- CHEMISTRY OF ORGANOSILICON COMPOUNDS. CLXXXIII. AN ESR STUDY ON β-TRIMETHYLSILYLAMINE- AND RELATED AMINE-N-OXYLS. UNUSUAL CONFORMATIONAL PREFERENCE OF THE β-SILYL GROUP
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Fifteen β-trimethylsilylamine- and related amine-N-oxyls were generated by oxidation of the parent amines with m-chloroperoxybenzoic acid.Studies on the preferred conformation of the radicals by ESR spectroscopy indicate that the β-trimethylsilyl group exerts a strong influence favouring the conformation in which the trimethylsilyl group lies in the same plane as the N-O bond.The ESR spectra of related alkyl radicals, as well as results of unrestricted CNDO/2 calculations on the silylmethylamine-N-oxyls, are discussed.
- Kira, Mitsuo,Osawa, Hiroyoshi,Sakurai, Hideki
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- Stereo-, Regio-, and Chemoselective [3 + 2]-Cycloaddition of (2E,4E)-Ethyl 5-(Phenylsulfonyl)penta-2,4-dienoate with Various Azomethine Ylides, Nitrones, and Nitrile Oxides: Synthesis of Pyrrolidine, Isoxazolidine, and Isoxazoline Derivatives and a Computational Study
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One-pot chemo-, regio-, and stereoselective synthesis of series of heterocyclic and spiroheterocyclic compounds was accomplished through mono- and bis[3 + 2]-cycloaddition reactions of (2E,4E)-ethyl 5-(phenylsulfonyl)penta-2,4-dienoate as a dipolarophile with azomethine ylides, nitrones, and nitrile oxides in good yields. The structures of the products were established by spectroscopic techniques as well as by single-crystal XRD study, and DFT calculations were performed to further understand the mechanism of this [3 + 2]-cycloaddition reaction.
- Sankar, Ulaganathan,Surya Kumar, Ch. Venkata,Subramanian,Balasubramanian,Mahalakshimi
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p. 2340 - 2354
(2016/04/04)
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- Single electron transfer promoted photoaddition reactions of α-trimethylsilyl substituted secondary N-alkylamines with fullerene C60
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Single electron transfer (SET) promoted photoaddition reactions of secondary N-α-trimethylsilyl-N-alkylamines to C60 were explored to gain a deeper understanding of the mechanistic pathways followed and to expand the library of novel types of organofullerenes that can be generated using this approach. The results show that photoreactions of 10% EtOH-toluene solutions containing C60 and N-α-trimethylsilyl-N-alkylamines produce either aminomethyl-1,2-dihydrofullerenes or symmetric fulleropyrrolidines as major products depending on the nature of alkyl substituents. In contrast, photoreactions of 10% EtOH-ODCB solutions of these amines with C60 mainly lead to the formation of symmetric fulleropyrrolidines. Based on the analysis of product distributions and the results of earlier studies, two feasible mechanistic pathways are proposed for these processes. One route is initiated by SET from the amine substrates to the triplet-excited state of C60 to form the corresponding aminium radicals and C60 anion radicals. EtOH-promoted desilylation of the aminium radicals then takes place to produce aminomethyl radicals which can either add to C60 or couple with the C60 radical anions to form respective radicals or anion precursors of aminomethyl-1,2-dihydrofullerene products. The competing pathway leading to the generation of symmetric fulleropyrrolidines also involves the formation of aminomethyl radicals by using the sequential SET-desilylation process. In this route, the aminomethyl radicals are oxidized by SET to C60 to form iminium ions, which are then transformed to azomethine ylides by a pathway involving a second molecule of the secondary amine. Dipolar cycloaddition of the azomethine ylides to C60 forms the symmetric fulleropyrrolidine cycloadducts. Importantly, the observation that symmetric fulleropyrrolidines are the sole products formed in photoreactions between N-α-trimethylsilyl-N-alkylamines and C60 in 10% EtOH-ODCB has synthetic significance.
- Jeong, Ho Cheol,Lim, Suk Hyun,Cho, Dae Won,Kim, Sung Hong,Mariano, Patrick S.
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supporting information
p. 10502 - 10510
(2016/11/18)
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- Discovery of a selective small-molecule melanocortin-4 receptor agonist with efficacy in a pilot study of sexual dysfunction in humans
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The relevance of the melanocortin system to sexual activity is well established, and nonselective peptide agonists of the melanocortin receptors have shown evidence of efficacy in human sexual dysfunction. The role of the MC4 receptor subtype has received particular scrutiny, but the sufficiency of its selective activation in potentiating sexual response has remained uncertain owing to conflicting data from studies in preclinical species. We describe here the discovery of a novel series of small-molecule MC4 receptor agonists derived from library hit 2. The addition of methyl substituents at C3 and C5 of the 4-phenylpiperidin-4-ol ring was found to be markedly potency-enhancing, enabling the combination of low nanomolar potencies with full rule-of-five compliance. In general, the series shows only micromolar activity at other melanocortin receptors. Our preferred compound 40a provided significant systemic exposure in humans on both sublingual and oral administration and was safe and well tolerated up to the maximum tested dose. In a pilot clinical study of male erectile dysfunction, the highest dose of 40a tested (200 mg) provided a similar level of efficacy to sildenafil.
- Lansdell, Mark I.,Hepworth, David,Calabrese, Andrew,Brown, Alan D.,Blagg, Julian,Burring, Denise J.,Wilson, Peter,Fradet, David,Brown, T. Bruce,Quinton, Faye,Mistry, Neela,Tang, Kim,Mount, Natalie,Stacey, Peter,Edmunds, Nick,Adams, Cathryn,Gaboardi, Samantha,Neal-Morgan, Stevie,Wayman, Chris,Cole, Susan,Phipps, Joanne,Lewis, Mark,Verrier, Hugh,Gillon, Val,Feeder, Neil,Heatherington, Anne,Sultana, Stefan,Haughie, Scott,Martin, Steven W.,Sudworth, Maria,Tweedy, Sarah
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supporting information; scheme or table
p. 3183 - 3197
(2010/09/15)
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- Use of Mc4 Receptor Agonist Compounds
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This invention relates to the use of an MC4 receptor agonist compound for the manufacture of a medicament for the treatment of lower urinary tract dysfunction.
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Page/Page column 28
(2008/12/08)
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- PIPERIDINOYL-PYRROLIDINE AND PIPERIDINOYL-PIPERIDINE COMPOUNDS
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The present invention relates to a class of compounds of general formula (I) and the salts, hydrates, solvates, polymorphs and prodrugs wherein n, R6, R7 and R10 are as defined herein and especially to MCR4 agonist compounds of formula (I), to their use in medicine, particularly in the treatment of sexual dysfunction and obesity, to intermediates useful in their synthesis and to compositions containing them.
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Page/Page column 68
(2010/11/25)
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- ACYLATED SPIROPIPERIDINE DERIVATIVES AS MELANOCORTIN-4 RECEPTOR MODULATORS
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Certain novel N-acylated spiropiperidine derivatives are ligands of the human melanocortin receptor(s) and, in particular, are selective ligands of the human melanocortin-4 receptor (MC-4R). They are therefore useful for the treatment, control, or prevention of diseases and disorders responsive to the modulation of MC-4R, such as obesity, diabetes, nicotine addiction, alcoholism, sexual dysfunction, including erectile dysfunction and female sexual dysfunction.
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Page/Page column 83
(2008/06/13)
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- Pharmaceutically active compounds
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The present invention relates to a class of melanocortin MCR4 agonists of general formula (I) wherein R1, R2, R3, R4 and R5 are as defined herein and especially to selective MCR4 agonist compounds, to
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Page/Page column 56
(2010/02/13)
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- PIPERIDINE DERIVATIVES AS MELANOCORTIN-4 RECEPTOR AGONISTS
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Certain novel piperidine derivatives are agonists of the human melanocortin receptor(s) and, in particular, are selective agonists of the human melanocortin-4 receptor (MC-4R). They are therefore useful for the treatment, control, or prevention of diseases and disorders responsive to the activation of MC-4R, such as obesity, diabetes, sexual dysfunction, including erectile dysfunction and female sexual dysfunction.
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Page/Page column 71; 72
(2010/02/10)
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- BICYCLIC PIPERIDINE DERIVATIVES AS MELANOCORTIN-4 RECEPTOR AGONISTS
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Certain novel bicyclic N-acylated piperidine derivatives are agonists of the human melanocortin receptor(s) and, in particular, are selective agonists of the human melanocortin-4 receptor (MC-4R). They are therefore useful for the treatment, control, or p
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Page/Page column 56
(2010/02/08)
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- ACYLATED PIPERIDINE DERIVATIVES AS MELANOCORTIN-4 RECEPTOR AGONISTS
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Certain novel 4-substituted N-acylated piperidine derivatives are agonists of the human melanocortin receptor(s) and, in particular, are selective agonists of the human melanocortin-4 receptor (MC-4R). They are therefore useful for the treatment, control, or prevention of diseases and disorders responsive to the activation of MC-4R, such as obesity, diabetes, sexual dysfunction, including erectile dysfunction and female sexual dysfunction.
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- EPR spectroscopic studies of N-alkyl-N-trialkylsilylmethylaminyl radicals in solution
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Photochemically generated trialkylsilyl radicals R3Si (R = Me, Et, Pri) add rapidly to N-methylene-tert-butylamine (H2C=NBut) to give silylmethylaminyl radicals R3SiCH2NBut which have been studied by EPR spectroscopy.These aminyl radicals prefer conformations in which the β-C-Si bond eclipses the N-2p? orbital, formally occupied by the unpaired electron, and lineshape effect resulting from hindered rotation about the R3SiCH2-N bond are evident in the EPR spectra.The aminyl radicals Me3SiCH2NBut and Me3SiCH2NMe have been generated by displacement from aminophosphanes of the type (EtO)2PN(R)CH2SiMe3 using photochemically-generated alkoxyl radicals.The proposal in the literature that Me3SiCH2NR radical (R = Me or But) rearranges to give CH2N(R)SiMe3 radical has been confirmed and this process has been monitored by EPR spectroscopy.Since no free silyl radicals could be trapped by But2C=CH2, the rearrangement probably proceeds by an intramolecular 1,2-shift of the Me3Si group from carbon to nitrogen.The rearranged radicals CH2N(R)SiMe3 have been generated independently by hydrogen-atom abstraction from the corresponding aminosilanes Me3SiN(R)CH3.
- Roberts, Brian P.,Vazquez-Persaud, Anthony R.
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p. 1087 - 1096
(2007/10/02)
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- Hydrogen Abstraction from Silylamines; an Investigation of the 1,2-Migration of the Trimethylsilyl Group in Aminyl Radicals
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Hydrogen abstraction from a series of silyl-substituted amines, Me3SiCHRNHR', by tert-butoxyl radicals has been examined by EPR spectroscopy.For each amine hydrogen is abstracted from both the methylene (or methine) group and from the amino group to give
- Harris, Joanna M.,Walton, John C.,Maillard, Bernard,Grelier, Stephane,Picard, Jean-Paul
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p. 2119 - 2124
(2007/10/02)
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