[formula: see text] 9-Substituted analogues of (-)-cytisine were synthesized in high yields via palladium-mediated couplings of either 9-(-)-bromocytisine and organostannanes or 9-(-)-trimethylstannylcytisine and fluorobromobenzene. The protection of the amine with a nitroso group and the use of PdCl2(PPh3)2 to carry out the Stille reaction allowed the rapid synthesis of 9-(4'-[18F]fluorophenyl)cytisine (18F: t1/2 = 109.7 min), a new promising radioligand (radiochemical yield: 10% from [18F]KF, 150 min, four steps) for positron emission tomography studies of alpha 4 beta 2 nicotinic receptors.

Aims Capmatinib, an orally bioavailable, highly potent and selective MET inhibitor, was recently approved to treat adult patients with metastatic nonsmall cell lung cancer with METex14 skipping mutations. The study investigated the effect of capmatinib on the pharmacokinetics of a single oral dose of digoxin and rosuvastatin in patients with MET‐dysregulated advanced solid tumours. Methods This was a multicentre, open‐label, single‐sequence study. An oral drug cocktail containing 0.25 mg digoxin and 10 mg rosuvastatin was administered to adult patients with MET‐dysregulated advanced solid tumours on Day 1, and then on Day 22 with capmatinib. Between Days 11 and 32, capmatinib 400 mg was administered twice daily to ensure the attainment of steady state for drug–drug interaction assessment. Pharmacokinetics of cocktail drugs and safety of capmatinib were evaluated. Results Thirty‐two patients were enrolled. Compared to digoxin alone, the geometric mean ratios (90% confidence interval) of area under the concentration–time curve from time zero to infinity and maximum concentration for digoxin plus capmatinib were 1.47 (1.28, 1.68) and 1.74 (1.43, 2.13), respectively. Compared to rosuvastatin alone, the geometric mean ratios (90% confidence interval) of area under the curve to infinity and maximum concentration for rosuvastatin plus capmatinib were 2.08 (1.56, 2.76) and 3.04 (2.36, 3.92), respectively. Most frequent adverse events (≥25% for all grades) were nausea, asthenia, constipation, vomiting, peripheral oedema and pyrexia. Most frequent Grade 3/4 adverse events (≥5%) were anaemia, pulmonary embolism, asthenia, dyspnoea, nausea and vomiting. Conclusion This study demonstrated that capmatinib is an inhibitor of P‐gp and BCRP transporters, with clinically relevant drug–drug interaction potential. Capmatinib was well‐tolerated and no unexpected safety concerns were observed.

Sulfines are formed by the reaction of xanthates with m-chloroperoxybenzoic acid; they are spontaneously converted at ambient temperature to thiocarbonates and dithioperoxycarbonates unless kinetic steric protection provided by a substituent makes the sulfine stable.Xanthates are among the most used thiocarbonyl compounds in organic synthesis. 1 Strangely enough, very little information is available about their oxidation, despite the potential of the expected sulfine products. 2-4 Zwanenburg and Bonini have recently shown evidence 5 for the existence of the first two xanthate oxides, generated by the reaction of phenylthio chloro sulfine and an alcohol. This prompts us to report our study of the direct oxidation of dithiocarbonates to give the corresponding sulfines, evaluation of their stabilities and isolation of a stable example bearing sterically bulky groups.A variety of xanthates 1 were submitted to reaction with m-chloroperoxybenzoic acid (MCPBA) in dichloromethane at 0 ЊC. NMR analysis of the product from 1a (R 1 = Pr i , R 2 = CH 2 Ph), conducted rapidly after reaction, reveals that the sulfine 2a is indeed formed. The (E) isomer is predominantly obtained (E : Z ratio 80 : 20), revealing that oxygen delivery occurs opposite to the SR 2 group. 13 C NMR spectroscopy confirms the sulfinyl structure with a C᎐ ᎐ S᎐ ᎐ O signal at 191.1 ppm for the (E) isomer at higher field than the starting dithiocarbonate (217.2 ppm).As no information is available about the stabilities of the two sulfines reported in the literature, 5 we have examined the thermal behaviour of 2a. After 4 weeks at ambient temperature it was transformed into a mixture of thiocarbonate 4a and dithioperoxycarbonate 5a, which could be separated by careful chromatography with yields of respectively 24 and 36%. These structures 6 were assigned by 1 H and 13 C NMR spectroscopy (C᎐ ᎐ O at 168.6 ppm for 4a and 170.2 for 5a) and IR spectroscopy (C᎐ ᎐ O at 1706 cm Ϫ1 for 4a and 1730 for 5a). Formation of 4a and 5a may be explained by an electrocyclisation 2,7 to afford an intermediate oxathiirane 3 which can follow two pathways (i) extrusion of sulfur, (ii) rearrangement with migration of the SR 2 group on the electrophilic sulfur with opening of the three membered ring. We have observed that the transformation of sulfine 2a is accelerated in an acidic medium (TsOH), inhibited by a base (Et 3 N) and that a radical scavenger (2,6-di-tertbutylphenol) has no effect. At this stage the mechanism of the transformation into 4 and 5 is unclear but does not appear to involve radicals. Scheme 1 † In this communication sulfine = S-oxide of a dithiocarbonate; xanthate = O-ester of dithiocarbonic acid.Similar results were obtained in the oxidation of xanthate 1b (R 1 = Pr i , R 2 = Me). Sulfine 2b was formed (E : Z ratio 68 : 32) and after 3 weeks at ambient temperature it was transformed into 4b and 5b (40 : 60 ratio). With less substitution on R 1 and R 2 (1c R 1 = R 2 = Me and 1d R 1 = Et, R 2 = Me) the expected sulfines 2c and 2d were not detected but instead th...