- TETRAHYDRO-BENZOAZEPINE GLYCOSIDASE INHIBITORS
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Compounds of formula (I') wherein A, R1, R2, T1, T2, T3, T4, L, W, Z, R''', m and n have the meaning according to the claims can be employed, inter alia, for the treatment of tauopathies and Alzheimer's disease.
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Page/Page column 165-166
(2020/03/15)
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- Methanol as hydrogen source: Transfer hydrogenation of aromatic aldehydes with a rhodacycle
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A cyclometalated rhodium complex has been shown to perform highly selective and efficient reduction of aldehydes, deriving the hydrogen from methanol. With methanol as both the solvent and hydrogen donor under mild conditions and an open atmosphere, a wide range of aromatic aldehydes were reduced to the corresponding alcohols, without affecting other functional groups.
- Aboo, Ahmed H.,Bennett, Elliot L.,Deeprose, Mark,Robertson, Craig M.,Iggo, Jonathan A.,Xiao, Jianliang
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supporting information
p. 11805 - 11808
(2018/11/10)
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- Synthesis of phenylpiperazine derivatives of 1,4-benzodioxan as selective COX-2 inhibitors and anti-inflammatory agents
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1-((2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-4-substituted-phenylpiperazine moiety was prepared and has been found to be a new and selective ligand for the enzyme cyclooxygenase-2 (COX-2). The biological activity of compound 3k as anti-inflammatory agent was further investigated both in vitro and in vivo. Notably, compound 3k exhibited the best anti-inflammatory activity among the eleven designed compounds with no toxicity, as determined by the ulcerogenic activity. Computational docking studies also showed that compound 3k has interaction with COX-2 key residues in the active site. Compound 3k maybe a new anti-inflammatory lead-candidate as powerful and novel non-ulcerogenic.
- Sun, Juan,Wang, Su,Sheng, Gui-Hua,Lian, Zhi-Min,Liu, Han-Yu,Zhu, Hai-Liang
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p. 5626 - 5632
(2016/10/24)
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- Compositions for Treatment of Cystic Fibrosis and Other Chronic Diseases
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The present invention relates to pharmaceutical compositions comprising an inhibitor of epithelial sodium channel activity in combination with at least one ABC Transporter modulator compound of Formula A, Formula B, Formula C, or Formula D. The invention also relates to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis using the pharmaceutical combination compositions.
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Paragraph 1627
(2015/09/22)
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- Synthesis, in vitro antimycobacterial and antibacterial evaluation of IMB-070593 derivatives containing a substituted benzyloxime moiety
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A series of novel IMB-070593 derivatives containing a substituted benzyloxime moiety and displaying a remarkable improvement in lipophilicity were synthesized and evaluated for their in vitro antimycobacterial and antibacterial activity. Our results reveal that the target compounds 19a-m have considerable Gram-positive activity (MIC: 0.008-32 μg/mL), although they are generally less active than the reference drugs against the Gram-negative strains. In particular, compounds 19h, 19j, 19k and 19m show good activity (MICs: 0.008-4 μg/mL) against all of the tested Gram-positive strains, including ciprofloxacin (CPFX)- and/or levofloxacin (LVFX)-resistant MSSA, MRSA and MSSE. Moreover, compound 19l (MIC: 0.125 μg/mL) is found to be 2-4 fold more active than the parent IMB070593, CPFX and LVFX against M. tuberculosis H37Rv ATCC 27294.
- Wei, Zengquan,Wang, Jian,Liu, Mingliang,Li, Sujie,Sun, Lanying,Guo, Huiyuan,Wang, Bin,Lu, Yu
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p. 3872 - 3893
(2013/06/05)
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- Synthesis and in vitro antibacterial activity of gemifloxacin derivatives containing a substituted benzyloxime moiety
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A series of novel gemifloxacin (GMFX) derivatives containing a substituted benzyloxime moiety with remarkable improvement in lipophilicity were synthesized. The target compounds evaluated for their in vitro antibacterial activity against representative strains. Our results reveal that most of the target compounds have considerable potency against all of the tested Gram-positive strains including MRSA and MRSE (MIC: 90: 1 μg/mL) is 8-fold more active than GMFX, and 2-fold more active than GMFX and moxifloxacin against MRSE clinical isolates (MIC90: 4 μg/mL). Crown Copyright
- Feng, Lianshun,Lv, Kai,Liu, Mingliang,Wang, Shuo,Zhao, Jing,You, Xuefu,Li, Sujie,Cao, Jue,Guo, Huiyuan
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p. 125 - 136
(2012/11/07)
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- Synthesis and biological activity of pyridopyridazin-6-one p38α MAP kinase inhibitors. Part 2
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This manuscript concludes the Structure Activity Relationship (SAR) on the pyridazinone scaffold and identifies a compound with subnanomolar p38α activity and 24 h coverage in the rat arthritis efficacy model.
- Tynebor, Robert M.,Chen, Meng-Hsin,Natarajan, Swaminathan R.,O'Neill, Edward A.,Thompson, James E.,Fitzgerald, Catherine E.,O'Keefe, Stephen J.,Doherty, James B.
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p. 5971 - 5975
(2012/11/07)
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- COMPOSITIONS FOR TREATMENT OF CYSTIC FIBROSIS AND OTHER CHRONIC DISEASES
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The present invention relates to pharmaceutical compositions comprising an inhibitor of epithelial sodium channel activity in combination with at least one ABC Transporter modulator compound of Formula A, Formula B, Formula C, or Formula D. The invention also relates to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis using the pharmaceutical combination compositions.
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- Evaluation of quinazoline analogues as glucocerebrosidase inhibitors with chaperone activity
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Gaucher disease is a lysosomal storage disorder (LSD) caused by deficiency in the enzyme glucocerebrosidase (GC). Small molecule chaperones of protein folding and translocation have been proposed as a promising therapeutic approach to this LSD. Most small molecule chaperones described in the literature contain an iminosugar scaffold. Here we present the discovery and evaluation of a new series of GC inhibitors with a quinazoline core. We demonstrate that this series can improve the translocation of GC to the lysosome in patient-derived cells. To optimize this chemical series, systematic synthetic modifications were performed and the SAR was evaluated and compared using three different readouts of compound activity: enzymatic inhibition, enzyme thermostabilization, and lysosomal translocation of GC.
- Marugan, Juan J.,Zheng, Wei,Motabar, Omid,Southall, Noel,Goldin, Ehud,Westbroek, Wendy,Stubblefield, Barbara K.,Sidransky, Ellen,Aungst, Ronald A.,Lea, Wendy A.,Simeonov, Anton,Leister, William,Austin, Christopher P.
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experimental part
p. 1033 - 1058
(2011/04/25)
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- FLUOROISOQUINOLINE SUBSTITUTED THIAZOLE COMPOUNDS AND METHODS OF USE
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The invention relates to thiazole compounds of Formula (I) and compositions thereof useful for treating diseases mediated by protein kinase B (PKB) where the variables have the definitions provided herein. The invention also relates to the therapeutic use of such thiazole compounds and compositions thereof in treating disease states associated with abnormal cell growth, cancer, inflammation, and metabolic disorders.
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Page/Page column 149-150
(2010/08/08)
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- MODULATORS OF CFTR
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Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette ("ABC") transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator ("CFTR"). The present invention also relates to methods of treating CFTR mediated diseases using compounds of the present invention.
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Page/Page column 76
(2009/01/20)
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- Modulators of ATP-binding cassette transporters
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Compounds of the present invention and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention.
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Page/Page column 103
(2008/06/13)
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- NITROGEN-CONTAINING BICYCLIC HETEROCYCLES FOR USE AS ANTIBACTERIALS
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Cyclohexane and cyclohexene derivatives and pharmaceutically acceptable derivatives hereof useful in methods of treatment of bacterial infections in mammals, particularly man.
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Page/Page column 43
(2010/02/07)
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- Enantiomeric and enantiotopic analysis of cone-shaped compounds with C3 and C3v symmetry using NMR spectroscopy in chiral anisotropic solvents
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We describe the enantiomeric and enantiotopic analysis of the NMR spectra of compounds derived from the functionalized cone-shaped core, cyclotriveratrylenes (CTV), dissolved in weakly oriented lyotropic chiral liquid crystals (CLCs) based on organic solutions of poly-γ-benzyl-L-glutamate. The CTV core lacks prostereogenic as well as stereogenic tetrahedral centers. However, depending on the pattern of substitution, chiral and achiral compounds with different symmetries can be obtained. Thus, symmetrically nonasubstituted CTVs (C3 symmetry) are optically active and exhibit enantiomeric isomers, while symmetrically hexasubstituted (C3v symmetry) derivatives are prochiral and possess enantiotopic elements. In the first part we use 2H and 13C NMR to study two nonasubstituted (-OH or -OCH3) CTVs, where the ring methylenes are fully deuterated, and show for the first time that the observation of enantiomeric discrimination of chiral molecules with a 3-fold symmetry axis is possible in a CLC. It is argued that this discrimination reflects different orientational ordering of the M and P isomers, rather than specific chiral short-range solvent-solute interactions that may affect differently the magnetic parameters of the enantiomers or even their geometry. In the second part we present similar measurements on hexasubstituted CTV with flexible side groups (-OC(O)CH3 and the, partially deuterated bidentate, -OCH2CH2O-), having on the average C3v symmetry. No spectral discrimination of enantiotopic sites was detected for the -OC(O)CH3 derivative. This is consistent with a recent theoretical work (J. Chem. Phys. 1999, 111, 6890) that indicates that in C3v molecules no chiral discrimination between enantiotopic elements, based on ordering, is possible. In contrast, a clear splitting was observed in the 2H spectra of the enantiotopic deuterons of the side groups in the tri(dioxyethylene)-CTV. It is argued that this discrimination reflects different ordering characteristics of the various, rapidly (on the NMR time scale) interconverting conformers of this compound. Assuming two twisted structures for each of the dioxyethylene side groups, four different conformers are expected, comprising two sets of enantiomeric pairs with, respectively, C3 and C1 symmetries. Differential ordering and/or fractional population imbalance of these enantiomeric pairs leads to the observed spectral discrimination of sites in the side chains that on average form enantiotopic pairs.
- Lesot, Philippe,Merlet, Denis,Sarfati, Muriel,Courtieu, Jacques,Zimmermann, Herbert,Luz, Zeev
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p. 10071 - 10082
(2007/10/03)
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- Microwave assisted solid reaction: Reduction of esters to alcohols by potassium borohydride-lithium chloride
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Esters can be successfully reduced to the corresponding alcohols with potassium borohydride/lithium chloride under microwave irradiation without solvent. The reactions are generally completed in 2-8 minutes, with the yields varying from 55% to 95%.
- Feng,Liu,Dai,Yang,Tu
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p. 1875 - 1877
(2007/10/03)
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- Synthesis of isoquinolines and tetrahydroisoquinolines as potential antitumour agents
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The isoquinoline 17 and the tetrahydroisoquinoline 16 were synthesized from 2,3-dihydro-1,4-benzodioxin (1) by different synthetic strategies. Preparation of arylethylamines and their cyclization in Bischler-Napieralski conditions have been studied. Another approach to isoquinolines was based on the amination of the ketone 13 followed by cyclization in acidic media. The route via the amide 15 was found to be more successful with respect to both yield and ease of reaction.
- Capilla,Romero,Pujol,Caignard,Renard
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p. 8297 - 8303
(2007/10/03)
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- Synthetic Approaches to Phthalazines: C-N Bond Cleavage in 2'-Benzylbenzohydrazides During Reaction with Polyphosphoric Acid
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Reaction of 2'-benzylbenzohydrazides with concentrated polyphosphoric acid gave 2,5-diaryl-1,3,4-oxadiazoles and a polybenzyl.Cyclodehydration to phthalazines was not observed.It is inferred from product substitution patterns that CH2-N bond cleavage occurs with polybenzyls forming from the benzyl moiety and oxadiazoles from the benzohydrazide fragment.Other reported reactions which generate benzyl fragments lead to bibenzyl and are considered to involve trapping of the cleavage products within a solvent cage.The observed production of polybenzyls is therefore interpreted in terms of the formation of free benzyl fragments.A tetrahydrophthalazine derivative was produced from the addition of diethyl azodicarboxylate to the photodiene of o-methylbenzophenone, but this could not be converted into a phthalazine.
- Paul, D. Brenton
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p. 893 - 901
(2007/10/02)
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