- Dirhodium(ii) tetraacetate catalysed reactions of diazo thioamides: Isolation and cycloaddition of anhydro-4-hydroxy-1,3-thiazolium hydroxides (thioisomuenchnones), an approach to analogues of dehydrogliotoxin
-
Dirhodium(II) tetraacetate catalysed reaction of the indoline diazo thioamide 8 gives the thioisomuenchnone 9, a stable characterisable solid. This masked thiocarbonyl ylide undergoes 1, 3-dipolar cycloaddition with N-methylmaleimide and maleic anhydride to give the exo-cycloadducts 10 and 11, characterised by X-ray crystallography. The thioisomuenchnone 18, derived from diazo thioamide 17, is an extremely stable crystalline mesoionic system which can be characterised by X-ray crystallography but fails to undergo intramolecular cycloaddition. The related thioisomnchnone 19 can be generated by reaction of indoline-2-thione 7 with bromoacetyl chloride in the presence of triethylamine, and undergoes cycloaddition, to give adducts 20 and 21.
- Moody, Christopher J.,Slawin, Alexandra M.Z.,Willows, David
-
-
Read Online
- Study of the Fatigue Process and the Yellowing of Polymeric Films Containing Spirooxazine Photochromic Compounds
-
Photochromic polyurethane films containing 5-substituted 1,3-dihydro-3,3-dimethyl-1-alkylspiropyridobenzoxazine> and 1,3-dihydro-1,3,3-trimethylspironaphthoxazine> were degraded under xenon light exposure.The loss of the photochromic response was monitored by spectrophotometry as a function of the irradiation time; meanwhile, the photoproduct formation and the amount of photochromic material still available were analyzed by chromatography after liquid-solid extraction.At the same time, the fade rateswere monitored after flash-excitation photolysis or after the photostationary state during degradation.It was clearly demonstrated that the loss of photochromism was due exclusively to a photooxidation process of the initial dye, and not to an acceleration of the bleaching or a potential screen effect caused by the photoproducts.
- Baillet, Gilles,Giusti, Gerard,Guglielmetti, Robert
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Read Online
- Influenza virus replication inhibitors and uses thereof
-
The invention belongs to the field of medicines, and particularly relates to novel compounds serving as an influenza virus replication inhibitor, a preparation method thereof, a pharmaceutical composition containing the compounds and application of the compounds and the pharmaceutical composition in treatment of influenza. The compounds are compounds as shown in a formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or prodrugs of the stereoisomer, the tautomer, the nitrogen oxide, the solvate, the metabolite and the pharmaceutically acceptable salt of the compound as shown in the formula (I). The compounds not only can well inhibit influenza viruses, but also have lower cytotoxicity, excellent in-vivo pharmacokinetic property and the in-vivo pharmacodynamic property and good liver microsome stability.
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Paragraph 0333-0337
(2021/07/01)
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- NOVEL COMPOUNDS USEFUL AS POLY(ADP-RIBOSE) POLYMERASE (PARP) INHIBITORS
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The present invention provides novel poly(ADP-ribose) polymerase (PARP) inhibitors, methods of preparing them, pharmaceutical compositions containing them and methods for the treatment, prevention and/or amelioration of PARP mediated diseases or disorders using them. In particular, the compounds described herein are useful for the treatment of carcinoma of the breast, ovarian cancer, carcinoma of the liver, carcinoma of the lung, small cell lung cancer, esophageal cancer, gall bladder cancer, pancreatic cancer and stomach cancer.
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Paragraph 216
(2021/11/06)
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- Palladium-Catalyzed Markovnikov Hydroaminocarbonylation of 1,1-Disubstituted and 1,1,2-Trisubstituted Alkenes for Formation of Amides with Quaternary Carbon
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Hydroaminocarbonylation of alkenes is one of the most promising yet challenging methods for the synthesis of amides. Herein, we reported the development of a novel and effective Pd-catalyzed Markovnikov hydroaminocarbonylation of 1,1-disubstituted or 1,1,2-trisubstituted alkenes with aniline hydrochloride salts to afford amides bearing an α quaternary carbon. The reaction makes use of readily available starting materials, tolerates a wide range of functional groups, and provides a facile and straightforward approach to a diverse array of amides bearing an α quaternary carbon. Mechanistic investigations suggested that the reaction proceeded through a palladium hydride pathway. The hydropalladation and CO insertion are reversible, and the aminolysis is probably the rate-limiting step.
- Yang, Hui-Yi,Yao, Ya-Hong,Chen, Ming,Ren, Zhi-Hui,Guan, Zheng-Hui
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supporting information
p. 7298 - 7305
(2021/05/26)
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- NovelN-transfer reagent for converting α-amino acid derivatives to α-diazo compounds
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A novel universalN-transfer reagent for direct and effective transformation of α-amino ketones, acetamides, and esters to the corresponding α-diazo products under mild basic conditions has been developed. This one-step synthetic approach not only allows for generation of α-substituted-α-diazo carbonyl compounds from α-amino acid derivatives but also permits preparation of α-diazo dipeptides fromN-terminal dipeptides (32 examples, up to 91%).
- Lu, Guan-Han,Huang, Tzu-Chia,Hsueh, Hsiao-Chin,Yang, Shin-Cherng,Cho, Ting-Wei,Chou, Ho-Hsuan
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supporting information
p. 4839 - 4842
(2021/05/25)
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- Preparation of Complexes Bearing N-Alkylated, Anionic or Protic CAACs Through Oxidative Addition of 2-Halogenoindole Derivatives
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CAAC precursors 2-chloro-3,3-dimethylindole 1 and 2-chloro-1-ethyl-3,3-dimethylindolium tetrafluoroborate 2BF4 have been prepared and oxidatively added to [M(PPh3)4] (M=Pd, Pt). Salt 2BF4 reacts with [Pd(PPh3)4] in toluene at 25 °C over 4 days to yield complex cis-[3]BF4 featuring an N-ethyl substituted CAAC, two cis-arranged phosphines and a chloro ligand. Compound trans-[3]BF4 was obtained from the same reaction at 80 °C over 1 day. Salt 2BF4 reacts with [Pt(PPh3)4] to give cis-[4]BF4. The neutral indole derivative 1 adds oxidatively to [Pt(PPh3)4] to give trans-[5] featuring a CAAC ligand with an unsubstituted ring-nitrogen atom. This nitrogen atom has been protonated with py?HBF4 to give trans-[6]BF4 bearing a protic CAAC ligand. The PdII complex trans-[7]BF4 bearing a protic CAAC ligand was obtained in a one-pot reaction from 1 and [Pd(PPh3)4] in the presence of py?HBF4.
- Termühlen, Sebastian,Blumenberg, Jonas,Hepp, Alexander,Daniliuc, Constantin G.,Hahn, F. Ekkehardt
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p. 2599 - 2602
(2020/12/03)
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- LACTAM COMPOUND AS FXR RECEPTOR AGONIST
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Disclosed is a compound as shown in formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof, and the present invention relates to the use of same in the preparation of a drug for treating FXR-related diseases.
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Paragraph 0232
(2020/04/21)
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- Kinase inhibitors (by machine translation)
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The present invention relates to certain 4 - (substituted anilino) -2 - (substituted piperi -1 -yl) pyrimidine -5 - carboxamide compounds useful for the treatment or prevention of diseases or medical conditions mediated by signal transduction of CaMMK1 isotype. For example, such compounds and salts thereof may be used to treat or prevent a variety of different cancers. Diseases (including 2 diabetes) and/or immune-mediated diseases. (by machine translation)
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Paragraph 0492-0493
(2020/12/31)
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- Enantioselective Synthesis of C?N Axially Chiral N-Aryloxindoles by Asymmetric Rhodium-Catalyzed Dual C?H Activation
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The first enantioselective Satoh–Miura-type reaction is reported. A variety of C?N axially chiral N-aryloxindoles have been enantioselectively synthesized by an asymmetric rhodium-catalyzed dual C?H activation reaction of N-aryloxindoles and alkynes. High yields and enantioselectivities were obtained (up to 99 % yield and up to 99 % ee). To date, it is also the first example of the asymmetric synthesis of C?N axially chiral compounds by such a C?H activation strategy.
- Li, Honghe,Yan, Xiaoqiang,Zhang, Jitan,Guo, Weicong,Jiang, Jijun,Wang, Jun
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supporting information
p. 6732 - 6736
(2019/04/17)
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- Design, synthesis and biological evaluation of novel human monoamine oxidase B inhibitors based on a fragment in an X-ray crystal structure
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Herein we report our efforts of developing reversible selective hMAO-B inhibitors based on isatin, a fragment in an X-ray crystal structure. Five different scaffolds were designed and many compounds were synthesized. Among them, compound A3 demonstrated very high potency and isoform selectivity against hMAO-B, 11 and 13 times more potent (IC50 = 3 nM) and 23.64 and 6.8 times more selective than the marked drugs, selegiline and safinamide. However, the endeavors to modify the polar 3-one group of isatin, that is in a hydrophobic environment in the binding site of hMAO-B, to small nonpolar hydrophobic groups did not bring about improved hMAO-B inhibitors, which may challenge our understanding of molecular interactions and molecular recognition in biological systems.
- Cheng, Kai,Li, Shiyu,Lv, Xiao,Tian, Yongbin,Kong, Haiyan,Huang, Xufeng,Duan, Yajun,Han, Jihong,Xie, Zhouling,Liao, Chenzhong
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supporting information
p. 1012 - 1018
(2019/02/24)
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- Optimization of a novel series of potent and orally bioavailable GPR119 agonists
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We describe the discovery and optimization of a novel series of furo[3,2-d]pyrimidines as G protein-coupled receptor 119 agonists. Agonistic activity of 4 (EC50?=?129?nM) was improved by replacing the intramolecular hydrogen bond between the fluorine atom and the aniline hydrogen in the head moiety with a covalent C-C bond to enhance conformational restriction, which consequently gave a lead compound 12 (EC50?=?53?nM). Optimized compound 26, which was identified by the further optimization of 12, exhibited potent activity (EC50?=?42?nM) with improved clearance in liver microsomes and induced a 33% reduction in blood glucose area under the curve at a dose of 10?mg/kg in an oral glucose tolerance test in C57BL/6N mice.
- Koshizawa, Tomoaki,Morimoto, Toshiharu,Watanabe, Gen,Watanabe, Toshiaki,Yamasaki, Nao,Sawada, Yoshikazu,Fukuda, Tomoaki,Okuda, Ayumu,Shibuya, Kimiyuki,Ohgiya, Tadaaki
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supporting information
p. 3249 - 3253
(2017/07/07)
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- Substituted ring compound and its method and use thereof
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The invention provides a substituted cyclic compound as well as a use method and application thereof. The compound is a compound as shown in a formula (I) or stereoisomers, stereomers, tautomers, nitric oxides, solvates, metabolites and pharmaceutically acceptable salts or prodrugs of the compound as shown in the formula (I). The invention further provides a medicament composition containing the compound. The compound and the medicament composition are capable of regulating the activity of protein kinase in a biological sample body and are used for protecting, treating or relieving proliferative diseases of patients. The formula (I) is as shown in the specification.
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Paragraph 0470; 0471; 0472; 0473
(2017/08/25)
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- Phenyl Benzenesulfonylhydrazides Exhibit Selective Indoleamine 2,3-Dioxygenase Inhibition with Potent in Vivo Pharmacodynamic Activity and Antitumor Efficacy
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Tryptophan metabolism has been recognized as an important mechanism in immune tolerance. Indoleamine 2,3-dioxygenase plays a key role in local tryptophan metabolism via the kynurenine pathway and has emerged as a therapeutic target for cancer immunotherapy. Our prior study identified phenyl benzenesulfonyl hydrazide 2 as a potent in vitro (though not in vivo) inhibitor of indoleamine 2,3-dioxygenase. Further lead optimization to improve in vitro potencies and pharmacokinetic profiles resulted in N′-(4-bromophenyl)-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl hydrazide 40, which demonstrated 59% oral bioavailability and 73% of tumor growth delay without apparent body weight loss in the murine CT26 syngeneic model, after oral administration of 400 mg/kg. Accordingly, 40, is proposed as a potential drug lead worthy of advanced preclinical evaluation.
- Lin, Shu-Yu,Yeh, Teng-Kuang,Kuo, Ching-Chuan,Song, Jen-Shin,Cheng, Ming-Fu,Liao, Fang-Yu,Chao, Min-Wu,Huang, Han-Li,Chen, Yi-Lin,Yang, Chun-Yu,Wu, Mine-Hsine,Hsieh, Chia-Ling,Hsiao, Wenchi,Peng, Yi-Hui,Wu, Jian-Sung,Lin, Li-Mei,Sun, Manwu,Chao, Yu-Sheng,Shih, Chuan,Wu, Su-Ying,Pan, Shiow-Lin,Hung, Ming-Shiu,Ueng, Shau-Hua
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p. 419 - 430
(2016/01/28)
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- Fragment Screening of Soluble Epoxide Hydrolase for Lead Generation - Structure-Based Hit Evaluation and Chemistry Exploration
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Soluble epoxide hydrolase (sEH) is involved in the regulation of many biological processes by metabolizing the key bioactive lipid mediator, epoxyeicosatrienoic acids. For the development of sEH inhibitors with improved physicochemical properties, we performed both a fragment screening and a high-throughput screening aiming at an integrated hit evaluation and lead generation. Followed by a joint dose-response analysis to confirm the hits, the identified actives were then effectively triaged by a structure-based hit-classification approach to three prioritized series. Two distinct scaffolds were identified as tractable starting points for potential lead chemistry work. The oxoindoline series bind at the right-hand side of the active-site pocket with hydrogen bonds to the protein. The 2-phenylbenzimidazole-4-sulfonamide series bind at the central channel with significant induced fit, which has not been previously reported. On the basis of the encouraging initial results, we envision that a new lead series with improved properties could be generated if a vector is found that could merge the cyclohexyl functionality of the oxoindoline series with the trifluoromethyl moiety of the 2-phenylbenzimidazole-4-sulfonamide series.
- Xue, Yafeng,Olsson, Thomas,Johansson, Carina A,?ster, Linda,Beisel, Hans-Georg,Rohman, Mattias,Karis, David,B?ckstr?m, Stefan
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supporting information
p. 497 - 508
(2016/03/12)
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- Imidazole derivatives as accelerators for ruthenium-catalyzed hydroesterification and hydrocarbamoylation of alkenes: Extensive ligand screening and mechanistic study
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Imidazole derivatives are effective ligands for promoting the [Ru3(CO)12]-catalyzed hydroesterification of alkenes using formates. Extensive ligand screening was performed to identify 2-hydroxymethylated imidazole as the optimal ligand. Neither carbon monoxide gas nor a directing group was required, and the reaction also showed a wide substrate generality. The Ru-imidazole catalyst system also promoted intramolecular hydrocarbamoylation to afford lactams. A Ru-imidazole complex was unambiguously analyzed by X-ray crystallography, and it had a trinuclear structure derived from one [Ru3(CO)12] and two ligands. This complex was also successfully used for hydroesterification. The mechanism was examined in detail by using D- and 13C-labeled formates, indicating that the hydroesterification reaction proceeds by a decarbonylation-recarbonylation pathway. Effective imidazole assistant: [Ru3(CO)12]-catalyzed hydroesterification of alkenes by using formates is drastically accelerated by imidazole derivatives and exhibits a broad substrate scope for both alkenes and formates. The Ru-imidazole complex also catalyzes the intramolecular hydrocarbamoylation of alkenes.
- Konishi, Hideyuki,Muto, Takashi,Ueda, Tsuyoshi,Yamada, Yayoi,Yamaguchi, Miyuki,Manabe, Kei
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p. 836 - 845
(2015/03/14)
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- SUBSTITUTED CYCLIC COMPOUNDS AND METHODS OF USE
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The present invention provides novel substituted alkynyl compounds, pharmaceutical acceptable salts and formulations thereof useful in modulating the protein tyrosine kinase activity, and in modulating cellular activities such as proliferation, differentiation, apoptosis, migration and invasion. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.
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Paragraph 0202
(2014/06/24)
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- A new method for the cleavage of nitrobenzyl amides and ethers
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A mild and efficient o- and p-nitrobenzyl cleavage protocol was developed. o- and p-nitrobenzyl groups were easily removed from a variety of substrates using 20% aqueous NaOH in methanol at 75 °C, presumably via oxidation at the benzylic position by oxygen dissolved in the solution. These easily introducible and removable nitrobenzyl groups can serve as valuable protecting groups for the synthesis of multifunctional, complex molecules.
- Han, Seo-Jung,Fernando De Melo, Gabriel,Stoltz, Brian M.
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p. 6467 - 6469
(2015/01/16)
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- Regiodivergent access to five- and six-membered benzo-fused lactams: Ru-catalyzed olefin hydrocarbamoylation
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We report herein a new strategy of the Ru-catalyzed intramolecular olefin hydrocarbamoylation for the regiodivergent synthesis of five- and six-membered benzo-fused lactams starting from N-(2-alkenylphenyl)formamides. Using a combined catalyst of Ru3
- Li, Bin,Park, Yoonsu,Chang, Sukbok
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supporting information
p. 1125 - 1131
(2014/02/14)
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- Gold nanoparticles assisted formation of cobalt species for intermolecular hydroaminomethylation and intramolecular cyclocarbonylation of olefins
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The intermolecular hydroaminomethylation and the intramolecular cyclocarbonylation efficiently proceeded on cobalt oxide supported gold nanoparticles. The intermolecular reaction employing terminal olefins and N-isopropylaniline afforded hydroaminomethylated products as a mixture of regioisomers via a common reaction path consisting of hydroformylation, imine formation, and hydrogenation. In contrast, indolinone derivatives were exclusively obtained in the case of 2-alkenylanilines based on the intramolecular cyclocarbonylation mechanism. Both of these reactions were catalyzed by cobalt species derived from cobalt oxide. The active cobalt species were formed via reduction of the oxide support promoted by deposited gold nanoparticles. Characterization of the catalysts before and after the reaction was also performed.
- Liu, Xiaohao,Hamasaki, Akiyuki,Yamane, Yoshihiro,Aikawa, Shohei,Ishida, Tamao,Haruta, Masatake,Tokunaga, Makoto
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p. 3000 - 3006
(2013/11/06)
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- Conformationally constrained ortho- Anilino diaryl ureas: Discovery of 1-(2-(1′-Neopentylspiro[indoline-3,4′-piperidine]-1-yl)phenyl) -3-(4-(trifluoromethoxy)phenyl)urea, a potent, selective, and bioavailable P2Y1 antagonist
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Preclinical antithrombotic efficacy and bleeding models have demonstrated that P2Y1 antagonists are efficacious as antiplatelet agents and may offer a safety advantage over P2Y12 antagonists in terms of reduced bleeding liabilities. In this article, we describe the structural modification of the tert-butyl phenoxy portion of lead compound 1 and the subsequent discovery of a novel series of conformationally constrained ortho-anilino diaryl ureas. In particular, spiropiperidine indoline-substituted diaryl ureas are described as potent, orally bioavailable small-molecule P2Y1 antagonists with improved activity in functional assays and improved oral bioavailability in rats. Homology modeling and rat PK/PD studies on benchmark compound 3l will also be presented. Compound 3l was our first P2Y1 antagonist to demonstrate a robust oral antithrombotic effect with mild bleeding liability in the rat thrombosis and hemostasis models.
- Qiao, Jennifer X.,Wang, Tammy C.,Ruel, Réjean,Thibeault, Carl,L'Heureux, Alexandre,Schumacher, William A.,Spronk, Steven A.,Hiebert, Sheldon,Bouthillier, Gilles,Lloyd, John,Pi, Zulan,Schnur, Dora M.,Abell, Lynn M.,Hua, Ji,Price, Laura A.,Liu, Eddie,Wu, Qimin,Steinbacher, Thomas E.,Bostwick, Jeffrey S.,Chang, Ming,Zheng, Joanna,Gao, Qi,Ma, Baoqing,McDonnell, Patricia A.,Huang, Christine S.,Rehfuss, Robert,Wexler, Ruth R.,Lam, Patrick Y. S.
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supporting information
p. 9275 - 9295
(2014/01/06)
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- Efficient copper-catalyzed intramolecular N-arylation for the synthesis of oxindoles
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An efficient copper-catalyzed intramolecular N-arylation was performed by using substituted 2-(2-bromoaryl)acetamide with a small amount of Cu 2O and benzene-1,2-diamine as catalytic system under aerobic conditions, which provided good to excellent yields of oxindoles with tolerance of a wide variety of substrates.
- Jhan, Yu-Huei,Kang, Ting-Wei,Hsieh, Jen-Chieh
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p. 1155 - 1159
(2013/03/13)
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- A special focus on the photodegradation of 6'-indolino-1-isobutyl-3,3- dimethylspiro[indoline-2,3'-[3H]naphtho[2,1-b][1,4]oxazine]
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The photodegradation of 6'-indolino-1-isobutyl-3,3-dimethylspiro[indoline- 2,3'-[3H]naphtho[2,1-b][1,4]oxazine] (1) following exposure to polychromatic light, was investigated in fluid solution (toluene, T) and in a solid matrix (polyurethane, PU). The ph
- Alberti, Angelo,Aubert, Claude,Campredon, Mylene,Demadrille, Renaud
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p. 1048 - 1052,5
(2020/08/24)
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- Copper-catalyzed domino coupling reaction: An efficient method to synthesize oxindoles
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An efficient and novel procedure for a copper catalyzed domino coupling reaction has been developed, which afforded various oxindoles in good to excellent yields with tolerance of various substituents. In addition, this method could be applied to synthesize horsfiline and coerulescine in few steps with high total yields. The Royal Society of Chemistry 2012.
- Hsieh, Jen-Chieh,Cheng, An-Yi,Fu, Jun-Hao,Kang, Ting-Wei
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supporting information; experimental part
p. 6404 - 6409
(2012/09/05)
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- NOVEL COMPOUNDS
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The present invention relates to new CGRP-antagonists of general formula I wherein U, V, X, Y, R1, R2, R3 and R4 are defined as mentioned in the description, the tautomers thereof, the isomers thereof, the diastereomers thereof, the enantiomers thereof, the hydrates thereof, the mixtures thereof and the salts thereof as well as the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, medicaments containing these compounds, the use thereof and processes for the preparation thereof.
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Page/Page column 86
(2011/08/22)
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- Synthesis of oxindoles by palladium-catalyzed C-H bond amidation
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Treatment of N-tosylphenylacetamide derivatives with cop-per(II) acetate in the presence of a catalytic amount of palladi-um(II) acetate affords 3,3-disubstituted oxindoles. The reaction proceeds through the intramolecular metallation of an aromatic C-H b
- Miura, Tomoya,Ito, Yoshiteru,Murakami, Masahiro
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experimental part
p. 328 - 329
(2010/01/16)
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- Synthesis and activity of 1-(3-amino-1-phenylpropyl)indolin-2-ones: A new class of selective norepinephrine reuptake inhibitors
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Norepinephrine and serotonin play an important role in a wide variety of biological processes and are implicated in a number of neurological disorders. A novel class of 1-(3-amino-1-phenylpropyl)indolin-2-ones was designed and synthesized that displays po
- McComas, Casey C.,Vu, An T.,Mahaney, Paige E.,Cohn, Stephen T.,Fensome, Andrew,Marella, Michael A.,Nogle, Lisa,Trybulski, Eugene J.,Ye, Fei,Zhang, Puwen,Alfinito, Peter,Bray, Jenifer,Johnston, Grace,Koury, Elizabeth,Deecher, Darlene C.
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scheme or table
p. 4929 - 4931
(2009/05/07)
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- DIHYDROBENZOFURANYL DERIVATIVES AND METHODS OF THEIR USE
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The present invention is directed to dihydrobenzofuranyl derivatives of formula I: or a pharmaceutically acceptable salt thereof, which are monoamine reuptake inhibitors, compositions containing these derivatives, and methods of their use for the prevention and treatment of conditions, including, inter alia, vasomotor symptoms sexual dysfunction, gastrointestinal disorders and genitourinary disorder, depression disorders, endogenous behavioral disorder, cognitive disorder, diabetic neuropathy, pain, and other diseases or disorders.
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Page/Page column 22
(2008/12/06)
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- Synthesis of β-, γ-, and δ-lactams via Pd(II)-catalyzed C-H activation reactions
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Pd(II)-catalyzed intramolecular amination of sp2 and sp3 C-H bonds are developed using a combination of CuCl2 and AgOAc as the oxidant. The reaction protocol tolerates the presence of a double bond in the substrates. This catalytic reaction provides practical access to a wide range of β-, γ-, and δ-lactams. Copyright
- Wasa, Masayuki,Yu, Jin-Quan
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supporting information; experimental part
p. 14058 - 14059
(2009/03/11)
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- N-(2,2-Dimethyl-2-(2-nitrophenyl)acetyl)-4-aminocyclophosphamide as a potential bioreductively activated prodrug of phosphoramide mustard
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N-(2,2-Dimethyl-2-(2-nitrophenyl)acetyl)-4-aminocyclophosphamide isomers (DMNA-NH-CPA, 4) were synthesized stereospecifically from Boc-l-Hse(OBn)-OH and the degradation of the corresponding reduced amine 5a was investigated by UV/vis spectroscopy and LC/M
- Jiang, Yongying,Hu, Longqin
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scheme or table
p. 4059 - 4063
(2009/04/06)
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- Phenylaminopropanol derivatives and methods of their use
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The present invention is directed to phenylaminopropanol derivatives of formulae I, II, and III: [image] or a pharmaceutically acceptable salt thereof, compositions containing these derivatives, and methods of their use for the prevention and treatment of conditions ameliorated by monoamine reuptake including, inter alia, vasomotor symptoms (VMS), sexual dysfunction, gastrointestinal and genitourinary disorders, chronic fatigue syndrome, fibromyalgia syndrome, nervous system disorders, and combinations thereof, particularly those conditions selected from the group consisting of major depressive disorder, vasomotor symptoms, stress and urge urinary incontinence, fibromyalgia, pain, diabetic neuropathy, schizophrenia, and combinations thereof.
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Page/Page column 66
(2010/11/26)
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- Process for preparing 3,3-disubstituted oxindoles and thio-oxindoles
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Methods for preparing oxindole and thio-oxindole compounds are provided, which compounds are useful as precursors to useful pharmaceutical compounds. Specifically provided are methods for preparing 5-pyrrole-3,3-oxindole compounds and 5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile. Also provided are methods for preparing iminobenzo[b]thiophene and benzo[b]thiophenone compounds.
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Page/Page column 22-23
(2008/06/13)
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- N-linked heterocyclic antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
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The present invention provides novel ureas containing N-aryl or N-heteroaryl substituted heterocycles of Formula (I): or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate form thereof, wherein the variables A, B, D and W are as defined herein. These compounds are selective inhibitors of the human P2Y1 receptor which can be used as medicaments.
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Page/Page column 71
(2010/11/25)
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- Spiroquinazoline support studies: methods for the preparation of imidazoloindolines from oxindoles
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Two methods for the annulation of glycine to the 1 and 2 positions of oxindoles are described. The first method involves introduction of an α-azidoacetyl group on the oxindole nitrogen followed by an intramolecular Staudinger reaction to complete the annu
- Ortiz Barbosa, Yomadis A.,Hart, David J.,Magomedov, Nabi A.
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p. 8748 - 8754
(2007/10/03)
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- Oxyindole derivatives
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This invention relates to compounds of the formula (I): or a pharmaceutically acceptable salt thereof, wherein: A, R1, R2, R3, R4 and R5 are each as described herein or a pharmaceutically acceptable s
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Page/Page column 40
(2008/06/13)
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- Urea antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
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The present invention provides novel ureas containing N-aryl or N-heteroaryl substituted heterocycles and analogues thereof, which are selective inhibitors of the human P2Y1 receptor. The invention also provides for various pharmaceutical compositions of the same and methods for treating diseases responsive to modulation of P2Y1 receptor activity.
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Page/Page column 52
(2008/06/13)
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- Bicyclic androgen and progesterone receptor modulator compounds and methods
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The present invention is directed to compounds, pharmaceutical compositions, and methods for modulating processes mediated by AR and PR. More particularly, the invention relates to nonsteroidal compounds and compositions that are high affinity, high specificity agonists, partial agonists (i.e., partial activators and/or tissue-specific activators) and antagonists for AR and PR. Also provided are methods of making such compounds and pharmaceutical compositions, as well as critical intermediates used in their synthesis.
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- Kinase inhibitors
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Compounds having the formula are useful for inhibiting protein kinases. Also disclosed are compositions which inhibit protein kinases and methods of inhibiting protein kinases in a patient.
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- 5′-(2-Nitrophenylalkanoyl)-2′-deoxy-5-fluorouridines as potential prodrugs of FUDR for reductive activation
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Four 5′-(2-nitrophenylalkanoyl)-2′-deoxy-5-fluorouridines (1a-d) were designed and synthesized as potential prodrugs of FUDR for reductive activation. Two methyl groups were introduced α to the ester carbonyl to increase both the rate of cyclization activation and the stability of the conjugates towards serum esterases. Chemical reduction of the nitro group into an amino leads to cyclization and release of the active FUDR. Kinetic analysis of the cyclization activation process indicates that the two methyl groups α to the ester carbonyl restrict the rotational freedom of ground state molecule and promote the cyclization reaction. However, the two methyl groups also were found to render the conjugates as poor substrates of E. coli B nitroreductase. Conjugate 1c, without the two methyl groups, was reduced by E. coli B nitroreductase (t1/2=8 h) to give two products, a N-hydroxyl lactam and the drug FUDR, suggesting that the enzymatic reduction and subsequent cyclization activation proceeded through the hydroxylamine intermediate. These results indicate that cyclization activation will occur once the nitro group is reduced either to an amino or to a hydroxylamino group. The fact that the amino intermediates cyclized easily to release the incorporated drug FUDR suggests the feasibility of using peptide-linked acyl 2-aminophenylalkanoic acid esters as potential prodrugs for proteolytic activation.
- Liu, Bin,Hu, Longqin
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p. 3889 - 3899
(2007/10/03)
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- 2,2-Dimethyl-2-(o-nitrophenyl)acetyl (DMNA) as an assisted cleavage protecting group for amines
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2,2-Dimethyl-2-(o-nitrophenyl)acetyl group (DMNA) was explored as an assisted cleavage protecting group for amines and a one-step deprotection condition was developed for its efficient removal using hydrogenation in the presence of Pd-C or PtO2 catalyst and 10% HOAc in MeOH. DMNA was found to be especially useful for the synthesis of gem-diamino compounds using Hofmann rearrangement.
- Jiang, Yongying,Zhao, Jun,Hu, Longqin
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p. 4589 - 4592
(2007/10/03)
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- New progesterone receptor antagonists: 3,3-disubstituted-5-aryloxindoles.
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A new series of 3,3-disubstituted-5-aryloxindoles has been synthesized and evaluated for progesterone receptor antagonist (PR) activity in a T47D cell alkaline phosphatase assay and for their ability to bind PR in competition binding studies. In this comm
- Fensome, Andrew,Bender, Reinhold,Cohen, Jeffrey,Collins, Mark A,Mackner, Valerie A,Miller, Lori L,Ullrich, John W,Winneker, Richard,Wrobel, Jay,Zhang, Puwen,Zhang, Zhiming,Zhu, Yuan
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p. 3487 - 3490
(2007/10/03)
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- Intramolecular organolithium addition to indol-2(3H)-ones; an approach to the synthesis of pyrrolo[1,2-a]indoles and pyrido[1,2-a]indoles
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Cyclisation of 3 and 10 by lithium-halogen exchange followed by reduction with lithium aluminium hydride gives pyrrolo[1,2-a]indoles 11 and 13 respectively. Similar treatment of bromides 4a and 4b gives pyrido[1,2-a]indoles 12a and 12b. The Royal Society
- Jones, Keith,Storey, John M. D.
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p. 769 - 774
(2007/10/03)
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- First total synthesis of ent-gelsedine via a novel iodide-promoted allene N-acyliminium ion cyclization
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The first total synthesis of the oxindole alkaloid gelsedine (1) starting from (S)-malic acid is described. The key step is a novel iodide-promoted intramolecular reaction of an allene with an N-acyliminium ion intermediate which provided in a single step the bicyclic vinyl iodide 11. Other important steps are the highly stereoselective Pd-catalyzed Heck cyclization of N-methylanilide 23a which led to the desired spiro-oxindole 24a, the fully regioselective intramolecular oxymercuration of 25a to the desired cyclic ether, and the remarkable oxindole N-demethylation of 29 via a radical mechanism by using dibenzoyl peroxide. The total synthesis was concluded by the stereoselective introduction of the ethyl group from the bis-Boc compound. 41 followed by methoxylation of the oxindole nitrogen. This total synthesis leads to the unnatural (+)-enantiomer of gelsedine in 21 steps and 0.10% overall yield.
- Van Henegouwen,Fieseler,Rutjes,Hiemstra
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p. 8317 - 8325
(2007/10/03)
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- 29. Synthesis of Indole Derivatives by [2 + 2] Photocycloaddition of Indoline-2-thiones with Alkenes and Photodesulfurization of Indoline-2-thiones
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The photochemical synthesis of indole derivatives starting from the indoline-2-thiones 1 is described. Irradiation of indoline-2-thiones 1 in the presence of alkenes 3 gave 2-alkyl-3H-indoles 4-7 or 2-alkylindoles 8-22 through the ring cleavage of the intermediates, spirocyclic amino-thietanes, initially derived by [2 + 2] cycloaddition of the C=S bond of 1 and the C=C bond of 3. Irradiation of 1 in the presence of trialkylamines 26 gave desulfurization products 27-32 and unexpected 3-alkylindoles 33-40. N-Acylindoline-2-thiones 1l-p yielded the deacylated products, indoline-2-thiones 1a-b, and ethyl esters 43 through γ-H abstraction by the excited thioamide S-atom when irradiated in CDCl3/EtOH or benzene/EtOH. Oxygen analogues 2a-d also underwent intramolecular H abstraction to give the indolin-2-ones 2e-f and ethyl esters 43 in a similar way.
- Nishio, Takehiko,Oka, Mitsuru
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p. 388 - 397
(2007/10/03)
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- Regioselective palladium(II)-catalyzed synthesis of five- or seven-membered ring lactones and five-, six- or seven-membered ring lactams by cyclocarbonylation methodology
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2-Allylphenols react with carbon monoxide and hydrogen in the presence of catalytic quantities of a cationic palladium(II) complex [(PCy3)2Pd(H)(H2O)]+BF4- or palladium acetate and 1,4-bis(diphenylpho
- El Ali, Bassam,Okuro, Kazumi,Vasapollo, Giuseppe,Alper, Howard
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p. 4264 - 4270
(2007/10/03)
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- INDOLONES USEFUL AS SEROTONERGIC AGENTS
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This invention relates to compounds of the formula: STR1 which are useful as 5-HT 4 agonists or antagonists and 5-HT 3 antagonists.
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- RADIOLYTIC STUDIES OF THE REDUCTIVE CYCLIZATION OF 2-NITROARYLAMIDES: CYCLIZATION VIA HYDROXYLAMINE INTERMEDIATES
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The reductive cyclozation of several 2-nitroarylamides was studied by radiolytic reduction, examining the effects of substituents on the nitrophenyl ring and on the leaving aniline and variations in the nature of the link between the nitrophenyl ring and the leaving aniline.The stoichiometry of the reduction and the identification of N-hydroxylactam and aniline products suggest that the major initial products of such a reduction of the nitroamides are the corresponding hydroxylamines.Under anaerobic conditions, cyclization via the hydroxylamines was considerably faster (up to 160-fold) than via the corresponding amines under comparable conditions, but was similarly influenced by changes in geometry.Unlike cyclization via the amines, rates of cyclization via the hydroxylamines were sensitive to substitution on the leaving aniline, being accelerated by electron-withdrawing groups.The rate-determining step in the cyclization of teh hydroxylamines is proposed to be breakdown of the terahedral intermediate.
- Sykes, Bridget M.,Atwell, Graham J.,Denny, William A.,O'Connor, Charmian J.
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p. 587 - 596
(2007/10/02)
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- Kinetics and Mechanism of the Cyclization of Substituted N-Phenyl-2-methyl-2-(2-aminophenyl)propanamides and Analogues
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The cyclization of six N-aryl-2-(2-aminophenyl)alkylamides has been studied at various pH values.Compounds 1a, 2a and 3a had a similar leaving group (4-methoxyaniline) and varying degrees of steric bulk adjacent to the amide, while compounds 1a-1d had varying substituents on the leaving amine.The cyclization of all the compounds was found to be subject to general catalysis by acidic buffer components, with the buffer-independent pH profiles obeying the equation ko=kH2O+ +> + kH2O.Broensted analysis of the rate coefficients for buffer catalysis gave α values of ca. 0.4 for all compounds.The relative observed pseudo-first-order rate coefficients at pH 6.6 for compounds 3a, 2a and 1a were 1, 9 and 800, respectively, indicating the importance of 'stereopopulation control' (Milstein and Cohen, J.Am.Chem.Soc., 1972, 94, 9158) on the rate of cyclization.However, cyclization rates were found to be independent of the electronic properties of the leaving amine.The mechanism of cyclization was considered to be rate-determining, concerted attack by the neutral amine, followed by proton transfer from a general acid to the amide oxygen.
- Sykes, Bridget M.,Atwell, Graham J.,Denny, William A.,McLennan, Duncan J.,O'Connor, Charmian J.
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p. 337 - 342
(2007/10/02)
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- Oxidative degradation of organic photochromes
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Photo-oxidation of some representative spiropyrans and spiro-oxazines does not seem to involve singlet oxygen O2(1Δg). The photochromes rather behave, in the spiro and merocyanine form, as O2(1Δg) quenchers. Only a methoxy-nitro benzopyran derivative was found to promote formation of singlet oxygen. Superoxide anion O2 is likely the activated oxygen species responsible for their oxidative photodegradation.
- Malatesta,Milosa,Millini,Lanzini,Bortolus,Monti
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p. 303 - 310
(2007/10/02)
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- PREPARATION AND PHOTOLYSIS OF 1-HETEROSUBSTITUTED 1-(1-ALKENYL)BENZOTRIAZOLES
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A Paterson olefination reaction involving 1-trimethylsilanylmethyl-1H-benzotriazole and either adamantanone or acetone, in the presence of n-butyllithium, is used to prepare 1-adamantylidenemethyl-1H-benzotriazole and 1-(2-methylpropenyl)-1H-benzotriazole respectively.Further treatment of these compounds with n-butllithium and an electrophile affords a variety of 1-heterosubstituted 1-(1-alkenyl)benzotriazoles.Photolysis of the latter compounds yields products from three competing pathways: cyclisation with C-C bond formation, cyclisation with C-S bond formation and halogen atom transfer.
- Johnson, A. Peter,Dutton, Jonathan K.,Pleynet, David P. M.
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p. 1913 - 1932
(2007/10/02)
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