Showing papers in "Archiv Der Pharmazie in 1993"

Synthesis and antimicrobial evaluation of novel oxa(thia)diazolylquinolines and oxa(thia)diazepino[7,6-b] quinolines.

Abstract: Three novel series of quinoline derivatives have been prepared by cyclization of the intermediate 3[(substituted)thiocarbamoyl-hydrazonomethyl]-2-chloroquinoline s and 3-aroylhydrazonomethyl-2-chloroquinolines: 3-(3-Acetyl-5-(substituted)-2,3-dihydro-1,3,4-oxa(thia)diazol-2-yl )-2- chloroquinolines (4; 5), 3-(5-(substituted)-1,3,4-oxa(thia)diazol-2-yl)-2-chloroquinolin es (6; 7), and 2-(substituted)-1,3,4-oxa(thia)diazepino[7,6-b]quinolines (8; 9). The antimicrobial activity of these compounds was studied.

Phenytoin-Lipid Conjugates as Potential Prodrugs of Phenytoin

Abstract: Phenytoin-1-triglycerides and phenytoin-2-triglycerides were synthesized as potential prodrugs of phenytoin by covalent binding of 3-hydroxymethylphenytoin by succinic acid to the positions 1 and 2 of diglycerides, respectively. The corresponding 1- and 2-monoglycerides were prepared. In addition, replacement of glycerol by 3-hydroxy-2-hydroxymethylpropionic acid furnished lipids that allowed direct coupling of 3-hydroxymethylphenytoin. The lipid conjugates proved to be substrates for pancreatic lipase in vitro.

Carvedilol stereopharmacokinetics in rats: affinities to blood constituents and tissues.

Abstract: Carvedilol, a lipophilic β-adrenoceptor antagonist with vasodilating activities, is characterized by a high as well as stereoselective metabolic clearance and distribution volume. Tissue distribution of carvedilol enantiomers and their conjugates were determined under steady-state conditions in rats (p.o., 10 mg/kg, repetitive dosage; n = 5) and after single i.v. administration in control rats and rats with surgical portacaval shunt (pcs) (10 mg/kg; n = 3 each group). In addition, in vitro plasma protein binding was evaluated. - The plasma protein binding of carvedilol in rats is > 98% for total plasma (tp) and > 96% for rat serum albumin (rsa) solution (4%), with enantioselectivity ratios of 1.53 (tp) and 1.27 (rsa). Significantly higher unbound fractions were observed in pcs rats, in part due to reduced protein concentrations. - In contrast to plasma, where a preponderance of the R-enantiomer with an S/R ratio of 0.6 was found, S-carvedilol was predominant in all tissues (heart, liver, kidneys, lung, spleen, muscle, and adipose tissue), with S/R ratios of 1.3-1.4 in most of these tissues and 2.3 in liver. This preferential tissue partitioning of S-carvedilol was in accordance with its higher unbound fraction in plasma. Carvedilol accumulated predominantly in the highly perfused and/or eliminating organs liver, kidneys, and lung (tissue/plasma ratios; lung: S 76, R 34; liver: S 21, R 5; kidney: S 8, R 3). A similarly enantioselective distribution into the heart of control as well as pcs rats was observed, where the S-enantiomer concentrations exceeded the plasma concentrations 7-fold. Probably because of the impaired liver function in pcs rats with increased importance of the renal route, kidney concentrations were higher in these rats. The kidney/plasma ratio was elevated approximately 2-fold for the parent compound (control: S 7, R 2; pcs: S 14, R 4) and 4-fold for the R-carvedilol conjugate (control: S 2, R 1; pcs: S 3, R 4). The conjugates of carvedilol were detectable in all organs, with significantly smaller concentrations than those of the aglycones and with varying stereoselectivities. Stereopharmakokinetik von Carvedilol bei der Ratte: Affinitat zu Blutbestandteilen und Geweben Carvedilol, ein lipophiler β-Adrenozeptor-Antagonist mit zusatzlicher vasodilatierender Wirkung, ist charakterisiert durch eine hohe und stereoselektive metabolische Clearance sowie ein hohes und stereoselektives Verteilungsvolumen. Die Verteilung der Enantiomere von Carvedilol und der entsprechenden Konjugate in verschiedene Gewebe bei der Ratte wurde unter steady-state-Bedingungen (p.o., 10 mg/kg, Mehrfachgabe; n = 5) und 5 h nach einmaliger i.v.-Gabe bei Kontrolltieren sowie bei Ratten mit operativ angelegtem portakavalem Shunt (pcs) (10 mg/kg; je n = 3) untersucht. Zusatzlich wurde die in-vitro-Plasmaproteinbindung von Carvedilol bestimmt. Sie betrug > 98% fur Gesamtplasma (tp) und > 96% fur Rattenserumalbumin (rsa) in 4proz. Losung mit einem Enantioselektivitatsverhaltnis der Bindung von 1.53 (tp) sowie 1.27 (rsa). Signifikant hohere ungebundene Fraktionen als bei Kontrolltieren wurden nach pcs beobachtet. Dies ist z.T. durch eine reduzierte Gesamtplasma- bzw. Albuminkonzentration zu erklaren. - Im Gegensatz zu Plasma, wo die Konzentration des R-Enantiomers uberwog und ein S/R-Verhaltnis von 0,6 gefunden wurde, dominierte S-Carvedilol in allen untersuchten Geweben (Herz, Leber, Nieren, Lunge, Milz, Muskel und Fettgewebe) mit einem S/R-Verhaltnis von 1.3–1.4 auser in der Leber, wo es mit 2.3 deutlich hoher lag. Die Anreicherung von S-Carvedilol im Gewebe ist u.a. zu erklaren uber die hohere ungebundene Fraktion im Plasma. Carvedilol kumuliert uberwiegend in gut perfundierten Organen und/oder Eliminationsorganen wie Leber und Nieren sowie in der Lunge (Gewebe/Plasma-Verhaltnisse; Lunge: S 76, R 34; Leber: S 21, R 5; Niere: S 8, R 3). Die Enantioselektivitat der Verteilung in das Herz ist bei Kontroll- und pcs-Ratten ahnlich, dabei wird das S-Enantiomer gegenuber dem Gehalt in Plasma 7fach angereichert. Wahrscheinlich aufgrund der reduzierten Leberfunktionen bei pcs-Ratten mit gleichzeitiger Erhohung der renal ausgeschiedenen Fraktion waren die Konzentrationen in den Nieren bei den pcs-Ratten deutlich hoher. Der Nieren/Plasma-Quotient der Muttersubstanz war 2mal (Kontrolle: S 7, R 2; pcs: S 14, R 4) und der fur das R-Carvedilolkonjugat (Kontrolle: S 2, R 1; pcs: S 3, R 4) 4mal so hoch bei den pcs-Tieren. - Die Konjugate des Carvedilols sind in allen Organen mesbar, allerdings mit signifikant niedrigeren Konzentrationen als ihre Aglyca und auch mit variteren den Stereoselektivitaten.

Alkaloids of Cynanchum vincetoxicum: Efficacy against MDA-MB-231 Mammary Carcinoma Cells

Abstract: Alkaloids 1-4 from Cynanchum vincetoxicum (asclepiadaceae) (Scheme 1) do not have affinity to the oestrogen receptor but they inhibit the growth of the hormone-independent mammary carcinoma cells MDA-MB-231 (Fig. 1) and bind to nucleosides and nucleotides (Table 1). Intercalation was not observed.

New 4-amino-7,8-dimethoxy-5H-pyrimido[5,4-b]indole derivatives: synthesis and studies as inhibitors of phosphodiesterases.

Abstract: A series of 4-amino-7,8-dimethoxy-5h-pyrimido[5,4-b]indole derivatives has been synthesized. These compounds resemble carbazeram and other pyridazino compounds with activity in the cardiovascular system. Some of these new compounds possess inotropic activity (Table 2), with a complementary effect on the inhibition of different CGI-PDE (Table 3). The most active compounds 5, 6d, and 7 also possess activity as vasodilators (Table 4). Some of these new compounds inhibit blood platelet aggregation induced by ADP and AA and are active as inhibitors of human platelet PDEs (Tables 5 and 6). Neue 4-Amino-7,8-dimethoxy-5H-pyrimido[5,4-b]indole; Synthese und Prufung als Phosphodiesterase-Hemmer Eine Reihe von 4-Amino-7,8-dimethoxy-5H-pyrimido[5,4-b]indolen wurde synthetisiert. Diese neue Verbindungen besitzen eine gewisse Ahnlichkeit mit Carbazeram und anderen Pyridazin-Verbindungen mit Aktivitat im kardiovaskularem System. Einige der hier beschriebenen Verbindungen besitzen inotrope Aktivitat (Tab. 2) und hemmen zusatzlich verschiedene CGI-PDE (Tab. 3). Die wirksamsten Verbindungen 5, 6d und 7 besitzen auch eine gefaβerweiternde Aktivitat (Tab. 4). Einige der neuen Verbindungen hemmen die Blutplattchenaggregation, die durch ADP und AA induziert wird, und die Phosphodiesterasen menschlicher Blutplattchen (Tab. 5 und 6).

Δ2-1,2,4-Oxadiazoline durch Kondensation von Amidoximen mit Ketonen und Aldehyden

Abstract: Ketone und aromatische Aldehyde cyclisieren in Eisessig mit aromatischen Amidoximen des Typs 1 zu Δ2-1,2,4-Oxadiazolinen 3, in neutralen Solventien hingegen bleibt die Reaktion aus. Dieses unterschiedliche Verhalten wird durch MNDO-Berechnungen erklart; als reaktive Spezies sind die protonierten Carbonylverbindungen anzunehmen. Δ2-1,2,4-Oxadiazolines by Condensation of Amidoximes with Ketones and Aldehydes Using acetic acid as a solvent, ketones and aromatic aldehydes react with amidoximes 1 to cyclic products, Δ2-1,2,4-oxadiazolines 3. The lack of reactivity in neutral milieu is explained by MNDO calculations. Protonated carbonyl compounds are discussed to be the reactive species.

New NO-donors with antithrombotic and vasodilating activities, I: 3-Arylalkyl-N-nitroso-5-sydnone imines.

Abstract: Fifteen 3-alkyl-, four 3-cycloalkyl-N-nitroso-5-sydnone imines and five 3-alkyl-N-nitro-5-sydnone imines were synthesized and their ability to inhibit platelet aggregation induced by collagen (Born-test) was studied in vitro. Dependent on the chemical structure, the IC50-values for the inhibition of platelet aggregation were in the range of 0.2-140 μmol/L. It is suggested that this scale reflects different binding properties of the nitrosimines with respect to the platelet membrane. Highest activities were observed for the 3-hexyl (2f) and the 3-cyclohexyl (2p) derivative. Three nitrimines (3e, 3f, 3i) also showed IC50 values below 10 μmol/L. For the nitrosimines 2a, 2f, and 2m antithrombotic activity was demonstrated in vivo. They inhibited laser induced arterial thrombosis in anesthetized rats up to 70% two h after oral administration. In conscious renal-hypertensive dogs, the decrease in systolic blood pressure and left ventricular enddiastolic pressure suggests an antianginal activity of the compound 2a similar to that of molsidomine (M). The smoother onset and the longer duration of action of the new compound as compared to M could be a significant advantage of 2a in the therapy of angina pectoris. Neue NO-Pharmaka mit antithrombotischen und gefaserweiternden Eigenschaften, 2: Mitt.: 3-Alkyl-N-nitroso-5-sydnonimine Funfzehn 3-Alkyl-, vier 3-Cycloalkyl-N-nitroso-5-sydnonimine und funf 3-Alkyl-N-nitro-5-sydnonimine wurden dargestellt und im Born-Test auf ihre Hemmwirkungen bezuglich der durch Collagen ausgelosten Aggregation von menschlichen Thrombocyten gepruft. Die beobachteten Effekte waren stark strukturabhangig (IC50 = 0,2-140μmol/L). Als Ursache kommt unterschiedliches Bindungsvermogen an die Plattchenmembran in Frage. Die geringsten Hemmkonzentrationen wurden fur das 3-Hexyl (2f) und das 3-Cyclohexylnitrosimin (2p) gemessen. Drei N-Nitrosydnonimine (3e, 3f, 3i) zeigten ebenfalls IC50-Werte unterhalb 10 μmol/L. Drei ausgewahlte Nitrosimine (2a, 2f, 2m) hemmten bei Ratten die durch Laserstrahl induzierte Thrombose in Mesenterialgefasen um bis zu 70%. Das 3-Methylnitrosimin 2a senkte am wachen renal hypertensive Hund den systolischen und den linksventrikularen enddiastolischen Blutdruck. Diese Eigenschaften machen auch antianginose Effekte vergleichbar mit Molsidomin wahrscheinlich. Der mildere Wirkungsbeginn und die langere Wirkungsdauer von 2a konnten im Vergleich zu Molsidomin von Vorteil bei der Behandlung der angina pectoris sein.

Synthesis and biological activity of bromolignans and cyclolignans.

Abstract: Nine lignan derivatives (4-12) have been obtained from (-)-yatein by treatment with DDQ and NBS. They showed moderate antineoplastic activity (P-388, A-549, HT-29) compared with podophyllotoxin, but some of them have a better therapeutic index. None of the tested compounds shows anti-viral (HSV-1, VSV) or enzyme inhibitor (ADA, DHFR, GST) activities.

Asymmetric Reductive Amination of Cycloalkanones, XIII: Enantioselective Amidoamination: A New Regiospecific Strategy for the Synthesis of Chiral Cyclohexane‐1,2‐diamino‐Derivatives

Abstract: Asymmetric synthesis of trans- and cis-2-Benzamido- or 2-Phenyl-acet-amido-cyclohexane-amines 7 and 8 by means of reductive amination and hydrogenolysis is described. Condensation of the amido-ketones 3 with chiral auxiliary (R)-(+) and (S)-(-)-1-phenylethylamine, respectively, leads to the amido-imines 4, which are hydrogenated over Raney-Ni to yield simultaneously enantiomerically pure secondary trans- and cis-2-amidocyclohexane-amines 5 and 6. Asymmetrische, reduktive Aminierung von Cycloalkanonen, 13. Mitt.: Enantioselektive Amidoaminierung: Eine neue regiospezifische Strategie zur Synthese von chiralen Cyclohexan-1,2-diamino-Derivaten Die asymmetrische Synthese von trans- und cis-2-Benzamido- oder -2-Phenylacetamido-cyclohexanaminen 7 und 8 mittels reduktiver Aminierung und Hydrogenolyse wird beschrieben. Die Kondensation der Amidoketone 3 mit den chiralen Hilfsaminen (R)-(+)- oder (S)-(-)-1-Phenylethylamin fuhrt zu den Amido-iminen 4, die sich mit Raney-Nickel zu den enantiomerenreinen sekundaren trans- und cis-2-Amido-cyclohexanaminen 5 und 6 hydrieren lassen.

Biotransformation of benzamidine and benzamidoxime in vivo.

Abstract: After administration of benzamidine (1) or benzamidoxime (2), respectively, to rats and rabbits, plasma from rats and rabbits as well as urine from rats were examined for the presence of benzamidoxime (2) or benzamidine (1). Some of the samples were worked-up directly and the others after enzymatic pretreatment with beta-glucuronidase or arylsulfatase, respectively. HPLC analysis was employed for the detection of the metabolites. After administration of 1, an in vivo N-hydroxylation of an amidine to an amidoxime was demonstrated for the first time. The metabolite 2 could only be detected after enzymatic cleavage of the glucuronide or sulfate, respectively, and only in plasma at a low concentration. After administration of benzamidoxime (2), on the other hand, benzamidine (1) was detected in very high concentrations in all biological samples. Benzamidine was present in the free state but indications for glucuronidization and sulfatation were also detectable. These investigations suggest that the benzamidoxime (2) formed by an in vivo N-hydroxylation undergoes ready retro-reduction but that further transformations of the metabolite 2, such as conjugation to a glucuronide or a sulfate, respectively, prevent complete back reaction. Furthermore, benzamide (3) could be detected as a transformation product in urine after administration of either 1 or 2.

Nonsteriodal Antiinflammatory Agents, XVII: Inhibition of Bovine Cyclooxygenase and 5-Lipoxygenase by N-Alkyldiphenyl-pyrrolyl Acetic and Propionic Acid Derivatives†

Abstract: A series of 19 N-alkyl-diarylpyrrolyl-acetic and -propionic acid derivatives was synthesized and tested Using bovine blood as enzyme source the inhibition of cyclooxygenase and 5-lipoxygenase, respectively, was applied to determine the antiinflammatory activity In general all compounds tested inhibit 5-lipoxygenase more effectively than cyclooxygenase A structure-activity relationship is discussed Nichtsteroidale Antiphlogistica, 17 Mitt: Inhibierung von Rinder-Cyclooxygenase und 5-Lipoxygenase durch N-Alkyldiphenylpyrrolyl-Essigsaure- und Propionsaure-Derivate Die Synthese und inhibitorische Aktivitat von 19 N-Alkylphenyl-substituierten Pyrrolyl-essigsaure- bzw -propionsaure-Derivaten wird beschrieben Als Testsysteme dienen die aus Rinderblut gewonnenen Enzyme Cyclooxygenase und 5-Lipoxygenase Die Hemmung beider Enzyme, mit einer starkeren Beeinflussung der 5-Lipoxygenase, wird unter Einbeziehung struktureller Variationen diskutiert

Aqua[1-(2,6-dichloro-4-hydroxyphenyl)-2-phenylethylenediamine]sulfatoplatinum(II) complexes with variable substituents in the 2-phenyl ring. II. Correlation of molecular structure and estrogenic activity of breast and prostate cancer inhibiting [erythro-1-(2,6-dichloro-4-hydroxyphenyl)-2-(2-halo-4-hydroxyphenyl)ethylenediamine]platinum(II) complexes

Abstract: Complete three-dimensional x-ray crystal structure analyses of estrogenic [erythro-1-(2,6-dichloro-4-hydroxyphenyl)-2-(2-halo-4-hydroxyphenyl)ethylenediamine]diiodoplatinum(II) complexes [halo = fluoro:erythro-8-PtI2 (I) and halo = chloro:erythro-9-PtI2 (II)] which were synthesized for application in breast and prostate cancer, have been carried out. The 6239 as well as the 6521 reflexes were measured and refined to an R-value of 0.105 and 0.066, resp. The mols. of erythro-8-PtI2 are displayed laterally from a possible Pt-Pt axis sepd., alternatingly, by Pt-Pt-distances of 3.62 .ANG. and 6.27 .ANG.. A comparable structure possesses erythro-9-PtI2 with Pt-Pt-distances of 3.59 .ANG. and 6.32 .ANG.. The ethylenediamine ligands of erythro-8-PtI2 and erythro-9-PtI2 are puckered and exist in half chair conformations. For both complexes, the 2,6-dichloro-4-hydroxyphenyl ring is equatorially arranged, while the 2-halo-4-hydroxyphenyl ring is nearly perpendicular to the N-Pt-N plane. The O-O-distance between the phenolic oxygens amts. to 8.1 .ANG. in erythro-8-PtI2 and to 7.8 .ANG. in erythro-9-PtI2. Though these O-O-distances differ strongly from that (12.1 .ANG.), which is considered to be necessary for the binding of an estrogen to its receptor, [1-(2,6-dichloro-4-hydroxyphenyl)-2-(2-halo-4-hydroxyphenyl)ethylenediamine]platinum(II) complexes show estrogenic effects which are, however, strongly reduced compared to that of therapeutically used estrogens like diethylstilbestrol. The relation between mol. structure and estrogenicity as well as the significance of the latter for antitumor activity and untoward side effects are thoroughly discussed.

Stereoselektive Synthese neuer zentral wirksamer Tricyclen vom Benzomorphan-Typ mit 2-Phenylethylamin Partialstruktur

Abstract: Die Addition des mit LDA deprotonierten Glycinesters 6 an das Homophthalaldehydmonoacetal 5 liefert den β-Hydroxyester 7, der sich nach Reduktion zu den racemischen 2,6-Epoxy-3-benzoxocin-5-aminen (+/−)-12 und (+/−)-13 cyclisieren las. Die Schlusselverbindungen fur die Gewinnung von 12 und 13 in enantiomerenreiner Form sind die Hydroxyacetale (R,S,R)-22 und (R,S,S)-23: (R,S,R)-22 last sich stereoselektiv durch Addition der Aryllithiumverbindung 21b bzw. der Aryltitanverbindung 21c an das neue Serinal-Aquivalent (R,S)-20 gewinnen; die Reduktion des Ketons (R,S)-24 mit LiAlH4 bei −78°C fuhrt uberwiegend (>95%) zu dem diastereomeren Hydroxyacetal (R,S,S)-23. Mit Saure werden (R,S,R)-22 und (R,S,S)-23 in die tricyclischen Urethane (S,S,R)-25 und (R,S,S)-30 uberfuhrt, die sich zu den Dimethylaminen (S,S,R)-12 und (R,S,S)-13 reduzieren und methylieren lassen (ee > 97%). Analog werden die enantiomeren Amine (R,R,S)-12 und (S,R,R)-13 ausgehend von (R)-Serin dargestellt. Die relative Konfiguration von (R,S,R)-22 wird mit Hilfe von Molecular Dynamics Rechnungen (Sybyl 5.4) in Kombination mit NOE-Messungen bewiesen.- Nach Applikation beider Enantiomere von 12, 13, 27 und 32 lassen sich bei Mausen typische Symptome fur eine zentrale Dampfung beobachten. Im Essigsaure Writhing-Test sind (S,S,R)-12, (S,R,R)-13, (R,S,S)-13, (S,S,R)-27, (R,R,S)-27 und (R,S,S)-32 stark analgetisch wirksam mit ED50 Werten in der Grosenordnung des ED50-Wertes von Tramadol-HCl. Stereoselective Synthesis of Novel Centrally Active Benzomorphan- Type Tricycles with 2-Phenylethylamine Substructure Addition of the LDA-deprotonated glycine ester 6 to the homophthalaldehyde monoacetal 5 yields the β-hydroxyester 7 which is cyclized after reduction to give the racemic 2,6-epoxy-3-benzoxocin-5-aminens (+/−)-12 and (+/−)-13. The key intermediates for the synthesis of 12 and 13 in enantiomerically pure form are the hydroxyacetals (R,S,R)-22 and (R,S,S)-23: (R,S,R)-22 is stereoselectively prepared by addition of the aryllithiumcompound 21b or the aryltitan-compound 21c to the new serinal equivalent (R,S)-20; reduction of the ketone (R,S)-24 with LiAlH4 at −78°C affords the diastereomeric hydroxyacetal (R,S,S)-23 predominantly (>95%). With acid (R,S,R)-22 and (R,S,S)-23 are transformed into the tricyclic ure-thanes (S,S,R)-25 and (R,S,S)-30, which are reduced and methylated to yield the dimethylamines (S,S,R)-12 and (R,S,S)-13 (ee > 97%), respectively. Analogously the enantiomeric amines (R,R,S)-12 and (S,R,R)-13 are prepared starting form (R)-serine. The relative configuration of (R,S,R)-22 is confirmed by molecular dynamics calculations (Sybyl 5,4) combined with NOE-measurements.- Symptoms typical for sedation are observed after application of both enantiomers of 12, 13, 27, and 32 to mice. In the acetic acid writhing test (mouse) (S,S,R)-12, (S,R,R)-13. (R,S,S)-13, (S,S,R)-27, (R,R,S)-27, and (R,S,S)-32 exhibit strong analgesic effects with ED50-values in the range of the ED50-value of tramadol-HCl.

The hypolipidemic effects of 2-furoic acid in Sprague-Dawley rats.

Abstract: 2-Furoic acid was shown to be effective in lowering both serum cholesterol and serum triglyceride levels significantly in rats with an elevation of HDL cholesterol level at 20 mg/kg/day orally. LDL receptor activity was reduced in hepatocytes, aorta foam cells, small intestinal epithelium cells and fibroblasts. HDL receptor activity was elevated in the rat hepatocytes and small intestinal cells. These activities were correlated with inhibition of acyl CoA cholesterol acyl transferase activity. Neutral cholesterol ester hydrolase activity was elevated in rat hepatocytes and human fibroblasts. Thus, 2-furoic acid appears to interfere directly with activity of intracellular enzymes rather than affecting high affinity-mediated lipoprotein membrane receptors. In vivo treatment with 2-furoic acid led to reduction in the liver and small intestine ATP dependent citrate lyase, acetyl CoA synthetase, acyl CoA cholesterol acyl transferase, sn-glycerol 3-phosphate acyl transferase, phosphatidylate phosphohydrolase and heparin induced lipoprotein lipase activities. 2-Furoic acid reduced biliary cholesterol levels but the agent increased bile salts which are lithogenic. Acute toxicity studies in mice suggest that the agent has some hepatic toxicity effects. The LD50 was relatively low at 250 mg/kg IP in mice.

Synthesis and molluscicidal activity of new derivatives of 1-(hydroxy/substituted phenyl)-3-arylpropenones.

Abstract: Several 1-(hydroxy/substituted phenyl)propenones were tested as molluscicidal agents among which the 1-(2-hydroxy/substituted phenyl)-3-(2-furyl)propenones 1a-c show the most promising results. In an attempt to improve their activity, new dihydropyrazolo[1,5-c][1,3]benzoxazines, their thio and their dehydrogenated derivatives were prepared. The pyrazolo[1,5-c][1,3]benzoxazines 4a,b were hydrolyzed affording the 3-(2-furyl)-5-(2-hydroxy/substituted phenyl) pyrazoles 8a,b. The hydroxyimino derivatives 10a-c were synthesized together with their corresponding isoxazole derivatives 11a-c. - Molluscicidal assay indicated that the oximes 10b, c. the isoxazole 11b, the pyrazole 8b, and its N-carbamoyl derivative 9b are most effective. They have in common the conjugated system shown in Fig. 1 which is presumably the active core. Synthese und molluscicide Wirkung neuer 1-(substituierter Hydroxyphenyl)-3-arylpropenone Einige 1-(substituierte Hydroxyphenyl)-3-arylpropenone wurden auf molluscicide Wirkung gepruft. Die 1-(substituierten 2-Hydroxyphenyl)-3-(2-furyl)-propenone 1a-c zeigten die besten Ergebnisse. Um ihre Wirkung zu verstarken, wurden neue Dihydropyrazolo[1,5-c][1,3]benzoxazine, ihre Thio- und Dehydro-Derivate hergestellt. Die Pyrazolo[1,5-c][1,3]benzoxazine 4a,b wurden zu den 3-(2-Furyl)-5-(substituierten 2-hydroxyphenyl)-pyrazolen 8a,b hydrolysiert. Die Hydroxyimino-Derivate 10a-c wurden zusammen mit den Isoxazolen 11a-c hergestellt. - Die Prufung auf molluscicide Wirkung zeigte, das die Oxime 10b, c, das Isoxazol 11b, das Pyrazol 8b und sein N-Carbamoyl-Derivat 9b am starksten wirken. Alle beinhalten das in Abb. 1 dargestellte konjugierte System, das moglicherweise die aktive Gruppe darstellt.

Protoberberine aus Reissert-Verbindungen, 2. Mitt.: Eine neue Synthese von 8-Methyldibenzo[a,g]chinolizidinen

Abstract: Die Reissert-Verbindungen 16 werden mit dem Benzylbromid 14 zu den Dihydroisochinolinen 5 benzyliert. Durch alkalische Spaltung bilden sich daraus die 1-Benzylisochinoline 6, die mit Saure spontan zu den desoxygenierten Coralynen 4 cyclisieren. 4a sowie das aus 4b erhaltene Chinoliziniumsalz 18 werden mit NaBH4 zu den 8-Methyl-trans-dibenzochinolizidinen 19 reduziert. Die Sequenz 5 6 4 19 beinhaltet einen neuen, effizienten Zugang u.a. zu Coralyn-Analoga und 8-substituierten Tetrahydroprotoberberinen.- Die Bromierung von 2-Methylacetophenon 8 fuhrt nicht zu 2-Brommethylacetophenon sondern zum Benzalbromid 9 oder zum Phenacylbromid 11. Protoberberines from Reissert Compounds, II: A New Synthesis of 8-Methyldibenzo[a,g]quinolizidines The Reissert compounds 16 are benzylated by 2-bromomethylacetophenone dioxolane 14 to give the dihydroisoquinolines 5. Treatment of 5 with KOH yields the 1-benzylisoquinolines 6 which spontaneously form the deoxygenated coralynes 4 in acidic solution. 4a and 18 are reduced by NaBH4 to give the 8-methyl-trans-dibenzoquinolizidines 19. The sequence 5 6 4 19 is a new efficient access to coralyne analogues and 8-substituted tetrahydroprotoberberines.- Bromination of 2-methylacetophenone does not lead to 2-bromomethylacetophenone but to the benzalbromide 9 or to the phenacylbromide 11.

Pseudopeptides Containing Isothiazolidine‐1,1‐dioxide‐3‐carboxylic Acid: Synthesis and Properties of (S)‐Isothiazolidine‐1,1‐dioxide‐3‐carboxylic Acid, a New γ ‐ Sultam Analogue of Pyroglutamic Acid

Abstract: A synthesis of (S)-isothiazolidine-1,1-dioxide-3-carboxylic acid (2), the sulphonamido analogue of pyroglutamic acid, is reported. The protocol of its insertion into a peptide molecule, including protection and deprotection steps, is also described. Synthese und Eigenschaften der (S)-Isothiazolidin-1,1-dioxid-3-carbonsaure. Ein neues γ-Sultam-Analogon der Pyroglutaminsaure Die Synthese von (S)-Isothiazolidin-1,1-dioxid-3-carbonsaure (2), dem Sulfonamid-Analogon der Pyroglutaminsaure und der Einbau der Saure 2 in ein Peptidmolekul, einschlieslich der Schutz- und Abspaltungsreaktionen, werden beschrieben.

Synthese homochiraler 5,9‐Epoxybenzocyclooctene mit Aminsubstituenten: Zusammenhang zwischen Struktur und ZNS‐Aktivität

Abstract: Wir berichten uber Synthese und psychopharmakologische Eigenschaften von Variationen der sedierend und analgetisch wirksamen tricyclischen Amine 3a und 3b: Ausgehend von dem homochiralen Keton 4 werden die Amine 5 (primare Aminogruppe in aquatorialer Position), 7 (axial angeordnete Dimethylaminogruppe), 9 (zusatzlicher Phenylring in 7-Stellung), 13b und 14b (aquatorial bzw. axial stehende Dimethylaminomethylgruppe) und 23 und 24 (in 9-Position verschobene, axial standige Aminogruppe) dargestellt. BBr3 spaltet die beiden Phenolether des sekundaren Amins (±)-3a zu dem Aminodiphenol (±)-10. Die Beobachtung von Mausen auf Verhaltensanomalien (Irwin-Screen) und analgetische Wirksamkeit (Writhing Test) zeigt, das die Amine 5, 7, 9, (±)-10, 13b, 14b und 23 die sedativen und analgetischen Effekte der von uns bereits beschriebenen Amine 3a und 3b nicht erreichen. Synthesis of Homochiral 5,9-Epoxybenzocyclooctenes with Aminosubstituents: Relationship between Structure and CNS-Activity This paper deals with the synthesis and psychopharmacological effects of variations of the sedative and analgesic tricyclic amines 3a and 3b: Starting with the homochiral ketone 4 the amines 5 (primary amino group in equatorial position), 7 (axially oriented dimethylamino group), 9 (additional phenyl residue in position 7), 13b, and 14b (equatorially and axially arranged dimethylaminomethyl group) and 23 and 24 (axial amino group shifted to position 9) are prepared. BBr3 cleaves the phenolic ethers of the secondary amine (±)-3a to yield the aminodiphenol (±)-10. - Keeping mice under observation for behavioral anomalies (Irwin screen) and analgesic activity (writhing test) shows, that the amines 5, 7, 9, (±)-10, 13b, 14b, and 23 do not reach the sedative and analgesic effects of the amines 3a and 3b, described by us.

[Synthesis and biological effects of new N,N-disubstituted 5-alkyliden- and 5-aralkyliden-3-aminorhodanines].

Abstract: Numerous novel N,N-disubstituted 5-alkyliden- or 5-aralkyliden-3-aminorhodanines 2 have been prepared by condensation of carbonyl compounds with 1. The effectiveness of some derivatives in an "akanthose test" with hairless mice was shown.

[Indoles. 9. 4-Arylated tetrahydro-beta-carbolines--synthesis and first pharmacologic data].

Abstract: Two different routes lead to the 4-arylated tetrahydro-beta-carbolines 5, 11, 12. One includes Pictet-Spengler cyclization of tryptamines 9, the other follows our "lactone-route", starting with 1 via 2-4. In a first pharmacological screening some target compounds show significant affinity at the 5-HT2-receptor but no or only low affinity to other binding sites.

Properties and Reactions of Substituted 1,2-Thiazetidine 1,1-Dioxides: Alkylation and Acylation of 3-Haloalkyl β-Sultams and Synthesis of Bicyclic β-Sultams

Abstract: Alkylation of the 3-chloroethyl substituted β-sultam 1 with bromoacetates yields the N- and 3-substituted β-sultams 2; exchange of halogens affords esters 3. Reactions of 1 or of the analogues 8 with isocyanates make the carbamoyl derivatives 5, 6, and 9 available. While cyclization of 6 with n-BuLi in the presence of HMPT yields the bicyclic β-sultams 7, the analogous reaction of 9 failed. The bicyclic β-sultams 12 and 14 are obtained from 3-hydroxyalkyl β-sultams 11 and 13 and carbonyl compounds. None of the prepared β-sultams showed any antibacterial activity. Eigenschaften und Reaktionen substituierter 1,2-Thiazetidin-1,1-dioxide: Alkylierung und Acylierung von 3-Haloalkyl-β-sultamen und Synthese von bicyclischen β-Sultamen Das 3-Chlorethyl substituierte β-Sultam 1 gibt bei der Alkylierung mit Bromessigestern die disubstituierten β-Sultame 2 bzw. nach Halogenaustausch 3. Reaktionen von 1 bzw. 8 mit Isocyanaten fuhren zu den Carbamoylverbindungen 5, 6 und 9. Wahrend 6 mit n-BuLi und HMPT zu den Bicyclen 7 cyclisiert werden kann, mislingt die analoge Reaktion bei 9. Die bicyclischen β-Sultame 12 und 14 werden aus Hydroxyalkyl-β-sultamen wie 11 bzw. 13 und Carbonylverbindungen erhalten. Keine der dargestellten Verbindungen ist antibakteriell aktiv.

Synthesis of the Naphthalenic Bioisostere of Indorenate. Synthese des Naphthalin‐Bioisosters von Indorenat

Abstract: The relationships between some physiological processes and central nervous system or peripheral activity of serotonin (5-HT; A) has resulted in extensive studies of the chemistry and biological properties of many serotoninergic (agonists or antagonists) compounds1) and the existence of multiple serotoninergic receptors subtypes is supported by pharmacological evidence2). So, central 5-HT binding sites can be classified into 5-HT1 (1A, 1B, 1C, 1D), 5-HT2, 5-HT3 and 5-HT4 subtypes3,4) There is some basis for considering that central serotoninergic agonists might be antihypertensives acting via 5-HT1A receptors5,6,7) Indorenate (B), a synthetic indole. closely related to serotonin, has antihypertensive properties resulting from agonist activity at central serotoninergic receptors with a relatively high affinity for 5-HT1A sites8). A possible approach in the design of new serotoninergic ligands and more generally new drug candidates may consist in the application of the bioisosteric theory. So, the NH group is a classical bioisostere of the vinyl increment and the naphthalene nacleus could be considered as a bioisostere of the indole ring. Few examples of the naphthalene-indole bioisosterism have emerged in the lit.9,10,11) Here we describe the synthesis of the naphthalenic bioisostere C of B (Scheme 1).

Mammary tumor inhibiting [1,2-bis(2,6-dihalo-3-hydroxyphenyl)ethylenediamine]platinum(II) complexes, III: Relationship between structure and estrogenic activity of the diamine ligands, their sulfatoplatinum(II) and diiodoplatinum(II) complexes

Abstract: 1,2-Bis(2,6-dihalo-3-hydroxyphenyl)ethylenediamines with 2,6-Cl2, 2-F-6-Cl, 2-Cl,6-F, and 2,6-F2 substituents (meso-1 to meso-4, D,L-1 and D,L-4) and their sulfatoplatinum(II) complexes were tested in the immature mouse uterine weight test. The only complex with marked estrogenic properties proved to be meso-1-PtSO4. Surprisingly its diamine ligand meso-1 was only marginally active. 1H-NMR spectroscopic studies on the 1,2-diphenylethylenediamine ligand reveal that the 2,6-standing Cl-atoms in meso-1 (antiperiplanar phenyl residues) hinder the rotation of the aromatic rings, which results in very stable conformers with different O-O distances owing to the unsymmetric arrangement of the ring substituents. On transformation into the Pt(II) complex the conformations of meso-1 change (synclinal phenyl residues) and a delta and lambda interconversion takes place already at physiological temp. (37 degrees C). This process is accompanied by a rotation of phenyl rings, which is supposed to allow an optimal fit for the formation of hydrogen bridges to the estrogen receptor, resulting in a marked estrogenic activity. The other ligands and complexes are inactive presumably due to a diminished hydrophobic interaction with the estrogen receptor, resulting from their R,R/S,S-configuration or the reduced number of Cl-atoms.

Nitrosierungen an Hydrazinderivaten, 9. Mitt.: Neuartige oxidative C‐N‐Verknüpfungen von Indazolen und Benzotriazolen mit Cycloheptatrien sowie Di‐ und Triphenylmethanderivaten

Abstract: Indazole und Benzotriazole reagieren unter Einwirkung von 2,3-Dichlor-5,6-dicyanbenzochinon (DDQ) mit Verbindungen, die zur Bildung stabilisierter Carbeniumionen neigen, wie Cycloheptatrien, Di- und Triphenylmethan, Fluoren, Xanthen und Thioxanthen zu C-N-verknupften Produkten. Nitrosation of Derivatives of Hydrazines, IX: Novel Oxidative C-N-Coupling of Indazoles and Benzotriazoles with Cyclohepatriene, Di- and Triphenylmethane Derivatives In the presence of 2,3-dichloro-5,6-dicyano-benzoquinone (DDQ) indazoles and benzotriazoles react with compounds forming stabilized carbenium ions like cycloheptatriene, di- and triphenylmethane, fluorene, xanthene and thioxanthene, yielding C-N-coupled products.

Synthesis and antitumor activity of some new 2-chloroethylnitrosoureas.

Abstract: The synthesis of a series of N-(2-chloroethyl)-N′-(9H-xanthen-9-yl)-N-nitrosoureas and N-(2-chloroethyl)-N′-(9H-thioxanthen-9-yl)-N-nitrosoureas is described. The title compounds were evaluated against NSCLCN6 L16 bronchial epidermoid carcinoma in vitro and some of them were found to be active. N-(2-chloroethyl)-N′-(2-methoxy-9H-xanthen-9-yl)-N-nitrosourea (8e) was active against leukemia P388 tumor system in mice. Synthese und pharmakologische Prufung von neuen 2-Chlorethylnitrosoharnstoffen Eine Reihe von neuen N-(2-chlorethyl)-N′-(9H-xanthen-9-yl)-N-nitrosoharnstoffen und N-(2-chlorethyl)-N′-(9H-thioxanthen-9-yl)-N-nitrosoharnstoffen wurde dargestellt. Die neuen Verbindungen wurden auf Aktivitat gegen NSCLCN6 L16 (Epidermoides Bronchialkarzinom) in vitro gepruft: einige erwiesen sich als wirksam. Verbindung 8e ist auch gegen das Leukamie P388-Tumorsystem in vivo wirksam.

Synthese von basisch substituierten 5H-Pyrimido[4,5-c]-2-benzazepinen

Abstract: Die potentiell ZNS-wirksamen Titelverbindungen 19a-c lassen sich durch eine neunstufige Synthese ausgehend von Phthalaldehydsaure herstellen. Durch Knoevenagel-Kondensation von 5 mit den Acetonitrilen 2a-g und folgender Reduktion mit NaBH4 erhalt man die Dihydrozimtsaurenitrile 3. Nur 3a last sich zu den 2-Benzazepinnitrilen 9a,b cyclisieren. Ammonolyse von 9a fuhrt zum Enaminonitril 10, das mit den Orthoestern 11a-c die Imidsaureester 12a-c gibt. Nachfolgende Ammonolyse liefert die Tricyclen 16a,b. Nach Umwandlung der Lactamfunktion von 16 in das Imidoylchlorid 17 folgt Aminolyse mit den Aminen 18a-c zu den Titelverbindungen 19a-c. Synthesis of Basically Substituted 5H-Pyrimido[4,5-c]-2-benzazepines The potentially CNS-active title compounds 19a-c can be prepared by a nine step synthesis beginning with phthalaldehydic acid. Knoevenagel condensation of 5 with the acetonitriles 2a-g and subsequent reduction with NaBH4 lead to the dihydrocinnamic acid nitriles 3. Only 3a can be cyclized to the 2-benzazepinnitriles 9a,b. Ammonolysis of 9a yields the enaminonitrile 10, which is reacted with the orthoesters 11a-c to the imidic acid esters 12a-c. Ammonolysis leads to the tricycles 16a,b. After transformation of the lactam group in 16 to an imidoyl chloride 17, aminolysis with the amines 18a-c provides the title compounds 19a-c.