New tetracycline analogs modified at position 5, 6 and 2 were synthetized. The 5-deoxy-5-oxo-derivatives, 2a and 3a, were obtained by DMSO/acetic anhydride oxidation of doxycycline (2) and methacycline (3), respectively; the 6-demethyl-6-hydroxymethyl-6-alpha-hydroxyoxytetracycline (3b) by methacycline oxidation with the KCIO3/0s04 system and the 6-hydroxyanhydrooxytetracycline (4) treating 3b with periodic acid.The 2-ethoxycarbonyl-2-decarboxamidodoxycycline (2b), was synthetized by treating doxycycline nitrile (2c) with EtOH and anhydrous HCI, 2-thiocarboxamide-2-decarboxamidodoxycycline (2d) by reaction of doxycycline with P2Sg in dioxane and 2-aminomethyl-2-decarboxamidodoxycycline (2e) by RANEY-Nickel reduction of 2d. All the synthetized compounds proved to be almost inactive on agar plates both on Gram-positive and Gram-negative bacteria.Tetracycline antibiotics continue also today to play an important role in human and veterinary medicine and in animal nutrition.The greatest success in the development of new active tetracycline has been up to now obtained by modifications at the position 6. The position 5 also seems not very critical for antimicrobial activity influencing mainly the pharmacokinetics properties1.2).During a research program aimed at finding new and possibly clinically useful tetracycline derivatives, our synthetic efforts followed mainly two routes: on one side we took up the synthesis of some new derivatives (compounds 2a, 3a, 3b, 4) modified at position 5 and 6 starting from the easily available, acid stable doxycycline (2) and methacycline (3) and, on the other side, we paid also our attention to modifications at position 2.From structure-activity relationships studies it is in fact shown that only a carbonyl substituent at position 2 and not the whole carboxamide group is essential for maintenance of activity: the nitrile (1a)3) has no activity but derivatives bearing at the 2 positions an aldehyde (1b)4), aldimine (1c)5) or acetyl (1d)6) group retain a certain degree of antimicrobial activity.It seemed therefore interesting'), in order to define the role of the C-2 carboxamidic group, to synthetize new C-2 derivatives, namely the 2-ethoxycarbonyl (2b), the 2-thiocarboxamide (2d), the 2-aminomethyl (2e) and the 2-N-methylaminomethyl doxycycline.
A series of 2-(2-aminothiazol-4-yl)-2-hydrazonoacetamido cephalosporins 1a-h was prepared. Whenever possible, E and Z isomers were isolated, and their relative stabilities and their interconversions were tested. The antibacterial activity was tested against Gram-positive and Gram-negative bacteria. For compound 1c, whose Z and E forms do not interconvert rapidly, the Z form was the more active one. Among the other compounds, for which the E form is the only stable one for practical purposes, compound 1a was the most active. When compared with cefuroxime and cefotaxime, compound 1a showed slightly lower antibacterial activity but good serum level and half-life values.
Desoxycorticosteron (I) reagiert über das Acetal (II) mit mono‐Perphthalsäur zu den Epoxiden (IV) und (VI), von denen letzteres mit Methylmagnesiumjodid und folgender Verseifung zum Methyl‐pregnan‐diol‐dion (VIII) umgesetzt wird.
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