50670-83-2Relevant articles and documents
Carbapenem antibiotic compounds
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, (2008/06/13)
A carbapenem compound of the formula (I) STR1 wherein: R1 is 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl; R2 is hydrogen or C1-4 alkyl; R3 is hydrogen or C1-4 alkyl; R4 is hydroxy or carboxy; and the phenyl ring is optionally further substituted by one or two substituents selected from halo, cyano, C1-4 alkyl, nitro, hydroxy, carboxy, C1-4 alkoxy, trifluoromethyl, C1-4 alkoxycarbonyl, carbamoyl, C1-4 alkylcarbamoyl, di-C1-4 alkylcarbamoyl, amino, C1-4 alkylamino, di-C1-4 alkylamino sulphonic acid, C1-4 alkylS(O)n --(wherein n is 0-2), N-C1-4 alkanesulphonamido, C1-4 alkanoylamino and C1-4 alkanoyl(N-C1-4 alkyl)amino: provided that the phenyl ring is substituted by at least one carboxy; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
Design and synthesis of 4H-3,1-Benzoxazin-4-ones as potent alternate substrate inhibitors of human leukocyte elastase
Krantz,Spencer,Tam,Liak,Copp,Thomas,Rafferty
, p. 464 - 479 (2007/10/02)
4H-3,1-Benzoxazin-4-ones are alternate substrate inhibitors of the serine proteinase human leukocyte elastase (HL elastase) and form acyl enzyme intermediates during enzyme catalysis. We have synthesized a large variety of benzoxazinones using specific methods that have been adapted to achieve the pattern of ring substitution dictated by theoretical considerations. The results of the inhibition of HL elastase by 175 benzoxazinones are reported herein with reference to hydrophobicity constants D, alkaline hydrolysis rates κ(OH-), inhibition constants K(i), and their component acylation and deacylation rate constants, κ(on) and κ(off), respectively. The ranges for the compounds are considerable; alkaline hydrolysis rates and κ(on) span 6, κ(off) covers 5, and K(i) spans 8 orders of magnitude. Multiple regression on this large data set has been used to isolate the contributions of electronic and steric effects, as well as other factors specific to compound stability and elastase inhibition. Essentially, a simple electronic parameter is sufficient to account for almost all the variance in the alkaline hydrolysis data, indicating that electronic factors are the major determinants of this type of benzoxazinone reactivity. Factors that significantly enhance the potency of benzoxazinones I are R5 alkly groups and electron withdrawal by R2. Bulk in R7 and R8 and compound hydrophobicity are not significant, but substitution in R6 is highly unfavorable as are substituents linked via carbon to C2. The physicochemical factors that underlie these trends in K(i) are further analyzed in terms of equations that describe κ(on) and κ(off). A conclusion that emerges is that chemically stable, potent benzoxazinone inhibitors of HL elastase with inhibition constants in the nanomolar range can be designed with (1) R5 alkyl groups to inhibit enzyme-catalyzed deacylation, (2) small alkyl substituents linked via heteroatoms to C2 to enhance acylation and limit deacylation rates, and (3) strongly electron-donating groups at C7 to stabilize the oxazinone ring to nucleophilic attack. Thus, 2-(isopropylamino)-5-n-propyl-7-(dimethylamino)benzoxazinone 95 has κ(OH-) = 0.01 M-1 s-1, which extrapolates to a half-life at pH 7.4 of over 8.5 years, and 2-ethoxy-5-ethylbenzoxazinone 38 has K(i) = 42 pM.
