Purpose: Osimertinib is a potent and selective EGFR tyrosine kinase inhibitor (EGFR-TKI) of both sensitizing and T790M resistance mutations. To treat metastatic brain disease, blood–brain barrier (BBB) permeability is considered desirable for increasing clinical efficacy. Experimental Design: We examined the level of brain penetration for 16 irreversible and reversible EGFR-TKIs using multiple in vitro and in vivo BBB preclinical models. Results: In vitro osimertinib was the weakest substrate for human BBB efflux transporters (efflux ratio 3.2). In vivo rat free brain to free plasma ratios (Kpuu) show osimertinib has the most BBB penetrance (0.21), compared with the other TKIs (Kpuu ≤ 0.12). PET imaging in Cynomolgus macaques demonstrated osimertinib was the only TKI among those tested to achieve significant brain penetrance (Cmax %ID 1.5, brain/blood Kp 2.6). Desorption electrospray ionization mass spectroscopy images of brains from mouse PC9 macrometastases models showed osimertinib readily distributes across both healthy brain and tumor tissue. Comparison of osimertinib with the poorly BBB penetrant afatinib in a mouse PC9 model of subclinical brain metastases showed only osimertinib has a significant effect on rate of brain tumor growth. Conclusions: These preclinical studies indicate that osimertinib can achieve significant exposure in the brain compared with the other EGFR-TKIs tested and supports the ongoing clinical evaluation of osimertinib for the treatment of EGFR-mutant brain metastasis. This work also demonstrates the link between low in vitro transporter efflux ratios and increased brain penetrance in vivo supporting the use of in vitro transporter assays as an early screen in drug discovery.

The reaction of the σ-bonded (PCP)Pd-Me complex (PCP = 2,6-bis [(di-tert-butylphosphino)methyl]phenyl) with CO 2 is first-order in palladium and first-order in CO 2 with a rate constant k s = 8.9 ( 0.8 M -1 s -1 at 353 K. Activation parameters are ΔH q = 73 ( 7 kJ/mol and ΔS q = -118 ( 19 J/K mol. Based on this and theoretical calculations we propose an S E 2 mechanism where the coordinated methyl group attacks a completely noncoordinated carbon dioxide molecule in a bimolecular reaction. The PCPPd-crotyl complex was synthesized in an 65:35 E:Z mixture, and it was shown to react with CO 2 to give the complex PCPPd-O(CO)CH(CH 3 )CHCH 2 as a single isomer, where the former γ-carbon has been carboxylated. Theoretical calculations again suggest an S E 2 mechanism with a noncoordinated carbon dioxide reacting with the terminal carbon on the allyl group, forming an η 2 -bonded olefin complex as an intermediate. The rearrangement of this intermediate to the O-bonded product is concluded to be rate determining. The crystal structure of PCPPd-O(CO)C(CH 3 ) 2 CHCH 2 is reported and as well as the solubility of carbon dioxide in benzene-d 6 at different pressures and temperatures.

Arynes derived from any position of the ubiquitous indole nucleus are unknown. We have now provided the first evidence for the formation and trapping of the 4,5-, 5,6-, and 6,7-indolynes. A series of o-dihalo indoles (Cl, Br, F) were synthesized and reacted under metal-halogen exchange conditions to give Diels-Alder cycloadducts in high yield with furan. The use of an excess of tert-butyllithium resulted in the rearrangement of the initially formed cycloadduct; however, employing only a slight excess of n-butyllithium cleanly gave cycloadducts with furan.

Cyclometallation of 2-(1-naphthyl)-pyridine is described. While cyclopalladation results in a five-membered metallacycle, cycloauration displays a completely orthogonal regioselectivity, resulting in the six-membered ring analogue. Bromination of the gold metallacycle results in the new C-H functionalisation product 2-(8-bromonaphth-1-yl)pyridine.

First ruthenium complexes with a ferrocene based pincer ligand were synthesized. The cyclometallation of 1,3 bis[(di tert butylphosphino)methyl]ferrocene with RuCl 2 (DMSO) 4 in 2 methoxyethanol afforded the RuCl(CO)[{2,5 (Bu t 2 PCH 2 ) 2 C 5 H 2 }Fe(C 5 H 5 )] (RuCl(CO)[ Bu t P,C,P Fe ]) complex (5). Complex 5 reversibly binds CO to form the RuCl(CO) 2 [ Bu t P,C,P Fe ] complex (6). The analogous reaction in the presence of NaBAr´4 (Ar´ = 3,5 (CF 3 ) 2 C 6 H 3 ) produced the cationic complex {Ru(CO) 2 [ Bu t P,C,P Fe ]}BAr´4 (7). The structures of complexes 5 and 7 were established by single crystal X ray diffraction. The X ray diffraction study revealed an agostic interaction between one of the C-H bonds of the axial (exo oriented with respect to the ferrocene iron atom) tert butyl group and the Ru atom in complexes 5 and 7.Organometallic complexes with tridentate mono anionic aryl ligands, so called pincer complexes, have been extensively studied in recent years. 1,2 These com plexes have attracted interest due to their high stability and ability of catalyzing various organic reactions.Recently, we have studied a new type of pincer complexes, viz., metallocene based bimetallic pincer complexes. 3 The availability of these complexes was ex emplified by the cyclometallation of 1,3 bis[(dialkyl phosphino)methyl]ferrocene 3,4 and bis[(dialkylphos phino)methyl]ruthenocene. 4 Platinum metal com plexes with metallocene based pincer ligands 2-7 proved to be as stable as their benzene analogs. Recently, we have demonstrated 8 that the iridium complexes IrH 2 [{2,5 (Bu t 2 PCH 2 ) 2 C 5 H 2 }M(C 5 H 5 )] (M = Fe or Ru) are the most active of all the known homogeneous cata lysts for alkane dehydrogenation.The sandwich nature of metallocene pincer ligands provides new possibilities for fine controlling the steric and electronic effects of chelated metal atoms serving as the catalytic centers, for example, by introducing sub stituents into the unmetallated cyclopentadienyl ring 9 (not only the electron density on the chelated metal atom but also the steric accessibility of this atom for the substrate can be controlled), varying the nature of the central atom of the metallocene moiety 8 and its redox state, 7,8 and constructing planar chiral structures. The synthesis of metallocene based rhodium, 3,10 iridium, 4,8 and palla dium 5-7,9 pincer complexes was documented. However, related ruthenium complexes have not been described in the literature. The properties of ruthenium complexes as excellent catalysts for the hydrogenation of carbonyl com pounds 11 and olefin metathesis 12 are well known.In the present study, we report the synthesis and prop erties of first ferrocene based ruthenium pincer complexes. Results and Discussion Synthesis of ruthenium complexesAs mentioned earlier, the choice of the cyclo metallating agent can play a decisive role in the synthesis of metal pincer complexes. Our first attempt, as well as attempts of other researchers, 10 to use the RuCl 2 (PPh 3 ) 3 complex as the starting reagent for the cyc...

2-(1-Naphthyl)-pyridine () possesses sp(2) C-H bonds in both the γ- and δ-positions and is therefore a suitable substrate for studying the cyclometallation selectivity with different reagents and conditions. Such selectivity studies are reported. Based on deuterium-exchange experiments it is concluded that cycloruthenation with RuCl2(p-cymene) dimer is reversible with kinetic and thermodynamic preference for γ-substitution. Electrophilic cycloborylation, on the other hand, shows unusual δ-substitution. The previously published cyclopalladation and cycloauration of the substrate was studied in detail and was shown to be irreversible; they proceed under kinetic control and give γ- and δ-substitution for palladium and gold, respectively.

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