amides from chiral and achiral carboxylic acids using the deoxo-fluor fluorinating reagent
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(Matrix presented) The reagent [bis(2-methoxyethyl)amino]sulfur trifluoride (Deoxo-Fluor reagent) converts carboxylic acids to the corresponding acid fluorides, which then react with N,N-dimethylhydroxylamine to give the corresponding Weinreb amides in high yields. The reaction proceeds without racemization when optically active acids are used as the starting material. This method is operationally simple and provides the products in high purity.
- Tunoori, Ashok Rao,White, Jonathan M.,Georg, Gunda I.
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p. 4091 - 4093
(2007/10/03)
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