H2-Antihistaminika, 15. Mitt.1) 1,n-Bis(2-imidazolyl)alkane

H₂-Antihistaminics, XV: 1,n-Bis(2-imidazolyl)alkanes 1,n-Bis(2-imidazolyl)alkanes with histamine H₂-functional side-chains at C-4 of the imidazole rings were prepared and tested for H₂-antihistaminic activity.     

Induction of P-450 cytochromes 2E2, 1A1, and 1A2 by imidazole in neonatal rabbits.

Cytochrome P-450 2E1 is induced in adult rabbits by treatment with alcohol, imidazole, and a variety of other agents, as shown earlier in this laboratory, but it is not known whether the highly homologous P-450 2E2 is similarly induced. In this study, the effects of imidazole on 2E2 expression were examined in neonatal rabbits, in which 2E1 is not detectable. Treatment of the animals with imidazole on days 8 through 11 after birth caused a 3-fold increase in the content of total P-450 in liver microsomes. In contrast, the microsomal content of cytochrome b5 and NADPH-P450 reductase was not changed. Immunoblot analysis revealed a significant increase in the level of P-450 2E2 (3-fold) as well as 1A1 (> 10-fold) and 1A2 (> 2-fold) in hepatic microsomes from imidazole-treated neonatal rabbits. The rates of microsomal N-demethylation of N-nitrosodimethylamine and O-deethylation of 7-ethoxyresorufin were similarly increased from 1.3 and 0.03 nmol/min/mg protein, respectively, to 5.6 and 0.24 nmol/min/mg protein, respectively, by imidazole treatment. Blot analysis indicated that the levels of 2E2, 1A1, and 1A2 mRNAs are not increased by imidazole treatment and that 2E1 mRNA is not detectable in either untreated or imidazole-treated neonates. The induction of P-450 2E2 was confirmed by NH2-terminal amino acid sequence analysis of immunopurified 2E protein from hepatic microsomes of imidazole-treated neonatal rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antiprotozoal thiazoles. 2. 2-(5-Nitro-2-furyl-, thiazolyl-, and 1-methylimidazolyl-)thiazoles.

Ten 2-substituted 4-thiazolecarboxaldehyde hydrazones bearing 5-nitro-2-furyl, 5-nitro-2-thiazolyl, and 1-methyl-5-nitro-2-imidazolyl functions have been prepared and screened for activity against Trypanosoma cruzi infections in mice. The results permitted the ranking of these substituents in decreasing order of activity: 1-methyl-5-nitro-2-imidazolyl greater than 5-nitro-2-furyl greater than 5-nitro-2-thiazolyl, the last being inactive. Some structural features of the side chain necessary for optimum activity are discussed. The most active compound, 4-[[[2-(1-methyl-5-nitro-2-imidazolyl)-4-thiazolyl]methylene]amino]thiomorpholine 1,1-dioxide, compared favorably with the standard Nifurtimox against three recent clinical isolates of T. cruzi, including one with a high myocardial tissue infiltration.     

Potentielle Antineoplastica, 1. Mitt. Cyclophosphamidanaloge 2-Arylamino-tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide

Arylaminotetrahydro-2H-1,2,3-oxazaphosphorine 2-oxides, Analogues of Cyclophosphamide The cyclophosphamide derivatives 7--11 without the mustard residue are synthesized and characterized by UV, IR, ¹H-NMR and mass spectroscopic measurements. 7 is not active against the Walker carcinoma 256 of the rat, and no formation of acrolein is observed during the incubation of 7 with the mixed function oxidase system in vitro.     

Imidlactone, 2. Mitt. N-(2-Phenylethyl)-isochroman-1-imine

Imidolactones, II: N-(2-Phenylethyl)-isochromane-1-imines Starting with the N-(2-phenylethyl)-2-(2-hydroxyethyl)-benzamides 1 the N-(2-phenylethyl)-isochromane-1-imines 2 are prepared in good yields. In a one-pot-method the crude 6-membered imidolactone-hydrochlorides 2·HCl formed from the δ-hydroxyamides 1 may be reduced to the δ- hydroxyamines 3 and – contrary to the 5-membered compounds – isomerised to the δ-chloroamides 5 ; under more vigorous conditions the lactames 4 are formed. These reactions are described in detail.     

Asymmetrische reduktive Aminierung von Cycloalkanonen, 7. Mitt. Die asymmetrische Synthese von cis-1R,2R- und cis-1S,2S-2-Arylcyclohexanaminen

Asymmetric Reductive Amination of Cycloalkanones, VII: Asymmetric Synthesis of cis-1R,2R- and cis-1S,2S-2-Arylcyclohexanamines The asymmetric synthesis of cis-2-arylcyclohexanamines 4 by a three-step procedure is reported: condensation of racemic 2-arylcyclohexanones 1 with the chiral auxiliary R-(+)- or S-(?)-1-phenylethylamin, respectively, leads to a mixture of the imin isomers 2 . Upon hydrogenation with Raney-Nickel just one secondary amin of type 3 is obtained, which is hydrogenolized to the optically active primary cis-2-arylcyclohexanamines 4 . The relative configuration as well as the conformation were derived from ¹H-NMR data. The absolute configuration of the highly enantiomerically pure compounds 4 was determined by CD spectra.