- Synthesis and structure-activity studies on N-[5-(1H-imidazol-4-yl)-5,6,7,8-tetrahydro-1-naphthalenyl]methanesulfonamide, an imidazole-containing α1A-adrenoceptor agonist
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Structure-activity studies were performed on the α 1A-adrenoceptor (AR) selective agonist N-[5-(1H-imidazol-4-yl)-5,6,7,8-tetrahydro-1-naphthalenyl]methanesulfonamide (4). Compounds were evaluated for binding activity at the α1A, α1b, α1d, α2a, and α2B subtypes. Functional activity in tissues containing the α1A (rabbit urethra), α1B (rat spleen), α1D (rat aorta), and α2A (rat prostatic vas deferens) was also evaluated. A dog in vivo model simultaneously measuring intraurethral pressure (IUP) and mean arterial pressure (MAP) was used to assess the uroselectivity of the compounds. Many of the compounds that were highly selective in vitro for the α1A-AR subtype were also more uroselective in vivo for increasing IUP over MAP than the nonselective α1-agonists phenylpropanolamine (PPA) (1) and ST-1059 (2, the active metabolite of midodrine), supporting the hypothesis that greater α1A selectivity would reduce cardiovascular side effects. However, the data also support a prominent role of the α1A-AR subtype in the control of MAP.
- Altenbach, Robert J.,Khilevich, Albert,Kolasa, Teodozyj,Rohde, Jeffrey J.,Bhatia, Pramila A.,Patel, Meena V.,Searle, Xenia B.,Yang, Fan,Bunnelle, William H.,Tietje, Karin,Bayburt, Erol K.,Carroll, William A.,Meyer, Michael D.,Henry, Rodger,Buckner, Steven A.,Kuk, Jane,Daza, Anthony V.,Milicic, Ivan V.,Cain, John C.,Kang, Chae H.,Ireland, Lynne M.,Carr, Tracy L.,Miller, Thomas R.,Hancock, Arthur A.,Nakane, Masaki,Esbenshade, Timothy A.,Brune, Michael E.,O'Neill, Alyssa B.,Gauvin, Donna M.,Katwala, Sweta P.,Holladay, Mark W.,Brioni, Jorge D.,Sullivan, James P.
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- Oxidation of Nonactivated Anilines to Generate N-Aryl Nitrenoids
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A low-temperature, protecting-group-free oxidation of 2-substituted anilines has been developed to generate an electrophilic N-aryl nitrenoid intermediate that can engage in C-NAr bond formation to construct functionalized N-heterocycles. The exposure of 2-substituted anilines to PIFA and trifluoroacetic acid or 10 mol percent Sc(OTf)3 triggers nitrenoid formation, followed by productive and selective C-NAr and C-C bond formation to yield spirocyclic- or bicyclic 3H-indoles or benzazepinones. Our experiments demonstrate the breadth of these oxidative processes, uncover underlying fundamental elements that control selectivity, and demonstrate how the distinct reactivity patterns embedded in N-aryl nitrenoid reactive intermediates can enable access to functionalized 3H-indoles or benzazepinones.
- Deng, Tianning,Mazumdar, Wrickban,Ford, Russell L.,Jana, Navendu,Izar, Ragda,Wink, Donald J.,Driver, Tom G.
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p. 4456 - 4463
(2020/03/05)
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- The application of the schmidt reaction and beckmann rearrangement to the synthesis of bicyclic lactams: Some mechanistic considerations
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The syntheses of some methoxy-substituted bicyclic lactams, of the types 3 and 4, are reported employing two different conditions for the Schmidt reaction of appropriate ketones and employing two different conditions for the Beckmann rearrangement of the corresponding ketoximes. The alkyl to aryl migration ratios of the reactions were determined by high-performance liquid chromatography analysis of the reactions. The mechanisms of the reactions reported are discussed, some limitations of the reported mechanisms identified, and an alternative mechanism proposed in light of the outcomes of the various reactions. Application of the Schmidt reaction and Beckmann rearrangement was used for the synthesis of some chloro bicyclic lactams, of the types 3 and 4. CSIRO 2010.
- Crosby, Ian T.,Shin, James K.,Capuano, Ben
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experimental part
p. 211 - 226
(2011/06/21)
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- Benzo-fused lactams that promote the release of growth hormone
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There are disclosed certain novel compounds identified as benzo-fused lactams which promote the release of growth hormone in humans and animals. This property can be utilized to promote the growth of food animals to render the production of edible meat products more efficient, and in humans, to increase the stature of those afflicted with a lack of a normal secretion of natural growth hormone. Growth promoting compositions containing such benzo-fused lactams as the active ingredient thereof are also disclosed.
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- Synthesis of 7-phenylpyrimido[5,4-d][1]benzazepin-2-ones
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The syntheses of the 7-phenylpyrimido[5,4-d][1]benzazepin-2-ones 3, 4, and 5 are described. The 7-phenyl group was introduced by phenylation of the lactam nitrogen in 10, 13 and 16 respectively. One of these compounds, 5, showed moderate activity as a CNS agent.
- Chen,Gilman
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p. 663 - 666
(2007/10/02)
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