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A simple procedure for the preparation of 1,7-disubstituted-1,2,3,4-tetrahydroisoquinolines from 3,4-dihydroisoquinoline (2) is presented. This strategy overcomes the limitation of cyclisation appr...

A facile, two step synthesis of the 3-amino-5,6,7,8-tetrahydro[1,6]naphthyridine system 1 and its more substituted homologues 2–5 via the condensation of mono- and bicyclic-4-piperidinones 11a–c, 12–14 with 3,5-dinitro-1-methyl-2-pyridone 6 in the presence of ammonia is described.

3-Substituted hexahydroindeno[2,1-b]pyrroles were prepared in a stereoselective manner in high yield via an intramolecular azomethine ylide cycloaddition. Olefin geometry in the ylide precursor controlled the stereochemistry at the 3-position.

The radical ring-opening reactions of cyclopropyl ketones, mediated by samarium (II) iodide and other electron transfer agents are described. This strategy allows tandem rearrangement cyclisation reactions and the trapping of the resultant samarium (III) enolates by a variety of electrophiles, for the construction of complex bicyclic systems.

The radical ring-opening reactions of cyclopropyl ketones, mediated by samarium (II) iodide and other electron transfer agents are described. This strategy allows tandem rearrangement cyclisation reactions and the trapping of the resultant samarium (III) enolates by a variety of electrophiles, for the construction of complex bicyclic systems.

A series of N-(tetrahydroisoquinolinyl)-2-methoxybenzamides was identified by high-throughput screening at the novel SB-204269 binding site. SAR studies have provided compounds 4 and 14 with high affinity and good anticonvulsant activity in animal models.

3-Substituted hexahydroindeno[2,1-b]pyrroles were prepared in a stereoselective manner in high yield via an intramolecular azomethine ylide cycloaddition. Olefin geometry in the ylide precursor controlled the stereochemistry at the 3-position.

A facile, two step synthesis of the 3-amino-5,6,7,8-tetrahydro[1,6]naphthyridine system 1 and its more substituted homologues 2–5 via the condensation of mono- and bicyclic-4-piperidinones 11a–c, 12–14 with 3,5-dinitro-1-methyl-2-pyridone 6 in the presence of ammonia is described.

A simple procedure for the preparation of 1,7-disubstituted-1,2,3,4-tetrahydroisoquinolines from 3,4-dihydroisoquinoline (2) is presented. This strategy overcomes the limitation of cyclisation appr...

Regio- and stereospecific construction of bicyclic systems may be achieved by directed Simmons-Smith cyclopropanation of an allylic alcohol possessing a suitably positioned unsaturated acceptor, followed by a tandem free radical cyclopropylcarbinyl rearrangement-cyclisation reaction.

SAR studies around a series of N-(tetrahydroisoquinolinyl)-2-methoxybenzamides, identified by high-throughput screening at the novel SB-204269 binding site, have provided compounds such as 13, 29-33 with high affinity and excellent anticonvulsant activity in animal models.

For progression to clinical trials in stroke, putative neuroprotective compounds should show robust efficacy post-ischaemia in several experimental models of stroke. This paper describes the characterisation of (+)(1S, 2R)-cis-1-[4-(1-methyl-1-phenylethyl)phenoxy]-2-methylamino indane hydrochloride (SB-221420-A), a Ca(2+) and Na(+) channel antagonist. SB-221420-A inhibited (IC(50)=2.2 microM) N-type voltage-operated Ca(2+) channel currents in cultured superior cervical ganglion neurons, which were pretreated with 10 microM nimodipine to block L-type voltage-operated Ca(2+) channel currents. In dorsal root ganglion neurons pretreated with 1 microM omega-conotoxin GVIA to block N-type voltage-operated Ca(2+) channel currents, SB-221420-A inhibited the residual Ca(2+) current with an IC(50) of 7 microM. SB-221420-A also inhibited Na(+) currents in dorsal root ganglion neurons with an IC(50) of 8 microM. In rats, the pharmacokinetic profile of SB-221420-A shows that it has a half-life of 6.4 h, a high volume of distribution, is highly brain penetrating, and has no persistent metabolites. Following bilateral carotid artery occlusion in gerbils, SB-221420-A significantly reduced the level of ischaemia-induced hyperlocomotor activity and the extent of hippocampal CA1 cell loss compared to the ischaemic vehicle-treated group. SB-221420-A was also effective in focal models of ischaemia. In the mouse permanent middle cerebral artery occlusion model, SB-221420-A (10 mg/kg) administered intravenously, post-ischaemia significantly (P0.05) reduced lesion volume compared to the ischaemic vehicle-treated group. In the normotensive rat permanent middle cerebral artery occlusion model, SB-221420-A (10 mg/kg) administered intravenously over 1 h, beginning 30 min postmiddle cerebral artery occlusion, significantly (P0.05) reduced lesion volume from 291+/-16 to 153+/-30 mm(3), compared to ischaemic vehicle-treated controls when measured 24 h postmiddle cerebral artery occlusion. Efficacy was maintained when the same total dose of SB-221420-A was infused over a 6-h period, beginning 30 min postmiddle cerebral artery occlusion. SB-221420-A also significantly (P0.05) reduced lesion volume following transient middle cerebral artery occlusion in normotensive rats and permanent middle cerebral artery occlusion in spontaneously hypertensive rats (SHR). Investigation of the side effect profile using the Irwin screen in mice revealed that, at neuroprotective doses, there were no overt behavioural or cardiovascular changes. These data demonstrate that robust neuroprotection can be seen post-ischaemia with SB-221420-A in both global and focal ischaemia with no adverse effects at neuroprotective doses, and indicate the potential utility of a mixed cation blocker to improve outcome in cerebral ischaemia.

A series of N-(tetrahydroisoquinolinyl)-2-methoxybenzamides was identified by high-throughput screening at the novel SB-204269 binding site. SAR studies have provided compounds 4 and 14 with high affinity and good anticonvulsant activity in animal models.

Addition of ·CCl3 radicals to sabinene 1(R1= Pri) and a related bicyclo [4.1.0] derivative in BrCCl3 results in kinetic trapping of the exo ring opened intermediate but in CCl4 as solvent the major products are derived from the thermodynamically more stable endo radical; the radical and cationic regioselectivities are related to the features of a PM3 SCF-Mo orbital correlation diagram.