cas 6436-90-4, N-Benzylglycine ethyl ester

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EIF4E INHIBITORS AND USES THEREOF
The present invention provides compounds inhibiting elF4E activity and compositions and methods of using thereof.
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Paragraph 00337; 00363; 00373

(2021/09/11)

Novel KRAS G12C protein inhibitor as well as preparation method and application thereof
The invention belongs to the field of medicinal chemistry, and relates to a novel KRAS G12C protein inhibitor as well as a preparation method and application thereof. Specifically, the invention provides a compound with a structure as shown in a formula I, and the compound can be used as an efficient KRAS G12C protein inhibitor and has various pharmacological activities of resisting tumors, proliferative diseases, inflammation, autoimmune diseases and the like.
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Paragraph 0448-0451

(2021/03/24)

Structure-property relationship study of n-(hydroxy)peptides for the design of self-assembled parallel β-sheets
The design of novel and functional biomimetic foldamers remains a major challenge in creating mimics of native protein structures. Herein, we report the stabilization of a remarkably short β-sheet by incorporating N-(hydroxy)glycine (Hyg) residues into the backbone of peptides. These peptide- peptoid hybrids form unique parallel β-sheet structures by selfassembly upon hydrogenation. Our spectroscopic and crystallographic data suggest that the local conformational perturbations induced by N-(hydroxy)amides are outweighed by a network of strong interstrand hydrogen bonds.
Roche, Stéphane P.,Richaud, Alexis D.
p. 12329 - 12342
(2020/11/10)

N-benzyl glycine ethyl ester preparation and purification method
The invention provides an N-benzyl glycine ethyl ester preparation and purification method, which comprises: preparing a N-benzyl glycine ethyl ester hydrochloride, wherein benzylamine and halogenatedethyl acetate are taken, and are subjected to a room temperature stirring reaction in an organic solvent, water is added after the HPLC detection results show that the reaction is completed, extracting is performed, an organic mixed solution of hydrochloric acid is added into the organic layer in a dropwise manner, the pH value is adjusted to 1-2, the solid is precipitated, and filtering and drying are performed; and adding water into the N-benzyl glycine ethyl ester hydrochloride, carrying out stirring dissolving, adjusting the pH value to 7-8 by using an alkali, adding an organic solvent, extracting, drying the organic layer by using anhydrous sodium sulfate, filtering, and carrying out pressure reducing concentrating to achieve a dry state so as to obtain the product N-benzyl glycine ethyl ester hydrochloride. The preparation method of the invention is simple in process operation, high in product yield, high in product purity and easy for industrial production.
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Paragraph 0040-0043

(2020/02/14)

Selective Functionalization of Aliphatic Amines via Myoglobin-Catalyzed Carbene N-H Insertion
Engineered myoglobins have recently gained attention for their ability to catalyze a variety of abiological carbene transfer reactions including the functionalization of amines via carbene insertion into N-H bonds. However, the scope of myoglobin and other hemoprotein-based biocatalysts in the context of this transformation has been largely limited to aniline derivatives as the amine substrates and ethyl diazoacetate as the carbene donor reagent. In this report, we describe the development of an engineered myoglobin-based catalyst that is useful for promoting carbene N-H insertion reactions across a broad range of substituted benzylamines and α-diazo acetates with high efficiency (82-99percent conversion), elevated catalytic turnovers (up to 7,000), and excellent chemoselectivity for the desired single insertion product (up to 99percent). The scope of this transformation could be extended to cyclic aliphatic amines. These studies expand the biocatalytic toolbox available for the selective formation of C-N bonds, which are ubiquitous in many natural and synthetic bioactive compounds.
Fasan, Rudi,Sreenilayam, Gopeekrishnan,Steck, Viktoria
p. 224 - 229
(2020/02/15)

Peptide/peptoid hybrid oligomers: The influence of hydrophobicity and relative side-chain length on antibacterial activity and cell selectivity
Previous optimisation studies of peptide/peptoid hybrids typically comprise comparison of structurally related analogues displaying different oligomer length and diverse side chains. The present work concerns a systematically constructed series of 16 closely related 12-mer oligomers with an alternating cationic/hydrophobic design, representing a wide range of hydrophobicity and differences in relative side-chain lengths. The aim was to explore and rationalise the structure-activity relationships within a subclass of oligomers displaying variation of three structural features: (i) cationic side-chain length, (ii) hydrophobic side-chain length, and (iii) type of residue that is of a flexible peptoid nature. Increased side-chain length of cationic residues led to reduced hydrophobicity till the side chains became more extended than the aromatic/hydrophobic side chains, at which point hydrophobicity increased slightly. Evaluation of antibacterial activity revealed that analogues with lowest hydrophobicity exhibited reduced activity against E. coli, while oligomers with the shortest cationic side chains were most potent against P. aeruginosa. Thus, membrane-disruptive interaction with P. aeruginosa appears to be promoted by a hydrophobic surface of the oligomers (comprised of the aromatic groups shielding the cationic side chains). Peptidomimetics with short cationic side chains exhibit increased hemolytic properties as well as give rise to decreased HepG2 (hepatoblastoma G2 cell line) cell viability. An optimal hydrophobicity window could be defined by a threshold of minimal hydrophobicity conferring activity toward E. coli and a threshold for maximal hydrophobicity, beyond which cell selectivity was lost.
Frederiksen, Nicki,Hansen, Paul R.,Bj?rkling, Fredrik,Franzyk, Henrik
(2019/12/26)

Oxoindolespiro tetrahydrofuran fluoride, crystal, preparation method and application thereof
The invention discloses oxoindolespiro tetrahydrofuran fluoride and a preparation method thereof. The structural formula of oxoindolespiro tetrahydrofuran fluoride is shown as formula I. The inventionfurther discloses a crystal form of a compound shown as the formula I, the crystal form is a monoclinic system, cell parameters include that a=9.09964(19) angstrom, b=9.3177(3) angstrom, c=15.6040(4)angstrom, alpha is equal to 90 degrees, beta is equal to 99.228 (2) degrees, and gamma is equal to 90 degrees; space group is P21, Z=2, and cell volume is 1305.91(6) angstrom. The invention further discloses a preparation method of the crystal form, the compound or the crystal form thereof or a solvate thereof or application of pharmaceutically acceptable salt thereof in preparing antitumor drug.
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Paragraph 0047; 0049-0051

(2018/09/12)

Carbene Transfer and Carbene Insertion Reactions Catalyzed by a Mixed-Ligand Copper(I) Complex
The catalytic activity of the mixed-ligand copper(I) complex [Cu(PPh3)2(κ2-O,O"-lact)] (1) {lact = l-(+)-lactate} has been investigated in carbene transfer and carbene insertion reactions. Complex 1 catalytically promoted the diastereoselective cyclopropanation of olefins in the presence of ethyl diazoacetate (EDA), under mild conditions, and with a low catalyst loading (1 mol-%). In the case of internal alkenes, a trans/cis ratio of up to 93:7 was reached. Moreover, compound 1 easily promoted the insertion of the carbene fragment deriving from the decomposition of ethyl diazoacetate into O–H (alcohols and phenols) and N–H (amine) bonds, with formation of the corresponding ethyl 2-alkoxyacetate, ethyl 2-phenoxyacetate, and ethyl 2-aminoacetate derivatives in good to high yields.
Brenna, Stefano,Ardizzoia, G. Attilio
p. 3336 - 3342
(2018/07/13)

With the biological activity of 5, 6, 7, 8 - tetrahydro-pyrido [3, 4 - d] pyrimidine compound and its preparation method and application (by machine translation)
The invention discloses a has biological activity of 5, 6, 7, 8 - tetrahydro-pyrido [3, 4 - d] pyrimidine compound and its preparation method and application, which belongs to the with anti-tumor activity to the technical field of the synthesis of the compounds. The technical scheme of the present invention is to point: has biological activity of 5, 6, 7, 8 - tetrahydro-pyrido [3, 4 - d] pyrimidine compound, has the following structure:, wherein R1 For the ethyl carboxylic acid ester, ethylamine methyl, formyl methyl amine, dimethyl amino formyl, pyridine - 3 - methylene amino formyl, piperidine a acyl or anilino formyl, R2 For hydrogen or phenmethyl. The invention also discloses the has biological activity of 5, 6, 7, 8 - tetrahydro-pyrido [3, 4 - d] pyrimidine compound of preparation method and the preparation of anti-mammary tumor application of the medicament. The process of preparing the process is simple, easy to control, the target product high yield and good repeatability, prepared with anti-tumor activity of 5, 6, 7, 8 - tetrahydro-pyrido [3, 4 - d] pyrimidine compounds are all on breast cancer cell MCF - 7 has definite inhibitory effect. (by machine translation)
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Paragraph 0024-0027

(2017/08/02)

Sulfamide derivative and application thereof
The invention relates to a sulfamide derivative and a pharmaceutical composition comprising the compound as well as use of the sulfamide derivative and the pharmaceutical composition as a preparation drug, in particular, use of a drug for preparing a BCL-2 family protein antagonist and use of the drug for treating cancers.
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Paragraph 0172; 0173

(2017/08/29)

The discovery of new human coagulation factor XIa (FXIa) inhibitors by synthesis, biological evaluation, and structure-based modeling
Factor XIa (FXIa) is an enzyme that is activated during the earliest stage of initiation of the intrinsic pathway of the blood coagulation mechanism. In this study, we attempted to discover a new FXIa inhibitor based on structure-based molecular modeling. We found that compound 16 exhibits satisfactory predicted properties while maintaining important binding interactions with FX1a.
Lee, Myeong Hwi,Song, Ho Young,Kim, Hyoungrae,Park, Kyung Eun,Kim, Jinyeong,Park, Tae Kyo,Kim, Yong Ju,Kang, Nam Sook
p. 1105 - 1113
(2016/07/15)

A General and Selective Rhodium-Catalyzed Reduction of Amides, N-Acyl Amino Esters, and Dipeptides Using Phenylsilane
This article describes a selective reduction of functionalized amides, including N-acyl amino esters and dipeptides, to the corresponding amines using simple [Rh(acac)(cod)]. The catalyst shows excellent chemoselectivity in the presence of different sensitive functional moieties. A selective reduction of functionalized amides, including N-acyl amino esters and dipeptides, to the corresponding amines using simple [Rh(acac)(cod)] is described (see scheme). The catalyst shows excellent chemoselectivity in the presence of different sensitive functional moieties. Even the selective reduction of a secondary amide bond in the presence of a ketone is possible.
Das, Shoubhik,Li, Yuehui,Lu, Liang-Qiu,Junge, Kathrin,Beller, Matthias
supporting information
p. 7050 - 7053
(2016/05/19)

Substrate-Controlled Diastereoselectivity Reversal in NHC-Catalyzed Cross-Benzoin Reactions Using N-Boc-N-Bn-Protected α-Amino Aldehydes
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
p. 12075 - 12083
(2016/12/23)

MYOGLOBIN-BASED CATALYSTS FOR CARBENE TRANSFER REACTIONS
Methods are provided for carrying out carbene transfer transformations such as olefin cyclopropanation reactions, carbene heteroatom-H insertion reactions (heteroatom = N, S, Si), sigmatropic rearrangement reactions, and aldehyde olefination reactions with high efficiency and selectivity by using a novel class of myoglobin-based biocatalysts. These methods are useful for the synthesis of a variety of organic compounds which contain one or more new carbon-carbon or carbon-heteroatom (N, S, or Si) bond. The methods can be applied for conducting these transformations in vitro (i.e., using the biocatalyst in isolated form) and in vivo (i.e., using the biocatalyst in a whole cell system).
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Paragraph 0074; 00271

(2016/06/14)

Preparation method for 1-benzyl-3-piperidone hydrochloride
The invention discloses a preparation method for N-benzyl glycine ethyl ester. The method comprises the following steps: dissolving benzylamine in an organic solvent I, then adding 2-halogenated ethyl acetate, alkali and quaternary ammonium salt, and performing reaction to obtain the N-benzyl glycine ethyl ester. The invention also discloses a preparation method for 1-benzyl-3-piperidone hydrochloride. The method comprises the following specific steps: (1) preparing an intermediate IV (N-benzyl glycine ethyl ester); (2) dissolving the intermediate IV in an organic solvent II, then adding 4-halogenated ethyl acetate and alkali, and performing reaction to obtain an intermediate III; (3) performing reaction between the intermediate III and the alkali, reversely regulating a pH value to 6-8, performing concentration under reduced pressure, extracting by using ethyl acetate, performing washing and drying, and then performing concentration under reduced pressure to obtain an intermediate II; (4) performing reaction on the intermediate II and acid, performing rotary evaporation concentration, and adding a crystal solvent for crystallization to obtain a product. The route synthesis steps are short, the process is novel, the intermediates are high in purity, the product yield is high, and the cost is low.
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Paragraph 0024; 0046-0047

(2017/03/08)

ANTI-ANGIOGENESIS COMPOUND, INTERMEDIATE AND USE THEREOF
Disclosed are an anti-abnormal proliferation of angiogenesis compound represented by formula I, use and intermediate thereof. The compound has good effect against abnormal proliferation of angiogenesis, and the activity of the compound is produced by inhibiting VEGFR2. The compound can be used for treating diseases, such as wet macular degeneration, inflammation, malignant tumor and the like, caused by abnormity of angiogenesis and protein kinases such as VEGFR2, FGFR2 and the like.
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Paragraph 0086; 0087

(2016/04/10)

ANTI-ANGIOGENESIS COMPOUND, INTERMEDIATE AND USE THEREOF
Disclosed are an anti-abnormal proliferation of angiogenesis compound represented by formula I, use and intermediate thereof. The compound has good effect against abnormal proliferation of angiogenesis, and the activity of the compound is produced by inhibiting VEGFR2. The compound can be used for treating diseases, such as wet macular degeneration, inflammation, malignant tumor and the like, caused by abnormity of angiogenesis and protein kinases such as VEGFR2, FGFR2 and the like.
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Paragraph 0118-0119; 0121-0122

(2016/11/02)

Discovery, synthesis and biochemical profiling of purine-2,6-dione derivatives as inhibitors of the human poly(A)-selective ribonuclease Caf1
Eukaryotic mRNA contains a 3′ poly(A) tail, which plays important roles in the regulation of mRNA stability and translation. Well-characterized enzymes involved in the shortening of the poly(A) tail include the multi-subunit Ccr4-Not deadenylase, which contains the Caf1 (Pop2) and Ccr4 catalytic components, and poly(A)-specific ribonuclease (PARN). Two Mg2+ ions present in the active sites of these ribonucleases are required for RNA cleavage. Here, we report the discovery, synthesis and biochemical profiling of purine-2,6-dione derivatives as (sub)micromolar inhibitors of Caf1.
Jadhav, Gopal P.,Kaur, Ishwinder,Maryati, Maryati,Airhihen, Blessing,Fischer, Peter M.,Winkler, G. Sebastiaan
p. 4219 - 4224
(2015/11/03)

Efficient synthesis of some new antiproliferative N-fused indoles and isoquinolines via 1,3-dipolar cycloaddition reaction in an ionic liquid
Syntheses of some new pyrrolo-fused pyrrolo[1,2-a] indole derivatives have been achieved by combining N-allyl-indole-2-carbaldehyde with a variety of N-alkyl-glycine esters as well as tetrahydroisoquinolines in an ionic liquid, triethylammonium acetate (TEAA), a recyclable reaction medium, via intramolecular [3+2] cycloaddition reaction. This new method is highly efficient, and the ionic liquid employed is recyclable. The stereochemistry of all the compounds was confirmed by 2D NMR NOESY and in some cases single crystal X-ray diffraction data. The in vitro screening of all new candidates against various bacterial strains and representative human solid tumor cell lines, A549 (lung), HeLa (cervix), SW1573 (lung), T-47D (breast) and WiDr (colon), revealed that many of them have good antibacterial, antifungal and antitubercular and antiproliferative activities.
Sutariya, Tushar R.,Labana, Balvantsingh M.,Parmar, Narsidas J.,Kant, Rajni,Gupta, Vivek K.,Plata, Gabriela B.,Padrón, José M.
supporting information
p. 2657 - 2668
(2015/04/14)

β-Amino esters from the reductive ring opening of aziridine-2-carboxylates
A general study is undertaken to examine the scope of the reductive ring opening of aziridine-2-carboxylates with samarium diiodide. The competition between C-C and C-N bond cleavage is examined as a function of the nature of the N-substituent of the aziridine, the nature of the substituent in the 3-position of the aziridine, and whether the substituent in the 3-position is in a cis or trans relationship with the carboxylate in the 2-position. The desired C-N bond cleavage leads to β-amino esters that are the predominant products for most aziridines with an N-activating group. However, C-C cleavage products are observed with an aryl group in the 3-position; this can be particularly pronounced with cis-aziridines where a nearly equal mixture of the two is observed. Exclusive formation of the C-N cleavage product is observed for all aziridines with the strongly N-activating p-toluene sulfonate group. Similarly high selectivity is observed for the 2-trimethylsilylethyl sulfonate group (SES), which is easier to remove. The utility of these methods is illustrated in the synthesis of protected forms of (R)-β3-DOPA and l-DOPA from the same aziridine, the former by SmI2-mediated reductive opening at C-2 and the latter by palladium-mediated reductive opening at C-3.
Zhao, Wenjun,Lu, Zhenjie,Wulff, William D.
p. 10068 - 10080
(2015/02/19)

Base-promoted c→n acyl rearrangement: An unconventional approach to α-amino acid derivatives
We have discovered that N-alkyl aminomalonates undergo a fast and selective intramolecular C→N acyl rearrangement reaction in the presence of a strong base, leading to N-protected glycinates in excellent yield. Moreover, the fact that the reaction proceeds through a nucleophilic enolate intermediate has been used for implementing a tandem rearrangement/alkylation sequence that has been applied to the preparation of synthetically relevant nonproteinogenic tertiary and quaternary N-alkyl α-amino acids in a very simple and reliable way.
Ugarriza, Iratxe,Uria, Uxue,Carrillo, Luisa,Vicario, Jose L.,Reyes, Efraim
p. 11650 - 11654
(2014/10/15)

Lanthanum(III) triflate catalyzed direct amidation of esters
Lanthanum trifluoromethanesulfonate is an effective single-component catalyst for synthesizing a variety of amides directly from esters and amines under mild conditions. Highly selective amidation of esters and amines, as well as catalyst-controlled amidation of esters, demonstrated the effectiveness of the catalyst system.
Morimoto, Hiroyuki,Fujiwara, Risa,Shimizu, Yuhei,Morisaki, Kazuhiro,Ohshima, Takashi
supporting information
p. 2018 - 2021
(2014/05/06)

Iridium porphyrin catalyzed N-H insertion reactions: Scope and mechanism
Ir(TTP)CH3 catalyzed N-H insertion reactions between ethyl diazoacetate (EDA) or methyl phenyldiazoacetate (MPDA) and a variety of aryl, aliphatic, primary, and secondary amines to generate substituted glycine esters with modest to high yields. Aniline substrates generally gave yields above 80%, with up to 105 catalyst turnovers, and without slow addition of the diazo reagent. Good yields were also achieved with aliphatic amines, though higher catalyst loadings and slow addition of the amine were necessary in some cases. Primary amines reacted with EDA to generate both single- and double-insertion products, either of which could be produced selectively in high yield with the proper choice of stoichiometric ratios and reaction temperature. Notably, mixed trisubstituted amines, RN(CH2CO2Et) (CHPhCO2Me), were generated from the insertion of 1 equiv of EDA and 1 equiv of MPDA into primary amines. The N-H insertion mechanism was examined using substrate competition studies, trapping experiments, and multiple spectroscopic techniques. Substrate competition studies using pairs of amines with EDA or MPDA revealed Hammett correlations with respective slopes of ρ = 0.15 and ρ+ = -0.56 as well as kinetic isotope ratios of k H/kD = 1.0 ± 0.2 and 2.7 ± 0.2. Competitive amine binding to the iridium center was demonstrated by kinetics and equilibrium binding studies. Equilibrium binding constants ranged from 102 to 105. Monitoring the reaction by absorption spectroscopy revealed a transient metalloporphyrin complex. The lifetime of this species was dependent on the nature of the amine substrate, which suggests that the catalytic cycle proceeds through a metal-ylide intermediate.
Anding, Bernie J.,Woo, L. Keith
p. 2599 - 2607
(2013/06/26)

A convenient 1,3-dipolar cycloaddition-reduction synthetic sequence from 2-allyloxy-5-nitro-salicylaldehyde to aminobenzopyran-annulated heterocycles
A microwave-assisted, one-pot synthesis of some nitro benzopyran-annulated pyrroles as well as pyrrolo-fused isoquinolines via a 1,3-dipolar cycloaddition, which involves the in situ generation of azomethine ylide formed by reacting secondary amines with 2-allyloxy-5-nitro-salicylaldehyde, has been achieved in a solvent-free environment. Compared to methods of conventional and thermal heating, the present microwave-assisted method is rapid and highly efficient. In addition, amino analogous heterocycles were successfully accessed after treating the reaction mass further with iron in acidic medium, which also highlights a one-pot procedure for a new 1,3-dipolar cycloaddition-reduction synthetic sequence. All amino-products are new bioprofiles and anticipated to be effective drug-like candidates. All compounds were characterised based on their elemental analysis, mass, IR, and 1H and 13C NMR spectroscopic data. The stereochemistry of the product was confirmed by 2D NMR COSY and NOESY experiments, which, on the basis of single crystal X-ray diffraction data analysis, was further confirmed and supported.
Parmar, Narsidas J.,Pansuriya, Bhavesh R.,Labana, Balvantsingh M.,Kant, Rajni,Gupta, Vivek K.
p. 17527 - 17539
(2013/09/24)

Structure-activity relationship study of selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitor 2-amino-4-(4-methoxyphenyl)-7- (naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101) and absolute configurational assignment using infrared and vibrational circular dichroism spectroscopy in combination with ab initio hartree-fock calculations
The excitatory amino acid transporters (EAATs) play essential roles in regulating the synaptic concentration of the neurotransmitter glutamate in the mammalian central nervous system. To date, five subtypes have been identified, named EAAT1-5 in humans, and GLAST, GLT-1, EAAC1, EAAT4, and EAAT5 in rodents, respectively. In this paper, we present the design, synthesis, and pharmacological evaluation of seven 7-N-substituted analogues of UCPH-101/102. Analogue 9 inhibited EAAT1 in the micromolar range (IC50 value 20 μM), whereas analogues 8 and 10 were inactive (IC50 values >100 μM). The diastereomeric pairs 11a/11b and 12a/12b were separated by HPLC and the absolute configuration assigned by VCD technique in combination with ab initio Hartree-Fock calculations. Analogues 11a (RS-isomer) and 12b (RR-isomer) inhibited EAAT1 (IC50 values 5.5 and 3.8 μM, respectively), whereas analogues 11b (SS-isomer) and 12a (SR-isomer) failed to inhibit EAAT1 uptake (IC50 values >300 μM).
Huynh, Tri H. V.,Shim, Irene,Bohr, Henrik,Abrahamsen, Bjarke,Nielsen, Birgitte,Jensen, Anders A.,Bunch, Lennart
experimental part
p. 5403 - 5412
(2012/08/28)

Ammonolysis of morpholine-2,5-diones: Participation of the primary amide group. Part 2
The ammonolysis of three morpholine-2,5-dione derivatives was investigated and the mechanism ascertained by kinetic studies and theoretical calculations. The kinetics, followed by high-performance liquid chromatography analysis, evidenced the presence of two intermediates, which were isolated and characterized. The ammonolysis occurs with a complex mechanism involving two consecutive reactions followed by two parallel ones. The second step of the whole reaction involves an anchimeric assistance of the primary amide group. The pseudo-first-order rate constants were calculated by appropriate equations, which describe the single steps of the process. Computational density functional theory investigations of vicinal primary amide group participation were performed using a model compound, and the transition states were generated. The theoretical calculations evidenced the essential role exerted by ammonia, which acts as a proton transfer.
Arcelli, Antonio,Bongini, Alessandro,Porzi, Gianni,Rinaldi, Samuele
experimental part
p. 132 - 141
(2012/05/04)

BICYCLIC HETEROARYL DERIVATIVES HAVING INHIBITORY ACTIVITY FOR PROTEIN KINASE
The present invention relates to a novel bicyclic heteroaryl derivative, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a solvate thereof having an improved inhibitory activity for protein kinases, and a pharmaceutical composition for preventing or treating an abnormal cell growth disorder comprising same as an active ingredient.
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Page/Page column 33

(2012/12/13)

Antimicrobial activity of peptidomimetics against multidrug-resistant Escherichia coli: A comparative study of different backbones
Novel remedies in the battle against multidrug-resistant bacterial strains are urgently needed, and one obvious approach involves antimicrobial peptides and mimics hereof. The impact of α- and β-peptoid as well as β3-amino acid modifications on the activity profile against β-lactamase-producing Escherichia coli was assessed by testing an array comprising different types of cationic peptidomimetics obtained by a general monomer-based solid-phase synthesis protocol. Most of the peptidomimetics possessed high to moderate activity toward multidrug-resistant E. coli as opposed to the corresponding inactive peptides. Nevertheless, differences in hemolytic activities indicate that a careful choice of backbone design constitutes a significant parameter in the search for effective cationic antimicrobial peptidomimetics targeting specific bacteria.
Jahnsen, Rasmus D.,Frimodt-M?ller, Niels,Franzyk, Henrik
p. 7253 - 7261
(2012/11/07)

An improved microwave assisted one-pot synthesis, and biological investigations of some novel aryldiazenyl chromeno fused pyrrolidines
An improved microwave assisted one-pot method for the synthesis of twelve new aryldiazenylchromeno [4,3-b] pyrrolidines via intramolecular azomethine ylide cycloaddition route is described. The method is efficient and advantageous over conventional and solvent-free thermal methods. The stereochemistry of the compounds was confirmed on the basis of various NMR experiments, and finally by single crystal X-ray diffraction data. N-Methyl or ethyl pyrrolidine based heterocycles gave good biological activities.
Parmar, Narsidas J.,Pansuriya, Bhavesh R.,Barad, Hitesh A.,Kant, Rajni,Gupta, Vivek K.
supporting information; experimental part
p. 4075 - 4079
(2012/07/03)

A RuII-N-heterocyclic carbene (NHC) complex from metal-metal singly bonded diruthenium(I) precursor: Synthesis, structure and catalytic evaluation
A mononuclear Ru(II)-N-heterocyclic carbene (NHC) complex [Ru II(CO)2(κ2C,N-BIN)(H2O)Br] [OTf] (OTf = trifluoromethane sulphonate) (1) has been synthesized in high-yield by the oxidative cleavage of the metal-metal singly-bonded diruthenium(I) precursor [Ru2(CO)4(CH3CN)6(OTf) 2] with 1,8-naphthyridine functionalized NHC precursor 1-benzyl-3-(5,7-dimethyl-1,8-naphthyrid-2-yl)imidazolium bromide (BIN·HBr) at room temperature. Compound 1 catalyzes transfer hydrogenation of ketones to alcohols, and carbene-transfer from ethyl diazoacetate to a variety of substrates. It is shown to be an excellent catalyst for the insertion of carbene into the O-H and N-H bonds of alcohols and amines.
Sinha, Arup,Daw, Prosenjit,Rahaman, S.M. Wahidur,Saha, Biswajit,Bera, Jitendra K.
experimental part
p. 1248 - 1257
(2011/04/22)

BICYCLIC HETEROARYL DERIVATIVES HAVING INHIBITORY ACTIVITY FOR PROTEIN KINASE
The present invention relates to a novel bicyclic heteroaryl derivative, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a solvate thereof having an improved inhibitory activity for protein kinases, and a pharmaceutical composition for preventing or treating an abnormal cell growth disorder comprising same as an active ingredient.
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Page/Page column 70; 71

(2011/08/21)

Weinreb amide based synthetic equivalents for convenient access to 4-aryl-1,2,3,4-tetrahydroisoquinolines
New synthetic equivalents, N-methoxy-N-methyl-N′-phenylsulfonyl glycinamide and N-methoxy-N-methyl-N′-benzyl-N′-tert-butyloxy carbonyl glycinamide based on WA functionality were developed for the convenient synthesis of 4-aryl-1,2,3,4-tetrahydroisoquinoline framework. Two simple reactions, N-benzylation and addition of arylmagnesium halide on the WA functionality of the former afforded the key intermediate for convenient synthesis of N-phenylsulfonyl protected 4-aryl-1,2,3,4-tetrahydroisoquinoline, through reduction and acid promoted cyclization. With the latter, the addition of arylmagnesium halide on the WA functionality followed by the same protocol afforded the direct synthesis of 4-aryl-1,2,3,4-tetrahydroisoquinolines in good yields. The acid promoted cyclization step enabled concomitant removal of N-Boc protection.
Kommidi, Harikrishna,Balasubramaniam, Sivaraman,Aidhen, Indrapal Singh
scheme or table
p. 3723 - 3729
(2010/07/05)

PIPERIDINE INHIBITORS OF JANUS KINASE 3
The present invention relates to a new piperidine inhibitors of Janus Kinase 3 activity, pharmaceutical compositions thereof, and methods of use there-of.
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Page/Page column 70

(2010/11/05)

Towards Gram-negative antivirulence drugs: New inhibitors of HldE kinase
Gram-negative bacteria lacking heptoses in their lipopolysaccharide (LPS) display attenuated virulence and increased sensitivity to human serum and to some antibiotics. Thus inhibition of bacterial heptose synthesis represents an attractive target for the development of new antibacterial agents. HldE is a bifunctional enzyme involved in the synthesis of bacterial heptoses. Development of a biochemical assay suitable for high-throughput screening allowed the discovery of inhibitors 1 and 2 of HldE kinase. Study of the structure-activity relationship of this series of inhibitors led to highly potent compounds.
Desroy, Nicolas,Moreau, Francois,Briet, Sophia,Fralliec, Geraldine Le,Floquet, Stephanie,Durant, Lionel,Vongsouthi, Vanida,Gerusz, Vincent,Denis, Alexis,Escaich, Sonia
experimental part
p. 1276 - 1289
(2009/07/11)

5-Benzylidene-hydantoins: Synthesis and antiproliferative activity on A549 lung cancer cell line
Benzylidene hydantoins have been recently reported as a new class of EGFR inhibitors. We describe here a simple and efficient methodology for the parallel solution-phase synthesis of a library of 5-benzylidene hydantoins, which were evaluated for antiproliferative activity on the human lung adenocarcinoma A549 cell line. Various substituents at positions 1, 3 and 5 on the hydantoin nucleus were examined. In the presence of a 5-benzylidene group and of a lipophilic substituent at position 1, most of the tested compounds inhibited cell proliferation at a concentration of 20 μM. Compound 7 (UPR1024), bearing 1-phenethyl and (E)-5-p-OH-benzylidene substituents, was found to be the most active derivative of the series. It inhibited EGFR autophosphorylation and induced DNA damage in A549 cells. Compound 7 and other synthesized 5-benzylidene hydantoin derivatives increased p53 levels, suggesting that the dual mechanism of action was a common feature shared by compound 7 and other member of the series.
Zuliani, Valentina,Carmi, Caterina,Rivara, Mirko,Fantini, Marco,Lodola, Alessio,Vacondio, Federica,Bordi, Fabrizio,Plazzi, Pier Vincenzo,Cavazzoni, Andrea,Galetti, Maricla,Alfieri, Roberta R.,Petronini, Pier Giorgio,Mor, Marco
experimental part
p. 3471 - 3479
(2009/12/24)

Diastereoselective synthesis of pyrrolidines via 1,3-dipolar cycloaddition of a chiral azomethine ylide
1,3-Dipolar cycloaddition of d-glucose-derived azomethine ylides for the synthesis of chiral pyrrolidines accompanied an unexpected 1,2-elimination in the furanose moiety of the products. The C3′ alkoxy/hydroxy group of the furanose moiety was invariably eliminated under the reaction conditions. Also, in contrast to the previous reports, moderate to good exo-diastereoselectivity was observed in the reaction products.
Karthikeyan,Senthil Kumar,Muralidharan,Perumal
experimental part
p. 7175 - 7179
(2010/03/03)

Electroorganic synthesis of benzathine
Benzathine is prepared in good yields from cyanobenzene by a combination of electrochemical hydrogenation and Kolbe electrolysis using nickel and platinum electrodes in the presence of methanolic sodium methoxide in an undivided cell.
Lateef, Shaik,Reddy Krishna Mohan, Srinivasulu,Reddy Jayarama Reddy, Srinivasulu
p. 77 - 80
(2007/10/03)

Microwave-assisted solvent-free intramolecular 1,3-dipolar cycloaddition reactions leading to hexahydrochromeno[4,3-b]pyrroles: scope and limitations
We report the microwave-assisted solvent-free synthesis of hexahydrochromeno[4,3-b]pyrroles. Intramolecular 1,3-dipolar cycloadditions proceed under these conditions within 15-40 min in 16-84% yields. An influence of the microwave irradiation upon various [3+2] cycloaddition reaction intermediates was studied. Additionally, a scope and limitations of these reactions including an influence of the dipolarophile geometry upon the cycloaddition selectivity and steric demands of the dipole upon its reactivity were also disclosed. These observations led us to postulate a preferable transition state of the reaction. Finally, an influence of the microwave irradiation to the isomerization of activated olefins was also described.
Pospí?il, Ji?í,Potá?ek, Milan
p. 337 - 346
(2007/10/03)

Microwave-assisted synthesis of substituted hexahydropyrrolo[3,2-c] quinolines
New compounds with the ethyl hexahydro-1H-pyrrolo[3,2-c]quinoline-2- carboxylate skeleton were prepared by microwave-assisted intramolecular 1,3-dipolar cycloaddition reactions. The reactions were carried out under solvent-free conditions and compared with the same reaction in the presence of a solvent and a catalyst. Steric effects on the selectivity of the reaction were noted and evaluated.
Neuschl, Michal,Bogdal, Darek,Potacek, Milan
p. 49 - 59
(2008/02/04)

Microwave-assisted synthesis of 2,5-piperazinediones under solvent-free conditions
A general, efficient and environmentally friendly procedure for the synthesis of 2,5-piperazinediones is described, involving the microwave irradiation of N-Boc dipeptide esters. Georg Thieme Verlag Stuttgart.
Lopez-Cobenas, Alberto,Cledera, Pilar,Sanchez, J. Domingo,Lopez-Alvarado, Pilar,Ramos, M. Teresa,Avendano, Carmen,Menendez, J. Carlos
p. 3412 - 3422
(2007/10/03)

Electrogenerated cyanomethyl anion in organic synthesis: A simple diastereoselective synthesis of cis-3-alkyl-1-benzyl-4-ethoxycarbonyl-β- lactams
A ready diastereoselective synthesis of cis-3-alkyl-1-benzyl-4- ethoxycarbonyl-β-lactams has been developed by galvanostatic electrolysis of MeCN-Et4NPF6 solutions and subsequent addition of a N-(ethoxycarbonyl)methyl-N-benzyl-2-bromoalkylcarboxamide. The yields in β-lactams are very high and the cis isomers have been obtained in a large excess, the cis/trans ratios varying from 87/13 to 93/07.
Feroci, Marta,Lessard, Jean,Orsini, Monica,Inesi, Achille
p. 8517 - 8519
(2007/10/03)

Heterocyclic compounds as P2X7 ion channel blockers
The present invention relates to a novel series of 4,5-diphenyl-2-amino-4,5-dihydro-imidazole derivatives of the formula II: 1 wherein R, R1, R2, R3, R4, R5, X and Y are as defined herein. This invention also relates to methods of making these compounds. The compounds of this invention are P2X7 ion channel blockers and are therefore useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of diseases having an inflammatory component, including inflammatory bowel disease, rheumatoid arthritis and disease conditions associated with the central nervous system, such as stroke, Alzheimer''s disease, etc.
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Page/Page column 80

(2010/02/10)

A short preparation of an advanced intermediate for lactacystin synthesis: The complete carbon skeleton of clasto-lactacystin dihydroxyacid
An advanced intermediate 22 for lactacystin synthesis, containing the full carbon skeleton of the pyrrolidinone component, has been achieved in four steps from a protected glycine ester.
Page, Philip C. Bulman,Leach, David C.,Hayman, Colin M.,Hamzah, A. Sazali,Allin, Steven M.,McKee, Vickie
p. 1025 - 1027
(2007/10/03)

Design of selective peptidomimetic agonists for the human orphan receptor BRS-3
New tool substances may help to unravel the physiological role of the human orphan receptor BRS-3 and its possible use as a drug target for the treatment of obesity and cancer. In continuation of our work on BRS-3, the solid- and solution-phase synthesis of a library of low molecular weight peptidomimetic agonists based on the recently developed short peptide agonist 4 is described. Functional potencies of the compounds were determined measuring calcium mobilization in a fluorometric imaging plate reader (FLIPR) assay. Focusing on the N-terminus, the D-Phe-Gln moiety of 4 was modified in a combinatorial SAR-oriented medicinal chemistry approach. With the incorporation of N-arylated glycine and alanine building blocks azaglycine, piperazine, or piperidine and the synthesis of semicarbazides and semicarbazones, a number of highly potent and selective compounds with a reduced number of peptide bonds were obtained, which also should have enhanced metabolic stability.
Weber, Dirk,Berger, Claudia,Eickelmann, Peter,Antel, Jochen,Kessler, Horst
p. 1918 - 1930
(2007/10/03)

Short and versatile route to a key intermediate for lactacystin synthesis.
[reaction: see text] A key intermediate 14 for the synthesis of lactacystin 1 has been constructed in four steps and 33% overall yield. The key steps involve cyclization of a suitably functionalized glutamic acid derivative and concomitant alkylation of the resulting beta,beta-diketoester system, C-acylation of the cyclic alpha-amidoketone 9, and decarboxylbenzylation of 12. Alkylation of a related beta,beta-diketoester 5 was additionally achieved with several electrophiles.
Bulman Page, Philip C,Hamzah, A Sazali,Leach, David C,Allin, Steven M,Andrews, David M,Rassias, Gerasimos A
p. 353 - 355
(2007/10/03)

Tandem radical and non-radical reactions mediated with thiols - A new method of cleavage of allylic amines
Thiyl radical promotes the isomerisation of allylic amines into enamines via two consecutive hydrogen atom abstraction steps, and the subsequent polar addition of the corresponding thiol to the enamine results in the cleavage of the C-N bond via a thioaminal intermediate: this reaction provides a mild, metal-free methodology for the deprotection of allylated primary and secondary amines.
Bertrand, Michele P.,Escoubet, Stephanie,Gastaldi, Stephane,Timokhin, Vitaliy I.
p. 216 - 217
(2007/10/03)

Cesium effect: High chemoselectivity in direct N-alkylation of amines
A novel method for the mono-N-alkylation of primary amines, diamines, and polyamines was developed using cesium bases in order to prepare secondary amines efficiently. A cesium base not only promoted alkylation of primary amines but also suppressed overalkylations of the produced secondary amines. Various amines, alkyl bromides, and alkyl sulfonates were examined, and the results demonstrated this methodology was highly chemoselective to favor mono-N-alkylation over dialkylation. In particular, use of either sterically demanding substrates or amino acid derivatives afforded the secondary amines exclusively, offering wide applications in peptidomimetic syntheses.
Salvatore, Ralph Nicholas,Nagle, Advait S.,Kyung, Woon Jung
p. 674 - 683
(2007/10/03)

Kinetics and detemination of ethyl chloroacetate and ethyl bromoacetate with piperidine
A simple sensitive potentiometric method has been developed for determination of active haloester. It is based on the reaction of haloester with excess piperidine in ethanol at 40°. Under the optimum conditions the average recovery is 97%. The reaction proceeds kinetically as a pseudo-first order reaction. The reactivity of tested amines towards haloester follows the order : benzylamine n-butylamine ethylamine piperidine. The activation parameters have been calculated and relevant reaction mechanism has been suggested.
Iskander, Madlene L.,Badawy,Ahmed,Ayoub
p. 333 - 336
(2007/10/03)

5-alkoxy-2(3H)-oxazolone compounds and process for preparing the same
PCT No. PCT/JP97/04157 Sec. 371 Date May 12, 1999 Sec. 102(e) Date May 12, 1999 PCT Filed Nov. 14, 1997 PCT Pub. No. WO98/22449 PCT Pub. Date May 28, 19985-Alkoxy-2(3H)-oxazolone compounds represented by general formula (1); and a R1 process for the preparation thereof, wherein R1 is hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C2-C10 alkenyl or optionally substituted phenyl; R2 is hydrogen, optionally substituted C1-C10 alkyl, optionally substituted phenyl or unsubstituted C2-C10 alkenyl; R3 is optionally substituted C1-C10 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C2-C10 alkenyl excluding 2-alkenyl, or optionally substituted phenyl.
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(2008/06/13)