Inhibition of human leukocyte elastase. 2. Inhibition by substituted cephalosporin esters and amides

Pe, Finke; Bm, Ashe; Wb, Knight; Al, Maycock; Ma, Navia; Sk, Shah; Kr, Thompson; Dj, Underwood; Weston, Hazel; Zimmerman, M.D.

doi:10.1021/jm00171a029

Cited by 52 publications

(7 citation statements)

References 2 publications

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“…To our pleasure, the addition of several alcohols into diisopropylcarbodiimide (DIC) and 1,3-di- p -tolylcarbodiimide (DTC) was efficiently catalyzed by complexes 1 – 3 in benzene- d 6 to generate the corresponding isoureas (Table ). While organocopper reagents are most widely used to form isoureas, investigation of this product class remains limited, which is surprising especially considering the utility of isoureas as valuable biologically active molecules and versatile synthons for combinatorial total synthesis. − …”

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confidence: 99%

Actinide-Catalyzed Intermolecular Addition of Alcohols to Carbodiimides

et al. 2016

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The unprecedented actinide-catalyzed addition of alcohols to carbodiimides is presented. This represents a rare example of thorium-catalyzed transformations of an alcoholic substrate and the first example of uranium complexes showing catalytic reactivity with alcohols. Using the uranium and thorium amides U[N(SiMe3)2]3 and [(Me3Si)2N]2An[κ(2)-(N,C)-CH2Si(CH3)2N(SiMe3)] (An = Th or U), alcohol additions to unsaturated carbon-nitrogen bonds are achieved in short reaction times with excellent selectivities and high to excellent yields. Computational studies, supported by experimental thermodynamic data, suggest plausible models of the profile of the reaction which allow the system to overcome the high barrier of scission of the actinide-oxygen bond. Accompanied by experimentally determined kinetic parameters, a plausible mechanism is proposed for the catalytic cycle.

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confidence: 99%

Actinide-Catalyzed Intermolecular Addition of Alcohols to Carbodiimides

et al. 2016

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“…3-(Acetoxymethyl)-7a-methoxy-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic Acid (6). 13 To a cooled solution of trifluoroacetic acid (TFA) (75 mL) and anisóle (5 mL) at 0 °C was added tert-butyl 3-(acetoxymethyl)-7a-methoxy-8-oxo-5thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (5)13•21 (18 g,0.052 mol) as a solid or in a minimum amount of CH2CI2. The reaction was stirred at 0 °C until complete by TLC (1 h).…”

Section: Discussionmentioning

confidence: 99%

“…The organic layers were combined, dried over NagSOt, and evaporated. The crude product 6 (12)(13)(14) To an ice bath cooled solution of the crude acid 6(11.5 g, 40 mmol) in dioxane (100 mL) were sequentially added N-hydroxysuccinimide (5.7 g, 50 mmol) and dicyclohexylcarbodiimide (DCC) (12.4 g, 60 mmol). The reaction was stirred at room temperature under N2 for 30 min and then recooled in an ice bath.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of human leukocyte elastase. 4. Selection of a substituted cephalosporin (L-658,758) as a topical aerosol

Finke¹,

Shah²,

Ashe³

et al. 1992

J. Med. Chem.

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Human leukocyte elastase (HLE) is a serine protease which has been implicated as a causative agent in several pulmonary diseases. The continued modification of our previously reported cephalosporin-based HLE inhibitors has led to the identification of a series of C-2 amides with potent, topical activity in an in vivo hamster lung hemorrhage model. While the most potent in vitro HLE inhibition had previously been obtained with lipophilic ester derivatives, it was found that the less active, but more polar and stable, amide derivatives were much more effective in vivo. The development of the structure--activity relations for optimization of these activities is discussed. These results led to the selection of 3-(acetoxymethyl)-2-[(2(S)-carboxypyrrolidino)carbonyl]-7 alpha-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene, 5,5-dioxide (3, L-658,758) as a selective, potent, time-dependent HLE inhibitor suitable for formulation as a topical aerosol drug for possible clinical use.

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“…Finke and colleagues explored the formation of PMB esters with isourea 32 in their studies on cephalosporin esters for the inhibition of human leukocyte elastase. 27 PMB ester 35 was formed from 7α-methoxycephalosporanic acid and isourea 32 , although only in 19% yield. A similar reagent, 4-methoxybenzyl-1-piperidyl carbonate, has also been reported to be useful in the formation of PMB esters from carboxylic acids, but this method has not been widely utilized.…”

Section: Formation Of Pmb Estersmentioning

confidence: 99%