- Enantioselective synthesis of BMS-204352 (MaxiPost) using N-fluoroammonium salts of cinchona alkaloids (F-CA-BF4).
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The enantioselective synthesis of a potent Maxi-K potassium channel opener (BMS-204352) mediated by N-fluoroammonium salts of cinchona alkaloids is described. Two synthetic pathways were evaluated. An ee as high as 88% was achieved (>99% after a single re
- Zoute, Ludivine,Audouard, Christophe,Plaquevent, Jean-Christophe,Cahard, Dominique
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Read Online
- A radical approach to the copper oxidative addition problem: Trifluoromethylation of bromoarenes
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Transition metal–catalyzed arene functionalization has been widely used for molecular synthesis over the past century. In this arena, copper catalysis has long been considered a privileged platform due to the propensity of high-valent copper to undergo reductive elimination with a wide variety of coupling fragments. However, the sluggish nature of oxidative addition has limited copper’s capacity to broadly facilitate haloarene coupling protocols. Here, we demonstrate that this copper oxidative addition problem can be overcome with an aryl radical–capture mechanism, wherein the aryl radical is generated through a silyl radical halogen abstraction. This strategy was applied to a general trifluoromethylation of aryl bromides through dual copper-photoredox catalysis. Mechanistic studies support the formation of an open-shell aryl species.
- Le, Chip,Chen, Tiffany Q.,Liang, Tao,Zhang, Patricia,MacMillan, David W. C.
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p. 1010 - 1014
(2018/06/12)
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- Ligand-Promoted Meta-C-H Arylation of Anilines, Phenols, and Heterocycles
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Here we report the development of a versatile 3-acetylamino-2-hydroxypyridine class of ligands that promote meta-C-H arylation of anilines, heterocyclic aromatic amines, phenols, and 2-benzyl heterocycles using norbornene as a transient mediator. More than 120 examples are presented, demonstrating this ligand scaffold enables a wide substrate and coupling partner scope. Meta-C-H arylation with heterocyclic aryl iodides as coupling partners is also realized for the first time using this ligand. The utility for this transformation for drug discovery is showcased by allowing the meta-C-H arylation of a lenalidomide derivative. The first steps toward a silver-free protocol for this reaction are also demonstrated.
- Wang, Peng,Farmer, Marcus E.,Huo, Xing,Jain, Pankaj,Shen, Peng-Xiang,Ishoey, Mette,Bradner, James E.,Wisniewski, Steven R.,Eastgate, Martin D.,Yu, Jin-Quan
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supporting information
p. 9269 - 9276
(2016/08/05)
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- Substituted aryl pyrimidines as potent and soluble TRPV1 antagonists
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Clinical candidate AMG 517 (1) is a potent antagonist toward multiple modes of activation of TRPV1; however, it suffers from poor solubility. Analogs with various substituents at the R region of 3 were prepared to improve the solubility while maintaining
- Stec, Markian M.,Bo, Yunxin,Chakrabarti, Partha P.,Liao, Lillian,Ncube, Mqhele,Tamayo, Nuria,Tamir, Rami,Gavva, Narender R.,Treanor, James J.S.,Norman, Mark H.
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scheme or table
p. 5118 - 5122
(2009/05/07)
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- Design and synthesis of peripherally restricted transient receptor potential vanilloid 1 (TRPV1) antagonists
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Transient receptor potential vanilloid 1 (TRPV1) channel antagonists may have clinical utility for the treatment of chronic nociceptive and neuropathic pain. We recently advanced a TRPV1 antagonist, 3 (AMG 517), into clinical trials as a new therapy for t
- Tamayo, Nuria,Liao, Hongyu,Stec, Markian M.,Wang, Xianghong,Chakrabarti, Partha,Retz, Dan,Doherty, Elizabeth M.,Surapaneni, Sekhar,Tamir, Rami,Bannon, Anthony W.,Gavva, Narender R.,Norman, Mark H.
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p. 2744 - 2757
(2008/12/22)
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- Nucleus- and side-chain fluorinated 3-substituted indoles by a suitable combination of organometallic and radical chemistry
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Regioselectively fluoro-, trifluoromethyl- and trifluoromethoxy-substituted 3-methyleneindolines have been prepared using a four-step procedure involving metalation/bromination of fluorinated Boc-protected anilines, N-propargylation of the resulting o-bro
- Bellezza, Francesca,Cipiciani, Antonio,Ruzziconi, Renzo,Spizzichino, Sara
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- Vanilloid receptor ligands and their use in treatments
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Compounds having the general structure and compositions containing them, for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders.
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Page/Page column 56
(2008/06/13)
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- Vanilloid receptor ligands and their use in treatments
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Compounds having the general structure and compositions containing them, for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders.
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Page/Page column 54
(2010/11/24)
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- Catalytic enantioselective fluorination of oxindoles
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We have developed a highly efficient catalytic enantioselective fluorination of oxindole derivatives. In the presence of a catalytic amount of chiral Pd complex 2 (2.5 mol %), various substrates, including aryl- and alkyl-substituted oxindoles, were fluor
- Hamashima, Yoshitaka,Suzuki, Toshiaki,Takano, Hisashi,Shimura, Yuta,Sodeoka, Mikiko
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p. 10164 - 10165
(2007/10/03)
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- Synthesis of regiospecifically substituted quinolines from anilines
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A protocol for the synthesis of quinolines substituted on both pyridine and benzo-fused rings is reported. The method is based on the formylation of a substituted N-(tert-butoxycarbonyl)aniline followed by direct cyclisation and aromatisation of the inter
- Chelucci, Giorgio,Manca, Ilaria,Pinna, Gerard A.
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p. 767 - 770
(2007/10/03)
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- Synthesis and Biological Evaluation of New 1,2-Dihydro-4-hydroxy-2-oxo-3-quinolinecarboxamides for Treatment of Autoimmune Disorders: Structure-Activity Relationship
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Roquinimex-related 3-quinolinecarboxamide derivatives were prepared and evaluated for treatment of autoimmune disorders. The compounds were tested in mice for their inhibitory effects on disease development in the acute experimental autoimmune encephalomyelitis model and selected compounds in the beagle dog for induction of proinflammatory reaction. Structure-activity relationships are discussed. Compound 8c, laquinimod, showed improved potency and superior toxicological profile compared to the lead compound roquinimex (1b, Linomide) and was selected for clinical studies (currently in phase II).
- J?nsson, Stig,Andersson, Gunnar,Fex, Tomas,Fristedt, Tomas,Hedlund, Gunnar,Jansson, Karl,Abramo, Lisbeth,Fritzson, Ingela,Pekarski, Olga,Runstr?m, Anna,Sandin, Helena,Thuvesson, Ingela,Bj?rk, Anders
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p. 2075 - 2088
(2007/10/03)
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- Synthesis of 3H and 14C labeled (S)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6- (trifluoromethyl)-2H-indol-2-one, Maxipost. An agent for post-stroke neuroprotection
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The syntheses of tritium labeled (S)-3-(5-chloro-2-[OC3H3]methoxyphenyl-1, 3-dihydro-3-fluoro-6-(trifluoromethyl)-1H-indol-2-one, and carbon-14 (S)-3- (5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl) -2H-[2,3-
- Dischino, Douglas D.,Gribkoff, Valentin K.,Hewawasam, Piyasena,Luke, George M.,Rinehart, J. Kent,Spears, Tony L.,Starrett Jr., John E.
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p. 139 - 149
(2007/10/03)
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- Novel quinolinone-phosphonic acid AMPA antagonists devoid of nephrotoxicity.
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We reported previously the synthesis and structure-activity relationships (SAR) in a series of 2-(1H)-oxoquinolines bearing different acidic functions in the 3-position. Exploiting these SAR, we were able to identify 6,7-dichloro-2-(1H)-oxoquinoline-3-phosphonic acid compound 3 (S 17625) as a potent, in vivo active AMPA antagonist. Unfortunately, during the course of the development, nephrotoxicity was manifest at therapeutically effective doses. Considering that some similitude exists between S 17625 and probenecid, a compound known to protect against the nephrotoxicity and/or slow the clearance of different drugs, we decided to synthesise some new analogues of S 17625 incorporating some of the salient features of probenecid. Replacement of the chlorine in position 6 by a sulfonylamine led to very potent AMPA antagonists endowed with good in vivo activity and lacking nephrotoxicity potential. Amongst the compounds evaluated, derivatives 7a and 7s appear to be the most promising and are currently evaluated in therapeutically relevant stroke models.
- Cordi, Alex A,Desos, Patrice,Ruano, Elisabeth,Al-Badri, Hashim,Fugier, Claude,Chapman, Astrid G,Meldrum, Brian S,Thomas, Jean-Yves,Roger, Anita,Lestage, Pierre
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p. 787 - 802
(2007/10/03)
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