Cephems properties

Oxazines and thiazines were considered together in CHEC(1984) and this meant that the review was restricted. In CHEC-II(1996) <1996CHEC-II(6)383>, the individual heterocycles and their derivatives were reviewed separately, which allowed for a thorough coverage. This trend is continued in this edition where the 1,3-thiazines and their derivatives are discussed, and this includes a review of the chemistry, syntheses, and applications. It does not include the vast literature dealing with cephems and related systems and other fused systems are not included unless their chemistry illustrates some significant property of the 1,3-thiazine heterocycle itself. 

In vivo studies for many of the Merck yS-lactam inactivators have been reported. In the cephem series, these reports have focused on the i.t. profile of (16-7) which was determined to possess the best overall properties for an aerosol drug candidate. This compound had an ED50 of 5 fig /animal in the AHA model when dosed i.t. 30 min. prior to HLE challenge. It showed sustained duration of action in the AHA model with a tjo (the pre-insult time... 

In the first edition of Comprehensive Heterocyclic Chemistry (CHEC-I) 1,3-thiazines and 1,3-oxazines were reviewed together indeed, much of their chemistry is similar, providing justification for this arrangement. However, there are areas in which this is not so, and in this edition the two types of heterocycle are treated separately. This allows a more focused approach, but as Quiniou and Guilloton <90AHC(50)85> have already pointed out, one feature which complicates any survey of 1,3-thiazines is the interrelationship of these compounds to cephalosporins. The literature dealing with cephems and related systems is vast and requires individual treatment, so here the emphasis is on the synthesis and reactions of simple 1,3-thiazines and their benzo derivatives. Other fused systems are not included unless their chemistry illustrates some important property of the 1,3-thiazine heterocycle itself. 

Representatives of derivatives involved in this section were used for various applications. Thus, a number of tetrazolo[l,5-Z ]pyridazine derivatives were built into cephem derivatives as substituents and were evaluated for antibiotic properties <81JAN1456, 85PNA7096, 86JAP6ii0658l>. The N-methyl-tetrazoloquinazolone compound (86) showed excellent fungicide effect against Pyricularia oryzae <85H(23)2025>. Tetrazolo[5,l-a]phthalazine (87), on the other hand, proved to have a monoamine oxidase inhibitory effect. The fused tetrazolo[l,5-(i]pyridazine compound (88) was found to exhibit anticancer activity <76MI 818-02). 

The methods based on the selective oxidation were reported for penam and cephem analogs containing phenolic substitutes at C6 and C7, respectively. These methods permitted also selective determination of (3-lactam analogs in the presence of excipaents being in their pharmaceutical preparations. The application of oxidation properties of iron ions was used in analysis of a huge number of P-lactam analogs ... 

While Lilly scientists were working on the discoveries leading to cefaclor, scientists in Basel were searching for orally active cephalosporins. At that time it was well known that biological properties of cephalosporins were strongly influenced by the substituent at the 3-position of the cephem molecule, since this substituent is electronically linked via the 3,4-double bond with the p-lactam bond of the azetidinone ring (Murphy and Webber, 1973 Sweet and Dahl, 1970 Gorman and Ryan, 1973). 

Modification at C-2 of the cephalosporin skeleton has attracted limited interest, since those transformations which have been reported have not led to products with significantly improved antibiotic properties. Low-temperature methyl-thiolation of cephem sulphoxide (58) via its C-2 anion afforded thiomethyl derivative (59). The reaction proceeded stereospecifically from the least hindered side to give the a-isomer exclusively. When the reaction was carried out at a somewhat higher temperature (- 23 °C), the bis(methylthio)-compound... 

---