Piperidinylaminomethyl Trifluoromethyl Cyclic Ether Compound 1

Adventures with heterocycles

Elucidation of mechanisms and discovery of novel reactions are interconnected, as four research chapters from the Munich laboratory demonstrate. 1) In a new opening of the furan ring, 2-methoxyfuran and tetra-acceptor-substituted ethylenes furnish methyl acrylates, which are cis-3-substituted by a cyclopropyl ring that bears the four acceptor groups. Experiments with trans- and cis-1,2-bis(trifluoromethyl)-1,2-dicyanoethylenes (BTE) clarify the role of zwitterionic intermediates. 2) The concerted nature of 1,3-dipolar cycloaddition is well established. On reacting thiocarbonyl S-ylides as electron-rich 1,3-dipoles with tetra-acceptor-substituted ethylenes, the switching to a two-step pathway via zwitterion was diagnosed from a loss of stereospecificity and the formation of strained 7-membered cyclic ketene imines. 3) Stable as crystals, these ketene imines rearrange to 5-membered thiolanes in solution. In contrast to open-chain ketene imines, the cyclic representatives add vinyl ether at the C=N bond and show a novel pathway of dimerization. 4) Cycloadducts of isoquinolinium N-phenylimide with ethylenic dipolarophiles undergo an acid-catalyzed [3.3] sigmatropic hydrazo rearrangement. An exception is the conversion of the dimethyl maleate adduct (C21H20N2O4) by acid into a yellow compound C24H22N2O6; the structure and the astounding mechanism were clarified.

Silver-Mediated N-Trifluoromethylation of Sulfoximines

An unprecedented approach to N-trifluoromethylations of electron-rich nucleophilic sites following a radical pathway is reported. Accordingly, various sulfoximines (19 examples) have been N-trifluoromethylated, providing previously unreported products with satisfying functionality tolerance in moderate to good yields. With a C-N bond length at the N-CF3 moiety of 1.341 ? the respective linkage is shorter than a traditional C-N single bond and comparable with that of a C-N double bond.

New drugs to improve transplant outcomes

Fujisawa is committed to improving the outcomes of transplant patients worldwide. Research and development programs are underway for a new modified release dosage form of tacrolimus (MR-4), a new analog of leflunomide (FK 778), and several novel compounds (PG 490-88, AGI 1096) in collaboration with other companies. These programs are targeted to address many of the unmet medical needs in transplantation including (1) improving compliance, (2) reducing chronic rejection, and (3) improving long-term safety by reducing infectious and cardiovascular risk.

Potent, brain-penetrant, hydroisoindoline-based human neurokinin-1 receptor antagonists

3-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-2H-isoindol-2-yl]cyclopent-2-en-1-one (17) is a high affinity, brain-penetrant, hydroisoindoline-based neurokinin-1 (NK(1)) receptor antagonist with a long central duration of action in preclinical species and a minimal drug-drug interaction profile. Positron emission tomography (PET) studies in rhesus showed that this compound provides 90% NK(1) receptor blockade in rhesus brain at a plasma level of 67 nM, which is about 10-fold more potent than aprepitant, an NK(1) antagonist marketed for the prevention of chemotherapy-induced and postoperative nausea and vomiting (CINV and PONV). The synthesis of this enantiomerically pure compound containing five stereocenters includes a Diels-Alder condensation, one chiral separation of the cyclohexanol intermediate, an ether formation using a trichloroacetimidate intermediate, and bis-alkylation to form the cyclic amine.

Effects of histamine-trifluoromethyl-toluidide derivative (HTMT) on intracellular calcium in human lymphocytes

We have studied the effects of histamine trifluoromethyl-toluidide derivatives on calcium mobilization in human peripheral blood lymphocytes using spectrofluorometric analysis. HTMT (compound 1) induced two phases of increase in intracellular calcium concentration--a rapid intracellular calcium concentration peak (10-60 sec), partial recovery (1-3 min) and a sustained moderate elevation that persisted for more than 5 min. The EC50 value was 1.9 X 10(-5) M. Pretreatment of lymphocytes with the agonist resulted in receptor desensitization that recovered after 15 min when the cells were drug free. The presence of extracellular ethylene glycol bis(beta-aminoethyl ether)N,N'-tetraacetic acid did not abrogate the early phase of the calcium rise, suggesting that the calcium appearing in the cytosol during the early phase was derived from intracellular stores. The increase in intracellular calcium concentration by this compound was competitively antagonized by high concentrations of histamine but not by classic histamine receptor antagonists (H1, H2 or H3). Other cyclic AMP elevating agents, with the exception of prostaglandin E2, did not affect the increase in calcium levels induced by compound 1. Compound 1 caused phosphatidylinositol metabolism resulting in inositol phosphate production, suggesting that inositol triphosphate may be the second messenger for the mobilization of intracellular Ca2+ by compound 1. The data imply a specific binding site for histamine trifluoromethyl toluidide derivative on lymphocytes that is different than the classic H1, H2 or H3 receptors.