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Development of a multigram asymmetric synthesis of 2-(R)-2-(4,7,10-tris tert-butylcarboxymethyl-1,4,7,10-tetraazacyclododec-1-yl)-pentanedioic acid, 1-tert-butyl ester, (R)-tert-Bu4-DOTAGA1

A process for the multigram asymmetric synthesis of the chiral tetraazamacrocycle 2-(R)-2-(4,7,10-tris tert-butylcarboxymethyl- 1,4,7,10-tetraazacyclododec-1-yl)-pentanedioic acid, 1-tert-butyl ester ((R)-tert-Bu4-DOTAGA, 4) has been devised and demonstrated. The nine-step synthesis features an improved synthesis of 2-(S)-5- oxotetrahydrofuran- 2-carboxylic acid, tert-butyl ester 8, the precursor to the novel alkylating agent (S)-5-benzyl 1-tert-butyl 2-(methylsulfonyloxy) pentanedioate 12, which was used to introduce an orthogonally protected chiral glutarate arm to the 1,4,7,10-tetraazacyclododecane (cyclen) nucleus in high optical purity. Cyclen derivative (R)-t-Bu4-DOTAGA, 4, a key intermediate for the manufacture of a magnetic resonance imaging (MRI) candidate, was produced with high chemical (?95%) and optical (ee ? 97%) purity. The process developed was successfully applied to the kilogram-scale cGMP synthesis of (R)-t-Bu4-DOTAGA.

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In heterogeneous catalysis, the catalyst is in a different phase from the reactants. Application In Synthesis of (S)-( )-5-Oxo-2-tetrahydrofurancarboxylic Acid, At least one of the reactants interacts with the solid surface in a physical process called adsorption in such a way. 21461-84-7, name is (S)-( )-5-Oxo-2-tetrahydrofurancarboxylic Acid. In an article£¬Which mentioned a new discovery about 21461-84-7

Elucidating the interaction of gamma-hydroxymethyl-gamma-butyrolactone substituents with model membranes and protein kinase C-C1 domains

The protein kinase C (PKC) family of proteins is an attractive drug target. Dysregulation of PKC-dependent signalling pathways is related to several human diseases like cancer, immunological and other diseases. We approached the problem of altering PKC activities by developing C1 domain-based PKC ligands. In this report gamma-hydroxymethyl-gamma-butyrolactone (HGL) substituents were investigated in an effort to develop small molecule-based PKC regulators with higher specificity for C1 domain than the endogenous diacylglycerols (DAGs). Extensive analysis of membrane-ligands interaction measurements revealed that the membrane-active compounds strongly interact with the lipid bilayers and the hydrophilic parts of compounds localize at the bilayer/water interface. The pharmacophores like hydroxymethyl, carbonyl groups and acyl-chain length of the compounds are crucial for their interaction with the C1 domain proteins. The potent compounds showed more than 17-fold stronger binding affinity for the C1 domains than DAG under similar experimental conditions. Nonradioactive kinase assay confirmed that these potent compounds have similar or better PKC dependent phosphorylation capabilities than DAG under similar experimental conditions. Hence, our findings reveal that these HGL analogues represent an attractive group of structurally simple C1 domain ligands that can be further structurally altered to improve their potencies.

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Highly diastereoselective nucleophilic addition reactions of masked acyl cyanide reagents to tert-butanesulfiminides

Addition reactions of dicyanomethyl tert-butyldimethylsilyl ether (H-MAC-TBS) to optically active tert-butanesulfinimides afforded alpha-amino acid precursors in excellent yields and with high diastereoselectivities.

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NOVEL SUBSTITUTED AMINOTHIAZOLOPYRIMIDINEDIONE FOR THE TREATMENT AND PROPHYLAXIS OF VIRUS INFECTION

The present invention relates to compounds of formula (I), wherein R1 to R4 are as described herein, and their pharmaceutically acceptable salts, enantiomers or diastereomers thereof, and compositions including the compounds for use in the treatment of viral infections.

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MODULATORS OF G-PROTEIN COUPLED RECEPTORS

This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt and/or hydrate and/or prodrug of the compound) that modulate (e.g., agonize or partially agonize or antagonize) glucagon?like peptide?1 receptor (“GLP?1R”) and/or the gastric inhibitory polypeptide receptor (“GIPR”). The chemical entities are useful, e.g., for treating a subject (e.g., a human) having a disease, disorder, or condition in which modulation (e.g., agonism, partial agonism or antagonism) of GLP?1R and/or GIPR activities is benficial for the treatment or prevention of the underlying pathology and/or symptoms and/or progression of the disease, disorder, or condition. In some embodiments, the modulation results in an enhancment of (e.g., an increase in) existing levels (e.g., normal or below normal levels) of GLP?1R and/or GIPR activity (e.g., signaling). In some embodiments, the chemical entities described herein further modulate (e.g., attenuate, uncouple) -arrestin signaling relative to what is observed with the native ligand. This disclosure also features compositions as well as other methods of using and making the said chemical entities.

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Pyrene intercalating nucleic acids with a carbon linker

We have synthesized a carbon linker analogue of INA (oligonucleotides containing insertions of 1-O-(1-pyrenylmethyl)glycerol). Thermal stability studies showed an increase in melting temperature in favor of the carbon linker analogue. We also synthesized a carbon linker analogue with two pyrenes geminally attached. Fluorescence studies of this intercalating nucleic acid with the pyrene moieties inserted as a bulge showed formation of an excimer band. When a mismatch was introduced at the site of the intercalator, an excimer band was formed for the destabilized duplexes whereas an exciplex band was observed when the stability of the duplex was retained. Copyright Taylor and Francis Group, LLC.

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Probes for the position and mechanistic role of the second ‘catalytic’ magnesium ion in the inositol monophosphatase reaction

Two magnesium ions are required for the enzymatic hydrolysis of phosphate monoesters substrates of inositol monophosphatase.It has been suggesested that one (buried) Mg2+ ion binds to the enzyme and the phosphate dianion moiety of the ubstrate through one or more of its negatively charged O-atoms while the second Mg2+ ion binds to the substrate bridging phosphate ester O-atom and one other substrate-derived O-atom.This second Mg2+ ion may also position and active the attacking nucleophilic water molecule. (A.G.Cole and D.Gani, J.Chem Soc., Perkin Trans 1, 1995, previous article).To determine the minimum structural requirements for a substrate, as deduced from the proposed interactions for natural and synthetic substrates with both Mg2+ ions,ethane-1,2-diol 1-phosphate was prepared and was found to be a substrate.The design and preparation of a range of minimal structure synthetic probes based on this new substrate including propyl, 2-methoxyethyl, 2-(2-hydroxyethoxy)ethyl and 5-hydroxypentyl monophosphate ester and both antipodes of 1,5-dihydroxypentan-2-yl phosphate allowed the specific interaction between the substrate and the enzyme and/or the second Mg2+ ion to be assessed.The results support the proposed roles for the metal ions and provide information on the position of the second Mg2+ ion.This information rationalises the properties of known organophosphate substrates and inhibitors for the enzyme and, furthermore, facilitates the construction of a 3-D catalytic mechanism for the inositol monophosphatase reaction which is described.This new catalytic mechanism explains why Li+ behaves as an inhibitor and accounts for its unusual inhibitory properties.

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Synthesis of CMI-977, a potent 5-lipoxygenase inhibitor

CMI-977 is a potent 5-lipoxygenase inhibitor that intervenes in the production of leukotrienes and is presently being developed for the treatment of chronic asthma. It is a single enantiomer with an all-trans (2S,5S) configuration. Of the four isomers of CMI-977, the S,S isomer was found to have the best biological activity and was selected for further development. The enantiomerically pure product was synthesized on a 2-kg scale from (S)-(+)-hydroxymethyl-gamma-butyrolactone.

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Asymmetric synthesis of (+)-L-733, 060 and (+)-CP-99, 994 based on a new chiral 3-piperidinol synthon.

[reaction: see text] Selective and potent neurokinin substance P receptor antagonists (+)-L-733, 060 (1) and (+)-CP-99, 994 (2) have been synthesized starting from a new (3S)-piperidinol synthon derived from l-glutamic acid. The methods featured a C-2 regioselective reduction of glutarimide (9), Lewis acid-promoted Si to C-2 phenyl group migration of 10, and stereoselective reduction of acetylated oxime 19 as the key steps.

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HETEROCYCLIC AMIDE DERIVATIVES HAVING GLYCOGEN PHOSPHORYLASE INHIBITORY ACTIVITY

Heterocyclic amides of formula (1) wherein: Z is CH or nitrogen; R4 and R5 together are either -S-C(R6)=C(R7)-or -C(R7)=C(R6)-S- ; R6 and R7 are selected from for example hydrogen, halo, C1-4alkyl, and C1-4alkanoyl; A is phenylene or heteroarylene; n is 0, 1 or 2; R1 is selected from for example halo, nitro, cyano, hydroxy, carboxy; r is 1 or 2; Y is -NR2R3 or -OR3; R2 and R3 are selected from for example hydrogen, hydroxy, aryl, heterocyclyl and C1-4alkyl (optionally substituted by 1 or 2 R8 groups); R4 is selected from for example hydrogen, halo, nitro, cyano, hydroxy, C1-4alkyl, and C1-4alkanoyl; R8 is selected from for example hydroxy, -COCOOR9, -C(O)N(R9)(R10), -NHC(O)R9, (R9)(R10)N- and -COOR9 ; R9 and R10 are selected from for example hydrogen, hydroxy, C1-4alky1 (optionally substituted by 1 or 2R13 ); R13 is selected from hydroxy, halo, trihalomethyl and C1-4alkoxy; or a pharmaceutically acceptable salt or pro-drug thereof; possess glycogen phosphorylase inhibitory activity and accordingly have value in the treatment of disease states associated with increased glycogen phosphorylase activity. Processes for the manufacture of said heterocyclic amide derivatives and pharmaceutical compositions containing them are described

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