bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular Modelling‐Studien zur Hormonbindungsstelle des Estrogen‐Rezeptors
Authors: Höltje Hans‐Dieter
Published: October 2006

Mit Hilfe von Molecular Modelling‐Verfahren wurden die Struktureigenschaften von Liganden mit hoher Affinität zum Estrogen‐Rezeptor untersucht. Zur Bestimmung der biologisch aktiven Konformationen und Orientierungen innerhalb der Hormonbindungsstelle wurde eine vergleichende Studie auf der Basis von Molekülvolumina und molekularen Interaktionsfeldern durchgeführt. Der daraus abgeleitete Pharmakophor stellt die Grundlage für ein Aminosäure‐Modell der Hormonbindungsstelle dar, mit dem einige experimentelle Daten erklärt werden können.
Nitrosierungen an Hydrazinderivaten, 11. Mitt.: 5‐Nitrorhodanine aus 5‐monosubstituierten Rhodaninderivaten unter nitrosierenden Bedingungen
Authors: Hanefeld Wolfgang , Helfrich Volker
Published: October 2006

C‐5‐monosubstituierte Rhodaninderivate reagieren unter nitrosierenden oder nitrierenden Bedingungen zu 5‐Nitro‐rhodanin‐Derivaten.
Indole, 10. Mitt.: Synthese, Struktur und D2‐Affinität des β‐Carbolin‐Analogons von Flutrolin
Authors: Lehmann Jochen , Knoch Falk , Jiang Naicai
Published: October 2006

10 ist ein β‐Carbolin‐Analogon des Neuroleptikums Flutrolin2a,b) mit deutlich geringerer Affinität zum Dopamin D2‐Rezeptor. Verschiedene Synthesewege zu 10 und die Molekülstruktur im Kristall von 8 werden beschrieben, Struktur‐Wirkungsbeziehungen, insbesondere die Bedeutung der “S‐shape” ‐ und rigidisierten Dopamin‐Konformation diskutiert.
1,3‐Bis(pyridin‐2‐ylthio)propan‐2‐one, Bis(thieno[2,3‐b]pyridin‐2‐yl)‐ketone und 5H‐Bispyrido[3′,2′:4,5]thieno[2,3‐b:2′,3′‐e]pyridin‐11‐one
Authors: Leistner Siegfried , Dumke Stefan
Published: October 2006

Die Mercaptopyridincarbonitrile 1a‐d bzw. das Mercaptoisochinolincarbonitril 1e reagieren mit 1,3‐Dichloraceton zu den Bisthioethern 2a‐e. Durch basenkatalysierte Cyclisierung von 2a‐e werden die heterocyclisch substituierten Ketone 3a‐e erhalten. Erhitzen von 3a bzw. 3b in konz. H3PO4 gibt die Bispyridothienopyridine 5a bzw. 5b.
Synthesis and Anticonvulsant Activity of New Dibenzo[1,2]thiazepine S,S‐Dioxides
Authors: Diaz Juan A. , Montero Enrique , Vega Salvador , Darias Victoriano , Tello M. Luisa , Abdallah Suzanne S.
Published: October 2006

A new series of 11‐substituted 6,11‐dihydro‐6‐methyl‐dibenzo[c,f]‐[1,2]thiazepine S,S‐dioxides was synthesized. Some of the components show significant anticonvulsant activity in the MES, pentetrazol and strychnine tests. The more active compounds are devoid of neurotoxic effects.
Formation of 1H‐Aziridines from Chalcones and Hydroxylamine
Authors: Kammermeier Thomas , Kaiser Alexander , Lee Gwan Sun , Burgemeister Thomas , Wiegrebe Wolfgang
Published: October 2006

Highly substituted chalcones 1 do not react with two molecules of hydroxylamine affording dioximes 2 or hydroxyamino‐oximes 3 as expected according to von Auwers' procedure: only one molecule of hydroxylamine is consumed leading to trans‐configurated 2‐benzoyl‐3‐phenyl‐1H‐aziridines 4.
Synthesis of New 7‐Substituted 4‐Methylcoumarin Derivatives of Antimicrobial Activity
Authors: Eid A. I. , Ragab F. A. , El‐Ansary S. L. , El‐Gazayerly S. M. , Mourad F. E.
Published: October 2006

New cyclic derivatives derived from 4‐methyl‐7‐coumarinyloxyacetic acid hydrazide have been synthesized. Some representative examples were screened for antimicrobial activity.
Verbesserte Synthese von methyl‐ und phenylsubstituierten Pyrido[2,3‐d]pyrimidin‐2,4‐diaminen
Authors: Troschütz Reinhard , Dennstedt Thomas
Published: October 2006

Die Titelverbindungen 4b‐g, 10a,b und 13 lassen sich durch “Cyclokondensation” der 1,3‐Biselektrophile la‐e, 5b,f,g, 7b,d, 8a,b und 12 mit 2,4,6‐Triaminopyrimidin (2) in verbesserten Ausb. darstellen.
Synthesis and Anticancer Activity of 2‐Substituted 2,3‐Dihydro‐1,3,2‐benzoxazaphosphorin‐4‐one and its 2‐Oxide Derivatives
Authors: Kostka Krzysztof , Porada Marek , Graczyk Julita
Published: October 2006

As a result of the reaction of salicylic amide with PCl3 and POCl3 2‐chloro‐2,3‐dihydro‐1,3,2‐benzoxazaphosphorin‐4‐one (1) and its 2‐oxide 2 are obtained. Compounds 1 and 2 form amides with amines in 2‐position. Antineoplastic action of the derivatives containing the bis(2‐chloroethyl)amide group in 2‐position was found.
Anwendung der Grob‐Mengen‐Theorie zur Analyse der Struktur‐Wirkung‐Beziehungen von antifungiellen Pyridiniumverbindungen
Authors: Krysiński Jerzy
Published: October 2006

Die Beziehungen zwischen chemischer Struktur und antifungieller Wirkung von 72 quaternären Pyridiniumchloriden wurden mit der Grob‐Mengen‐Methode analysiert. Im Informationssystem wurden die Verbindungen mit acht Bedingungsattributen beschrieben und in drei Klassen der Aktivität eingeteilt. Die Berechnungen ergeben eine kleinste Untermenge von vier Bedingungsattributen, die signifikant für die hohe Qualität der Klassifikation und für die Genauigkeit der Klassen waren. Der resultierende Entscheidungsalgorithmus zeigt wesentliche Beziehungen zwischen der antifungiellen Wirkung von Pyridiniumverbindungen und den auf signifikante Bedingungsattribute reduzierte Strukturmerkmalen. Der Entscheidungsalgorithmus gibt Hinweise, die bei Synthesen neuer antifungiell wirksamer Verbindungen behilflich sein können.
Zur HPLC‐Trennung einiger Mandelsäureesterderivate mittels α1‐Glykoprotein (AGP)
Authors: Jira Thomas , Epperlein Ulrich , Beyrich Thorsten
Published: October 2006

Untersuchungen zur direkten HPLC‐Racemattrennung von chiralen Mandelsäureester‐ und Phenylessigsäureesterderivaten an einer AGP‐Säule wurden durchgeführt. Der Einfluß verschiedener geladener und ungeladener Modifizierer (Isopropanol, Octansäure, Dimethyloctylamin) sowohl einzeln als auch in Kombination in der mobilen Phase bei Variation des pH‐Wertes wurde untersucht.
Synthesis of 4‐Alkylpyrazoles as Inhibitors of Liver Alcohol Dehydrogenase
Authors: Echevarría Aurea , Martín Manuel , Pérez Concepcíon , Rozas Isabel
Published: October 2006

Theoretical studies by shape analysis of the molecular electrostatic potential on the van der Waals surfaces of a set of 4‐alkylpyrazoles predicted 4‐isopentyl derivative as a good inhibitor of liver alcohol dehydrogenase. Thus, the new 4‐isopentyl and the already known 4‐octylpyrazole have been prepared by a novel route. The isopentyl derivative has been tested as inhibitor of horse liver alcohol dehydrogenase giving the result predicted by the theoretical studies.
1,3‐Dinitropropane als Vorstufen von 1,3‐Diaminopropanen
Authors: Mahboobi Siavosh , Grothus Götz
Published: October 2006

Reduktion der Malodinitrile 4 und 10 zu den entspr. Diaminen gelingt nicht. ‐ 1,3‐Dinitro‐2‐(indol‐3‐yl)‐propane 13 und 16 lassen sich dagegen glatt reduzieren, die entspr. Diamine mit K2PtCl4 zu den Dichloroplatin(II)‐Komplexen 14 und 17 umsetzen. Die Komplexe 17 zeigen schwache Bindungsaffinitäten zum Estrogenrezeptor und wirken gegen MCF‐7‐ und MDA‐MB‐231‐Zellen nicht cytostatisch. ‐ Doppelte Addition von Nitromethan an Aldehyd 24 ist möglich.
New NO‐Donors with Antithrombotic and Vasodilating Activities, V: Oligonitroso Sydnone Imines
Authors: Rehse Klaus , Schleifer Klaus‐Jürgen , Martens Antje , Kämpfe Michael
Published: October 2006

Nine 4,4′‐bis‐ and four 4,4′‐tris‐N‐nitroso sydnone imines were synthesized. The sydnone imine moiety is connected either by aromatic 1,3‐phenylene or 1,3,5‐benzene or aliphatic methylene or propylene bridges. Compared to the corresponding sydnone imines the collagen induced platelet aggregation inhibiting activity is increased by several orders of magnitude by the nitroso derivatives. The most potent compound bears a hexyl substituent in 3‐position (1d: IC50 = 0.05 μmol/L). These data show that aromatic bridges (1d, 2d) are more favourable than aliphatic ones (4b). This indicates the mutual influence of the nitroso‐imino moieties via the aromatic bridges. In the series of 3,3′‐bis‐nitrososydnone imines (13 compounds) mostly additive effects of the nitroso groups are seen. The activities range from IC50 = 0.2 μmol/L (5i; 1,3‐xylene bridge) to IC50 = 8 μmol/L (5b; trimethylene bridge). The differences suggest different affinities to the platelet membrane.
Platelet Aggregation Inhibiting and Anticoagulant Effects of Oligoamines, XVIII: Oligoamines with Fluorescent Properties, Part B: Fluorophores in the Molecular Periphery
Authors: Rehse K. , Seidel T.
Published: October 2006

Seventeen N,N′‐benzene‐1,3‐dimethane and nine N,N′,N″‐benzene‐1,3,5‐trimethane derivatives with fluorescent properties have been synthesized. Three of them show antiplatelet activities (inducer collagen, IC50 Born‐test) in concentrations < 10 μmol/L. They are suitable for interaction studies with biological macromolecules and synthetical and biological membranes. Structure activity relationships demonstrate that heteropolycyclic fluorophores i.e. quinoline, dibenzofurane, or carbazole are favorable substituents for this purpose.
Oxidationen an Thiourethanen, 12. Mitt.: Oxidative Desulfurierung von Cyclischen Dithiocarbamaten und ‐carbazaten mittels Wasserstoffperoxid oder Wasserstoffperoxid/Natriumwolframat im Zweiphasen‐System
Authors: Hanefeld Wolfgang , Schlitzer Martin
Published: October 2006

Cyclische Dithiocarbamate und ‐carbazate wurden im Zweiphasensystem mittels H2O2 mit und ohne Zusatz von Na2WO4 zu den entsprechenden 2‐Oxo‐Analogen desulfuriert.
3‐Substituierte 2‐Phenylindole: Synthese und biologische Eigenschaften
Authors: Mahboobi Siavosh , Grothus Götz , Angerer Erwin Von
Published: October 2006

Knoevenagel‐Reaktion von Indol‐3‐carbaldehyden 5a,b und 7a,b mit Nitromethan führt zu den Nitroethenen 12 und 14, die analoge Reaktion mit Malodinitril zu den Methylidenmalonsäuredinitrilen 16.‐ Michael‐ Addition von Nitromethan an 12 und 14 führt zu den 1,3‐Dinitropropanen 13 und 15, Reduktion von 16 zu den Methylenmalonsäuredinitrilen 17.‐ Umsetzungen der Indole 3 mit n‐BuLi/Phenylsulfonylchlorid führen zu den 3‐Chlorindolen 18, Reaktion mit NaH/Ethyliodid sowie Etherspaltung und Acylierung zu den Acetoxyderivaten 19.‐ Verbindungen 7–11, 14–17 und 19 zeigen eine Affinität zum Estrogenrezeptor. Verbindungen 7b, 9–11, 17b und 19b hemmen das Wachstum von MCF‐7‐ und MDA‐MB‐231‐Zellen. IC50‐Werte werden bestimmt und Struktur‐Wirkungs‐Beziehungen diskutiert.
Nonsteroidal Antiinflammatory Agents, XVIII: C‐5 Functionalized 6,7‐Diphenyl‐2,3‐dihydro‐1H‐pyrrolizines as Inhibitors of Bovine Cyclooxygenase and 5‐Lipoxygenase
Authors: Dannhardt G. , Kiefer W.
Published: October 2006

6‐(4‐Chlorophenyl)‐7‐phenyl‐2,3‐dihydro‐1H‐pyrrolizines with functional groups at position 5 of the heterocyclic moiety were synthesized and tested. To determine their antiinflammatory activity bovine blood was used as enzyme source for the cyclooxygenase and 5‐lipoxygenase, respectively. The iminoxy acetic acid derivative and the iminotetrazole selectively inhibit the 5‐lipoxygenase, all the other compounds show medium or low affinity to the active sites of cyclooxygenase and 5‐lipoxygenase. In general all compounds inhibit 5‐lipoxygenase more effectively than cyclooxygenase. Concerning the inhibition of 5‐lipoxygenase the most active compounds found are equipotent to the corresponding propionic acid compounds, but they aren't well balanced dual inhibitors as shown for the carboxylic derivatives. A structure activity relationship and the enzyme selectivity are discussed.
Synthesis and Antiviral Evaluation of Hydantoin Analogues of AZT
Authors: El‐Barbary Ahmed A. , Khodair Ahmed I. , Pedersen Erik B.
Published: October 2006

3′‐Azidonucleosides 4 have been synthesized by condensation of silylated (Z)‐5‐ethylidenehydantoin and (Z)‐5‐benzylidenehydantoin with methyl 3‐azido‐5‐O‐tert‐butyldiphenylsilyl‐2,3‐dideoxy‐D‐erythro‐pentofuranoside (3). The nucleosides 4 were deblocked on treatment with tetrabutylammonium fluoride. The ethylidene group isomerized from Z to E configuration during the nucleoside synthesis. The new nucleosides did not show any appreciable activities against HIV‐1 or HSV‐1.
Constituents of Tropical Medicinal Plants, LXIII: Synthesis of 2‐Methoxyonychine Alkaloids ‐ Structure Revision of Oxylopidine
Authors: Achenbach Hans , Schwinn Andreas
Published: October 2006

Condensation of β‐aminocinnamic acid esters with 3‐chloro‐2‐methoxy‐crotonaldehyde opened an easy access to 2‐phenyl‐5‐methoxy‐4‐methylnicotinic acid esters which were cyclized by polyphosphoric acid to yield the corresponding 2‐methoxyonychines. By this method a number of 2‐methoxy‐substituted onychines were prepared for the first time, i.a. oxylopidine, the structure of which has to be revised.
Herstellung und Reaktionsverhalten eines schwefelverbrückten Bischinolons
Authors: Löwe Werner , Kietzmann Annette
Published: October 2006

Ausgehend vom tosylierten Enaminon 5 lassen sich mit Essigsäure, Sulfurylchlorid und Thionylchlorid die neuen Chinolon‐Derivate 3, 8, 9 und 10 herstellen. Das schwefelverbrückte Bischinolon 8 gibt bei der Alkylierung die N‐Alkylprodukte 11 und 12. Die Dehydratisierung von 8 führt zum neuen Heterocyclus 13. Aus Verbindung 8 entsteht mit POCI3 das 4‐Chlorchinolin‐Derivat 14, aus dem das Sulfoxid 15 herstellbar ist. Verbindung 14 reagiert mit Thioharnstoff zum Isothiuroniumsalz 16. Dieses kann entweder durch Erhitzen oder über das Thion 17 nach H2S‐Eliminierung in das Dithiinobischinolin 18 übergeführt werden.
Anti‐inflammatory Activity of Amine‐carboxyboranes in Rodents
Authors: Hall Iris H. , Rajendran K. G. , Chen S. Y. , Wong Oi T. , Sood A. , Spielvogel B. F.
Published: October 2006

Amine‐carboxyboranes are potent anti‐inflammatory agents reducing induced edema and pleural effusion at 8 mg/Kg, i.p. They protect against LPS (Salmonella) induced septic shock from 2–8 mg/Kg/day and are effective in blocking pain mediated both locally and centrally. The mode of action of these agents is by blocking release of cytokines from macrophages, thus reducing lysosomal hydrolytic and proteolytic enzyme activities of affected cells. The agents also reduce prostaglandin and leukotriene synthesis by blocking the activities of regulatory enzymes of the respective pathways.
Synthesis of 4‐Methylthio Analogues of FLT and AZT and their Evaluation against HIV
Authors: Abdel‐Rahman Adel A.‐H. , Abdel‐Bary Hamed M. , Pedersen Erik B. , Nielsen Claus
Published: October 2006

Silylated 4‐methylthiouracil and 4‐methylthiothymine were condensed in the presence of TMS triflate with methyl 2,3‐dideoxy‐3‐fluoro‐5‐O‐(4‐phenylbenzoyl)‐D‐erythro‐pentofuranoside (3) and methyl 3‐azido‐5‐O‐(tert‐butyldiphenylsilyl)‐2,3‐dideoxy‐D‐erythro‐pentofuroside (8), respectively, to give the corresponding nucleosides which were deprotected. The 3′‐azido nucleoside was reduced with triphenylphosphine to the corresponding 3′‐amino nucleoside. The 3′‐amino nucleoside was also obtained by condensation of 4‐methylthiothymidine with a 3‐phthalimido sugar 14 followed by deprotection. The 4‐methylthio analogue 11 of AZT showed moderate activity against HIV.
Peroxidase‐catalysed oxidation of different dibenzazepine derivatives
Authors: Liégeois Jean‐Francois , Rogister Francoise , Delarge Jacques , Pincemail Joël
Published: October 2006

According to a recent hypothesis suggesting the potential role of free radical formation in the clozapine‐induced agranulocytosis, we have evaluated the susceptibility to the peroxidase‐mediated oxidation of different dibenzazepine analogues. On the one hand, compounds with an arylamine group such as clozapine present a high reactivity in the horseradish peroxidase or myeloperoxidase systems and, on the other hand, fluperlapine, though known to induce agranulocytosis, and other debenzothiazepine and dibenzoxazepine derivatives appear insensitive to oxidation. Consequently, among tricyclic derivatives, the way of diaryloxa‐ and diarylthiazepine compounds could be an alternative for the development of safer drugs such as antipsychotics.
Synthesis of Phthalimido‐Desmuramylpeptide Analogues as Potential Immunomodulating Agents
Authors: Urleb Uroš , Krbavčič Aleš , Sollner Marija , Kikelj Danijel , Pečar Slavko
Published: October 2006

The preparation of immunologically active phthalimido desmuramylpeptide analogues 2e‐h, 4c‐d, and 7b is described. The N‐acetylmuramic acid in the muramyl dipeptide has been replaced by a phthaloylated acyclic moiety such as N‐phthaloylated amino acids 1a–c, 2‐(2‐phthalimidoethoxy)acetic acid 3, or by the carbocyclic rac. trans‐2‐(2′‐phthalimidocyclohexyloxy)acetic acid 6.
Synthesis of Some Thiazolo[3,2‐b]‐1,2,4‐triazole‐5(6H)‐ones as Potential Platelet Aggregation Inhibitors
Authors: Tozkoparan Birsen , Akgün Hülya , Ertan Mevlüt , Rübsemann Klaus
Published: October 2006

Twenty new compounds having 2‐methyl‐6‐benzylidenethiazolo[3,2‐b]‐1,2,4‐triazole‐5(6H)‐one (2a–d) and 2‐methyl‐6‐(α‐aminobenzyl)thiazolo‐[3,2‐b]‐1,2,4‐triazole‐5‐ol (5–20) structures were synthesized. Their structures were confirmed by elemental and spectroscopic analysis and their platelet aggregation inhibitory activities were investigated.
Struktur‐Wirkungs‐Beziehungen an Isochromanylpenicillinen
Authors: Unterhalt Bernard , Nocon Birgit
Published: October 2006

Der Isochromanring wird substituiert und in 1‐Position direkt oder über einen Spacer an 6‐Aminopenicillansäure gebunden. Zusätzlich werden zwei Homoisochromane in die Untersuchung eingebezogen. Die Wirkung der neuen Penicilline wird im grampositiven und gramnegativen Bereich der des Benzylpenicillins gegenübergestellt.
Cytotoxicity and Antimicrobial Activity of Some Naphthol Derivatives
Authors: Shen Ai Yu , Hwang Mei Han , Roffler Steve , Chen Chia Fu
Published: October 2006

2‐Hydroxymethyl‐1‐naphthol diacetate (TAC) and sixteen Mannich base derivatives of naphthol were prepared and examined for cytotoxicity and antimicrobial activity. Cytotoxicity was examined against four human carcinoma cell lines. Several derivatives were effective at concentrations < 4 μg/ml. TAC showed the highest cytotoxicity. Inhibition of DNA‐, RNA‐, and protein synthesis by TAC was also studied and discussed. TAC also exhibits potent antimicrobial activity against Enterobacter clocae 23355, Klebsiella pneumonia 13883, Proteus vulgaris 13315, Pseudomonas aeruginosa 27853, Candida parapsilosis, Candida tropicalis, Trichosposon beigelli, and Rhodotorul spp. with minimum inhibitory concentrations of 0.1 ∼ 0.4 μM. These results indicate that esterification by Bruson reaction of 1‐naphthol Mannich base to TAC enhances the cytotoxicity and antimicrobial activity.
A New Rapid and Sensitive High‐Performance Liquid Chromatographic Assay for Diclofenac in Human Plasma
Authors: Hanses Antje , Spahn‐Langguth Hildegard , Mutschler Ernst
Published: October 2006

A new rapid and sensitive reversed‐phase HPLC method for the routine analysis of diclofenac in human plasma is described. The method shows high selectivity, sensitivity, and reproducibility employing 4′‐methoxydiclofenac as internal standard (IS) with UV‐detection at 282 nm. The correlation of peak area ratios (diclofenac/IS) versus diclofenac plasma concentrations are linear between 5.0—2000 ng/ml with a detection limit of 3 ng/ml. Intra‐ and interday precision studies yielded coefficients of variation < 6.2 % for all concentrations (range 20.0—1600 ng/ml). The method was applied for the assay of diclofenac in plasma of healthy volunteers after p.o. and rectal dosage of 50 mg diclofenac sodium and was found to be highly suitable for routine analyses.
A Facile and Regioselective Synthesis of Donor‐Substituted 2‐(2‐Halophenyl)acetaldehyde Acetals
Authors: Wünsch Bernhard , Nerdinger Sven
Published: October 2006

Starting from vanillin (5a) a facile and high yielding procedure for the preparation of the donor substituted (2‐bromophenyl)‐ and (2‐iodophenyl)acetaldehyde acetals13cand16cis described. Homologization ofO‐benzylvanillin to obtain the phenylacetaldehyde acetal15csucceeds byWittigreaction with the phosphonium chloride11and subsequent addition of methanol.15cis brominated with pyridinium bromide perbromide in methanol to yield the bromo acetal13cin 65 % yield from vanillin. Iodination of15cwith iodine and iodic acid leads to the iodo acetal16c.
Pyridazines, LXXII: On the Synthesis of Azinium and Diazinium Compounds Structurally Related to Pyridazomycin
Authors: Easmon Johnny , Heinisch Gottfried , Holzer Wolfgang , Matuszczak Barbara
Published: October 2006

Preparation of series of pyridine‐, pyridazine‐, and pyrazine‐derived carboxamides bearing at the ring N‐atom an alkyl side‐chain with a terminal carboxylic group (7–11) or with a terminal acetylamino malonic ester moiety (13–17, 19–23) is described. Two desaza‐pyridazomycin derivatives (24, 26) and homologs thereof (25, 27) were synthesised. The novel compounds which are structurally related to the antifungal antibiotic pyridazomycin were screened for antifungal activity: preliminary in vitro tests showed no activity.
Synthesis and Dopamine Receptor Binding of 3‐Phenylazepino[5,4,3‐c,d]indole Derivatives
Authors: Gmeiner Peter , Sommer Josef , Höfner Georg
Published: October 2006

The 3‐phenylazepino[5,4,3‐c,d]indole derivatives 5 and 9–11, representing heterocyclic analogs of the selective dopamine D‐1 receptor ligands of the 3‐phenylbenzazepine class, were synthesized starting from the indole‐4‐carboxylate 7. Receptor binding studies employing bovine striatal membranes demonstrated that the test compounds 5, 10, and 11 are able to displace the D‐1 selective radioligand [3H]‐SCH 23390 as well as the D‐2 antagonist [3H]‐spiperone. Compound 5b turned out to be the most potent and selective ligand (ki = 1.8 μM for D‐1 and ki = 8.9 μM for D‐2). It is assumed that the moderate selectivity of 5b is due to the conformational inequality of the 7‐membered rings when compared to the benzazepines. This results in a spatial arrangement of the phenyl substituent which is not able to interact with a ‘subtype selectivity‐inducing site’.
Determination of the in vitro Dissolution Profiles of Ursodeoxycholic Acid Preparations by HPLC with On‐Line Sample Handling
Authors: Scalia S. , Giunchedi P. , Conte U. , Pazzi P.
Published: October 2006

A high‐performance liquid chromatographic (HPLC) technique with on‐line sample preparation was developed for monitoring the in vitro dissolution profiles of ursodeoxycholic acid (UDCA) formulations. Since UDCA lacks a strong chromophore, conventional UV determination of the dissolved drug is precluded. The proposed method involves direct injection of large volumes (1–2 ml) of the filtered dissolution medium onto a precolumn dry‐packed with large particulate (40–60 μm octadecylsilica and inserted at the loop position of the HPLC injector. After flushing the precolumn with water, the retained UDCA is transferred by the mobile phase onto the analytical column for analysis. The method is reproducible and rapid, minimizing sample manipulations. The dissolution profiles of different UDCA/polymer preparations in USP simulated gastric and intestinal fluid were determined by on‐line pre‐column purification and preconcentration and reversed‐phase HPLC.Key words: ursodeoxycholic acid; dissolution testing; excipient interference; on‐line sample processing; high‐performance liquid chromatography.
Heterolignanolides: Antitumor Activity of Furyl‐, Thienyl‐, and Pyridyl Analogs of Lignanolides
Authors: Medarde Manuel , de Clairac Rafael PeléEz‐Lamamié , Toém Fernando , López Jose Luis , Feliciano Arturo San , Grávalos Dolores Ga
Published: October 2006

A new class of heteroaromatic analogs of lignans, called heterolignanolides, have been tested against several tumor cell lines. These compounds carry diverse heterocyclic rings, instead of the trimethoxyphenyl ring found in the natural lignans yatein and podorhizol. They have moderate antineoplastic activity (P‐388, A‐549, HT‐29) compared with that of yatein. None of the tested compounds has discernible antiviral (HSV‐1, VSV) or enzyme inhibitor (ADA, DHFR, GST) activity.
Platelet Antiaggregant Methoxyphenylthienyl Ketoxime Ethers: Synthesis and Structure‐Activity Relationships
Authors: Varache‐Lembège Martine , Nuhrich Alain , Renard Pierre , Duboudin Françoise , Vercauteren Joseph , Devaux Guy
Published: October 2006

Some new oximinoalkanoic (n = 2,3,4) esters and acids derived from methoxyphenylthienyl ketones have been synthesized and evaluated in vitro for their inhibitory effects on arachidonic acid‐induced human platelet aggregation. Of the eighteen oximinoethers tested the most active derivatives, which were four times more active as aspirin, belonged to the para methoxy series with Z configuration and n = 2 or 3.
Synthesis of 1,2,5(6)‐Trisubstituted Benzimidazoles and Evaluation of Their Antimicrobial Activities
Authors: Göker Hakan , Kus Canan , Abbasoglu Ufuk
Published: October 2006

A series of 22 benzimidazoles, having several substituents on the azole and benzene nuclei, were prepared and evaluated in vitro for antimicrobial activity. At first 2‐chloro or 2‐chloromethyl‐5(6)‐substituted‐1H‐benzimidazoles were synthesized, which were then substituted at C‐2 with several piperazine or piperidine derivatives. The antibacterial activity of these compounds against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa, and the antifungal activity against Candida albicans, Candida stellatoidea, Candida parapsilosis, and Candida pseudotropicalis were determined as the MIC values. Since compound 12 exhibits good activity, in order to clarify the effect of substituents at C‐1 on the activity, benzimidazole derivatives having ethyl, allyl, benzyl, and p‐fluorobenzyl substituents at C‐1 were prepared, and slightly increased activity was seen.
Pyrazoles as Potential Histamine H3‐Receptor Antagonists
Authors: Kieć‐Kononowicz Katarzyna , Ligneau Xavier , Schwartz Jean‐Charles , Schunack Walter
Published: October 2006

In search of structure‐activity relationships among histamine H3‐receptor antagonists, the imidazole ring of known H3‐receptor antagonists was replaced by different heteroaromatic ring systems. Thus, pyrazoles with ether (4,5) and carbamate (6,7) moieties as functional groups were synthesized. Reaction of the hydrochloride of 4‐(3‐hydroxypropyl)pyrazole (1) with phenyl or benzyl isocyanates mainly gave the carbamates 6 and 7, whereas a similar reaction with 1 as the free base furnished the N‐carbamoylpyrazoles 8 and 9. The bifunctional pyrazoles 10 and 11 were formed as by‐products. The compounds obtained did not show significant H3‐receptor antagonist activity in vitro (rat brain cortex) or in vivo (mouse brain). These results demonstrate the importance of the imidazole moiety for H3‐receptor antagonists. The new compounds were also screened for H1‐receptor antagonist activity on the isolated guinea‐pig ileum and for H2‐receptor antagonist activity on the isolated spontaneously beating guinea‐pig right atrium. The substances showed only weak antagonistic activity at both histamine receptors H1 and H2.
Tricyclic CNS Active Agents by Intramolecular Oxa‐Pictet‐Spengler Reaction
Authors: Wünsch Bernhard , Zott Matthias , Höfner Georg , Bauschke Gerd
Published: October 2006

Mitsunobu inversion of the (S)‐configurated lactate (S)‐7, which is prepared in four steps starting form (S)‐tyrosine, leads to the (R)‐configurated lactate (R)‐7. The key step in the transformation of the enantiomeric lactates (S)‐7 and (R)‐7 into the benzomorphan analogous tricycles (R,S)‐16a,b, (S,R)‐16a,b, (S,S)‐22, and (R,R)‐22 is an intramolecular Oxa‐Pictet‐Spengler reaction: The amides (S)‐13, (R)‐13, (S)‐19 and (R)‐19, in which the carbonyl moiety — masked as an acetal — is linked to the 2‐phenylethanol moiety, are cyclized to give the tricyclic amides (R,S)‐15, (S,R)‐15, (S,S)‐21, and (R,R)‐21, respectively. In a concentration of 100 μM both enantiomers of 16a, 16b, and 22 are not able to compete with 3H‐(+)‐MK 801 for the phencyclidine binding sites of NMDA receptors. In vivo, only (R,S)‐16b and (S,S)‐22 exhibit weak sedative and analgesic activity.
Resolution, EPC‐Syntheses, Absolute Stereochemistry, and Pharmacology of the (S)‐(+)‐ and (R)‐(—)‐Isomers of the MAO‐A Inhibitor Tetrindole Hydrochloride
Authors: Bös Michael , Canesso Rolf , Kettler Rolf , Keller Hans H. , Schönholzer Peter
Published: October 2006

Resolution of (RS)‐tetrindole (3) and enantioselective reductions of the imine 7 yielded (S)‐(+)‐(4) and (R)‐(−)‐tetrindole (5). The absolute stereochemistry of 4 was established by X‐ray analysis of the corresponding Mosher amide 6. From in vitro as well as in vivo data (MAO‐inhibiton, levels of monoamines and their respective metabolites in rat brain), 4 was identified as the eutomer.
Quality Control of Peptide Drugs. Chiral Amino Acid Analysis versus Standard for Icatibant Acetate
Authors: Ermer Joachim , Gerhardt Jürgen , Siewert Martin
Published: October 2006

A method of chiral amino acid analysis versus standard is presented. By treating the peptide sample and a chiral standard whose intrinsic chiral composition is known in the same way, i.e. simultaneous hydrolysation and analysis, exact corrections can be made for the sequence‐related and many hydrolysation‐related racemisations. The accuracy obtained in this way permits use of the results for quality control of the chiral purity of peptide drugs. Using the bradykinin antagonist Icatibant acetate (INNM) the method was validated with respect to its precision, accuracy, specificity, limit of detection, and robustness.
Synthesis and Authentication of Iodoazidophenpyramine, a Photoaffinity Reporter Ligand Previously used for Histamine H1‐Receptor Labelling
Authors: Sorba Giovanni , Tertiuk Wasyl , Ganellin C. Robin
Published: October 2006

The synthesis is described of aminophenpyramine (7) (N‐{5‐[2‐(4‐aminophenyl)ethananmido]pentanyl}‐N′‐(4‐methoxybenzyl)‐N‐methyl‐N′‐(2‐pyridinyl)‐1,2‐ethandiamine), its monoiodo‐ and diiodo‐derivatives (8 and 9), and iodoazidophenpyramine (1). The last compound is synthesised by two different routes to confirm the identity of the [125I]iodinated ligand previously made only in solution and used for characterisation of the histamine H1‐receptor protein. The procedures employ the novel intermediates 4‐amino‐3‐iodo‐phenylacetic acid (11) and 4‐azido‐3‐iodo‐phenylacetic acid (13). They have general applicability to the synthesis of non‐radioactive iodinated photoaffinity receptor ligands which may be required for chemical authentication of the corresponding radiolabelled compounds.
New Indole and Pyridazinoindole Analogs — Synthesis and Study as Inhibitors of Phosphodiesterases and as Inhibitors of Blood Platelet Aggregation
Authors: Monge Antonio , Navarro María‐Eugenia , Font María , Santiago Esteban , Alberdi Elena , Martínez‐Irujo Juan‐José
Published: October 2006

This paper presents the synthesis of new indole, pyridazino[4,5‐b]indole, and pyridazino[4,5‐a]indole analogs as well as a study of their “in vitro” activity as inhibitors of different phosphodiesterases isolated from dog cardiac tissue, dog aorta, and bovine platelets; the study of their activity as inhibitors of platelet aggregation in guinea pig whole blood, with ADP and arachidonic acid (AA) as pro‐aggregants, is also included. The selected compounds 8‐benzyloxy‐3,4‐dihydro‐1‐(3,4,5‐trimethoxy)benzylideneaminopyridazino[4,5‐b]indole 14g, and 8‐benzyloxy‐4‐[(3,5‐dimethyl)pyrazolyl]pyridazino[4,5‐b]indole 20 present an interesting profile as potential inodilators, with a complementary, beneficial activity as inhibitors of the aggregation, activities which could possibly be related to the inhibition of the PDE's. Among the other compounds studied, 8‐benzyloxy‐3,4‐dihydro‐1‐[4‐(methyl)piperazino]acetamidopyridazino[4,5‐b]indol‐4‐one 16c and 8‐benzyloxy‐3,4‐dihydro‐1‐[4‐(2‐methoxyphenyl)piperazino]acetamidopyridazino[4,5‐b]indol‐4‐one 16f stood out as inhibitors of platelet aggregation, with a mechanism that could possibly be related to the AA cascade.
4‐(4‐Guanidinobenzoyl)‐2‐imidazolones and Related Compounds: Phosphodiesterase Inhibitors and Novel Cardiotonics with Combined Histamine H2 Receptor Agonist and PDE III Inhibitor Activity
Authors: Glaß D. , Buschauer A. , Tenor H. , Bartel S. , Will‐Shahab L. , Krause E.‐G.
Published: October 2006

A series of new positive inotropic agents was synthesized with the aim of combining the pharmacophores of the imidazolone‐type phosphodiesterase (PDE) inhibitor enoximone and guanidine‐type histamine H2 receptor agonists such as arpromidine. All compounds are para‐substituted 4‐benzoyl‐5‐alkyl‐2‐imidazolones. H2 agonism was incorporated by p‐(hetero)arylalkyl substituents, in particular by an imidazolylpropyl guanidine group. In addition analogous ureas, cyanoguanidines, alkyl guanidine carboxylates, and amides were prepared. These functional groups were either directly attached to the phenyl ring or linked by an appropriate spacer. The compounds were screened for positive inotropic activity in the isolated electrically stimulated guinea pig papillary muscle and for inhibition of PDE III (cGMP‐inhibited cAMP PDE, isolated from guinea pig heart). The cardiotonics obtained proved to be either PDE III inhibitors, some of them surmounting up to 3‐fold the potency of enoximone, or pharmacological hybrids combining both PDE III inhibitor and histamine H2 receptor agonist activities. These hybrids were the most potent positive inotropic substances at the papillary muscle, probably due to their synergistic mechanism of action. The participation of histamine H2 receptors could be demonstrated in the papillary muscle preparation by pretreatment with the H2 antagonist famotidine (10 μM) as well as by further pharmacological experiments using isolated perfused hearts of guinea pigs and rats, isolated guinea pig right atria, adenylyl cyclase and H2 receptor binding assays. At equieffective concentrations the moderate PDE III inhibitor and histamine H2 agonist N1‐{4‐[(1,3‐dihydro‐5‐methyl‐2‐oxo‐3H‐imidazol‐4‐yl)‐carbonyl]phenyl}‐N2‐[3‐(1H‐imidazol‐4‐yl)propyl]guanidine 65 and the 5‐ethyl homologue 66 were about 2 and 10 times more potent than enoximone at the papillary muscle. Moreover, both compounds produced a 2.5‐fold higher maximal response than the reference compound.
Asymmetric Synthesis and Enantiospecificity of Binding of 2‐(1,2,3,4‐Tetrahydro‐1‐isoquinolyl)‐ethanol Derivatives to μ and κ Receptors
Authors: Wanner Klaus Th. , Praschak Ilona , Höfner Georg , Beer Herbert
Published: October 2006

A number of 2‐(1,2,3,4‐tetrahydro‐1‐isoquinolyl)‐ethanol derivatives 7a—e have been synthesized in diastereomerically and enantiomerically pure form and have been evaluated for their binding affinity at μ and κ opioid receptors. The amido ketones 5a—c and ent‐5a—c, which were accessible by employing 3b and ent‐3b for Asymmetric Electrophilic Amidoalkylation reactions, served as starting compounds. Upon reduction of 5a—c and ent‐5a—c the amido alcohols l‐6a—c, u‐6a—c, ent‐l‐6a—c and ent‐u‐6a—c were obtained. Hydrolysis of these compounds yielded the secondary amino alcohols l‐7a—c, u‐7a—c, ent‐l‐7a—c and ent‐u‐7a—c and upon reductive methylation of l‐7b—c, u‐7b—c, ent‐l‐7b—c and ent‐u‐7b—c with CH2O and NaCNBH3 the tertiary amino alcohols l‐7d—e, u‐7d—e, ent‐l‐7d—e and ent‐u‐7d—e were obtained.

The binding affinities of the final compounds l‐7a—e, u‐7a—e, ent‐l‐7a—e and ent‐u‐7a—e at both the μ and the κ receptor were strongly dependent on their stereochemistry. In each case isomers exhibited higher affinity at the μ than at the κ receptor. For the secondary amino alcohols 7a—c the affinity at the μ receptor followed the stereochemical order l‐7 > ent‐l‐7 > ent‐u‐7 > u‐7 whereas for the tertiary amino alcohols the order l‐7 > u‐7 > ent‐l‐7 > ent‐u‐7 was found. The stereoisomers l‐7d and l‐7e of the tertiary amino alcohols were found to be the most active compounds the latter exhibiting a Ki value of 7.17 which is close to that of Morphine (Ki = 1.64). In an in vivo model, the Writhing Test, both compounds l‐7d and l‐7e displayed high analgetic activity.
Synthesis of Vitamin E Analogues: Possible Active Forms of Vitamin E
Authors: Fujishima Toshie , Kagechika Hiroyuki , Shudo Koichi
Published: October 2006

We synthesized several vitamin E analogues containing oxygenated functional groups in place of the 8‐methyl group which is common to all the natural vitamin E congeners, based on the hypothesis that the methyl group might be metabolically oxidized to produce active forms which might have specific functions other than the antioxidant function. All the vitamin E analogues examined had antioxidant activity. 8‐[6‐Hydroxy‐2,5,7‐trimethyl]‐2‐(4,8,12‐trimethyltridecanyl)chroman'methanol (1d) and 2,5,7‐trimethyl‐2‐(4,8,12‐trimethyltridecanyl)chroman‐6‐ol (4d) showed similar activity to α‐tocopherol. 6‐Hydroxy‐2,5,7‐trimethyl‐2‐(4,8,12‐trimethyltridecanyl) chroman‐8‐carbaldehyde (2d) and 6‐hydroxy‐2,5,7‐trimethyl‐2‐(4,8,12‐trimethyltridecanyl)chroman‐8‐carboxylic acid (3d) showed weaker activity than α‐tocopherol, but their duration of action, especially that of 3d was considerably longer.
Pyroglutamic Acid in Drug Synthesis, Part 1 A Method for the Synthesis of Enantiomerically Pure 4‐Alkyl‐4‐arylpyroglutamic Acids
Authors: Fleischhacker Wilhelm , Riedl Thomas , Völlenkle Horst , Noe Christian R.
Published: October 2006

Synthesis of the title compounds is described, starting from alkylation of the pyroglutaminol‐acetal 4a[1] at the α‐lactam position C‐6 with methyl iodide. Subsequent addition of 2‐cyclohexen‐1‐one led to diastereoselective formation of the 1,2‐aldol addition product 7b/7c, which after dehydratization was aromatized with DDQ to yield the 6‐methyl‐6‐phenyl derivative 7h. Acetal cleavage and Jones oxidation yielded 4,4‐disubstituted, enantiomerically pure pyroglutamic acid 3b. X‐ray analysis confirmed the assignment of the configuration of the newly created chiral centre.
Preparation of Novel Analogues of the Nonredox‐Type Non‐Competitive Leukotriene Biosynthesis Inhibitor AKBA
Authors: Sailer Eckart‐Roderich , Hoernlein Rainer F. , Subramanian Lakshminarayanapuram R. , Ammon Hermann P. T.
Published: October 2006

AKBA (acetyl‐11‐keto‐β‐boswellic acid, 1) and KBA (11‐keto‐β‐BA, 2) from Boswellia serrata Roxb. and Boswellia carterii Birdw. are direct, nonredox‐type inhibitors of 5‐lipoxygenase, the key enzyme for leukotriene biosynthesis (IC50 = 1.5 and 3μM in intact neutrophils, respectively). In order to study the impact of the carboxyl function for enzyme inhibition, we synthesized novel analogues of boswellic acids. The C‐4 alcohol derivative of KBA (4) still exerted 5‐lipoxygenase inhibitory activity (IC50 = 4.5 μM), whereas (8), the C‐4 alcohol analogue of β‐boswellic acid (7), the methyl ester analogue of KBA (5), and acetyl‐11‐keto‐amyrin (9) possessed no inhibitory potential in concentrations up to 50 μM. These findings reveal that a hydrophilic group at C4 in combination with an 11‐keto‐function is essential for 5‐lipoxygenase inhibition by boswellic acids.
New NO‐Donors with Antithrombotic and Vasodilating Activities, Part 15 Nitrolic Acids
Authors: Rehse Klaus , Herpel Martin , Piechocki Daniela
Published: October 2006

Five 1‐oximino‐1‐nitro compounds (nitrolic acids) were prepared and tested for antithrombotic and blood pressure lowering activities. 1‐Nitro‐ethanone 1‐oxime (1, ethylnitrolic acid) 2 h after oral administration to rats inhibited thrombus formation by a laser beam in mesenteric arterioles of rats by 69% and by 46% in venules (60 mg/kg). The blood pressure of SHR rats even at this high dose only was decreased by 10% suggesting that antithrombotic and blood pressure effects can be dissociated. The in vitro decomposition of 1 at 37 °C nearly exclusively gave N2O and acetic acid indicating that HNO primarily had been formed.
Synthesis and Pharmacology of Combined Histamine H1‐/H2‐Receptor Antagonists Containing Diphenhydramine and Cyproheptadine Derivatives
Authors: Wolf Cornelia , Schunack Walter
Published: October 2006

The classical histamine H1‐receptor antagonists diphenhydramine (3a) and cyproheptadine (9) and their derivatives (3b—d, 10) were connected with a 2‐guanidinothiazole containing structure (28) derived from the H2‐receptor antagonist tiotidine in order to obtain combined H1‐/H2‐receptor antagonists. The two moieties were not directly linked together, but were separated by a polymethylene spacer and a polar group (nitroethenediamine or urea). Thus 12 compounds were obtained that proved in vitro to possess high H1‐ and H2‐receptor antagonist activity at the isolated guinea‐pig ileum (H1) and the isolated guinea‐pig right atrium (H2), respectively. The incorporation of the diphenhydramine as well as the cyproheptadine component provides high affinity to H1‐receptors. The tricyclic cyproheptadine and its 10,11‐dihydro derivative (30–32, 34), however, cause a decrease of H2‐receptor antagonist potency compared to the diphenhydramines (29a—d, 33a—d). Using nitroethenediamine as the polar group is apparently more favourable to H1‐ and H2‐receptor affinity as the urea function. All compounds elicit a dual mode of competitive and noncompetitive antagonism. Among the novel compounds the nitroethenediamines with 4‐fluoro‐ or 4‐methyl‐substituted diphenhydramine as H1‐receptor antagonist moiety (29c, d) display the most potent H1‐ and H2‐receptor antagonist effects. The presented concept is a very promising way to combine H1‐ and H2‐receptor antagonist properties in one molecule.
From Chloroquine to Antineoplastic Drugs? The Story of Antibacterial Quinolones
Authors: Rádl Stanislav
Published: October 2006

Chemotherapy has not only proved valuable in treating many diseases but the history of discovery of some drugs makes exciting reading. The aim of this article is to outline one such story.
Synthesis and Biochemical Studies of Spirocyclic Amino Acid Esters, Part 3 Activity of 2‐Azaspiro[4.5]decane‐6‐carboxylates as GABA‐Uptake Inhibitors
Authors: Fleischhacker Wilhelm , Lauritz Silvia , Urban Ernst , Baumann Peter , Bittiger Helmut
Published: October 2006

Novel GABA analogous spirocyclic amino acid esters 7a—d and 8a—d were prepared and investigated for interaction with GABA‐A and GABA‐B receptors as well as the GABA uptake system. Starting from known bromoethyl lactones 1 or 2 and arylalkylamines spirocyclic hydroxyalkyl lactams 3a—d and 4a—d were obtained and reduced by LiAlH4 to yield spirocyclic hydroxymethyl pyrrolidines 5a—d and 6a—d. Oxidation by Jones reagent followed by subsequent esterification gave the title compounds 7a—d and 8a—d which represent conformationally restricted analogues of GABA. Whereas the new spirocyclic amino acid esters 7a—d and 8a—d showed no activity at GABA receptors they proved to be active as GABA uptake inhibitors. An examination of the relationship between structure and GABA uptake inhibition revealed a strong dependence of activity upon the length of the alkyl chain in N‐arylalkyl substituents and upon the ring size of underlying spirocyclic system.
Chitosan‐Indomethacin Conjugates. Effect of Different Substituents on the Polysaccharide Molecule on Drug Release
Authors: Orienti Isabella , Aiedeh Khaled , Gianasi Elisabetta , Ponti Cristina , Zecchi Vittorio
Published: October 2006

The conjugation of indomethacin with chitosan partially substituted with the hydrophilic residues triethylene glycol glutarate and triethylene glycol choline ether glutarate is described. Mucoadhesive conjugates were obtained showing gelling properties both in acid and basic environment. Among the substituents, triethylene glycol choline ether glutarate better enhances the gelling properties of the macromolecules. In all cases the kinetics of drug release from the macromolecules approached zero order.
Synthesis of Potent and Orally Active HIV‐Protease Inhibitors
Authors: Capraro Hans‐Georg , Bold Guido , Fässler Alexander , Cozens Robert , Klimkait Thomas , Lazdins Janis , Mestan Jürgen , Poncioni Bernard , Rösel Johannes L. , Stover David , Lang Marc
Published: October 2006

A series of potent HIV‐protease inhibitors has been prepared. Several of the newly synthesized compounds showed high plasma levels after oral administration to animals. Based on the overall biological profile, CGP 61755 was chosen for further preclinical evaluation. For this compound, a 10 step synthesis potentially suitable for large scale production was developed.
3‐(ω‐Aminoalkyl)‐5,5‐dialkyl(or spirocycloalkyl‐1′,5‐)hydantoins as New 5‐HT1A and 5‐HT2A Receptor Ligands
Authors: Byrtus Hanna , Pawlowski Maciej , Charakchieva‐Minol Sijka , Duszyńska Beata , Mokrosz Maria J. , Mokrosz Jerzy L. , Zejc Alfred
Published: October 2006

A series of new 3‐(ω‐aminoalkyl)‐5,5‐disubstituted hydantoins, containing 1‐phenylpiperazine, 1‐(o‐methoxyphenyl)piperazine or 1,2,3,4‐tetrahydroisoquinoline fragments, were synthesized by standard alkylation procedures and their 5‐HT1A and 5‐HT2A receptor affinities were determined. It has been shown that the investigated derivatives are recognized by 5‐HT1A and 5‐HT2A receptors due to the presence of a 1‐arylpiperazine fragment; however, the terminal hydantoin moiety plays an important role in stabilization of the receptor‐ligand complex. It has also been found that the two 1‐phenylpiperazine derivatives 32 and 36 are new, selective 5‐HT2A receptor ligands (Ki = 34 and 37 nM, respectively), whereas the derivative of 1‐(o‐methoxyphenyl)piperazine (38) is a new, highly potent 5‐HT1A receptor ligand (Ki = 0.51 nM) with a moderate affinity for 5‐HT2A receptors (Ki = 213 nM).
Asymmetric Synthesis and Structure‐Activity Relationship of the Four Stereoisomers of the Antibiotic Amidinomycin Part 1: The Synthesis
Authors: Sung Sun‐Young , Frahm August Wilhelm
Published: October 2006

The natural amidinomycin ((1R, 3S)‐14) and its three stereoisomers are synthesized from homochiral 3‐oxocyclopentanecarboxylic acids (1a) by asymmetric methods, which are based on an asymmetric reductive amination to produce methyl cis‐N‐(1‐phenylethyl)‐3‐aminocyclo‐pentanecarboxylates (3b) via optically active methyl N‐(1‐phenylethyl)‐3‐iminocyclopentane‐carboxylates (2b) for the cis‐isomers of 14. Optically pure trans‐3‐aminocyclopentane‐carboxylic acids (4a) are obtained from the homochiral keto acids 1a via asymmetric reductive amination of 3‐hydroxy‐iminocyclopentanecarboxylic acids (5a) and lead to the trans‐isomers of 14.
Synthesis and Antidepressant Evaluation of New Hetero[2,1]benzothiazepine Derivatives
Authors: Díaz Juan A. , Vega Salvador , Expósito María A. , Mateo Candelaria C. Sánchez , Darias Victoriano
Published: October 2006

As a part of a research program directed to the discovery of novel antidepressant agents, a series of new hetero[2,1]benzothiazepine derivatives was synthesized. Some of these compounds antagonized the ptosis and motor depression induced by tetrabenazine and were also active in the Porsolt forced swimming test.
Pyridazines 79[1] Novel Oxazolo[3′,2′:1,2]pyrrolo[3,4‐d]pyridazines and Imidazolo[1′,2′:1,2]pyrrolo[3,4‐d]pyridazines: Synthesis and Biological Evaluation
Authors: Barth Birgit , Dierich Manfred , Heinisch Gottfried , Matuszczak Barbara , Mereiter Kurt , Soder Josef , Stoiber Heribert
Published: October 2006

Starting from conveniently accessible ethyl 5‐aroyl‐4‐pyridazine‐carboxylates 6 representatives of the novel tricyclic systems 2 (with X = O and X = NH) were synthesised and screened as potential non‐nucleoside HIV‐1 reverse transcriptase inhibitors.