- Synthesis of pharmaceutical drugs from cardanol derived from cashew nut shell liquid
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Cardanol from cashew nut shell liquid extracted from cashew nut shells was successfully converted into various useful pharmaceutical drugs, such as norfenefrine, rac-phenylephrine, etilefrine and fenoprofene. 3-Vinylphenol, the key intermediate for the synthesis of these drugs, was synthesised from cardanol by ethenolysis to 3-non-8-enylphenol followed by isomerising ethenolysis. The metathesis reaction worked very well using DCM, but the greener solvent, 2-methyl tetrahydrofuran, also gave very similar results. Hydroxyamination of 3-vinylphenol with an iron porphyrin catalyst afforded norfenefrine in over 70% yield. Methylation and ethylation of norfenefrine afforded rac-phenylephrine and etilefrine respectively. A sequence of C-O coupling, isomerising metathesis and selective methoxycarbonylation afforded fenoprofene in good yield. A comparison of the routes described in this paper with some standard literature syntheses of 3-vinylphenol and of the drug molecules shows significant environmental advantages in terms of precursors, yields, number of steps, conditions and the use of catalysts. The Atom Economy of our processes is generally similar or significantly superior to those of the literature processes mainly because the side products produced during synthesis of 3-vinylphenol (1-octeme, 1,4-cyclohexadiene and propene) are easily separable and of commercial value, especially as they are bio-derived. The E Factor for the production of 2-vinylphenol by our process is also very low compared with those of previously reported syntheses.
- Shi, Yiping,Kamer, Paul C. J.,Cole-Hamilton, David J.
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p. 1043 - 1053
(2019/03/12)
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- Structure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase Inhibitors
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In recent years, thymidylate kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK (MtTMPK) inhibitors, and reported here the design of a novel series of non-nucleoside inhibitors of MtTMPK. The inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure-activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, experiments with efflux pump inhibitors and efflux pump knockout mutants were performed. The minimum inhibitory concentrations of particular inhibitors increased significantly when determined for the efflux pump mmr knockout mutant, which partly explains the observed dissonance.
- Song, Lijun,Merceron, Romain,Gracia, Bego?a,Quintana, Ainhoa Lucía,Risseeuw, Martijn D. P.,Hulpia, Fabian,Cos, Paul,Aínsa, José A.,Munier-Lehmann, Hélène,Savvides, Savvas N.,Van Calenbergh, Serge
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p. 2753 - 2775
(2018/04/23)
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- Design of CID-cleavable protein cross-linkers: Identical mass modifications for simpler sequence analysis
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The cross-linking Mass Spectrometry (XL-MS) technique has enormous potential for studying the interactions between proteins, and it can provide detailed structural information about the interaction interfaces in large protein complexes. Such information h
- Kandur, Wynne V.,Kao, Athit,Vellucci, Danielle,Huang, Lan,Rychnovsky, Scott D.
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p. 9793 - 9807
(2015/10/05)
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- COMPOUND EXHIBITING REGULATORY ACTIVITY ON LYSOPHOSPHATIDYLSERINE RECEPTOR FUNCTION
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The object of the present invention is to provide a compound having a lysophosphatidylserine receptor function modulation activity or a salt thereof. A compound having a lysophosphatidylserine receptor function modulation activity or a salt thereof, or a pharmaceutical composition or a lysophosphatidylserine receptor function moderator containing such compound or salt is provided by the present invention.
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Paragraph 0217
(2015/12/19)
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- Structure-activity relationships of lysophosphatidylserine analogs as agonists of G-protein-coupled receptors GPR34, P2Y10, and GPR174
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Lysophosphatidylserine (LysoPS) is an endogenous lipid mediator generated by hydrolysis of membrane phospholipid phosphatidylserine. Recent ligand screening of orphan G-protein-coupled receptors (GPCRs) identified two LysoPS-specific human GPCRs, namely, P2Y10 (LPS2) and GPR174 (LPS3), which, together with previously reported GPR34 (LPS1), comprise a LysoPS receptor family. Herein, we examined the structure-activity relationships of a series of synthetic LysoPS analogues toward these recently deorphanized LysoPS receptors, based on the idea that LysoPS can be regarded as consisting of distinct modules (fatty acid, glycerol, and l-serine) connected by phosphodiester and ester linkages. Starting from the endogenous ligand (1-oleoyl-LysoPS, 1), we optimized the structure of each module and the ester linkage. Accordingly, we identified some structural requirements of each module for potency and for receptor subtype selectivity. Further assembly of individually structure-optimized modules yielded a series of potent and LysoPS receptor subtype-selective agonists, particularly for P2Y10 and GPR174.
- Ikubo, Masaya,Inoue, Asuka,Nakamura, Sho,Jung, Sejin,Sayama, Misa,Otani, Yuko,Uwamizu, Akiharu,Suzuki, Keisuke,Kishi, Takayuki,Shuto, Akira,Ishiguro, Jun,Okudaira, Michiyo,Kano, Kuniyuki,Makide, Kumiko,Aoki, Junken,Ohwada, Tomohiko
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supporting information
p. 4204 - 4219
(2015/06/08)
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- Ti/Ni-mediated inter- and intramolecular conjugate addition of aryl and alkenyl halides and triflates
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In this work, we show that the unique combination of a nickel catalyst and Cp2TiCl allows the direct conjugate addition of aryl and alkenyl iodides, bromides, and to a lesser extent, chlorides and triflates to α,β-unsaturated carbonyls at room temperature, without requiring the previous formation of an organometallic nucleophile. The reaction proceeds inter- and intramolecularly with good functional group compatibility, which is key for the development of free protecting group methodologies. Carbo- and heterocycles of five- and six-membered rings are obtained in good yields. Moreover, some insights about the mechanism involved have been obtained from cyclic voltammetry, UV-vis, and HRTEM measurements.
- Marquez, Irene R.,Miguel, Delia,Millan, Alba,Marcos, M. Luisa,De Cienfuegos, Luis Alvarez,Campana, Araceli G.,Cuerva, Juan M.
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p. 1529 - 1541
(2014/03/21)
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- AROMATIC RING COMPOUND
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Provided is an aromatic ring compound having a GPR40 agonist activity. A compound represented by the formula (I): wherein each symbol is as described in the DESCRIPTION, or a salt thereof has a GPR40 agonist activity, and is useful as an agent for the prophylaxis or treatment of diabetes and the like.
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- Novel Compounds
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There is provided a compound of formula (I): processes for the manufacture thereof, pharmaceutical compositions thereof and uses in therapy.
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Page/Page column 76-77; 87
(2008/06/13)
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- Discovery of azetidinone acids as conformationally-constrained dual PPARα/γ agonists
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A novel class of azetidinone acid-derived dual PPARα/γ agonists has been synthesized for the treatment of diabetes and dyslipidemia. The preferred stereochemistry in this series for binding and functional agonist activity against both PPARα and PPARγ receptors was shown to be 3S,4S. Synthesis, in vitro and in vivo activities of compounds in this series are described. A high-yielding method for N-arylation of azetidinone esters is also described.
- Wang, Wei,Devasthale, Pratik,Farrelly, Dennis,Gu, Liqun,Harrity, Thomas,Cap, Michael,Chu, Cuixia,Kunselman, Lori,Morgan, Nathan,Ponticiello, Randy,Zebo, Rachel,Zhang, Litao,Locke, Kenneth,Lippy, Jonathan,O'Malley, Kevin,Hosagrahara, Vinayak,Zhang, Lisa,Kadiyala, Pathanjali,Chang, Chiehying,Muckelbauer, Jodi,Doweyko, Arthur M.,Zahler, Robert,Ryono, Denis,Hariharan, Narayanan,Cheng, Peter T.W.
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p. 1939 - 1944
(2008/09/20)
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- A short route to the macrocyclic core of biaryl ether-based cyclopeptides
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A new route based on an intramolecular Horner-Wadsworth-Emmons type olefination of amidophosphonates has been developed for the construction of a 17-membered macrocyclic scaffold related to some biologically important biaryl ether-based cyclic peptides.
- Chattopadhyay, Shital K.,Bandyopadhyay, Ayan,Pal, Benoy K.
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p. 3655 - 3659
(2008/02/03)
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- COMPOUNDS AND COMPOSITIONS AS PPAR MODULATORS
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The invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with the activity of the Peroxisome Proliferator-Activated Receptor (PPAR) families.
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Page/Page column 49-50
(2008/06/13)
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- COMPOUNDS AND COMPOSITIONS AS PPAR MODULATORS
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The invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with the activity of the Peroxisome Proliferator-Activated Receptor (PPAR) families.
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Page/Page column 34
(2010/11/27)
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- 3,4,5-Trisubstituted isoxazoles as novel PPARδ agonists. Part 2
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A series of PPARδ-selective agonists was investigated and optimized for a favorable in vivo pharmacokinetic profile. Isoxazole LCI765 (17d) was found to be a potent and selective PPARδ agonist with good in vivo PK properties in mouse (Cmax = 5.1 μM, t1/2 = 3.1 h). LCI765 regulated expression of genes involved in energy homeostasis in relevant tissues when dosed orally in C57BL6 mice. A co-crystal structure of compound LCI765 and the LBD of PPARδ is discussed.
- Epple, Robert,Azimioara, Mihai,Russo, Ross,Xie, Yongping,Wang, Xing,Cow, Christopher,Wityak, John,Karanewsky, Don,Bursulaya, Badry,Kreusch, Andreas,Tuntland, Tove,Gerken, Andrea,Iskandar, Maya,Saez, Enrique,Martin Seidel,Tian, Shin-Shay
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p. 5488 - 5492
(2007/10/03)
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- BICYCLIC DERIVATIVES AS PPAR MODULATORS
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The present invention is directed to compounds represented by the following structural formula, Formula (I), and stereoisomers, pharmaceutically acceptable salts, solvates and hydrates thereof, wherein: (a) R2 is selected from the group consisting of C0-C8 alkyl and C1-4- heteroalkyl; (b) X is selected from the group consisting of a single bond, O, S, S(O)2 and N; (c) U is an aliphatic linker wherein one carbon atom of the aliphatic linker is optionally replaced with O, NH or S, and wherein such aliphatic linker is optionally substituted with from one to four substituents each independently selected from R30; (d) Y is selected from the group consisting of C, O, S, NH and a single bond; and (e) E is C(R3)(R4)A or A.
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Page/Page column 52
(2008/06/13)
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- 1,2,4-TRIAZINES DERIVATIVES, PREPARATION THEREOF AND USE THEREOF IN HUMAN THERAPEUTICS
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The invention relates to 3,5-dioxo-(2H,4H)-1,2,4-triazine derivatives of general formulae (I or II), in which in particular: R1 represents hydrogen, a linear or branched C1-C6 alkyl or alkoxy radical, a C5-C6 cycloalkyl radical, a phenyl (C1-C2) alkyl radical or a phenyl radical;-R2 represents hydrogen, a linear or branched Cl-C7alkyl radical, or a C1-C6 alkyl radical substituted with groups such as trifluoromethyl or phenyl;- linker represents a C2-C6 alkyl chain or -(CH2)n-O- (n = 2 to 5), - R3 represents a group of general formula below for which X = O, linker can be connected to the ortho-, meta- or para-positions of the aromatic of the group R3, R4, R5, R6, R7 and R8 represent hydrogen or fluorine, R9, Rio and R11 represent hydrogen or a linear or branched Cl-C5 alkyl group, in particular R9 and Rio represent the methyl group and R11 represents hydrogen or the ethyl group.
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Page/Page column 24-25
(2010/02/13)
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- FUSED HETEROCYCLIC DERIVATIVES AS PPAR MODULATORS
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The present invention is directed to compounds represented by the following structural formula, Formula I: wherein (a) X is selected from the group consisting of a single bond, O, S. S(O)2 and N; (b) U is an aliphatic linker; (c) Y is selected from the group consisting of C, O, S, NH and a single bond; (d) E is C(R3) (R4)A or A and wherein (i) A is selected from the group consisting of carboxyl, tetrazole, C1-C6 alkylnitrile, carboxamidek, sulfonamide and acylsulfonamide; (e) B is selected from the group consisting of S, O, C, and N; (f) Z is selected from the group consisting of N and C; with the proviso that when B is C then Z is N.
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- THIOPHENE DERIVATIVE PPAR MODULATORS
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The present invention is directed to compounds represented by the following structural formula, Formula I: and stereoisomers, pharmaceutically acceptable salts, solvates and hydrates thereof, wherein: (a) X is selected from the group consisting of O, S, S(O)2, N, and a bond; (b) U is an aliphatic linker wherein one carbon atom of the aliphatic linker may be replaced with O, NH or S, and wherein such aliphatic linker is optionally substituted with R30; (c) Y is selected from the group consisting of C, O, S, NH and a single bond; and (d) E is C(R3)(R4)A or A.
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- Acylquanidine derivatives, method for preparing same, application as medicines and pharmaceutical compositions containing them
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Acylquanidines of the formula wherein the substituents are defined as in the specification which are antagonists of the vitronectin receptor and inhibitors of cell adhesion and bone resorption mediated by the osteoclasts.
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- Aryl carboxylic acid and aryl tetrazole derivatives as IP receptor modulators
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This invention relates to compounds which are generally IP receptor modulators, particularly IP receptor agonists, and which are represented by Formula I: wherein R1, R2, R3, R4, R5, A, and B are as defined in the specification, and individual isomers, racemic or non-racemic mixtures of isomers, and pharmaceutically acceptable salts or solvates thereof. The invention further relates to pharmaceutical compositions containing such compounds and methods for their use as therapeutic agents.
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- Amide derivatives and intermediates for the synthesis thereof
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Novel compounds which are amide derivatives represented by general formula (I) and medicinal preparations containing the same having an eosinophilic infiltration inhibitory effect based on a potent interferon (α,γ)-inducing activity and an exellent percutaneous absorbability and being efficacious in treating allergic inflammatory diseases such as atopic dermatitis, various tumors and viral diseases. In said formula, each symbol has the following meaning: R1 and R2 : each lower alkyl, etc.; X and Y: independently representing each oxygen, NR4, CR5 etc. (wherein R4 and R5 independently represent each hydrogen, an aromatic group, etc.); Z: an aromatic ring or heterocycle; R3 : hydrogen, lower alkoxy, etc.; g, i and k: independently representing each an integer of from 0 to 6; h, i and l: independently representing each an integer of 0 or 1; m: an integer of from 0 to 5; and n: an integer of from 2 to 12.
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- Development of an Immunochemical Technique for the Analysis of Trichlorophenols Using Theoretical Models
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An immunoassay has been developed for trichlorophenol analysis on the basis of theoretical chemistry modeling studies. These data have allowed us to choose the optimum chemical structure of the immunizing hapten according to realistic similarities with the target analyte. The synthesis of this hapten and the subsequent application of an appropriate immunization protocol have lead to the production of poryclonal antibodies against the target analyte. A homologous direct competitive ELISA has been developed that can be carried out in about 1 h. It has a limit of detection of 0.2 ± 0.06 μg/L (1.01 ± 0.3 nM) and it has been proven to tolerate a wide range of ionic strengths and pH values. Thus, the assay has acceptable features in samples with ionic strength between 4 and 56 mS/cm and pH values between 5.5 and 9.5. Studies on the selectivity of this immunoassay have demonstrated a high recognition of the corresponding brominated analogues. Other phenolic compounds do not interfere significantly in the analysis of 2,4,6-trichorophenol using this immunochemical technique. The accuracy of the assay has been evaluated using certified and spiked samples.
- Galve, Roger,Camps, Francisco,Sanchez-Baeza, Francisco,Marco, M.-Pilar
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p. 2237 - 2246
(2007/10/03)
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- Cyclic nitrones
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The present invention is directed to novel cyclic nitrones and their use in the prevention of oxidation tissue damage by free radicals, their use in the treatment of a number of disease states in which radicals either damage or destroy tissues via oxidation, and pharmaceutical compositions containing these cyclic nitrones.
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- Lipase-catalysed chemoselective monoacetylation of hydroxyalkylphenols and chemoselective removal of a single acetyl group from their diacetates
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It was demonstrated that Pseudomonas cepacia PS lipase adsorbed on Celite, has the ability to catalyse the chemoselective monoacetylation of various hydroxyalkylphenols or the chemoselective removal of a single acetyl group from the corresponding acetate.
- Allevi, Pietro,Ciuffreda, Pierangela,Longo, Alessandra,Anastasia, Mario
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p. 2915 - 2924
(2007/10/03)
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