- Discovery and Characterization of Potent Pan-Genotypic HCV NS5A Inhibitors Containing Novel Tricyclic Central Core Leading to Clinical Candidate
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The identification of a novel class of potent pan-genotypic NS5A inhibitors with good pharmacokinetic profile suitable for potential use in treating HCV infections is disclosed here. The present series of compounds are with less complex tricyclic central core, identified through a systematic SAR study carried out on biphenyl moiety. The SAR outcome has confirmed the requirement of near planar and linear conformation of the molecule to achieve the best pan-genotypic activity. In addition, SAR with substituted imidazoles on improvement of antiviral activity is disclosed. The newly identified compounds 12, 16, 19-21 have shown desirable pharmacokinetic profiles with a favorable uptake of compounds in liver and maintained a significant concentration for up to 8 h in the liver. In addition, compounds 20 and 21 have shown superior pan-genotypic anti-HCV activity compared to ledipasvir and daclatasvir. Additional characterization and preliminary safety assessment resulted in the identification of compound 20 as a potential clinical candidate.
- Ramdas, Vidya,Talwar, Rashmi,Banerjee, Moloy,Joshi, Advait Arun,Das, Amit Kumar,Walke, Deepak Sahebrao,Borhade, Prashant,Dhayagude, Usha,Loriya, Rajesh,Gote, Ganesh,Bommakanti, Apparao,Sivaram, Aruna,Agarwal, Gautam,Goswami, Arnab,Nigade, Prashant,Mehta, Maneesh,Patil, Vinod,Modi, Dipak,Kumar, Hemant,Mallurwar, Sadanand,Dash, Amruta,Modi, Falguni,Kuldharan, Sandip,Srivastava, Pratima,Singh, Minakshi,Narasimham, Lakshmi,Gundu, Jayasagar,Sharma, Sharad,Kamboj, Rajender Kumar,Palle, Venkata P.
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- Synthesis, characterization, photophysical properties of a novel organic photoswitchable dyad in its pristine and hybrid nanocomposite forms
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In the present paper the method of synthesis and characterization of a novel organic dyad, 3-(1-Methoxy-3,4-dihydro-naphthalyn-2-yl-)-1-p-chlorophenyl propenone, have been reported. In this paper our main thrust is to fabricate new hybrid nanocomposites by combining the organic dyad with different noble metals, semiconductor nanoparticle and noble metal-semiconductor core/shell nanocomposites. In this organic dyad, donor part is 1-Methoxy-3, 4-dihydro-naphthalen- 2-carboxaldehyde with the acceptor p-chloroacetophenone. We have carried out steady state and time-resolved spectroscopic measurements on the dyad and its hybrid nanocomposite systems. Some quantum chemical calculations have also been done using Gaussian 03 software to support the experimental findings by theoretical point of view. Both from the theoretical predictions and NMR studies it reveals that in the ground state only extended (E-type or trans-type) conformation of the dyad exists whereas on photoexcitation these elongated conformers are converted into folded forms (Z- or cis-type) of the dyad, showing its photoswitchable character. Time resolved fluorescence spectroscopic (fluorescence lifetime by TCSPC method) measurements demonstrate that in chloroform medium all the organic-inorganic hybrid nanocomposites, studied in the present investigation, possess larger amount of extended conformers relative to folded ones, even in the excited singlet state. This indicates the possibility of slower energy destructive charge recombination rates relative to the rate processes associate with charge-separation within the dyad. It was found that in CHCl3 medium, the computed charge separation rate was found to be ~108 s?1 for the dyad alone and other hybrid nanocomposite systems. The rate is found to be faster than the energy wasting charge recombination rate ~102-10 1 s?1, as observed from the transient absorption measurements for the corresponding hybrid systems. It indicates the conformational geometry has a great effect on the charge-separation and recombination rate processes. The suitability for the construction of efficient light energy conversion devices especially with Ag-Dyad nanocomposite of all the systems studied here is hinted from the observed long ion-pair lifetime. Copyright
- Mandal, Gopa,Chakraborty, Amrita,Sur, Ujjal Kumar,Ankamwar, Balaprasad,De, Asish,Ganguly, Tapan
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- Synthesis of amides from (E)-3-(1-chloro-3,4-dihydronaphthalen-2-yl)acrylic acid and substituted amino acid esters as NorA efflux pump inhibitors of Staphylococcus aureus
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Inhibitors for NorA efflux pump of Staphylococcus aureus have attracted the attention of many researchers towards the discovery and development of novel efflux pump inhibitors (EPIs). In an attempt to find specific potent inhibitors of NorA efflux pump of S. aureus, a total of 15 amino acid conjugates of 3-(1-chloro-3,4-dihydronaphthalen-2-yl)acrylic acid (4–18) were synthesized using a simple convenient synthetic approach and bioevaluated against NorA efflux pump. Two compounds 7 and 8 (each having MEC of 1.56 μg/mL) were found to restore the activity of ciprofloxacin through reduction of the MIC elucidated by comparing the ethidium bromide efflux in dose dependent manner in addition to ethidium bromide efflux inhibition and accumulation study using NorA overexpressing strain SA-1199B. Most potent compounds among these were able to restore the antibacterial activity of ciprofloxacin completely against SA-1199B. Structure activity relationship (SAR) studies and docking study of potent compounds 7 and 8 could elucidate the structural requirements necessary for interaction with the NorA efflux pumps. On the whole, compounds 7 and 8 have ability to reverse the NorA efflux mediated resistance and could be further optimized for development of potent efflux pump inhibitors.
- Rath, Santosh K.,Singh, Samsher,Kumar, Sunil,Wani, Naiem A.,Rai, Rajkishor,Koul, Surrinder,Khan, Inshad A.,Sangwan, Payare L.
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Read Online
- Photoactuators based on the dynamic molecular crystals of naphthalene acrylic acids driven by stereospecific [2+2] cycloaddition reactions
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The photomechanical effects of the dynamic molecular crystals of halogen-substituted naphthalene acrylic acids (1FNaAA, 1ClNaAA, 1BrNaAA, 1INaAA and 6BrNaAA) have been investigated. Upon UV irradiation, the needle-like crystal of 1FNaAA curls away from the light source, while the slice-like crystal of 6BrNaAA bends towards the light source. Moreover, the light-induced bending, flipping and bursting are observed for the elongated needle-like crystals of 1FNaAA, and the slice-like crystals of 1ClNaAA and 1BrNaAA show bending, cracking, coiling, rotating and twisting triggered by 365 nm light. It is found that stereospecific [2+2] cycloaddition reactions take place in the crystals to afford one stereoisomer of β-type cyclobutanes, since 1FNaAA, 1ClNaAA, 1BrNaAA and 6BrNaAA pack in a head-to-head mode, which satisfies the Schmidt's topo-photochemical criteria. The strain can be generated and accumulated during the photodimerization, and the release of the strain leads to the photomechanical effects. This provides new clues for the development of photomechanical molecular crystals based on acrylic acids bearing halogen-substituted aromatic units.
- Liu, Jiaxi,Ye, Kaiqi,Shen, Yanbing,Peng, Jiang,Sun, Jingbo,Lu, Ran
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supporting information
p. 3165 - 3175
(2020/03/19)
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- Tricyclic heteroaromatic system amide derivative as well as preparation and application thereof
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The invention discloses a tricyclic heteroaromatic system amide derivative. The general formula is as shown in a formula (I), wherein the definitions of R, W1, W2, W3 and W4 are as shown in the specification for details. In addition, the invention also discloses a preparation method and a medicinal composition of the compound. The compound which the invention relates to has high alpha7 receptor binding activity, high selectivity and medium-high-level excitement effect. (The formula is as shown in the description).
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Paragraph 0332; 0333; 0334
(2018/11/22)
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- Two-Step Synthesis of 3,4-Dihydropyrrolopyrazinones from Ketones and Piperazin-2-ones
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An expedient two-step synthesis of 3,4-dihydropyrrolopyrazinones has been achieved via a Vilsmeier-Haack reaction of ketones, followed by an annulation of the corresponding chloroaldehydes with commercially available piperazin-2-ones. A variety of cyclic and acyclic ketones and piperazin-2-ones participated in this two-step chemistry, affording the desired 3,4-dihydropyrrolopyrazinones in up to 78% yield.
- Sandoval, Cosme,Lim, Ngiap-Kie,Zhang, Haiming
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p. 1252 - 1255
(2018/02/22)
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- 4H-Thieno[3,2-c]chromene based inhibitors of Notum Pectinacetylesterase
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A group of small molecule thienochromenes inhibitors of Notum Pectinacetylesterase are described. We developed SAR on three series based on carbon, oxygen and sulfur replacement of the 5-position. In each series, highly potent Notum Pectinacetylesterase inhibitors were identified.
- Han, Qiang,Pabba, Praveen K.,Barbosa, Joseph,Mabon, Ross,Healy, Jason P.,Gardyan, Michael W.,Terranova, Kristen M.,Brommage, Robert,Thompson, Andrea Y.,Schmidt, James M.,Wilson, Alan G.E.,Xu, Xiaolian,Tarver, James E.,Carson, Kenneth G.
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p. 1184 - 1187
(2016/02/23)
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- Base-Promoted Intermolecular Cyclization of Substituted 3-Aryl(Heteroaryl)-3-chloroacrylaldehydes and Tetrahydroisoquinolines: An Approach to Access Pyrrolo[2,1-a]isoquinolines
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We have developed a new base-promoted intermolecular cascade cyclization reaction of substituted 3-aryl(heteroaryl)-3-chloroacrylaldehydes and tetrahydroisoquinolines in one pot. The reaction provides a facile and practical synthesis of pyrrolo[2,1-a]isoquinolines. A number of pyrrolo[2,1-a]isoquinolines were synthesized in moderate to high yields (up to 97%).
- Yang, Ziqi,Lu, Ning,Wei, Zhonglin,Cao, Jungang,Liang, Dapeng,Duan, Haifeng,Lin, Yingjie
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p. 11950 - 11955
(2016/12/09)
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- Antiviral Compounds with a Heterotricycle Moiety
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Disclosed are compounds of formula (I) for use as antiviral agents, particularly as anti-hepatitis virus C agents, wherein A, B, U, R1-R7, m, n, and q are as described herein. Also disclosed are pharmaceutical compositions and methods of treating or preventing viral infection in a host by the use of these compounds, either alone or in combination with other pharmaceutically active agents. Further disclosed are methods of preparing such compounds.
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Paragraph 0165; 0166; 0110; 0111; 0109
(2015/02/18)
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- Modular Synthesis of Highly Substituted Pyridines via Enolate α-Alkenylation
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A novel methodology for the synthesis of highly substituted pyridines based on the palladium-catalyzed enolate α-alkenylation of ketones is presented; the formation of aromatic compounds is a new direction for this catalytic C-C bond forming reaction. In the key step, a protected β-haloalkenylaldehyde participates in α-alkenylation with a ketone to afford a 1,5-dicarbonyl surrogate, which then undergoes cyclization/double elimination to the corresponding pyridine product, all in one pot. The β-haloalkenylaldehyde starting materials can be obtained from the corresponding methylene ketone via Vilsmeier haloformylation. Using this concise route, a variety of highly substituted pyridines were synthesized in three steps from commercially available compounds. (Chemical Equation Presented).
- Hardegger, Leo A.,Habegger, Jacqueline,Donohoe, Timothy J.
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supporting information
p. 3222 - 3225
(2015/07/15)
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- Novel benzophenanthrene derivatives typed compound and the organic electroluminescence display device using same
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The present invention refers to novel benzo [...] derivative composition is provided to improve quality of an organic light emitting including, more specifically a device [...] benzothiazole derivatives represented by formula 1 relates to compounds derivatives. Derivative compound [...] benzo of the present invention a low driving voltage and including a first electrode and a second electrode, having excellent pixel layer and luminous efficiency.. [Formula 1]
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Paragraph 0094-0097
(2016/10/08)
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- Thermolysis of N-aryl enaminoimine hydrochloride derivatives: A short and general method for the synthesis of pyranoquinolin-3-one and pyranoacridin-3-one derivatives
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A short synthesis of 3H-pyrano[3,2-f]quinolin-3-one, 3H-acenaphtho[1,2-b]pyrano-[3,2-f]quinolin-3-one, and 3H-benzo[h]pyrano[3,2-a]acridin-3-one derivatives are described via thermolysis of suitable enaminoimine hydrochloride derivatives.
- Patra, Prasanta,Kar, Gandhi K.,Khatua, Biswajit
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p. 1306 - 1310
(2015/04/27)
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- Microwave-Assisted Synthesis of Fused and Substituted 2-Aminopyridines from β-Halo α,β-Unsaturated Aldehydes
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2-Aminopyridines were synthesized from β-halo α,β-unsaturated aldehydes by a microwave-assisted Knoevenagel reaction. The β-halo-α,β-unsaturated aldehydes were, in turn, efficiently synthesized from the corresponding ketones by a Vilsmeier formylation reaction. The protocol was used to synthesize several novel steroidal and nonsteroidal fused 2-aminopyridine derivatives.
- Gogoi, Junali,Gogoi, Pranjal,Goswami, Limi,Boruah, Romesh C.
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p. 1905 - 1912
(2015/06/30)
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- Synthesis, in vitro evaluation and cocrystal structure of 4-oxo-[1]benzopyrano[4,3-c]pyrazole cryptosporidium parvum inosine 5′-monophosphate dehydrogenase (Cp IMPDH) inhibitors
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Cryptosporidium inosine 5′-monophosphate dehydrogenase (CpIMPDH) has emerged as a therapeutic target for treating Cryptosporidium parasites because it catalyzes a critical step in guanine nucleotide biosynthesis. A 4-oxo-[1]benzopyrano[4,3-c]pyrazole derivative was identified as a moderately potent (IC50 = 1.5 μM) inhibitor of CpIMPDH. We report a SAR study for this compound series resulting in 8k (IC50 = 20 ± 4 nM). In addition, an X-ray crystal structure of CpIMPDH·IMP·8k is also presented.
- Sun, Zhuming,Khan, Jihan,Makowska-Grzyska, Magdalena,Zhang, Minjia,Cho, Joon Hyung,Suebsuwong, Chalada,Vo, Pascal,Gollapalli, Deviprasad R.,Kim, Youngchang,Joachimiak, Andrzej,Hedstrom, Lizbeth,Cuny, Gregory D.
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supporting information
p. 10544 - 10550
(2015/02/19)
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- Synthesis of novel β-aryl-β-(methylthio)acroleins via Vilsmeier-Haack protocol as potential 1,3-dielectrophilic three-carbon building blocks
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A new general route for the synthesis of novel β-aryl-β- (methylthio)acroleins, a class of stable potential 1,3-dielectrophilic synthons, has been reported. The overall protocol involves treatment of either β-chloroacroleins or their precursor iminium salts (generated in situ from the corresponding active methylene ketones under Vilsmeier-Haack reaction conditions) with S,S-dimethyldithiocarbonates (DDC)/aqueous KOH in either a one-pot or two-step process. The dimethyldithiocarbonate (DDC)/30% aqueous KOH has been shown to be an excellent source of methylthiolate anion.
- Byre Gowda,Charanraj,Pradeepa Kumara,Ramesh,Thomas,Sadashiva,Junjappa
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p. 4475 - 4479
(2014/08/05)
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- β-Iminoenamine-BF2 complexes: Aggregation-induced emission and pronounced effects of aliphatic rings on radiationless deactivation
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The synthesis, photophysical, and electrochemical attributes of a novel class of boron difluorides containing an aromatic-fused alicyclic/hetero- alicyclic ring built on a β-iminoenamine chromophoric backbone are reported. The compounds displayed large Stokes shifts (86-121 nm), and were emissive in the solid state. The quantum yields obtained in solution at room temperature were unusually lower by an order of magnitude compared to those in the solid state. Some of the tested compounds displayed aggregation-induced emission (AIE). Single crystal XRD analyses revealed a lack of interplanar π-π interactions, which are presumed to be absent owing to non-planarity of the alicyclic component in the molecule. For most of the studied compounds, time-dependent DFT (TD-DFT) calculations invariably reveal intramolecular charge transfer (π-π*) characteristics with the frontier orbitals concentrated on the boron-nitrogen heterocycle. The participation of boron and fluorine atoms was found to be negligible. Copyright
- Perumal, Karthikeyan,Garg, Jai Anand,Blacque, Olivier,Saiganesh, Ramanathan,Kabilan, Senthamaraikannan,Balasubramanian, Kallupattu Kuppusamy,Venkatesan, Koushik
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p. 2670 - 2677
(2013/01/15)
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- A general and efficient approach to 2H-indazoles and 1H-pyrazoles through copper-catalyzed intramolecular N-N bond formation under mild conditions
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A new efficient copper-catalyzed intramolecular amination reaction has been developed to readily synthesise a wide variety of multi-substituted 2H-indazole and 1H-pyrazole derivatives from easily accessible starting materials under mild conditions. A highly selective ligand for estrogen receptor β was prepared in three steps by employing this method. The Royal Society of Chemistry 2011.
- Hu, Jiantao,Cheng, Yongfeng,Yang, Yiqing,Rao, Yu
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supporting information; experimental part
p. 10133 - 10135
(2011/10/09)
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- Substituted dihydronaphthalenes as efflux pump inhibitors of Staphylococcus aureus
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A new series of 3-(substituted-3,4-dihydronaphthyl)-2-propenoic acid amides has been prepared through convergent synthetic strategies and tested in combination with ciprofloxacin against NorA overexpressing Staphylococcus aureus 1199B as test strain for potentiating of the drug activity. Out of 24 compounds evaluated, 12 compounds potentiated the activity of ciprofloxacin and resulted in 2-16 fold reduction in the MIC (4-0.5 μg/mL) of the drug. The failure of these efflux pump inhibitors (EPIs) to potentiate the activity of ciprofloxacin when tested against NorA knock out S. aureus SA-K1758 established their identity as NorA inhibitors. The structure of all these newly synthesised compounds was confirmed by spectral data. The present communication describes the synthesis, bioevaluation, structure activity relationship and mechanism of action of these EPIs. Design and synthesis of new series of 3-(substituted 3,4-dihydronaphthyl)- propenoic acid amides as efflux pump inhibitors has resulted in the MIC reduction of ciprofloxacin.
- Thota, Niranjan,Reddy, Mallepally V.,Kumar, Ashwani,Khan, Inshad A.,Sangwan, Payare L.,Kalia, Nitin P.,Koul, Jawahir L.,Koul, Surrinder
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experimental part
p. 3607 - 3616
(2010/09/18)
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- Efficient synthesis of a new type of baylis-hillman adducts and their stereoselective bromination
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A new type of Baylis-Hillman adducts derived from chlorovinyl aldehydes were prepared via Vilsmeier reaction of ketones with a bis(trichloromethyl) carbonate (BTC)/DMF system to construct chlorovinyl aldehydes, followed by sonochemical Baylis-Hillman reaction under solvent-free conditions. The stereoselective bromination of these new compounds with a Br2-Ph3P system has been achieved efficiently with good to excellent yields under mild conditions. Copyright Taylor & Francis Group, LLC.
- Zhong, Weihui,Jiang, Lingbo,Guo, Baoming,Wu, Yaotiao,Hong, Lingjuan,Chen, Yanhui
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experimental part
p. 2441 - 2456
(2010/09/05)
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- Intramolecular Fe(II)-Catalyzed N-O or N-N bond formation from aryl azides
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(Figure presented) Iron(II) bromide catalyzes the transformation of aryl and vinyl azides with ketone or methyl oxime substituents into 2,1-benzisoxazoles, indazoles, or pyrazoles through the formation of an N-O or N-N bond. This transformation tolerates a variety of different functional groups to facilitate access to a range of benzisoxazoles or indazoles. The unreactivity of the Z-methyloxime indicates that N-heterocycle formation occurs through a nucleophilic attack of the ketone or oxime onto an activated planar iron azide complex.
- Stokes, Benjamin J.,Vogel, Carl V.,Urnezis, Linda K.,Pan, Minjie,Driver, Tom G.
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supporting information; experimental part
p. 2884 - 2887
(2010/08/21)
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- Synthesis of a novel series of thieno[3,2-d]pyrimidin-4-(3H)-ones
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2-Aminothieno[3,2-d]pyrimidin-4-ones were synthesized in one step by condensation of 3-amino(benzo)thiophene car-boxylate with chloroformamidine hydrochloride. Georg Thieme Verlag Stuttgart.
- Abdillahi, Ismail,Kirsch, Gilbert
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scheme or table
p. 1428 - 1430
(2010/10/03)
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- NOVEL EFFLUX PUMP INHIBITORS
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This invention relates to compounds, which are in general potentiators of antiinfeective agents and inhibitors of bacterial efflux pumps in particular. These novel compounds i.e. substituted dihydronaphtalene derivatives and tetralin derivatives and/or their salts are useful against antibiotic-resistant microbial pathogens, for treating microbial infections by reducing the extrusion of a co-administered antimicrobial agent. This invention also provides processes for the preparation of such efflux pump inhibitors and their compositions with anti infective agents and methods for treatment of microbial infections.
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Page/Page column 33
(2009/10/22)
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- Synthesis and biological evaluation of guanylhydrazone coactivator binding inhibitors for the estrogen receptor
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Most patients with hormone-responsive breast cancer eventually develop resistance to traditional antiestrogens such as tamoxifen, and this has become a major obstacle in their treatment. We prepared and characterized the activity of a series of 16 guanylhydrazone small molecules that are designed to block estrogen receptor (ER) activity through a non-traditional mechanism, by directly interfering with coactivator binding to agonist-liganded ER. The inhibitory activity of these compounds was determined in cell-based transcription assays using ER-responsive reporter gene and mammalian two-hybrid assays. Several of the compounds gave IC50 values in the low micromolar range. Two secondary assays were used to confirm that these compounds were acting through the proposed non-traditional mode of estrogen inhibitory action and not as conventional antagonists at the ligand binding site.
- LaFrate, Andrew L.,Gunther, Jillian R.,Carlson, Kathryn E.,Katzenellenbogen, John A.
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experimental part
p. 10075 - 10084
(2009/04/06)
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- PIM KINASE INHIBITORS AS CANCER CHEMOTHERAPEUTICS
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Inhibitors of Pim kinases, ways to make them and methods of treating patients using them are disclosed.
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Page/Page column 11
(2008/12/06)
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- PIM KINASE INHIBITORS AS CANCER CHEMOTHERAPEUTICS
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Inhibitors of Pim kinases, ways to make them and methods of treating patients using them are disclosed.
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Page/Page column 12
(2008/12/06)
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- 1,1-Dioxonaphtho[1,2-b]thiophene-2-methyloxycarbonyl (α-Nsmoc) and 3,3-dioxonaphtho[2,1-b]thiophene-2-methyloxycarbonyl (β-Nsmoc) amino-protecting groups
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Of the three theoretically possible, Bsmoc-related, naphthothiophene sulfone-based amino-protecting groups, the two most readily available derivatives, the α- and β-Nsmoc analogues, have been examined as substitutes for the Bsmoc residue in cases where the latter lead to oily protected amino acids or amino acid fluorides. All of the naphtho systems gave easily handled solid amino acid derivatives. The intermediate sulfone alcohol 11 used as the key reagent for introduction of the α-Nsmoc protecting group was readily made from α-tetralone (Scheme 1). The corresponding β-analogue 17 was made similarly on a small scale, but due to the high cost of β-tetralone, an alternate route involving reaction of rhodanine with a-naphthaldehyde was used for large-scale work (Scheme 2). All proteinogenic amino acids were converted to their α- and β-Nsmoc derivatives. Deblocking studies showed that the reactivity toward deblocking by piperidine followed the order α-Nsmoc > Bsmoc > β-Nsmoc. 1H NMR experiments showed that deblocking of the two new systems was mechanistically similar to that previously established for the Bsmoc derivative in that the reaction is initiated by Michael addition to the β-carbon atom of the α,β-unsaturated sulfone system. Application of α- and β-Nsmoc amino acids to the solid-phase synthesis of two model peptides was examined. An advantage of the α-Nsmoc system over the long-known Bsmoc system proved to be the milder conditions needed for the deblocking step relative to the Bsmoc case, which is itself more readily deblocked than the classic Fmoc analogue.
- Carpino, Louis A.,Abdel-Maksoud, Adel Ali,Ionescu, Dumitru,Mansour,Zewail, Mohamed A.
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p. 1729 - 1736
(2007/10/03)
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- Selective synthesis of some 4,5-dihydro-2H-benzo[g]indazoles and 8,9-dihydro-2H-benzo[e]indazoles via the Vilsmeier-Haack reaction under thermal and microwave assisted conditions
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A selective and easy method is described for the synthesis of 4,5-dihydro-2H-benzo[g]indazoles and 8,9-dihydro-2H-benzo[e]indazoles by the Vilsmeier-Haack reaction of various tetralone phenylhydrazones under thermal and microwave irradiation conditions.
- Sivaprasad, Ganesabaskaran,Sridhar, Radhakrishnan,Perumal, Paramasivan T.
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p. 389 - 394
(2007/10/03)
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- SUBSTITUTED THIOPHENE CARBOXAMIDE COMPOUNDS FOR THE TREATMENT OF INFLAMMATION
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The present invention provides substituted thiophene carboxamide compounds having structural Formula I and isomers, tautomers, polymorphs, carriers, prodrugs, and pharmaceutically acceptable salts thereof, compositions comprising such, and methods for treating diseases associated with kinase activity. More specifically, the present invention provides methods of treatment of a variety of diseases associated with IKK2 including the treatment of inflammation, other inflammation-associated disorders, such as, as an analgesic in the treatment of pain and headaches, arthritis, including but not limited to rheumatoid arthritis, asthma, gastrointestinal conditions such as inflammatory bowel disease, vascular diseases, viral infections such as AIDS, and cancer.
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- A versatile aminobenzannulation method based on the deprotonation of 2-(1-alkynyl)-benzaldimines and similar 2-aza-2,4-heptadienyl-6-ynes: A multistep rearrangement cascade
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Two ring closures, a ring opening, and two intermolecular proton shifts are the crucial steps in a cascade reaction that is triggered by the simple deprotonation of alkynylimines and leads ultimately to aminobenzannulation products (see scheme). The reactions proceed in good to very good yield and with excellent chemoselectivity.
- Sagar, Pramod,Froehlich, Roland,Wuerthwein, Ernst-Ulrich
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p. 5694 - 5697
(2007/10/03)
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- Synthesis of phenanthrenes and polycyclic heteroarenes by transition-metal catalyzed cycloisomerization reactions
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Readily available biphenyl derivatives containing an alkyne unit at one of their ortho-positions are converted into substituted phenanthrenes on exposure to catalytic amounts of either PtCl2, AuCl, AuCl3, GaCl3 or InCl3 in toluene. This 6-endo-dig cyclization likely proceeds through initial π-complexation of the alkyne unit followed by interception of the resulting η2-metal species by the adjacent arene ring. The reaction is inherently modular, allowing for substantial structural variations and for the incorporation of substituents at any site of the phenanthrene product. Moreover, it is readily extended to the heterocyclic series as exemplified by the preparation of benzoindoles, benzocarbazoles, naphthothiophenes, as well as bridgehead nitrogen heterocycles such as pyrrolo[1,2-a]quinolines. Depending on the chosen catalyst, biaryls bearing halo-alkyne units can either be converted into the corresponding 10-halo-phenanthrenes or into the isomeric 9-halo-phenanthrenes; in the latter case, the concomitant 1,2-halide shift is best explained by assuming a metal vinylidene species as the reactive intermediate. The scope of this novel method for the preparation of polycyclic arenes is illustrated by the total synthesis of a series of polyoxygenated phenanthrenes that are close relatives of the anticancer agent combretastatin A-4, as well as by the total synthesis of the aporphine alkaloid O-methyl-dehydroisopiline and its naturally occurring symmetrical dimer.
- Mamane, Victor,Hannen, Peter,Fuerstner, Alois
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p. 4556 - 4575
(2007/10/03)
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- Chlorine directed formylation of chloroindanones under Vilsmeier-Haack reaction condition
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Highly selective bisformylation of 4-chloroindanone derivatives on treatment with POCl3 + DMF have been discovered.
- Mahato, Tapan K.,Pan, Dipanjan,Mal, Sajal Kanti,Ray, Jayanta K.
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p. 969 - 970
(2007/10/03)
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- A rapid access to coumarin derivatives (using Vilsmeier-Haack and Suzuki cross-coupling reactions)
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A four-step preparation of compounds containing a coumarinic moiety is presented. This synthesis involves notably a Suzuki cross-coupling reaction (performed in aqueous media) and a ring closure by formation of δ-lactone.
- Hesse, Stéphanie,Kirsch, Gilbert
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p. 1213 - 1215
(2007/10/03)
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- Synthesis of new thieno[b]azepinediones from α-methylene ketones
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New substituted 6,7-dihydro-4H-thieno[3,2-b]azepine-5,8-diones were synthesized in seven steps, starting from substituted α-methylene ketones, via 3-aminothiophene-2-carboxylic acid alkyl esters.
- Migianu, Evelyne,Kirsch, Gilbert
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p. 1096 - 1100
(2007/10/03)
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- A Novel Route to Isoannulated Hetereoaromatic Compounds, 2. - The Dipole Route to Furo/Thieno Pyrroles and α-Pyridones, and Their Benzo Derivatives
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A new methodology involving 1,7-dipolar cyclizations of conjugated dipoles followed by a multistep rearrangement affording ring-contracted products has been employed for the synthesis of various examples of the title compounds.Under different thermolysis conditions the annulated alkynyl nitrones 15-19, 45, and 46 are converted into isoannulated pyrroles and α-pyridones, respectively, with yields up to 90percent (general reaction A --> B + C).The product distribution is strongly influenced by the nature of the thermal substituent R, hence supporting a mechanism with oxo carbenes as central intermediates which undergo either 6-? cyclization to the pyrrole systems or Wolff rearrangement leading to conjugated ketenes, the precursors of the observed α-pyridones (see Scheme 1).Diels-Alder reactions were performed with benzofuropyridone 40a, naphthopyridone 62 as well as with the corresponding dihydronaphtho compounds 64a, b.Whereas the tert-butyl derivatives 22b, 23b and 41b are rather unreactive against dienophiles, they are easily transformed into the cyclic imides 31, 32 and 52, respectively, under the influence of oxygen anf light suggesting the formation and subsequent cycloaddition of 1O2 as important steps. - Key Words: Pyrroles, heteroannulated / α-Pyridones, heteroannulated / Pentalenes, dihetero- / Nitrones / Heterocyclizations, 1,7-dipolar / Diels-Alder reactions / Singlet oxygen
- Bussenius, Joerg,Laber, Norbert,Mueller, Thomas,Eberbach, Wolfgang
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p. 247 - 260
(2007/10/02)
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- Novel substituted 3H-1,2,3,5-oxathiadiazole 2-oxides useful as anthihyperglycemic agents
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This invention relates to novel substituted 3H-1,2,3,5-oxathiadiazole 2-oxides, to the processes for their preparation, to methods for using the compounds, and to pharmaceutical compositions thereof. The compounds have pharmaceutical properties which render them beneficial for the treatment of diabetes mellitus and associated conditions.
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