- COMPOUNDS AND METHODS FOR THE TREATMENT OF CYSTIC FIBROSIS
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The invention relates to a compound of Formula I, pharmaceutical compositions comprising a compound of Formula I, and pharmaceutically acceptable slats thereof, pharmaceutical compositions comprising such compounds and methods of treating cystic fibrosis comprising the step of administering a therapeutically effective amount of a compound of Formula I to a subject in need thereof.
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Page/Page column 217-218
(2020/08/22)
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- Transition-Metal-Free C-C, C-O, and C-N Cross-Couplings Enabled by Light
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Transition-metal-catalyzed cross-couplings to construct C-C, C-O, and C-N bonds have revolutionized chemical science. Despite great achievements, these metal catalysts also raise certain issues including their high cost, requirement of specialized ligands, sensitivity to air and moisture, and so-called "transition-metal-residue issue". Complementary strategy, which does not rely on the well-established oxidative addition, transmetalation, and reductive elimination mechanistic paradigm, would potentially eliminate all of these metal-related issues. Herein, we show that aryl triflates can be coupled with potassium aryl trifluoroborates, aliphatic alcohols, and nitriles without the assistance of metal catalysts empowered by photoenergy. Control experiments reveal that among all common aryl electrophiles only aryl triflates are competent in these couplings whereas aryl iodides and bromides cannot serve as the coupling partners. DFT calculation reveals that once converted to the aryl radical cation, aryl triflate would be more favorable to ipso substitution. Fluorescence spectroscopy and cyclic voltammetry investigations suggest that the interaction between excited acetone and aryl triflate is essential to these couplings. The results in this report are anticipated to provide new opportunities to perform cross-couplings.
- Liu, Wenbo,Li, Jianbin,Querard, Pierre,Li, Chao-Jun
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supporting information
p. 6755 - 6764
(2019/05/06)
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- Organic metal compounds and organic light emitting diodes comprising the same
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PURPOSE: An organic metal compound is provided to have excellent thermal properties and light emitting efficiency, thereby being useful for a display and lighting device. CONSTITUTION: An organic metal compound is represented by chemical formula 1. In chemical formula 1, each of R and Z is hydrogen, deuterium, cyano, halogen hydroxy, nitro, C1-40 alkyl, C1-40 alkoxy, C1-40 alkylamino, C6-40 arylamino, C3-40 heteroarylamino, C1-40 alkoxy group, C1-40 alkylamino, C6-40 aryl group, C3-40 aryloxy group, germanium, phosphorous, and boron; each of A, B, C, D, and E is a substituted or unsubstituted aromatic cycle, or substituted or unsubstituted hydrocycle, X is carbon or nitrogen, G is chemical bond or C1-4 alkylene which can be substituted by (R-Zi)n.
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Paragraph 0488-0489; 0492-0494
(2018/12/01)
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- Covalently Interlocked Cyclohexa-m-phenylenes and Their Assembly: En Route to Supramolecular 3D Carbon Nanostructures
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In our search to cluster as many phenylene units as possible in a given space, we have proceeded to the three-dimensional world of benzene-based molecules by employing covalently interlocked cyclohexa-m-phenylenes, as present in the unique paddlewheel-sha
- Dumslaff, Bastian,Reuss, Anna N.,Wagner, Manfred,Feng, Xinliang,Narita, Akimitsu,Fytas, George,Müllen, Klaus
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supporting information
p. 10602 - 10606
(2017/08/22)
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- Selective arylation and vinylation at the α position of vinylarenes
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In intermolecular Heck reactions of styrene and vinylarenes, the aryl and vinyl groups routinely insert at the β position. However, selective insertion at the α position has been very rare. Herein, we provide a missing piece in the palette of Heck reaction, which gave >20:1 α selectivity. The key to our success is a new ferrocene 1,1′-bisphosphane (dnpf) that carries 1-naphthyl groups. Our mechanistic studies revealed that the high α selectivity is partly attributable to the steric effect of dnpf. The rigid and bulky 1-naphthyl groups of dnpf sterically disfavor β insertion. What the Heck! In intermolecular Heck reactions, insertion at the β position of aromatic olefins is very common, but reversal of the selectivity for selective α insertion has been a longstanding problem. A general method to couple aryl and vinyl triflates with aromatic olefins in >20:1 α selectivity is presented. The key to this successful approach is a new ferrocene bisphosphane with naphthyl groups on the phosphorus atom (see scheme; OTf=triflate). Copyright
- Zou, Yinjun,Qin, Liena,Ren, Xinfeng,Lu, Yunpeng,Li, Yongxin,Zhou, Jianrong
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supporting information
p. 3504 - 3511
(2013/07/05)
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- Achieving vinylic selectivity in Mizoroki-heck reaction of cyclic olefins
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In Heck reactions of cyclic olefins, the products usually have aryl groups that end up at the allylic and/or homoallylic position. We herein report new selectivity that adds aryl groups to the vinylic position. Cyclic olefins of various ring size worked well. The desired isomers were produced by palladium-hydride-catalyzed isomerization of the initial products. Thus, a specific catalyst must be used so that it can perform two jobs under one set of reaction conditions. Copyright
- Wu, Xiaojin,Lu, Yunpeng,Hirao, Hajime,Zhou, Jianrong
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supporting information
p. 6014 - 6020
(2013/06/26)
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- Intermolecular mizoroki-heck reaction of aliphatic olefins with high selectivity for substitution at the internal position
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New ligand for old reaction: The title reaction of aryltriflates with aliphatic olefins leads to substitution at the internal position with high selectivity. The ratio of the desired isomer (shown in the scheme) to the sum of all other isomers is generall
- Qin, Liena,Ren, Xinfeng,Lu, Yunpeng,Li, Yongxin,Zhou, Jianrong
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supporting information; experimental part
p. 5915 - 5919
(2012/07/30)
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- Highly potent macrocyclic BACE-1 inhibitors incorporating a hydroxyethylamine core: Design, synthesis and X-ray crystal structures of enzyme inhibitor complexes
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A series of P1-P3 linked macrocyclic BACE-1 inhibitors containing a hydroxyethylamine (HEA) isostere scaffold has been synthesized. All inhibitors comprise a toluene or N-phenylmethanesulfonamide P2 moiety. Excellent BACE-1 potencies, both in enzymatic an
- Sandgren, Veronica,Agback, Tatiana,Johansson, Per-Ola,Lindberg, Jimmy,Kvarnstr?m, Ingemar,Samuelsson, Bertil,Belda, Oscar,Dahlgren, Anders
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supporting information; scheme or table
p. 4377 - 4389
(2012/08/28)
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- Chemical synthesis and evaluation of 17α-alkylated derivatives of estradiol as inhibitors of steroid sulfatase
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Steroid sulfatase (STS) controls the levels of 3-hydroxysteroids available from circulating steroid sulfates in several normal and malignant tissues. This and the known involvement of active estrogens and androgens in diseases such as breast and prostate cancers thus make STS an interesting therapeutic target. Here we describe the chemical synthesis and characterization of an extended series of 17α-derivatives of estradiol (E2) using different strategies. A variant of the samarium-Barbier reaction with stoichiometric samarium metal and catalytic Kagan reagent formation was used for introducing low reactive benzyl substrates in position 17 of estrone (E1) whereas heterocyclic substrates were metalated and reacted with either the carbonyl or the 17-oxirane of E1. In vitro evaluation of the inhibitory potency of the new compounds against STS identified new inhibitors and allowed a more complete structure-activity relationship study of this family of 17α-derivatives of E2.
- Fournier, Diane,Poirier, Donald
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experimental part
p. 4227 - 4237
(2011/11/12)
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- (3-HYDROXY-4-AMINO-BUTAN-2-YL) -3- (2-THIAZOL-2-YL-PYRROLIDINE-1-CARBONYL) BENZAMIDE DERIVATIVES AND RELATED COMPOUNDS AS BETA-SECRETASE INHIBITORS FOR TREATING
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The present invention provides novel beta-secretase inhibitors and methods for their use, including methods of treating of Alzheimer's disease. (Formula)
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Page/Page column 91
(2009/05/29)
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- Macrocyclic Compounds Useful as Bace Inhibitors
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The invention relates to novel macrocyclic compounds of the formula (I), in which all of the variables are as defined in the specification, the number of ring atoms included in the macrocyclic ring being 14, 15, 16 or 17, in free base form or in acid addition salt form, to their preparation, to their use as medicaments and to medicaments comprising them.
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Page/Page column 50
(2008/12/05)
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- MACROCYCLIC COMPOUNDS AND COMPOSITIONS USEFUL AS BACE INHIBITORS
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The invention relates to novel macrocyclic compounds of the formula in which R1, R3, V1, V2, X1, X2, Y, Z, Ar, AA and n are as defined in the specification, the number of ring atoms include
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Page/Page column 30
(2008/06/13)
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- METHODS FOR TREATING RETINOID RESPONSIVE DISORDERS USING SELECTIVE INHIBITORS OF CYP26A AND CYP26B
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The invention provides methods for treating an individual having a retinoid responsive disorder. In one embodiment, a method involves administering to the individual an effective amount of a selective CYP26B inhibitor, the selective CYP26B inhibitor having at least 10-fold selectivity for CYP26B relative to CYP26A. In another embodiment, a method involves administering to the individual an effective amount of a selective CYP26A inhibitor, the selective CYP26A inhibitor having a chemical formula set forth in the specification. The invention further provides screening methods for identifying a selective CYP26A inhibitor or selective CYP26B inhibitor.
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Page/Page column 170-171
(2008/06/13)
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- COMPOUNDS HAVING SELECTIVE CYTOCHROME P450RAI-1 OR SELECTIVE CYTOCHROME P450RAI-2 INHIBITORY ACTIVITY AND METHODS OF OBTAINING THE SAME
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Compounds of formulas 1 through 17 provided in the specification specifically or selectively inhibit either the cytochrome P450RAI-1 enzyme or the cytochrome P450RAI-2 enzyme.
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Page/Page column 132-133
(2010/02/12)
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- Regiospecific synthesis of alkylphenanthrenes using a combined directed ortho and remote metalation - Suzuki-Miyaura cross coupling strategy
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Using a combined directed ortho metalation (DoM) - Suzuki-Miyaura cross coupling - directed remote metalation (DreM) approach, the alkylphenanthrenes (APs) 1-methyl- (5a), 1,7-dimethyl- (5b), 2,7-dimethyl- (Sc), 7-ethyl-1-methyl- (15), and 7-tert-butyl-1-methylphenanthrenes (27) have been synthesized in four to seven steps and 21%-36% overall yields. In contrast to classical protocols, this method, which may be scaled to gram quantities, provides single isomers of APs in high purity of value as analytical standards for environmental studies. Aminocarbonylation of triflates to N,N-diethylbenzamides (9 → 10) and anionic Fries rearrangement (23 → 24) provide other potential links to DoM chemistry.
- Cai, Xiongwei,Brown, Stephen,Hodson, Peter,Snieckus, Victor
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p. 195 - 205
(2007/10/03)
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- 2-substituted (2SR)-2-amino-2-((1SR,2SR)-2-carboxycycloprop-1- yl)glycines as potent and selective antagonists of group II metabotropic glutamate receptors. 2. Effects of aromatic substitution, pharmacological characterization, and bioavailability
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In this paper we describe the synthesis of a series of α-substituted analogues of the potent and selective group II metabotropic glutamate receptor (mGluR) agonist (1S,1'S,2'S)-carboxycyclopropylglycine (2, L-CCG 1). Incorporation of a substituent on the amino acid carbon converted the agonist 2 into an antagonist. All of the compounds were prepared and tested as a series of four isomers, i.e., two racemic diastereomers. On the basis of the improvement in affinity realized for the α-phenylethyl analogue 3, in this paper we explored the effects of substitution on the aromatic ring as a strategy to increase the affinity of these compounds for group II mGluRs. Affinity for group II mGluRs was measured using [3H]glutamic acid (Glu) binding in rat forebrain membranes. Antagonist activity was confirmed for these compounds by measuring their ability to antagonize (1S,3R)-1- aminocyclopentane-1,3-dicarboxylic acid-induced inhibition of forskolin stimulated cyclic-AMP in RGT cells transfected with human mGluR2 and mGluR3. Meta substitution on the aromatic ring of 3 with a variety of substituents, both electron donating (e.g., methyl, hydroxy, amino, methoxy, phenyl, phenoxy) and electron withdrawing (e.g., fluorine, chlorine, bromine, carboxy, trifluoromethyl) gave from 1.5- to 4.5-fold increases in affinity. Substitution with p-fluorine, as in 97 (IC50 = 0.022 ± 0.002), was the exception. Here, a greater increase in affinity was realized than for either the ortho- or meta-substituted analogues; 97 was the most potent compound resulting from monosubstitution of the aromatic. At best, only modest increases in affinity were realized for certain compounds bearing either two chlorines or two fluorines, and two methoxy groups gave no improvement in affinity (all examined in a variety of substitution patterns). Three amino acids, 4, 5, and 104, were resolved into their four constituent isomers, and affinity and functional activity for group II mGluRs was found to reside solely in the S,S,S-isomers of each, consistent with 1. With an IC50 = 2.9 ± 0.6 nM, the resolved xanthylmethyl compound 168 was the most potent compound from this SAR. Amino acid 168 demonstrated high plasma levels following intraperitoneal (ip) administration and readily penetrated into the brain. This compound, however, had only limited (~5%) oral bioavailability. Systemic administration of 168 protected mice from limbic seizures produced by the mGluR agonist 3,5-dihydroxyphenylglycine, with an ED50 = 31 mg/kg (ip, 60 min preinjection). Thus, 168 represents a valuable tool to study the role of group II mGluRs in disease.
- Ornstein, Paul L.,Bleisch, Thomas J.,Arnold, M. Brian,Kennedy, Joseph H.,Wright, Rebecca A.,Johnson, Bryan G.,Tizzano, Joseph P.,Helton, David R.,Kallman, Mary Jeanne,Schoepp, Darryle D.,Hérin, Marc
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p. 358 - 378
(2007/10/03)
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