- Piv-Proψ[CH2-NH-O]Gly-NHiPr
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The pseudodipeptide, (S)-N-isopropyl {[N-(pivaloytypyrrolidin-2-yl]methylaminooxy)acetamide, C15F29N3O3, adopts a global extended conformation with the hydroxylamine group in the g+lg- structure. The C-terminal amide NH interacts intramolecularly with the hydroxylamine O atom. Both NH bonds of each molecule are hydrogen bonded to the C-terminal amide carbonyl of a neighbouring molecule.
- Corbier, Catherine,Didierjean, Claude,Thevenet, Laurent,Vanderesse, Regis,Marraud, Michel
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- Boosting the hydrolytic stability of phosphite ligand in hydroformylation by the construction of superhydrophobic porous framework
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The development of a catalyst that delivers high activities and selectivities with excellent durability is of great importance. Numerous efficient catalysts suffer from the inherent hydrolysis liabilities, plaguing their practical applications. Herein, we show that this challenge can be tackled by constructing them into superhydrophobic porous frameworks, as exemplified by a water-sensitive phosphite ligand, tris(2-tert-butylphenyl) phosphite. The efficiency and long-term stability of the developed system are remarkably high in the hydroformylation of internal olefins after metalation with Rh species, superior to the corresponding homogeneous analogues. The significantly boosted hydrolytic stability allows for catalytic transformations using water as a green solvent, which not only facilitates the isolation of the products, but also furnishes the aldehydes with higher regioselectivities for the desired linear form in comparison with that operated under benchmark conditions using toluene as a reaction medium. Given these promising results, we anticipate the strategy advanced herein will form the basis for constructive perspectives in the enhancement of the water resistance of catalysts and the development of high performance hydroformylation catalysts.
- Tang, Yongquan,Dong, Ke,Wang, Sai,Sun, Qi,Meng, Xiangju,Xiao, Feng-Shou
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- Total synthesis and isolation of citrinalin and cyclopiamine congeners
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Many natural products that contain basic nitrogen atoms-for example alkaloids like morphine and quinine-have the potential to treat a broad range of human diseases. However, the presence of a nitrogen atom in a target molecule can complicate its chemical synthesis because of the basicity of nitrogen atoms and their susceptibility to oxidation. Obtaining such compounds by chemical synthesis can be further complicated by the presence of multiple nitrogen atoms, but it can be done by the selective introduction and removal of functional groups that mitigate basicity. Here we use such a strategy to complete the chemical syntheses of citrinalinB and cyclopiamineB. The chemical connections that have been realized as a result of these syntheses, in addition to the isolation of both 17-hydroxycitrinalinB and citrinalinC (which contains a bicyclo[2.2.2]diazaoctane structural unit) through carbon-13 feeding studies, support the existence of a common bicyclo[2.2.2]diazaoctane-containing biogenetic precursor to these compounds, as has been proposed previously.
- Mercado-Marin, Eduardo V.,Garcia-Reynaga, Pablo,Romminger, Stelamar,Pimenta, Eli. F.,Romney, David K.,Lodewyk, Michael W.,Williams, David E.,Andersen, Raymond J.,Miller, Scott J.,Tantillo, Dean J.,Berlinck, Roberto G. S.,Sarpong, Richmond
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- Synthesis and in Vitro Characterization of Novel Amino Terminally Modified Oxotremorine Derivatives for Brain Muscarinic Receptors
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A series of novel 2-substituted acetylenic pyrrolidines and piperidines related to oxotremorine (1) were prepared and evaluated in vitro as muscarinic cholinergic agents at brain M1 and M2 receptors.One analogue, 3-(2-oxo-1-pyrrolidinyl)-1--1-propyne hydrogen oxalate (6a), was found to be a partial agonist producing a PI hydrolysis response at cortical M1 receptors approximately 3-fold larger than that produced by 1.The intrinsic activity profile of 6a at brain muscarinic receptors is similar to those of azetidine oxo analogue 2 and dimethylamino oxo analogue (3).All three compounds are partial M1 agonists and full M2 agonists; however, the profile of 6a in binding studies is significantly different.While 2 and 3 exhibit large M2 selectivities ranging between 8-fold to several hundred-fold, the binding profile of 6a shows almost no subtype selectivity.
- Garvey, David S.,Wasicak, James T.,Chung, John Y.-L.,Shue, Youe-Kong,Carrera, George M.,et al.
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- Synthesis of a tetracyclic substructure of manzamine A via the Diels-Alder reaction of dihydropyridinones
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Synthesis of the tetracyclic core (19) of manzamine A (1) was achieved via Diels-Alder reaction of the dihydropyridinones (5, 6). Conversion of the two D-A products (7, 8) to the key tricyclic ketone (10) was conducted through a conventional pathway as well as a new pathway developed. For effective construction of the required azocine ring systems, model studies were carried out to find intramolecular amide formation by pentafluorophenyl ester and DPPA methods, which were successfully applied to the real substrate to furnish the titled core structure (19).
- Torisawa, Yasuhiro,Hosaka, Toshihiro,Tanabe, Kiyoshi,Suzuki, Naoko,Motohashi, Yumiko,Hino, Tohru,Nakagawa, Masako
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- Asymmetric synthesis of (1R,8S)- and (1S,8S)-1-Hydroxypyrrolizidin-3-ones via the aldol reaction between N-Boc-(S)-Prolinal and chiral acetate enolate equivalents derived from (S)- and (R)-5-C5H5)Fe(CO)(PPh3)COCH3>
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Syntheses of both title compounds have been achieved with excellent stereocontrol using chiral acetate enolate equivalents derived from the iron acetyl complex 5-C5H5)Fe(CO)(PPh3)COCH3>.The different diastereoselectivities in the two syntheses are rationalised in terms of the concept of double asymmetric induction and the transition state models for the aldol reactions of such enolates are discussed.
- Beckett, R. Paul,Davies, Stephen G.,Mortlock, Andrew A.
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- Highly selective bisphosphine ligands for asymmetric hydroformylation of heterocyclic olefins
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The bisphosphine ligand 1c is highly efficient and selective for the asymmetric hydroformylation (AHF) of dihydrofuran and pyrrolines. The AHF of 2,3-dihydrofuran yielded the 2-carbaldehyde in up to 93% ee. The remarkable highest regioselectivity of 2,5-dihydrofuran was obtained to date up to 499 β-isomer/α-isomer with ligand 1c. Furthermore, the highest 96% and 92% ee values were accomplished using the same catalytic system in the AHF of N-Boc pyrroline 11 and 14.
- Zheng, Xin,Xu, Kun,Zhang, Xumu
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- Larger scale Stahl oxidation with instant Cu removal in convenient synthesis of chiral bidentate N–heterocyclic carbene precursor
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Commercially available N-Boc protected L-proline can be efficiently converted into a chiral, bidentate, aminoalkyl N-heterocyclic carbene ligand precursor in high yield (50% total after 4 steps) without column chromatography purification at any moment. The developed synthetic path includes: (1) redox step leading to an aldehyde, (2) imine condensation and in situ reduction to 1,2-diamine; (3) heterocyclization; (3) removal of the protecting group. Instant separation of Cu traces after the key Stahl oxidation at gram-scale was facilitated by the use of bis(isocyanide) scavenger, SnatchCat, forming insoluble, easy to remove RNC:→[Cu] complexes that allowed usto obtain crude intermediate suitably pure for next steps without tedious purification.
- Grudzień, Krzysztof,Noga?, Wojciech,Szczepaniak, Grzegorz,Grela, Karol
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- Synthesis, characterisation, cytotoxicity and radioprotective effect of novel chiral nitronyl nitroxyl radicals
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Nitroxyl compounds have been previously investigated as potential radioprotection drugs. To develop new radioprotectors, two kinds of novel chiral nitronyl nitroxyl radicals: Z-tert-butyl 2-(4, 5-dihydro-4, 4, 5, 5-tetramethyl- 3-oxido-1H-imidazol-3-ium-1
- Qin, Xiang-Yang,Ding, Gui-Rong,Wang, Xiao-Wu,Tan, Juan,Guo, Guo-Zhen,Sun, Xiao-Li
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- Enantiospecific Synthesis of (-)-Slaframine and Related Hydroxylated Indolizidines. Utilization of a Nucleophilic Alaninol Synthon Derived from Serine 1
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A general methodology for the synthesis of indolizidine alkaloids δ-coniceine (12), 1-hydroxyindolizidine (20), desacetoxy slaframine (24), slaframine (34), and an analogue (37) has been developed. This convergent approach utilizes the available chirality in proline and serine and is conceptually different from other approaches. A highly stereoselective coupling of the prolinals with a nucleophilic alaninol synthon provides the precursors for the key cyclization. A novel thermolytic annulation of an oxazolidinone is the key step in the formation of the six-membered piperidine ring. Further elaboration provides the target natural products 24, 34, and 37 in good overall yields.
- Sibi, Mukund P.,Christensen, James W.
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- A formal synthesis of (-)-cephalotaxine
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(Chemical Equation Presented) An enantioselective formal synthesis of the alkaloid (-)-cephalotaxine has been completed, using an alkylidene carbene 1,5-CH insertion reaction as a key step to construct the spiro[4.4]azanonane core D/E-ring system. A Heck-type cyclization was used to close the tetrahydroazepine C-ring and a selective epoxidation-rearrangement sequence was used to elaborate the E-ring.
- Esmieu, William R.,Worden, Stephen M.,Catterick, David,Wilson, Claire,Hayes, Christopher J.
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- A Novel Thermolytic Annulation of an Oxazolidinone: An Enantiospecific Synthesis of (-)-Slaframine
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Optically pure β-aminopiperidines can be prepared in high yields through a thermolytic annulation sequence involving ring opening of an oxazolidinone.
- Sibi, Mukund P.,Christensen, James W.,Li, Biqin,Renhowe, Paul A.
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- Enantiospecific synthesis of functionalised indolizidines. Synthesis of (8S, 8aR)-6,7-dehydro-8-hydroxyindolizidine
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A stereocontrolled route for the title compound has been realised using L-proline as starting material. The route is amenable to modifications to provide a variety of stereoisomers of glycosidase inhibitors.
- Koskinen,Paul
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- Prolyl 4-hydroxylase: Substrate isosteres in which an (E)- or (Z)-alkene replaces the prolyl peptide bond
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Collagen prolyl 4-hydroxylases (CP4Hs) catalyze a prevalent posttranslational modification, the hydroxylation of (2S)-proline residues in protocollagen strands. The ensuing (2S,4R)-4-hydroxyproline residues are necessary for the conformational stability of the collagen triple helix. Prolyl peptide bonds isomerize between cis and trans isomers, and the preference of the enzyme is unknown. We synthesized alkene isosteres of the cis and trans isomers to probe the conformational preferences of human CP4H1. We discovered that the presence of a prolyl peptide bond is necessary for catalysis. The cis isostere is, however, an inhibitor with a potency greater than that of the trans isostere, suggesting that the cis conformation of a prolyl peptide bond is recognized preferentially. Comparative studies with a Chlamydomonas reinhardtii P4H, which has a similar catalytic domain but lacks an N-terminal substrate-binding domain, showed a similar preference for the cis isostere. These findings support the hypothesis that the catalytic domain of CP4Hs recognizes the cis conformation of the prolyl peptide bond and inform the use of alkenes as isosteres for peptide bonds.
- Vasta, James D.,Choudhary, Amit,Jensen, Katrina H.,McGrath, Nicholas A.,Raines, Ronald T.
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- Short asymmetric synthesis of (S,S)-PDP using l-prolinol derivative as economic starting material
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(S,S)-PDP (5d) and its backbone (2S,2′S)-bipyrrolidine (1) have been extensively applied as the scaffold of various chiral ligands in catalytic asymmetric syntheses. In this study, new short asymmetric syntheses of these two important C2-symmetrical nitrogen heterocycles have been accomplished employing economically available l-prolinol derivative 10 as the starting material. Excellent diastereoselectivity was achieved of the key Grignard addition to imine intermediate utilizing (S)-N-tert-butanesulfinamide as the chiral auxiliary.
- Song, Xiao-Nan,Yao, Zhu-Jun
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- Facile synthesis of diastereoisomerically and optically pure 2-substituted hexahydro-1H-pyrrolizin-3-ones
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We report a short synthetic route that provides optically active 2-substituted hexahydro-1H-pyrrolizin-3-ones in four steps from commercially available Boc (tert-but(oxy)carbonyl))-protected proline. Diastereoisomers (-)-11 and (-)-12 were assembled from the proline-derived aldehyde (-)-8 and ylide 9 via a Wittig reaction and subsequent catalytic hydrogenation (Scheme 3). Cleavage of the Boc protecting group under acidic conditions, followed by intramolecular cyclization, afforded the desired hexahydro-1H-pyrrolizinones (-)-1 and (+)-13. Applying the same protocol to ylide 19 afforded hexahydro-1H-pyrrolizinones (-)-25 and (-)-26 (Scheme 5). The absolute configuration of the target compounds was determined by a combination of NMR studies (Figs. 1 and 2) and X-ray crystallographic analysis (Fig. 3).
- Siegrist, Romain,Baumgartner, Corinne,Seiler, Paul,Diederich, Francois
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- Synthesis and 11C-labelling of two selective high affinity nicotinic cholinergic agonists for evaluation as radioligands for PET studies
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ABT-418 ((S)-3-methyl-5-[1-methyl-2-pyrrolidinyl]isoxazole) and N-methylcytisine (N-methyl- 1,2,3,4,5,6-hexahydro-1,5-methano-8H-pyrido-[1,2-a][1,5]diazocin-8-one) are two high affinity nicotinic cholinergic agonists. ABT-418 was synthesized in 7 steps from commercially available (S)-Boc- proline in 35% overall yield. Methylation of commercial cytisine cleanly gave N-methyl-cytisine. ABT-418 and N-methylcytisine were labelled using [11C]methyl iodide by methylation of the corresponding nor-precursors for their in vivo evaluation as positron emission tomography (PET) probes of the nicotinic cholinergic receptors in baboon brain. As for [11C]nicotine, specific binding in vivo could not be demonstrated for ABT-418. Therefore, further experiments are needed to determine the full PET pharmacological profile and the subsequent potential clinical applications of ABT-418 as a tracer for PET experiments. For labelled N-methyl-cytisine, radioactivity in the cerebral cortex and in tile blood were similar. Thus, 11C-labelled N-methylcytisine does not appear to be a suitable ligand for mapping brain nAChR.
- Dolle, Frederic,Dolci, Lilian,Valette, Heric,Bottlaender, Michel,Fournier, Denis,Fuseau, Chantai,Vaufrey, Francoise,Crouzel, Christian
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- Photo-induced Substitutive Introduction of the Aldoxime Functional Group to Carbon Chains: A Formal Formylation of Non-Acidic C(sp3)?H Bonds
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A photo-induced substitutive introduction of an aldoxime functional group to carbon chains was achieved using photo-excited 4-benzoylpyridine as a C(sp3)?H bond cleaving agent and arylsulfonyl oxime as an aldoxime precursor. The non-acidic C?H bonds in various substances, including cycloalkanes, ethers, azacycles, and cyclic sulfides, were chemoselectively converted at ambient temperature under neutral conditions. The present transformation is a formal formylation of non-acidic C(sp3)?H bonds in a single step.
- Kamijo, Shin,Takao, Go,Kamijo, Kaori,Hirota, Masaki,Tao, Keisuke,Murafuji, Toshihiro
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- Syn-SN2' Pathway in the Reaction of Certain γ-(Mesyloxy)α,β-Enoates with RCu(CN)MgX*BF3 Reagents. Importance of MgX and Bulky R Group upon the Diastereoselectivity
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The reactions of protected serine- and threonine-derived γ-(mesyloxy)α,β-unsaturated esters with various magnesio organocyanocopper Lewis acid complexes have been investigated.The formation of syn-SN2'products, in addition to the normally expected anti-SN2'products, is taken as an indication that the reaction proceeds by a mechanism involving coordination of the magnesiocuprate with the C(δ)-N:C(γ)-O syn-γ-(mesyloxy) α,β-enoates.
- Ibuka, Toshiro,Taga, Tooru,Habashita, Hiromu,Nakai, Kazuo,Tamamura, Hirokazu,et al.
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- Dihydropyridinone approach to manzamines: An expedient construction of the tetracyclic core of manzamine A
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A construction of the central tetracyclic core (19) of manzamine A (1) was successfully achieved by a highly efficient Diels-Alder reaction of the suitably protected dihydropyridinones (5) and Danishefsky's diene as a key strategy. Expedient conversion of
- Nakagawa, Masako,Torisawa, Yasuhiro,Hosaka, Toshihiro,Tanabe, Kiyoshi,Date, Tadamasa,Okamura, Kimio,Hino, Tohru
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- Diastereoselective Pictet-Spengler reactions of L-(Boc)prolinal: A biomimetic synthesis of eudistomins H and I, and woodinine
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The carbon skeleton present in eudistomins H, I and woodinine may be envisioned to be biosynthetically derived from tryptamine and L-prolinal by a Pictet-Spengler type reaction. The diastereoselectivity (> 5:1) of this reaction, and the elaboration of the Pictet-Spengler products into the title compounds is described. The absolute stereochemistry of (-) woodinine is thereby established.
- McNulty,Still
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- First stereoselective synthesis of a pro-pro E-alkene dipeptide isostere
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A stereoselective synthesis of a proline-proline E-alkene isostere is described. Starting from N-Boc-L-proline the new stereocenter is generated by diastereoselective alkenylation and subsequent Ireland-Claisen rearrangement. The relative configuration of the double bond and the new generated stereocenter were determined by X-ray crystallography.
- Bandur, Nina G.,Harms, Klaus,Koert, Ulrich
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- Rapid “high” temperature batch and flow lithiation-trapping of N-Boc pyrrolidine
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The development of suitable reaction conditions for the rapid “high” temperature lithiation-trapping of N-Boc pyrrolidine under batch and flow conditions is described. For optimisation of batch conditions, the lithiation-trapping was explored using s-BuLi at temperatures of ?30 to 20 °C. Two new batch lithiation conditions were discovered using the biomass-derived, sustainable solvent, 2-MeTHF: diamine-free lithiation in 2-MeTHF gave α-substituted pyrrolidines in 50–69% yields at ?20 °C or 0 °C. The requirement for very short lithiation times is explained by the chemical instability of the lithiated intermediate at high temperatures. A practical flow chemistry reaction manifold (s-BuLi, TMEDA, THF, 0 °C, 5 s) has been developed which delivered an α-substituted pyrrolidine in 59% yield. This flow process opens up new opportunities for scaling-up of lithiation-trapping reactions of N-Boc heterocycles.
- Kwong, Alice,Firth, James D.,Farmer, Thomas J.,O'Brien, Peter
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- Synthesis of chiral α-acetylenic cyclic amines from α-amino acids: Applications to differentially constrained oxotremorine analogues as muscarinic agents
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Application of the Cory-Fuchs reaction on Boc-prolinal, Boc-4-hydroxyprolinal, Boc-piperidinal and Boc-serinal derivatives to give chiral 2-pyrrolidinyl-, 2-piperidinyl- and 4-oxazolidinyl-acetylene derivatives provided rapid access to a number of differentially constrained oxotremorine analogues as muscarinic agents.
- Chung,Wasicak
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- Natural product derived inhibitors of lipoprotein associated phospholipase a2, synthesis and activity of analogues of sb-253514
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The synthesis of analogues of SB-253514, a novel natural product derived inhibitor of lipoprotein associated phospholipase A2 (Lp-PLA2), is described together with their ability to inhibit Lp-PLA2. (C) 2000 Elsevier Science Ltd.
- Pinto, Ivan L.,Boyd, Helen F.,Hickey, Deirdre M.B.
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- Organocatalysis Intermediates as Platforms to Study Noncovalent Interactions: Integrating Fluorine Gauche Effects in Iminium Systems to Facilitate Acyclic Conformational Control
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Achieving acyclic conformational control over several bonds has been realized by the strategic installation of a vicinal difluoroethane bridge in a generic proline-derived organocatalyst. The torsion angle φFCCF is governed by stabilizing hyperconjugative interactions (σ→σ?), thus ensuring a 60° relationship. This effect has been telescoped by positioning a stereogenic fluorine center proximal to the nucleophilic amine. Upon iminium formation, this center is rendered electron deficient, thus triggering a dynamic fluorine iminium ion gauche effect. Consequently, conformational control over five atoms and four bonds can be achieved by reversible formation of an iminium π-bond.
- Molnár, István Gábor,Holland, Mareike C.,Daniliuc, Constantin,Houk,Gilmour, Ryan
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- X-ray Structure-Guided Discovery of a Potent, Orally Bioavailable, Dual Human Indoleamine/Tryptophan 2,3-Dioxygenase (hIDO/hTDO) Inhibitor That Shows Activity in a Mouse Model of Parkinson’s Disease
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Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan 2,3-dioxygenase (hTDO) have been closely linked to the pathogenesis of Parkinson’s disease (PD); nevertheless, development of dual hIDO1 and hTDO inhibitors to evaluate their potential efficacy against PD is still lacking. Here, we report biochemical, biophysical, and computational analyses revealing that 1H-indazole-4-amines inhibit both hIDO1 and hTDO by a mechanism involving direct coordination with the heme ferrous and ferric states. Crystal structure-guided optimization led to23, which manifested IC50values of 0.64 and 0.04 μM to hIDO1 and hTDO, respectively, and had good pharmacokinetic properties and brain penetration in mice.23showed efficacy against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse motor coordination deficits, comparable to Madopar, an anti-PD medicine. Further studies revealed that different from Madopar,23likely has specific anti-PD mechanisms involving lowering IDO1 expression, alleviating dopaminergic neurodegeneration, reducing inflammatory cytokines and quinolinic acid in mouse brain, and increasing kynurenic acid in mouse blood.
- Ning, Xiang-Li,Li, Yu-Zhi,Huo, Cui,Deng, Ji,Gao, Cheng,Zhu, Kai-Rong,Wang, Miao,Wu, Yu-Xiang,Yu, Jun-Lin,Ren, Ya-Li,Luo, Zong-Yuan,Li, Gen,Chen, Yang,Wang, Si-Yao,Peng, Cheng,Yang, Ling-Ling,Wang, Zhou-Yu,Wu, Yong,Qian, Shan,Li, Guo-Bo
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p. 8303 - 8332
(2021/06/30)
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- Process Development and GMP Production of a Conjugate Warhead: Auristatin F-HPA-Ala/TFA (XMT-1864/TFA)
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An efficient, large-scale manufacturing process is described for XMT-1864/TFA (1-TFA), an auristatin F derivative, used as a novel, highly potent, cytotoxic warhead in Mersana's oncology antibody-drug conjugate platforms. The process achieves high diastereomeric purity and controls the impurities with all intermediates readily isolated by crystallization or precipitation in high yield and purity. Protecting groups were selected to ensure tolerability, scalability, and stability of the intermediates under various solution-phase peptide coupling conditions. Crystallization of the final product was developed to remove specified impurities and provide a high-purity active warhead molecule for use in the bioconjugation processing. The convergent synthesis involving six non-GMP steps and five GMP steps has been carried out in multiple cGMP productions on 1-kg scale to produce 1-TFA in >98% chemical purity and 1% total diastereomeric contamination with ～50% overall yield for the GMP steps.
- Conlon, Patrick R.,Gurijala, Venu Reddy,Kaufman, Michael,Li, Dachang,Li, Jiuyuan,Li, Yuanyuan,Reddy, Bollu Satyanarayan,Wagler, Thomas,Wang, Zedong,Xu, Zhongmin,Yin, Mao,Yurkovetskiy, Aleksandr V.,Zhu, Lei
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- l -Proline as a Valuable Scaffold for the Synthesis of Novel Enantiopure Neonicotinoids Analogs
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In this research, six neonicotinoid analogs derived from l-proline were synthesized, characterized, and evaluated as insecticides against Xyleborus affinis. Most of the target compounds showed good to excellent insecticidal activity. To the best of our knowledge, this is the first report dealing with the use of enantiopure l-proline to get neonicotinoids. These results highlighted the compound 9 as an excellent candidate used as the lead chiral insecticide for future development. Additionally, molecular docking with the receptor and compound 9 was carried out to gain insight into its high activity when compared to dinotefuran. Finally, the neurotoxic evaluation of compound 9 showed lower toxicity than the classic neonicotinoid dinotefuran.
- Bonilla-Landa, Israel,Cuapio-Mu?oz, Ulises,Luna-Hernández, Axel,Reyes-Luna, Alfonso,Rodríguez-Hernández, Alfredo,Ibarra-Juarez, Arturo,Suarez-Mendez, Gabriel,Barrera-Méndez, Felipe,Caram-Salas, Nadia,Enríquez-Medrano, J. Francisco,Díaz De León, Ramón E.,Olivares-Romero, José Luis
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p. 1455 - 1465
(2021/02/16)
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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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- NOVEL CONNECTED BODY AND USE THEREOF IN SPECIFIC CONJUGATION BETWEEN BIOMOLECULE AND DRUG
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PROBLEM TO BE SOLVED: To provide: a method for producing a connected body; a method for using the connected body in the production of a uniform conjugate; and a method for applying the conjugate in the treatment of cancer, infectious diseases, and autoimmune diseases. SOLUTION: A novel connected body is provided that includes a 2,3-di-substituted succinic acid group or a 2-mono-substituted or 2,3-di-substituted fumaric acid or maleic acid (trans (E)- or cis (Z)-butenedioic acid) group for conjugating 2 or more compounds/cytotoxic agents per connected body with a cell-binding molecule by specifically bridge-linking to a pair of thiol on the cell-binding molecule. The connected body is exemplified by the following general formula. SELECTED DRAWING: None COPYRIGHT: (C)2021,JPOandINPIT
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- POTENT HUMAN NEURONAL NITRIC OXIDE SYNTHASE INHIBITORS
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Disclosed are 2-aminopyridine derivative compounds for use as inhibitors of nitric oxide synthase (NOS). In particular, the field of the invention relates to 2-aminopyridine derivative compounds for use as inhibitors of neuronal nitric oxide synthase (nNOS), which are formulated as pharmaceutical compositions for treating diseases and disorders associated with nNOS such as Alzheimer's, Parkinson's, and Huntington's diseases, and amytrophic lateral sclerosis, cerebral palsy, stroke/ischemic brain damage, and migraine headaches.
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Paragraph 00355; 00356
(2021/09/04)
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- Preparation Method for Tyrosine Kinase Inhibitor and Intermediate Thereof
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Provided is a preparation method for a tyrosine kinase inhibitor and an intermediate thereof. Specifically, a preparation method for a cyanoquinoline compound is provided. The method has a high yield, good product purity, and mild reaction conditions.
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Paragraph 0094
(2020/08/19)
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- CONJUGATION LINKERS CONTAINING 2,3-DIAMINOSUCCINYL GROUP
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Provided is a conjugate of a cytotoxic drug/molecule to a cell-binding molecule with a bis-linker (adual-linker) containing a 2, 3-diaminosuccinyl group. It also relates to preparation of the conjugate of a cytotoxic drug/molecule to a cell-binding molecule with the bis-linker, particularly when the drug having functional groups of amino, hydroxyl, diamino, amino-hydroxyl, dihydroxyl, carboxyl, hydrazine, aldehyde and thiol for conjugation with the bis-linker in a specific manner, as well as the therapeutic use of the conjugates.
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- AZAARYL DERIVATIVE, PREPARATION METHOD THEREFOR, AND APPLICATION THEREOF FOR USE IN PHARMACY
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An azaaryl derivative with the structure of formula (I), a preparation method therefor and a pharmaceutical use thereof are disclosed in the present invention. The series of compounds of the present invention can be widely applied in the preparation of dr
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Paragraph 0116-0117
(2020/04/21)
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- A One-Pot Iodo-Cyclization/Transition Metal-Catalyzed Cross-Coupling Sequence: Synthesis of Substituted Oxazolidin-2-ones from N-Boc-allylamines
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A one-pot iodo-cyclization/transition metal-catalyzed cross-coupling sequence is reported to access various C5-functionalized oxazolidin-2-ones from unsaturated N-Boc-allylamines. Depending on the Grignard reagents used for the cross-coupling, e.g., aryl- or cyclopropylmagnesium bromide, a cobalt or copper catalyst has to be used to obtain the functionalized oxazolidin-2-ones in good yields.
- Chaumont-Olive, Pauline,Cossy, Janine
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supporting information
(2020/05/14)
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- NOVEL POTASSIUM CHANNEL INHIBITORS
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The present invention relates to novel compounds, pharmaceutical compositions comprising such compounds and their use for treating, alleviating or preventing diseases or disorders relating to the activity of potassium channels.
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Page/Page column 56; 72
(2020/10/20)
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- Compound, preparation method thereof, pharmaceutical composition and application of compound
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The invention discloses a compound, a preparation method thereof, a pharmaceutical composition and application of the compound. The compound I, and a stereoisomer or a pharmacologically acceptable salt thereof can serve as a CDK7 kinase inhibitor, are high in inhibition activity, and can be used for treatment of various malignant tumors.
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Paragraph 0108; 0112-0114
(2020/01/03)
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- METHOD FOR PREPARING TYROSINE KINASE INHIBITOR AND DERIVATIVE THEREOF
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The present invention relates to a method for preparing a tyrosine kinase inhibitor and a derivative thereof. The present method has a short synthesis route, low costs, easy operation, and is suitable for large-scale production.
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Paragraph 0061-0063
(2019/05/15)
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- MACROCYCLIC COMPOUNDS AS TRK KINASE INHIBITORS AND USES THEREOF
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The present disclosure describes novel TRK kinase inhibitors and methods for preparing them. The pharmaceutical compositions comprising such TRK kinase inhibitors and methods of using them for treating cancer, infectious diseases, and other disorders are also described.
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Paragraph 173
(2019/05/30)
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- Arylation of Aldehydes to Directly Form Ketones via Tandem Nickel Catalysis
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A nickel-catalyzed arylation of both aliphatic and aromatic aldehydes proceeds with air-stable (hetero)arylboronic acids, with an exceptionally wide substrate scope. The neutral condition tolerates acidic hydrogen and sensitive polar groups and also preserves α-stereocenters of some chiral aldehydes. Interestingly, this nickel(0) catalysis does not follow common 1,2-insertion of arylmetal species to aldehydes and β-hydrogen elimination.
- Lei, Chuanhu,Zhu, Daoyong,Tangcueco, Vicente Iii Tiu,Zhou, Jianrong Steve
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p. 5817 - 5822
(2019/08/26)
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- CONJUGATION OF A CYTOTOXIC DRUG WITH BIS-LINKAGE
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What provided is the conjugation of cytotoxic to a cell-binding molecule with a bis-linker(dual-linker) as shown in Formula (I). It provides bis-linkage methods of making a conjugate of a cytotoxic drug molecule to a cell-binding agent in a specific manner. It also relates to application of the conjugates for the treatment of a cancer, or an autoimmune disease, or an infectious disease.
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- Optimization of Blood-Brain Barrier Permeability with Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibitors Having a 2-Aminopyridine Scaffold
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Effective delivery of therapeutic drugs into the human brain is one of the most challenging tasks in central nervous system drug development because of the blood-brain barrier (BBB). To overcome the BBB, both passive permeability and efflux transporter liability of a compound must be addressed. Herein, we report our optimization related to BBB penetration of neuronal nitric oxide synthase (nNOS) inhibitors toward the development of new drugs for neurodegenerative diseases. Various approaches, including enhancing lipophilicity and rigidity of new inhibitors and modulating the pKa of amino groups, have been employed. In addition to determining inhibitor potency and selectivity, crystal structures of most newly designed compounds complexed to various nitric oxide synthase isoforms have been determined. We have discovered a new analogue (21), which exhibits not only excellent potency (Ki 30 nM) in nNOS inhibition but also a significantly low P-glycoprotein and breast-cancer-resistant protein substrate liability as indicated by an efflux ratio of 0.8 in the Caco-2 bidirectional assay.
- Do, Ha T.,Li, Huiying,Chreifi, Georges,Poulos, Thomas L.,Silverman, Richard B.
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supporting information
p. 2690 - 2707
(2019/03/11)
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- Compounds for inhibiting HCV (hepatitis C virus), pharmaceutical composition and application of compounds or pharmaceutical composition
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The invention discloses compounds for inhibiting HCV (hepatitis C virus), pharmaceutical composition and an application of the compounds or the pharmaceutical composition. The compounds are compoundsshown in formula (I) or a stereoisomer, geometric isomer, a tautomer, an enantiomer, sulfur oxide, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compounds shown in formula (I); the compounds are effective antiviral drugs, especially can be used for inhibiting the function of NS5A protein encoded by the HCV, thereby effectively inhibiting the HCV.The method for preventing and/or treating drugs or diseases associated with the HCV by the compounds or the composition containing the new compounds has good market development prospects.
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Paragraph 0104; 0105; 0106; 0107
(2019/02/04)
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- Compound (E)-3-(1-methylpyrrolidine-2-yl)-acrylic hydrochloride and synthetic method
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The invention discloses a compound (E)-3-(1-methylpyrrolidine-2-yl)-acrylic hydrochloride and a synthetic method. The compound is structurally as shown in a formula (I). The synthetic method of the compound comprises the following steps: using BOC-L-prolinol (or BOC-D-prolinol) as an initial material, and by oxidization, forming aldehyde; removing a BOC protective agent; then reacting with haloalkane; then by a Wittig reaction, synthesizing (S,E)-3-(1-methylpyrrolidine-2-yl)-ethyl acrylate; after hydrolysis, salifying to obtain (S,E)-3-(1-methylpyrrolidine-2-yl)-acrylic hydrochloride [or (R,E)-3-(1-methylpyrrolidine-2-yl)-acrylic hydrochloride]. The compound, as a medical intermediate, can be used for preparing quinazoline or quinolines medicine derivatives. The formula is shown in the description.
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Paragraph 0069; 0070; 0071
(2018/08/03)
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- CONJUGATION LINKERS, CELL BINDING MOLECULE-DRUG CONJUGATES CONTAINING THE LIKERS, METHODS OF MAKING AND USES SUCH CONJUGATES WITH THE LINKERS
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The present invention relates to linkers having a group of propiolyl, substituted acryl (acryloyl), or disubstituted propanoyl, and using such linkers for the conjugation of compounds, in particular, cytotoxic agents to a cell-binding molecule.
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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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p. 996 - 1001
(2018/09/21)
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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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- AMINOPYRIDINE COMPOUNDS AND METHODS FOR THE PREPARATION AND USE THEREOF
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The present invention relates generally to therapeutics targeting the bacterium Porphyromonas gingivalis, including its proteases arginine gingipain A/B (Rgp), and their use for the treatment of disorders associated with P. gingivalis infection, including brain disorders such as Alzheimer's disease. In certain embodiments, the invention provides compounds according to Formula I and Formula III, as described herein, and pharmaceutically acceptable salts thereof.
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- NOVEL BETULINIC SUBSTITUTED AMIDE DERIVATIVES AS HIV INHIBITORS
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The present invention relates to novel betulinic substituted amide compounds of formula (I); and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, X, Y, Z1, Z2, Z3 and are Formula (II) as defined herein. The invention novel betulinic substituted amide derivatives, related compounds, and pharmaceutical compositions useful for the therapeutic treatment of viral diseases and particularly HIV mediated diseases.
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- Synthesis and biological activity evaluation of dolastatin 10 analogues with N-terminal modifications
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We have described the synthesis of the two complex units (2R,3R,4S)-dolaproine (Dap) and (3R,4S,5S)-dolaisoleuine (Dil) of dolastatin 10 from natural amino acids. The stereoselective syntheses of N-Boc-Dap (4a) and N-Boc-(2S)-iso-Dap (4b) were performed by employing crotylation of N-Boc-L-prolinal as a key step. Barbier-type allylation of N-Boc-L-isoleucinal provided a mild and convenient approach for the synthesis of N-Boc-Dil (5a) and N-Boc-(3S)-iso-Dil (5b). Ten dolastatin 10 analogues have been designed and synthesized with N-terminal modifications based on the known compound monomethylauristatin F (MMAF, 3). In comparison with MMAF (3), four of the compounds showed enhanced potency against HCT 116 human colon cancer cells in?vitro.
- Wang, Xin,Dong, Suzhen,Feng, Dengke,Chen, Yazhou,Ma, Mingliang,Hu, Wenhao
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p. 2255 - 2266
(2017/03/24)
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- As hepatitis c inhibitor spiro compound and its use in medicine
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The invention provides a spiro compound serving as a hepatitis c inhibitor and application thereof in a medicine. The compound is a compound as shown in a formula (I) or a stereisomer, a geometric isomer, a tautomer, nitric oxide, an aquo-complex, a solvate, a metabolite, pharmaceutically acceptable salt or prodrug of the compound as shown in the formula (I). The invention also provides a pharmaceutical composition containing the compound, application of the compound and the pharmaceutical composition in inhibition of HCV (Hepatitis C Virus) copy and HCV virus protein, as well as the application of the compound and the pharmaceutical composition in prevention, handling, treatment or relieving of HCV infection or hepatitis c disease for a patient. The formula I is as shown in the specification.
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- PYRROLOBENZODIAZEPINE ANTIBODY DRUG CONJUGATES AND METHODS OF USE
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The invention provides antibody-drug conjugates comprising an antibody conjugated to a pyrrolobenzodiazepine drug moiety via a disulfide linker, pyrrolobenzodiazepine linker-drug intermediates, and methods of using the antibody-drug conjugates.
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Paragraph 0581; 0582; 0688; 0689; 0690
(2017/04/23)
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- METHOD FOR PRODUCING ALDEHYDE
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PROBLEM TO BE SOLVED: To provide a new method for producing aldehyde capable of evading reduction under low temperature conditions and having higher selectivity. SOLUTION: Provided is a method for producing aldehyde where activated ester is prepared from carboxylic acid such as saturated fatty acid, unsaturated fatty acid, hydroxy acid, aromatic carboxylic acid and amino acid and an activation ester agent such as halogenated carbonic acid aryl, a carbodiimide-based condensation agent, an imidazole-based condensation agent and a triazine-based condensation agent, and the activated ester is reduced, and being a method for producing aldehyde in which an environmental load is reduce, and having high yield and high selectivity. SELECTED DRAWING: None COPYRIGHT: (C)2017,JPOandINPIT
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Paragraph 0016; 0017-0018
(2017/05/27)
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- Backbone-Modified Bisdiazaphospholanes for Regioselective Rhodium-Catalyzed Hydroformylation of Alkenes
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A series of tetraaryl bisdiazaphospholane (BDP) ligands were prepared varying the phosphine bridge, backbone, and substituents in the 2- and 5-positions of the diazaphospholane ring. The parent acylhydrazine backbone was transformed to an alkylhydrazine via a borane reduction procedure. These reduced ligands contained an all sp3 hybridized ring mimicking the all sp3 phospholane of (R,R)-Ph-BPE, a highly selective ligand in asymmetric hydroformylation. The reduced bisdiazaphospholane (red-BDP) ligands were shown crystallographically to have an increased C-N-N-C torsion angle - this puckering resembles the structure of (R,R)-Ph-BPE and has a dramatic influence on regioselectivity in rhodium catalyzed hydroformylation. The red-BDPs demonstrated up to a 5-fold increase in selectivity for the branched aldehyde compared to the acylhydrazine parent ligands. This work demonstrates a facile procedure for increased branched selectivity from the highly active and accessible class of BDP ligands in hydroformylation.
- Wildt, Julia,Brezny, Anna C.,Landis, Clark R.
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p. 3142 - 3151
(2017/09/05)
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- A base promoted multigram synthesis of aminoisoxazoles: Valuable building blocks for drug discovery and peptidomimetics
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A practical multigram metal free synthesis of isoxazole-containing building blocks from commercially available amino acids was elaborated. The key reaction was a regioselective [3 + 2]-cycloaddition of in situ generated nitrile oxides with alkynes/enamines. The obtained building blocks were used in the preparation of bioactive compounds and peptidomimetics.
- Chalyk, Bohdan A.,Kandaurova, Inna Y.,Hrebeniuk, Kateryna V.,Manoilenko, Olga V.,Kulik, Irene B.,Iminov, Rustam T.,Kubyshkin, Vladimir,Tverdokhlebov, Anton V.,Ablialimov, Osman K.,Mykhailiuk, Pavel K.
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p. 25713 - 25723
(2016/03/25)
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- 6-AMINO QUINAZOLINE OR 3-CYANO QUINOLINE DERIVATIVES, PREPARATION PROCESS AND PHARMACEUTICAL USE THEREOF
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The present disclosure relates to 6-amino quinazoline or 3-cyano quinoline derivatives, preparation processes and pharmaceutical compositions containing them. Specifically, the present disclosure relates to novel 6-amino quinazoline or 3-cyano quinoline derivatives presented by formula (I), or its tautomer, enantiomer, diastereomer, racemate or pharmaceutically acceptable salts thereof, or metabolite, metabolic precursor or prodrug thereof, and the uses for treatment especially for protein kinase inhibitors, in which each substitute group of general formula (I) is as defined in the specification.
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- NOVEL BETULINIC PROLINE IMIDAZOLE DERIVATIVES AS HIV INHIBITORS
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The present invention relates to novel betulinic proline imidazole derivatives and related compounds, compositions useful for therapeutic treatment of viral diseases and particularly HIV mediated diseases.
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- SPECIFIC CONJUGATION LINKERS, SPECIFIC IMMUNOCONJUGATES THEREOF, METHODS OF MAKING AND USES SUCH CONJUGATES THEREOF
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The present invention relates to novel linkers containing a 2,3-disubstituted succinic group, or 2-monosubstituted, or 2,3-disubstituted fumaric or maleic (trans (E)- or cis (Z)- butenedioic), or acetylenedicarboxyl group for conjugation of a cytotoxic agent, and/or one or more different functional molecules per linker to a cell-binding molecule, through bridge linking pairs of thiols on the cell-binding molecule specifically. The invention also relates to methods of making such linkers, and of using such linkers in making homogeneous conjugates, as well as of application of the conjugates in treatment of cancers, infections and autoimmune disorders.
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- Benzimidazole-2-piperazine compound, its pharmaceutical composition and its preparation and use
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The invention relates to a benzimidazole-2-piperazine derivative and a preparing method and application of the benzimidazole-2-piperazine derivative in medicine, in particular to a novel benzimidazole-2-piperazine derivative shown in the general formula (I), a preparing method of the derivative, a pharmaceutical composition containing the derivative and application of the derivative serving as a therapeutic agent, especially serving as a poly (ADP-ribose) polymerase (PARP) inhibitor. In the general formula (I), R refers to hydrogen or halogen, G refers to carbonyl or methylene, m is 1-2, n is 1-3, and Q refers to hydrogen or C1-C4 alkyl. When X is methylene and Y is NR1 or methylene, X is NR1; R1 refers to hydrogen, C1-C6 alkyl, benzyl, COR2 or SO2R2; R2 refers to the following groups which are not substituted or groups substituted by 1-3 substituent groups, including C1-C6 alkyl, C3-C8 naphthenic base, phenyl, benzyl, naphthyl and C5-C10 aromatic heterocycle base, heterocycle in the C5-C10 aromatic heterocycle base comprises 1-3 heteroatoms selected from N, O and S, and the substituent groups are selected from the following atoms or groups of C1-C6 alkyl, C1-C6 alkoxy, halogen, amidogen, nitryl, sulfydryl, hydroxyl, cyanogroup and trifluoromethyl. The general formula (I) is shown in the specification.
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Paragraph 0205; 0208; 0209
(2016/10/20)
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- Chiral Phosphorus-Olefin Ligands for the RhI-Catalyzed Asymmetric Addition of Aryl Boronic Acids to Electron-Deficient Olefins
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New chiral phosphorus-olefin hybrid ligands derived from the rigid "privileged" l-proline have been conveniently prepared and applied in the rhodium-catalyzed asymmetric arylation of electron-deficient olefins with arylboronic acids at room temperature; t
- Chen, Qian,Li, Liang,Zhou, Guangli,Ma, Xiaoli,Zhang, Lu,Guo, Fang,Luo, Yi,Xia, Wujiong
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supporting information
p. 1518 - 1522
(2016/06/01)
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- Substrate-Controlled Diastereoselectivity Reversal in NHC-Catalyzed Cross-Benzoin Reactions Using N-Boc-N-Bn-Protected α-Amino Aldehydes
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The effectiveness of utilizing N-Bn-N-Boc-α-amino aldehydes in cross-benzoin reactions with heteroaromatic aldehydes is demonstrated. The reaction is both chemoselective and syn-selective, making it complementary to the anti-selective cross-benzoin reaction of NHBoc-α-amino aldehydes. Good diastereoselectivity is obtained for a variety of amino aldehydes, including nonhindered ones. A Felkin-Anh model can be used to rationalize the observed diastereoselectivity.
- Haghshenas, Pouyan,Quail, J. Wilson,Gravel, Michel
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p. 12075 - 12083
(2016/12/23)
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- A Recyclable Organocatalyst for Asymmetric Michael Addition
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In this study, a new organocatalyst derived from proline was developed and shown to be an efficient catalyst for asymmetric Michael addition reactions of ketones and aldehydes to nitroolefins with high diastereo- and enantioselectivities. (syn;anti up to
- Yang, Mei,Zhang, Yuecheng,Zhao, Jiquan,Yang, Qiusheng,Ma, Yi,Cao, Xiaohui
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p. 587 - 595
(2016/03/01)
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- One-Pot Three-Component Synthesis of Vicinal Diamines via In Situ Aminal Formation and Carboamination
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A synthesis of vicinal diamines via in situ aminal formation and carboamination of allyl amines is reported. Employing highly electron-poor trifluoromethyl aldimines in their stable hemiaminal form was key to enable both a fast and complete aminal formation as well as the palladium-catalyzed carboamination step. The conditions developed allow the introduction of a wide variety of alkynyl, vinyl, aryl, and hetereoaryl groups with complete regioselectivity and high diastereoselectivity. The reaction exhibits a high functional-group tolerance. Importantly, either nitrogen atom of the imidazolidine products can be selectively deprotected, while removal of the aminal tether can be achieved in a single step under mild conditions to reveal the free diamine. We expect that this work will promote the further use of mixed aminal tethers in organic synthesis.
- Orcel, Ugo,Waser, Jerome
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supporting information
p. 12881 - 12885
(2016/10/04)
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- PHARMACEUTICAL COMPOUNDS
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This invention relates to compounds that inhibit or modulate the activity of Chk-1 kinase. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds.
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Page/Page column 97; 178
(2015/09/23)
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- BICYCLIC AZA COMPOUNDS AS MUSCARINIC M1 RECEPTOR AGONISTS.
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This invention relates to compounds that are agonists of the muscarinic M1 receptor and/or M4 receptor and which are useful in the treatment of muscarinic M1/M4 receptor mediated diseases. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds. Compounds include those according to formula 1, or a salt thereof, wherein Q, R1 , R2, R3 and R4 are as defined herein.
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Page/Page column 94; 95
(2015/09/22)
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- Bridged Ring compounds As Hepatitis C Virus (HCV) Inhibitors And Pharmaceutical Applications Thereof
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Provided herein is a compound having Formula (I), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, which can be used for treating HCV infection or a HCV disorder. Also provided herein are pharmaceutical compositions comprising the compounds disclosed herein, which can be used for treating HCV infection or a HCV disorder.
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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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- 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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- AURISTATIN ANALOGUES AND THEIR CONJUGATES WITH CELL-BINDING MOLECULES
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This invention relates to analogues of auristatins, in particular monomethyl auristatin F (MMAF), as cytotoxic agents, conjugates of such cytotoxic agents with a cell-binding agent, the preparation and the therapeutic uses of these cytotoxic agents and conjugates thereof to arrest or retard abnormal cell growth and /or proliferation.
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