Showing papers in "Archiv Der Pharmazie in 1995"

Anti-elastase and anti-hyaluronidase activities of saponins and sapogenins from Hedera helix, Aesculus hippocastanum, and Ruscus aculeatus: factors contributing to their efficacy in the treatment of venous insufficiency.

Abstract: Triterpene and steroid saponins and sapogenins of medicinal plants (Aesculus hippocastanum L., Hedera helix L., Ruscus aculeatus L.) are claimed to be effective for the treatment/prevention of venous insufficiency. In this work we evaluated the inhibitory effects of these plant constituents on the activity of elastase and hyaluronidase, the enzyme systems involved in the turnover of the main components of the perivascular amorphous substance. The results evidence that for Hedera helix L., the sapogenins only non-competitively inhibit hyaluronidase activity in a dose-dependent fashion, showing comparable IC50 values (hederagenin IC50 = 280.4 microM; oleanolic acid IC50 = 300.2 microM); both the saponins hederacoside C and alpha-hederin are very weak inhibitors. The same behaviour is observed for serine protease porcine pancreatic elastase: the glycosides are devoid of inhibitory action, while genins are potent competitive inhibitors (oleanolic acid IC50 = 5.1 microM; hederagenin IC50 = 40.6 microM). Constituents from Aesculus hippocastanum L. show inhibitory effects only on hyaluronidase, and this activity is mainly linked to the saponin escin (IC50 = 149.9 microM), less to its genin escinol (IC50 = 1.65 mM). By contrast, ruscogenins from Ruscus aculeatus L., ineffective on hyaluronidase activity, exhibit remarkable anti-elastase activity (IC50 = 119.9 microM; competitive inhibition). The mechanism of elastase inhibition by triterpene and steroid aglycones, with a nitroanilide derivative as substrate, is discussed.

Synthesis of pyrryl aryl sulfones targeted at the HIV-1 reverse transcriptase

Abstract: Various aryl 1-pyrryl sulfones were synthesized and tested as inhibitors of HIV-1. 2-Nitrophenyl-2-ethoxycarbonyl-1-pyrryl sulfone, the most active among test derivatives, was selected as lead compound of the aryl pyrryl sulfone series. The in vitro anti-HIV-1 activity and cytotoxicity of 41 compounds is reported. Some structure-activity relationships are discussed also in comparison with the known NPPS (2-nitrophenyl phenyl sulfone).

Structure‐Activity Relationship Studies of CNS Agents, Part 25: 4,6‐Di(heteroaryl)‐2‐(N‐methylpiperazino)pyrimidines as New, Potent 5‐HT2A Receptor Ligands: A Verification of the Topographic Model

Abstract: A series of new 4,6-di(heteroaryl)pyrimidines containing an N-methylpiperazino group (6-13) or an ethylenediamine chain (15-20) in position 2 were synthesized and their 5-HT 1A and 5-HT 2A receptor affinities were determined. It was shown that the substituent effects on the 5-HT 2A affinity are additive and could be described quantitatively. In a behavioral model is was also demonstrated that 6-11 are 5-HT 2A receptors antagonists. The molecular modelling results suggested that the distances between the basic nitrogen atom and the two aromatic centers (d 1 = 5.2-8.4 A, d 2 = 5.7-8.5 A, and d 3 = 4.6-7.3 A) define the molecular topography of the 5-HT 2A receptor antagonists under study.

Synthesis of 1,2,5(6)‐Trisubstituted Benzimidazoles and Evaluation of Their Antimicrobial Activities

Abstract: 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.

Cytotoxicity and antimicrobial activity of some naphthol derivatives.

Abstract: 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. Zytotoxische und antimikrobielle Wirkung von Naphthol-Derivaten 2-Hydroxymethyl-1-naphthol (TAC) und die Naphtholderivate 1–1i und 2–2i wurden hergestellt und auf ihre zytotoxische und antimikrobielle Wirkung gepruft. Die Zytotoxizitat wurde an vier Karzinom-Zellinien des Menschen untersucht. Einige Verbindungen sind bei < 4 μg/ml wirksam, TAC zeigte die starkste Zytotoxizitat. Die Hemmwirkung von TAC auf die DNA-, RNA-, und Protein-Synthese wurde untersucht. TAC wirkt auch antimikrobiell auf Enterobacter clocae 23355, Klebsiella pneumonia 13883, Proteus vulgaris 13315, Pseudomonas aeruginosa 27853, Candida parapsilosis, Candida tropicalis, Trichosposon beigelli, und Rhodotorul spp. Die kleinsten Hemmkonzentrationen betragen 0.1–0.4 μM

Construction of a Detailed Serotoninergic 5‐HT2a Receptor Model

Abstract: We 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.

New NO-donors with antithrombotic and vasodilating activities, XII: Mesoionic oxatriazoles and related noncyclic nitrosohydrazine derivatives.

Abstract: Mesoionic 1,2,3,4-oxatriazolimines and the corresponding oxatriazolones were prepared and tested for their antiplatelet and antithrombotic activities. In the Born-test 5-amino-3-phenyl-1,2,3,4-oxatriazolimine chloride inhibited the platelet aggregation halfmaximally in a concentration of 50 nmol/L. Its N-ethoxycarbonyl derivative inhibited thrombus formation in arterioles of rats by 48% (10 mg/kg, 2 h after p.o. administration). These effects appear to be related to the formation of intermediate nitrosohydrazine derivatives. This aspect was supported by the activities in noncyclic nitrosohydrazines (2 compds.), nitrosohydrazones (2) and nitrosohydrazides (11). Five of them exhibited an IC50 < 100 nmol/L in the Born-test. In a thrombotic model strong inhibition of thrombus formation was observed after intravenous application. The 1-nitroso-1-benzylhydrazine even exhibited strong inhibitory effects after oral administration.

Peroxides as Constituents of Plants, Part 19: A C50-Hydroperoxide from Hypericum perforatum

Abstract: A new C 50 -hydroperoxide (1) with a hitherto unknown constitution, containing cadinane hydroperoxide and hyperforin (2) as partial structures, was isolated from the stems and leaves of St. John's wort (Hypericum perforatum L., Hypericaceae). The structure was elucidated by high-resolution NMR techniques (1D and 2D NMR experiments).

Azines and diazines as potential histamine H3-receptor antagonists.

Abstract: 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, azines and diazines with ether (6-13) and carbamate (15-24) moieties as functional groups were synthesized. The obtained compounds did not show significant H3-receptor antagonist activity in vitro (rat brain cortex) or in vivo (mice brain). 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.

Anti-inflammatory activity of amine-carboxyboranes in rodents.

Abstract: 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. Anti-inflammatorische Wirkung von Amin-carboxyboranen bei Nagern Amin-carboxyborane sind stark anti-inflammatorisch wirkende Verbindungen, die bereits nach i.p. Applikation von 8 mg/Kg Oedeme und Pleura-Ergusse vermindern. Sie schutzen gegen Salmonellen-induzierten septischen Schock in der Dosierung 2–8 mg/kg/Tag und wirken gegen lokal und zentral induzierten Schmerz. Das Wirkprinzip beruht auf der blockierten Freisetzung von Cytokinen aus Makrophagen, und sie vermindern so die lysosomale hydrolytische und proteolytische Aktivitat der betroffenen Zellen. Die Verbindungen vermindern die Prostaglandin- und Leukotrien-Biosynthese, indem sie die Aktivitaten der regulatorischen Enzyme der entspr. Biosynthesewege blockieren.

An Improved and Large Scale Synthesis of the Natural Coumarin Scopoletin

Abstract: Isovanillin was oxidized with magnesium monoperoxyphthalate to 4-methoxyresorcinol (2) and the latter was reacted with 3-oxo-propionic acid ethylester prepared in situ to give scopoletin (1) These reactions can be achieved in kg scale in high yields

Structure-activity relationship studies of CNS agents, XIX: Quantitative analysis of the alkyl chain effects on the 5-HT1A and 5-HT2 receptor affinities of 4-alkyl-1-arylpiperazines and their analogs.

Abstract: The 5-HT1A and 5-HT2 receptor affinity of a set of 44 N-alkylated 1-aryl-piperazines and their analogs has been analyzed: the n-hexyl derivatives were the most potent and the most selective 5-HT1A ligands of all the investigated N-alkyl homologues. The alkyl chain may stabilize the 5-HT1A receptor-ligand complex by hydrophobic forces. A set of the alkyl substituent contributions (CHT1A) for prediction of the 5-HT1A affinity of N-alkyl derivatives of 1-arylpiperazines and related compounds have been defined on the basis of the Free-Wilson analysis.

[Lipoxygenase inhibitors. IV. Synthesis and cyclization reactions of open-chain N1-aryl-substituted amidrazones].

Abstract: Ausgehend von α-Carbonylcarbonsaurearylhydrazonochloriden, die durch Japp-Klingemann-Spaltung erhalten werden, werden α-Carbonylcarbonsaurearylhydrazonoamide,-ester sowie -thioester synthetisiert, deren inhibitorische Wirkung gegenuber 15- bzw. 5-Lipoxygenase beschrieben wird. Umsetzungen der Amidrazonderivate mit Formaldehyd fuhren zu Triazol-,Triazolin- und in unerwarteter Weise zu Benzotriazepinderivaten. Lipoxygenase Inhibitors, IV: Synthesis and Cyclization Reactions of Open-Chain N1-Aryl-Substituted Amidrazones α-Carbonyl carboxylic acid arylhydrazonochlorides obtained by Japp-Klingemann reaction are the starting substances for the synthesis of α-carbonyl carboxylic acid arylhydrazonoamides, -esters and -thioesters. The inhibiting activity of these compounds against 15- and 5-lipoxygenase is described. Reactions of derivatives of amidrazones with formaldehyde give triazole, triazoline and unexpected benzotriazepine derivatives.

Structure‐Activity Relationships in a Series of 8‐Substituted Xanthines as Bronchodilator and A1‐Adenosine Receptor Antagonists

Abstract: Four new derivatives of 8-piperazine ethyl xanthine were synthesized and their bronchospasmolytic activity and A1-adenosine affinity were studied. Their relaxant action in the tracheal muscle was lower than that of theophylline and that of theophylline derivatives substituted at the 7-position. Only compound 9, where the methyl group in the 1-position of the theophylline was substituted by an isobutyl group, shows a good affinity towards the A1-adenosine receptor.

Synthesis of Some Thiazolo[3,2-b]-1,2,4-triazole-5(6H)-ones as Potential Platelet Aggregation Inhibitors

Abstract: 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. Synthese einiger Thiazolo[3,2-b]-1,2,4-triazol-5(6H)-one als potentielle Plattchenaggregations-Hemmer Zwanzig neue Derivate des 2-Methyl-6-benzylidenethiazolo[3,2-b]-1,2,4-triazole-5-(6H)-ones (2a–d) und des 2-Methyl-6-(α-aminobenzyl)thiazolo-[3,2-b]-1,2,4-triazole-5-ols (5–20) wurden synthetisiert. Deren Struktur wurde durch Elementaranalyse und spektroskopische Daten bestimmt. Die Thrombocytenaggregationshemmung wurde getestet.

Structure‐Activity Relationship Studies of CNS Agents, Part 22: A Search for New Trazodone‐Like Antidepressants: Synthesis and Preliminary Receptor Binding Studies

Abstract: New 1-phenyl- and 1-(3-chlorophenyl)piperazines containing a 4-[3-(heterocyclic)propyl] fragment were synthesized. It was found that of all the investigated compounds 11b (K i = 13 ± 2 nM) and 8b (K i = 38 ± 2 nM) were the most active 5-HT 1A and 5-HT 2A ligands, respectively. Several derivatives (3a, 4a, 8b, 11b, 12b, 13a, and 13b) were selected as good candidates for new, potential antidepressants on the basis of their 5-HT 1A /5-HT 2A receptor binding profiles.

Vorstellungen zur Freisetzung von Stickstoffmonoxid aus NO‐Pharmaka. Modellreaktionen in Gegenwart von Licht und Übergangsmetallkomplexen, 1. Mitt.

Abstract: Mit Hilfe von Modellreaktionen fur Cytochrom P-450 wird der Mechanismus der Metabolisierung von NO-Pharmaka untersucht. Um diese Versuche zu begrunden, wird einleitend auf bisher erarbeitete theoretische Hintergrunde 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. Fur 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 Lichtausschlus vollig stabil. Erst nach Aktivierung unter reduktiven Bedingungen in Gegenwart von FeIITPP oder unter Bestrahlung mit sichtbarem Licht wird in allen Fallen NO freigesetzt. Besonders bemerkenswert ist die uberadditive Verstarkung 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 moglich erscheint. Ideas Concerning the Release of Nitric Oxide from NO-containing Drugs. Model Reactions in the Presence of Light and Metal Complexes The metabolism of NO-containing compounds was imitated with reductive model reactions for cytochrome P-450. First this model is compared with the theoretical background of the literature. Then a system with low molecular tetraphenylporphrin complexes (TPP), with the transition metals iron and manganese as central ions instead of the iron chelate in cytochrome P-450, was established. We use NaBH4 as a reducing agent in these cases. In the detection of nitric oxide we succeeded with a chemiluminescence method using ozone to activate nitric oxide. Under these conditions different NO-containing drugs. e.g. sodium nitroprusside (SNP), inorganic nitrite, glycerol trinitrate (GTN), and S-nitroso-N-acetyl-penicillamine (SNAP), are investigated. A spontaneous release of nitric oxide was only observed in the case of SNAP, while SNP, nitrite, and GTN are stable in the dark under anaerobic or aerobic conditions. If these compounds are activated under reductive conditions with FeIITPP or by illumination with visible light, we measure NO-release in all cases. Particularly remarkable is the enhancement of the NO-release when these two activation methods are combined. With these experiments the activation mechanism of NO-containing compounds is discussed, and an enzymatic pathway involving the reductive site of cytochrome P-450 seems to be possible.

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

Abstract: Eine Reihe von 3-Mercaptoalkylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dionen 3 wurde synthetisiert und auf immunstimulatorische Wirksamkeit gepruft. 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 verzogerten Typ (delayed type hypersensitivity; DTH) immunstimulatorische Aktivitat im Wirkungsbereich von Isoprinosine. Polycyclic Azines, XL: Synthesis of Heterocyclic Immunomodulators, II: 3-Mercaptoalkylthieno[2,3-d]pyrimidine-2,4(1H,3H)-diones: Synthesis and Test for Immuno-stimulating Activity A series of 3-mercaptoalkylthieno[2,3-d]pyrimidine-2,4(1H,3H)-diones 3 was prepared and their immuno-stimulating activity was examined. The title compounds were obtained conveniently by hydrolytic ring cleavage of fused thiazolo- or 1,3-thiazino-thicnopyrimidines 1 under alkaline or acidic reaction conditions. The ms fragmentation of the thieno[2,3-d]pyrimidine-2,4-diones 3 is discussed. In the delayed type hypersensitivity (DTH) test some compounds 3 showed immuno-stimulating activities in the range of isoprinosine.

Synthesis of Phthalimido‐Desmuramylpeptide Analogues as Potential Immunomodulating Agents

Abstract: 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. Synthese von Phthalimido-desmuramylpeptid-Analogen mit potentiell immunmodulierenden Eigenschaften Die Synthese der immunologisch wirksamen Phthalimido-desmuramylpeptid-Analoga 2e-h, 4c-d und 7b mit einem N-phthaloylierten acyclischen Teil wie z.B. N-phthaloylierten Aminosauren 1a–c, sowie 2-(2-phthalimidoethoxy)essigsaure 3 oder einer carbocyclischen rac. trans-2-(2′-Phthalimidocyclohexyloxy)acetyl Gruppe 6 als Ersatz fur den N-Acetylmuramylsaure Rest wird beschrieben.

Synthesis and in vitro degradation of testosterone-lipid conjugates.

Abstract: Testosterone-lipid conjugates were obtained by covalent binding of the drug to 1,3-dipalmitoylglycerol via succinic acid to 4-(1,3-dipalmitoyl-2-glyceryl)butyric acid and to 3-palmitoyloxy-2-palmitoyloxmethylpropionic acid. In contrast to the corresponding bis-deacyl derivatives, the lipids were not significantly hydrolyzed in aqueous buffers and in plasma. Incubation with pancreatic lipase yielded primarily the bis-deacyl compounds, which are comparable to monoglycerides, and subsequently slowly liberated testosterone. It is concluded that the lipid conjugates are substrates for pancreatic lipase. However, the drug was released very slowly due to steric hindrance.

Peroxidase‐catalysed oxidation of different dibenzazepine derivatives

Abstract: 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 or isoclozapine present a high reactivity in the horseradish peroxidase or myeloperoxidase systems and, on the other hand, fluperlapine, though known to induce agranulocytosis, and other dibenzothiazepine 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 the First Penicillin Derivatives with Medium-Sized Lactam Ring and of Related Thiazolidines

Abstract: The novel concept of penicillin derivatives 4 with a medium-sized instead of a β-lactam ring is presented. Two synthetic paths were invented, resulting in the evaluation of the synthetic potential in the succinic, glutaric, and adipic acid series. A number of novel penicillin-derived thiazolidines were prepared, notably the derivatives 16 and 22 with anellated 7- and 13-membered lactam ring.

1,5-Benzodiazepine, 2. Mitt.: Entgegengesetzte zentralnervöse Wirkungen der Enantiomere von zwei 3,3-Dialkyl-1,5-benzodiazepin-2,4-dionen†

Abstract: Nach i.p.-Applikation (50–200 mg) an Ratten zeigten rac. 1, S(+)-1 und R(−)-1 nur eine schwach ausgepragte dosisunabhangige Verlangerung der Hexobarbitalschlafzeit ohne enantioselektive Wirkungsunterschiede. Rac. 3 verlangerte die Hexobarbitalschlafzeit uberhaupt nicht. Die Untersuchung der Gewebeverteilung und der Konzentration im Serum ergab, das 1 und 3 nach i.p.-Applikation im Serum und Gehirn zwar nachweisbar, aber nicht quantifizierbar waren. Nach i.v. Applikation erwiesen sich die S(+)-Enantiomere von 1 und 3 uberraschenderweise als konvulsiv wirksam. Sie sind in der Wirkungsintensitat dem Pentetrazol um den Faktor 2.5-5 uberlegen. R(−)-1 und R(−)-3 verlangerten dagegen nach i.v. Gabe die Hexobarbitalschlafzeit, und zwar R(−)-1 dosisabhangig. Die durch S(+)-1 ausgelosten Krampfe wurden durch Vorbehandlung mit Diazepam unterdruckt, nicht aber durch Flumazenil. Die Enantiomere R(−)-1 und R(−)-3 sind schwache Agonisten, S(+)-1 undS(+)-3 offensichtlich starke inverse Agonisten. Enantioselektive Unterschiede traten auch bei der Bindung der 1-Enantiomere an Humanserumalbumin auf: R(−)-1 wurde starker gebunden als S(+)-1. 1,5-Benzodiazepines, II: Diametrically Opposite CNS-Effects Between the Enantiomers of two 3,3-Dialkyl-1,5-benzodiazepine-2,4-diones I.p. applicated S(+)-1, R(−)-1 und rac. 1 prolonged hexobarbital sleeping in rats. The rac. 8-chloro compound 3 given i.p. produced no prolongation. Determination of rac. 1 in serum and tissues of rats 30 min after i.p. administration of 50 mg/kg showed that rac. 1 was detectable in serum and brain, yet its concentration was below the limit of determination. l.v. applicated, the enantiomers of 1 and 3 showed diametrically opposite CNS-effects: The S(+)-enantiomers were convulsively active as pentetrazol, whereas the R(−)-enantiomers were CNS depressant active prolonging hexobarbital sleeping time dose-dependently High doses of diazepam antagonized dose-dependently the convulsive action of S(+)-1 supporting the hypothesis that this enantiomer acted as a strong inverse agonist, whereas R(−)-1 produced weak agonistic activity at the benzodiazepine binding site of the GABA-receptor. - Enantioselective differences for the binding of the 1-enantiomers to human serum albumin were found, too. R(−)-1 was bound to a greater extent than S(+)-1.

Synthesis and biological investigations of some new thiazolylbenzimidazoles and benzimidazolylthiazolo[3,2-a]pyridines.

Abstract: 2-[(4-Oxo-4,5-dihydrothiazol-2-yl)methyl]-1H-benzimidazole (2) was prepared through the reaction of 2-cyanomethyl-1H-benzimidazole (1) with thioglycolic acid. The syntheses of its arylidene 3 and diazo-coupled compounds 5 and the cyclization of the aforementioned thiazolylbenzimidazole to benzimidazolylthiazolo[3,2-a]pyridines 8 were also performed. The prepared compounds were screened for their in-vitro antibacterial, antifungal, anti-HIV, and anticancer activities: they show promising antifungal activity. Synthese und biologische Untersuchungen von einigen neuen Thiazolylbenzimidazolen und Benzimidazolylthiazolo[3,2-a]pyridinen 2[(4-Oxo-4,5-dihydrothiazol-2-yl)methyl]-1H-benzimidazol (2) wurde durch Reaktion von 2-Cyanomethyl-1H-benzimidazol (1) mit Thioglycolsaure hergestellt. Die synthese der entspr. Aryliden-3 und Arylazo-Derivate 5 und die Cyclizierung des Thiazolyl-benzimidazoles 2 zu Benzimidazolylthiazolo[3,2-a]pyridinen 8 wird beschrieben. Die so hergestellten Verbindungen wurden in-vitro auf antibakterielle, antimykotische, anti-HIV und anti-Tumor-Aktivitaten gepruft: sie zeigen signifikante antimykotische Aktivitat.

Structure-activity relationship studies of CNS agents, Part 23: N-(3-phenylpropyl)- and N-[(E)-cinnamyl]-1,2,3,4-tetrahydroisoquinoline mimic 1-phenylpiperazine at 5-HT1A receptors.

Abstract: The 5-HT 1A receptor affinities and ionization constants of a set of 1-arylpiperazine (4) 1,2,3,4-tetrahydroisoquinoline (6), and -quinoline (7) containing N-(ω-arylalkyl) or N-(E)-cinnamyl substituents as well as two morpholine derivatives (8a, 8b) were determined. It was shown that some tetrahydroisoquinoline (6c, 6d) and morpholine (8a) derivatives were 5-HT 1A ligands equipotentto 1-phenylpiperazine (4a) and 1,2,3,4,4a,5-hexahydropyrazino[1,2-a]indole (5). On the basis of molecular modelling studies it was also demonstrated that 6c, 6d and 8a mimicked very well the reference structures of 4a and its rigid analog 5. Another, more complex 1,2,3,4-tetrahydroisoquinoline derivative 3, which served as a model compound to confirm the previously reported 5-HT 1A binding mode of derivatives 1a-d and 2, had the highest 5-HT 1A affinity (K i = 6.7 ± 0.5 nM) of all the investigated compounds

Pyrazoles as potential histamine H3-receptor antagonists.

Abstract: 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.