cas 348-28-7, 4-FLUORO-2-HYDROXYBENZALDEHYDE

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Structure-Based Design of Potent and Orally Active Isoindolinone Inhibitors of MDM2-p53 Protein-Protein Interaction
Inhibition of murine double minute 2 (MDM2)-p53 protein-protein interaction with small molecules has been shown to reactivate p53 and inhibit tumor growth. Here, we describe rational, structure-guided, design of novel isoindolinone-based MDM2 inhibitors. MDM2 X-ray crystallography, quantum mechanics ligand-based design, and metabolite identification all contributed toward the discovery of potent in vitro and in vivo inhibitors of the MDM2-p53 interaction with representative compounds inducing cytostasis in an SJSA-1 osteosarcoma xenograft model following once-daily oral administration.
Chessari, Gianni,Hardcastle, Ian R.,Ahn, Jong Sook,Anil, Burcu,Anscombe, Elizabeth,Bawn, Ruth H.,Bevan, Luke D.,Blackburn, Timothy J.,Buck, Ildiko,Cano, Celine,Carbain, Benoit,Castro, Juan,Cons, Ben,Cully, Sarah J.,Endicott, Jane A.,Fazal, Lynsey,Golding, Bernard T.,Griffin, Roger J.,Haggerty, Karen,Harnor, Suzannah J.,Hearn, Keisha,Hobson, Stephen,Holvey, Rhian S.,Howard, Steven,Jennings, Claire E.,Johnson, Christopher N.,Lunec, John,Miller, Duncan C.,Newell, David R.,Noble, Martin E. M.,Reeks, Judith,Revill, Charlotte H.,Riedinger, Christiane,St. Denis, Jeffrey D.,Tamanini, Emiliano,Thomas, Huw,Thompson, Neil T.,Vinkovi?, Mladen,Wedge, Stephen R.,Williams, Pamela A.,Wilsher, Nicola E.,Zhang, Bian,Zhao, Yan
supporting information
p. 4071 - 4088
(2021/05/04)

Anion Recognition in Water by Charge-Neutral Halogen and Chalcogen Bonding Foldamer Receptors
A novel strategy for the recognition of anions in water using charge-neutral σ-hole halogen and chalcogen bonding acyclic hosts is demonstrated for the first time. Exploiting the intrinsic hydrophobicity of halogen and chalcogen bond donor atoms integrated into a foldamer structural molecular framework containing hydrophilic functionalities, a series of water-soluble receptors was constructed for an anion recognition investigation. Isothermal titration calorimetry (ITC) binding studies with a range of anions revealed the receptors to display very strong and selective binding of large, weakly hydrated anions such as I- and ReO4-. This is achieved through the formation of 2:1 host-guest stoichiometric complex assemblies, resulting in an encapsulated anion stabilized by cooperative, multidentate, convergent σ-hole donors, as shown by molecular dynamics simulations carried out in water. Importantly, the combination of multiple σ-hole-anion interactions and hydrophobic collapse results in I- affinities in water that exceed all known σ-hole receptors, including cationic systems (β2 up to 1.68 × 1011 M-2). Furthermore, the anion binding affinities and selectivity trends of the first example of an all-chalcogen bonding anion receptor in pure water are compared with halogen bonding and hydrogen bonding receptor analogues. These results further advance and establish halogen and chalcogen bond donor functions as new tools for overcoming the challenging goal of anion recognition in pure water.
Borissov, Arseni,Marques, Igor,Lim, Jason Y.C.,Félix, Vítor,Smith, Martin D.,Beer, Paul D.
supporting information
p. 4119 - 4129
(2019/03/07)

Phosphine-Catalyzed [3+2] Annulation of β-Sulfonamido-Substituted Enones with Sulfamate-Derived Cyclic Imines
Phosphine-catalyzed [3+2] annulation of β-sulfonamido-substituted enones and sulfamate-derived cyclic imines has been developed, giving a series of imidazoline derivatives in moderate to excellent yields with good to excellent diastereoselectivities. A scale-up reaction worked well under mild reaction conditions. A possible mechanism was proposed on the basis of the results obtained.
Shi, Wangyu,Zhou, Leijie,Mao, Biming,Wang, Qijun,Wang, Chang,Zhang, Cheng,Li, Xuefeng,Xiao, Yumei,Guo, Hongchao
supporting information
p. 679 - 685
(2019/01/24)

Effects of Substituents on Metastable-State Photoacids: Design, Synthesis, and Evaluation of their Photochemical Properties
Recently, metastable-state photoacids have been widely used to control proton transfer in numerous chemical and biological processes as well as applications with visible light. Generally, substituents have a great influence on the photochemical properties of molecules, which will further affect their applications. Yet, the effects of substituents on metastable-state photoacids have not been studied systematically. In this work, 16 metastable-state photoacid derivatives were designed and synthesized on the basis of substituents having a large range of σ–π electron–donor–acceptor capabilities. The effects of substituents on the color display [or maximum absorption band(s)], solubility, pKa values, dark/photoacidity, photosensitivity, and relaxation kinetic(s) were investigated in detail. This study will be helpful for the targeted design and synthesis of promising photoacids and the application of their photocontrolled proton-release processes in functional materials/devices.
Liu, Junning,Tang, Wenqi,Sheng, Lan,Du, Zhen,Zhang, Ting,Su, Xing,Zhang, Sean Xiao-An
supporting information
p. 438 - 445
(2019/01/08)

Enantioselective Construction of Tetrahydroquinazoline Motifs via Palladium-Catalyzed [4 + 2] Cycloaddition of Vinyl Benzoxazinones with Sulfamate-Derived Cyclic Imines
A palladium-catalyzed enantioselective [4 + 2] cycloaddition reaction of vinyl benzoxazinones with sulfamate-derived cyclic imines is described, affording the tetrahydroquinazolines bearing several functional rings in high yields (up to 99% yield) with good to excellent diastereoselectivities and excellent enantioselectivities (up to 96% ee). This reaction represents the first Pd-catalyzed asymmetric decarboxylative cycloaddition of vinyl benzoxazinones with imines.
Wang, Chang,Li, Yan,Wu, Yang,Wang, Qijun,Shi, Wangyu,Yuan, Chunhao,Zhou, Leijie,Xiao, Yumei,Guo, Hongchao
supporting information
p. 2880 - 2883
(2018/05/29)

ISOINDOLINONE INHIBITORS OF THE MDM2-P53 INTERACTION HAVING ANTICANCER ACTIVITY
The invention provides a compound of formula (I): (I) or tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein the various substituents are as defined in the claims. Also provided are pharmaceutical compositions containing the compounds of formula (I), processes for making the compounds and the medical uses of the compounds.
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Page/Page column 138-139

(2017/05/07)

C- ARYL GLYCOSID DERIVATIVES, PHARMACEUTICAL COMPOSITION, PREPARATION PROCESS AND USES THEREOF
This invention relates to a kind of C-aryl glycoside derivatives, its pharmaceutical compositions, preparation methods, and uses thereof. The preparation method comprises: method 1: in a solvent, deprotecting the acetyl protecting groups of compound 1-f in the presence of a base; method 2: 1) compound 2-g reacts with via Mitsunobu reaction; 2) deprotecting the acetyl protecting groups of compound 2-f obtained from step 1; method 3: 1) compound 2-g reacts with via nucleophilic substitution reaction; 2) deprotecting the acetyl protecting groups of compound 3-f obtained from step 1. The pharmaceutical composition comprises a kind of C-aryl glycoside derivatives; it's pharmaceutically acceptable salts and/or prodrugs thereof and excipient thereof. This invention further relates to a kind of C-aryl glycoside derivatives, it's pharmaceutically acceptable salts or pharmaceutical compositions thereof for the use in preparation of a SGLT inhibitor. The C-aryl glycoside derivatives of this invention provides a new direction for the study of SGLT inhibitors.
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Paragraph 0375; 0376; 0377

(2017/04/19)

Lysosome-Targeting Amplifiers of Reactive Oxygen Species as Anticancer Prodrugs
Cancer cells produce elevated levels of reactive oxygen species, which has been used to design cancer specific prodrugs. Their activation relies on at least a bimolecular process, in which a prodrug reacts with ROS. However, at low micromolar concentratio
Daum, Steffen,Reshetnikov, M. S. Viktor,Sisa, Miroslav,Dumych, Tetyana,Lootsik, Maxim D.,Bilyy, Rostyslav,Bila, Evgenia,Janko, Christina,Alexiou, Christoph,Herrmann, Martin,Sellner, Leopold,Mokhir, Andriy
supporting information
p. 15545 - 15549
(2017/11/16)

Efficient synthesis of chiral benzofuryl β-amino alcohols via a catalytic asymmetric Henry reaction
Chiral β-amino alcohol ligands were found effective for the copper(ii)-catalyzed asymmetric Henry reaction of benzofuran-2-carbaldehydes with nitromethane, which led to the formation of (S)-enriched benzofuryl β-nitro alcohols with satisfactory enantioselectivities (up to 98% ee). Using this catalytic protocol, bioactive (S)-benzofuryl β-amino alcohols could be conveniently prepared in short steps.
Chen, Wei,Zhou, Zhao-Hui,Chen, Hong-Bin
supporting information
p. 1530 - 1536
(2017/02/15)

Metabolic epoxidation is a critical step for the development of benzbromarone-induced hepatotoxicity
Benzbromarone (BBR) is effective in the treatment of gout; however, clinical findings have shown it can also cause fatal hepatic failure. Our early studies demonstrated that CYP3A catalyzed the biotransformation of BBR to epoxide intermediate(s) that reacted with sulfur nucleophiles of protein to form protein covalent binding both in vitro and in vivo. The present study attempted to define the correlation between metabolic epoxidation and hepatotoxicity of BBR by manipulating the structure of BBR. We rationally designed and synthesized three halogenated BBR derivatives, fluorinated BBR (6-F-BBR), chlorinated BBR (6-Cl-BBR), and brominated BBR (6-Br-BBR), to decrease the potential for cytochrome P450-mediated metabolic activation. Both in vitro and in vivo uricosuric activity assays showed that 6-F-BBR achieved favorable uricosuric effect, while 6-Cl-BBR and 6-Br-BBR showed weak uricosuric efficacy. Additionally, 6-F-BBR elicited much lower hepatotoxicity in mice. Fluorination of BBR offered advantage to metabolic stability in liver microsomes, almost completely blocked the formation of epoxide metabolite(s) and protein covalent binding, and attenuated hepatic and plasma glutathione depletion. Moreover, the structural manipulation did not alter the efficacy of BBR. This work provided solid evidence that the formation of the epoxide(s) is a key step in the development of BBR-induced hepatotoxicity.
Wang, Wenbao,Wang, Shaojie,Zhang, Tingjian,Lan, Qunsheng,Pang, Jianxin,Wang, Hui,Peng, Ying,Zhao, Huimin,Zhao, Yufei,Wang, Xu,Zheng, Jiang
supporting information
p. 1354 - 1363
(2019/01/12)

Structure-based design of tricyclic NF-κB inducing kinase (NIK) inhibitors that have high selectivity over phosphoinositide-3-kinase (PI3K)
We report here structure-guided optimization of a novel series of NF-κB inducing kinase (NIK) inhibitors. Starting from a modestly potent, low molecular weight lead, activity was improved by designing a type 11/2 binding mode that accessed a back pocket past the methionine-471 gatekeeper. Divergent binding modes in NIK and PI3K were exploited to dampen PI3K inhibition while maintaining NIK inhibition within these series. Potent compounds were discovered that selectively inhibit the nuclear translocation of NF-κB2 (p52/REL-B) but not canonical NF-κB1 (REL-A/p50).
Castanedo, Georgette M.,Blaquiere, Nicole,Beresini, Maureen,Bravo, Brandon,Brightbill, Hans,Chen, Jacob,Cui, Hai-Feng,Eigenbrot, Charles,Everett, Christine,Feng, Jianwen,Godemann, Robert,Gogol, Emily,Hymowitz, Sarah,Johnson, Adam,Kayagaki, Nobuhiko,Kohli, Pawan Bir,Knüppel, Kathleen,Kraemer, Joachim,Krüger, Susan,Loke, Pui,McEwan, Paul,Montalbetti, Christian,Roberts, David A.,Smith, Myron,Steinbacher, Stefan,Sujatha-Bhaskar, Swathi,Takahashi, Ryan,Wang, Xiaolu,Wu, Lawren C.,Zhang, Yamin,Staben, Steven T.
supporting information
p. 627 - 640
(2017/02/05)

Enantioselective Synthesis of 6,6-Disubstituted Pentafulvenes Containing a Chiral Pendant Hydroxy Group
Simple enantioselective synthesis of 6,6-disubstituted pentafulvenes bearing chiral pendant hydroxy groups are attained by cascade reactivity using commercially available proline-based organocatalysts. Condensation of cyclopentadiene with the acetyl function of a 1,2-formylacetophenone, followed by cyclization of a resulting fulvene-stabilized carbanion with the formyl group, generates bicyclic chiral alcohols with initial er values up to 94:6. Exceptional enantio-enrichment of the resultant alcohols results upon crystallization—even near racemic samples spontaneously de-racemize. This enables new families of substituted cyclopentadienes that are both enantiomerically and diastereomerically pure to be rapidly attained.
Nouch, Ryan,Cini, Melchior,Magre, Marc,Abid, Mohammed,Diéguez, Montserrat,Pàmies, Oscar,Woodward, Simon,Lewis, William
supporting information
p. 17195 - 17198
(2017/11/27)

Phosphine-Catalyzed [4 + 2] Annulation of Allenoate with Sulfamate-Derived Cyclic Imines: A Reaction Mode Involving γ′-Carbon of α-Substituted Allenoate
A phosphine-catalyzed [4 + 2] cycloaddition of cyclic α-substituted allenoates with sulfamate-derived cyclic imines has been reported. Using dibenzylphenylphosphine as the nucleophilic catalyst, the reaction worked efficiently to yield various fused multicyclic heterocyclic compounds in high yields with excellent diastereoselectivities. It undergoes a new reaction mode involving γ′-carbon of α-substituted allenoate.
Mao, Biming,Shi, Wangyu,Liao, Jianning,Liu, Honglei,Zhang, Cheng,Guo, Hongchao
supporting information
p. 6340 - 6343
(2017/12/08)

List fluoro Radicamine compounds and their use and preparation method
The invention discloses a mono-fluorinated Radicamine compound which has a structure as shown in a formula (1), and further provides a preparation method for the mono-fluorinated Radicamine compound with the structure as shown in the formula (1) and an application of the mono-fluorinated Radicamine compound or the mono-fluorinated Radicamine compound prepared with the method to preparation of drugs for preventing and/or treating diabetes, drugs for preventing and/or treating Gaucher's diseases, drugs for preventing and/or treating tumors or antiviral drugs. The mono-fluorinated Radicamine compound provided by the invention is good in glycosidase inhibition activity.
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Paragraph 0086-0088

(2017/12/02)

4-Isopropylchroman-3-ol derivatives
The present invention relates to a novel 4-isopropylchroman-3-ol compound, a pharmaceutical composition comprising the novel compound as an effective component, and to an intermediate compound useful for synthesizing the compound. When administered to a patient with a drug causing toxicity, the novel 4-isopropylchroman-3-ol compound exhibits efficacy of reducing toxicity of the drug by reducing antagonism regarding a T-type calcium channel and/or activity of cytochrome P450 isozyme.
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Paragraph 0156-0158

(2017/04/19)

5-AMINO-4-CARBAMOYL-PYRAZOLE COMPOUNDS AS SELECTIVE AND IRREVERSIBLE T790M OVER WT-EGFR KINASE INHIBITORS AND USE THEREOF????
Disclosed are compounds of Formula (I), pharmaceutical compositions comprising the same, processes for the preparation thereof, and the use thereof.
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Paragraph 0410

(2016/03/13)

Fluorinated Radicamine A and B: Synthesis and Glycosidase Inhibition
Fluorinated derivatives of radicamine A and radicamine B have been synthesized from D-arabinose-derived cyclic nitrone. Structure-activity relationship studies showed that glycosidase inhibition of these fluorinated derivatives was significantly influenced by the position of the fluorine atom. C-7 or C-11 fluorination of the aromatic ring decreased α-glucosidase inhibition of the derivatives, whereas C-8 or C-10 fluorination preserved glycosidase inhibitory activities. Fluorinated derivatives of radicamine A and B have been synthesized from D-arabinose-derived cyclic nitrone. Structure-activity relationship studies revealed that glycosidase inhibition of these fluorinated derivatives was significantly influenced by the position of the fluorine atom.
Li, Yi-Xian,Iwaki, Ren,Kato, Atsushi,Jia, Yue-Mei,Fleet, George W. J.,Zhao, Xuan,Xiao, Min,Yu, Chu-Yi
p. 1429 - 1438
(2016/03/16)

Structure-activity relationship study of E6 as a novel necroptosis inducer
Necroptosis inducers represent a promising potential treatment for drug-resistant cancer. We herein describe the structure modification of E6, which was identified recently as a potent and selective necroptosis inducer. The studies described herein demonstrate for the first time that functionalized biphenyl derivatives possess necroptosis inducer activity. Furthermore, these studies have led to the identification of two promising compounds (5h and 5j) that can be used for further optimization studies as well as mechanism of action investigations.
Mou, Jianfeng,Park, Ann,Cai, Yu,Yuan, Junying,Yuan, Chengye
supporting information
p. 3057 - 3061
(2015/06/22)

Discovery of 7-tetrahydropyran-2-yl chromans: β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors that reduce amyloid β-protein (Aβ) in the central nervous system
In an attempt to increase selectivity vs Cathepsin D (CatD) in our BACE1 program, a series of 1,3,4,4a,10,10a-hexahydropyrano[4,3-b]chromene analogues was developed. Three different Asp-binding moieties were examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines in order to modulate potency, selectivity, efflux, and permeability. Using structure-based design, substitutions to improve binding to both the S3 and S2′ sites of BACE1 were explored. An acyl guanidine moiety provided the most potent analogues. These compounds demonstrated 10-420 fold selectivity for BACE1 vs CatD, and were highly potent in a cell assay measuring Aβ1-40 production (5-99 nM). They also suffered from high efflux. Despite this undesirable property, two of the acyl guanidines achieved free brain concentrations (C free,brain) in a guinea pig PD model sufficient to cover their cell IC50s. Moreover, a significant reduction of Aβ1-40 in guinea pig, rat, and cyno CSF (58%, 53%, and 63%, respectively) was observed for compound 62.
Thomas, Allen A.,Hunt, Kevin W.,Volgraf, Matthew,Watts, Ryan J.,Liu, Xingrong,Vigers, Guy,Smith, Darin,Sammond, Douglas,Tang, Tony P.,Rhodes, Susan P.,Metcalf, Andrew T.,Brown, Karin D.,Otten, Jennifer N.,Burkard, Michael,Cox, April A.,Do, Mary K. Geck,Dutcher, Darrin,Rana, Sumeet,Delisle, Robert K.,Regal, Kelly,Wright, Albion D.,Groneberg, Robert,Scearce-Levie, Kimberly,Siu, Michael,Purkey, Hans E.,Lyssikatos, Joseph P.,Gunawardana, Indrani W.
p. 878 - 902
(2014/03/21)

CONDENSED TRICLYCLIC COMPOUNDS AS INHIBITORS OF HIV REPLICATION
Compounds of formula (I) and pharmaceutical compositions thereof: wherein A1 A2 and A3 are each independently selected from the group consisting of N and CR3, wherein R1 is an optionally substituted heterocyclyl or an optionally substituted -(C1-6)alkyl-heterocyclyl, R2 is an optionally substituted aryl or an optionally subsisted heteroaryl, R4 is an optionally substituted aryl, an optionally substituted heterocyclyl or an optionally substituted heteroaryl, useful as an inbitor of HIV replication.
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Page/Page column 37

(2013/07/05)

Discovery of novel dual inhibitors of the wild-type and the most prevalent drug-resistant mutant, S31N, of the M2 proton channel from influenza A virus
Anti-influenza drugs, amantadine and rimantadine, targeting the M2 channel from influenza A virus are no longer effective because of widespread drug resistance. S31N is the predominant and amantadine-resistant M2 mutant, present in almost all of the circulating influenza A strains as well as in the pandemic 2009 H1N1 and the highly pathogenic H5N1 flu strains. Thus, there is an urgent need to develop second-generation M2 inhibitors targeting the S31N mutant. However, the S31N mutant presents a huge challenge to drug discovery, and it has been considered undruggable for several decades. Using structural information, classical medicinal chemistry approaches, and M2-specific biological testing, we discovered benzyl-substituted amantadine derivatives with activity against both S31N and WT, among which 4-(adamantan-1-ylaminomethyl)-benzene-1,3-diol (44) is the most potent dual inhibitor. These inhibitors demonstrate that S31N is a druggable target and provide a new starting point to design novel M2 inhibitors that address the problem of drug-resistant influenza A infections.
Wang, Jizhou,Ma, Chunlong,Wang, Jun,Jo, Hyunil,Canturk, Belgin,Fiorin, Giacomo,Pinto, Lawrence H.,Lamb, Robert A.,Klein, Michael L.,DeGrado, William F.
supporting information
p. 2804 - 2812
(2013/05/21)

Structure based optimization of chromen-based TNF-α converting enzyme (TACE) inhibitors on S1′ pocket and their quantitative structure-activity relationship (QSAR) study
A series of coumarin based TACE inhibitors were designed to bind in S1′ pocket of TACE enzyme based on their docking study. Twelve analogues were synthesized and most of compounds were active in vitro TACE enzyme inhibition as well as cellular TNF-α inhibition. Among these, 15l effectively inhibited the production of serum TNF-α by oral administration at a dose of 30 mg/kg. Compound 15l also showed a good oral bioavailability at 42% and effectively inhibited paw edema in rat carrageenan model. Quantitative structure-activity relationship (QSAR) study using genetic function approximation technique (GFA) and docking study were performed to confirm the series of coumarin core TACE inhibitors. QSAR model have been evaluated internally and externally using test set prediction. Through docking study of each molecule, it is validated that the electrostatic descriptors from the QSAR equation could explain the importance of S1′ pocket and the TACE inhibitory activity well.
Yang, Jee Sun,Chun, Kwangwoo,Park, Jung Eun,Cho, Misun,Seo, Jeongjea,Song, Doona,Yoon, Hongchul,Park, Chun-Ho,Joe, Bo-Young,Choi, Jong-Hee,Kim, Myung-Hwa,Han, Gyoonhee
experimental part
p. 8618 - 8629
(2011/02/25)

INDOLE AND BENZOFURAN 2-CARBOXAMIDE DERIVATIVES
Compounds of Formula (I) or Formula (II) or pharmaceutically acceptable salts thereof, wherein m, n, p, Ar R1 R2, R4 R5 and R6 are as defined herein. The invention also provides methods for preparing, compositions comprising, and methods for using these compounds in the treatment of Alzheimer's disease or as cognitive enhancer.
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Page/Page column 42-43

(2008/12/05)

Aminostyrylbenzofuran derivatives as potent inhibitors for Aβ fibril formation
The synthesis of a novel series of aminostyrylbenzofuran derivatives 1a-w and their inhibitory activities for Aβ fibril formation were described. All the synthesized compounds were evaluated by thioflavin T (ThT) assay and displayed potent inhibitory activities for Aβ fibril formation. Among them, compounds 1i and 1q exhibited excellent inhibitory activities (IC50 = 0.07 and 0.08 μM, respectively) than those of Curcumin (IC50 = 0.80 μM) and IMSB (IC50 = 8.00 μM) as reference compounds. Both compounds were selected as promising candidates for further biological evaluation.
Byun, Ji Hun,Kim, HyeYun,Kim, YoungSoo,Mook-Jung, Inhee,Kim, Dong Jin,Lee, Won Koo,Yoo, Kyung Ho
scheme or table
p. 5591 - 5593
(2009/06/18)

NOVEL CHROMEN-2-ONE BASED HYDROXAMIC ACID DERIVATIVES HAVING ANTI-INFLAMMATORY ACTIVITY, THE PREPARATION THEREOF AND A COMPOSITION CONTAINING THE SAME FOR TREATING INFLAMMATORY DISEASE
The present invention relates to novel chromen-2-one based hydroxamic acid derivatives having anti-inflammatory activity, the preparation thereof and a composition containing the same for treating inflammatory disease.
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Page/Page column 34

(2010/11/25)

SUBSTITUTED ACIDS FOR THE TREATMENT OF RESPIRATORY DISEASES
The invention relates to substituted acids of formula (I), where T,W,X,Y,Z, R1 and R2 as defined in the claims, as useful pharmaceutical compounds for treating asthma and rhinitis, pharmaceutical compositions containing them, and a processes for their preparation.
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Page/Page column 38

(2010/02/15)

BENZOPYRAN COMPOUNDS USEFUL FOR TREATING INFLAMMATORY CONDITIONS
The subject invention concerns methods and compounds that have utility in the treatment of a condition associated with cyclooxygenase-2 mediated disorders. Compounds of particular interest are benzopyrans and their analogs defined by formula (1). Wherein Z, X, R1, R2, R3, and R4 are as described in specification.
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Page 504

(2010/02/08)

CHROMENE DERIVATIVES AS ANTI-INFLAMMATORY AGENTS
The subject invention concerns methods and compounds that have utility in the treatment of a condition associated with cyclooxygenase-2 mediated disorders. Compounds of particular interest are benzopyrans and their analogs defined by formula (I). Wherein Z, X, R1, R2, R3, and R4 are as described in the specification.
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Page 504

(2010/02/08)

Non-metallocene compounds, method for the production thereof and use of the same for the polymerisation of olefins
The invention relates to a method for producing special transition metal compounds, to novel transition metal compounds and to the use of the same for the polymerisation of olefins.
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(2008/06/13)

Pyrano, piperidino, and thiopyrano compounds and methods of use
The present invention provides novel compounds of formula I which may be useful in hyperpolarizing cell membranes, opening potassium channels, relaxing smooth muscle cells, and inhibiting bladder contractions.
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(2008/06/13)

Potassium channel openers
Compounds having the formula I: are useful in treating diseases prevented by or ameliorated with potassium channel openers. Also disclosed are potassium channel opening compositions and a method of opening potassium channels in a mammal.
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(2008/06/13)

Effect of ring fluorination on the pharmacology of hallucinogenic tryptamines
A series of fluorinated analogues of the hallucinogenic tryptamines N,N-diethyltryptamine (DET), 4-hydroxy-N,N-dimethyltryptamine (4-OH-DMT, psilocin), and 5-methoxy-DMT was synthesized to investigate possible explanations for the inactivity of 6-fluoro-DET as a hallucinogen and to determine the effects of fluorination on the molecular recognition and activation of these compounds at serotonin receptor subtypes. The target compounds were evaluated using in vivo behavioral assays for hallucinogen-like and 5-HT(1A) agonist activity and in vitro radioligand competition assays for their affinity at 5-HT(2A), 5-HT(2C), and 5-HT(1A) receptor sites. Functional activity at the 5-HT(2A) receptor was determined for all compounds. In addition, for some compounds functional activity was determined at the 5-HT(1A) receptor. Hallucinogen-like activity, evaluated in the two-lever drug discrimination paradigm using LSD-trained rats, was attenuated or abolished for all of the fluorinated analogues. One of the tryptamines, 4-fluoro-5-methoxy-DMT (6), displayed high 5-HT(1A) agonist activity, with potency greater than that of the 5-HT(1A) agonist 8-OH-DPAT. The ED50 of 6 in the two-lever drug discrimination paradigm using rats trained to discriminate the 5-HT(1A) agonist LY293284 was 0.17μmol/kg, and the K(i) at [3H]8-OH-DPAT-labeled 5-HT(1A) receptors was 0.23 nM. The results indicate that fluorination of hallucinogenic tryptamines generally has little effect on 5-HT(2A/2C) receptor affinity or intrinsic activity. Affinity at the 5-HT(1A) receptor was reduced, however, in all but one example, and all of the compounds tested were full agonists but with reduced functional potency at this serotonin receptor subtype. The one notable exception was 4-fluoro-5-methoxy-DMT (6), which had markedly enhanced 5-HT(1A) receptor affinity and functional potency. Although it is generally considered that hallucinogenic activity results from 5-HT(2A) receptor activation, the present results suggest a possible role for involvement of the 5-HT(1A) receptor with tryptamines.
Blair,Kurrasch-Orbaugh,Marona-Lewicka,Gumbay,Watts,Barker,Nichols
p. 4701 - 4710
(2007/10/03)

Magnesium-mediated ortho-Specific Formylation and Formaldoximation of Phenols
Deprotonation of phenols using magnesium methoxide, followed by distillative removal of free methanol and addition of paraformaldehyde results in ortho-specific magnesium mediated formylation to give the corresponding salicyladehyde magnesium salts, from which the salicylaldehydes can be isolated by acidic work-up.Addition of aq. hydroxylamine sulfate to the salicylaldehyde magnesium salt, in place of the acid work-up, gives the corresponding salicylaldoximes.
Aldred, Robert,Johnston, Robert,Levin, Daniel,Neilan, James
p. 1823 - 1832
(2007/10/02)