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The zwitterionic tetrafluoro(pyrrolidiniomethyl)silicate (6) was synthesized by the reaction of trimethoxy(pyrrolidinomethyl) silane (7) with hydrogen fluoride in ethanol/hydrofluoric acid (yield 83%). 6 crystallizes in the space group P2\(_1\)fc with two crystallographically distinct molecules in the asymmetric unit. In both molecules the pentacoordinate silicon atom is surrounded by four fluorine atoms and one carbon atom, the latter being in an equatorial position. The coordination polyhedron of the silicon atoms can be described as a slightly distorted trigonal bipyramid. The zwitterionic structure was also proved for dissolved 6 (solution in CD\(_3\)CN, NMRspectroscopic studies).
The zwitterionic \(\lambda_5\) Si-spirosilicate bis[ citrato(2-)-0\(^3\) ,0\(^4\) )[ ( dimethylammonio) methyl]silicate (4) was synthesized by reaction of (MeO)\(_3\)SiCH\(_2\)NMe\(_2\) (3) with citric acid (molar ratio 1 :2) in acetonitrile at room temperature and isolated, after crystallization from water, as the hydrate 4 · H\(_2\)O (yield 81 %). The crystal structure of 4 · H\(_2\)O was studied by single-crystal X-ray diffraction. The alcoxide oxygen atoms and central carboxylate oxygen atoms of two citrato(2-) ligands and one carbon atom coordinate to the silicon atom of 4 · H\(_2\)O. The coordination polyhedron around the pentacoordinate silicon atom (SiO\(_4\)C framework) can be described as a distorted trigonal bipyramid, the two carboxylate oxygen atoms occupying the axial sites. The \(\lambda_5\) Si~silicon(IV) complex 4 also exists in solution (DMSO, H\(_2\)O).
Die (Acyloxymethyl)diorganylsilane R\(^1\)R\(^2\)Si(H)CH\(_2\)OC(O)R\(^3\) (2a- d) unterliegen einer thermisch induzierten Umlagerung zu den entsprechenden Acyloxy(methyl)diorganylsilanen R\(^1\)R\(^2\)Si(CH\(_3\))OC(O)R\(^3\) (3a- d). Diese Reaktion beinhaltet formal einen Austausch des am Silicium gebundenen Wasserstoffs mit dem am Kohlenstoff gebundenen Acyloxy-Rest. Bezüglich der 1,2- Wasserstoff-Verschiebung konnte experimentell ein intramolekularer Prozeß bewiesen werden.
The synthesis of the potent and highly selective silicon-containing antimuscarinic agent o-methoxysila- hexocyclium methyl sulfate and its corresponding tertiary amine (isolated as the dihydrochloride) is described. The quarternary compound is an omethoxy derivative of sila-hexocyclium methyl sulfate, which represents one of the tools currently used in experimental pharmacology for the subclassification of muscarinic receptors. The omethoxy derivative, the pharmacological profile of which differs substantially from tbat of the nonmethoxy compound, is also recommended as a tool for the investigation of muscarinic receptor heterogeneity.
Starting from chlorodimethyl(phenyl)silane (3), acetyldimethyl(phenyl)silane (l) was prepared by a two-step synthesis in a total yield of 90% [PhMe\(_2\)SiCl (3)-> PhMe\(_2\)SiCCOMe)=CH\(_2\) (4)-> PhMe\(_2\)SiC(O)Me (1)]. The prochiral acetylsilane 1 was transfonned enantioselectively into (R)-(1-hydroxyethyl)dimethyl(phenyl)silane [(R)-2] using plant cell Suspension cultures of Symphytum officinale L. or Ruta graveolens L. Under preparative conditions (300-mg scale, not optimized), (R)-2 was isolated in 15% (Symphytum) and 9% yield (Ruta), respectively. The enantiomeric purities of the products were 81% ee (Syrnphytum) and 60% ee (Ruta), respectively.
Racemic dimethylphenyl(l-(phenylacetamido)ethyl)silane [rac-5) has been made by a four-step synthesis starting from (chloromethyl)dimethylphenylsilane [PhMe\(_2\)SiCH2Cl (1) ~ PhMe\(_2\)SiCH(Cl)Me (rac-2) - PhMe\(_2\)SiCH(l)Me (rac-3) - PhMe2SiCH(NH2)Me (rac-4) ~ PhMe\(_2\)SiCH[N(H)C(O)CH\(_2\)Ph]Me ( rac-5); total yield 41% ). Enantioselective enzymatic hydrolysis of rac-5, catalyzed by immobilized penicillin G acylase (E.C. 3.5.1.11) from Escherichia coli 5K (pHM 12), gave (R)-(1- aminoethyl)dimethylphenylsilane [( R )-4] in 40% yield with an enantiomeric purity of 92% ee.
No abstract available
In der vorliegenden Arbeit wird die Darstellung einer Reihe monoarylsubstituierter Bisdimethylamino-1-bromo-2-arlydiborane(4) beschrieben. Sowohl die Umsetzung der monoarylsubstituierten Ligandenvorstufen mit einem weiteren Äquivalent Lithium- oder Natriumaryl in einem Ether/Toluol-Gemisch als auch die Umsetzung von 1,2-Dibrom-bis(dimethylamino)diboran(4) mit einem mehrfachen Überschuss Lithium- oder Natriumaryl führte zur Bildung von diarylsubstituierten Diboranen(4). Umsetzung der Ligandenvorstufen mit Lithiumorganylen, wie beispielsweise Li[CH3] oder Li[C4H9] führt zu doppelt deprotonierten Verbindungen. Werden die dilithiierten Verbindungen mit Metallhalogeniden der Gruppe 4 in einem Toluol/Ether-Gemisch umgesetzt, können [2]Borametallocenophane erhalten werden. Von einigen der Verbindungen konnte die Struktur im Festkörper mittels Einkristallstrukturanalyse bestimmt werden. Die Verbindungen zeigen in Lösung ein dynamisches Gleichgewicht, welches durch die Flexibilität der B-B-Brücke ermöglicht wird. Dieses konnte mittels NMR Spektroskopie untersucht werden. Auch die Reaktivität der Verbindungen wurde erforscht. Versuche zur oxidativen Addition von Platin(0) in die B-B-Bindung, wie sie bereits für ähnliche Systeme beschrieben waren, scheiterten. Ebenfalls nicht erfolgreich war der versuchte Austausch der Dimethylaminogruppen an den Bor-Atomen. Di(fluorenyl)substituierte [2]Borametallocenophane zeigen in der Reihe der dargestellten Verbindungen ein einzigartiges Verhalten. Wird die dilithiierte Liganden-Vorstufe bei der Umsetzung mit den Metallhalogeniden der Gruppe 4 Licht ausgesetzt, so lagert sie zum 1,3-Diboretan um. Auch oxidativ kann diese Umlagerung ausgelöst werden. Das Umlagerungsprodukt war von anderen Reaktionen bereits bekannt, konnte im Rahmen dieser Arbeit aber erstmals strukturell charakterisiert werden. Die Dichloroverbindungen der [2]Borametallocenophane können mittels Li[CH3] in die entsprechenden Dimethylkomplexe überführt werden. Damit besteht die Möglichkeit, die Verbindungen nicht nur mit MAO, sondern auch mit alternativen Co-Katalysatoren, wie beispielsweise Tris-(pentafluorphenyl)boran für die Olefinpolymerisation zu aktivieren. Die Aktivierung mittels MAO wurde sowohl mittels NMR- als auch mittels UV/Vis-Spektroskopie bei verschiedenen [Al]/[Zr] Verhältnissen untersucht. Neben den [2]Borametallocenonphanen konnte mit Verbindung [(n5-C29H37)2ZrCl2] das erste Metallocen mit dem neuen OctafluH-Liganden und zwei koordinierenden Arylgruppen dargestellt werden. Um die Polymerisationseigenschaften der Verbindungen zu untersuchen, wurde ein neuer Versuchsaufbau entworfen. Zur Überwachung der Polymerisationen wurde ein Programm entwickelt, was in der Lage war, verbrauchte Gasmenge und Temperatur im Reaktoraufzuzeichnen. Hier wurden die katalytischen Eigenschaften einer Serie von [2]Borametallocenophanen und des dargestellten Metallocens [(n5-C29H37)2ZrCl2] in der Ethen-Homopolymerisation untersucht. Diese Polymere wurden mittels DSC auf ihre thermischen Eigenschaften hin geprüft. Ausgewählte Polymere wurden in Zusammenarbeit mit der LyondellBasell Industries, Basell Polyolefine GmbH, Frankfurt mittels GPC auf ihr mittleres Molekulargewicht und dessen Verteilung hin untersucht. Alle Daten wurden mit denen von industriell verwendeten Katalysatoren und den von Kraft bekannten [1]Borametallocenophanen verglichen. In weiteren Untersuchungen wurde überprüft, in wie weit die Polymerisationsbedingungen, wie beispielsweise das [Al]/[Zr]-Verhältnis, die Temperatur oder der Druck Auswirkungen auf die Eigenschaften des Polymers haben. Eine Reihe von Komplexen wurde überdies in der Ethen/[1]Hexen-Copolymerisation untersucht. Die erhaltenen Copolymere wurden mittels DSC-, GPC-, IR- und NMR- Spektroskopie analysiert. Zusammenfassend lässt sich feststellen, dass eine Reihe neuer Verbindungen dargestellt und charakterisiert werden konnte, wobei insbesondere der neuartige Ligand OctafluH (C29H38) eingesetzt wurde. Die dargestellten [2]Borametallocenophane sind aktive Katalysatoren in der Ziegler-Natta ähnlichen Olefinpolymerisation. Die dargestellten Polymere wurden mittels verschiedener Methoden untersucht. Es zeigte sich, dass [2]Borametallocenophane langkettige Polyolefine und Ethen/1-Hexen Copolymere liefern können.
Umsetzungen N-heterocyclischer Carbene mit Boranen führen zur Bildung von „Lewis-Säure-Base-Addukten“. In Abhängigkeit des Substitutionsmusters der eingesetzten Borane bzw. Carbene eignen sich die erhaltenen Addukte als Ausgangsverbindungen zur Realisierung verschiedener Strukturmotive. Mit geeigneten Übergangsmetallfragmenten gelingt die Darstellung von sigma-Boran-Komplexen bzw. Basen-stabilisierter Boryl-Komplexe, welche mittels spektroskopischer Methoden sowohl im Festkörper, als auch in Lösung untersucht wurden. Ebenfalls gelingt die Synthese Basen-stabilisierter Borirane und einer tetraedrischen Borid-Spezies. Zudem wird ein selektiver Zugang zu Basen-stabilisierten Diborenen entwickelt, wobei deren Bindungssituation und Reaktivität im Detail diskutiert wird. So kann das B=B-Fragment in polymere Spezies eingebunden werden oder als Ligand an Übergangsmetalle koordinieren.
Die vorliegende Arbeit stellt einen Beitrag zur Chemie des höherkoordinierten Siliciums dar. Im Vordergrund standen die Synthese und Charakterisierung neuer neutraler penta- und hexakoordinierter Silicium(IV)-Komplexe sowie die Synthese, Charakterisierung und Untersuchung der Reaktivität eines neuartigen Donor-stabilisierten Silylens.
No abstract available.
Synthese und Eigenschaften von (Hydroxymethyl)dimethylgerman und (Hydroxymethyl)diphenylgerman
(1988)
Die (Hydroxymethyl)diorganylgermane (CH\(_3\))\(_2\)Ge(H)CH\(_2\)OH und (C\(_6\)H\(_5\))\(_2\)Ge(H)CH\(_2\)OH wurden - ausgehend von GeCl\(_4\) - durch eine jeweils vierstufige Synthese mit einer Gesamtausbeute von 15 bzw. 32% dargestellt (GeCl\(_4\) ---+ Cl\(_3\)GeCH\(_2\)Cl -> R \(_2\)Ge(Cl)CH \(_2\)Cl ->R \(_2\)Ge(OAc)CH\(_2\)OAc--) R \(_2\)Ge(H)CH\(_2\)OH; R = CH\(_3\) bzw. C\(_6\)H\(_5\) ). Die chemische Reaktivität der Germane (CH\(_3\))\(_2\)Ge(H)CH\(_2\)OH und (C\(_6\)H\(_5\))\(_2\)Ge(H)CH\(_2\)OH wird durch deren Ge-H- und 0-H-Bindung bestimmt.
The synthesis of the (hydroxymethyl)diorganylsilanes R\(^1\)R\(^2\)Si(H)CH\(_2\)OH (4a: R\(^1\) = R\(^2\) = CH\(_3\), 2-silaisobutanol; 4b: R\(^1\) = CH\(_3\), R\(^2\) == C\(_6\)H\(_5\); 4c: R\(^1\) == R\(^2\) = C\(_6\)H\(_5\))is achieved bythereactionof R\(^1\)R\(^2\)Si(Cl)CH\(_2\)Cl (2a-c) with AcOH/NEt\(_3\) to R\(^1\)R\(^2\)Si(OAc)CH\(_2\)OAc (Ja-c), followed by treating with LiAlH\(_4\) and hydrolysis.
Die Synthese des selektiven Antimuskarinikums Cyclohexylpheny\{3-piperidinopropyl)sila· nol (1 b) wird beschrieben. 1 b wurde - ausgehend von (3·Chlorpropyl)trimethoxysilan - durch eine vierstufige Reaktionsfolge erhalten und als Hydrochlorid 2b mit einer Gesamtausbeute von etwa 45°/o isoliert. - 1 b ist aufgrund seiner großen pharmakologischen Se· lektivität zu einer Standardsubstanz in der experimentellen Pharmakologie bei der Differenzierung von Muskarinrezeptoren geworden.
Sila-Hexocyclium-methylsulfat (7b), ein Silicium-Analogon des therapeutisch eingesetzten Antimuscarinileums Hexocyclium-methylsulfat (7a), wurde durch eine sechsstufige Synthese - ausgehend von (CH\(_3\)0)\(_3\)SiCH\(_2\)Cl - dargestellt (Gesamtausbeute 16%). Außerdem wurden die hiervon abzuleitende freie Base 9b (fünfstufige Synthese, ausgehend von (CH\(_3\)0)\(_3\)SiCH\(_2\)O; Gesamtausbeute 29%) und das strukturverwandte (Aminomethyl)silanol 13 (dreistufige Synthese, ausgehend von cyclo-C\(_6\)H\(_{11}\)(C\(_6\)H\(_5\))Si(OCH\(_3\))CH\(_2\)Cl, Gesamtausbeute 46$) synthetisiert. 7b ist ein hochwirksames und selektives Antimuscarinikum, das in der experimentellen Pharmakologie aufgrund seines bemerkenswerten Selektivitätsprofils zur Klassifizierung von Subtypen muscarinischer Rezeptoren eingesetzt wird.
Das zwitterionische Tctratluoro[2-(pyrrolidinio) ethyl]silicat (4) wurde durch Reaktion von Trimethoxy( 2-pyrrolidinoethyl)silan (5) mit Fluorwasserstoff in einem Ethanol/Flußsäure-Gemisch bei 0 °C synthetisiert. Die Kristall- und Molekülstruktur von 4 wurde bei - 100 °C mittels einer Einkristall-Röntgenstrukturanalyse untersucht. Außerdem wurde 4 durch NMR-Untersuchungen in Lösung charakterisiert (CD\(_3\)CN: \(^1\)H, \(^{13}\)C).
The racemic Si-functional acetylsilanes tBu(Me\(_3\)SiCH\(_2\))[ MeC(O)]SiF (1) and tBu(Me\(_3\)SiCH\(_2\))[MeC(O)]SiH (2) and the racemic acetylsilanol tBu(Me\(_3\)SiCH\(_2\))[MeC(O)]SiOH (3) were synthesized from Si(OMe)\(_4\) (4) as substrates for microbial reductions [4 -> tBuSi(OMe)\(_3\) (5) -> tBu(Me\(_3\)SiCH\(_2\))Si(OMe)\(_2\) (6) -> tBu(Me\(_3\)SiCH\(_2\))SiF\(_2\) (7)-> tBu(Me\(_3\)SiCH\(_2\))(CH\(_2\) = C(OMe))SiF (8) -> 1; 8 -> tBu(Me\(_3\)SiCH\(_2\))[CH\(_2\) = C(OMe)]SiH (9) -> 2; 6 -> tBu(Me\(_3\)SiCH\(_2\))[CH\(_2\) = C(OMe)]SiOMe (10) -> 3]. Compounds 1-3 were found to be reduced by cells of Trigonapsis variabilis (DSM 70714) ( = SiC(O)Me -> = SiCH(OH)Me}. The crystal and molecular structure of 3 was studied by singlecrystal X-ray diffraction. In the crystal, racemic 3 forms infinite chains built up by intermolecular 0-H .. ·O bonds between the hydroxyl and acetyl groups of molecules of the same absolute configuration.
No abstract available
The goals of the present study were: (1) to investigate thc binding properlies oi (R)- and (S)-procyclidine and two aehiral derivatives of muscarinic M\(_1\)• M\(_2\) and M\(_4\) receptor subtypes and (2) to identify the interaetions which allow these receptors to diseriminate between the two stereoisomers. (R)-Procyclidine showed a higher affinity for human neuroblastoma NB-OK 1 muscarinie M\(_1\) and rat striatum musearinie M\(_4\) receptors. a~ compared to rat cardiac M\(_2\) receptors. (S)-Procyclidine had a 130-iold lower affinity than (R)-procyclidine for M\(_1\) and M\(_4\) receptors. and a 40-fold lower affinity for M\(_2\) receptors. Pyrrinol. the aehiral diphenyl derivative with the eyclohexyl g.roup of (S}-procyclidine replaeed by a phenyl group, has an eight-fold lower affinity for M\(_1\) and M\(_4\) receptors. as eompared to (R)-procyclidine, and a three-fold lower affinity for M\(_2\) receptors. Hexahydro-procyclidine. the eorresponding achiral dicyclohexyl compound, had a 10- to 20-fold lower affinity than (R)-procyclidine for the three reeeptors. The inerease in binding free energy, which is observed when the phenyl and eyclohexyl groups of procyelidine are separately replaeed by cyclohexyJ and phenyl groups, respectively. was additive in the ease of M\(_1\)• M\(_2\) and M\(_4\) receptcrs. This indicates that the musearinic reeeptor s!ereoseleetivity was based on the eoexistence of two binding sites, one preferring a phenylrather than eyclohexyl group and the seeond preferring a cyclohexyl rather than a phenyl group. In addition. there were aiso binding sites for the hydroxy moiety and the protonated amino group of the ligands. The greater affinity and stereoselectivity of M\(_1\) and M\(_4\) muscarinic receptors for (R)-procyelidine reflected the better fit of the eyclohexyl group of (R)-procyclidine to the subsite of M\(_1\) and M\(_4\) as compared to M\(_2\) receptors.
(R)-Hexahydro-difenidol has a higher affinity for M\(_1\) receptors in NB-OK 1 cells, pancreas M\(_3\) and striatum M\(_4\) receptors (pKi 7.9 to 8.3) than for cardiac M2 receptors (pKi 7 .0). (8)-Hexahydro-difenidol, by contrast, is nonselective (pKi 5.8 to 6.1). Our goal in the present study was to evaluate the importance ofthe hydrophobic phenyl, and cyclohexyl rings of hexahydro-difenidol for the stereoselectivity and reeeptor selectivity of hexahydro-difenidol binding to the four muscarinic receptors. Our results indieated that replacement of the phenyl ring of hexahydro-difenidol by a cyclohexyl group <~ dicyclidol) and ofthe cyclohexyl ring by a phenyl moiety <~ difenidol) indueed a !arge (4- to 80-fold) decrease in binding affinity for all musearlnie receptors. Difenidol had a signifieant preference for M\(_1\) , M\(_3\) , and M\(_4\) over M\(_2\) receptors; dicyclidol, by eontrast, had a greater affinity for M\(_1\) and M\(_4\) than for M\(_2\) and M\(_3\) receptors. The binding free energy deerease due to replacement ofthe phenyl and the cyelohexyl groups of(R)-hexahydro-difenidol by, respectively, a eyclohexyl and a phenyl moiety was almostadditive in the ease of M\(_4\) (striatum) binding sites. In the ease ofthe cardiac M\(_2\), pancreatic M\(_3\) , or NB-OK 1 M\(_1\) receptors the respective binding free energies were not eompletely additive. These results suggest that the four (R)-hexahydro-difenidol ''binding moieties" (phenyl, cyclohexyl, hydroxy, and protonated amino group) cannot simultaneously form optimal interaetions with the M\(_1\), M\(_2\), and M\(_3\) muscarinic receptors. When eaeh of the hydrophobic groups is modified, the position of the whole molecule, relative to the four subsites, was changed to allow an optimal overall interaction with the musearlnie receptor.
(SiR,CR)- and (SiS,CR)-t-butyl(l-hydroxyethyl)methylphenylsilane [(SiR,CR)-2 and (SiS,CR)-3] have been prepared by (R)-selective microbial rcduction of racemic acetyl(t-butyl)methylphenylsilane (rac-1) using resting free cells of the yeast Trigonopsis variabilis (DSM 70714) or the bacterium Corynebacterium dioxydans (ATCC 21766). The biotransfonnations were carried out on a 10 g scale. Afterseparation by column chromatography on silica gel, the optically active diastereomers (SiR,CR)-2 and (SiS,CR)-3 produccd by T. variabilis were obtained in good yields [74% ((SiR,CR)-2). 78% ((SiS,CR)-3)]. The products obtained from the reduction with C. dioxydans were isolated in significantly lower yields [20% ((SiR,CR)-2), 20% ((SiS,CR)-3)]; reaction conditions not optimized). Both bioconversions gave products with high enantiomeric purities (T. variabilis: 91% ee ((SiR,CR)-2), 96% ee ((SiS,CR)-3); C. dioxydons: ~ 991 ee ((SiR,CR)-l), ~ 99% ee ((SiS,CR)-3)). To throw light on the stereochemical aspects of these biotransfonnations, an X-ray diffraction study was carried out on the 3,5-dinitrobenzoate of rac-(SiR,CS/SiS,CR)-3. In addition, 1H NMR spectroscopic stereochemical correlation studies were performed with the (S)-MTPA esters derived from (SiR,CR)-l, (SiS,CR)-3, rac-(SiR,CRjSiS,CS)-2 and rac-(SiR,CSjSiS,CR)-3 [rac-(SiR,CR/ SiS,CS)-2 and rac-(SiR,CS/SiS,CR)-3 were obtained by reduction of rac-1 with LiAIH\(_4\) in diethylether, followed by chromatographic separation of the diastereomers on silica gel]. These stereochemical studies allowed assignment of the absolute configurations and enantiomeric purities of the biotransformation products.
Wc invcstigatcd thc binding properlies of thc (R)- and (Sl-cnantiomcrs of thc muscarinic antagonists trihcxyphcnidyl, procyclidinc, hcxahydro-difcnidol. p-fluoro-hcxahydro-difcnidol. hcxbutinol, p-fluoro-hcxbutinnl. and thcir corrcsponding methiodidcs at muscarinic M\(_1\), M\(_2\)• M\(_3\) and M\(_4\) receptor subtypes. In addition. binding properlies of thc (R)- and (S)-cnantiomcrs of oxyphcncycliminc wcrc studicd. The {R)- cnantiomcrs (cutomcrs} of all the compounds had a grcatcr affinity than the (S)-isomcrs for thc four muscarinic rcccptor subtypcs. Thc binding pattcrns of thc (R)- and (S)-enantiomers wcrc gcncrally different. We did not obscrvc any gcncral corrclation hctwccn thc potcncy of thc high-affinity enantiomer and Lhc affinity ratio (cudismic ratio) of the two cnantiomcrs. Thc rcsuhs arc discusscd in tcrms of a 'four suhsitcs' binding modcl.
1 Tbc affinities of the (R)- and (S)-enantiomers of hexahydro-difenidol (1) and its acetylenie analogues hexbutinol (2), hexbutinol methiodide (3) and p-fluoro-hexbutinol (4) (stereochemieal purity > 99.8%) for musearlnie receptors in rabbit vas deferens (M1), guinea-pig atria (M2) and guinea-pig ileum (M3) were measured by dose-ratio experiments. 2 The (R)-enantiomers consistently showed higher aßinities than the (S)-isomers. The stereosclectivity ratios [(R)/(S)] wcrc greatest with thc enantiomers of 1 (vas deferens: 550; ilcum: 191; atria: 17) and least with thosc ofthc p-Fluoro-analogue 4 (vas defercns: 34; ileum: 8.5; atria: 1.7). 3 The enantiomerie potency ratios for compounds 1-4 were highest in rabbit vas deferens, intermediate in guinea-pig ileum and much less in guinea-pig atria. Thus, these ratios may serve as a predietor of muscarinic receptor subtype identity. 4 (S)-p-Fluoro-hexbutinol [(S)-4] showed a novel receptor selectivity profile with preference for M\(_3\) receptors: M\(_3\) > M\(_2\) \(\geq\) M\(_1\)• 5 These results do not conform to Pfeiffer's rule that aetivity differences between enantiomers are greater with more potent compounds.
No abstract available
Silylation of cellulose
(1977)
Ethane-l:2-diol and propane-l:3-diol reaet with 1: 1:3:3-tetramethyl-l:3-dichlorodisiloxane forming the corresponding rings. However, no ring compounds could be traced tbrough the reaction between butane-l :4-diol, glycerol and the dichlorodisiloxane respectively, where only polymeric compounds are formed. The silylation products of the di- and trihydroxy alcohols, as model compounds, has confirmed that the ring formation during silylation of cellulose with dichlorodisiloxane is uncertain.
Sila-Procyclidin (1 b) sowie dessen Derivate 2b (Sila-Tribexyphenidyl), 3b und 4b (Sila-Cycrimin) wurden - ausgehend von Cl\(_3\)SiCH\(_2\)Cl - durch eine neue, sechsstufige Synthese mit einer Gesamtausbeute von 16 (lb), t9 (2b), 8 (3b) bzw. 7% (4b) dar· gestellt. - Vergleichende in-vivo-Untcrsuchungen (Maus, per-osApplikation) hinsichtlich der peripheren und zentralen auticholincrgen Wirkung haben gezeigt, daß die Silicium-Verbindung 1 b dem Kohlenstoff-Analogon Ia (Procyclidin) überlegen ist.
Sila-Pridinol (2 b), ein Sila-Analogon des Anticholinergicums Pridinol (2a), wurde auf zwei verschiedenen Wegen dargestellt. Die Kristall- und Molekülstrukturen von 2 a und 2 b wurden röntgenstrukturanalytisch bestimmt. 2a bildet im festen Zustand intramolekulare Wasserstoffbrückenbindungen aus, während sich in kristallinem 2 b zentrosymmetrische, durch intermolekulare H-Brückenbindungen verknüpfte cyclische Dimere finden. IR- und \8^1\)H-NMR-spektroskopische sowie kryoskopische Untersuchungen ergaben Informationen über die Strukturen von 2a und 2 b in verschiedenen Lösungsmitteln. - Die pharmakologischen und toxikologischen Eigen" schaften von 2a und 2b wurden unter dem Gesichtspunkt bekannter Struktur-Wirkungs-Beziehungen vergleichend untersucht. 2 b erwies sich als ein etwa fünfmal so starkes Anticholincrgicum wie 2a.
15 new C/Si-analogue pairs (C-compounds and sila- or disila-substituted derivatives, respectively), which are structurally related to nifedipine, have been synthesized. These and some further C/Si-pairs have been investigated comparatively with respect to their physicochemical and pharmacological properties. Using reversed-phase thin-layer chromatography it was shown that both the sila- and disila-analogues are more Iipophilic than the corresponding C-compounds. With respect to the in vitra spasmolytic potencies the Si-compounds show approximately similar structure-activity relationships to their carba-analogues. However, in some cases marked differences in in vivo effects (cardiovascular and antihypertensive activity) could be demonstrated.
Starting from trichloro(vinyl)silane (Cl\(_3\)SiCH=CH\(_2\)), the musearinic antagonists sila-biperiden [rac-(SiRS,C2SR>-ao-2] and endosila- biperiden [rac-(SiRS,C2SR)-endo-2] were prepared by a seven-step synthesis. Both silanols are configurationally stableininert organic solvents but undergo slow epimerization in aqueous solution (pH 7.4, 32°C) by inversion of the configuration at the silicon atom. The relative configurations of sila-biperiden and endo-sila-biperiden were detennined by single-crystal X-ray diffraction. Both compounds form intennolecular 0-H · · · N hydrogen bonds in the crystal leading to the fonnation of centrosymmetric dimers (sila-biperiden) and infinite chains (endo-sila-biperiden), respectively. Sila-biperiden is a silicon analogue (C/Si exchange) of the antiparkinsonian drug biperiden [rac-(CRS/C2SR}-exo-1]. In functional phannacological experiments, as well as in radioligand competition studies, biperiden, sila-biperiden and endo-sila-biperiden behaved as simple competitive antagonists at muscarinic Ml-, M2-, M3- and M4-receptors. The three compounds displayed the highest affinity for Ml-receptors (pA\(_2\) values: 8.72-8.80; pK\(_i\) values: 8.8-9.1), intermediate affinity for M4- and M3-receptors, and lowest affinity for M2-receptors (pA\(_2\) values: 7.57-7.79; pK\(_i\) values: 7.7-7.8). The affinity profile (Ml >. M4 > M3 > M2) of biperiden, sila-biperiden and endo-sila-biperiden is qualitatively similar to that of the M1-selective muscarinic antagonist pirenzepine. The antimuscarinic properlies of the C/Si analogues biperiden and sila-biperiden are almost identical.
Sila-Tiemoniumiodid (16b), ein Sila-Analogon des Anticholinergicums Tiemoniumiodid (16a), und das Sila-Analogon 14b der entsprechenden Tiemonium-Base 14a wurden erstmalig synthetisiert.14b und 16b sowie die Vorstufen 10-13 und 15 wurden in ihren physikalischen und chemischen Eigenschaften charakterisiert und in ihrer Struktur durch Elementaranalysen sowie \(^1\)H-NMR- und Massenspektren sichergestellt. Die spasmolytischen Eigenschaften der Paare 14a/14b und 16a/16b wurden am isolierten Meerschweinchendarm vergleichend untersucht.
Sila-Analogon des Rythmols
(1980)
Sila-Rythmol (llb), ein Sila-Analogon des Antiarrhythmieums Rythmol (lla), wurde erstmalig dargestellt. llb sowie die Vorstufen und Nebenprodukte 4, 5, 6, 7, 9b und lOb wurden in ihren physikalischen und chemischen Eigenschaften charakterisiert und in ihrer Struktur sichergestellt. Die pharmakologischen und toxikologischen Eigenschaften der Analoga lla und llb wurden vergleichend untersucht.
Sila-Analogues B 2 and A 2 of the spasmolytic ciclonium bromide (B 1) respectively the corresponding free base A 1 were synthesized for the first time according to the reaction steps sho·wn in scheme 1, and they and their precursors I and II were characterized by ph;ysical (Table 1} and chemical properties and their structures confirmed by NMR, and mass spectroscopy (Tables 2 and 3}. The pharmacological effects of A 2 and B 2 were investigated and compared with those of the parent carbon compound B 1 (chapter 5).
Es wurden Silanale RR'R"SiOH 7 dargestellt, die Carbinolen RR'R"COH 1 (R = CH\(_3\) , R' = CH\(_3\) , CH = CH\(_2\) , C\(_2\)H\(_5\) , R" = CH\(_2\)C\(_6\)H\(_5\) , CH\(_2\)CH\(_2\)C\(_6\)H\(_5\)) mit starker Duftwirkung im Bereich blumiger Noten (Maiglöckchen-Hyazinthe-Rose) analog waren. Ihr Syntheseweg verläuft über die Reaktionsschritte (3) mit teilweise bisher unbekannten Zwischenstufen 6. Die Sila-Riechstoffe 7 sind in Intensität und Duftbereich den Carbinolen 1 ähnlich, doch ist allgemein eine Verschiebung der Duftnote von Maiglöckchen zu Hyazinthe zu beobachten.
Sila-Analogues A 2, B 2 and C 2 of the drug mephenhydramine from the class of benzhydryl ethers were synthesized for the first time by the steps shown in scheme 1, and they and their precursors I-V characterized by their physical {table 1) and chemical properties, and their structures confirmed by NMR, n1ass and infrared spectroscopy (tables 3-5). Their physiological effects were investigated a.nd compared -with those of the parent carbon compounds (section 5).
Sila-analogues A 2, B 2 and C 2 of the drug mebrophenhydramine from the class of benzhydryl ethers -were synthesized for the first time by the steps shown in scheme 1, and they and their precurso:rs I-Ill were characterized by their physical (Table 1) and chemical properties, a.nd their structures confirmed by NMR, mass and infrared spectroscopy (Tables 3-5). The histaminolytic and anticholinergic effects of A 2 and C 2 were investigated and compared with some structure-activity relationships of analogue carbon compounds.
Sila-ana.logues A 2 and B 2 of two drugs from the benzhydryl ether class, chlorphenoxamine and clofenetamine, were synthesized for the first time by the steps shown in scheme 1. They and their precursors I-VI v;rere characterized by their physical (Table 1) and chemical properties and their structures confirmed by n.m.r., mass and infrared spectroscopy (Tab]es 2-5). Their physiological effects were invest.igated and compared with those of the carbon analogues (Chapter 5).
Sila-Chlorphencyclan (8b), ein Sila-Analogon des Chlorphencyclans (8a), die Derivate 7 und 9, deren Ammoniumsalze 11, 12, 13 und 14b, das Hydrolyseprodukt 10 sowie die Vorstufen 3-6 wurden erstmalig dargestellt. Die neuen Verbindungen wurden in ihren chemischen und physikalischen Eigenschaften charakterisiert, ihre Struktur wurde sichergestellt. Chlorphencyclan, Sila-Chlorphencyclan und einige seiner Derivate wurden vergleichend pharmakologisch und toxikologisch untersucht.
Die Umsetzung von Diphenyl-vinylsilan mit zyklischen sekundären Aminen (z.B. Morpholin) in Gegenwart der entsprechenden Lithium-amide führt zu einer Substitution des an Silicium gebundenen H-Atoms durch eine Aminogruppe und zu einer Addition des Amins an die Vinylgruppe. 2-Thienylphenyl- vinylsilan reagiert jedoch zusätzlich unter Spaltung der Si-e-Bindung und Aminosubstitution der 2-Thienylgruppe.
A method was developed to detennine the affinities of antimuscarinic drugs at M\(_1\) receptors. [\(^3\)H](±)-Telenzepine served as radioligand in crude preparations of calf superior cervical ganglia and showed high affinity for a single receptor population. consisting of M1 receptors (K\(_D\) = 1.12 nM). Kinetic experiments showed monophasic association (k\(_1\) =0.017 min\(^{-1}\) nM\(^{-1}\) ) and dissociation (k\(_1\) = 0.017 min\(^{-1}\) ) kinetics, the half-life of dissociation being 41 min at 37°C. The kinetie K\(_D\) value amounted to 1.00 nM. M\(_1\) affinities for pirenzepine, methoctramine. hexahydro-sila-difenidol and p-fluoro-hexahydro-sila-difenidol detennined in competition experiments were similar to those found in functional studies with MI receptors in rabbit isolated vas deferens. The binding assay was used to deterriline the affinities of the (R) and (S) enantiomers of tertiary (trihexyphenidyl, hexahydro-difenidol. hexbutinol, p-fluoro-hexbutinol) and quatemary musearlnie antagonists (trihexyphenidyl methiodide. hexbutinol methiodide). Comparison of results obtained with the rabbit vas deferens suggested that the ionic environment may influence the affinities.
The present study served to investigate the ability of seven selective muscarinic antagonists to inhibit carbachol-induced drinking in the rat. The muscarinic antagonists were given by intracerebroventricular (i.c.v.) injection 1 min before the i.c.v. injection of carbachol (1 \(\mu\)g/rat). The M\(_2\) antagonist, methoctramine, was inactive up to 80.3 nmol/rat. The M\(_3\) antagonist, p-fluoro-hexahydro-sila-difenidol, elicited a modest (42%) but statistically significant inhibition of drinking only at 80 nmol/rat. On the other band, the selective M\(_1\) antagonists, (R)-trihexyphenidyl, o-methoxy-sila-hexocyclium and pirenzepine, produced a marked and dose-dependent inhibition of carbachol-induced drinking, their 1050 values being 0.51. 7.36 and 9.31 nmoljrat. Also the M\(_1\)/M\(_3\) antagonists, 4-diphenylacetoxy-Nmethylpiperidine methiodide and hexahydro-sila-difen.idol, were potent inhibitors of carbachol-induced drinking, their ID\(_50\) values (0.28 and 11.09 nmoljrat) being related to their pA\(_2\) values for M1 receptors in rabbi t vas deferens. These data suggest that carbachol-induced drinking may be mediated by activation of muscarinic M\(_1\) receptors.
Es wird die Reaktivität eines hochgespannten und reaktiven [1],[1]-Disilamolybdänocenophanes gegenüber ungesättigten Substraten, E–H Funktionen und E–E-Bindungen untersucht. Die Produkte wurden mittels spektroskopischer Methoden in Lösung sowie im Festkörper identifiziert und charakterisiert. Weiterhin wird die Reaktivität eines [2]-Disilamolybdänocenophanes ebenfalls gegenüber ungesättigten Substraten und E–E-Bindungen sowie gegenüber Pt(0)-Verbindungen erforscht. Die erhaltenen Komplexe wurden sowohl im Festkörper, als auch in Lösung spektroskopisch untersucht und charakterisiert.
Die Reaktivität von Diboranen(4) (1,2-Dihalogendiboranen(4)) gegenüber von metallischen und nicht-metallischen Lewis-Basen wurde untersucht. Die Ergebnisse zeigen, dass die oxidative Addition einer Bor-Halogen-Bindung an ein Platin(0)-Komplex selektiv verläuft und in trans-Diboran(4)yl-Bisphosphan-Platin-Komplexen resultiert. Bei Verwendung von 1,2-Dihalogen-1,2-diaryldiboranen(4) findet sich in den korrespondierenden trans-Diboran(4)yl-Platin-Komplexen eine dative Bindung des Platin-Zentralatoms zum entfernten zweiten Bor-Atom, welche sowohl in Lösung als auch im Festkörper beobachtet wird. Die erhaltenen trans-Diboran(4)yl-Komplexe wurden auf ihre Reaktivität untersucht, hierbei konnte erstmals durch Reduktion ein Diboren-Platin-Komplex synthetisiert werden. Die Untersuchung der Reaktivität von nicht-metallischen Lewis-Basen ergab eine Reihe von sp2-sp3-Diboranen an die entweder PEt3 oder PMeCy2 koordiniert ist. In Abhängigkeit des sterischen Anspruches finden sich zwei Isomere mit 1,2- und 1,1'-Anordnung der Halogene. Die 1,2-Isomere zeigen hierbei im Festkörper eine Bor-Halogen-Bor-Brücke mit einer dativen Halogen-Bor-Bindung zwischen dem Halogen und dem sp2-Borzentrum.
The present study was designed to further charaeterize the presynaptie musearlnie M\(_1\)-reeeptor responsible for the inhibition of neuragenie eontraetions in the isolated rabbit vas deferens. Eleetrically induced twiteh eontraetions of this preparation were inhibited by the M\(_1\)-agonist, MeN-A-343, and by some of its analogs: 4-ehloro-phenyl derivative> MeN-A-343 > trans-olefinie analog> cis-olefinie analog. The same rank order of potency was observed for these agonists to raise the blood pressure of pithed rats by stimulation of M\(_1\)-receptors in sympathetie ganglia. A highly signifieant eorrelation was found between the antimusearinie potencies of atropine, pirenzepine and a series of 9 antagonists strueturally related to the ganglionie M\(_{1\beta}\)-receptor selective compounds, hexocyclium and hexahydro-difenidol, to antagonize the MeN-A-343-indueed inhibition of twitch eontraetions in rabbit vas deferens or the musearine-indueed depolarization in rat isolated superior eerVieal ganglia. It is suggested that the presynaptie musearlnie receptor that mediates inhibition of neuragenie contraetions in rabbit vas deferens is of the ganglionic M\(_{1\beta}\)-type.
Pharmacokinetic properties of the antimuscarinic drug [\(^3\)H]-hexahydro-sila-difenidol in the rat
(1990)
The pharmacokinetics of tritiated hexahydrosila- difenidol ([\(^3\)H]-HHSiD) were examined in rats. Furthermore, the distribution of radioactivity was studied by means of whole body autoradiography. After i. v. administration of 2.9 mg/kg HHSiD plus [\(^3\)H]-HHSiD to anaesthetized rats bearing a catheter implanted in the ductus choledochus and receiving a mannitol infusion, HHSiD was rapidly distributed and metabolized. Only 5% ofthe radioactivity was recovered in blood after 23 s and 0.4% after 2.5 h. 64% of the plasma radioactivity could be extracted with hexane from the samples taken 23 s after administration. 52% of the radioactivity was eliminated within 2.5 h, 13% by urinary and 39% by biliary excretion. Following oral administration of 8.6 mg/kg HHSiD plus [\(^3\)H]-HHSiD there was an absorption of approximately one fourth of the administered radioactivity within 4 h. By means of whole body autoradiography (i. v. injection) as well as by tissue distribution measurement the highest Ievels of radioactivity were found in bile, urine, lung, kidney, adrenals, liver and .pancreas. Thus, after i. v. administration to rats HHSiD is rather quickly distributed, metabolized and excreted. This explains its low antimuscarinic potency in vivo.
Novel pharmacological profile of muscarinic receptors mediating contraction of the guinea-pig uterus
(1990)
The present study was designed to further characterize the muscarinic receptors mediating contraction of the guinea-pig uterus. The affinities of various selective muscarinic antagonists were determined and compared with those obtained at M\(_1\) (rabbit vas deferens), M\(_2\) (guinea-pig atria) and M\(_3\) receptors (guinea-pig ileum). The contractile responses of uterine smooth muscle from immature guinea-pigs to carbachol (pD\(_2\) = 5.73) were competitively antagonized by pirenzepine (pA\(_2\) = 7.04), AF-DX 116 (11-[[2-[(diethylamino)methyl]-1-piperidinyl] acetyl]- 5,11-dihydro-6H -pyrido[2,3-b][1 ,4]benzo. diazepin-6-one) (pA\(_2\) = 6.96), himbacine (pA\(_2\) = 7.92), methoctramine (pA\(_2\) = 7.52), 4-DAMP (4-diphenylacetoxy- N-methylpiperidine methiodide) (pA\(_2\) = 8.87) and sila-hexocyclium (pA\(_2\) = 8.81). A comparison of affinity values indicates that the muscarinic receptors present in guinea-pig uterus display a novel pharmacological profile which is not consistent with the presence of either an M\(_1\), M\(_2\) or M\(_3\) receptor. The affinities determined for the different antagonists rather showed a close similarity to those obtained at muscarinic receptors present in rat striatum and NG108-15 cells which are considered pharmacological equivalents (M\(_4\) receptors) of the m4 gene product. We thus hypothesize that the guinea-pig isolated uterus preparation may serve as a simple functional assay system to study the pharmacology of M\(_4\) receptors.
The zwitterionic spirocyclic \(\lambda_5\) -Silicates bis(3,4,5,6-tetrabromo- 1,2-benzenediolato(2- ))[2-(pyrrolidinio)ethyl]silicate (5; and its monohydrate 5 · H\(_2\)O) and bis[1,2-benzenediolato(2- )][( dimethylammonio)methyl]silicate (6) were synthesized by various methods including Si-C bond cleavage reactions. The crystal structures of 5, 5 · H\(_2\)O, and 6 were investigated by Xray düfraction. Furthermore, 5, 5 · H\(_2\)O, 6, and the related zwitterionic \(\lambda_5\)-spirosilicates 1 · 1/4 CH\(_3\)CN, 2 · CH\(_3\)CN, 3 · CH\(_3\)CN, and 4 were characterized by solid-state NMR spectroscopy (\(^{29}\)Si and \(^{15}\)N CP/MAS). The pentacoordinate silicon atoms of 5, 5 · H\(_2\)O (two crystallographically independent ZWitterions and two crystallographically independent water molecules), and 6 (two crystallographically independent zwitterions) are surrounded by four oxygen atoms and one carbon atom. The coordination polyhedrons around the silicon atoms of 5 and 6 can be described as distorted (5) or nearly ideal (6) trigonal bipyramids, the carbon atoms being in equatorial positions. 5 forms intramolecular and 6 intermolecular (--+ formation of dimeric units) N- H···O hydrogen bonds. The coordination polyhedrons around the two crystallographically independent silicon atoms of 5 · H\(_2\)O can be described as a nearly ideal and slightly distorted square pyramid, respectively, the carbon atoms being in the apical positions. In the crystal lattice of 5 · H\(_2\)O, intermolecular N-H···O and 0-H···O hydrogen bonds between the zwitterions and water molecules are observed. The results obtained by X-ray diffraction and solid-state NMR spectroscopy are consistent for each compound studied.
Die quartären Ammoniumsalze 1-10 einiger bioaktiver Sila-benzhydryläther wurden erstmalig durch Reaktion der entsprechenden freien Basen A-E mit CH\(_3\)J, CH\(_3\)Br bzw. CH\(_3\)Cl in CH\(_3\)CN dargestellt. Die Strukturen von 1-10 wurden durch Elementaranalysen und 1 H-NMR-Spektren bestätigt. Die pharmakologischen Effekte einiger Verbindungen wurden sowohl mit den Eigenschaft der entsprechenden freien Basen als auch mit einigen Struktur-Wirkungsbeziehungen analoger Kohlenstoffverbindungen verglichen.
Cholinergie agents arepotent modulators of insulin release that aet via musearinie reeeptors. We now investigated the muscarinic receptor subtype present in rat panereatic islets in binding and funetional studies. Binding of 5 nM [ \(^3\)H]N-methylscopolamine ([\(^3\)H]NMS) was half maximal at 30 min. At 60 min, the maximal total bindingwas 1.29% and the non-specifie binding (presence of 100 ,uM atropine) was 0.18% of the total radioaetivity per 10 f.'g islet protein. Unlabelled atropine inhibited [\(^3\)H]NMS binding with an IC50 of ca. 30 nM. The rank order of antagonist high-affinity binding was atropine > sila-hexocyelium methyl sulfate (SiHC; M\(_1\) > M\(_3\) > M\(_2\) ) > pirenzepine (M\(_1\)> M\(_2\) = M\(_3\) ) = methoctramine (M\(_2\) > M\(_1\) > M\(_3\) ). The high-affinity K\(_d\)s were 8.5, 56, 1300 and 1300 nM, respectively. The high affinity Kd of the muscarinie receptor agonist, arecaidine propargyl ester (APE), was 8.1 nM. The EC\(_{50}\) for the biologieal effects of APE on insulin and glucagon secretion was 3.2 and 2.3 nM. The rank order for the high-affinity biological effects of antagonists (inhibition of APE-mediated insulin/ glucagon release) was almost the same as for binding. The data indicate that rat pancreatie islets contain neither an M\(_1\) subtype (high-affinity for pirenzepine) nor an M\(_2\) subtype (high-affinity for methoctramine) receptor. However, the data evidence an M\(_3\) receptor subtype, since SiHC in the absence of the M\(_1\) receptor subtype shows a relatively high affinity to the receptors in rat panereatic islets.
Die Kristall- und Molekülstrukturen der Akarizide Chlortrineophylstannan (Ia), Chlortris[ ( dimethylphenylsilyl)methyl]stannan (tb) und Trineophyl(1,2,4-triazol-1- yl)stannan-hemihydrat (2a · 0.5H\(_2\)0) wurden durch Einkristall-Röntgenstrukturanalysen bestimmt. Zu V ergleichszwecken wurde ausserdem die Struktur des 2,5-Dimethyl-2,5-diphenylhexans (Bineophyl, 4) untersucht. Die Knüpfung von drei sehr raumerfüllenden N eophyl-Resten an ein Zinnatom führt zu einer deutlichen Verzerrung der tetraedrischen Geometrie [ta: C-Sn-C 117.2°, C-Sn-Cl99.7°; 2a·0.5H20: C-Sn-C 116.9° (Mittelwert), C-Sn-N 100.2° (Mittelwert)]. Austausch der zentralen Kohlenstoffatome in den Neophyt-Substituenten von la durch Siliciumatome führt zu einer Verringerung des Raumbedarfs und dadurch zu einer erkennbaren Angleichung an die tetraedrische Geometrie [lb: C-Sn-C 113.3° (Mittelwert), C-Sn-Cl 105.3° (Mittelwert)].
No abstract available
The zwitterionic dispirocyclic \(\lambda^5\)Si,\(\lambda^5\)Si'-disilicate meso-[1 ,4-piperaziniumdiylbis( methylene)]bis{ bis[ 2-methyllactato(2-)-O\(^1\),O\(^2\)]silicate} octahydrate (6-8H\(_2\)O) was synthesized by reaction of 1,4-bis[(trimethoxysilyl}methyl] piperazine (8) with 2-methyllactic acid (molar ratio 1:4) in water/acetone (yield 82%). The molecular dinuclear silicon(IV) complex 6 contains two pentacoordinate (formally negatively charged) silicon atoms and two tetracoordinate (formally positively charged) nitrogen atoms. The crystal structure of 6•8H20 was studied by X-ray diffraction.
Durch Umsetzung der jeweiligen Chiaraphosphane mit den entsprechenden Natriumdithiocarbamaten können folgende Verbindungen erhalten werden: Verbindungen des Typs RP(S\(_2\)CNR\(_2\)')\(_2\) mit R = CH\(_3\), C\(_6\)H\(_5\); R' = CH\(_3\) , C\(_2\)H\(_5\), CH(CH\(_3\))\(_2\). C\(_6\)H\(_5\) ; Verbindungen des Typs (C\(_6\)H\(_5\)) \(_2\)PS\(_2\)CNR\(_2\) mit R' = CH\(_3\) , CH(CH\(_3\))\(_2\) sowie [(C\(_6\)H\(_5\)))\(_2\)PS\(_2\)CN(CH\(_3\))CH\(_2\)--]\(_2\). Die Kristallstruktur von C\(_6\)H\(_5\)P(S\(_2\)CN(C\(_2\)H\(_5\))\(_2\))\(_2\) zeigt, daß sich der Trend zu schwächer ausgeprägter zweizähniger Bindungsweise der Dithiocarbamatliganden in der homologen Reihe RE(S\(_2\)CN(C\(_2\)H\(_5\))\(_2\))\(_2\); E = Bi, Sb, As, P für E = P fortsetzt.
Isoelectronic derivatives (A and B) and a homolog (C) of the two sila-antihistamines sila-clofenetamine and silamebrophenhydramine were synthesized for the first time by the steps shown in scheme 1. They and their unknown precursors II-IV were characterized by their physical (Table 1) and chemical properties and their structures confinned by lH-NMR and rnass spectroscopy (Tables 2 and 3). The pharrnacological effects of A and B were investigated and compared with those of the corresponding 0-isosteric sila-antihistarnines (Chapter 5).
Five different musearlnie receptor subtypes ean be distinguished by the differenees in their amino aeid sequence, the eoupled signal transduetion system, pharmaeologieal binding properties and aetivation of ionie fluxes. The present study served to eharaeterize the binding profile of musearlnie receptors in human eolon eareinoma eells (HT-29) using seleetive musearlnie antagonists. The affinities of the compounds were eompared with their poteney to inhibit cholinergieally-aetivated phosphoinositide metabolism. Pirenzepine displaced [\(^3\)H]N-methyl-scopolamine binding and inhibited inositolphosphate (IP) release with potencies typieal of those of non-M\(_1\) receptors. The M\(_3\) subtype-selective antagonists sila-hexocyelium and hexahydro-sila-difenidol bad high affinity to the musearlnie reeeptors in HT-29 cells (K0 = 3.1 nM and 27 nM, respectively) and inhibited IP release at nanomolar concentrations. The M\(_2\) receptor antagonists, AF-DX 116 and methoctramine, had low antimusearinic poteneies. Our results demonstrate that HT-29 human colon earcinoma cells contain an apparently pure population of M\(_3\) receptors. These cells could serve as a model system for further investigations coneerning regulatory and signal transduction mechanisms associated with glandular muscarinic M\(_3\) receptors.
No abstract available
Acetyldimethylphenylsilan (2) reagiert bei Raumtemperatur mit TBAF · 3H\(_2\)O in THF bzw. mit KF in DMSO/H\(_2\)O zu [(CH\(_3\))\(_2\)SiO]\(_x\) und 1-Phenylethanol (3), welches mit praktisch quantitativer Ausbeute isoliert werden kann. Dieses Reaktionsverhalten von 2 gegenüber F\(^-\) weicht drastisch ab von dem in der Literatur beschriebenen Verhalten einiger Aroyl- und Heteroaroyltrimethylsilane. Ein Reaktionsmcchanismus, der u.a. eine 1,2-Phenylverschiebung und eine BrookUmlagerung beinhaltet, wird zur Diskussion gestellt.
Twenty silanes of the type R\(^1\)R\(^2\)Si(H)CH\(_2\)OR\(^3\) (A) were syn- and entropy of activation) of these reactions were studied by thesized {R\(^1\), R\(^2\) = Me, Ph, 1-naphthyl, PhCH\(_2\), Me\(_3\)SiCH\(_2\); OR\(^3\) means of düferential scanning calorimetry (DSC). In addition, = OC(O)Me, OC(O)Ph, OC(O)CF\(_3\) , OS(0)\(_2\)CF\(_3\), OP(O)Ph\(_2\), the kinetics of all reactions were investigated by 1H-NMR OC(O)Cl, and studied for their thermal behaviour. The silanes spectroscopy. The transition state of the rearrangement was A undergo a thermally induced rearrangement to give the investigated by an ab initio study based on the model comcorresponding silanes R\(^1\)R\(^2\)Si(OR\(^3\))Me (B). For compounds with pound H\(_3\)SiCH\(_2\)OC(O)H (-> MeH\(_2\)SiOC(O)H]. The theoretical OR3 = OC(O)Cl, an additional decarboxylation takes place to data and the experimentally obtained energetic and kinetic yield the chlorosilanes R1R2Si(Cl)Me. Except for the deriva- data are discussed in terms of mechanistic aspects of the retives with OR\(^3\) = OC(O)Cl, the energetic (reaction enthalpy) arrangement reaction A -> B. and kinetic data (reaction order, frequency factor, enthalpy ...
Die Synthese des (Hydroxymethyl)[(trimethylsilyl)methyl]silans (3) sowie des hiervon abzuleitenden Acetats 4 und Chlorformiats 6 wird beschrieben. 4 und 6 unterliegen einer thermisch induzierten Umwandlung zu den difunktionellen Silanen 5 bzw. 8. Die Umwandlungen 4 -> 5 und 6 -> 8 erfolgen gemäß einer Kinetik 1. Ordnung mit Halbwertszeiten von 10.0 bzw. 3.6 h (135 ° C, in C\(_6\)D\(_6\)).
Thirty strains of microorganisms (bacteria, yeasts, fungi and green algae) were tested as resting free cells for their ability to transform acetyldimethylphenylsilane (1) enantioselectively into (R)-(1-hydroxyethyl) dimethylphenylsilane [(R)-2]. The biotransformations were monitared by GC (packed OV-17 column), and the enantiomeric purities of the products isolated were determined by HPLC (cellulose triacetate column, UV detection). All microorganisms tested were found to reduce 1 enantioselectively to give (R)-2. Under the test conditions used, the yeast Trigonapsis variabilis (DSM 70714) was found to 1 exhibif the highest specific activity (1.5 mg product x g cell wet mass\(^{-1}\) x min\(^{-1}\) ), whereas the highest enantioselectivities were observed for the bacteria Acinetobacter ca lcoaceticus (ATCC 31012) (>95% ee), Brevfbacterium species (ATCC 21860) (90% ee) and Corynebacterium dioxydans (ATCC 21766) (>95% ee), the yeast Candida humico la (OSM 70067) (90% ee), the fungus Cunninghame lla e legans (ATCC 26269) (94% ee), as well as the cyanobacterium Synechococcus leopoliensis (94% ee).· From the green algae tested, Chlamydomonas reinhardii showed the highest.enantioselectivity (85% ee).
Enantioselective reduction of acetyldimethylphenylsilane by Trigonopsis variabilis (DSM 70714)
(1987)
Growing and resting cells of the yeast Trigonapsis variabilis (DSM 70714) can be used for the enantioselective reduction of the organosilicon compound acetyldimethylphenylsilane (J) to give optically active (R)-(1-hydroxyethyl)dimethylphenylsilane [(R)-2] in good yields. The enantiomeric purity of the isolated product was determined tobe 62-86% ee depending on the substrate concentration used. Both substrate and product caused an inhibition of the reaction at concentrations higher than 0.35 and 0.5 g/1, respectively. Besides, higher substrate and product concentrations led to increased formation of the by-product 1,1,3,3-tetramethyl-1,3-diphenyldisiloxane. Considering the limiting substrate and product concentrations, it was possible to use the same biomass at least 5 times without significant loss of enzyme activity. 3-Methyl-3-phenyl-2-butanone (5) and acetyldimethylphenylgermane (7), which represent carbon and germanium analogues of 1, were also found to be accepted as substrates by Trigonapsis variabilis (DSM 70714). The reduction rates of the silicon {1) and germanium compound {7) were much higher than the transformation rate of the corresponding carbon analogue 5.
(R)-1,1-Dimethyl-1-sila-cyclohexan-2-ol [(R)-2] was prepared by enantioselective microbial reduction of 1,1-dimethyl-1-sila-cyclohexan-2-one (1) with growing cells of the yeast Kloeckera corticis (ATCC 20109). At a substrate concentration of 0.5 g/1 (temperature 27° C, incubation time 16 h), (R}-2 was obtained on a preparative scale in 60% yield and with an enantiomeric purity of 92% ee. Repeated recrystallization of the biotransformation product from n-hexane raised the enantiomeric purity to 99% ee.
The enantiomers of the antimuscarinic agent 1-cyclohexyl-1- (4-fluorophenyl)-4-piperidino-1-butanol [(R)- and (S)-p-fluorohexahydro- difenidol] ((R)- and (S)-2a] and their methiodides (R)- 3 and (S)-3 were prepared with high enantiomeric purity. (R)- 2a and (S)-2a (isolated as hydrochlorides) were obtained by catalytic hydrogenation (Pd/C contact) of the corresponding enantiomers of 1-cyclohexyl-1-( 4-fl uorophen yl)-4-piperidino- 2-butyn-1-ol [(R)- and (S)-4]. Reaction of (R)-2a and (S)-2a with rnethyl iodide led to (R)-3 and (S)-3, respectively. The unsaturated precursors (R)- and (S}-4 (enantiorneric purity ~ 99.80 and ~99.94% e.e.; calorimetric analysis) were prepared by res-sepaolution of rac-4 [available from 4-FC\(_6\)H\(_4\)C(O)C\(_6\)H\(_{11}\) by reaction with LiC ~ CCH\(_2\)NC\(_5\)H\(_{10}\)] using (R)- and (S)-mandelic acid as resolving agents. The absolute configurations of the (R) and (S) enantiomers of 2a, 3, and 4 were determined by an X-ray crystal-structure analysis of (S)-5, the methiodide of (S)-4. (R)- 2a and (R)-3 exhibit a higher affinity for muscarinic M1, M2, M3, and M4 receptors (by up to two orders of magnitude) than their corresponding antipodes (S)-2a and (S)-3, the degree of stereoselectivity depending on the receptor subtype involved. (R)-2a represents a useful tool for rnuscarinic receptor research (affinity profile: M1 ~ M3 ~ M4 > M2).
A new in situ preparation of trimethylsilyl trifluoromethanesulfonate (3) is described: 3 is generated by a thermally induced rearrangement of (dimethylsilyl)methyl trifluoromethanesulfonate (2), which can be prepared by reaction of (CH\(_3\))\(_2\)Si(H)CH\(_2\)OH (1) with (CF\(_3\)SO\(_2\))\(_2\)O. Starting with C\(_6\)H\(_5\)(CH\(_3\))Si(H)CH\(_2\)OH (5), the derivative (methylphenylsilyl)methyl trifluoromethanesulfonate (6) can be obtained by a similar method. Its thermally induced rearrangement Ieads to dimethylphenylsilyl trifluoromethanesulfonate (7). The rearrangements 2---> 3 and 6---> 7 were found to be first-order reactions with half-lifes at 80 oc of 0.75 and 1.7 h, respectively.
No abstract available
Derivatives A and B of the two sila-antihistam.ines silamephenhydramine and sila-chlorphenoxamine were synthesized for the first time by the steps shown in scheme 1. They and their precursors III and IV were characterized by their physical (Table 1) and chemical properties and their structures confirmed by NMR and mass spectroscopy (Tables 2 and 3). Their pharmacological effects were investigated and compared with those of the corresponding sila-antihistamines.
Die Darstellung der Verbindungen 3a (sowie 3b) und 10, die sich vom 1-(4-Chlorphenyl)-1-(2~ diethylaminoethoxy)silacyclohexan (Sila-Chlorphencyclan, II a) ableiten, wird beschrieben. Die Verbindung 3 b wurde pharmakologisch und toxikologisch untersucht. Die biologischen Eigen· schaften von 3b wurden mit denen von Ila (sowie Chlorphencyclan) und seinem Hydrochiarid Ilb verglichen.
No abstract available
Die Synthese der Organosilicium· Verbindungen 3 a- d wird erstmalig beschrieben. Sie wurden durch ihre physikalischen, chemischen und pharmakologischen Eigenschaften charakterisiert. Ja- d wirken als uKurzzeit-Muskelrelaxantien", deren Entgiftung durch Hydrolyse der Si- OeBindungen (Sollbruchstellen) erfolgt.
Die potentiell curarewirksamen Silicium-Verbindungen Sa, Sc, Sd, Sg, Sh und 9a-9d wurden dargestellt. \(^1\)H-NMR-spektroskopische Untersuchungen ergaben Informationen über die Konformationen von 5 a- Sc in Lösung. Die Kristall- und Molekülstruktur von 5 c wurde röntgenstrukturanalytisch bestimmt. Die muskelrelaxierenden Eigenschaften von S a- 5 h und 9 a-9 d wurden vergleichend an der Maus (i.v., LD50-Werte) untersucht. Die ermittelten Struktur-WirkungsBeziehungen werden in Hinblick auf die unterschiedlichen kovalenten Radien des Kohlenstoffund Siliciumatoms und die hieraus resultierenden N ... N-Abstände diskutiert.