Nalidixic acid is a synthetic antibacterial agent active against Gram-negative organism. Since the introduction of Nalidixic acid in 1962, a large number of quinolone carboxylic acids have been synthesized. Early in the 1980's new agents such as norfloxacin, enoxacin, ofloxacin and ciprofloxacin, possessing the 6-fluoro substituent and the 7-piperazinyl group on the quinolone pharmacophore and collectively known as new quinolones or fluoroquinolones, were reported to have greatly improved potency and antibacterial spectra relative to old quinolones. Subsequently, considerable interest has been increasingly given to the structural manipulation of substituents on quinolone nucleus and detailed data for structure-activity relationships have been accumulated. This review will focus primarily on the recent advance in medicinal chemical studies of new quinolones in consideration of in vitro antibacterial activity, pharmacological properties, and physicochemical properties.
Hexythiazox, trans-5- (4-chlorophenyl) -N- cyclohexyl- 4- methyl- 2- oxothiazolidine- 3- carboxamide is a new potent miticide discovered and developed by Nippon Soda Co., Ltd. This compound shows broad miticidal spectrum and excellent ovicidal, larvicidal and nymphcidal actions. The discovery of a lead compound originated in the studies of fungicidal thiazolotriazines which showed weak miticidal activity, and the structural modifications of them led to discover the 2-oxazolidinones as the second lead of miticides. As the result of the lead optimization, we developed 2-thiazolidinone derivatives among which hexythiazox was selected as the best compound. In the synthesis of hexythiazox, stereoselective processes were required because the trans configuration of 4-methyl and 5-p-chlorophenyl groups is essential for the biological activity. We have investigated the stereoselective synthesis of the trans-2-thiazolidinones, and established a novel method via erythro-aminoalcohol as a key intermediate. Furthermore, some improvements in the synthesis of the erythro-aminoalcohol from p-chloropropiophenone have also contributed to the success in the industrial production of hexythiazox.
The Ireland-Claisen rearrangement of the enolates of allyl esters, frequently used for the stereocontrolled C-C bond formation, is not suited for the substrate-controlled asymmetric induction. In order to cover the shortcoming, we investigated the thermal rearrangement of amide enolates and found the 1) the enolate derived from N- (2 E) -butenyl-N-butylpropanamide rearranged with excellent internal asymmetric induction (syn : anti= 199 : 1), that 2) the reaction of those containing chiral alkyl groups on the nitrogen proceeded with high selectivity (up to 19 : 1) in relative asymmetric induction, and that 3) the rearrangement can satisfactorily be extended to the acetamides with a heteroatom at the a-position. Utilyzing the reaction, (-) -verrucarinolactone, D-allo-isoleucine, and (-) -isoiridomyrmecin were synthesized with excellent stereoselectivity in short steps. Through the study, an efficinet, mild and versatile method for the hydrolysis of N-monosubstituted carboxamides, and N, N, N′, N′-tetramethylazodicarboxamide (TMAD) -Bu3P, a new reagent system applicable to the Mitsunobu reaction of Brønsted acid of pKα up to 13.5 were developed. The latter provides an efficient general method for the preparation of allylic secondary amines.
We have found the reactions giving various heterocyclic compounds by intramolecular nucleophilic substitution of vinyl cations and by intramolecular electrocyclic reaction of vinyl nitrenes. These selective reactions are not only important in organic synthesis, but also singificant for clarifying the chemistry of these reactive intermediates. This paper describes the review on the course of development of these chemistry and is focused on the ipso substitution in vinyl cations and on the ring expansion reaction of azirines.
Recent studies on the synthesis, structure, and reactivity of kinetically stabilized double-bond compounds between group 14 metals (M=Si, Ge, and Sn) and heavier chalcogens such as sulfur or selenium are reviewed. Three different approaches for the formation of “heavy ketones” were examined, i. e., (i) the thermal retrocycloaddition of 1, 2, 4, 3-trichalcogenametallolanes bearing a new steric protection group, 2, 4, 6-tris- [bis (trimethylsilyl) methyl] phenyl (denoted as Tb), (ii) the reactions of kinetically stabilized divalent group 14 metal species, Tb (Ar) M, with an epichalcogenide or elemental chalcogen, and (iii) the dechalcogenation reactions of 1, 2, 3, 4, 5-tetrachalcogenametallolanes, Tb (Ar) MY4 (Y=, S, Se). As a result of kinetic stabilization by the combination of Tb and 2, 4, 6- triisopropylphenyl (Tip) group, silanethione Tb (Tip) Si S and germanethione Tb (Tip) Ge=S were successfully isolated as monomeric and stable crystalline compounds, while the corresponding stannanethione Tb (Tip) Sn = S was synthesized as a monomeric species stable in solution, Of particular note is the X-ray crystallographic structure analysis of germanethione, which revealed the completely trigonal planar geometry for the germathiocarbonyl unit and the remarkable bond shortening for the Ge-S double bond.
During our search for heterocyclic N-oxides which could serve as an agent for the efficient oxidation of various substrates, without accompanying photochemical intramolecular rearrangements, we found that 1, 3, 7, 9-tetrasubstituted pyrimido [5, 4-g] pteridine-2, 4, 6, 8 (1H, 3H, 7H, 9H) -tetrone 5-oxides are suitable for this purpose. In this review, syntheses, structures, photochemical properties, and applications of the novel heterocyclic N-oxides are described. In particular, it is documented that the excited N-oxides behave as a multifunctional oxidant just like iron-oxenoid species (Fev=O) and also function as a mimic or a generator of active oxygen species.