271ChemInform Abstract The reactions of the new (malonato)-Pt(II) complexes (III) with various amines (trans-1,2-cyclohexanediamine, 2,2-dimethyl-1,3-propanediamine, tetrahydro-4H-pyran-4,4-dimethanamine, cyclohexylamine, propylamine, benzylamine) lead to a new general synthesis of antitumor sym. and dissym. (malonato)-Pt(II) complexes of the type (V) and (X). Reaction of (IIIa) with trans-(-)-1,2-cyclohexanediamine (IV) is studied in detail. Structures of the intermediate (VI)•13 H2O (space group P1, Z=1), formed at 40 rc C and isolated with 90% yield, and of the end product (Va)•H2O (C2, Z=4), obtained from (VI) in 80% yield (H2O, 100 rc C), are determined.
[1,1-Cyclobutanedicarboxylato(2)-O,O'](1,3-dioxane-5,5-dimethan amine- N,N')platinum(II), 3a, a third generation, very water-soluble platinum complex, has been synthesized along with several of its analogues. All members of the new family contain a 1,3-dioxane or 1,3-dioxolane-1,3-diamine as their basic ligand, a moiety which contributes to their increased water solubility, and a bidentate acid ligand, which is responsible for their good stability. They were all easily crystallized and characterized by 1H NMR and elemental analysis, and the parent complex 3a was further characterized by 13C NMR. Their very desirable physical properties combined with their broad spectrum of antitumor activity and reduced toxicity make them good candidates of further development.
Some novel 6-fluoro-7-substituted-1,4-dihydro-4-oxoquinoline-3-carboxylic acids have been prepared. At the N-1 position "standard" substitution was employed with the ethyl, cyclopropyl, and p-fluorophenyl groups being used. At C-7 the introduction of some novel piperazines was made. Most notably, 2-(fluoromethyl)piperazine (10) and hexahydro-6-fluoro-1H-1,4-diazepine (16, fluorohomopiperazine) at the quinolone C-7 position produced products with similar in vitro antibacterial activity as the ciprofloxacin reference. The in vivo efficacy of 1-cyclopropyl-6-fluoro-7-[3-(fluoromethyl)piperazinyl]-1,4-dihydro-4- oxoquinoline-3-carboxylic acid (20) was excellent with better oral absorption than ciprofloxacin (2).
The synthesis, stability, and antitumor activity of a series of water-soluble third generation platinum(II) complexes have been described. Among these complexes, [2,2-bis(aminomethyl)-1,3- propanediol-N,N'] [1,1-cyclobutanedicarboxylato(2-)-O,O']platinum(II) and [1,1-cyclobutanedicarboxylate(2-)-O,O'](tetrahydro-4H-pyran-4,4- dimethanamine-N,N'-)platinum(II) have shown the greatest promise for further investigation and are currently under clinical evaluation.
A series of new 2,3‐diamino‐4‐pyrimidinones and 3‐amino‐2‐hydrazino‐4‐pyrimidinones were synthesized by the reactions of β‐ketoesters with amino or diaminoguanidines.
A series of novel aminomethyl tetrahydrofuranyl (THF)-1β-methylcarbapenems which have excellent broad-spectrum antibacterial activities exhibit modest efficacies against acute lethal infections (3.8 mg/kg of body weight against Escherichia coli and 0.9 mg/kg against Staphylococcus aureus) in mice when they are administered orally. In an effort to improve the efficacies of orally administered drugs through enhanced absorption by making use of a peptide-mediated transport system, several different amino acids were added at the aminomethyl THF side chains of the carbapenem molecules. The resulting peptidic prodrugs withl-amino acids demonstrated improved efficacy after oral administration, while the d forms were less active than the parent molecules. After oral administration increased (3 to 10 times) efficacy was exhibited with the alanine-, valine-, isoleucine-, and phenylalanine-substituted prodrugs against acute lethal infections in mice. Median effective doses (ED50s) of <1 mg/kg against infections caused by S. aureus, E. coli,Enterobacter cloacae, or penicillin-susceptibleStreptococcus pneumoniae were obtained after the administration of single oral doses. Several of the peptidic prodrugs were efficacious against Morganella morganii,Serratia marcescens, penicillin-resistant S. pneumoniae, extended-spectrum β-lactamase-producingKlebsiella pneumoniae, and E. coli infections, with ED50s of 1 to 14 mg/kg by oral administration compared with ED50s of 14 to >32 mg/kg for the parent molecules. In general, the parent molecules demonstrated greater efficacy than the prodrugs against these same infections when the drugs were administered by the subcutaneous route. The parent molecule was detectable in the sera of mice after oral administration of the peptidic prodrugs.
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