Synthesis and cytotoxic properties of 7α-chloro-3-methyl-1,1-dioxoceph-3-ems, substituted with amide or keto group at position 4

Abstract

activity.We have shown previously that the intensity and selectivity of cytotoxic properties in vitro of esters of 7α-chloro-3-methyl-1,1-dioxoceph-3-em-4-carboxylic acid relative to cancer and normal cells depend on the structure of the substituent at position 4 [1]. In a continuation of this work we have synthesized and studied the cytotoxic activity of 7α-chloro-3-methyl-1,1-dioxoceph-3-ems with amide and keto groups in position 4 some representatives of, which according to literature data, are effective inhibitors of human leucocyte elastases [2, 3].Amides of 7α-chloro-3-methyl-1,1-dioxoceph-3-em-4-carboxylic acid 5a-o were obtained, starting from 7α-chloro-3-methyl-1,1-dioxoceph-3-em-4-carboxylic acid (1) by conversion into the acid chloride using the Vilsmeier reagent. The latter was treated with the corresponding mono-or disubstituted amines 4a-o without isolation (Scheme). Along with the amides of 7α-chloro-3-methyl-1,1-dioxoceph-3-em-4-carboxylic acid 5a-o, the cephems 6a,d,f,g,l, containing N,N-dimethylaminomethyl group at position 2, were obtained from the reaction mixture when tert-butylamine 4a, benzhydrylamine 4d, 3-pyridylmethylamine 4f, paramethoxycarbonylaniline 4g, and piperidine 4l were used.By analogy with the 1 H NMR spectra of esters of 2,N,N-dimethylaminomethylene-7α-chloro-3-methyl-1,1-dioxoceph-3-em-4-carboxylic acid [1], the characteristic shift of the resonance signals of the protons of the =CN(CH 3 ) 2 group in the E-isomers to the 3.00-3.10 ppm region and of the Z-isomers to the 3.30-3.35 ppm region, indicates that in the cephems 6a,d,l the group =CN(CH 3 ) 2 is a mixture of the E-and Z-isomers, whereas in cephems 6f,g it is predominantly in the form of the E-isomer.

Synthesis of Chlorinated Bicyclic C-Fused Tetrahydrofuro[3,2-c]azetidin-2-ones

“…Accordingly, some apparently otherwise nonactivated monocyclic N -aryl-α-chloro-β-lactams have been reported to exhibit promising antibacterial, − antifungal, − and antitubercular activities and activities against nonmicrobial diseases such as antitumor, anticonvulsant, anti-Parkinson, CNS, and HLE inhibitory activities . Some 6-chloropenams possess β-lactamase inhibitory activities and 7-chlorocephems display anticancer and HLE- and PPE-inhibitory activities.…”