A regioselective double Stille coupling reaction of bicyclic stannolanes.

A regioselective double Stille coupling reaction was explored using bicyclic stannolanes that were easily prepared from the radical cascade reaction of ß-amino-α-methylene esters. Various 1-bromo-2-iodoarenes underwent the double coupling reaction to afford benzoisoindole derivatives in a regioselective manner, where the carbon attached to the iodine selectively coupled with the vinylic carbon, and then the carbon attached to bromine coupled with the alkyl carbon. The combination of intra- and intermolecular coupling reactions provided hexahydroindeno[1,2-b]pyrrole derivatives in good yields. The yields were further improved in the presence of excess amounts of CsF. An attempt to identify the reaction intermediate was made wherein the decomposition of the stannolanes with aqueous HCl and HBr afforded trigonal bipyramidal (TBP) pentacoordinated tin complexes, as confirmed by microanalyses and (119)Sn NMR. Using DCl for the decomposition selectively introduced a deuterium to the E-position of the exomethylene unit. The complexes smoothly underwent the intramolecular Stille coupling reaction in the presence of both a palladium catalyst and DABCO, affording hexahydroindeno[1,2-b]pyrroles in good yields. These results suggest that the double coupling reaction progresses through a TBP tin complex, promoting the second intramolecular coupling reaction between the aryl halide and Csp(3)-tin bond.

Safety and Effectiveness of Micafungin in Japanese Pediatric Patients: Results of a Postmarketing Surveillance Study.

Limited data are available about the safety and efficacy of micafungin in children. A postmarketing surveillance study was conducted to assess the safety and effectiveness of micafungin, an echinocandin antifungal, in pediatric patients. A prospective multicenter postmarketing observational study was carried out between October 2006 and September 2008 in Japan. Pediatric patients under 16 years received an intravenous infusion of micafungin at a dose of 1 mg/kg for candidiasis and 1 to 3 mg/kg for aspergillosis, with the option of increasing the dose if required to 6 mg/kg once daily. All adverse events were recorded. A total of 201 pediatric patients were enrolled. There were 55 adverse drug reactions reported among 42 of 190 patients evaluated for safety (22.1%); the most frequently reported adverse drug reaction was hepatobiliary disorders. No adverse drug reactions were reported in 18 neonates (aged below 4 wk). The overall clinical response rate in 91 patients evaluated for efficacy was 86.8%. The response rate in neonates was 90.0%, and there were no differences in the response rate by age. Micafungin was found to have sufficient safety and effectiveness for the treatment of fungal infections in pediatric patients with various backgrounds.

Safety and efficacy of micafungin for prophylaxis against invasive fungal infections in Japanese patients undergoing hematopoietic stem cell transplantation: Results of a post-marketing surveillance study.

Invasive fungal infections are a major cause of morbidity and mortality in patients with hematopoietic stem cell transplantation. A prospective multicenter post-marketing observational surveillance study was conducted from July 2007 to June 2010 to assess the safety and efficacy of micafungin, an echinocandin antifungal, for prophylaxis against invasive fungal infections in Japanese patients undergoing hematopoietic stem cell transplantation. Among 241 patients evaluated for safety, 143 adverse drug reactions were reported in 86 patients (35.7%), with hepatobiliary disorders the most frequently reported adverse drug reactions. The success rate for prophylaxis at the end of observation was 72.8% (131/180 patients), and the incidence of breakthrough infections was only 4.4% (8/180 patients). In conclusion, micafungin had sufficient safety and efficacy for prophylaxis against invasive fungal infections in Japanese patients with various backgrounds undergoing hematopoietic stem cell transplantation.

Kinetic study of the 7-endo selective radical cyclization of N-tert-butyl-o-bromobenzylmethacryl amides: kinetic investigation of the cyclization and 1,7-hydrogen transfer of aromatic radicals.

A kinetic investigation of the radical cyclization of N-tert-butyl-o-bromobenzylmethacryl amides to give 2-benzazepines via 7-endo selective cyclization was undertaken. The aryl radical generated from the amide precursor by treatment with Bu3SnH gave the three compounds, which are a 7-endo cyclized adduct, a 6-exocyclized adduct, and a reduced product. The cyclization reactions under various Bu3SnH concentrations were traced by GC analysis. The 7-endo/6-exo selectivity was constant irrespective of variation in Bu3SnH concentration. These results revealed that regioselectivity is controlled in a kinetic manner and that there is no possibility of a neophyl rearrangement. The use of Bu3SnD revealed that 1,7-hydrogen transfer, in which an aryl radical abstracts a hydrogen atom from the methallylic methyl group, occurs during the reaction. Hydrogen abstraction from toluene, the reaction solvent, was also observed. The 1,7-transfer rate depended on the Bu3SnX (X = H or D), and the reaction kinetics was examined. The k(H)/k(D) value for the hydrogen abstraction of aryl radical from Bu3SnX (X = H or D) was estimated using 4-bromoanisol. The utilization of these values revealed the overall reaction kinetics and relative rates for the cyclization and reduction by Bu3SnX (X = H or D). Kinetic parameters for hydrogen abstraction from toluene by aryl radicals were also estimated.

Concise synthesis of 2-benzazepine derivatives and their biological activity.

2-Benzazepines, which are potentially good candidates for new drug therapies to treat skin wounds, were readily prepared from substituted cinnamylamide via an intramolecular Friedel-Crafts reaction. With few steps and effective reactions, the procedure enables a rapid derivatization of 2-benzazepines. Moreover, optically active 4-substituted-2-benzazepines were prepared from chiral α-substituted cinnamylamides, which were readily prepared by asymmetric α-alkylation of chiral cinnamyl oxazolidinone amides. We have easily prepared a library of more than 20 derivatives and examined the biological activity of the compounds.

An efficient preparation of N-alkyl-2-benzazepine derivatives and investigation of their biological activity.

N-Alkyl-2-benzazepine derivatives are readily prepared through N-alkylation of secondary 2-benzazepines that are constructed via 7-endo selective cyclization of radical cyclization of N-boc-N-(2-bromo-5-methoxyphenylmethyl) methacrylamides. The structure and activity relationship of these derivatives are examined.

Pd-catalyzed tandem sp2-sp3 coupling reactions of chiral stannolanes: an efficient preparation of optically active tetrahydrobenz[f]isoindoles.

A novel double Migita-Kosugi-Stille coupling reaction with dihydrostannolanes, which are readily available from a radical cascade reaction, was achieved with dihalobenzenes in the presence of a palladium catalyst. Use of unsymmetrical 1-bromo-2-iodobenzene derivatives accomplished the double coupling reaction which gave tetrahydrobenz[f]isoindoles in a regioselective manner.

Treatment of congenital absence of the mammary gland.

Breast reconstruction for breast deformity is significant not only for esthetic purposes but also from a psychological perspective. There have been a few reports on treatment of congenital simple absence of the mammary gland. For patients in puberty, even if they are in the middle of the growth phase, breast reconstruction is very important for the mental quality of life. In our two cases of congenital absence of unilateral mammary gland, breast reconstruction with a tissue expander worked well in terms of esthetic results and the psychological condition of the young patients. In our institute, operative indications are as follows: (1) a girl over 15 years old (this age is selected as breast growth can be determined at this time), (2) no endocrine-related disorders, (3) preoperative examination of breast MRI or US showing the absence or significant hypoplasia of mammary gland, and (4) a wish for breast reconstruction by the patient herself. For patients in the middle of the growth phase, silicone breast implant does not require a donor site and is easily adjustable in terms of volume to match the growth of the breast on the unaffected side by exchanging the silicone breast implant. Therefore, silicone breast implant is a better procedure than skin flaps with their accompanying large donor sites.

Unexpected formation of stannolanes and trigonal bipyramidal tin complexes by radical cyclization reaction.

Optically active stannolanes and trigonal bipyramidal pentacoordinated tin complexes were readily prepared by radical cyclization of N-propargylated chiral aza-Morita-Baylis-Hillman adducts induced by Bu(3)SnH. A translocated radical through the cyclization attacked the Bu(3)Sn group in an S(H)2 manner.