New fluorinated erythromycins obtained by mutasynthesis.

Following the previously described semisynthetic preparation of new aglycones (8S)-8-fluoroerythronolide A (I), (8S)-8-fluoroerythronolide B (II) and the monoglycoside 3-O-mycarosyl-(8S)-8-fluoroerythronolide B (III), their conversion into new fluoroerythromycins was attempted by mutational biosynthesis. The strain Streptomyces erythraeus ATCC 31772, a mutant blocked in the biosynthesis of erythromycin, was employed in the present investigation. Four new antibiotics, (8S)-8-fluoroerythromycin A (IV), (8S)-8-fluoroerythromycin B (V), (8S)-8-fluoroerythromycin C (VI) and (8S)-8-fluoroerythromycin D (VII) were successfully derived by such an approach. The result is also discussed in terms of the substrate specificity of the enzymes involved in the biosynthesis of erythromycins. The new antibiotics exhibited promising biological properties.

Synthesis and topical antiinflammatory properties of 17,21-bis(acetyloxy)-6beta,9-difluoro-11beta-hydroxypregna-1,4-diene-3,20-dione and related 2-halogenated compounds.

Introduction of a halogen atom at C-2 of steroid 3-ketofluorohydrins, obtained from the corresponding 5alpha,6alpha-epoxides by trans-diaxial opening with hydrofluoric acid, prevents the 6beta-fluorine atom from undergoing rearrangement to the more stable 6alpha configuration when the 5-tert-hydroxyl is split off to yield to yield a conjugated double bond. Two processes were investigated for the synthesis of 17,21-bis(acetyloxy)-6beta-fluoro-1,4,9(11)-triene-3,20-dione (24a) and the related 2-bromo compound 24b starting from the known 21-(acetyloxy)-6beta-fluoro-5alpha,11alpha,17-trihydroxypregnane-3,20-dione (13). Successive reaction with hypobromous acid, epoxidation, and fluorination converted 24a and 24b into the title compound 27a and the analogue 2-bromo compound 27b. In addition, a synthesis of 17,21-bis(acetyloxy)-2-chloro-6beta,9-difluoropregna-1,4-diene-3,20-dione (27c) is reported. The antiinflammatory activity of 17,21-bis-(acetyloxy)-6beta,9-difluoropregna-1,4-diene-3,20-dione (27a) and its 2-halogenated analogues 27b and 27c in comparison with the corresponding 6alpha,9-difluoro epimers was studied. Some 6beta-fluoro compounds displayed high topical antiinflammatory activity without systemic effects.

Derivatives of 2-bromo-6beta-fluoropregna-1,4-diene-3,20-dione and their antiinflammatory activity.

As part of a systematic study of the effects of chemical modifications on the antiinflammatory activity of 17,21-bis(acetyloxy)-2-bromo-6beta,9-difluoro-11beta-hydroxypregna-1,4-diene-3,20-dione (halopredone acetate, Topicon), a new potent antiinflammatory, a series of derivatives of 2-bromo-6beta-fluoropregna-1,4-diene-3,20-dione was prepared for pharmacological screening. Different synthetic approaches are described. All the synthesized compounds had topical antiinflammatory activity, with no side effects, but were lower in activity than halopredone acetate. Most of them showed topical antiinflammatory activity comparable to that of fluocinolone acetonide. Only two of the synthesized compounds were found to have systemic anti-inflammatory activity comparable to that of betamethasone.

Basic derivatives of 6,7-dihydroindolo(1,7-ab)(1) benzazepine and 6H-indolo(7,1-cd)(1,5) benzoxazepine as potential antidepressant agents.

Basic derivatives of 6,7-dihydroindolo[1,7-ab][1]benzazepine and 6H-indolo[7,1-cd][1,5]benzoxazepine incorporating the imipramine basic side chain were synthesized and screened for antidepressant activity in mice. With few exceptions, the compounds unsubstituted at C-2 antagonized reserpine-induced ptosis and hypothermia showing negligible anticholinergic and antihistaminic properties. The compound 1-[2-(N-methyl-N-benzylamino)ethyl]-6,7-dihydroindolo[1,7-ab][1]benzazepine had the highest toxicity-activity ratio.

Synthesis and central nervous system effects of 8.9-dihydro(1)benzazepino(3,2.1-ak)(1,4)benzodiazepin-1(2H)-ones and (1) binzazepino(3,2,1-jk)(1,4)benzodiazepin-1(2H)-ones.

A series of 4-alkyl-8,9-dihydro[1]benzazepino[3,2,1-jk][1,4]benzodiazepin-1(2H)-ones and brominated derivatives was synthesized. Two approaches for the synthesis of 4-alkyl[1]benzazepino[3,2,1-jk][1,4]benzodiazepin-1(2H)-ones and brominated derivatives are described. All compounds were evaluated for CNS activity. None showed significant activity. The results obtained indicate that in the case of the 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one a phenyl group at the 1 position causes a fall in CNS activity not only when it is free but also when fused to the benzodiazepine system.