- Process development and scale-up for the preparation of the 1-methyl-quinazoline-2,4-dione wnt inhibitor SEN461
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A practical and scalable route to the Wnt inhibitor SEN461 1 is described herein. The optimized route consists of nine chemical steps. The intermediates are solids and were isolated by filtrations. Critical reactions steps in the medicinal chemistry route were modified for an initial scale-up process, and as a result, we developed a synthetic procedure for the preparation of multihundred gram quantities of the final product. A further process development for the phase 1 clinical batch campaign is reported.
- Betti, Matteo,Genesio, Eva,Panico, Alessandro,Sanna Coccone, Salvatore,Wiedenau, Paul
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Read Online
- Synthesis of Ring-Fused, N-Substituted 4-Quinolinones Using p Ka-Guided, Base-Promoted Annulations with Isatoic Anhydrides: Total Synthesis of Penicinotam
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An anionic annulation strategy employing isatoic anhydrides and a wide assortment of enolizable partners was developed to afford over 80 novel ring-fused, N-substituted 4-quinolinones, an underrepresented privileged template. Multiple factors governing the efficiency of the transformation were determined, resulting in a reliable and tunable synthetic platform applicable for a broad range of substrates with variable deprotonation susceptibility, such as tetramic and tetronic acids, cyclic 1,3-diketones, and cycloalkanones. Application to the synthesis of bioactive, pyrrolizine-fused 4-quinolinone, penicinotam 3, resulted in the most brief and highest yielding total synthesis of the alkaloid in three steps and a 36% overall yield.
- Khalifa, Muhammad M.,Philkhana, Satish Chandra,Golden, Jennifer E.
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p. 464 - 481
(2019/12/24)
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- Benzimidazoquinazolines as new potent anti-TB chemotypes: Design, synthesis, and biological evaluation
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In search for new molecular entities as anti-TB agents, the benzimidazoquinazoline polyheterocyclic scaffold has been designed adopting the scaffold hopping strategy. Thirty-two compounds have been synthesized through an improved tandem decarboxylative nucleophilic addition cyclocondensation reaction of o-phenylenediamine with isatoic anhydride followed by further cyclocondensation of the intermediately formed 2-(o-aminoaryl)benzimidazole with trialkyl orthoformate/acetate. The resultant benzimidazoquinazolines were evaluated in vitro for anti-TB activity against M. tuberculosis H37Rv (ATCC27294 strain). Fourteen compounds exhibiting MIC values in the range of 0.4–6.25 μg/mL were subjected to cell viability test against RAW 264.7 cell lines and were found to be non-toxic (30% inhibition at 50 μg/mL). The active compounds were further evaluated against INH resistant Mtb strains. The most active compound 6x [MIC (H37Rv) of 0.4 μg/mL] and the compound 6d [MIC (H37Rv) of 0.78 μg/mL] were also found to be active against INH resistant Mtb strain with MIC values of 12.5 and 0.78 μg/mL, respectively.
- Chakraborti, Asit K.,Dhameliya, Tejas M.,Jadhavar, Pradeep S.,Krishna, Vagolu Siva,Patel, Kshitij I.,Saha, Nirjhar,Sriram, Dharmarajan,Vaja, Maulikkumar D.
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- Fluorescent biaryl uracils with C5-dihydro- And quinazolinone heterocyclic appendages in PNA
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There has been much effort to exploit fluorescence techniques in the detection of nucleic acids. Canonical nucleic acids are essentially nonfluorescent; however, the modification of the nucleobase has proved to be a fruitful way to engender fluorescence. Much of the chemistry used to prepare modified nucleobases relies on expensive transition metal catalysts. In this work, we describe the synthesis of biaryl quinazolinone-uracil nucleobase analogs prepared by the condensation of anthranilamide derivatives and 5-formyluracil using inexpensive copper salts. A selection of modified nucleobases were prepared, and the effect of methoxy- or nitro- group substitution on the photophysical properties was examined. Both the dihydroquinazolinone and quinazolinone modified uracils have much larger molar absorptivity (~4-8×) than natural uracil and produce modest blue fluorescence. The quinazolinone-modified uracils display higher quantum yields than the corresponding dihydroquinazolinones and also show temperature and viscosity dependent emission consistent with molecular rotor behavior. Peptide nucleic acid (PNA) monomers possessing quinazolinone modified uracils were prepared and incorporated into oligomers. In the sequence context examined, the nitro-substituted, methoxy-substituted and unmodified quinazolinone inserts resulted in a stabilization (?Tm = +4.0/insert; +2.0/insert; +1.0/insert, respectively) relative to control PNA sequence upon hybridization to complementary DNA. All three derivatives responded to hybridization by the “turn-on” of fluorescence intensity by ca. 3-to-4 fold and may find use as probes for complementary DNA sequences.
- Heidari, Ali,Ghorbani-Choghamarani, Arash,Hajjami, Maryam,Hudson, Robert H.E.
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- Target protein degradation inducing compound, preparation method thereof and pharmaceutical composition for preventing or treating targeted protein related diseases containing the same as an active ingredient
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The present invention relates to a degraducer for inducing the decomposition of target protein, a producing method thereof, and a pharmaceutical composition for preventing or treating target protein-related diseases by containing the degraducer as an active ingredient. A novel compound represented by chemical formula 1, ULB-L-PTM, by the present invention, as a degraducer compound inducing the decomposition of target protein using cereblon E3 ubiquitin ligase, is able to significantly achieve a target protein degradation-inducing activity with an excellent binding activity of a cereblon E3 ubiquitin ligase binder thereby, being able to achieve an excellent protein degradation activity by targeting protein or polypeptide related to various diseases. The bromodomain-containing pharmaceutical composition for preventing or treating protein-related diseases or conditions contains the novel compound represented by chemical formula 1 as an active ingredient and has a useful effect of providing a health functional food composition for prevention or improvement.(AA) Example 22 (nM, 24h)COPYRIGHT KIPO 2020
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Paragraph 0671; 0673-0675
(2020/05/01)
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- NOVEL PIPERIDINE-2,6-DIONE DERIVATIVE AND USE THEREOF
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The present disclosure relates to a novel piperidine-2,6-dione derivative and a use thereof and, more specifically, to a piperidine-2,6-dione derivative compound having a structure of a thalidomide analog. A compound of chemical formula 1 according to the present disclosure specifically binds with CRBN protein, and is involved in functions thereof. Therefore, the compound of the present disclosure can be favorably used in the prevention or treatment of leprosy, chronic graft versus host disease, an inflammatory disease, or cancer, which are caused by actions of CRBN protein.
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Paragraph 0177-0179
(2020/03/09)
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- Synthesis and nematicidal activities of 1,2,3-benzotriazin-4-one containing 4,5-dihydrothiazole-2-thiol derivatives against Meloidogyne incognita
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A series of novel 1,2,3-benzotriazin-4-one derivatives containing 4,5-dihydrothiazole-2-thiol were synthesized and characterized by 1H NMR, 13C NMR, 19F NMR and HRMS. The bioassay results showed that compounds 3-(3-((4,5-dihydrothiazol-2-yl)thio)propyl)-7-methoxybenzo[d][1–3]triazin-4(3H)-one, 3-(3-((4,5-dihydrothiazol-2-yl)thio)propyl)-6-nitrobenzo[d][1–3]triazin-4(3H)-one, 7-chloro-3-(3-((4,5-dihydrothiazol-2-yl)thio)propyl)benzo[d][1–3]triazin-4(3H)-one exhibited good control efficacy against the cucumber root-knot nematode disease caused by Meloidogyne incognita at the concentration of 10.0 mg L?1 in vivo. Compound 7-chloro-3-(3-((4,5-dihydrothiazol-2-yl)thio)propyl)benzo[d][1–3]triazin-4(3H)-one showed excellent nematicidal activity with inhibition 68.3% at a concentration of 1.0 mg L?1. It suggested that the structure of 1,2,3-benzotriazin-4-one containing 4,5-dihydro-thiazole-2-thiol could be optimized further.
- Chen, Xiulei,Zhou, Zhen,Li, Zhong,Xu, Xiaoyong
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p. 194 - 200
(2019/09/13)
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- Synthesis and nematicidal evaluation of 1,2,3-benzotriazin-4-one derivatives containing piperazine as linker against Meloidogyne incognita
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To explore new skeleton with nematicidal activity, a series of novel 1,2,3-benzotriazin-4-one derivatives containing piperazine as linker were synthesized and varied fragments were also introduced to increase structure diversity of the new skeleton. Their inhibitory activities in vivo were evaluated against Meloidogyne incognita. The newly prepared compounds A6, A8, A21, A28 and A38 exhibited more than 50% inhibition at the concentration of 20 mg/L. Especially compound A6 displayed 71.4% inhibition against Meloidogyne incognita at the concentration of 20 mg/L. The nematicidal activities varied significantly depending on the types and positions of the substituents, which provided guidance for further structure modification.
- Chen, Xiulei,Jia, Haowu,Li, Zhong,Xu, Xiaoyong
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supporting information
p. 1207 - 1213
(2019/03/29)
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- Gold-Catalyzed Selective 6-exo-dig and 7-endo-dig Cyclizations of Alkyn-Tethered Indoles to Prepare Rutaecarpine Derivatives
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An efficient method to synthesize rutaecarpine derivatives via the gold-catalyzed selective cyclization of alkyn-tethered indoles under mild conditions is described. The alkyn-tethered indole can undergo 6-exo-dig cyclization by oxidation and sequential gold catalysis, while it goes through 7-endo-dig cyclization by gold catalysis and sequential oxidation. Substrate scope studies reveal that the selectivity of cyclization was controlled by the substrates with sp3 and sp2 hybridization of carbon at the 2 position in quinazolinone. Furthermore, the rutaecarpine scaffold was prepared in 67% yield at gram scale easily in four steps from isatoic anhydride.
- Kong, Xiang-Fei,Zhan, Feng,He, Guo-Xue,Pan, Cheng-Xue,Gu, Chen-Xi,Lu, Ke,Mo, Dong-Liang,Su, Gui-Fa
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p. 2006 - 2017
(2018/02/23)
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- Palladium-Catalyzed Cyclization Reaction of o-Iodoanilines, CO2, and CO: Access to Isatoic Anhydrides
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Isatoic anhydrides, a class of valuable synthetic intermediates and RNA structure probing reagents, are usually prepared with highly toxic phosgene or stoichiometric oxidants. Herein we report a highly selective palladium-catalyzed cyclization reaction for the efficient synthesis of isatoic anhydrides from readily available o-iodoanilines, CO2, and CO. The reaction proceeds under mild conditions and is redox-neutral. Both CO2 and CO are indispensable C1 building blocks for this catalytic reaction.
- Zhang, Wen-Zhen,Zhang, Ning,Sun, Yu-Qian,Ding, Yu-Wei,Lu, Xiao-Bing
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p. 8072 - 8076
(2017/12/08)
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- Optimization of substituted imidazobenzodiazepines as novel asthma treatments
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We describe the synthesis of analogs of XHE-III-74, a selective α4β3γ2 GABAAR ligand, shown to relax airway smooth muscle ex vivo and reduce airway hyperresponsiveness in a murine asthma model. To improve properties of this compound as an asthma therapeutic, a series of analogs with a deuterated methoxy group in place of methoxy group at C-8 position was evaluated for isotope effects in preclinical assays; including microsomal stability, cytotoxicity, and sensorimotor impairment. The deuterated compounds were equally or more metabolically stable than the corresponding non-deuterated analogs and increased sensorimotor impairment was observed for some deuterated compounds. Thioesters were more cytotoxic in comparison to other carboxylic acid derivatives of this compound series. The most promising compound 16 identified from the in vitro screens also strongly inhibited smooth muscle constriction in ex vivo guinea pig tracheal rings. Smooth muscle relaxation, determined by reduction of airway hyperresponsiveness with a murine ovalbumin sensitized and challenged model, showed that 16 was efficacious at low methacholine concentrations. However, this effect was limited due to suboptimal pharmacokinetics of 16. Based on these findings, further analogs of XHE-III-74 will be investigated to improve in vivo metabolic stability while retaining the efficacy at lung tissues involved in asthma pathology.
- Jahan, Rajwana,Stephen, Michael Rajesh,Forkuo, Gloria S.,Kodali, Revathi,Guthrie, Margaret L.,Nieman, Amanda N.,Yuan, Nina Y.,Zahn, Nicolas M.,Poe, Michael M.,Li, Guanguan,Yu, Olivia B.,Yocum, Gene T.,Emala, Charles W.,Stafford, Douglas C.,Cook, James M.,Arnold, Leggy A.
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p. 550 - 560
(2016/12/09)
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- Identification of a Novel 1,2,3,4-Tetrahydrobenzo[b][1,6]naphthyridine Analogue as a Potent Phosphodiesterase 5 Inhibitor with Improved Aqueous Solubility for the Treatment of Alzheimer's Disease
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Phosphodiesterase 5 (PDE5) hydrolyzes cyclic guanosine monophosphate (cGMP) leading to increased levels of the cAMP response element binding protein (CREB), a transcriptional factor involved with learning and memory processes. We previously reported poten
- Fiorito, Jole,Vendome, Jeremie,Saeed, Faisal,Staniszewski, Agnieszka,Zhang, Hong,Yan, Shijun,Deng, Shi-Xian,Arancio, Ottavio,Landry, Donald W.
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p. 8858 - 8875
(2017/11/14)
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- Synthesis and Structure-Activity Relationships of Tool Compounds Based on WAY163909, a 5-HT2C Receptor Agonist
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The development of probe molecules that can be used to investigate G protein-coupled receptor (GPCR) pharmacology, trafficking, and relationship with other GPCRs is an important and growing area of research. Here, we report the synthesis of analogues of t
- Chen, Ying-Chu,Hartley, Rachel M.,Anastasio, Noelle C.,Cunningham, Kathryn A.,Gilbertson, Scott R.
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p. 1004 - 1010
(2017/05/29)
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- New Synthetic Routes to Triazolo-benzodiazepine Analogues: Expanding the Scope of the Bump-and-Hole Approach for Selective Bromo and Extra-Terminal (BET) Bromodomain Inhibition
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We describe new synthetic routes developed toward a range of substituted analogues of bromo and extra-terminal (BET) bromodomain inhibitors I-BET762/JQ1 based on the triazolo-benzodiazepine scaffold. These new routes allow for the derivatization of the me
- Baud, Matthias G. J.,Lin-Shiao, Enrique,Zengerle, Michael,Tallant, Cynthia,Ciulli, Alessio
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p. 1492 - 1500
(2016/03/08)
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- QUINAZOLINE-2,4(1H,3H)-DIONE DERIVATIVES AS TRCP5 MODULATORS FOR THE TREATMENT OF NEUROPSYCHIATRY DISORDERS
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This invention relates to novel Quinazoline-2,4(1H,3H)-dione derivatives of Formula (I): and their use as TRPC5 modulators, pharmaceutical compositions containing the same, and methods of using the same as agents for the treatment of TRPC5 receptor mediated disorders or conditions. R1, R2, R3 and R4 have meanings given in the description.
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- METHOD OF PRODUCING NITROGEN-CONTAINING HETEROCYCLIC COMPOUND
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PROBLEM TO BE SOLVED: To provide a chemical compound production method realizing easy and high-yield production of a nitrogen-containing heterocyclic compound useful as a synthetic intermediate and the like in many fields such as medicine, agriculture and synthetic resin additives. SOLUTION: In the production method, an ortho-substituted benzene azide derivative represented by formula (1) is reacted with carbon dioxide in the presence of a reductant to obtain a compound represented by formula (2). [R is H and/or a substituent; A is an intramolecular cyclizable group; and B is a divalent linking group of C, N and O. COPYRIGHT: (C)2016,JPOandINPIT
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Paragraph 0045
(2016/10/08)
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- 2-Pyridylquinolone antimalarials with improved antimalarial activity and physicochemical properties
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A series of 2-pyridylquinolones has been prepared in 5-7 steps and through lead optimisation, antimalarial activity as low as 12 nM against Plasmodium falciparum (Pf) has been achieved. Compared with previous analogues in this series, selected molecules h
- Charoensutthivarakul, Sitthivut,Hong, W. David,Leung, Suet C.,Gibbons, Peter D.,Bedingfield, Paul T.P.,Nixon, Gemma L.,Lawrenson, Alexandre S.,Berry, Neil G.,Ward, Stephen A.,Biagini, Giancarlo A.,O'Neill, Paul M.
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supporting information
p. 1252 - 1259
(2015/07/15)
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- Recyclable (PhSe)2-catalyzed selective oxidation of isatin by H2O2: a practical and waste-free access to isatoic anhydride under mild and neutral conditions
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After a series of careful conditional optimizations and catalyst screenings, a methodology to prepare isatoic anhydrides through organoselenium-catalyzed selective oxidation of isatins by H2O2 under mild and neutral conditions was developed. The reactions were very practical because of the recyclability of the catalyst and solvent and the convenient isolation procedures of the products. This work reports the organoselenium-catalyzed oxidation of heterocycles that greatly expands the application scopes of organoselenium catalysis. It also indicates that the organoselenium catalysts are robust enough to be recycled in industrial production if suitable isolation procedures are developed.
- Yu, Lei,Ye, Jianqing,Zhang, Xu,Ding, Yuanhua,Xu, Qing
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p. 4830 - 4838
(2015/10/05)
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- Synthesis of hydroxylated tryptanthrins as possible metabolites and characterization
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A series of dihydroxytryptanthrins was prepared by the reaction of a suitably substituted isatoic anhydride and isatin as possible metabolites of tryptanthrin. A high-performance liquid chromatography analysis of the synthetic compounds confirmed that 8,9-dihydroxytryptanthrin is the metabolite isolated from rat liver cytosolic metabolites. Although tryptanthrin shows strong cytotoxicity against human cancer cell lines, none of the hydroxylated tryptanthrins exhibit any significant cytotoxicity against selected human cancer cell lines up to 50 μm.
- Kim, Dong Hyeon,Karim, Moinul,Lu, Yang,Jahng, Yurngdong
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- Structure-activity relationship and properties optimization of a series of Quinazoline-2,4-diones as inhibitors of the canonical Wnt pathway
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Wnt signaling pathway plays a critical role in numerous cellular processes, including tumor initiation, proliferation, invasion/infiltration, metastasis formation and resistance to chemotherapy. In a drug discovery project aimed at the identification of inhibitors of the canonical Wnt pathway, we selected a series of quinazoline 2,4-diones as starting point for the therapeutic treatment of glioblastoma multiforme. Despite of poor physico-chemical properties of hit compound 1, our medicinal chemistry effort allowed the discovery and characterization of lead compound 33 (SEN461), with improved ADME profile, good bioavailability and active in vitro and in vivo in glioblastoma, gastric and sarcoma tumors.
- Nencini, Arianna,Pratelli, Carmela,Quinn, Joanna M.,Salerno, Massimiliano,Tunici, Patrizia,De Robertis, Alessandra,Valensin, Silvia,Mennillo, Federica,Rossi, Marco,Bakker, Annette,Benicchi, Tiziana,Cappelli, Federico,Turlizzi, Elisa,Nibbio, Martina,Caradonna, Nicola P.,Zanelli, Ugo,Andreini, Matteo,Magnani, Matteo,Varrone, Maurizio
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supporting information
p. 526 - 545
(2015/04/14)
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- NOVEL PHOSPHODIESTERASE INHIBITORS AND USES THEREOF
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The invention provides for novel benzonaphthyridine derivatives and compositions comprising novel benzonaphthyridine derivatives. In some embodiments, the compounds are phosphodiesterase inhibitors. The invention further provides for methods for inhibitio
- -
-
Paragraph 00273-00274
(2015/02/02)
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- Palladium-catalyzed carbonylation of o-iodoanilines for synthesis of isatoic anhydrides
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A novel palladium-catalyzed oxidative double carbonylation of o-iodoanilines for the synthesis of isatoic anhydrides has been developed. The reaction employs readily available o-iodoanilines as the starting materials and proceeds under mild conditions. For extension, palladium-catalyzed oxidative carbonylation of anthranilic acids was developed for the synthesis of substituted isatoic anhydrides in high to excellent yields.
- Gao, Sha,Chen, Ming,Zhao, Mi-Na,Du, Wei,Ren, Zhi-Hui,Wang, Yao-Yu,Guan, Zheng-Hui
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p. 4196 - 4200
(2014/05/20)
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- Is the 2,3-carbon-carbon bond of indole really inert to oxidative cleavage by Oxone?-Synthesis of isatoic anhydrides from indoles
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A recent report has indicated that the oxidizing agent Oxone does not possess the ability to cleave the 2,3-carbon-carbon bond of indole. Work in our laboratory shows that this is not the case. Indole and a variety of aryl ring substituted derivatives readily react to form synthetically important isatoic anhydrides.
- Nelson, Amber C.,Kalinowski, Emily S.,Czerniecki, Nikolas J.,Jacobson, Taylor L.,Grundt, Peter
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supporting information
p. 7455 - 7457
(2013/11/06)
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- The development of potential new fluorine-18 labelled radiotracers for imaging the GABAA receptor
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Positron emission tomography (PET) using the tracer [11C] Flumazenil has shown changes in the distribution and expression of the GABA A receptor in a range of neurological conditions and injury states. We aim to develop a fluorine-18 labelled PET agent with comparable properties to [11C]Flumazenil. In this study we make a direct comparison between the currently known fluorine-18 labelled GABAA radiotracers and novel imidazobenzodiazepine ligands. A focussed library of novel compound was designed and synthesised where the fluorine containing moiety and the position of attachment is varied. The in vitro affinity of twenty-two compounds for the GABAA receptor was measured. Compounds containing a fluoroalkyl amide or a longer chain ester group were eliminated due to low potency. The fluorine-18 radiochemistry of one compound from each structural type was assessed to confirm that an automated radiosynthesis in good yield was feasible. Eleven of the novel compounds assessed appeared suitable for in vivo assessment as PET tracers.
- Jackson, Alexander,Guilbert, Benedicte B.,Plant, Stuart D.,Goggi, Julian,Battle, Mark R.,Woodcraft, John L.,Gaeta, Alessandra,Jones, Clare L.,Bouvet, Denis R.,Jones, Paul A.,O'Shea, Dennis M.,Zheng, Penny Hao,Brown, Samantha L.,Ewan, Amanda L.,Trigg, William
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supporting information
p. 821 - 826
(2013/03/13)
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- Structure-activity relationships and pharmacophore model of a noncompetitive pyrazoline containing class of GluN2C/GluN2D selective antagonists
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Here we describe the synthesis and structure-activity relationship for a class of pyrazoline-containing dihydroquinolone negative allosteric modulators of the NMDA receptor that show strong subunit selectivity for GluN2C- and GluN2D-containing receptors over GluN2A- and GluN2B-containing receptors. Several members of this class inhibit NMDA receptor responses in the nanomolar range and are more than 50-fold selective over GluN1/GluN2A and GluN1/GluN2B NMDA receptors, as well as AMPA, kainate, GABA, glycine, nicotinic, serotonin, and purinergic receptors. Analysis of the purified enantiomers of one of the more potent and selective compounds shows that the S-enantiomer is both more potent and more selective than the R-enantiomer. The S-enantiomer had an IC 50 of 0.17-0.22 μM at GluN2D- and GluN2C-containing receptors, respectively, and showed over 70-fold selectivity over other NMDA receptor subunits. The subunit selectivity of this class of compounds should be useful in defining the role of GluN2C- and GluN2D-containing receptors in specific brain circuits in both physiological and pathophysiological conditions.
- Acker, Timothy M.,Khatri, Alpa,Vance, Katie M.,Slabber, Cathryn,Bacsa, John,Snyder, James P.,Traynelis, Stephen F.,Liotta, Dennis C.
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supporting information
p. 6434 - 6456
(2013/09/23)
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- Neuroprotective tri- and tetracyclic BChE inhibitors releasing reversible inhibitors upon carbamate transfer
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Tri- and tetracyclic nitrogen-bridgehead compounds were designed and synthesized to yield micromolar cholinesterase (ChE) inhibitors. Structure-activity relationships identified potent compounds with butyrylcholinesterase selectivity. These compounds were selected as starting points for the design and synthesis of carbamate-based (pseudo)irreversible inhibitors. Compounds with superior inhibitory activity and selectivity were obtained and kinetically characterized also with regard to the velocity of enzyme carbamoylation. Structural elements were identified and introduced that additionally showed neuroprotective properties on a hippocampal neuronal cell line (HT-22) after glutamate-induced intracellular reactive oxygen species generation. We have identified potent and selective pseudoirreversible butyrylcholinesterase inhibitors that release reversible inhibitors with neuroprotective properties after carbamate transfer to the active site of cholinesterases.
- Darras, Fouad H.,Kling, Beata,Heilmann, J?rg,Decker, Michael
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supporting information
p. 914 - 919
(2013/01/15)
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- WNT PATHWAY ANTAGONISTS
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The present invention relates to known and novel compounds of formula (I) as herein described and pharmaceutical compositions thereof. The compounds of formula (I) have inhibitory effect on the Wnt pathway and are therefore useful in the preparation of a medicament, in particular for the treatment of cancer.
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Page/Page column 48
(2011/04/26)
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- [18 F] - LABELLED ANALOGUES OF FLUMAZENIL AS IN VIVO IMAGING AGENTS
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The present invention provides radiofluorinated compounds useful for in vivo imaging GABAA receptors. Also provided by the present invention is a method of synthesis for the radiofluorinated compounds of the invention, in particular an automate
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Page/Page column 16-17
(2011/04/26)
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- COMPOUNDS FOR THE PREVENTION AND TREATMENT OF CARDIOVASCULAR DISEASE
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Disclosed are novel compounds that are useful for regulating the expression of apolipoprotein A-I (ApoA-l), and their use for the treatment and prevention of cardiovascular disease and related disease states, including cholesterol- or lipid-related disorders, such as, for example, atherosclerosis. Also disclosed are pharmaceutical compositions comprising the novel compounds.
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Page/Page column 61-63
(2010/08/04)
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- BICYCLIC HETEROCYCLE DERIVATIVES AND USE THEREOF AS GPR119 MODULATORS
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The present invention relates to Bicyclic Heterocycle Derivatives of formula (I), compositions comprising a Bicyclic Heterocycle Derivative, and methods of using the Bicyclic Heterocycle Derivatives for treating or preventing obesity, diabetes, a metabolic disorder, a cardiovascular disease or a disorder related to the activity of GPR1 19 in a patient.
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Page/Page column 140
(2009/12/27)
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- NEW DS DNA BINDING FLUORESCENT DYES
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The present invention is directed to a fluorescent dye comprising a benzothiazolium moiety and a pyrimidinium moiety connected by a mono-methine bridge, characterized in that (i) the 2-position of the pyrimidine carries a substituent which starts with a C
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Page/Page column 22; Sheet 4
(2008/12/05)
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- 1,4-Benzodiazepines as inhibitors of respiratory syncytial virus
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Respiratory syncytial virus (RSV) is the cause of one-fifth of all lower respiratory tract infections worldwide and is increasingly being recognized as a serious threat to patient groups with poorly functioning immune systems. Our approach to finding a novel inhibitor of this virus was to screen a 20 000-member diverse library in a whole cell XTT assay. Parallel assays were carried out in the absence of virus in order to quantify any associated cell toxicity. This identified 100 compounds with IC50's less than 50 μM. A-33903 (18), a 1,4-benzodiazepine analogue, was chosen as the starting point for lead optimization. This molecule was moderately active and demonstrated good pharmacokinetic properties. The most potent compounds identified from this work were A-58568 (47), A-58569 (44), and A-62066 (46), where modifications to the aromatic substitution enhanced potency, and A-58175 (42), where the amide linker was modified.
- Carter, Malcolm C.,Alber, Dagmar G.,Baxter, Robert C.,Bithell, Sian K.,Budworth, Jo,Chubb, Ann,Cockerill, G. Stuart,Dowdell, Verity C. L.,Henderson, Elisa A.,Keegan, Sally J.,Kelsey, Richard D.,Lockyer, Michael J.,Stables, Jeremy N.,Wilson, Lara J.,Powell, Kenneth L.
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p. 2311 - 2319
(2007/10/03)
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- PIPERIDINE DERIVATIVES HAVING CCR3 ANTAGONISM
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The invention provides low molecular compounds having activity which inhibits binding of CCR3 ligands to CCR3 on target cells, i.e. CCR3 antagonists. The invention also provides compounds represented by formula (I) below, pharmaceutically acceptable acid adducts thereof, or pharmaceutically acceptable C1-C6 alkyl adducts thereof, as well as pharmaceutical compositions comprising them as effective ingredients, which are useful for treatment or prevention of diseases associated with CCR3, such as asthma and allergic rhinitis.
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Page/Page column 373
(2008/06/13)
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- 4,4-DISUBSTITUTED PIPERIDINE DERIVATIVES HAVING CCR3 ANTAGONISM
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The invention provides low molecular compounds having activity which inhibits binding of CCR3 ligands to CCR3 on target cells, i.e. CCR3 antagonists. The invention also provides 4,4-(disubstituted)piperidine derivatives represented by formula (I) below, pharmaceutically acceptable acid adducts thereof, or pharmaceutically acceptable C1-C6 alkyl adducts thereof, as well as pharmaceutical compositions comprising them as effective ingredients, which are useful for treatment or prevention of diseases associated with CCR3, such as asthma and allergic rhinitis.
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Page/Page column 373
(2008/06/13)
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- Exploiting the dual reactivity of o-isocyanobenzamide: Three-component synthesis of 4-imino-4H-3,1-benzoxazines
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(Chemical Equation Presented) A multicomponent synthesis of 4-imino-4H-3,1-benzoxazines is developed. Heating a toluene solution of an aldehyde (6), an amine (7), and an isonitrile (5) in the presence of a stoichiometric amount of ammonium chloride at 60°C for 12 h produces the title compound in good to excellent yields.
- Bonne, Damien,Dekhane, Mouloud,Zhu, Jieping
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p. 5285 - 5288
(2007/10/03)
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- Synthesis and Biological Evaluation of New 1,2-Dihydro-4-hydroxy-2-oxo-3-quinolinecarboxamides for Treatment of Autoimmune Disorders: Structure-Activity Relationship
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Roquinimex-related 3-quinolinecarboxamide derivatives were prepared and evaluated for treatment of autoimmune disorders. The compounds were tested in mice for their inhibitory effects on disease development in the acute experimental autoimmune encephalomyelitis model and selected compounds in the beagle dog for induction of proinflammatory reaction. Structure-activity relationships are discussed. Compound 8c, laquinimod, showed improved potency and superior toxicological profile compared to the lead compound roquinimex (1b, Linomide) and was selected for clinical studies (currently in phase II).
- J?nsson, Stig,Andersson, Gunnar,Fex, Tomas,Fristedt, Tomas,Hedlund, Gunnar,Jansson, Karl,Abramo, Lisbeth,Fritzson, Ingela,Pekarski, Olga,Runstr?m, Anna,Sandin, Helena,Thuvesson, Ingela,Bj?rk, Anders
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p. 2075 - 2088
(2007/10/03)
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- Studies in search of diazepam-insensitive subtype selective agents for GABA/Bz receptors
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In search of more selective ligands for "diazepam-insensitive" (DI) GABA receptors (i.e. receptors containing either an α4 or α6 subunit), a series of 3- and 8-substituted 6-oxo-imidazo [1,5a] [1,4]-benzodiazepines were synthesized and evaluated in vitro on recombinant human GABAA (receptor) subtypes to study their structure activity relationships. In agreement with previous findings,1,2 it was found the size of ring-D exerted a marked influence on the binding affinity at all receptor subtypes. Based on this finding, the most DI selective ligands in vitro [CM-D45 (10) and XHeIII-74 (37)] have been synthesized.
- Li, Xiaoyan,Ma, Chunrong,He, Xiaohui,Yu, Jianming,Han, Dongmei,Zhang, Chunchun,Atack, John R.,Cook, James M.
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p. 504 - 537
(2007/10/03)
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- Substituted imidazo [1,5-a] [1,2,4] triazolo [4,3-d] [1,4] benzodiazepine derivatives
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The present invention is a compound of formula The compound and derivatives or pharmaceutically acceptable salts thereof of the invention have a good affinity and selectivity to the GABA A α5 receptor and are useful for the treatment of diseases related t
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- Synthesis of Novel Imidazobenzodiazepines as Probes of the Pharmacophore for "Diazepam-Insensitive" GABAA Receptors
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The syntheses of a series of novel imidazobenzodiazepines and their affinities for diazepam sensitive (DS) and diazepam insensitive (DI) GABAA receptors are described.Imidazobenzodiazepines belong to one of the very few chemical families which
- Zhang, Puwen,Zhang, Weijiang,Liu, Ruiyan,Harris, Bradford,Skolnick, Phil,Cook, James M.
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p. 1679 - 1688
(2007/10/02)
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- Inhibitors of cyclic AMP phosphodiesterase. 1. Analogues of cilostamide and anagrelide
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Evaluation of a series of lactam heterocyclic analogues of cilostamide as inhibitors of cyclic AMP phosphodiesterase derived from both human platelets and rat heart in comparison with their corresponding methoxy-substituted heterocycles has revealed that the N-cyclohexyl-N-methyl-4-oxybutyramide side chain of 2 is an important lipophilic and/or steric pharmacophore. Attachment of this side chain to the parent heterocycle of the potent cyclic AMP phosphodiesterase inhibitor anagrelide afforded the hybrid structure RS-82856, shown to be more potent than either of its progenitors as an inhibitor of cyclic AMP phosphodiesterase or of ADP-induced platelet aggregation. The available in vitro data suggest that 1 possesses potentially useful antithrombotic and cardiotonic properties.
- Jones,Venuti,Alvarez,Bruno,Berks,Prince
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p. 295 - 303
(2007/10/02)
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- Pyrazoloquinazolin-9-ones: A New Series of Antiallergic Agents
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A new series of antiallergic agents, pyrazoloquinazolin-9-ones, was synthesized and evaluated for inhibitory effects in the rat reaginic passive cutaneous anaphylaxis (PCA) screen.Several analogues were found to be more potent than cromolyn sodium intravenously.Structure-activity relationships are discussed.One of the compounds, 4,9-dihydro-5-methoxy-9-oxopyrazoloquinazoline-2-carboxylic acid (36), was found to be approximately 250 times more potent than cromolyn sodium intravenously.
- Sircar, Jagadish C.,Capiris, Thomas,Kesten, Stephen J.,Herzig, David J.
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p. 735 - 742
(2007/10/02)
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