cas 58885-60-2, (3-OXO-PROPYL)-CARBAMIC ACID TERT-BUTYL ESTER

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Self-Assembly of C3 Symmetric Rigid Macrolactams into Very Polar and Porous Trigonal Crystals
Cyclohexane and cyclotri-β-alanyl have been used as scaffolds for the design of new C3-symmetric rings incorporating conjugated alkenes and dienes. All three C3-symmetric lactams share the same triangular shape and their crystal system is trigonal. They all belong to the R3 space group, R3m, R3 and R3c, for the increasingly large 12-, 18- and 24-membered rigid rings, respectively. All lactams stack on top of each other, through H-bonds and van der Waals noncovalent interactions, leading to endless supramolecular cylinders and tubes. The largest member of the family leads to tubes, the central pores of which is wide enough to let water in. A common feature of all the lactams is their very large dipole, of around 9 D, according to DFT calculations. Surprisingly, all the resulting cylinders and tubes pack side by side in the crystals, with all the dipoles pointing to the same direction. As a result, all three crystals are anisotropic and appear to be the first members of a new kind of highly polar crystals.
Marmin, Thomas,Dory, Yves L.
p. 6707 - 6711
(2019)
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Synthesis and antimalarial evaluation of new N1-(7-chloro-4- quinolyl)-1,4-bis(3-aminopropyl)piperazine derivatives
Synthesis and evaluation of the activity of new N1-(7-chloro-4- quinolyl)-1,4-bis(3-aminopropyl)piperazine derivatives against a chloroquine-resistant strain of Plasmodium falciparum are described. Selectivity indices were improved for two compounds versus the lead 1, the bis-cyclopropylmethyl derivative, thus increasing the therapeutic interest of our family. As our previous studies conducted on the mode of action of our compounds made us hypothesize the existence of original mechanisms and/or original targets, terminal amino derivatives can be considered as promising tools further mechanistical studies, as probes for affinity chromatography.
Ryckebusch, Adina,Debreu-Fontaine, Marie-Ange,Mouray, Elisabeth,Grellier, Philippe,Sergheraert, Christian,Melnyk, Patricia
p. 297 - 302
(2005)
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Asymmetric total synthesis of novel pentacyclic indole alkaloid, kopsiyunnanine E, isolated from Kopsia arborea
A new pentacyclic indole alkaloid, kopsiyunnanine E, was isolated from Yunnan Kopsia arborea, and its structure, which was inferred from spectroscopic data, was established by a 16-step asymmetric total synthesis that proved that the natural alkaloid was not enantiomerically pure.
Kitajima, Mariko,Murakami, Yosuke,Takahashi, Nobuaki,Wu, Yuqiu,Kogure, Noriyuki,Zhang, Rong-Ping,Takayama, Hiromitsu
p. 5000 - 5003
(2014)
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De-novo designed β-lysine derivatives can both augment and diminish the proliferation rates of E. coli through the action of Elongation Factor P
An investigation into the effect of modified β-lysines on the growth rates of eubacterial cells is reported. It is shown that the effects observed are due to the post translational modification of Elongation Factor P (EFP) with these compounds catalysed b
Connon, Stephen J.,Ghanim, Magda,Kelly, Vincent P.,McDonnell, Ciara M.,Mike Southern, J.
(2022/01/24)

Phosphine-Catalyzed Synthesis of Chiral N-Heterocycles through (Asymmetric) P(III)/P(V) Redox Cycling
Phosphine-catalyzed tandem Michael addition/intramolecular Wittig reactions have been developed for the synthesis of chiral 2,5-dihydro-1H-pyrrole and tetrahydropyridine derivatives. These processes have been rendered catalytic in phosphine, thanks to the in situ reduction of phosphine oxide by phenylsilane. Furthermore, catalytic and asymmetric P(III)/P(V) processes were implemented using enantiopure chiral phosphines.
Lorton, Charlotte,Saleh, Nidal,Voituriez, Arnaud
p. 3340 - 3344
(2021/06/26)

VISIBLE-LIGHT MEDIATED ORGANOPHOTOREDOX CATALYTIC DEUTERATION OF AROMATIC AND ALIPHATIC ALDEHYDES
Described are methods for preparing a deuterated aldehyde using with a photocatalyst and a hydrogen atom transfer agent in a H2O free solvent comprising D2O and an organic solvent under an inert gas. The methods may be used to convert a wide variety of aldehydes (e.g., aryl, alkyl, or alkenyl aldehydes) to C-1 deuterated aldehydes under mild reaction conditions.
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Paragraph 0059-0060; 0061-0062; 0065-0066

(2021/06/22)

Novel method for synthesizing 2-(1-methylimidazole-5-yl) ethylamine hydrochloride
The invention discloses a novel method for synthesizing 2-(1-methylimidazole-5-yl) ethylamine hydrochloride, which comprises the following steps: 1, reacting 3-amino propanol serving as an initial raw material with di-tert-butyl dicarbonate to obtain 3-(Boc-amino) propanol; 2, carrying out Swen oxidation reaction: carrying out Swen oxidation on the obtained 3-(Boc-amino) propanol to obtain 3-(Boc-amino) propionaldehyde; 3, cyclization reaction: reacting the obtained 3-(Boc-amino) propionaldehyde with a methylamine methanol solution to generate Schiff base, and directly carrying out Van Lessel reaction on the Schiff base and p-toluenesulfonyl methyl isocyanide without separation to synthesize 2-(1-methyl-1H-imidazole-5-yl) tert-butyl ethylcarbamate; and 4, reacting the obtained 2-(1-methyl-1H-imidazole-5-yl) tert-butyl ethylcarbamate with a hydrogen chloride isopropanol solution to remove Boc, thereby obtaining the final product 2-(1-methylimidazole-5-yl) ethylamine hydrochloride. The method has the beneficial effects that the method is prepared from cheap raw materials which are easy to obtain, the reaction yield is high, the total steps are few, the operation is simple, the production cost is low, and industrialization is easy to realize.
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(2021/04/28)

Optimization of Naphthyridones into Selective TATA-Binding Protein Associated Factor 1 (TAF1) Bromodomain Inhibitors
Bromodomain containing proteins and the acetyl-lysine binding bromodomains contained therein are increasingly attractive targets for the development of novel epigenetic therapeutics. To help validate this target class and unravel the complex associated biology, there has been a concerted effort to develop selective small molecule bromodomain inhibitors. Herein we describe the structure-based efforts and multiple challenges encountered in optimizing a naphthyridone template into selective TAF1(2) bromodomain inhibitors which, while unsuitable as chemical probes themselves, show promise for the future development of small molecules to interrogate TAF1(2) biology. Key to this work was the introduction and modulation of the basicity of a pendant amine which had a substantial impact on not only bromodomain selectivity but also cellular target engagement.
Bamborough, Paul,Chung, Chun-Wa,Clegg, Michael A.,Craggs, Peter D.,Demont, Emmanuel H.,Gordon, Laurie J.,Humphreys, Philip G.,Liwicki, Gemma M.,Phillipou, Alex,Prinjha, Rab K.,Theodoulou, Natalie H.,Tomkinson, Nicholas C. O.
supporting information
p. 1308 - 1317
(2021/08/24)

NOVEL IMIDAZOPYRAZINE DERIVATIVES
The invention provides novel imidazopyrazine derivatives having the general formula (I), wherein Rx and R3 to R5 are as described herein (formula (I)) or pharmaceutically acceptable salts thereof. Further provided are pharmaceutical compositions including the compounds, processes of manufacturing the compounds and methods of using the compounds as medicaments, in particular methods of using the compounds as antibiotics for the treatment or prevention of bacterial infections and resulting diseases.
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Page/Page column 51; 191-192

(2021/12/31)

PROCESS OF MAKING CFTR MODULATORS
The disclosure provides processes for synthesizing Compound I, and pharmaceutically acceptable salts thereof.
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Paragraph 0740

(2021/02/19)

DIMERS FOR USE IN SYNTHESIS OF PEPTIDOMIMETICS
Dimers for use in synthesis of peptidomimetics are described. Uses of dimers as synthons in synthesis of azapeptides and other peptidomimetics, azapeptides and other peptidomimetics synthesized from the dimers and uses of azapeptides and other peptidomimetics are also described.
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Paragraph 00325-00326

(2021/11/13)

BICYCLIC COMPOUNDS
Provided herein are compounds and pharmaceutical compositions comprising said compounds that are useful for treating cancers. Specific cancers include those that are mediated by YAP/TAZ or those that are modulated by the interaction between YAP/TAZ and TEAD.
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(2020/06/01)

Identification of the hydantoin alkaloids parazoanthines as novel CXCR4 antagonists by computational and in vitro functional characterization
CXCR4 chemokine receptor represents an attractive pharmacological target due to its key role in cancer metastasis and inflammatory diseases. Starting from our previously-developed pharmacophoric model, we applied a combined computational and experimental approach that led to the identification of the hydantoin alkaloids parazoanthines, isolated from the Mediterranean Sea anemone Parazoanthus axinellae, as novel CXCR4 antagonists. Parazoanthine analogues were then synthesized to evaluate the contribution of functional groups to the overall activity. Within the panel of synthesized natural and non-natural parazoanthines, parazoanthine-B was identified as the most potent CXCR4 antagonist with an IC50 value of 9.3 nM, even though all the investigated compounds were able to antagonize in vitro the down-stream effects of CXC12, albeit with variable potency and efficacy. The results of our study strongly support this class of small molecules as potent CXCR4 antagonists in tumoral pathologies characterized by an overexpression of this receptor. Furthermore, their structure–activity relationships allowed the optimization of our pharmacophoric model, useful for large-scale in silico screening.
Vitale, Rosa Maria,Thellung, Stefano,Tinto, Francesco,Solari, Agnese,Gatti, Monica,Nuzzo, Genoveffa,Ioannou, Efstathia,Roussis, Vassilios,Ciavatta, Maria Letizia,Manzo, Emiliano,Florio, Tullio,Amodeo, Pietro
(2020/10/29)

DERIVATIVES OF PIPERLONGUMINE AND USES THEREOF
The present invention relates to a group of 1-[(E)-3-(3,4,5-trimethoxyphenyl)prop-2-enoyl]-2,3-dihydropyridin-6-one (piperlongumine) derivatives, analogs and pharmaceutically acceptable salts thereof. The present invention also relates to a pharmaceutical composition and formulation containing a derivative of piperlongumine; and use of the derivatives and analogs for treating cancer, reducing inflammation and/or treating an autoimmune or inflammatory disease.
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Paragraph 0958-0959

(2020/12/13)

Structure-activity relationship studies on the inhibition of the bacterial translation of novel Odilorhabdins analogues
A structure–activity relationship (SAR) study of NOSO-95179, a nonapeptide from the Odilorhabdin class of antibacterials, was performed by systematic variations of amino acids in positions 2 and 5 of the peptide. A series of non-proteinogenic amino acids was synthesized in high enantiomeric purity from Williams’ chiral diphenyloxazinone by highly diastereoselective alkylation or by aldol-type reaction. NOSO-95179 analogues for SAR studies were prepared using solid-phase peptide synthesis. Inhibition of bacterial translation by each of the synthesized Odilorhabdin analogues was measured using an in vitro test. For the most efficient analogues, antibacterial efficacy was measured against two wild-type Enterobacteriaceae (Escherichia coli and Klebsiella pneumoniae) and against an efflux defective E. coli strain (ΔtolC) to evaluate the impact of efflux on the antibacterial activity.
Cao, Sha,Gualtieri, Maxime,Hjort, Karin,Hughes, Diarmaid,Huseby, Douglas L,Ikaunieks, Martins,Katkevics, Martins,Kukosha, Tatyana,Loza, Einars,Pantel, Lucile,Racine, Emilie,Ryabova, Victoria,Sarciaux, Matthieu,Serri, Marine,Shubin, Kirill,Suna, Edgars,Trufilkina, Nadezhda,Yadav, Kavita
(2020/04/15)

HERBICIDAL COMPOUNDS
Use of the compounds of the formula (I) wherein the substituents are as defined herein as herbicides. Compounds of formula (I) are also claimed.
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Page/Page column 67

(2020/06/05)

Allylation of aldehydes by dual photoredox and nickel catalysis
Here we report the application of dual nickel/photoredox catalysis to the allylation of aliphatic, aromatic and heteroaromatic aldehydes by using commercially available reagents. The process utilizes the combination of a Ni(ii) complex, [Ru(bpy)3]2+ as a photoredox catalyst, and allylacetate under blue LED irradiation, and allows the synthesis of a large variety of homoallylic alcohols.
Gualandi, Andrea,Rodeghiero, Giacomo,Faraone, Adriana,Patuzzo, Filippo,Marchini, Marianna,Calogero, Francesco,Perciaccante, Rossana,Jansen, Thomas Paul,Ceroni, Paola,Cozzi, Pier Giorgio
supporting information
p. 6838 - 6841
(2019/06/18)

Design, Synthesis, and Conformational Analysis of Oligobenzanilides as Multifacial α-Helix Mimetics
The design, synthesis, and conformational analysis of an oligobenzanilide helix mimetic scaffold capable of simultaneous mimicry of two faces of an α-helix is reported. The synthetic methodology provides access to diverse monomer building blocks amenable to solid-phase assembly in just four synthetic steps. The conformational flexibility of model dimers was investigated using a combination of solid and solution state methodologies supplemented with DFT calculations. The lack of noncovalent constraints allows for significant conformational plasticity in the scaffold, thus permitting it to successfully mimic residues i, i+2, i+4, i+6, i+7, and i+9 of a canonical α-helix.
Flack, Theo,Romain, Charles,White, Andrew J. P.,Haycock, Peter R.,Barnard, Anna
p. 4433 - 4438
(2019/06/27)

IRAK DEGRADERS AND USES THEREOF
The present invention provides compounds, compositions thereof, and methods of using the same.
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Paragraph 2694; 2695

(2019/07/10)

Fragment-Based Covalent Ligand Screening Enables Rapid Discovery of Inhibitors for the RBR E3 Ubiquitin Ligase HOIP
Modification of proteins with polyubiquitin chains is a key regulatory mechanism to control cellular behavior and alterations in the ubiquitin system are linked to many diseases. Linear (M1-linked) polyubiquitin chains play pivotal roles in several cellular signaling pathways mediating immune and inflammatory responses and apoptotic cell death. These chains are formed by the linear ubiquitin chain assembly complex (LUBAC), a multiprotein E3 ligase that consists of 3 subunits, HOIP, HOIL-1L, and SHARPIN. Herein, we describe the discovery of inhibitors targeting the active site cysteine of the catalytic subunit HOIP using fragmentbased covalent ligand screening. We report the synthesis of a diverse library of electrophilic fragments and demonstrate an integrated use of protein LC-MS, biochemical ubiquitination assays, chemical synthesis, and protein crystallography to enable the first structure-based development of covalent inhibitors for an RBR E3 ligase. Furthermore, using cell-based assays and chemoproteomics, we demonstrate that these compounds effectively penetrate mammalian cells to label and inhibit HOIP and NF-κB activation, making them suitable hits for the development of selective probes to study LUBAC biology. Our results illustrate the power of fragment-based covalent ligand screening to discover lead compounds for challenging targets, which holds promise to be a general approach for the development of cell-permeable inhibitors of thioester-forming E3 ubiquitin ligases.
Johansson, Henrik,Tsai, Yi-Chun Isabella,Fantom, Ken,Chung, Chun-Wa,Kümper, Sandra,Martino, Luigi,Thomas, Daniel A.,Eberl, H. Christian,Muelbaier, Marcel,House, David,Rittinger, Katrin
supporting information
p. 2703 - 2712
(2019/02/14)

DERIVATIVES OF PIPERLONGUMINE AND USES THEREOF
The present invention relates to a group of 1-[(E)-3-(3,4,5-trimethoxyphenyl)prop-2-enoyl]-2,3- dihydropyridin-6-one (piperlongumine) derivatives, analogs and pharmaceutically acceptable salts thereof. The present invention also relates to processes for preparing the same; a pharmaceutical composition and formulation containing a derivative of piperlogumine; and use of the derivatives and analogs for treating cancer.
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Page/Page column 223; 224

(2019/06/11)

AMINOPYRROLOTRIAZINES AS KINASE INHIBITORS
The disclosure relates to compounds of formula I which are useful as kinase modulators including RIPK1 modulation. The disclosure also provides methods of making and using the compounds for example in treatments related to necrosis or inflammation as well as other indications.
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Page/Page column 739; 740

(2019/08/12)

Catalytic Asymmetric Cycloadditions between Aldehydes and Enolizable Anhydrides: Cis-Selective Dihydroisocoumarin Formation
In the presence of a trityl-substituted cinchona alkaloid-based catalyst, homophthalic, aryl succinic, and glutaconic anhydride derivatives reacted with aromatic and aliphatic aldehydes to produce cis-lactones in up to 90:10 dr and 99% ee. A DFT study has shown how the catalyst is uniquely able to bring about the opposite sense of diastereocontrol to that usually observed.
Aiello, Maria Luisa,Farid, Umar,Trujillo, Cristina,Twamley, Brendan,Connon, Stephen J.
p. 15499 - 15511
(2019/01/04)

Orthogonally Protected Diaminoterephthalate Scaffolds: Installation of Two Functional Units at the Chromophore
The 2,5-diaminoterephthalate structural motif is a powerful chromophore with remarkable fluorescence properties. Containing two carboxylate and two amino functions, it defines a colored molecular scaffold which allows for orthogonal functionalization with different functional units. Therefore, different applications in life sciences and materials science could be addressed. In this study, the two amino functions were alkylated by reductive amination with side chains carrying amino (orthogonally protected as Boc or Alloc) and carboxylate functions (orthogonally protected as tBu or allyl ester). After sequential deprotections, functional units were introduced by amidation reactions. As three examples, the chromophore was coupled with retinoic acid and fullerene C60 in order to obtain a triad for studying photoinduced electron transfer processes. Furthermore, cyclooctyne and azide moieties were introduced as functional units, allowing for ligation by click reactions. These two clickable groups were applied in combination with maleimide units which are reactive toward thiol residues. The latter dyes define so-called turn on probes, since the fluorescence quantum yields increased by one order of magnitude upon reaction with the molecular target.
Buschbeck, Leon,Christoffers, Jens
p. 4002 - 4014
(2018/04/14)

DIAGNOSIS, TREATMENT AND PREVENTION OF NEUROTENSIN RECEPTOR-RELATED CONDITIONS
The present invention describes a compound of formula (I) which can be used in the diagnosis, treatment or prevention of neurotensin receptor-related conditions such as tumors and hematological malignancies.
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(2018/03/01)

Dynamic kinetic resolution of bis-aryl succinic anhydrides: Enantioselective synthesis of densely functionalised γ-butyrolactones
The efficient Dynamic Kinetic Resolution (DKR) of disubstituted anhydrides has been shown to be possible for the first time. Using an ad hoc designed organocatalyst and an enantio- and diastereoselective cycloaddition process with aldehydes, stereochemically complex γ-butyrolactone derivatives can be obtained-with control over three contiguous stereocentres, one of which is all carbon quaternary.
Claveau, Romain,Twamley, Brendan,Connon, Stephen J.
p. 3231 - 3234
(2018/04/05)

Synthesis and Absolute Stereochemical Reassignment of Mukanadin F: A Study of Isomerization of Bromopyrrole Alkaloids with Implications on Marine Natural Product Isolation
Synthesis of both enantiomers of mukanadin F was achieved by using a seven step synthesis. Comparison of the optical rotation data of synthetic samples to that reported for the isolated natural product determined that the absolute configuration of the natural product is 9S and not the reported 9R. Further studies established that the reported low magnitude of optical rotation in the isolated sample is due to compounds of this type undergoing isomerization and racemization under benign laboratory conditions. Additionally the synthetic methods developed were applied to synthesize mukanadins B and D.
van Rensburg, Michelle,Copp, Brent R.,Barker, David
p. 3065 - 3074
(2018/07/06)

DNA-Encoded Dynamic Chemical Library and Its Applications in Ligand Discovery
Dynamic combinatorial library (DCL) has emerged as an efficient tool for ligand discovery and become an important discovery modality in biomedical research. However, the applications of DCLs have been significantly hampered by low library diversity and limited analytical methods capable of processing large libraries. Here, we report a strategy that has addressed this limitation and can select cooperatively binding small-molecule pairs from large-scale dynamic libraries. Our approach is based on DNA-mediated dynamic hybridization, DNA-encoding, and a photo-cross-linking-based decoding scheme. To demonstrate the generality and performance of this approach, a 10 000-member DNA-encoded dynamic library has been prepared and selected against six protein targets. Specific binders have been identified for each target, and we have validated the biological activities of selected ligands for the targets that are implicated in important cellular functions including protein deacetylation and sumoylation. Notably, a series of novel and selective sirtuin-3 inhibitors have been developed. Our study has circumvented a major obstacle in DCL and may provide a broadly applicable method for ligand discovery against biological targets.
Zhou, Yu,Li, Chen,Peng, Jianzhao,Xie, Liangxu,Meng, Ling,Li, Qingrong,Zhang, Jianfu,Li, Xiang David,Li, Xin,Huang, Xuhui,Li, Xiaoyu
supporting information
p. 15859 - 15867
(2018/12/10)

HETEROARYL-CARBOXAMIDES AS HISTONE DEMETHYLASE INHIBITORS
The invention relates to heteroaryl-carboxamides as described herein, useful as histone demethyiase inhibitors. The invention also relates to pharmaceutical compositions comprising these compounds and to their use in therapy, including e.g., in the treatment of cancer.
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Page/Page column 103; 104

(2019/01/04)

Stable Yellow Imidazolium Compounds
Described herein is a yellow imidazolium chromophore having a structure according to Formula V.
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Paragraph 0178; 0179

(2018/04/13)

CONJUGATE OF MONOMETHYL AURISTATIN F AND TRASTUZUMAB AND ITS USE FOR THE TREATMENT OF CANCER
The present invention relates to an antibody-drug-conjugate or pharmaceutical composition comprising the same. From one aspect, the invention relates to an antibody-drug-conjugate (ADC) comprising an antibody consisting of the Trastuzumab or a biosimilar thereof, said antibody being conjugated to at least one drug consisting of a monomethyl auristatin F derivative. The invention also comprises method of treatment of cancer comprising administering to the subject an effective amount of said antibody-drug-conjugate or composition comprising the same.
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Paragraph 0301; 0302

(2017/05/15)

COMPOSITION FOR THE TREATMENT OF IGF-1R EXPRESSING CANCER
The present invention relates to a method for the treatment of IGF-IR expressing cancers as well as to a compositions and a kit for said traitment. From one aspect, the invention reates to the combined use of a first antibody for the determination of the IGF-IR status of a cancer and a second antibody used as an ADC for the treatment of said cancer.
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Page/Page column 118; 119

(2017/05/17)

Stable peptide-based PACE4 inhibitors
It is provided PACE4 inhibitors and their uses for treating infection, cancer. Particularly, it is provided a method or use for the treatment of a cancer in a subject, comprising administering to the subject a therapeutically effective amount of the PACE4 inhibitors or the composition disclosed.
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Page/Page column 29; 30; 37

(2017/12/27)

Exploring endoperoxides as a new entry for the synthesis of branched azasugars
A new class of nitrogen-containing endoperoxides were synthesised by a photochemical [4 + 2]-cycloaddition between a diene and singlet oxygen. The endoperoxides were dihydroxylated and protected to provide a series of endoperoxide building blocks for organic synthesis, with potential use as precursors for the synthesis of branched azasugars. Preliminary exploration of the chemistry of these building blocks provided access to a variety of derivatives including tetrahydrofurans, epoxides and protected amino-tetraols.
Domeyer, Svenja,Bjerregaard, Mark,Johansson, Henrik,Pedersen, Daniel Sejer
p. 644 - 647
(2017/06/20)

Multicomponent Catalytic Asymmetric Synthesis of trans-Aziridines
A multicomponent trans-aziridination of aldehydes, amines, and diazo compounds with BOROX catalysts is developed. The optimal protocol is slightly different for aryl aldehydes than for aliphatic aldehydes. The key to the success with aryl aldehydes was allowing the catalyst, aldehyde, and amine to react for 20 min before addition of the diazo compound. A variety of 11 different electron-poor and electron-rich aryl aldehydes were screened to give trans-aziridines in 73-90% yield with 82-99% ee and trans/cis selectivities of 19:1 to >99:1. The optimal protocol for the trans-aziridination of aliphatic aldehydes did not require prereaction of the catalyst, aldehyde, and amine, and instead, the diazo compound could be added directly. The scope of the reaction is limited to unbranched aliphatic aldehydes and was tolerant of a number of functional groups including ethers, esters, epoxides, carbamates, and phthalimides. A total of 10 aliphatic aldehydes were examined and found to give trans-aziridines in 60-88% yield with 60-98% ee and trans/cis selectivities of 6:1 to >99:1. Alkenyl aldehydes did not react, but an alkynyl aldehyde gave a 71% yield and 95% ee of an aziridine that was found to be the cis- and not the trans-diastereomer. The aryl and aliphatic aldehydes both gave the trans-aziridines with the same absolute configuration with the same catalyst; however, in those cases where cis-aziridines were formed, the configuration was opposite for those formed from aryl versus aliphatic aldehydes.
Zhou, Yubai,Gupta, Anil K.,Mukherjee, Munmun,Zheng, Li,Wulff, William D.
p. 13121 - 13140
(2017/12/26)

HETEROARYL-CARBOXYLIC ACIDS AS HISTONE DEMETHYLASE INHIBITORS
The invention relates to heteroaryl-carboxylic acids as described herein, useful as histone demethylase inhibitors. The invention also relates to pharmaceutical compositions comprising these compounds and to their use in therapy, including e.g., in the treatment of cancer.
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Page/Page column 127

(2018/01/17)

CONJUGATE OF MONOMETHYL AURISTATIN F AND TRASTUZUMAB AND ITS USE FOR THE TREATMENT OF CANCER
The present invention relates to an antibody-drug-conjugate. From one aspect, the invention relates to an antibody-drug-conjugate comprising an antibody consisting of the Trastuzumab, said antibody being conjugated to at least one drug consisting of a monomethyl auristatin F derivative. The invention also comprises method of treatment and the use of said antibody-drug-conjugate for the treatment of cancer.
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Page/Page column 47

(2016/11/17)

ANTIBACTERIAL COMPOUNDS HAVING BROAD SPECTRUM OF ACTIVITY
The present invention relates to novel antibacterial compounds, pharmaceutical compositions containing them and their use as antimicrobials.
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Page/Page column 34

(2016/07/05)

QUINAZOLINE AND QUINOLINE COMPOUNDS AND USES THEREOF
This invention provides compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein T, J, R, R4, Rq, o, RA, W and RB and subsets thereof are as described in the specification. The compounds are inhibitors of NAMPT and are thus useful for treating cancer, inflammatory conditions, and/or T-cell mediated autoimmune disease.
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Paragraph 00379

(2016/08/17)

IGF-1R ANTIBODY-DRUG-CONJUGATE AND ITS USE FOR THE TREATMENT OF CANCER
The present invention relates to an antibody-drug-conjugate capable of binding IGF-1R. From one aspect, the invention relates to an antibody-drug-conjugate comprising an antibody capable of binding to IGF-1R, said antibody being conjugated to at least one drug selected from derivatives of dolastatin 10 and auristatins. The invention also comprises method of treatment and the use of said antibody-drug- conjugate for the treatment of cancer.
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Page/Page column 117

(2015/11/16)

ANTIBODY-DRUG-CONJUGATE AND ITS USE FOR THE TREATMENT OF CANCER
The present invention relates to an antibody-drug-conjugate. From one aspect, the invention relates to an antibody-drug-conjugate comprising an antibody capable of binding to a Target, said antibody being conjugated to at least one drug selected from derivatives of dolastatin 10 and auristatins. The invention also comprises method of treatment and the use of said antibody-drug-conjugate for the treatment of cancer.
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Page/Page column 137

(2015/11/10)

Synthesis of parazoanthine B and analogs
A versatile synthesis of the natural product parazoanthine B (2) and its analogs, parazoanthine C (3) and 18-deoxy-parazoanthine B (4), has been accomplished by a key coupling reaction between a hydantoinic compound and an α-bromo-acetophenone derivative. The synthetic approach is designed to address preparation of a wider group of parazoanthine B analogs characterized by the presence of the 5,6-double bond of Z-configuration.
Tinto, Francesco,Pagano, Dario,Manzo, Emiliano
p. 4379 - 4384
(2015/06/08)

Octahydrocyclopenta[c]pyridine and octahydrocyclopenta[c]pyran analogues as a protease activated receptor 1 (PAR1) antagonist
Protease activated receptor 1 (PAR1) has been considered as a promising antiplatelet target to prevent thrombotic cardiovascular events in patients with prior myocardial infarction or peripheral arterial diseases. Previously, we found a series of octahydroindene analogues to have high potency on PAR1 and no significant cytotoxicity but poor metabolic stability in human and rat liver microsomes. We have designed and synthesized fused 6/5 heterobicycle analogues with octahydrocyclopenta[c]pyridine or octahydrocyclopenta[c]pyran core scaffold by the insertion of heteroatom at C5 of octahydroindene ring aiming to improvement of metabolic stability. Both heterobicycle analogues showed much more improved metabolic stability compared with octahydroindenes without remarkable decrease in activity. Compounds 22 (IC50 = 110 nM) and 33 (IC50 = 50 nM) from this series showed good activity on PAR1 with moderate metabolic stability.
Wadood, Abdul,Kim, Haejin,Park, Chul Min,Song, Jong-Hwan,Lee, Sunkyung
p. 2029 - 2041
(2015/11/24)

DERIVATIVES OF DOLASTATIN 10 AND AURISTATINS
The present invention concerns a compound of following formula (I): where: - R1 is H or OH, - R2 is a (C1-C6)alkyl, COOH, COO-((C1-C6)alkyl) or thiazolyl group, - R3 is H or a (C1-C6)alkyl group, and - R4 is: ■ a straight-chain or branched, saturated or unsaturated hydrocarbon group having 1 to 8 carbon atoms substituted by one or more groups chosen from among OH and NR5R6, ■ -(CH2CH2X1)(CH2CH2X2)a2(CH2CH2X3)a3(CH2CH2X4)a4(CH2CH2X5)a5R7, ■ an aryl-(C1-C8)alkyl group substituted by one or more groups chosen from among OH and NR9R10 groups, or ■ a heterocycle-(C1-C8)alkyl group optionally substituted by one or more groups chosen from among (C1-C6)alkyl, OH and NR12R13 groups, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and its uses in particular for the treatment of cancer, pharmaceutical compositions containing the same and the preparation methods thereof.
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Page/Page column 39; 40

(2014/11/13)

DERIVATIVES OF DOLASTATIN 10 AND AURISTATINS
The present invention concerns a compound of following formula (I) where: - R1 is H or OH, - R2 is a (C1-C6)alkyl, COOH, COO-((C1-C6)alkyl) or thiazolyl group, - R3 is H or a (C1-C6)alkyl group, and - R4 is an aryl-(C1-C8)alkyl group substituted by one or more groups chosen from among OH and NR9R10 groups, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and its uses in particular for the treatment of cancer, pharmaceutical compositions containing the same and the preparation methods thereof.
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Page/Page column 33

(2014/11/13)

DERIVATIVES OF DOLASTATIN 10 AND AURISTATINS
The present invention concerns a compound of following formula (I) where: - R1 is H or OH, - R2 is a (C1-C6)alkyl, COOH, COO-((C1-C6)alkyl) or thiazolyl group, - R3 is H or a (C1-C6)alkyl group, and - R4 is: - an aryl-(C1-C8)alkyl group substituted by one or more groups chosen from among OH and NR9R10 groups, or - a heterocycle-(C1-C8)alkyl group optionally substituted by one or more groups chosen from among (C1-C6)alkyl, OH and NR12R13 groups, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and its uses in particular for the treatment of cancer, pharmaceutical compositions containing the same and the preparation methods thereof.
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Page/Page column 36

(2014/11/13)

1-(1H-indol-3-yl)ethanamine derivatives as potent Staphylococcus aureus NorA efflux pump inhibitors
The synthesis of 37 1-(1H-indol-3-yl)ethanamine derivatives, including 12 new compounds, was achieved through a series of simple and efficient chemical modifications. These indole derivatives displayed modest or no intrinsic anti-staphylococcal activity. By contrast, several of the compounds restored, in a concentration-dependent manner, the antibacterial activity of ciprofloxacin against Staphylococcus aureus strains that were resistant to fluoroquinolones due to overexpression of the NorA efflux pump. Structure-activity relationships studies revealed that the indolic aldonitrones halogenated at position 5 of the indole core were the most efficient inhibitors of the S. aureus NorA efflux pump. Among the compounds, (Z)-N-benzylidene-2-(tert-butoxycarbonylamino)-1-(5- iodo-1H-indol-3-yl)ethanamine oxide led to a fourfold decrease of the ciprofloxacin minimum inhibitory concentration against the SA-1199B strain when used at a concentration of 0.5 mg L-1. To the best of our knowledge, this activity is the highest reported to date for an indolic NorA inhibitor. In addition, a new antibacterial compound, tert-butyl (2-(3-hydroxyureido)-2-(1H- indol-3-yl)ethyl)carbamate, which is not toxic for human cells, was also found. A pump turn off: 1-(1H-Indol-3-yl)ethanamine derivatives such as the one shown here, were synthesized through simple chemical modifications and were shown to be efficient NorA efflux pump inhibitors. They are able to restore ciprofloxacin activity against fluoroquinolone-resistant Staphylococcus aureus strains.
Hequet, Arnaud,Burchak, Olga N.,Jeanty, Matthieu,Guinchard, Xavier,Le Pihive, Emmanuelle,Maigre, Laure,Bouhours, Pascale,Schneider, Dominique,Maurin, Max,Paris, Jean-Marc,Denis, Jean-Noel,Jolivalt, Claude
p. 1534 - 1545
(2014/07/21)

Discovery of N-substituted oseltamivir derivatives as potent and selective inhibitors of H5N1 influenza neuraminidase
To discover group-1-specific neuraminidase (NA) inhibitors that are especially involved in combating the H5N1 virus, two series of oseltamivir derivatives were designed and synthesized by targeting the 150-cavity. Among these, compound 20l was the most potent N1-selective inhibitor, with IC50 values of 0.0019, 0.0038, and 0.0067 μM against NAs from three H5N1 viruses. These values are better than those of oseltamivir carboxylate. Compound 32 was another potent N1-selective inhibitor that exhibited a 12-fold increase in activity against the H274Y mutant relative to oseltamivir carboxylate. Molecular docking studies revealed that the 150-cavity was an auxiliary binding site that may contribute to the high selectivity of these compounds. The present work is a significant breakthrough in the discovery of potent group-1-specific neuraminidase inhibitors, which may be further investigated for the treatment of infection by the H5N1 virus.
Xie, Yuanchao,Xu, Dongqing,Huang, Bing,Ma, Xiuli,Qi, Wenbao,Shi, Fangyuan,Liu, Xinyong,Zhang, Yingjie,Xu, Wenfang
p. 8445 - 8458
(2014/12/10)

3,5-DIAMINO-6-CHLORO-N-(N-(4-PHENYLBUTYL)CARBAMIMIDOYL) PYRAZINE-2- CARBOXAMIDE COMPOUNDS
The present invention relates compounds of the formula: or pharmaceutically acceptable salts thereof, useful as sodium channel blockers, as well as compositions containing the same, processes for the preparation of the same, and therapeutic methods of use therefore in promoting hydration of mucosal surfaces and the treatment of diseases including cystic fibrosis, chronic obstructive pulmonary disease, asthma, bronchiectasis, acute and chronic bronchitis, emphysema, and pneumonia.
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Page/Page column 70; 98; 104; 106

(2014/07/08)

3,5-DIAMINO-6-CHLORO-N-(N-(4-PHENYLBUTYL)CARBAMIMIDOYL) PYRAZINE-2- CARBOXAMIDE COMPOUNDS
The present invention relates compounds of the formula: or pharmaceutically acceptable salts thereof, useful as sodium channel blockers, as well as compositions containing the same, processes for the preparation of the same, and therapeutic methods of use therefore in promoting hydration of mucosal surfaces and the treatment of diseases including cystic fibrosis, chronic obstructive pulmonary disease, asthma, bronchiectasis, acute and chronic bronchitis, emphysema, and pneumonia.
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Paragraph 0366; 0381

(2014/06/25)

Enantioselective synthesis of allylboronates and allylic alcohols by copper-catalyzed 1,6-boration
Chiral secondary allylboronates are obtained in high enantioselectivities and 1,6:1,4 ratios by the copper-catalyzed 1,6-boration of electron-deficient dienes with bis(pinacolato)diboron (B2(pin)2). The reactions proceed efficiently using catalyst loadings as low as 0.0049 mol %. The allylboronates may be oxidized to the allylic alcohols, and can be used in stereoselective aldehyde allylborations. This process was applied to a concise synthesis of atorvastatin, in which the key 1,6-boration was performed using only a 0.02 mol % catalyst loading. 1,6-Borations of electron-deficient dienes with bis(pinacolato)diboron using copper catalyst loadings as low as 0.0049 mol % provided chiral allylboronates that, after oxidation, result in allylic alcohols in high enantioselectivities and 1,6:1,4 ratios. The allylboronates can also be used in stereoselective allylations of aldehydes. This process was applied to a concise synthesis of atorvastatin.
Luo, Yunfei,Roy, Iain D.,Madec, Amael G. E.,Lam, Hon Wai
supporting information
p. 4186 - 4190
(2014/05/06)