- Benzylic C-H isocyanation/amine coupling sequence enabling high-throughput synthesis of pharmaceutically relevant ureas
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C(sp3)-H functionalization methods provide an ideal synthetic platform for medicinal chemistry; however, such methods are often constrained by practical limitations. The present study outlines a C(sp3)-H isocyanation protocol that enables the synthesis of diverse, pharmaceutically relevant benzylic ureas in high-throughput format. The operationally simple C-H isocyanation method shows high site selectivity and good functional group tolerance, and uses commercially available catalyst components and reagents [CuOAc, 2,2′-bis(oxazoline) ligand, (trimethylsilyl)isocyanate, andN-fluorobenzenesulfonimide]. The isocyanate products may be used without isolation or purification in a subsequent coupling step with primary and secondary amines to afford hundreds of diverse ureas. These results provide a template for implementation of C-H functionalization/cross-coupling in drug discovery.
- Krska, Shane W.,Lin, Shishi,Nkulu, Leah E.,Stahl, Shannon S.,Suh, Sung-Eun
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p. 10380 - 10387
(2021/08/12)
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- Alkyl Isocyanates via Manganese-Catalyzed C-H Activation for the Preparation of Substituted Ureas
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Organic isocyanates are versatile intermediates that provide access to a wide range of functionalities. In this work, we have developed the first synthetic method for preparing aliphatic isocyanates via direct C-H activation. This method proceeds efficiently at room temperature and can be applied to functionalize secondary, tertiary, and benzylic C-H bonds with good yields and functional group compatibility. Moreover, the isocyanate products can be readily converted to substituted ureas without isolation, demonstrating the synthetic potential of the method. To study the reaction mechanism, we have synthesized and characterized a rare MnIV-NCO intermediate and demonstrated its ability to transfer the isocyanate moiety to alkyl radicals. Using EPR spectroscopy, we have directly observed a MnIV intermediate under catalytic conditions. Isocyanation of celestolide with a chiral manganese salen catalyst followed by trapping with aniline afforded the urea product in 51% enantiomeric excess. This represents the only example of an asymmetric synthesis of an organic urea via C-H activation. When combined with our DFT calculations, these results clearly demonstrate that the C-NCO bond was formed through capture of a substrate radical by a MnIV-NCO intermediate.
- Huang, Xiongyi,Zhuang, Thompson,Kates, Patrick A.,Gao, Hongxin,Chen, Xinyi,Groves, John T.
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supporting information
p. 15407 - 15413
(2017/11/06)
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- CYCLIC INHIBITORS OF 11BETA-HYDROXYSTEROID DEHYDROGENASE 1
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This invention relates to novel compounds of the Formula (I), (II), (II-A), (Il-B), (ll-C), (ll-D), (III). (III-A). (IIIl-B). (IIl-C). (IIl-D), (III-E) (IV), (IV-A), (IV-B). (IV-C), (IV-D). (V), (V-A), (V-B), (V-C), (V-D), pharmaceutically acceptable salt
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Page/Page column 85
(2011/02/24)
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- CYCLIC INHIBITORS OF 11BETA-HYDROXYSTEROID DEHYDROGENASE 1
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This invention relates to novel compounds of the Formula Ik, Im1, Im2, Im5, In1, In2, In5, Io1, Io2, Io5, Ip1, Ip3, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful for the therapeutic treatment of diseases associated with the modulation or inhibition of 11β-HSD1 in mammals. The invention further relates to pharmaceutical compositions of the novel compounds and methods for their use in the reduction or control of the production of cortisol in a cell or the inhibition of the conversion of cortisone to cortisol in a cell.
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Page/Page column 23; 25; 26
(2011/01/05)
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- CYCLIC INHIBITORS OF 11BETA-HYDROXYSTEROID DEHYDROGENASE 1
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This invention relates to novel compounds of an 11 β-HSD1 inhibitor disclosed herein, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful for the therapeutic treatment of diseases associated with the modula
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Page/Page column 54
(2010/08/18)
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- SYNTHESIS OF INHIBITORS OF 11BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 1
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Disclosed are syntheses of 11 beta-HSD1 inhibitors and corresponding intermediates that are promising for the treatment of a variety of disease states including diabetes, metabolic syndrome, obesity, glucose intolerance, insulin resistance, hyperglycemia, hypertension, hypertension-related cardiovascular disorders, hyperlipidemia, deleterious gluco-corticold effects on neuronal function (e.g. cognitive impairment, dementia, and/or depression), elevated intra-ocular pressure, various forms of bone disease (e.g., osteoporosis), tuberculosis, leprosy (Hansen's disease), psoriasis, and impaired wound healing (e.g., in patients that exhibit impaired glucose tolerance and/or type 2 diabetes).
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Page/Page column 33
(2010/04/03)
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- Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor
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Compounds of formula (I) are novel VR1 antagonists that are useful in treating pain, inflammatory thermal hyperalgesia, urinary incontinence and bladder overactivity, wherein X1, X2, X3, X4, X5, R5, R6, R7, R8a, R8b, R9, Z1, Z2 and L are as defined in the description.
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- Synthesis of rigid receptors based on triphenylene ketals
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The synthesis of rigid receptors based on triphenylene ketals, including some improved procedures, is described in detail. Since chemical transformations are strongly influenced by the rigid character and steric bulkiness of the receptors, the constructio
- Schopohl, Matthias C.,Faust, Andreas,Mirk, Daniela,Froehlich, Roland,Kataeva, Olga,Waldvogel, Siegfried R.
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p. 2987 - 2999
(2007/10/03)
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- Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor
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Compounds of formula (I) are novel VR1 antagonists that are useful in treating pain, inflammatory thermal hyperalgesia, urinary incontinence and bladder overactivity.
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Page/Page column 52
(2010/02/11)
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- Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor
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Compounds of formula (I) are novel VR1 antagonists that are useful in treating pain, inflammatory thermal hyperalgesia, urinary incontinence and bladder overactivity.
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- GLUCAGON ANTAGONISTS/INVERSE AGONISTS
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A novel class of compounds, which act to antagonize the action of the glucagon hormone on the glucagon receptor. Owing to their antagonizing effect of the glucagon receptor the compounds may be suitable for the treatment and/or prevention of any diseases and disorders, wherein a glucagon antagonistic action is beneficial, such as hyperglycemia, Type 1 diabetes, Type 2 diabetes, disorders of the lipid metabolism and obesity.
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