bluuebunny/crossref_metadata_2025_split huggingface dataset:
Zur Umsetzung von o‐funktionellen Benzylmalononitrilen mit N‐Bisnucleophilen sowie Alkoholaten
Authors: Troschütz Reinhard , Grün Lothar 
Published: October 2006

AbstractDie o‐funktionellen Benzylmalononitrile 1, 16 und 22 reagieren unterschiedlich gegenüber N‐Bisnucleophilen und Alkoholaten. 16 und 22 cyclisieren mit Guanidin nur zu den Pyrimidintriaminen 17 und 23, während 1 durch Doppelringschluß direkt zu 4 reagiert. 1 setzt sich mit Hydrazin bzw. Ethylendiamin zu den 2‐Benzazepinen 7 bzw. 12 um. Beim Erhitzen von 22 mit Na‐methylat bzw. Na‐ethylat wurden die 2‐Benzazepin‐cyanenolether 26a bzw. 26b erhalten. Analoge Umsetzungen mit 16 führten nicht zum Ringschluß.
Synthesis of 10‐(N′‐Methylpiperazino)‐5H‐pyrido[2,3‐c]‐2‐benzazepine (“Azaperlapine”)
Authors: Troschütz Reinhard , Grün Lothar 
Published: October 2006

AbstractIm Rahmen von Studien zu Struktur‐Wirkungsbeziehungen von ZNS‐Wirkstoffen haben wir uns mit der Synthese von Azaloga des Hypnotikums Perlapin bzw. des Antidepressivums Fluperlapin (Schema) beschäftigt. Nach dem die Synthese eines Diazanalogons1) des Perlapins gelungen war, orientierten wir uns beim Versuch, “Azaperlapin” (9b) herzustellen, an den Industrieverfahren2). Hierbei wird u.a. o‐Aminodiphenylmethan (1a) mit Phosgen zum stabilen Isocyanat (2a) umgesetzt, das in siedendem o‐Dichlorbenzol mit AlCl3 zum Morphanthridin‐6(5H)‐on (7a) cyclisiert. Reaktion mit POCl3 und nachfolgend mit N‐Methylpiperazin (5) führt dann zum Perlapin.
Intramolecular Alkylations of Aromatic Compounds, XXX: Synthesis of cis‐A‐8,11a‐Dimethyl‐7a,8,9,10,11,11ahexahydro‐7H‐naphtho[1,8‐fg]quinoline andcis‐B‐6b,10‐Dimethyl‐6b,7,8,9,10,10a‐hexahydro‐11H‐naphtho[2,1‐g]‐1‐pyrindine
Authors: Reimann Eberhard , Pöschl Klaus , Lotter Hermann 
Published: October 2006

AbstractVorausgegangene Untersuchungen hatten die Synthese der bisher nicht bekannten partiell hydrierten Naphthochinoline des Typs 3 zum Ziel, die aufgrund der integrierten Arylpiperidin‐Struktur als potentielle zentrale Analgetika anzusehen und deshalb pharmakologisch interessant sind. Versuche, das 1‐Naphthyltetrahydropyridin 1 unter Standardbedingungen, d.h. mit Bromwasserstoff‐ oder Polyphosphorsäure bei Temp. > 100°C zu 3 zu cyclisieren, verliefen bisher ergebnislos.
Nitrosierungen an Hydrazinderivaten, 6. Mitt.: Neuartige Reaktion oraler Antidiabetica vom Sulfonylsemicarbazid‐Typ unter nitrosierenden Bedingungen
Authors: Hanefeld Wolfgang , Hartmann Michael 
Published: October 2006

AbstractOrale Antidiabetica vom Sulfonylsemicarbazid‐Typ wie Tolazamid (1) und Glisoxepid (2) wurden unter milden nitrosierenden Bedingungen, auch annähernd physiologischen in vitro Bedingungen, nach einem neuartigen Reaktionsverlauf in Sulfonyltriazene 3a, b umgewandelt. Modellverbindungen mit N4‐Acyl‐semicarbazidstruktur 4 zeigen abweichendes Reaktionsverhalten, wobei Säureamide 5 neben Nitrosaminen 6 gebildet werden.
2‐Amino‐2‐oxazolines, VII: Influence of Structural Parameters on the Antidepressant Activity of 5‐(1‐Aryl‐4‐piperazino)methyl‐2‐amino‐2‐oxazolines
Authors: Bosc Jean Jacques , Forfar Isabelle , Jarry Christian , Laguerre Michel , Carpy Alain 
Published: October 2006

AbstractA series of 5‐(1‐aryl‐4‐piperazino)methyl‐2‐amino‐2‐oxazolines has been prepared and screened for antidepressant activity. Their lipophilic behaviour has been discussed in relation to the nature and the position of substituents on the aromatic ring. The influence of steric effects on the pharmacological activity has been investigated using experimental methods (X‐ray diffraction, NMR) and theoretical calculations (semi‐empirical quantum mechanics). The ortho‐substitution on the phenyl ring or the C‐α substitution on the piperazine ring by a methyl group results in the same effects i.e. an increase of the angle between the two rings up to 64° (X‐ray and calculation) and a loss of the antidepressant activity. Using NMR, only the influence of the ortho‐substitution has been observed.
Trennung des Fencamfamins in die Diastereomeren und Synthese einiger seiner Metaboliten
Authors: Rücker Gerhard , Neugebauer Michael , Vollberg Gerhard 
Published: October 2006

AbstractEs wird erstmalig die sc Trennung der Diastereomeren [la, lb] des Fencamfamins INN (1) und die Synthese einiger seiner potentiellen Metaboliten [2a, 2b, 3, 7a, 7b, 8] beschrieben.
New NO‐Donors with Antithrombotic and Vasodilating Activities, IV: Chemical Reactivity of Nitrosimines and its Implications for their Pharmacologic Properties
Authors: Rehse Klaus , Schleifer Klaus‐Jürgen , Lüdtke Eberhard , Böhme Eyke 
Published: October 2006

AbstractNitrososydnone‐5‐imines and Thiazole‐2‐nitrosimines are susceptible to photolytic cleavage of the NNO bond. This can be achieved with a tungsten lamp. In water the corresponding syndnone imine salts are formed in 90% yield at 37°C. Only at higher temp. (70°C) ring opening is observed. In methanol about 25% of sydnones are obtained. On the other hand NO⋅ and N2O were detected in the head space of the reaction vials when oxygen was excluded. The formation of N2O from nitrososydnone imine was increased up to elevenfold by glutathione while the amount of NO⋅ was decreased. In the presence of light and thiols soluble guanylate cyclase (s‐GC) was stimulated. The results suggest that the nitroxylate anion NO− plays an important role in the stimulation of s‐GC.
Bindung von Quercetin sowie einiger seiner O‐β‐Hydroxyethylderivate an Humanserumalbumin. Binding of Quercetin and Some of its O‐β‐Hydroxyethyl Derivatives to Human Albumin
Authors: Lembke Beate , Kinawi Abdelwahab , Wurm Gotthard 
Published: October 2006

AbstractFlavonoide sind Derivate des 2,3‐Dihydro‐2‐phenyl‐4H‐1‐benzopyrans (Flavan). Sie zeichnen sich durch eine bemerkenswerte Strukturvielfalt aus und zeigen ein breites biologisches Wirkungsspektrum. Einige Flavonoide, vor allem O‐β‐Hydroxyethylrutinderivate, sind Bestandteil zugelassener Arzneimittel. Von großer physiologischer Relevanz ist ihre Bindung an Humanserumalbumin (HSA). Es liegen jedoch nur wenige Arbeiten über Bindungsstudien von dieser Stoffklasse vor. Eine Arbeit befaßt sich mit der Bindung von Rutin und seinen Mono‐, Di‐, Tri‐ und Tetrahydroxyethylderivaten an Humanserumproteine, eine andere Publikation untersucht die Bindung von 14C‐markierten O‐β‐Hydroxyethylrutinderivaten an Humanserumproteine.
Aminocyclanols, II: Stereochemical Studies on a New Ciramadol Analogue by NMR‐Spectroscopy
Authors: Burgemeister Thomas , Wiegrebe Wolfgang , Ertan Mevlüt , Akgün Hülya , Özarslan Özdemir 
Published: October 2006

AbstractThe absol. configuration of a Ciramadol analogue obtained from (‐)‐menthone is established by 1H‐NMR‐, simulated NMR‐, COSY‐90‐, and NOE‐measurements. The final compound 2‐(α‐1‐pyrrolidino)benzyl‐4‐isopropyl‐1‐methyl‐cyclohexan‐3‐one (4b), e.g., has 1R,2S,4S,11S‐configuration due to stereoselective Michael‐type addition of pyrrolidine to the pertinent benzylidene intermediate 3.
Synthesis of 15Nω‐Hydroxy‐L‐arginine and ESR and 15N‐NMR Studies for the Elucidation of the Molecular Mechanism of Enzymic Nitric Oxide Formation from L‐Arginine
Authors: Clement Bernd , Schnörwangen Elke , Kämpchen Thomas , Mordvintcev Peter , Mülsch Alexander 
Published: October 2006

AbstractNω‐Hydroxy‐L‐arginine (2) was prepared by a multi‐stage synthesis; the key step was the addition of hydroxylamine to the protected cyanamide 8. The presence of N‐hydroxyguanidines was confirmed, above all, by 15N‐NMR investigations. 15Nω‐Hydroxy‐L‐arginine (2) was converted quantitatively to 15NO by NO synthases from macrophages. 15NO was identified by ESR‐spectroscopy. These experiments confirm that 15Nω‐hydroxy‐L‐arginine (2) is an intermediate in the biosynthesis of NO from arginine (1) and that the N‐hydroxylated N‐atom is present in the NO formed.
(2R,4S)‐2‐Aminomethyl‐5,5‐dimethyl‐1,3‐thiazolidine‐4‐carboxylic Acid Dihydrochloride: Synthesis, Epimerization, and Derivatives
Authors: Imming Peter 
Published: October 2006

AbstractThe preparation of the title compound 6a from penicillamine 5 or from penicillins 7, the spectroscopic data and stereochemical assignments are given. 6a quickly epimerizes at C‐2 in dilute aqueous solution. Details are given along with the preparation of the new thiazolidines 10–13 from 6.
Platelet Aggregation Inhibiting and Anticoagulant Effects of Oligoamines, XXVIII: Oligoamines with Fluorescent Properties. Part C: Fluorescent Oligoamines with Enhanced Hydrophilic Properties
Authors: Rehse Klaus , Seidel Torsten 
Published: October 2006

AbstractFifteen fluorescent oligoamines with one or two fluorescent groups and two or three basic N‐functions were prepared and tested for antiplatelet activity (Born‐test). Five compounds involving three different fluorophores, i.e. 2‐fluorenyl, 1‐pyrenyl, and 9‐phenanthryl, show an IC50 of 7–11 μmol/L. They are suitable to serve as probes in the field of oligoamine‐biopolymere interactions.
Thioacetate aus Canrenon und 2‐Methylencanrenon
Authors: Görlitzer Klausy , Moormann Peter 
Published: October 2006

AbstractDas aus Canrenon und Dibrommeldrumsäure erhaltene 2α‐Brom‐Derivat 5 reagiert mit Kaliumthioacetat zur 2α‐Acetylthio‐Verbindung 6. Aus 2‐Methylencanrenon lassen sich mit Thioessigsäure die Mono‐ und Bis‐Addukte 8 und 9 darstellen.
Mehrcyclische Azine mit Heteroatomen in 1‐ und 3‐Stellung, 40. Mitt. Synthese heterocyclischer Immunmodulatoren, 2. Mitt.: 3‐Mercaptoalkylthieno[2,3‐d]pyrimidin‐2,4(1H,3H)‐dione: Synthese und Prüfung auf immunstimulatorische Wirksamkeit
Authors: Gütschow Michael , Drößler Karl , Leistner Siegfried 
Published: October 2006

AbstractEine Reihe von 3‐Mercaptoalkylthieno[2,3‐d]pyrimidin‐2,4(1H,3H)‐dionen 3 wurde synthetisiert und auf immunstimulatorische Wirksamkeit geprüft. Die Titelverbindungen wurden auf bequeme Weise durch hydrolytische Ringspaltung von thiazolo‐ bzw. 1,3‐thiazino‐anellierten Thienopyrimidinen 1 unter alkalischen oder auch sauren Bedingungen erhalten. Die ms Fragmentierung der Thieno[2,3‐d]pyrimidin‐2,4‐dione 3 wird diskutiert. Einige Verbindungen 3 zeigten in einer Hautreaktion vom verzögerten Typ (delayed type hypersensitivity; DTH) immunstimulatorische Aktivität im Wirkungsbereich von Isoprinosine.
Vorstellungen zur Freisetzung von Stickstoffmonoxid aus NO‐Pharmaka. Modellreaktionen in Gegenwart von Licht und Übergangsmetallkomplexen, 1. Mitt.
Authors: Duchstein Hans‐Jürgen , Riederer Sabine 
Published: October 2006

AbstractMit Hilfe von Modellreaktionen für Cytochrom P‐450 wird der Mechanismus der Metabolisierung von NO‐Pharmaka untersucht. Um diese Versuche zu begründen, wird einleitend auf bisher erarbeitete theoretische Hintergründe hingewiesen. In einem Modell werden dazu niedermolekulare Tetraphenylporphyrinkomplexe (TPP) mit Eisen und Mangan als Zentralatome in Gegenwart von NaBH4 als Reduktionsmittel statt des Eisenchelats im Cytochrom P‐450 eingesetzt. Für die NO‐Messung wurde eine Chemilumineszenzmethode, bei der NO durch Ozon aktiviert wird, etabliert.Unter diesen Bedingungen werden die NO‐freisetzenden Substanzen Nitroprussidnatrium (SNP), anorganisches Nitrit, Glyceroltrinitrat (GTN) und S‐Nitroso‐N‐acetyl‐penicillamin (SNAP) untersucht. Eine spontane Freisetzung von NO erfolgt nur durch SNAP, SNP, anorganisches Nitrit und GTN sind unter Lichtausschluß völlig stabil. Erst nach Aktivierung unter reduktiven Bedingungen in Gegenwart von FeIITPP oder unter Bestrahlung mit sichtbarem Licht wird in allen Fällen NO freigesetzt. Besonders bemerkenswert ist die überadditive Verstärkung der NO‐Freisetzung durch die Kombination der beiden Aktivierungsmethoden. Mit Hilfe dieser Ergebnisse wird der Aktivierungsmechanismus von NO‐freisetzenden Verbindungen diskutiert, wobei ein enzymatischer Weg unter Beteiligung des reduktiven Teils im katalytischen Cyclus von Cytochrom P‐450 möglich erscheint.
Synthesis and Histamine H2‐Receptor Antagonist Activity of 4‐(1‐Pyrazolyl)butanamides, Guanidinopyrazoles, and Related Compounds
Authors: Buschauer Armin , Mohr Rainer , Schunack Walter 
Published: October 2006

AbstractA series of 4‐(1‐pyrazolyl)butanamides, pyrazolylalkyl cyanoguanidines, and related compounds with diverse functional groups (e.g. nitro, amino, guanidino groups) in the 3‐position of the pyrazole ring was prepared via 4‐(3‐nitro‐1‐pyrazolyl)butanenitrile (5) and the corresponding carboxylic acid 7 as central intermediates. The amides 9a–d were prepared from the primary amines 8a–d which represent partial structures of the H2‐receptor antagonists roxatidine, cimetidine, ranitidine, and famotidine. The roxatidine‐derived 4‐(3‐nitro‐1‐pyrazolyl)butanamide (9a) proved to be the compound with the highest H2‐receptor antagonist activity of 23 compounds tested at the isolated guinea pig right atrium preparation, achieving about 6 times famotidine's or 160 times cimetidine's potency. By contrast, in Ghosh‐Schild rats 9a did not inhibit histamine‐stimulated gastric acid secretion at a dosage of 0.1 μmol/kg i.v. Compounds 20a (the 3‐(trifluoroethylguanidino)pyrazole analogue of 9a, 12a (the cyanoguanidine analogue) and N‐{4‐[3‐(trifluoroethylguanidino)‐1‐pyrazolyl]butyl}cyanoguanidine (29), which are about as active as famotidine in the atrium, turned out to be very potent inhibitors of gastric acid secretion as well (e.g., 29: 74 % inhibition at 0.025 μmol/kg). These compounds are comparable to famotidine in the rat stomach and by far superior to cimetidine and ranitidine in this test system.
Preparation of Amino‐ and Carboxy‐Protected L‐α‐Amino‐ω‐iodocarboxylic Acids
Authors: Easmon Johnny , Heinisch Gottfried , Holzer Wolfgang , Matuszczak Barbara 
Published: October 2006

AbstractThe synthesis of L‐α‐amino‐ω‐iodobutyric, valeric, and caproic acid esters protected at the amino function by a benzyloxycarbonyl group is reported.
Iminiumkohlensäurederivat‐Salze, 7. Mitt. Teil I: Elektrophile Reaktionen von 2‐Methylthio‐5,6‐dihydro‐4H1,3‐thiaziniumiodiden, 2‐Methylthio‐4,5‐dihydrothiazoliumiodiden und 2‐Methylthio‐5‐methylthiazoliumiodiden mit N‐Nucleophilen
Authors: Hanefeld Wolfgang , Harms Helge , Schlitzer Martin 
Published: October 2006

AbstractCyclische Salze des Dithiokohlensäure‐diester‐imidium Typs (3, 5) wurden mit NH2‐Nucleophilen zu den cyclischen Isothioharnstoffen 6–8 umgesetzt. Einige dieser Verbindungen konnten zu cyclischen Isothioharnstoff‐S,S‐dioxiden (9, 10) oxidiert werden.
Synthesis and Antibacterial Activity of 7β‐[3‐(Un)substituted‐2‐aminopropionamido]‐3‐vinylcephalosporins and Related Compounds
Authors: Nestorova Boyka , Pajpanova Tamara , Simova Svetlana , Tabakova Svoboda , Golovinsky Evgeny , Haimova Marietta 
Published: October 2006

AbstractA series of new 7β‐[3‐(un)substituted‐alanyl]‐3‐vinylcephalosporins and some related compounds, 4a–1 is described. They incorporate residues of proteinogenic L‐α‐aminocarboxylic acids, their antimetabolites and enantiomers as well as a dipeptide in the 7β‐acylamido side chain. The acylation of diphenyl‐methyl 7‐amino‐3‐vinyl‐3‐cephem‐4‐carboxylate (2: R2 = DPM) with various protected α‐aminocarboxylic acids 1a–k and the dipeptide 1l is carried out using TBTU as coupling reagent. The compounds, except 4f, are active in vitro against S. aureus and S. lutea, but only 4a, 4k, and 4l inhibit some of the Gram‐negative strains.
Zum Fluoreszenznachweis von Oxazepam und Lorazepam mit Phthalaldehyd und Analoga
Authors: Troschütz Reinhard , Heinemann Oliver , Waibel Reiner , Troschütz Jutta 
Published: October 2006

AbstractDurch Erhitzen von Oxazepam (1) bzw. Lorazepam (2) in ethanolischer NaOH‐Lösung und nachfolgender saurer Hydrolyse lassen sich die 1,3‐Diamine 5 und 6 gewinnen. Ihre Umsetzung mit Phthalaldehyd (11a) und Analoga 11b‐e führt zu fluoreszierenden Reaktionsprodukten vom Typ 14 und 16.Auf der Basis dieser Untersuchungen wird für Oxazepam (1) und Lorazepam (2) ein hochspezifischer DC‐Fluoreszenznachweis entwickelt.
Construction of a Detailed Serotoninergic 5‐HT2a Receptor Model
Authors: Höltje Hans‐Dieter , Jendretzki Uwe Klaus 
Published: October 2006

AbstractWe have been able to show that the most important 5‐HT2a antagonists and agonists, belonging to chemically diverse classes can be fitted accurately into a common pharmacophoric pattern. In this paper we make use of the developed pharmacophore models to construct a fragmental amino acid model reflecting binding properties and affinity data of the structures under study. The proposed fragment model is then superimposed onto the transmembraneous part of the 5‐HT2a receptor. For this purpose the helix coordinates from the known structure of bacteriorhodopsin serve as a matrix. New structures with high affinity for the 5‐HT2a sites were designed and their biological activities were predicted on the basis of interaction energies calculated with the fragment model. The predicted data show excellent agreement with experimental binding affinities.
Synthesis and Dopamine Receptor Binding Studies of Homochiral 8‐Aminopyrido[1,2‐a]indoles
Authors: Gmeiner Peter , Kärtner Annerose , Mierau Joachim 
Published: October 2006

AbstractStarting from L‐aspartic acid the preparation of 8‐aminopyrido[1,2‐a]indole derivatives as benzo‐fused analogs of the dopamine autoreceptor agonist 1 is reported. The key step of the synthesis is the Tf2O induced cyclization of the 1,2‐amino alcohol 6. Receptor binding studies indicated selective affinity for the D‐2 autoreceptor. Among the tested compounds, the dipropylamino derivative 2 showed the highest affinity for the D‐2 receptor labelled with the selective autoreceptor agonist pramipexole (IC50 value: 450 nM). Thus, 2 is 15 times less potent than the aminoindolizine 1.
Direct Determination of the Enantiomeric Purity of (R)‐(+)‐Aminoglutethimide and its Main Metabolite
Authors: Chilmonczyk Zdzislaw , Ksycińska Hanna , Cybulski Jacek 
Published: October 2006

AbstractDirect chiral separation of aminoglutethimide (1), an anticancer agent, and its major metabolite — acetylaminoglutethimide (2), on tris(3,5‐dimethylphenyl‐carbamoyl)cellulose working in the reverse‐phase mode with the use of aqueous‐methanolic mobile phases is described.
Structure‐Activity Relationship Studies of CNS Agents, Part 26 4‐[2‐(Cycloalkanecarboxamido)ethyl]‐1‐(2‐methoxyphenyl)‐piperazines: High‐Affinity 5‐HT1A Agonists
Authors: Mokrosz Jerzy L. , Paluchowska Maria H. , Klodzińska Aleksandra , Charakchieva‐Minol Sijka , Chojnacka‐Wójcik Ewa 
Published: October 2006

AbstractCycloalkanecarboxamido)ethyl‐1‐(2‐methoxyphenyl)piperazin es 8a–c, 8e, and 8h were obtained by acylation of 4‐(2‐aminoethyl)‐1‐(2‐methoxyphenyl)piperazine, and their 5‐HT1A, 5‐HT1A, 5‐HT2A and α receptor affinities were determined. It was found that the terminal cycloalkane moiety strongly stabilizes both the 5‐HT1A and 5‐HT2A receptor‐ligand complexes. It was demonstrated that the most active 5‐HT1A ligands 8e and 8h (Ki = 2.1 and 0.21 nM, respectively) behaved as potent agonists of these receptors, i.e. both derivatives mimicked 8‐OH‐DPAT in the lower lip retraction (LLR) model and the effect was susceptible to blockade by reasonable doses of the selective 5‐HT1A receptor antagonist (S)‐WAY‐100135.
Syntheses and Biological Activities of New N1‐Aryl Substituted Quinolone Antibacterials
Authors: Jürgens Jens , Schedletzky Holger , Heisig Peter , Seydel Joachim K. , Wiedemann Bernd , Holzgrabe Ulrike 
Published: October 2006

AbstractA series of quinolones with a systematically varied substitution at the phenyl ring at N1 has been synthesized. Three lipophilicity descriptors (log K, log P, Rm) and the pKa values have been determined as well as the microbiological activity: The MIC values for eight different strains of three Gram‐positive and three Gram‐negative species and the inhibitory concentrations of DNA supercoiling (IC90 and IC100) were determined. From a principal component and a QSAR analysis relationships between the antibacterial activity concerning the whole‐cell system and electronic properties as well as the length of the substituents at the phenyl rings could be derived. The activity in a cell‐free system was governed by the lipophilicity and width of the substituents. It is speculated that the quinolones take a defined place in the DNA gyrase‐DNA complex which is characterized by polar amino acids. This is in agreement with findings from studies of mutant gyrases.
Novel Histamine H3‐Receptor Antagonists with Benzyl Ether Structure or Related Moieties: Synthesis and Structure‐Activity Relationships
Authors: Hüls Annette , Purand Katja , Stark Holger , Reidemeister Sibylle , Ligneau Xavier , Arrang Jean‐Michel , Schwartz Jean‐Charles , Schunack Walter 
Published: October 2006

AbstractIn search of new histamine H3‐receptor ligands sixteen ether derivatives of 3‐(1H‐imidazol‐4‐yl)propanol with benzylic partial structure or related moieties were prepared and investigated as H3‐receptor antagonists. The new compounds belong to a general construction pattern developed by other histamine H3‐receptor antagonists. Structural modifications were introduced in an attempt to optimize in vitro as well as in vivo activity. Structure‐activity relationships of the new histamine H3‐receptor antagonists are discussed. All ether derivatives showed in vitro activities in the nanomolar concentration range, but only compounds with bulky lipophilic residues were also active under in vivo conditions. The most active compound within this series was 3‐(1H‐imidazol‐4‐yl)propyl 1‐naphthylmethyl ether (4n) presenting an ED50 of 3.2 ± 1.9 mg/kg regarding enhancement of endogenous histamine in brain after p.o. administration to mice. Furthermore, comparison of the H3‐receptor activities measured on synaptosomes of rat cerebral cortex and on guinea pig ileum gave a good correlation indicating homogeneity of central and peripheral H3‐receptor test models. The most interesting compounds were also evaluated in functional in vitro assays with regard to their activities at histamine H1‐, H2‐, and muscarinic M3‐receptors. The tested compounds showed very weak activities at these receptor subtypes demonstrating their H3‐receptor selectivity.
Synthesis and Smooth Muscle Calcium Channel Antagonist Effects of Alkyl 1,4‐Dihydro‐2,6‐dimethyl‐4‐(pyridinyl)‐5‐[2‐(4,5‐dihydro‐4,4‐dimethyloxazolin‐2‐yl)]‐3‐pyridinecarboxylates
Authors: Anana Raymond D. , Knaus Edward E. 
Published: October 2006

AbstractA group of racemic alkyl 1,4‐dihydro‐2,6‐dimethyl‐4‐(3‐ or 4‐pyridinyl)‐5‐[2‐(4,5‐dihydro‐4,4‐dimethyloxazolin‐2‐yl)]‐3‐pyridinecarboxylates 11a—e were prepared by using the Hantzsch reaction involving condensation of the Knoevenagel adducts 9a—e with 1‐[2‐(4,5‐dihydro‐4,4‐dimethyloxazolin‐2‐yl)]‐1‐propen‐2‐amine (10). In contrast, the 4‐(2‐pyridinyl) analogue 11f was prepared by thionyl chloride mediated cyclization of the 5‐{N‐(1,1‐dimethyl‐2‐hydroxyethyl)aminocarbonyl} moiety of 16 to the 5‐[2‐(4,5‐dihydro‐4,4‐dimethyloxazolin‐2‐yl)] ring system (11f). In vitro calcium channel antagonist activity was determined by using the guinea pig ileum longitudinal smooth muscle (GPILSM) assay. Compared to the reference drug nifedipine (IC50 = 1.43 × 10−8 M), the title compounds 11 exhibited weak calcium channel antagonist activity (10−5 to 10−6 M range). A comparison of compounds 11 having a C‐4 3‐pyridinyl substituent showed that with respect to the alkyl ester R2‐subsituent, the relative potency order was i‐Bu (11c) ≥ i‐Pr (11e) > Me (11a). The point of attachment of the C‐4 pyridinyl substituent in the isopropyl ester isomeric series of compounds was a determinant of activity where the potency profile was 4‐py (11d) ≥ 3‐py (11e) > 2‐py (11f). Although less effective, the 4,5‐dihydro‐4,4‐dimethyloxazolin‐2‐yl moiety acts as a bioisostere of the alkyl ester substituent present in classical 1,4‐dihydropyridine calcium channel antagonists. The 4,5‐dihydro‐4,4‐dimethyl‐oxaxolin‐2‐yl ring system is not an effective bioisostere of the 3‐nitro group present in 1,4‐dihydropyridine calcium channel agonists since isopropyl 1,4‐dihydro‐2,6‐dimethyl‐4‐(2‐pyridinyl)‐5‐[2‐(4,5‐dihydro‐4,4‐dimethyloxazolin‐2‐yl)]‐3‐pyridinecarboxylate (11f) produced a modest 10% increase in the in vitro contractile force of guinea pig left atrium at a concentration of 1.64 × 10−7 M, relative to the reference 3‐nitro analogue 1 (EC50 = 9.6 × 10−6 M).