6712-12-5Relevant academic research and scientific papers
Novel Potassium-Channel Openers: Preparation and Pharmacological Evaluation of Racemic and Optically Active N-(6-Amino-3-pyridyl)-N'-bicycloalkyl-N"-cyanoguanidine Derivatives
Eda, Masahiro,Takemoto, Tadahiro,Ono, Shin-ichiro,Okada, Takehiro,Kosaka, Keigo,et al.
, p. 1983 - 1990 (2007/10/02)
The previous paper reported on the synthesis and pharmacological evaluation of N-(6-amino-3-pyridyl)-N'-bicycloalkyl-N"-cyanoguanidine derivatives, from among which three compounds were selected as potent potassium-channel openers. In the present study, selected compounds were tested for antagonism of potassium-induced contraction of rat aorta, hypotensive activity in normotensive rats, and diuretic activity in spontaneously hypertensive rats. This led to further evaluation of compound (+/-)-10 and selection of (+)-N-(6-amino-3-pyridyl)-N'-hept-2-yl>-N"-cyanoguanidine ((+)-10) (AL0670) for development as an antihypertensive agent. Although AL0670 is regarded as a pinacidil-type K+-channel opener, it showed different pharmacological and conformational profiles from pinacidil.
Rearrangements of 5- and 6-Cyano-2-norbornyl Cations
Fermann, Michael,Herpers, Ekkehard,Kirmse, Wolfgang,Neubauer, Regina,Renneke, Franz-Josef,et al.
, p. 975 - 984 (2007/10/02)
Hydroboration of the 5-norbornene-2-carbonitriles 11 afforded 5- and 6-hydroxynorbornane-2-carbonitriles (9a, 10a) along with the analogous ketones 12, 13. 5- and 6-aminonorbornane-2-carbonitriles (17a, 18a) were obtained either from the endo-brosylates 1
Enzymatic Preparation of Optically Active Bicycloheptene Derivatives, Building Blocks of Terpenoid Natural Products. An Attractive Alternative to Enantioselective Diels-Alder Syntheses
Eycken, J. Van der,Vandewalle, M.,Heinemann, G.,Laumen, K.,Schneider M. P.,et al.
, p. 306 - 308 (2007/10/02)
Bicycloheptene derivatives (1)-(3), building blocks of terpenoid natural products, have been prepared with high enantiometric purities by enzymatic hydrolysis of their racemic esters in the presence of porcine liver esterase (PLE) and an ester hydrolase from Pseudomonas sp. (SAM-II).
Synthesis of 2,5- and 2,6-Norbornane Derivatives with Prostaglandin-like Side Chains
Davies, David I.,Gomez, Peter M.,Hallett, Peter
, p. 843 - 848 (2007/10/02)
Norborn-5-en-2-endo-ylmethyl toluene-4-sulphonate, readily prepared from Diels-Alder adduct of cyclopentadiene and acrylic acid, has been converted, in six and seven stages respectively, into the prostaglandin-like compounds 2-endo-(6-carboxyhex-2-enyl)norbornan-5- and -6-exo-yl 2-hydroxyheptyl ethers.The synthesis of the former compounds involves a novel hydroxyethoxy mercuriation of a norbornene double bond.
Carbon Participation in the Solvolysis of 6-exo-substituted 2-exo- and 2-endo-Norbornyl p-Toluenesulfonates. Norbornanes Part 5
Fischer, Walter,Grob, Cyril A.,Hanreich, Reinhard,Sprecher, Georg von,Waldner, Adrian
, p. 2298 - 2311 (2007/10/02)
The solvolysis rates and products of the 6-exo-substituted 2-exo- 1a-1u, and 2-endo-norbornyl p-toluenesulfonates 2a-2u, have been determined.In general, the rate constants for 1 and 2 (log k) correlate well with the inductive constants ?qI of the substituents at C(6); however, their sensitivity to ?qI is much larger in the 2-exo-series 1 than in the 2-endo-series 2.This differential transmission of polar effects is the cause of decreasing 2-exo/2-endo rate ratios from 2388 for R=t-C4H9 to 0.37 for R=Br, i.e., with increasing electron attraction by the substituent.The high sensitivity of the rate constants for the 2-exo-p-toluenesulfonates 1 to ?qI indicates an unusually strong inductive interaction between C(6) and the incipient cationic center at C(2).This interaction is ascribed to the participation of the pentacoordinate C(6)-atom, i.e. to 1,3-bridging, a consequence of steric hindrance of nucleophilic solvent participation in norbornanes.Donor substituents enhanche 1,3-bridging, lead to faster reactions and to the formation of 2-exo substitution products.Conversely, acceptor substituents reduce 1,3-bridging, decrease rates and facilitate the formation of 2-endo substitution products.Graded 1,3-bridging is discussed in the light of Winstein's nonclassical ion concept.
Die Hydrolyse von 6exo-substituierten 2exo- und 2endo-Norbornylestern der p-Toluolsulfonsaeure
Fischer, Walter,Grob, Cyril A.,Sprecher, Georg von,Waldner, Adrian
, p. 928 - 937 (2007/10/02)
Hydrolysis of the 6exo-substituted 2exo- and 2endo-norbornyl p-toluenesulfonates 1b-l and 2b-l, respectively, in 70percent dioxane led to different amounts of the following products: Unrearranged 2exo-norbornanols 3 and norbornenes 5, accompained in somes cases by small amounts of the rearranged Rendo-epimers 4 and 6 and by nortricyclenes 7.When the 6exo-substituent was a nucleophile group as in 1e-l and 2e-l, various amounts of tricyclic products were also formed by endo-cyclozation.These results show that the 2exo- and 2endo-esters 1 and 2, respectively, react by way of different intermediates.In cases where the 6exo-substituent was an n-electron donor, as in 1m-r and 2m-r, quantitative fragmentation to (3-cyclopentenyl)acetaldehyde (13) occurred.
Hydroxy-group Participation in the Hydrolysis of Amides and its Effective Concentration in the Absence of Strain Effects
Morris, Jeffrey J.,Page, Michael I.
, p. 679 - 684 (2007/10/02)
Rate constants are reported for the alkaline- and acid-catalysed hydrolysis of endo-6-hydroxybicycloheptane-endo-2-carboxamides in aqueous solution.The product of the acid-catalysed reaction is endo-6-hydroxybicycloheptane-endo-2-carboxylic acid lactone and this lactone is also formed as an intermediate in alkaline solution before giving the hydroxy-acid anion as the product.The effective concentration of the intramolecular alkoxide ion group is ca. 1E8M.This is in good agreement with the maximum entropic advantage predicted for intramolecular reactions as the system is thought to be free of major strain energy and solvation effects.Variation of substituents in the amine leaving group gives a βlg value of +0.30 for the hydroxide-ion-catalysed lactonisation reaction.This is interpreted in terms of rate-limiting breakdown of the tetrahedral intermediate in which there is cconsiderable positive charge on the amine nitrogen.Mechanisms consistent with this involve either proton transfer from water to the amine nitrogen occuring synchronously with carbon-nitrogen bond fission or a stepwise process in which the nitrogen of the tetrahedral intermediate is fully protonated and the rate-limiting step is either diffusion apart of this intermediate and hydroxide ion or collapse of this intermediate with hydroxide ion acting as a 'spectator'.The βlg value for the acid-catalysed lactonisation reaction is 0.0.
Structure-Reactivity Relationships and the Mechanism of General Base Catalysis in the Hydrolysis of a Hydroxy-amide. Concerted Breakdown of a Tetrahedral Intermediate
Morris, Jeffrey J.,Page, Michael I.
, p. 685 - 692 (2007/10/02)
Kinetic general base catalysis is observed in the lactonisation of N-substituted endo-6-hydroxybicycloheptane-endo-2-carboxamides.The reaction mechanism is thought to involve the kinetically equivalent general-acid-catalysed breakdown of the tetrahedral intermediate, T-.The Broensted β values for the catalysed lactonisation of the N-propyl- and N-trifluoroethyl-amides are 0.70 and 0.50, respectively which are equivalent to α values of 0.30 and 0.50, respectively.These values are indicative of a concerted reaction in which proton transfer occurs synchronously with carbon-nitrogen bond fission.The dependence of the rate of reaction of N-substituted amides upon the acidity of the catalyst shows that βlg decreases with increasing acidity of the catalyst.The behaviour of the observed structure-reactivity coefficients is discussed with the aid of energy diagrams and it is concluded that proton transfer makes a significant contribution to the reaction co-ordinate.The structure-reactivity coefficients also indicate a degree of charge imbalance in the transition state.
Intramolecular Nucleophilic and General Acid Catalysis in the Hydrolysis of an Amide. Some Comments on the Mechanism of Catalysis by Serine Proteases
Morris, Jeffrey J.,Page, Michael I.
, p. 1131 - 1136 (2007/10/02)
The lactonisation of N-(2-aminoethyl)-6-endo-hydroxybicycloheptane-2-endo-carboxamide shows a sigmoid pH-rate profile which is interpreted, kinetically, in terms of the hydroxide-ion-catalysed hydrolysis of the amide with the terminal amino-group unprotonated and protonated.Reaction of the latter species occurs with a rate enhancement of ca. 109 compared with an amide lacking the hydroxy- and protonated amino-groups.This is attributed to intramolecular nucleophilic and general acid-catalysis.The relative effectiveness of these two processes are compared and it is concluded that intramolecular general acid-catalysis makes a relatively minor contribution to the rate enhancement even though the breakdown of the tetrahedral intermediate is thought to be a concerted process.Some comments are made about the mechanisms proposed for the chymotrypsin-catalysed hydrolysis of amides and concerted breakdown of the tetrahedral intermediate is suggested as a possible mechanism.
