- 1-(dibromomethyl)-4-methoxy-2-methylbenzene
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The title compound, C9H10Br2O, is a major product of the radical bromination of 4-methoxy-1,2-dimethylbenzene. Each Br atom is involved in a close contact with the O atom of a neighbouring molecule, forming a geometry that is suggestive of weak intermolecular O→Br charge-transfer interactions.
- Liu, Xiaoming,Kilner, Colin A.,Thornton-Pett, Mark,Halcrow, Malcolm A.
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Read Online
- Syntheses of new hydroxy-[3.3]orthocyclophanes as models for the galactose oxidase Tyr-Cys cofactor
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The syntheses of 3,4-benzo-8,9-(3′-hydroxybenzo)bicyclo[4,4,1]undeca-3,8-dien-11-one, 3,4-benzo-8,9-(3′-hydroxy-4′-methylsulfanylbenzo)bicyclo[4,4,1] undeca-3,8-dien-11-one and their ethylene acetals have been achieved. Crystallographic, UV/Vis and NMR data show that the two ketones adopt boat/chair conformations that are fluxional in solution, while the acetals exhibit chair/chair conformations with layered benzo rings. Comparison of the oxidation potentials of the four compounds suggests that an ortho-methylsulfanyl substituent and a π-π interaction both thermodynamically stabilise the phenoxonium radical species derived from these compounds, by approximately equal amounts.
- Liu, Xiaoming,Barrett, Simon A,Kilner, Colin A,Thornton-Pett, Mark,Halcrow, Malcolm A
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Read Online
- Structure-Activity Relationships of Benzamides and Isoindolines Designed as SARS-CoV Protease Inhibitors Effective against SARS-CoV-2
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Inhibition of coronavirus (CoV)-encoded papain-like cysteine proteases (PLpro) represents an attractive strategy to treat infections by these important human pathogens. Herein we report on structure-activity relationships (SAR) of the noncovalent active-site directed inhibitor (R)-5-amino-2-methyl-N-(1-(naphthalen-1-yl)ethyl) benzamide (2 b), which is known to bind into the S3 and S4 pockets of the SARS-CoV PLpro. Moreover, we report the discovery of isoindolines as a new class of potent PLpro inhibitors. The studies also provide a deeper understanding of the binding modes of this inhibitor class. Importantly, the inhibitors were also confirmed to inhibit SARS-CoV-2 replication in cell culture suggesting that, due to the high structural similarities of the target proteases, inhibitors identified against SARS-CoV PLpro are valuable starting points for the development of new pan-coronaviral inhibitors.
- Welker, Armin,Kersten, Christian,Müller, Christin,Madhugiri, Ramakanth,Zimmer, Collin,Müller, Patrick,Zimmermann, Robert,Hammerschmidt, Stefan,Maus, Hannah,Ziebuhr, John,Sotriffer, Christoph,Schirmeister, Tanja
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supporting information
p. 340 - 354
(2020/10/19)
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- A Spiroalkylation Method for the Stereoselective Construction of α-Quaternary Carbons and Its Application to the Total Synthesis of (R)-Puraquinonic Acid
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Cyclic α-quaternary carbon stereocenters were prepared from biselectrophillic substrates and an easily prepared chiral bicyclic sulfonyl lactam. This was achieved in two steps by spiroalkylation, employing biphasic reaction conditions with a phase-transfer catalyst, followed by reduction and alkylation with a series of alkyl halide electrophiles. The products of this method were isolated in good yields with with high levels of diastereoselectivity. This methodology was employed in the enantioselective total synthesis of (R)-puraquinonic acid (1) for a late-stage installation of the α-quaternary carbon stereocenter. This enabled the shortest synthesis of 1 to date, an eight-pot sequence providing an overall yield of 14%.
- Elmehriki, Adam A. H.,Gleason, James L.
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supporting information
p. 9729 - 9733
(2019/12/02)
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- SPIRO-COMPOUNDS AS S1P MODULATORS
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The invention relates to heterocyclic compounds of formula (I) as SIP modulators, pharmaceutical compositions comprising such compounds, and uses thereof in the treatment or alleviation of diseases or disorders mediated by an SIP receptor.
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Page/Page column 54; 55
(2018/05/24)
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- Discovery of an orally efficacious inhibitor of anaplastic lymphoma kinase
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Anaplastic lymphoma kinase (ALK) is a promising therapeutic target for the treatment of cancer, supported by considerable favorable preclinical and clinical activities over the past several years and culminating in the recent FDA approval of the ALK inhib
- Gingrich, Diane E.,Lisko, Joseph G.,Curry, Matthew A.,Cheng, Mangeng,Quail, Matthew,Lu, Lihui,Wan, Weihua,Albom, Mark S.,Angeles, Thelma S.,Aimone, Lisa D.,Haltiwanger, R. Curtis,Wells-Knecht, Kevin,Ott, Gregory R.,Ghose, Arup K.,Ator, Mark A.,Ruggeri, Bruce,Dorsey, Bruce D.
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experimental part
p. 4580 - 4593
(2012/07/28)
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- ISOINDOLINE COMPOUNDS FOR THE TREATMENT OF SPINAL MUSCULAR ATROPHY AND OTHER USES
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Disclosed is a compound of Formula (I) in which W and R1-R6 are defined herein. Also disclosed is a method of treating spinal muscular atrophy, as well as methods of using such compounds to increase SMN expression, increase EAAT2 expression, or increase the expression of a nucleic acid that encodes a translational stop codon introduced directly or indirectly by mutation or frameshift.
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Page/Page column 61-62
(2009/05/29)
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- SAR studies of capsazepinoid bronchodilators. Part 1: The importance of the catechol moiety and aspects of the B-ring structure
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Capsazepine as well as its derivatives and analogues are general inhibitors of constriction of human small airways. From a systematic variation of the capsazepine structure, divided into four regions, SARs were established. This part concerns the catechol moiety of the A-ring as well as the 2,3,4,5-tetrahydro-1H-2-azepine moiety (the B-ring) of capsazepine. It is revealed that a conformational constrain (as a fused ring) is important and that compounds with a six-membered B-ring (as a 1,2,3,4-tetrahydroisoquinoline) in general are more potent than the corresponding isoindoline, 2,3,4,5-tetrahydro-1H-2-benzazepine and 2,3,4,5-tetrahydro-1H-3-benzazepine derivatives.
- Dalence-Guzman, Maria F.,Berglund, Magnus,Skogvall, Staffan,Sterner, Olov
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p. 2499 - 2512
(2008/09/21)
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- Design, synthesis, and evaluation of fused heterocyclic analogs of SCH 58261 as adenosine A2A receptor antagonists
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SCH 58261 is a reported adenosine A2A receptor antagonist which is active in rat in vivo models of Parkinson's Disease upon ip administration. However, it has poor selectivity versus the A1 receptor and does not demonstrate oral activity. Quinoline analogs have improved upon the selectivity and pharmacokinetics of SCH 58261, but were difficult to handle due to poor aqueous solubility. We report the design and synthesis of fused heterocyclic analogs of SCH 58261 with aqueous solubility as well as improved A2A receptor binding selectivity and pharmacokinetic properties. In particular, the tetrahydronaphthyridine 4s has excellent A2A receptor in vitro binding affinity and selectivity, is active orally in a rat in vivo model of Parkinson's Disease, and has aqueous solubility of 100 μM at physiological pH.
- Shah, Unmesh,Lankin, Claire M.,Boyle, Craig D.,Chackalamannil, Samuel,Greenlee, William J.,Neustadt, Bernard R.,Cohen-Williams, Mary E.,Higgins, Guy A.,Ng, Kwokei,Varty, Geoffrey B.,Zhang, Hongtao,Lachowicz, Jean E.
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scheme or table
p. 4204 - 4209
(2009/04/10)
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- Formation of 4,5,6,7-tetrahydroisoindoles by palladium-catalyzed hydride reduction
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(Chemical Equation Presented) Substituted 1,3-dihydro-2H-isoindoles (2, isoindolines) were prepared and subjected to palladium-catalyzed formate reduction. Alkyl isoindolines were reduced to 4,5,6,7-tetrahydro-2H-isoindoles (1). Only partial reduction was observed for 5-methoxyisoindoline, and 4-methoxy-, 5-carbomethoxy-, amino-, and amidoisoindolines were inert to the reaction. Halogen-substituted isoindolines were dehalogenated and reduced to 4,5,6,7-tetrahydro-2H-isoindoles. Isoindole 24 was also reduced to a mixture of an isoindoline and a 4,5,6,7-tetrahydro-2H-isoindole. In contrast, 2,3-dihydro-1H-indoles 21 underwent dehydrogenation to give thermodynamically stable indoles. Theoretical calculations show the significant difference in aromaticity between isoindoles and indoles, corresponding to the observed differences in reactivities. Tetrahydro-2H-isoindoles 1 were oxidized to 4,5,6,7-tetrahydroisoindole-1,3-diones in the presence of NBS and air.
- Hou, Duen-Ren,Wang, Ming-Shiang,Chung, Ming-Wen,Hsieh, Yih-Dar,Tsai, Hui-Hsu Gavin
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p. 9231 - 9239
(2008/03/13)
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- Structure activity relationship studies of carboxamido-biaryl ethers as opioid receptor antagonists (OpRAs). Part 2
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A series of 6-bicycloaryloxynicotinamides were identified as opioid receptor antagonists at mu, kappa, and delta receptors. Compounds in the 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide scaffold exhibited potent in vitro functional antagonism at all three receptors.
- Takeuchi, Kumiko,Holloway, William G.,Mitch, Charles H.,Quimby, Steven J.,McKinzie, Jamie H.,Suter, Todd M.,Statnick, Michael A.,Surface, Peggy L.,Emmerson, Paul J.,Thomas, Elizabeth M.,Siegel, Miles G.
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p. 6841 - 6846
(2008/09/17)
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- Bronchorelaxing agents based on indol- and isoquinoline derivatives
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A compound of formula (I) and its acid addition salts, wherein R1-FIj are H, lower (CrC6) alkyl; halogen; NR5R6, wherein R5, R6 are H, lower alkyl, C2-C6 acyl, SO2R7, wherein R7 is lower alkyl, CF3, aryl, substituted aryl; CN; COR8, wherein R8 is H, OH, lower alkyl, lower alkoxy; SO2R9, wherein R9 is OR10, wherein R10 is H, lower alkyl or NRnR12, wherein R11 and R12 is H or lower alkyl; ORi3, wherein R13 is H, lower alkyl, C2-C6 acyl, C1-C8 carboxy, C1-C8 carbamoyl; X is O or S; A is H, lower alkyl; B is C1-C18 alkyl optionally substituted; M is zero or 1; with the proviso that no more than three of R1-R4 are H, for treating and preventing bronchoconstructive pulmonary disease.
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(2010/11/25)
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- COMPOUND INHIBITING DIPEPTIDYL PEPTIDASE IV
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The invention aims to provide a dipeptidyl peptidase IV inhibitor which is satisfactory in respect of activity, stability and safety and has an excellent action as a pharmaceutical agent. The invention is directed to a compound represented by the following general formula or a pharmaceutically acceptable salt thereof: wherein R1 and R2 each represents hydrogen, an optionally substituted C1-6 alkyl group, or -COOR5 whereupon R5 represents hydrogen or an optionally substituted C1-6 alkyl group, or R1 and R2, together with a carbon atom to which they are bound, represent a 3- to 6-membered cycloalkyl group, R3 represents hydrogen or an optionally substituted C6-10 aryl group, R4 represents a hydrogen or a cyano group, D represents -CONR6-, -CO- or -NR6CO-, R6 represents hydrogen or an optionally substituted C1-6 alkyl group, E represents -(CH2)m- whereupon m is an integer of 1 to 3, -CH2OCH2-, or -SCH2-, n is an integer of 0 to 3, and A represents an optionally substituted bicyclic heterocyclic group or bicyclic hydrocarbon group.
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Page/Page column 28
(2010/02/14)
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- New synthetic route to [bis-1,2-(aminomethyl)benzene]dichloroplatinum(II) complexes, screening for cytotoxic activity in cisplatin-sensitive and resistant human cancer cell lines, and reaction with glutathione
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A new synthetic route to [bis-1,2-(aminomethyl)benzene]dichloroplatinum(II) complexes is described. o-Xylene and the 4-methoxy substituted derivative were used as starting points for the synthesis: benzylic bromination with N-bromosuccinamide /benzoylperoxide followed by the substitution of the benzyl bromides for azide and finally a catalytic hydrogenation with Pd/C of the diazides gave the desired diamines ligands. An attempt to synthesize the 4,6-dimethoxy derivative was unsuccessful due to the bromination of the aromatic ring. The diamines were complexed with K2PtCl4 to give the target Pt(II) complexes: [1,2-bis(aminomethyl)benzene]dichloroplatinum(II) (4a) and [1,2-bis(aminomethyl)-4-methoxy-benzene]dichloroplatinum(II) (4b). Screening for cytotoxic activity was done in comparison to cisplatin in a panel of eight human cancer cell lines; in all cases, the 4-methoxy derivative 4b was less active than the unsubstituted analog, 4a. In four cell lines 4a was as potent as cisplatin, while in the other four lines cisplatin was considerably more potent then 4a. The 5637 bladder cancer cell line was made 4-5 fold resistant to either cisplatin or [d,l-trans-1,2-diaminocyclohexane]dichloroplatinum(II); 4a showed some cross resistance (2-3 fold) to both resistant cell lines. The reactivity of 4a towards substitutions with glutathione (GSH), a biological thiol involved in intrinsic and acquired resistance to Pt-complexes, was measured by a RP-HPLC method. It was found that the second-order rate constant for the reaction of 4a with GSH was similar to that that reported for CDDP, indicating that reactivity towards GSH does not explain the different levels of cross resistance.
- Rinke,Gruenert,Bednarski
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p. 763 - 769
(2007/10/03)
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- Synthetic Study of Selective Benzylic Oxidation
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Oxidation of bisbenzyl ethers was studied using 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ). Compared to other benzylic oxidations such as Kornblum type reaction of benzyl bromides or MnO2 oxidation of benzyl alcohols, DDQ oxidation offered advantages of being mild and highly selective to provide monoaldehyde products. We have explored factors which influence the course of the reaction and exemplified the synthetic value of the approach by preparing a number of aromatic intermediates (7-8, 15-25).
- Wang, Wuyi,Li, Tiechao,Attardo, Giorgio
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p. 6598 - 6602
(2007/10/03)
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- 7-Spiroindanyl derivatives of naltrexone and oxymorphone as selective ligands for δ opioid receptors
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A series consisting of spiroindanyl (5-7), benzospiroindanyl (8-10), and spiroperinaphthyl (11) derivatives of naltrexone and oxymorphone were synthesized in order to investigate the role of an orthogonal-oriented 'address' for δ opioid receptors. All of
- Ohkawa,DiGiacomo,Larson,Takemori,Portoghese
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p. 1720 - 1725
(2007/10/03)
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- Photoexcited proton transfer from enhanced photoacids
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Naphthols with electron-withdrawing groups such as cyano or methanesulfonyl at C-5 and C-8 exhibit greatly enhanced photoacidity. This increase in photoacidity enables the substituted naphthols to undergo excited-state proton transfer (ESPT) in alcohols and Me2SO in the absence of water. In aqueous tetrahydrofuran solution, efficient proton transfer to water occurs at much lower water concentrations than with the parent naphthol, and the kinetics of proton transfer indicate that a smaller water cluster is involved.
- Tolbert, Laren M.,Haubrich, Jeanne E.
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p. 10593 - 10600
(2007/10/02)
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- A synthesis of two novel benzo[f]ninhydrin analogs: 6-methoxybenzo[f]ninhydrin and thieno[f]ninhydrin
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Improved methodology for the synthesis of benzo[f]ninhydrin (1) is described. The generality of this approach is illustrated with the synthesis of two novel analogs, 6-methoxybenzo[f]ninhydrin (3) and thieno[f]ninhydrin (4).
- Heffner,Joullie
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p. 1055 - 1069
(2007/10/02)
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