4.08 – Imidazoles and their Benzo Derivatives: (iii) Synthesis and Applications

Pyrrolidine-modified and 6-substituted analogs of nicotine: A structure—affinity investigation

Publisher Summary This chapter describes the quantitative analysis of steric effects in heteroaromatics. This chapter illustrates that, important progress in the quantitative analysis of steric effects in heteroaromatics has been made recently by linear free energy relationships (LFER), geometrical, and theoretical methods. Heterocycles have been used to propose and exemplify new concepts and new parameters in physical organic chemistry. This chapter is concerned with the importance of steric effects in rationalizing the reactivity and dynamic stereochemistry of heteroaromatics and with recent attempts to bridge the gap between them. There has been a decisive evolution in the treatment of steric effects in heteroaromatic chemistry. A better knowledge of static and dynamic stereochemistry has helped greatly in understanding not only intramolecular but also intermolecular steric effects associated with rates and equilibria. Quantum and molecular mechanics calculations will certainly be used in the future to a greater extent. Heteroaromatics have features in common with aromatic hydrocarbons. However, the variety of geometrical situations, the number of heteroatoms and their associated reactivity, and the ease of monitoring stereochemistry often associated with the presence of heteroatoms all have made, and continues to make, heterocycles exceptional probes for better understanding of reactivity, structures, and the relations between them.

The Quantitative Analysis of Steric Effects in Heteroaromatics

The following compound is provided as an agent for treating a disease induced by production, secretion and/or deposition of amyloid β protein, for example, a compound represented by the formula (I): wherein ring A is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group, R1 is optionally substituted lower alkyl or the like, R2a and R2b are each independently hydrogen, optionally substituted lower alkyl or the like, R3a and R3c are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl or the like, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

Sulfur-containing heterocyclic derivative having beta secretase inhibitory activity

2,3,4,5-Tetrahydro-1-(imidazol-4-ylalkyl)-1,4-benzodiazepines were found to be potent inhibitors of farnesyltransferase (FT). A hydrophobic substituent at the 4-position of the benzodiazepine, linked via a hydrogen bond acceptor, was important to enzyme inhibitory activity. An aryl ring at position 7 or a hydrophobic group linked to the 8-position through an amide, carbamate, or urea linkage was also important for potent inhibition. 2,3,4,5-Tetrahydro-1-(1H-imidazol-4-ylmethyl)-7-(4-pyridinyl)-4-[2-(trifluoromethoxy)benzoyl]-1H-1,4-benzodiazepine (36), with an FT IC50 value of 24 nM, produced 85% phenotypic reversion of Ras transformed NIH 3T3 cells at 1.25 μM and had an EC50 of 160 nM for inhibition of anchorage-independent growth in soft agar of H-Ras transformed Rat-1 cells. Selected analogues demonstrated ip antitumor activity against an ip Rat-1 tumor in mice.

Discovery and structure-activity relationships of imidazole-containing tetrahydrobenzodiazepine inhibitors of farnesyltransferase

Die Synthese von homologen, vinylogen und Kernalkylierten N,N-Dimethylnicotinamiden wird beschrieben und die Energiebarriere bei der gehinderten Rotation der Amidgruppe mittels 1H-NMR-Spektroskopie bestimmt.



Nicethamide Analogues, V. Investigations of Hindered Internal Rotation in N,N-Dimethylpyridinamides



The synthesis of homologue, vinylogue and ringalkylated N,N-dimethyl nicotinamides is described and the energy barrier of the hindered rotation of the amide group determined by means of 1H-n. m. r. spectroscopy.

Nicethamid‐Analoge, V Untersuchungen zur gehinderten internen Rotation bei N,N‐Dimethylpyridinamiden

NMR-Spektroskopie an Heterocyclen, 4. Mitt.: 13C-NMR-spektroskopische Zuordnung 1,4-und 1,5-substituierter Imidazole

Die Cyclisierung der 4,5-substituierten 2-(2-Aminoethyl)imidazole 5 mit Dimethyl-N-cyandithioimidocarbonat (2), 1,1′-Carbonyldiimidazol (10a) oder 1,1′-Thiocarbonyldiimidazol (10b) ergibt die bisher nicht beschriebenen Titel-Verbindungen 7, 11 und 14. Die 1H- und 13C-NMR-Daten sowie des Verhalten gegenuber Nucleophilen werden beschrieben.

7,8‐Dihydroimidazo[1,2‐c]pyrimidin‐5(6H)‐one, ‐5(6H)‐thione und ‐5(6H)‐ylidencyanamide

Von kernalkylierten und isomeren Nicethamidderivaten wurden die 13C-NMR-Shiftwerte ermittelt und mit Hilfe der 1H-NMR-Spektroskopie die Energiebarriere bei der gehinderten Rotation der Amidgruppe bestimmt.



Ringalkylated and Isomeric Nicethamide Derivatives



The 13C-n.m.r. shifts were determined for ringalkylated and isomeric nicethamide derivatives and the energy barrier of the hindered rotation of the amide group was evaluated by means of 1H-n.m.r.

NMR-Spektroskopie an Heterocyclen, 2. Mitt. Kernalkylierte und isomere Nicethamidderivate

Es wird die 13C-NMR- und massenspektrometrische Untersuchung verschiedener N-substituierter Methoxy- und Hydroxy-athylimidazole beschrieben. Fur den Zerfall von 1,2-Diathyl-4-(2-hydroxyathyl)-imidazol wird ein ausfuhrliches Fragmentierungsschema angegeben.



NMR-Spectroscopy of Heterocyclic Compounds, V: 13C-NMR and Mass Spectrometry of N-Substituted (2-Methoxyethyl)- and (2-Hydroxyethyl)-imidazoles



The 13C-NMR and mass spectra of various N-substituted (2-methoxyethyl)- and (2-hydroxyethyl)imidazoles are described. A scheme for the fragmentation of 1,2-diethyl-4-(2-hydroxyethyl)imidazole is reported.

Hans-Joachim Sattler

Papers

Nicethamid‐Analoge, V Untersuchungen zur gehinderten internen Rotation bei N,N‐Dimethylpyridinamiden

NMR-Spektroskopie an Heterocyclen, 4. Mitt.: 13C-NMR-spektroskopische Zuordnung 1,4-und 1,5-substituierter Imidazole

7,8‐Dihydroimidazo[1,2‐c]pyrimidin‐5(6H)‐one, ‐5(6H)‐thione und ‐5(6H)‐ylidencyanamide

NMR-Spektroskopie an Heterocyclen, 2. Mitt. Kernalkylierte und isomere Nicethamidderivate

NMR‐Spektroskopie an Heterocyclen, 5. Mitt. 13C‐NMR‐ und massenspektrometrische Untersuchung N‐substituierter Methoxy‐ und Hydroxy‐äthylimidazole