- Supramolecularly regulated copper-bisoxazoline catalysts for the efficient insertion of carbenoid species into hydroxyl bonds
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The catalytic insertion of copper carbenoids into O-H bonds affords synthetically useful α-alkyl/aryl-α-alkoxy/aryloxy derivatives. Herein, the design, preparation and application of supramolecularly regulated copper(i) complexes of bisoxazoline ligands is reported. We have demonstrated that the catalytic performance of these systems can be modulated by the use of an external molecule (i.e.the regulation agent), which interacts with a polyethyleneoxy chain on the ligand (i.e.the regulation site)viasupramolecular interactions. This approach has been applied to an array of structurally diverse alcohols (cycloalkyl, alkyl and aryl derivatives). Moreover, we have used this methodology to synthesise advanced synthetic intermediates of biologically relevant compounds.
- Iniesta, Ester,Vidal-Ferran, Anton
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p. 6364 - 6367
(2020/06/21)
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- INHIBITORS TO TARGET HIV-1 NEF-CD80/CD86 INTERACTIONS FOR THERAPEUTIC INTERVENTION
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The compounds of Formula I, II, and III along with their stereoisomers, pharmaceutically acceptable salts, polymorphs, solvates and hydrates thereof are described in the present disclosure. The said compounds restore immune activation in case of infections or a disease associated with an HIV infection in a subject in need thereof.
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Paragraph 000169; 000186
(2020/03/05)
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- PRMT5 INHIBITORS AND USES THEREOF
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Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting PRMT5 activity. Methods of using the compounds for treating PRMT5-mediated disorders are also described.
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Paragraph 0265-0266
(2019/04/05)
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- (C6F5)3B Catalyzed Chemoselective and ortho-Selective Substitution of Phenols with α-Aryl α-Diazoesters
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The development of an efficient method for the site-selective substitution of unprotected phenols has long been considered as an attractive but challenging task. Herein, we describe a highly chemo- and ortho-selective substitution reaction of phenols with α-aryl α-diazoacetates with commercially available (C6F5)3B as the catalyst. This reaction proceeds under simple and mild conditions with high efficiency, it features a wide substrate scope and can be easily scaled up.
- Yu, Zhunzhun,Li, Yongfeng,Shi, Jiameng,Ma, Ben,Liu, Lu,Zhang, Junliang
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supporting information
p. 14807 - 14811
(2016/11/23)
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- PRMT5 INHIBITORS CONTAINING A DIHYDRO- OR TETRAHYDROISOQUINOLINE AND USES THEREOF
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Described herein are compounds of Formula (A), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting PRMT5 activity. Methods of using the compounds for treating PRMT5- mediated disorders are also described.
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Paragraph 00274
(2014/07/08)
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- Resolution of (R, S)-ethyl-2-(4-hydroxyphenoxy) propanoate using lyophilized mycelium of Aspergillus oryzae WZ007
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The mycelium of Aspergillus oryzae WZ007 was successfully developed to kinetic resolution of (R, S)-ethyl-2-(4-hydroxyphenoxy) propanoate ((R, S)-EHPP) for production of (R)-ethyl-2-(4-hydroxyphenoxy) propanoate ((R)-EHPP). The key biocatalytic process parameters (pH, temperature, rotation speed and substrate concentration) were optimized. Under the optimum conditions, the optical purity of (R)-EHPP was improved up to >99% when the conversion was above 49%. A. oryzae WZ007 whole-cell lipase exhibited high reaction capacity, enantioselectivity and good reusability. The tolerable substrate concentration was 0.5 mol/L, and dry mycelium of A. oryzae WZ007 maintains over 80% of its initial activity after eight repeating cycles. Therefore the enzymatic preparation of (R)-EHPP route was suitable for industrial application.
- Zheng, Jian-Yong,Wu, Jia-Yu,Zhang, Yin-Jun,Wang, Zhao
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- Optimization of benzoxazole-based inhibitors of Cryptosporidium parvum inosine 5′-monophosphate dehydrogenase
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Cryptosporidium parvum is an enteric protozoan parasite that has emerged as a major cause of diarrhea, malnutrition, and gastroenteritis and poses a potential bioterrorism threat. C. parvum synthesizes guanine nucleotides from host adenosine in a streamlined pathway that relies on inosine 5′-monophosphate dehydrogenase (IMPDH). We have previously identified several parasite-selective C. parvum IMPDH (CpIMPDH) inhibitors by high-throughput screening. In this paper, we report the structure-activity relationship (SAR) for a series of benzoxazole derivatives with many compounds demonstrating CpIMPDH IC50 values in the nanomolar range and >500-fold selectivity over human IMPDH (hIMPDH). Unlike previously reported CpIMPDH inhibitors, these compounds are competitive inhibitors versus NAD +. The SAR study reveals that pyridine and other small heteroaromatic substituents are required at the 2-position of the benzoxazole for potent inhibitory activity. In addition, several other SAR conclusions are highlighted with regard to the benzoxazole and the amide portion of the inhibitor, including preferred stereochemistry. An X-ray crystal structure of a representative E·IMP·inhibitor complex is also presented. Overall, the secondary amine derivative 15a demonstrated excellent CpIMPDH inhibitory activity (IC 50 = 0.5 ± 0.1 nM) and moderate stability (t1/2 = 44 min) in mouse liver microsomes. Compound 73, the racemic version of 15a, also displayed superb antiparasitic activity in a Toxoplasma gondii strain that relies on CpIMPDH (EC50 = 20 ± 20 nM), and selectivity versus a wild-type T. gondii strain (200-fold). No toxicity was observed (LD 50 > 50 μM) against a panel of four mammalian cells lines.
- Gorla, Suresh Kumar,Kavitha, Mandapati,Zhang, Minjia,Chin, James En Wai,Liu, Xiaoping,Striepen, Boris,Makowska-Grzyska, Magdalena,Kim, Youngchang,Joachimiak, Andrzej,Hedstrom, Lizbeth,Cuny, Gregory D.
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p. 4028 - 4043
(2013/06/27)
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- An application of second-order UV-derivative spectrophotometry for study of solvolysis of a novel fluocinolone acetonide ester
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A novel topical corticosteroid FA-21-PhP, 2-phenoxypropionate ester of fluocinolone acetonide, has been synthesized in order to investigate the possibility of decreasing systemic side effects. In this study model system for in vitro solvolytic reaction of FA-21-PhP has been analyzed in ethanol/water (90:10, v/v) with excess of sodium hydrogen carbonate. The selected conditions have been used as in vitro model for activation of corticosteroid C-21 ester prodrug. The second-order derivative spectrophotometric method (DS) using zero-crossing technique was developed for monitoring ternary mixture of solvolysis. Fluocinolone acetonide (FA) as a solvolyte was determined in the mixture in the concentration range 0.062-0.312 mM using amplitude 2D274.96. Experimentally determined LOD value was 0.0295 mM. The accuracy of proposed DS method was confirmed with HPLC referent method. Peak area of parent ester FA-21-PhP was used for solvolysis monitoring to ensure the initial stage of changes. Linear relationship in HPLC assay for parent ester was obtained in the concentration range 0.054-0.54 mM, with experimentally determined LOD value of 0.0041 mM. Investigated solvolytic reaction in the presence of excess of NaHCO3 proceeded via a pseudo-first-order kinetic with significant correlation coefficients 0.9891 and 0.9997 for DS and HPLC, respectively. The values of solvolysis rate constant calculated according to DS and HPLC methods are in good accordance 0.038 and 0.043 h-1, respectively.
- Markovic, Bojan,Vladimirov, Sote,Cudina, Olivera,Savic, Vladimir,Karljikovic-Rajic, Katarina
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experimental part
p. 930 - 935
(2010/04/01)
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- PYRIMIDINYL-PROPIONIC ACID DERIVATIVES AND THEIR USE AS PPAR AGONISTS
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The present invention disclosed compounds of Structural Formula (I), and enantiomer, racemic body, pharmaceutically acceptable salts, solvates or hydrates thereof, wherein variable groups are as defined within, as well as methods for preparing such compou
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Page/Page column 13
(2010/10/03)
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- Design, synthesis, and pharmacological effects of structurally simple ligands for MT1 and MT2 melatonin receptors
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A series of phenoxyalkyl and phenylthioalkyl amides were prepared as melatoninergic ligands. Modulation of affinity of the newly synthesized compound by applying SARs around the terminal amide moiety, the alkyl chain, and the methoxy group on the aromatic ring provides compounds with nanomolar affinity for both melatonin receptor subtypes. Affinity towards MT1 and MT2 receptors were modulated also exploiting chirality. The investigation of intrinsic activity revealed that all the tested compounds behave as full or partial agonists.
- Carocci, Alessia,Catalano, Alessia,Lovece, Angelo,Lentini, Giovanni,Duranti, Andrea,Lucini, Valeria,Pannacci, Marilou,Scaglione, Francesco,Franchini, Carlo
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experimental part
p. 6496 - 6511
(2010/10/02)
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- PYRIMIDINYL-PROPIONIC ACID DERIVATIVES AND THEIR USE AS PPAR AGONISTS
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The present invention disclosed compounds of Structural Formula (I), and enantiomer, racemic body, pharmaceutically acceptable salts, solvates or hydrates thereof, wherein variable groups are as defined within, as well as methods for preparing such compou
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Page/Page column 19
(2009/05/30)
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- Discovery of novel dual functional agent as PPARγ agonist and 11β-HSD1 inhibitor for the treatment of diabetes
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PPARγ and 11β-HSD1 are attractive therapeutic targets for type 2 diabetes. However, PPARγ agonists induce adipogenesis, which causes the side effect of weight gain, whereas 11β-HSD1 inhibitors prevent adipogenesis and may be beneficial for the treatment of obesity in diabetic patients. For the first time, we designed, synthesized a series of α-aryloxy-α-methylhydrocinnamic acids as dual functional agents which activate PPARγ and inhibit 11β-HSD1 simultaneously. The compound 11e exhibited the most potent inhibitory activity compared to that of the lead compound 2, with PPARγ (EC50 = 6.76 μM) and 11β-HSD1 (IC50 = 0.76 μM) in vitro. Molecular modeling study for compound 11e was also presented. Compound 11e showed excellent efficacy for lowering glucose, triglycerides, body fat, in well established mice and rats models of diabetes and obesity and had a favorable ADME profile.
- Ye, Yang-liang,Zhou, Zhou,Zou, Han-jun,Shen, Yu,Xu, Ti-fei,Tang, Jing,Yin, Hua-zhong,Chen, Min-li,Leng, Ying,Shen, Jian-hua
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scheme or table
p. 5722 - 5732
(2009/12/28)
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- Stereospecific synthesis and bio-activity of novel β3-adrenoceptor agonists and inverse agonists
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Since it is widely distributed into the body, β3-adrenoceptor is becoming an attractive target for the treatment of several pathologies such as obesity, type 2 diabetes, metabolic syndrome, cachexia, overactive bladder, ulcero-inflammatory disorder of the gut, preterm labour, anxiety and depressive disorders, and heart failure. New compounds belonging to the class of arylethanolamines bearing one or two stereogenic centres were prepared in good yields as racemates and optically active forms. They were, then, evaluated for their intrinsic activity towards β3-adrenoceptor and their affinity for β1- and β2-adrenergic receptors. Stereochemical features were found to play a crucial role in determining the behaviour of such compounds. In particular, α-racemic, (αR)- and (αS)-2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}-2- methylpropanoic acid, (α-rac, β-rac)-, (αR, βS)- and (αR, βR)- 2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}propanoic acid were found to be endowed with β3-adrenoceptor agonistic activity. Whereas, (αS, βS)- and (αS, βR)-2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}propanoic acid behaved as β3-adrenoceptor inverse agonists. Such compounds showed no affinity for β1- and β2-adrenergic receptor, respectively. Thus, resulting highly selective β3-adrenoceptor ligands.
- Perrone, Maria Grazia,Santandrea, Ernesto,Bleve, Laura,Vitale, Paola,Colabufo, Nicola Antonio,Jockers, Ralf,Milazzo, Ferdinando Maria,Sciarroni, Anna Floriana,Scilimati, Antonio
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p. 2473 - 2488
(2008/09/21)
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- Conversion of human-selective PPARα agonists to human/mouse dual agonists: A molecular modeling analysis
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To understand the species selectivity in a series of α-methyl- α-phenoxy carboxylic acid PPARα/γ dual agonists (1-11), structure-based molecular modeling was carried out in the ligand binding pockets of both human and mouse PPARα. This study suggested that interaction of both 4-phenoxy and phenyloxazole substituents of these ligands with F272 and M279 in mouse PPARα leads to the species-specific divergence in ligand binding. Insights obtained in the molecular modeling studies of these key interactions resulted in the ability to convert a human-selective PPARα agonist to a human and mouse dual agonist within the same platform.
- Wang, Minmin,Winneroski, Leonard L.,Ardecky, Robert J.,Babine, Robert E.,Brooks, Dawn A.,Etgen, Garret J.,Hutchison, Darrell R.,Kauffman, Raymond F.,Kunkel, Aaron,Mais, Dale E.,Montrose-Rafizadeh, Chahrzad,Ogilvie, Kathleen M.,Oldham, Brian A.,Peters, Mary K.,Rito, Christopher J.,Rungta, Deepa K.,Tripp, Allie E.,Wilson, Sarah B.,Xu, Yanping,Zink, Richard W.,McCarthy, James R.
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p. 6113 - 6116
(2007/10/03)
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- Oxazolyl-aryloxyacetic acid derivatives and their use as ppar agonists
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Novel compounds that are modulators of PPAR receptors, and pharmaceutically acceptable salts, solvates and hydrates thereof, processes for making the compounds, pharmaceutical compositions containing the compounds, or pharmaceutically acceptable salts, solvates and hydrates thereof.
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- Design and Synthesis of α-Aryloxy-α-methylhydrocinnamic Acids: A Novel Class of Dual Peroxisome Proliferator-Activated Receptor α/ γ Agonists
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The design and synthesis of the dual peroxisome proliferator activated receptor (PPAR) α/γ agonist (S)-2-methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)ethoxy]phenyl} -2-phenoxypropionic acid (2) for the treatment of type 2 diabetes and associated d
- Xu, Yanping,Rito, Christopher J.,Etgen, Garret J.,Ardecky, Robert J.,Bean, James S.,Bensch, William R.,Bosley, Jacob R.,Broderick, Carol L.,Brooks, Dawn A.,Dominianni, Samuel J.,Hahn, Patric J.,Liu, Sha,Mais, Dale E.,Montrose-Rafizadeh, Chahrzad,Ogilvie, Kathy M.,Oldham, Brian A.,Peters, Mary,Rungta, Deepa K.,Shuker, Anthony J.,Stephenson, Gregory A.,Tripp, Allie E.,Wilson, Sarah B.,Winneroski, Leonard L.,Zink, Richard,Kauffman, Raymond F.,McCarthy, James R.
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p. 2422 - 2425
(2007/10/03)
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- Oxazolyl-arylpropionic acid derivatives and their use as ppar agonists
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Compounds represented by the following structural formula (I), and pharmaceutically acceptable salts, solvates and hydrates thereof, wherein: n is 2, 3, or 4 and W is CH2, CH(OH), C(O) or O; R1 is an unsubstituted or substituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryl-alkyl, heteroaryl-alkyl, cycloalkyl-alkyl, or t-butyl; R2 is H, alkyl, haloalkyl or phenyl; Y is an unsubstituted or substituted thiophen-2,5-diyl or phenylene; R3 is alkyl or haloalkyl; R4 is a substituted or unsubstituted phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, quinolyl, pyridyl or benzo[1,3]dioxol-5-yl group; and R5 is H, alkyl, or aminoalkyl; are useful for modulating a peroxisome proliferator activated receptor, particularly in the treatment of diabetes mellitus.
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- Kinetics and mechanism of thermal gas-phase elimination of α-substituted carboxylic acids: Role of relative basicity of α-substituents and acidity of incipient proton
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2-Phenoxypropanoic acid together with five of its aryl derivatives, its phenylthio and its N-phenylamino analogues were pyrolyzed at 494-566 K. The reactions were homogeneous, polar and free from catalytic and radical pathways, and obeyed a first-order rate equation. The limits of the Arrhenius log A (s-1) and E (kJ mol-1) values obtained for these reactions averaged 11.98 ± 1.71 and 158.1 ± 17.4, respectively. Analysis of the pyrolysates showed the elimination products to be carbon monoxide, acetaldehyde and the corresponding phenol, thiophenol or aniline compounds. The pyrolysis of 2-phenoxy- and 2-(N-phenylamino)-1-propanol was also investigated over the temperature range 638-792 K. The kinetic results and products analysis lend support to a reaction pathway involving a five-membered cyclic polar transition state. Copyright
- Al-Awadi, Nouria A.,Kaul, Kamini,El-Dusouqui, Osman M. E.
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p. 499 - 504
(2007/10/03)
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- Methods for the manufacture of neofazodone
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Process for the manufacture of triazolone compounds and in particular nefazodone and intermediates useful in the manufacture thereof.
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- Switched enantiopreference of Humicola lipase for 2-phenoxyalkanoic acid ester homologs can be rationalized by different substrate binding modes
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Humicola lanuginosa lipase was used for enantioselective hydrolyses of a series of homologous 2-phenoxyalkanoic acid ethyl esters. The enantioselectivity (E-value) of the enzyme changed from an (R)-enantiomer preference for the smallest substrate, 2-pheno
- Berglund, Per,Vallikivi, Imre,Fransson, Linda,Dannacher, Heinz,Holmquist, Mats,Martinelle, Mats,Bjoerkling, Fredrik,Parve, Omar,Hult, Karl
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p. 4191 - 4202
(2007/10/03)
-
- Novel juvenoids of the 2-(4-hydroxybenzyl)cyclohexan-1-one series
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A series of insect juvenile hormone analogs (juvenoids) was synthesized and studied. The basic skeleton of these juvenoids contains three rings and a short aliphatic subunit and bears two or three chiral centers (depending on the appropriate structure; see 6-9). The chiral center located in the 1,2-diphenoxypropane subunit has the configuration (RS), (R) (a series), or (S) (b series). The juvenoids were subjected to a biological screening, the preliminary results of which are briefly described.
- Wimmer,Saman,Francke
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p. 502 - 508
(2007/10/02)
-
- Facile syntheses of 2-alkyl-2,3-dihydro-2-methylbenzofuran derivatives
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Various 2-alkyl-2,3-dihydro-2-methylbenzofurans 4 can be easily synthesized from 2-aryloxypropionic acid ethyl esters 1 by 3 steps in good yields.
- Kim,Kim,Chung,Song,Ryu
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p. 1859 - 1870
(2007/10/02)
-
- Optical resolution of aryloxypropionic acids and their esters by HPLC on cellulose tris-3,5-dimethyl-triphenylcarbamate derivative
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Chiral chromatographic resolution of a series of antiphlogistic 2- aryloxypropionic acids and their methyl and ethyl esters was performed using a Chiralcel OD column. The CSP selected resolved most of the acids and esters efficiently, the enantiomers being well separated without requiring time consuming analysis. Chromatographic separation of R enriched samples was performed to determine the correct elution order. Using eluting systems such as hexane and 2-propanol, or hexane, 2-propanol and formic acid, the S enantiomer of all acids and esters was always found to elute first. We also considered the role of electron-donating or electron-withdrawing substituents (at the aryloxylic moiety) on the chiral resolution. It was shown that the electronic features of the substituents have more influence on the chiral interactions between the solutes and the CSP than their steric hindrance. Finally we determined, by molecular models, the interaction between CSP and solutes. In this way were able to determine all the potential sites for interactions, which are compatible with the conformations of the compounds and the structure of the stationary phase, and point out those interactions which enable chiral resolution.
- Azzolina,Collina,Ghislandi
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p. 1401 - 1416
(2007/10/02)
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- Syntheses des alkyl-1 cyclanols fonctionnalises aux positions α, β et γ de la chaine hydrocarbonee
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We have developed a general and versatile synthesis of N,N-dialkylaminoalkyl-, 1-chloroalkyl-, 1-phenoxyalkyl-, 1-thiophenoxyalkyl-, 1-diethoxyalkyl-, and 1-(1,3-dithiolane)alkylcyclanols in good yields by the reaction of α,ω-bis(bromomagnesio)alkanes with the corresponding functionalized carboxylic acid esters.
- Canonne, P.,Belley, M.,Fytas, G.,Plamondon, J.
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p. 168 - 173
(2007/10/02)
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- 2-[4-(4-Chlorophenoxymethyl)-phenoxy]-propionic acid compounds as herbicides
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Compounds of the formula STR1 wherein R1 and R2 are each hydrogen, chlorine or fluorine; and R3 is --CH2 OH, --CH2 --O--COR4, --CH2 --O--CONHR5, --COOH, --COOCat, --CO
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