- A highly selective colorimetric chemosensor for cobalt(ii) ions based on a tripodal amide ligand
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A tripodal amide based ligand, tris-{(2-carbamoyl-5-carbomethoxy-pyridine)- 2-ethyl}amine (H3L, 1), was synthesized and structurally characterized by single crystal X-ray diffraction. Investigation of the cation recognition behavior showed that the ligand has selective colorimetric sensing properties for cobalt(ii) ions by an obvious color change from colorless to yellow. To investigate the sensing mechanism of H3L for Co 2+ ions, UV-vis absorption spectroscopy and single-crystal structural analysis were performed. The mixture of the ligand and cobalt(ii) ions displayed selective colorimetric sensing properties for weak acid anions, such as CO32-, Ac-, HCO3-, SO32-, and PO43-. Detailed 1H NMR experiments revealed that the basicity of the anions played an important role in the intensity of the interaction between the ligand and anions. The structures of compounds CoL (2), Co-Ac-HL (3), H4L- NO3 (4), and H4L-ClO4 (5) were also determined by single crystal diffraction studies. This journal is the Partner Organisations 2014.
- Zhou, Jing-Ru,Liu, Da-Peng,He, Yue,Kong, Xiang-Jian,Zhang, Zhi-Ming,Ren, Yan-Ping,Long, La-Sheng,Huang, Rong-Bin,Zheng, Lan-Sun
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Read Online
- DNA-Encoded Libraries: Hydrazide as a Pluripotent Precursor for On-DNA Synthesis of Various Azole Derivatives
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DNA-encoded combinatorial chemical library (DEL) technology, an approach that combines the power of genetics and chemistry, has emerged as an invaluable tool in drug discovery. Skeletal diversity plays a fundamental importance in DEL applications, and relies heavily on novel DNA-compatible chemical reactions. We report herein a phylogenic chemical transformation strategy using DNA-conjugated benzoyl hydrazine as a common versatile precursor in azole chemical expansion of DELs. DNA-compatible reactions deriving from the common benzoyl hydrazine precursor showed excellent functional group tolerance with exceptional efficiency in the synthesis of various azoles, including oxadiazoles, thiadiazoles, and triazoles, under mild reaction conditions. The phylogenic chemical transformation strategy provides DELs a facile way to expand into various unique chemical spaces with privileged scaffolds and pharmacophores.
- Ma, Fei,Li, Jie,Zhang, Shuning,Gu, Yuang,Tan, Tingting,Chen, Wanting,Wang, Shuyue,Ma, Peixiang,Xu, Hongtao,Yang, Guang,Lerner, Richard A.
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supporting information
p. 8214 - 8220
(2021/05/03)
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- Rh-Catalyzed Annulative Insertion of Terminal Olefin onto Pyridines via a C-H Activation Strategy Using Ethenesulfonyl Fluoride as Ethylene Provider
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A Rh(III)-catalyzed annulative insertion of ethylene onto picolinamides was achieved, providing a portal to a class of unique pyridine-containing molecules bearing a terminal olefin moiety for diversification. Application of this method for modification of Sorafenib was also accomplished.
- Li, Chen,Qin, Hua-Li
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p. 4495 - 4499
(2019/06/27)
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- Heterocyclic phosphodiesterase inhibitor and uses thereof
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The present invention belongs to the technical field of medicine, and particularly relates to a heterocyclic phosphodiesterase inhibitor compound represented by a formula (I), or a pharmaceutically acceptable salt and a stereoisomer thereof, and a pharmaceutical preparation, a pharmaceutical composition and applications of the compound, wherein R1, R2, R3, R4, ring A, m and n are defined in the specification. According to the present invention, the compound can be used for preparing drugs for treatment or prevention of diseases associated with PDE9 kinase.
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Paragraph 0170-0174; 0184-0188
(2019/11/04)
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- ARYL HYDROCARBON RECEPTOR MODULATORS AND USES THEREOF
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Provided are compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, isotopically labeled derivatives, polymorphs, and prodrugs thereof, wherein X1-X4, RX, RC, RB, n, and Ring A are as defined herein. The compounds may be aryl hydrocarbon receptor agonists or partial aryl hydrocarbon receptor agonists. Also provided are pharmaceutical compositions comprising a compound of Formula (I) and methods of using such compounds for treating diseases and conditions related to the activity of an aryl hydrocarbon receptor, such as, for example, inflammatory diseases, autoimmune diseases, metabolic disorders, and proliferative diseases.
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Paragraph 00455
(2019/10/29)
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- SUBSTITUTED BICYCLIC HETEROARYL COMPOUNDS AS RXR AGONISTS
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The present invention relates to certain substituted bicyclic compounds that are agonists of RXR and which are therefore useful in the treatment of certain disorders that can be prevented or treated by activation of this receptor. In addition the invention relates to the compounds, methods for their preparation, pharmaceutical compositions containing the compounds and the uses of these compounds in the treatment of certain disorders.
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Paragraph 0638
(2016/12/01)
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- NOVEL COMPOUNDS
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Disclosed are novel retinoid-related orphan receptor gamma (RORγ) modulators and their use in the treatment of diseases mediated by RORγ.
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Page/Page column 76
(2015/12/17)
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- Rhodium(III)-catalyzed oxidative olefination of picolinamides: Convenient synthesis of 3-alkenylpicolinamides
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A rhodium(III)-catalyzed selective olefination of picolinamide derivatives has been developed. The reaction shows high regioselectivity, low catalyst loading (0.5 mol%), high yield and good functional group tolerance, providing a convenient strategy for the synthesis of 3-alkenylpicolinamides.
- Zhou, Jun,Li, Bo,Qian, Zhen-Chao,Shi, Bing-Feng
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supporting information
p. 1038 - 1046
(2014/04/03)
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- Synthesis and structure-activity relationships of novel, potent, orally active hypoxia-inducible factor-1 inhibitors
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Hypoxia-inducible factor-1 (HIF-1) is the chief transcription factor regulating hypoxia-driven gene expression. HIF-1 overexpression is associated with poor prognosis in several cancers and therefore represents an attractive target for novel antitumor agents. We explored small molecule inhibitors of the HIF-1 pathway. Using high-throughput-screening, we identified benzanilide compound 1 (IC50= 560 nM) as a seed. Subsequent extensive derivatization led to the discovery of compounds 43a and 51d, with anti-HIF-1 activities in vitro (IC50= 21 and 0.47 nM, respectively), and in vivo. Additionally, 43a (12.5-100 mg/kg) also displayed in vivo anti-tumor efficacy, without influencing body weight.
- Nagao, Satoshi,Yamane, Yoshinobu,Funasaka, Setsuo,Tanaka, Keigo,Miyazaki, Kazuki,Kotake, Yoshihiko,Kamata, Jun-Ichi,Watanabe-Miyano, Saori,Toyama, Osamu,Ozawa, Yoichi,Mizui, Yoshiharu,Okamoto, Kiyoshi,Ito, Daisuke
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p. 5513 - 5529
(2014/12/10)
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- THERAPEUTIC COMPOUNDS
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The invention provides compounds of formulae (I), (II), (III), and (IV): and salts thereof, as well as pharmaceutical compositions comprising such compounds. The compounds are useful for treating cancers and Alzheimer's disease.
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Page/Page column 21
(2013/03/28)
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- A palladium-catalyzed enantioselective addition of arylboronic acids to cyclic ketimines
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Sly as Nicox: A palladium-catalyzed addition of arylboronic acids to ketimines has been developed to efficiently provide products in up to 99 % yield and 96 % ee. The reactions could be run under aerobic conditions and with unpurified trifluoroethanol (TFE). A pyrrolidine compound bearing a chiral α-tertiary amine was synthesized in several steps without loss of enantioselectivity. TFA=trifluoroacetate. Copyright
- Yang, Guoqiang,Zhang, Wanbin
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supporting information
p. 7540 - 7544
(2013/07/26)
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- Modeling, synthesis, and biological evaluation of potential retinoid X receptor (RXR) selective agonists: Novel analogues of 4-[1-(3,5,5,8,8- Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and (E)-3-(3-(1,2,3,4-tetrahydro-1,1,
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Three unreported analogues of 4-[1-(3,5,5,8,8-pentamethyl-5-6-7-8- tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), otherwise known as bexarotene, as well as four novel analogues of (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6- pentamethylnaphthalen-7-yl)-4-hydr
- Jurutka, Peter W.,Kaneko, Ichiro,Yang, Joanna,Bhogal, Jaskaran S.,Swierski, Johnathon C.,Tabacaru, Christa R.,Montano, Luis A.,Huynh, Chanh C.,Jama, Rabia A.,Mahelona, Ryan D.,Sarnowski, Joseph T.,Marcus, Lisa M.,Quezada, Alexis,Lemming, Brittney,Tedesco, Maria A.,Fischer, Audra J.,Mohamed, Said A.,Ziller, Joseph W.,Ma, Ning,Gray, Geoffrey M.,Van Der Vaart, Arjan,Marshall, Pamela A.,Wagner, Carl E.
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p. 8432 - 8454
(2013/12/04)
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- HETEROCYCLIC COMPOUND AND HEMATOPOIETIC STEM CELL AMPLIFIER
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An expansion agent for hematopoietic stem cells and/or hematopoietic progenitor cells useful for improvement in the efficiency of gene transfer into hematopoietic stem cells for gene therapy useful for treatment of various disorders is provided. An expansion agent for hematopoietic stem cells and/or hematopoietic progenitor cells containing a compound represented by the formula (I) (wherein X, Y, Z, Ar1, R1, R2, R3, R4, R5, R6 and R7 are as defined in the description), a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof, which can expand hematopoietic stem cells and/or hematopoietic progenitor cells.
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Page/Page column 58
(2012/04/23)
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- Enantioselective Fujiwara-Moritani indole and pyrrole annulations catalyzed by chiral palladium(II)-NicOx complexes
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The catalytic asymmetric Fujiwara-Moritani ring closures of several indole-and pyrrole-based cyclization precursors are reported. These unprecedented oxidative palladium(II)-catalyzed annulations allow for the formation of a stereogenic quaternary carbon atom, and decent levels of enantiocontrol are seen in 5-exo-trig cyclizations (54% ee for an indole and 76% ee for a pyrrole) while 6-exo-trig ring closures afford essentially racemic material. Novel oxazoline ligands with a nicotine platform (NicOx) are pivotal for good catalytic turnover as conventional PyOx ligands failed to produce acceptable chemical yields. The preparation of these NicOx ligands as well as the syntheses of the cyclization precursors are described in detail.
- Schiffner, Julia A.,Woeste, Thorsten H.,Oestreich, Martin
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supporting information; experimental part
p. 174 - 182
(2010/04/02)
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- TRICYCLIC AMIDE COMPOUND
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A compound represented by the following general formula (I): [wherein R1 represents hydrogen atom or a C1-6 alkyl group, A and B represent -(CH2)2-, -(CH2)3- or -(CH2)4/sub
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Page/Page column 13
(2010/06/15)
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- PIPERIDINE DERIVATIVES AS NK3 RECEPTOR ANTAGONISTS
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The present application relates to compounds of formula (I) wherein the definitions are as described in claim 1. It has been found that the present compounds are high potential NK-3 receptor antagonists for the treatment of depression, pain, psychosis, Pa
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Page/Page column 25
(2010/10/03)
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- Aroylguanidine-based factor Xa inhibitors: The discovery of BMS-344577
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We report the design and synthesis of a novel class of N,N′-disubstituted aroylguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The structure-activity relationships (SAR) investigation led to the discovery of the nicotinoyl guanidine 22 as a potent FXa inhibitor (FXa IC50 = 4 nM, EC2×PT = 7 μM). However, the potent CYP3A4 inhibition activity (IC50 = 0.3 μM) of 22 precluded its further development. Detailed analysis of the X-ray crystal structure of compound 22 bound to FXa indicated that the substituent at the 6-position of the nicotinoyl group of 22 would be solvent-exposed, suggesting that efforts to attenuate the unwanted CYP activity could focus at this position without affecting FXa potency significantly. Further SAR studies on the 6-substituted nicotinoyl guanidines resulted in the discovery of 6-(dimethylcarbamoyl) nicotinoyl guanidine 36 (BMS-344577, IC50 = 9 nM, EC2×PT = 2.5 μM), which was found to be a selective, orally efficacious FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models.
- Shi, Yan,Li, Chi,O'Connor, Stephen P.,Zhang, Jing,Shi, Mengxiao,Bisaha, Sharon N.,Wang, Ying,Sitkoff, Doree,Pudzianowski, Andrew T.,Huang, Christine,Klei, Herbert E.,Kish, Kevin,Yanchunas Jr., Joseph,Liu, Eddie C.-K.,Hartl, Karen S.,Seiler, Steve M.,Steinbacher, Thomas E.,Schumacher, William A.,Atwal, Karnail S.,Stein, Philip D.
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scheme or table
p. 6882 - 6889
(2010/07/03)
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- Discovery of novel diarylketoxime derivatives as selective and orally active melanin-concentrating hormone 1 receptor antagonists
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Optimization of the lead 2a led to the identification of a novel diarylketoxime class of melanin-concentrating hormone 1 receptor (MCH-1R) antagonists. Our focus was directed toward improvement of hERG activity and metabolic stability. The representative derivative 4b showed potent and dose-dependent body weight reduction in diet-induced obese (DIO) C57BL/6J mice after oral administration. The synthesis and structure-activity relationships of the novel diarylketoxime MCH-1R antagonists are described.
- Suzuki, Takao,Kameda, Minoru,Ando, Makoto,Miyazoe, Hiroshi,Sekino, Etsuko,Ito, Satoru,Masutani, Kouta,Kamijo, Kaori,Takezawa, Akihiro,Moriya, Minoru,Ito, Masahiko,Ito, Junko,Nakase, Kazuho,Matsushita, Hiroko,Ishihara, Akane,Takenaga, Norihiro,Tokita, Shigeru,Kanatani, Akio,Sato, Nagaaki,Fukami, Takehiro
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scheme or table
p. 5339 - 5345
(2010/06/16)
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- Monofluoroalkyl derivatives
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The present invention provides certain monofluoroalkyl derivatives useful for potentiating glutamate receptor function in a mammal and therefore, useful for treating a wide variety of conditions, such as psychiatric and neurological disorders.
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Page/Page column 95
(2010/10/20)
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- BENZISOTHIAZOLES USEFUL FOR TREATING OR PREVENTING HCV INFECTION
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The present invention relates to benzisothiazoles and pharmaceutical compositions thereof that inhibit replication and/or proliferation of HCV virus. The present invention also relates to the use of the benzisothiazoles and pharmaceutical compositions comprising the compounds to treat or prevent HCV infections.
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Page/Page column 125-126
(2010/11/23)
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- Synthesis of a novel carboxy functionalized PyOX-ligand
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A short and convenient synthesis of a carboxy functionalized PyOX-core is presented. The carboxy functionality offers a wide variety of possibilities for further modification. In this paper, the core is functionalized with a mercapto tail.
- Oila, Markku J.,Tois, Jan E.,Koskinen, Ari M.P.
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p. 967 - 969
(2007/10/03)
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- Ligand creation via linking - A rapid and convenient method for construction of novel supported PyOX-ligands
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A novel supported amino alcohol linker was synthesized and utilized for attachment of picolinic acid derivatives onto different supports. When the resin bound molecule was further activated, the PyOX-moiety could be constructed reliably in enantiopure form. Furthermore, an efficient Pd-catalyzed modification of a picolinic acid derivative is presented.
- Oila, Markku J.,Tois, Jan E.,Koskinen, Ari M.P.
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p. 10748 - 10756
(2007/10/03)
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- A New Synthesis of Lysergic Acid
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(Equation presented) (±)-Lysergic acid (1) has been synthesized via an economical 8-step route from 4-bromoindole and isocinchomeronic acid without the need to protect the indole during the synthesis. Initial efforts to form the simpler 3-acylindole derivatives first and then cyclize these were unsuccessful in the cyclization step.
- Hendrickson, James B.,Wang, Jian
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- Determinants of retinoid X receptor transcriptional antagonism
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The synthesis and bioactivity of the retinoid X receptor (RXR) antagonist 4-[(3′-n-butyl-5′,6′,7′,8′-tetrahydro-5′, 5′,8′,8′-tetramethyl-2′-naphthalenyl)(cyclopropylidene) methyl]benzoic acid and several heteroatom-substituted analogues are described. Lig
- Cavasotto, Claudio N.,Liu, Gang,James, Sharon Y.,Hobbs, Peter D.,Peterson, Valerie J.,Bhattacharya, Ananyo A.,Kolluri, Siva K.,Zhang, Xiao-Kun,Leid, Mark,Abagyan, Ruben,Liddington, Robert C.,Dawson, Marcia I.
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p. 4360 - 4372
(2007/10/03)
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- Methods of treating periodontal disease
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The present invention relates to novel compounds of formula (I): processes for their preparation, pharmaceutical formulations containing them, and their use in medicine, particularly in the prophylaxis and treatment of inflammatory conditions, immune disorders, septic shock circulatory disorders, and gastrointestinal inflammation and disorders.
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- Synthesis of novel retinoid X receptor-selective retinoids
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Retinoids 1-5 have been identified as potent RXR agonists for evaluation in the treatment of non-insulin-dependent (type II) diabetes mellitus (NIDDM). Highly convergent syntheses of 1-5 have been developed. The core tetrahydronaphthalene 7, employed in the synthesis of 1 and 2, was prepared in 98% yield using an AlCl3-catalyzed (0.03 equiv) Friedel-Crafts alkylation of toluene with 2,5-dichloro-2,5-dimethylhexane 6. A nitromethane-mediated Fridel-Crafts acylation of 7 with chloromethylnicotinate 9 was developed to prepare ketone 10 in 68% yield. Chelate-controlled addition of MeMgCl to 10 followed by dehydration afforded olefin 11 in 65% yield. Cyclopropanation of 11 with trimethylsulfoxonium ylide, followed by saponification, completed a five-step synthesis of 1 in 33% yield. FeCl3-catalyzed (0.05 equiv) Friedel-Crafts acylation of 7 with chloromethyl-terephthalate 14 afforded ketone 15 in 81% yield. Saponification of 15 and reaction with 50% aqueous NH2OH in AcOH afforded a 9:1 mixture of cis and trans oximes, from which the desired cis-oxime 2 was isolated in 43% yield. The core bromo-dihydronaphthalene 29 required for the synthesis of 3-5 was prepared by a Shapiro reaction. Transmetalation of 29 and reaction with Weinreb amides 30b or 36 afforded ketones 32 and 37, which were converted into 3-5 using chemistry comparable to the tetrahydronaphthylene series. Suzuki coupling of boronic acids 41 and 42 with vinyl triflate 43 provided an alternative approach to the synthesis of this class of compounds.
- Faul,Ratz,Sullivan,Trankle,Winneroski
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p. 5772 - 5782
(2007/10/03)
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- Retinoidal pyrimidinecarboxylic acids. Unexpected diaza-substituent effects in retinobenzoic acids
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Several pyridine- and pyrimidine-carboxylic acids were synthesized as ligand candidates for retinoid nuclear receptors, retinoic acid receptors (RARs) and retinoic X receptors (RXRs). Although the pyridine derivatives, 6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]pyridine- 3-carboxylic acid (2b) and 6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido]pyridin e-3-carboxylic acid (5b) are more potent than the corresponding benzoic acid-type retinoids, Am80 (2a) and Am580 (5a), the replacement of the benzene ring of Am580 (5a), Am555 (6a), or Am55 (7a) with a pyrimidine ring caused loss of the retinoidal activity both in HL-60 cell differentiation assay and in RAR transactivation assay using COS-1 cells. On the other hand, pyrimidine analogs (PA series, 10 and 11) of potent RXR agonists (retinoid synergists) with a diphenylamine skeleton (DA series, 8 and 9) exhibited potent retinoid synergistic activity in HL-60 cell differentiation assay and activated RXRs. Among the synthesized compounds, 2-[N-n-propyl-N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)amino] pyrimidine-5-carboxylic acid (PA013, 10e) is most active retinoid synergist in HL-60 assay.
- Ohta, Kiminori,Kawachi, Emiko,Inoue, Noriko,Fukasawa, Hiroshi,Hashimoto, Yuichi,Itai, Akiko,Kagechika, Hiroyuki
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p. 1504 - 1513
(2007/10/03)
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- Design and synthesis of potent retinoid X receptor selective ligands that induce apoptosis in leukemia cells
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Structural modifications of the retinoid X receptor (RXR) selective compound 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2- naphthyl)ethenyl]benzoic acid (LGD1069), which is currently in phase I/IIA clinical trials for cancer and dermatological indications, have resulted in the identification of increasingly potent retinoids with > 1000-fold selectivity for the RXRs. This paper describes the design and preparation of a series of RXR selective retinoids as well as the biological data obtained from cotransfection and competitive binding assays which were used to evaluate their potency and selectivity. The most potent and selective of the analogs is 6-[1(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2- yl)cyclopropyl]nicotinic acid (12d; LG100268). This compound has proven useful for investigating RXR dependent biological pathways including the induction of programmed cell death (PCD) and transglutaminase (TGase) activity. Our studies indicate that the induction of PCD and TGase in human leukemic myeloid cells is dependent upon activation of RXR-mediated pathways.
- Boehm,Zhang,Zhi,McClurg,Berger,Wagoner,Mais,Suto,Davies,Heyman,Nadzan
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p. 3146 - 3155
(2007/10/03)
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