58841-52-4Relevant articles and documents
Discovery and mechanism of action studies of 4,6-diphenylpyrimidine-2-carbohydrazides as utrophin modulators for the treatment of Duchenne muscular dystrophy
Vuorinen, Aini,Wilkinson, Isabel V.L.,Chatzopoulou, Maria,Edwards, Ben,Squire, Sarah E.,Fairclough, Rebecca J.,Bazan, Noelia Araujo,Milner, Josh A.,Conole, Daniel,Donald, James R.,Shah, Nandini,Willis, Nicky J.,Martínez, R. Fernando,Wilson, Francis X.,Wynne, Graham M.,Davies, Stephen G.,Davies, Kay E.,Russell, Angela J.
supporting information, (2021/05/03)
Duchenne muscular dystrophy is a fatal disease with no cure, caused by lack of the cytoskeletal protein dystrophin. Upregulation of utrophin, a dystrophin paralogue, offers a potential therapy independent of mutation type. The failure of first-in-class utrophin modulator ezutromid/SMT C1100 in Phase II clinical trials necessitates development of compounds with better efficacy, physicochemical and ADME properties and/or complementary mechanisms. We have discovered and performed a preliminary optimisation of a novel class of utrophin modulators using an improved phenotypic screen, where reporter expression is derived from the full genomic context of the utrophin promoter. We further demonstrate through target deconvolution studies, including expression analysis and chemical proteomics, that this compound series operates via a novel mechanism of action, distinct from that of ezutromid.
Self-assembling behaviour of chiral calamitic monoacrylates targeted for polymer stabilisation of polar smectic phases in chiral liquid crystals
Dmochowska, Ewelina,Herman, Jakub,Czerwiński, Micha?,Stulov, Sergei,Bubnov, Alexej,Kula, Przemys?aw
, (2021/03/03)
The stabilisation and control of synclinic and anticlinic chiral liquid crystalline phases remain an actual and highlighted task. This work presents the design and mesomorphic properties of new chiral calamitic reactive mesogens, monoacrylates, based on biphenyl benzoate and phenyl biphenyl-4-carboxylate cores with reactive terminal groups placed far from the chiral chain. The compound's structures, compatible with the components of modern ferroelectric and antiferroelectric liquid crystalline mixtures, are confirmed by mass spectrometry (electron ionization) analysis and proton/carbon nuclear magnetic resonance. All the reactive mesogens possess the self-assembling, i.e. liquid crystalline behaviour with high tendency to create smectic phases in a broad temperature range, which was confirmed by a polarizing optical microscopy, differential scanning calorimetry and broad-band dielectric spectroscopy. Doping of advanced multicomponent mixtures possessing the chiral smectic phases by the designed monoacrylates with further cross-linking procedure, can be an effective and functional tool for stabilising ferroelectric and antiferroelectric phases in various states and hence, can allow the symmetrisation of the switching times in the modes employed surface stabilised geometry; this is a very highlighted task for optoelectronics. Moreover, an evident considerable tendency for thermal polymerisation of specific reactive mesogens can reduce the drawbacks of polymer stabilisation.
6-HETEROARYLOXY BENZIMIDAZOLES AND AZABENZIMIDAZOLES AS JAK2 INHIBITORS
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Paragraph 0369-0370, (2021/11/13)
The present disclosure provides 6-heteroaryloxy benzimidazole and azabenzimidazole compounds and compositions thereof useful for inhibiting JAK2.
Preparation method of high purity 2-benzyloxy bromoethane
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Paragraph 0062-0067, (2019/07/11)
The invention relates to a preparation method of an important intermediate 2-benzyloxy bromoethane (formula I) of umeclidinium bromide. The conditions of the preparation method are mild and controllable; post-treatment is simple; yield is high; and the purity of prepared 2-benzyloxy bromoethane is high.
Antibody drug conjugate, intermediate, preparation method, pharmaceutical composition and uses thereof
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Page/Page column 127-129, (2019/11/11)
Disclosed are an antibody drug conjugate IB, which uses ether linkages for connection, and improves the water solubility, stability and cytotoxicity in vivo and in intro, and an intermediate, a pharmaceutical composition, and uses of the antibody drug conjugate. The antibody drug conjugate has simple synthetic steps and a high yield.
TAU-PROTEIN TARGETING PROTACS AND ASSOCIATED METHODS OF USE
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Paragraph 0755, (2018/05/24)
The present disclosure relates to bifunctional compounds, which find utility as modulators of tau protein. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a VHL or cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds tau protein, such that tau protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of tau. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of tau protein. Diseases or disorders that result from aggregation or accumulation of tau protein are treated or prevented with compounds and compositions of the present disclosure.
Transition Metal-Catalysed Intramolecular Carbenoid C?H Insertion for Pyrrolidine Formation by Decomposition of α-Diazoesters
Solé, Daniel,Amenta, Arianna,Mariani, Francesco,Bennasar, M.-Llu?sa,Fernández, Israel
supporting information, p. 3654 - 3664 (2017/09/13)
The use of Pd-, Rh(II)- and Ru(II)-based catalysts has been explored in the transition metal-catalysed intramolecular carbenoid C?H insertion of α-diazoesters leading to pyrrolidines. Although the outcome of the reaction was highly substrate-dependent, in general, it was possible to control the chemoselectivity of the process towards pyrrolidines by adequate catalyst selection. The Pd(0)-catalysts were as efficient as [Rh(Ph3CCO2)2]2 in promoting the C(sp3)?H insertion of ortho-substituted anilines. In contrast, for anilines bearing meta- and para-substituents, the Rh(II)-catalyst provided the best chemoselectivities and reaction yields. On the other hand, [Ru(p-cymene)Cl2]2 was the most efficient catalyst for the insertion reaction of the N-benzyl-N-phenyl and N,N-dibenzyl α-diazoesters, while the C(sp3)?H insertion of the N-benzylsulfonamide substrate was only promoted by [Rh(Ph3CCO2)2]2. According to density functional theory (DFT) calculations, the mechanism involved in the Pd(0)- and Ru(II)-catalysed C(sp3)?H insertions differs considerably from that typically proposed for the Rh(II)-catalysed transformation. Whereas the Pd(0)-catalysed reaction involves a Pd-mediated 1,5-H migration from the C(sp3)?H bond to the carbenoid carbon atom leading to the formal oxidation of the transition metal, a Ru(II)-promoted Mannich type reaction involving a zwitterionic intermediate seems to be operative in the Ru(II)-catalysed transformation. (Figure presented.).
Indol-3-ylcycloalkyl ketones: Effects of N1 substituted indole side chain variations on CB2 cannabinoid receptor activity
Frost, Jennifer M.,Dart, Michael J.,Tietje, Karin R.,Garrison, Tiffany R.,Grayson, George K.,Daza, Anthony V.,El-Kouhen, Odile F.,Yao, Betty B.,Hsieh, Gin C.,Pai, Madhavi,Zhu, Chang Z.,Chandran, Prasant,Meyer, Michael D.
experimental part, p. 295 - 315 (2010/06/11)
Several 3-acylindoles with high affinity for the CB2 cannabinoid receptor and selectivity over the CB1 receptor have been prepared. A variety of 3-acyl substituents were investigated, and the tetramethylcyclopropyl group was found to lead to high affinity CB2 agonists (5, 16). Substitution at the N1-indole position was then examined. A series of aminoalkylindoles was prepared and several substituted aminoethyl derivatives were active (23-27, 5) at the CB2 receptor.Astudy of N1 nonaromatic side chain variants provided potent agonists at the CB2 receptor (16, 35-41, 44-47, 49-54, and 57-58). Several polar side chains (alcohols, oxazolidinone) were well-tolerated for CB2 receptor activity (41, 50), while others (amide, acid) led to weaker or inactive compounds (55 and 56). N1 aromatic side chains also afforded several high affinity CB2 receptor agonists (61, 63, 65, and 69) but were generally less potent in an in vitro CB2 functional assay than were nonaromatic side chain analogues.
QUINAZOLINE DERIVATIVES AND METHODS OF TREATMENT
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Page/Page column 34, (2009/10/22)
This invention relates to novel quinazoline derivatives, and their pharmaceutically acceptable salts. The invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and con
Diastereomerically and enantiomerically pure 2,3-disubstituted pyrrolidines from 2,3-aziridin-1-ols using a sulfoxonium ylide: A one-carbon homologative relay ring expansion
Schomaker, Jennifer M.,Bhattacharjee, Somnath,Yan, Jun,Borhan, Babak
, p. 1996 - 2003 (2007/10/03)
An ylide-based aza-Payne rearrangement of 2,3-aziridin-1-ols leads to an efficient process for the preparation of pyrrolidines. The aza-Payne rearrangement under basic reaction conditions favors the formation of epoxy amines. Subsequent nucleophilic attack of the epoxide by the ylide yields a bis-anion, which upon a 5-exo-tet ring-closure yields the desired pyrrolidine, thus completing the relay of the three-membered to the five-membered nitrogen-containing ring system. This process takes place with complete transfer of stereochemical fidelity and can be applied to sterically hindered aziridinols.
