- Simple, economical and environmentally benign selective regeneration of carbonyl compounds from oximes and N,N-dimethyl hydrazones
-
A mild, efficient, selective method for the regeneration of carbonyl compounds from oximes and N,N-dimethylhydrazones in MeCN at ambient temperature or aqueous media has been carried out in excellent yields under K 5CoW12O40·3H2O (0.01 equiv) catalysis.
- Bose, D. Subhas,Reddy, A. V. Narsimha,Das, A. P. Rudra
-
-
Read Online
- A direct and efficient stereoconservative procedure for the selective oxidation of N-protected β-amino alcohols
-
An efficient, very simple and eco-friendly procedure has been developed for the synthesis of highly enantioenriched α-amino aldehydes by IBX-mediated oxidation of the corresponding β-amino alcohols. The procedure has been applied to a wide range of substr
- Ocejo, Marta,Vicario, Jose L.,Badía, Dolores,Carrillo, Luisa,Reyes, Efraim
-
-
Read Online
- Asymmetric allylboration of 2-N,3-O-isopropylidene-N-Boc-L-serinal: Diastereoselective synthesis of the calicheamicin γ1(I) amino sugar
-
Syntheses of the calicheamicin amino sugar 6 and its erythro diastereomer 7 have been completed by a sequence involving the asymmetric allylboration of N-Boc-serinal acetonide L-8 with the tartrate ester modified allylboronates (R,R)-9 and (S,S)-9, respectively. The reaction of (R,R)-9 and L-8 in toluene provides 14 with 89:11 selectivity, whereas the reaction of (S,S)-9 with L-8 in Et2O provides the diastereomer 15 with 90:10 selectivity. It is shown that the relatively modest diastereoselectivity of these double asymmetric reactions is compromised by the low enantiomeric purity of 8 (86-87% ee), and data are provided indicating that these reactions should be highly diastereoselective (≥95:5 in each case) if performed with enantiomerically pure aldehyde. The two diastereomeric homoallylic alcohols, 14 and 15, are easily elaborated into the targeted amino sugars 6 and 7 via the acetamide-substituted pyranosides 22 and 26. Methyl pyranosides 22a and 22e were shown to adopt preferentially the unexpected conformations B and D, with axial acetamide substituents, in nonpolar solvents, while the expected conformations A and C were strongly favored in d6-DMSO because of hydrogen bonding interactions with the solvent. The syntheses of 6 and 7 reported herein are expected to facilitate the design and synthesis of analogs of the calicheamicin aryl tetrasaccharide 3, which should prove useful in further analysis and applications of oligosaccharides as DNA binders.
- Roush,Hunt
-
-
Read Online
- STEREOCONTROLLED ADDITION TO A PENALDIC ACID EQUIVALENT: AN ASYMMETRIC SYNTHESIS OF THREO-β-HYDROXY-L-GLUTAMIC ACID
-
The asymmetric synthesis of threo-β-hydroxy-L-glutamic acid (7) via a stereoselective addition to the chiral penaldic acid equivalent 3 is described.
- Garner, Philip
-
-
Read Online
- Preparation of the 4-Ethylamino Sugar of Calicheamicin: Assignment of Absolute Configuration
-
The absolute configuration of the 4-ethylamino sugar of calicheamicin is established to be 3S,4S by comparison with material obtained from asymmetric synthesis from L-serine.
- Kahne, Daniel,Yang, Dan,Lee, May D.
-
-
Read Online
- Synthesis and immobilization of ceramide analogs on silica particles
-
Ceramides are the major lipid components of the stratum corneum, the major permeability barrier of the skin. Here we report a chemical synthesis of ceramide analogs covalently bonded on the silica particles, that can be used to predict the skin permeability of chemicals via HPLC methods.
- Yin, Jianming,Liu, Hanlan,Pidgeon, Charles
-
-
Read Online
- Liposomal FRET Assay Identifies Potent Drug-Like Inhibitors of the Ceramide Transport Protein (CERT)
-
Ceramide transfer protein (CERT) mediates non-vesicular transfer of ceramide from endoplasmic reticulum to Golgi apparatus and thus catalyzes the rate-limiting step of sphingomyelin biosynthesis. Usually, CERT ligands are evaluated in tedious binding assays or non-homogenous transfer assays using radiolabeled ceramides. Herein, a facile and sensitive assay for CERT, based on F?rster resonance energy transfer (FRET), is presented. To this end, we mixed donor and acceptor vesicles, each containing a different fluorescent ceramide species. By CERT-mediated transfer of fluorescent ceramide, a FRET system was established, which allows readout in 96-well plate format, despite the high hydrophobicity of the components. Screening of a 2 000 compound library resulted in two new potent CERT inhibitors. One is approved for use in humans and one is approved for use in animals. Evaluation of cellular activity by quantitative mass spectrometry and confocal microscopy showed inhibition of ceramide trafficking and sphingomyelin biosynthesis.
- Aglar, ?znur,Arenz, Christoph,Banhart, Sebastian,Cong, Xiaojing,Hamdo, Housam H.,Heuer, Dagmar,Kleuser, Burkhard,M?ller, Heiko M.,Saied, Essa M.,Samaha, Doaa,Schumacher, Fabian
-
-
Read Online
- β-isocupreidine-catalyzed Baylis-Hillman reaction of chiral N-Boc-α-amino aldehydes
-
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
-
-
Read Online
- Direct Synthesis of N -Protected Serine- And Threonine-Derived Weinreb Amides via Diboronic Acid Anhydride-Catalyzed Dehydrative Amidation: Application to the Concise Synthesis of -Garner's Aldehyde
-
An efficient method for the direct synthesis of Weinreb amides derived from serine and threonine derivatives via diboronic acid anhydride-catalyzed hydroxy-directed amidation is described. This is the first successful example of the synthesis of serine- or threonine-derived Weinreb amides using catalytic dehydrative amidations. The methodology could be applied to the concise synthesis of Garner's aldehyde.
- Shimada, Naoyuki,Ohse, Naoki,Takahashi, Naoya,Urata, Sari,Koshizuka, Masayoshi,Makino, Kazuishi
-
-
Read Online
- Wet silica-supported permanganate for the cleavage of semicarbazones and phenylhydrazones under solvent-free conditions
-
Wet silica-supported potassium permanganate was used as an inexpensive and efficient reagent for conversion of semicarbazones and phenylhydrazones to the corresponding carbonyl compounds under solid-state conditions.
- Hajipour, Abdol R.,Adibi, Hadi,Ruoho, Arnold E.
-
-
Read Online
- Cyclic peptide-polymer complexes and their self-assembly
-
The efficient synthesis of novel chiral cyclic peptides cy-clo[NHCHX-CH=CHCH2CO(NHCH2-CH=CHCH2CO) 2] designed to develop hydrogen-bonding interactions with suitable polymers is described. Com-plexation of a carboxylic acid derivat-ized cyclic peptide 2 (X = CH2OCOCH2CH2CO2H) capable of self-assembling as "endless" tubes, with poly(vinyl alcohol) (PVA) led to a vast weak-interaction network, in which the cyclopeptide developed extensive hydrogen-bonding interactions with the hydroxyl groups of PVA through not only the carboxylic acid, but also its ester carbonyl and amide groups. In aqueous solution, the peptide/PVA complexes self-assemble into long-grain ricelike aggregates compatible with the stacking of cyclic peptides through intercycle hydrogen bonds. Upon casting on silicon wafer, the ani-sotropic aggregates can coalesce to form filaments tens of micrometers long. The study demonstrates that complexing functionalized cyclic peptides with polymers through hydrogen bonding is a useful approach for using polymers to mediate the self-assembly and self-organization of cyclic peptides.
- Belanger, Dominique,Tong, Xia,Soumare, Sadia,Dory, Yves L.,Zhao, Yue
-
-
Read Online
- A straightforward synthesis of N-BOC-L-serinal and N-BOC-L-threoninal acetonides
-
An improved procedure for the synthesis of optically active N-tert- butoxycarbonyl L-serinal acetonide and threoninal analogue from ester precursors is described.
- Meffre,Durand,Branquet,Le Goffic
-
-
Read Online
- Synthesis of a cisplatin derivative from lithocholic acid
-
A new steroidal-platinum(II) hybrid compound was synthesized using a simple and efficient methodology. The synthesis was performed by a convergent approach with cross metathesis (CM) as a key step. An olefin derived from lithocholic acid and a vinyl substituted ethylenediamine derived from L-serine were used as chiral building blocks, which were combined in the CM step. The most important advantage of this method was the utilization of L-serine as a cheap, stereoisomerically pure substrate. A steroid with a diamino system in the side chain was subjected to reaction with potassium tetrachloroplatinate to obtain the target platinum(II) complex. Attempts to synthesize similar diamine systems using the asymmetric Strecker reaction were unsuccessful.
- Hryniewicka, Agnieszka,?otowski, Zenon,Seroka, Barbara,Witkowski, Stanis?aw,Morzycki, Jacek W.
-
-
Read Online
- N-AS-triggered SPMs are direct regulators of microglia in a model of Alzheimer’s disease
-
Sphingosine kinase1 (SphK1) is an acetyl-CoA dependent acetyltransferase which acts on cyclooxygenase2 (COX2) in neurons in a model of Alzheimer’s disease (AD). However, the mechanism underlying this activity was unexplored. Here we show that N-acetyl sphingosine (N-AS) is first generated by acetyl-CoA and sphingosine through SphK1. N-AS then acetylates serine 565 (S565) of COX2, and the N-AS-acetylated COX2 induces the production of specialized pro-resolving mediators (SPMs). In a mouse model of AD, microglia show a reduction in N-AS generation, leading to decreased acetyl-S565 COX2 and SPM production. Treatment with N-AS increases acetylated COX2 and N-AS-triggered SPMs in microglia of AD mice, leading to resolution of neuroinflammation, an increase in microglial phagocytosis, and improved memory. Taken together, these results identify a role of N-AS in the dysfunction of microglia in AD.
- Bae, Jae-sung,Choi, Min-Koo,Han, Seung Hoon,Jin, Hee Kyung,Kim, Hee-Jin,Kim, Seung Hyun,Lee, Ju Youn,Park, Cheol-Min,Park, Min Hee,Schuchman, Edward H.,Song, Im-Sook,Yu, Eunsoo
-
-
Read Online
- An improved procedure for the preparation of the Garner aldehyde and its use for the synthesis of N-protected 1-halo-2-(R)-amino-3-butenes
-
An improved procedure for the preparation of 1,1-dimethylethyl 2.2-dimethyl-4-(S)-formyloxazolidine-3-carboxylate (Garner aldehyde) is described which avoids the need for methyl iodide and benzene. Elaboration of this aldehyde into the novel chiral building blocks mentioned in the title is also described.
- McKillop,Taylor,Watson,Lewis
-
-
Read Online
- An Expedient Total Synthesis of Chivosazole F: an Actin-Binding Antimitotic Macrolide from the Myxobacterium Sorangium Cellulosum
-
A unified strategy for the chemical synthesis of the chivosazoles is described. This strategy is based on two closely related approaches involving the late-stage installation of the isomerization-prone (2Z,4E,6Z,8E)-tetraenoate motif, and an expedient fra
- Williams, Simon,Jin, Jialu,Kan, S. B. Jennifer,Li, Mungyuen,Gibson, Lisa J.,Paterson, Ian
-
-
Read Online
- A convenient procedure for the preparation of Garner's aldehyde
-
The palladium/silane reduction of a serine thioester derivative allows for the preparation of enantiomerically pure Garner's aldehyde from serine, in gram quantities within 24 h.
- Trajkovic, Milos,Ferjancic, Zorana,Saicic, Radomir N.
-
-
Read Online
- Late-Stage Intermolecular Allylic C-H Amination
-
Allylic amination enables late-stage functionalization of natural products where allylic C-H bonds are abundant and introduction of nitrogen may alter biological profiles. Despite advances, intermolecular allylic amination remains a challenging problem due to reactivity and selectivity issues that often mandate excess substrate, furnish product mixtures, and render important classes of olefins (for example, functionalized cyclic) not viable substrates. Here we report that a sustainable manganese perchlorophthalocyanine catalyst, [MnIII(ClPc)], achieves selective, preparative intermolecular allylic C-H amination of 32 cyclic and linear compounds, including ones housing basic amines and competing sites for allylic, ethereal, and benzylic amination. Mechanistic studies support that the high selectivity of [MnIII(ClPc)] may be attributed to its electrophilic, bulky nature and stepwise amination mechanism. Late-stage amination is demonstrated on five distinct classes of natural products, generally with >20:1 site-, regio-, and diastereoselectivity.
- Clark, Joseph R.,Dixon, Charlie F.,Feng, Kaibo,Han, Wei,Ide, Takafumi,Koch, Vanessa,Teng, Dawei,Wendell, Chloe I.,White, M. Christina
-
p. 14969 - 14975
(2021/10/01)
-
- PYRROLE COMPOUNDS
-
Provided herein are compounds of Formula (I), or pharmaceutically acceptable salts thereof, pharmaceutical compositions that include a compound described herein (including pharmaceutically acceptable salts of a compound described herein) and methods of synthesizing the same. Also provided herein are methods of treating diseases and/or conditions with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
- -
-
Paragraph 0123
(2020/10/19)
-
- Stereoselective synthesis of unnatural (2S, 3S)-6-hydroxy-4-sphingenine-containing sphingolipids
-
6-Hydroxy-(4E)-sphingenine-containing sphingolipids are found in mammalian and bacterial membranes and have multiple intra- and intercellular functions. Most sphingolipids contain a (2S,3R)-2-amino-1,3-diol core structure, but only limited examples of unnatural (2S,3S)-2-amino-1,3-diol derivates have so far been reported. Using an underexplored hydrozirconation-transmetalation reaction and an unusual three-step-one-pot deprotection sequence, we were able to synthesize several unnatural (2S,3S)-6-hydroxy-(4E)-sphingenine-containing sphingolipids in only three (protected) or four (deprotected) consecutive steps, respectively, including a fluoresence-labeled derivative suitable for future biological studies.
- Leichnitz, Daniel,Pflanze, Sebastian,Beemelmanns, Christine
-
p. 6964 - 6969
(2019/08/01)
-
- Novel Easily Recyclable Bifunctional Phosphonic Acid Carrying Tripeptides for the Stereoselective Michael Addition of Aldehydes with Nitroalkenes
-
A novel bifunctional organocatalyst library combining both aminocatalysis and phosphonic acid activation was used for the first time as an efficient tool for the stereoselective Michael addition of aldehydes with several aromatic nitroalkenes with good selectivities up to 95:5 dr and 93:7 er. Due to their high water solubility, the catalysts were easily recyclable and could be reused over several cycles without any significant loss of selectivity.
- Cortes-Clerget, Margery,Gager, Olivier,Monteil, Maelle,Pirat, Jean-Luc,Migianu-Griffoni, Evelyne,Deschamp, Julia,Lecouvey, Marc
-
-
- Protein and peptide-free synthetic vaccines against streptococcus pneumoniae type 3
-
The present invention provides a protein- and peptide-free conjugate comprising a synthetic carbohydrate and a carrier molecule, wherein the synthetic carbohydrate is a Streptococcus pneumoniae type 3 capsular polysaccharide related carbohydrate and the carrier molecule is a glycosphingolipid. Said conjugate and pharmaceutical composition thereof are useful for immunization against diseases associated with Streptococcus pneumoniae, and more specifically against diseases associated with Streptococcus pneumoniae type 3.
- -
-
Paragraph 0090
(2015/03/31)
-
- PROTEIN AND PEPTIDE-FREE SYNTHETIC VACCINES AGAINST STREPTOCOCCUS PNEUMONIAE TYPE 3
-
The present invention provides a protein- and peptide-free conjugate comprising a synthetic carbohydrate and a carrier molecule, wherein the synthetic carbohydrate is a Streptococcus pneumoniae type 3 capsular polysaccharide related carbohydrate and the carrier molecule is a glycosphingolipid. Said conjugate and pharmaceutical composition thereof are useful for immunization against diseases associated with Streptococcus pneumoniae, and more specifically against diseases associated with Streptococcus pneumoniae type 3.
- -
-
Page/Page column 69; 70
(2015/04/15)
-
- POLYSACCHARIDE ANTIGEN-GLYCOLIPID CONJUGATE VACCINES
-
The present invention relates to the field of synthesizing and biologically evaluating of a novel class of carbohydrate-based vaccines. The new vaccines consist of a multi-modular structure which allows applying the vaccine to a whole variety of pathogenes. This method allows preparing vaccines against all pathogens expressing immunogenic carbohydrate antigens. As conjugation of antigenic carbohydrates to proteins is not required the conjugate vaccine is particularly heat stable. No refrigeration is required, a major drawback of protein-based vaccines.
- -
-
-
- CARBOHYDRATE-GLYCOLIPID CONJUGATE VACCINES
-
The present invention relates to the field of synthesizing and biologically evaluating of a novel class of carbohydrate-based vaccines. The new vaccines consist of a multi-modular structure which allows applying the vaccine to a whole variety of pathogenes. This method allows preparing vaccines against all pathogens expressing immunogenic carbohydrate antigens. As conjugation of antigenic carbohydrates to proteins is not required the conjugate vaccine is particularly heat stable. No refrigeration is required, a major drawback of protein-based vaccines.
- -
-
Paragraph 0229
(2015/09/28)
-
- A process for the preparation of N-(1,1-Dimethylethyl)-(S)-4-formyl-2,2-dimethyl-3-oxazolidine carboxylate
-
The present invention relates to a novel manufacturing method of N-Boc-(S)-4-formyl-2,2-dimethyl-3-oxazolidine carboxylate denoted by chemical formula 1, which does not go through a supercooling process whose temperature is 78 degree Celsius below zero by chemical formula 3 as a starting material, comprising a step of manufacturing N-[(1,1-dimethylethoxy)carbonyl]-2,2-dimethyloxazolidine methanol of a chemical formula 2 compound by reducing 3-(1,1-dimethylethyl)-4-methyl-(S)-2,2-dimethyloxazolidine-3,4-dicarboxylate of a chemical formula 3 compound under a reducing agent, an inorganic acid, or an acid catalyst of Lewis acid at room temperature.COPYRIGHT KIPO 2015
- -
-
Paragraph 0275-0280
(2016/12/22)
-
- Ugi four-component reaction of alcohols: Stoichiometric and catalytic oxidation/MCR sequences
-
A new, simple, and efficient procedure for the one-pot Ugi four-component reaction of alcohols instead of aldehydes is described. Using a stoichiometric amount of IBX or only 1-2% of sodium 2-iodobenzenesulfonate in the presence of Oxone, a wide range of primary alcohols were oxidized to the aldehyde that were directly engaged in the Ugi four-component reaction to afford α-acetamidoamides in good to excellent yields.
- Drouet, Fleur,Masson, Géraldine,Zhu, Jieping
-
supporting information
p. 2854 - 2857
(2013/07/26)
-
- Continuous flow-processing of organometallic reagents using an advanced peristaltic pumping system and the telescoped flow synthesis of (E/Z)-tamoxifen
-
A new enabling technology for the pumping of organometallic reagents such as n-butyllithium, Grignard reagents, and DIBAL-H is reported, which utilises a newly developed, chemically resistant, peristaltic pumping system. Several representative examples of its use in common transformations using these reagents, including metal-halogen exchange, addition, addition-elimination, conjugate addition, and partial reduction, are reported along with examples of telescoping of the anionic reaction products. This platform allows for truly continuous pumping of these highly reactive substances (and examples are demonstrated over periods of several hours) to generate multigram quantities of products. This work culminates in an approach to the telescoped synthesis of (E/Z)-tamoxifen using continuous-flow organometallic reagent-mediated transformations.
- Murray, Philip R. D.,Browne, Duncan L.,Pastre, Julio C.,Butters, Chris,Guthrie, Duncan,Ley, Steven V.
-
p. 1192 - 1208
(2013/10/08)
-
- Enantioselective synthesis of Garner's aldehyde by asymmetric hydroformylation
-
Both enantiomers of Garner's aldehyde (3) are prepared from the same alkene 4 by catalytic asymmetric hydroformylation.
- Clemens, Alexander J. L.,Burke, Steven D.
-
experimental part
p. 2983 - 2985
(2012/06/01)
-
- Relative tendency of carbonyl compounds to form enamines
-
Equilibria between carbonyl compounds and their enamines (from O-TBDPS-derived prolinol) have been examined by NMR spectroscopy in DMSO-d 6. By comparing the exchange reactions between pairs (enamine A + carbonyl B → carbonyl A + enamine B), a quite general scale of the tendency of carbonyl groups to form enamines has been established. Aldehydes quickly give enamines that are relatively more stable than those of ketones, but there are exceptions to this expected rule; for example, 1,3-dihydroxyacetone acetals or 3,5-dioxacyclohexanones (2-phenyl-1,3-dioxan-5-one and 2,2-dimethyl-1,3- dioxan-5-one) show a greater tendency to afford enamines than many α-substituted aldehydes.
- Sanchez, Dani,Bastida, David,Bures, Jordi,Isart, Carles,Pineda, Oriol,Vilarrasa, Jaume
-
supporting information; experimental part
p. 536 - 539
(2012/03/26)
-
- Multiple labeling of a potent CX3CR1 antagonist for the treatment of multiple sclerosis
-
Several methods for the preparation of five isotopologues of the CX 3CR1 antagonist 1 were developed. Volatile and radioactive 1-chloro- and 1-bromo-ethyl-benzene was handled in [2′-14C] and [3′, 5′-3H] labeling of 1. d-Le
- Malmquist, Jonas,Stroem, Peter
-
p. 387 - 392,6
(2020/08/24)
-
- Synthetic studies toward the mannopeptimycins: Synthesis of orthogonally protected β-hydroxyenduracididines
-
The asymmetric synthesis of the nonproteinogenic amino acids (2S,3S,4-S)-β-hydroxyenduracididine 3 and (2R,3S,4-S)-β- hydroxyenduracididine 4 in orthogonally protected form in 15 total steps from Garner's aldehyde is reported. The former and N-glycosylated form of the latter are found in the glycopeptide antibiotic mannopeptimycin.
- Olivier, Kevin S.,Van Nieuwenhze, Michael S.
-
supporting information; experimental part
p. 1680 - 1683
(2010/11/17)
-
- Stereoselective synthesis of the C1-C11 and C12-C34 fragments of mycalolide A
-
(Equation Presented). A convergent synthesis of the C1-C11 and C12-C34 fragments of mycalolide A is described. Synthetic highlights include a highly E-selective cross-metathesis between a vinyl-functionalized bis-oxazole unit and a polypropionate side cha
- Hoffman, Thomas J.,Kolleth, Amandine,Rigby, James H.,Arseniyadis, Stellios,Cossy, Janine
-
supporting information; experimental part
p. 3348 - 3351
(2010/11/04)
-
- A concise synthesis of (2 S,3 S,4 S)-2-(hydroxymethyl)pyrrolidine-3,4-diol (LAB1)
-
The synthesis of (2S,3S,4S)-2-(hydroxymethyl)pyrrolidine-3,4-diol (LAB1) from Garners aldehyde is described using the Sharpless asymmetric dihydroxylation as the key step. Georg Thieme Verlag Stuttgart - New York.
- Upadhyay, Puspesh K.,Kumar, Pradeep
-
scheme or table
p. 3063 - 3066
(2010/11/02)
-
- SPHINGOSINE COMPOUND, METHOD FOR PRODUCING THE SAME, AND SPHINGOMYELINASE INHIBITOR
-
An object of the invention is to provide a novel sphingosine compound with an inhibitory activity against sphingomyelinase, and a method for producing the sphingosine compound. The novel sphingosine compound or a salt thereof according to the invention is represented by Formula (1): wherein one of R1 and R2 is hydrogen, and the other is a group represented by Formula (G): wherein n is 0 or 1; and R3 is hydrogen, C1-23 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C1-6 alkoxy, C3-8 cycloalkyloxy, phenyl, or furil.
- -
-
Page/Page column 11
(2009/12/27)
-
- ASPARTYL PROTEASE INHIBITORS
-
The invention provides compounds of the formula (I) wherein A is selected from the partial structures A1, A2 and A3; Ry and Ry' are both hydrogen, or Ry and Ry' together with the nitrogen atom to which they are attached form a cyclic amine such as morpholine, piperidine, piperazine or pyrrolidine; L is NHNH, CH2NH, O or S; Y is NH, NHNH, NHC(=O), S(=O)2NH, NHS(=O)2, CH2, CH2NH, O, S or S(=0)p; Q is aryl or heterocyclyl; Z is O, S, NRa or S(=0)p; m is O, 1 or 2; n is O, 1, 2 or 3; p is independently 1 or 2; q is 0 or 1; Ra is H or C1-C4alkyl; R1 is hydrogen, C1-C6alkyl, C3-C7cycloalkylC0-C3alkyl, arylC0-C3alkyl or heterocyclylC0-C3alkyl, R4'' is H or C1-C6alkyl; or R4' and R4'' together with the carbon atom to which they are attached define a C3-C6cycloalkyl; W is H, C1-C6alkyl, C3-C7ycycloalkyl, aryl or heterocyclyl; or a pharmaceutically acceptable salt, hydrate or N-oxide thereof. The compounds of the invention are inhibitors of aspartyl proteases such as renin and are among other things useful for the treatment of conditions associated with activities of the RAS, such as hypertension, heart failure and renal insufficiency.
- -
-
Page/Page column 94
(2009/05/28)
-
- SELECTIVE INHIBITORS FOR CYCLIN-DEPENDENT KINASES
-
This invention provides a class of compounds which are useful for specifically inhibiting cyclin-dependent kinases. This class of compounds finds use in treating diseases resulting from inappropriate activity of cyclin-dependent kinases, including cancer, viral infections (e.g., HIV) neurodegenerative disorders (e.g. Alzheimer's disease), and cardiovascular disorders (e.g. atherosclerosis). Moreover, certain members of this class are particularly useful for inhibiting cyclin-dependent kinase 7 and are especially useful for the treatment of breast cancer.
- -
-
-
- NEW COMPOUNDS
-
The invention provides compounds of the formula I wherein Q is aryl or heterocyclyl any of which is optionally substituted; Z is O, S, NRa or S(=O)p; Y is NH, NHNH, CH2NH, O, S or S(=O)p; n is 0, 1, 2 or 3; m is 0, 1 or 2; p is 1 or 2; Ra is H or C1-C4alkyl; R1 is hydrogen, C1-C6alkyl, C0-C3alkanediylC3-C7cycloalkyl, C0-C3alkanediylaryl or C0- C3alkanediylheterocyclyl; R2 is hydrogen or C1-C6alkyl; X' is hydrogen, fluoro, hydroxy, amino or C1-C6alkoxy; X" is hydrogen, or when X' is fluoro, then X" may also be fluoro; R3is C1-C6alkyl; R4' is C1-C6alkyl; R4" is H or C1-C6alkyl; or R4' and R4" together with the carbon atom to which they are attached define a C3-C6cycloalkyl; W is C1-C6alkyl, C3-C7cycloalkyl, aryl or heterocyclyl any of which is optionally substituted; or a pharmaceutically acceptable salt, hydrate or N-oxide thereof. The compounds of the invention are inhibitors of aspartyl proteases such as renin and are among other things useful for the treatment of conditions associated with activities of the RAS, such as hypertension, heart failure and renal insufficiency.
- -
-
Page/Page column 56-57
(2008/12/07)
-
- Synthesis and biological evaluation of γ-aminophosphonates as potent, subtype-selective sphingosine 1-phosphate receptor agonists and antagonists
-
The synthesis of N-arylamide phosphonates and related arylether and arylamine analogues provided potent, subtype-selective agonists and antagonists of the five known sphingosine 1-phosphate (S1P) receptors (S1P1-5). To this end, the syntheses of phosphoserine mimetics-selectively protected and optically active phosphonoserines-are described. In vitro binding assays showed that the implementation of phosphonates as phosphate mimetics provided compounds with similar receptor binding affinities as compared to their phosphate precursors. meta-substituted arylamide phosphonates were discovered to be antagonists of the S1P1 and S1P3 receptors. When administered to mice, an antagonist blocked the lymphopenia evoked by a S1P receptor agonist and caused capillary leakage in both lung and kidney.
- Foss Jr., Frank W.,Snyder, Ashley H.,Davis, Michael D.,Rouse, Michael,Okusa, Mark D.,Lynch, Kevin R.,Macdonald, Timothy L.
-
p. 663 - 677
(2007/10/03)
-
- Structural confirmation of the dihydrosphinganine and fatty acid constituents of the dental pathogen Porphyromonas gingivalis
-
Porphyromonas gingivalis, a recognized periodontal pathogen, is a source of sphinganine bases, fatty acids, free ceramides as well as complex lipids that potentiate interleukin-1b-mediated secretory responses in gingival fibroblasts. The purpose of this study is the structural verification of the sphinganine bases and fatty acids that had been proposed as major components of the complex lipids found in P. gingivalis. The putative C17, C18, and C19 sphinganine bases were prepared from Garner's aldehyde (1) or from a protected serine Weinreb's amide (2). We confirmed that isobranched sphinganine bases are the major structural feature of the ceramides observed from P. gingivalis. We also prepared a C17 unsaturated fatty acid, along with an isobranched C17 3-hydroxy fatty acid, and determined that the major component of the active lipids was the latter. The Royal Society of Chemistry 2007.
- Mun, JiYoung,Onorato, Amber,Nichols, Frank C.,Morton, Martha D.,Saleh, Abdullah I.,Welzel, Morgan,Smith, Michael B.
-
p. 3826 - 3833
(2008/10/09)
-
- Aza-[3 + 3] annulations. Part 6. Total syntheses of putative (-)-lepadiformine and (-)-cylindricine C
-
Efforts in achieving an enantioselective total synthesis of (-)-cylindricine C along with the syntheses of putative lepadiformine, epi-lepadiformines, (-)-4-deoxo-cylindricine C, and (-?-2-epi-cylindricine C are described here in details. These syntheses feature a stereoselective intramolecular aza-[3 + 3] annulation as a unified strategy, and specifically, the total synthesis of (-)-cylindricine C was accomplished in 22 steps with a 4.5% overall yield from L-serine. In addition, we developed an interesting halohydrin formation for the construction of the C4-ketone of cylindricines.
- Wang, Jiashi,Swidorski, Jacob J.,Sydorenko, Nadiya,Hsung, Richard P.,Coverdale, Heather A.,Kuyava, Jennifer M.,Liu, Jia
-
p. 423 - 459
(2007/10/03)
-
- The Baylis-Hillman reaction with chiral α-amino aldehydes under racemization-free conditions
-
The Baylis-Hillman reaction with chiral α-amino aldehydes has been revisited. The reaction carried out under the influence of ultrasound avoids the aldehyde racemization almost completely, providing useful chiral substrates which can be used as starting materials for the synthesis of natural products. To demonstrate the synthetic applicability of these adducts, the easy preparation of a bicyclic lactam with an indolizidinic skeleton was accomplished. Georg Thieme Verlag Stuttgart.
- Coelho, Fernando,Diaz, Gaspar,Abella, Carlos A. M.,Almeida, Wanda P.
-
p. 435 - 439
(2007/10/03)
-
- A solid-phase approach to DDB derivatives
-
Since the discovery of 2,2′-dimethoxycarbonyl-4,4-dimethoxy-5,6, 5′,6′-biomethylenedioxy-biphenyl (DDB) as a potent anti-HBV agent, we have studied the structure-activity relationships of 4,4′-dimethoxy-5, 6,5′,6′-dimethenedioxy-2-alkyloxycarbonyl-2′-(4-substituted benzyl piperazin-1-yl)carbonyl-biphenyl as anti-HBV agents. Therefore, it is rational to extend this study to the 3,3′-disustituted-4,4′- dimethoxy-5,6,5′,6′-dimethenedioxy-2-alkyloxycarbonyl-2′- Serine derivatives. Thus, in an attempt to develop an efficient method for the preparation of a large number of DDB derivatives, the reaction between a DDB acid chloride and serine derivatives on solid support was studied. The structure of resulted compounds was confirmed by LC-MS and 1H NMR analysis. Compounds 2a, 2d, 2f, 2j showed in vitro anti-HBV activity without significant toxicity up to 100 μM.
- Qi, Xiuxiang,Wang, Xiaolai,Wang, Limin,Wang, Qiang,Cheng, Senxiang,Suo, Jishuan,Chang, Junbiao
-
p. 805 - 810
(2007/10/03)
-
- Preparation of enantiomerically pure 2-(1′-aminomethyl)furan derivatives and synthesis of an unnatural polyhydroxylated piperidine
-
Zinc-mediated propargylation of α-acylaminoaldehydes, and subsequent oxidative isomerization followed by Ag(I)-catalyzed cycloisomerization conveniently provides a new enantioselective route to the corresponding 2-aminoalkylfurans. One of these furans was
- Cong, Xin,Liu, Ke-Gang,Liao, Qing-Jiang,Yao, Zhu-Jun
-
p. 8567 - 8571
(2007/10/03)
-
- Stereoselective synthesis of new modified conformationally constrained L-tyrosine analogue with potential applications to SH2 domain ligands
-
This paper reports the stereoselective synthesis of a modified tricyclic tyrosine analogue 3, whose conformation is constrained by the covalent bonds and designed on the basis of X-ray and solution structures of SH2 domain and its natural peptide ligand.
- Liu, Fa,Hu, Tai-Shan,Yao, Zhu-Jun
-
p. 4971 - 4981
(2007/10/03)
-
- ORALLY AVAILABLE SPHINGOSINE 1-PHOSPHATE RECEPTOR AGONISTS AND ANTAGONISTS
-
The present invention relates to S1P analogs that have activity as S1Preceptor modulating agents and the use of such compounds to treat diseases associated with inappropriate S1P receptor activity. The compounds have the general structure (I) wherein R11 is C5-C18 alkyl or C5-C18 alkenyl; Q is selected from the group consisting of C3-C6 optionally substituted cycloalkyl, C3-C6 optionally substituted heterocyclic, C3-C6 optionally substituted aryl C3-C6 optionally substituted heteroaryl and; R2 is selected from the group consisting of H, C1-C4 alkyl, (C1-C4 alkyl)OH and (C1-C4 alkyl)NH2; R23 is H or C1-C4 alkyl, and R15 is a phosphonate ester or a phosphate ester or a pharmaceutically acceptable salt or tautomer thereof.
- -
-
Page/Page column 130-132
(2008/06/13)
-
- PPMP as a ceramide catabolism inhibitor for cancer treatment
-
The present invention relates to a method of treating a hyperproliferative disorder comprising administering a ceramide generating retinoid comprising a retinoic acid derivative or a pharmaceutically acceptable salt thereof, and D-threo-PPMP as a ceramide degradation inhibitor or a pharmaceutically acceptable salt thereof, wherein the hyperproliferative disorder is a tumor; and wherein the ceramide generating retinoid is administered in an amount effective to produce necrosis, apoptosis or both in the tumor, and the ceramide degradation inhibitor is administered in an amount effective to increase the necrosis, apoptosis or both in the tumor over that expected to be produced by the sum of that produced by the ceramide generating retinoid and the ceramide degradation inhibitor when administered separately.
- -
-
Page/Page column 5; sheet 6
(2010/02/11)
-
- RCM approaches toward the diastereoselective synthesis of vicinal trans-diaminocyclitols from L-serine
-
Starting from L-serine, the asymmetric synthesis of four diaminocyclitol derivatives as sugar-based glycosidase inhibitors has been achieved using ring-closing metathesis (RCM) as a key step. Introduction of vicinal trans-diamino functionality onto the ac
- Cong, Xin,Liao, Qing-Jiang,Yao, Zhu-Jun
-
p. 5314 - 5321
(2007/10/03)
-
- Practical synthesis of 1-aryl-6-(hydroxymethyl)-2-ketopiperazines via a 6-exo amide-epoxide cyclization
-
(Chemical Equation Presented) Chiral 1-aryl-6-(hydroxymethyl)-2- ketopiperazines can be prepared via an operationally simple, 6-exo epoxide ring-opening cyclization to form the ketopiperazine C6-N1 bond in high yields and with excellent enantiomeric purity.
- Powell, Noel A.,Ciske, Fred L.,Clay, Emma C.,Cody, Wayne L.,Downing, Dennis M.,Blazecka, Peter G.,Holsworth, Daniel D.,Edmunds, Jeremy J.
-
p. 4069 - 4072
(2007/10/03)
-
- Novel aliphatic compounds, process for their preparation and their usage
-
The present invention provides an aliphatic compound represented by the following formula (I) or pharmacologically acceptable salts thereof: where n denotes an integer of 1 to 11, and 1 denotes an integer of 1 to 16, the aliphatic compound being an optical isomer of the (2R,3S,2′S) configuration when the 8-position thereof is a double bond, or an optical isomer of the (2S,3R,2′RS) configuration when the 8-position is a single bond; methods for producing the compound or pharmacologically acceptable salts thereof; and uses of the compound in the treatment of cardiovascular diseases (e.g. arteriosclerosis, cardiac diseases), cancer, rheumatism, diabetic retinopathy, and respiratory diseases.
- -
-
Page/Page column 15
(2010/02/05)
-
- PIPERAZINE DERIVATIVE RENIN INHIBITORS
-
Disclosed are piperazine derivatives, their manufacture and use as inhibitors of renin. Formula (I):
- -
-
-
- Synthesis of "Garner" aldehyde-derived cyclopropylboronic esters
-
The "Garner" aldehyde has been used as a common intermediate for the preparation of the corresponding alkyne 7 and the alkenylboronic esters 12-16 (24-80%). Diastereoselective cyclopropanation afforded cyclopropylboronic esters 17-20 (60-84%, dr 22:78 to 92:8), the configurations of which were determined by chemical correlation (cyclopropanols 22), X-ray structural analysis (of 21a), and characteristic NMR spectroscopic data. The protected amino alcohols 23-26 and amino acids 27 have been synthesised from the cyclopropylboronic esters 19 by oxidation, Matteson homologation or Suzuki coupling. ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003).
- Pietruszka, Joerg,Witt, Andreas,Frey, Wolfgang
-
p. 3219 - 3229
(2007/10/03)
-
- Synthesis and growth inhibitory activity of chiral 5-hydroxy-2-N-acyl-(3E)-sphingenines: Ceramides with an unusual sphingoid backbone
-
The unusual sphingoid base 5-hydroxy-3-sphingenine was identified in the hydrolysate of brain sphingolipids more than 40 years ago. We present here the first synthesis of the 5R and 5S diastereoisomers of the N-acyl derivatives of 5-hydroxy-3-sphingenine, 2 and 3, respectively, which represent regioisomers of (2S,3R)-ceramide (1). The key steps include the synthesis of a,β-unsaturated ketone intermediates 4 and 5 from N-Cbz- and N-Boc -L-serine and diastereoselective reduction of the enones. The configuration at the new carbinol center was deduced by proton NMR analysis of (R)- and (S)-Mosher [methoxy(trifluoromethyl)phenylacetate] ester derivatives. Ceramide analogues 2 and 3 showed a markedly higher antiproliferative activity than 1 on MCF-7 cells.
- Chun, Jiong,Byun, Hoe-Sup,Arthur, Gilbert,Bittman, Robert
-
p. 355 - 359
(2007/10/03)
-
- Stereoselective synthesis of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid via C-H insertion of alkylidenecarbene.
-
(1S,3R)-1-Aminocyclopentane-1,3-dicarboxylic acid (ACPD), a potent agonist of metabotropic glutamate receptors, was synthesized from L-serine. The chiral quaternary center was constructed by C-H insertion of the alkylidenecarbene, this being generated by the reaction between lithiotrimethylsilyldiazomethane and the corresponding ketone.
- Ohira, Susumu,Akiyama, Megumi,Kamihara, Kumiko,Isoda, Yuichi,Kuboki, Atsuhito
-
p. 887 - 891
(2007/10/03)
-
- Convenient synthesis of a 2,3,6-tristhiazolyl-substituted pyridine skeleton [fragment A-C] of a macrocyclic antibiotic, GE 2270 A
-
Convenient synthesis of the 2,3,6-tristhiazolylsubstituted pyridine skeleton [Fragment A-C] of a macrocyclic antibiotic, GE 2270 A, was first achieved from a chiral 2-(2-{2-[(1R,2S)-(1-amino-2-hydroxy-2-phenyl)ethyl]- thiazol-4-yl}thiazol-4-yl)pyridine derivative [Fragment A] and H-L-Ser-L- Pro-NH2 as the precursor of Fragment C.
- Okumura, Kazuo,Suzuki, Taishi,Shin, Chung-Gi
-
p. 765 - 770
(2007/10/03)
-
