A new procedure for regioselective synthesis of 8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine (LY134046) and its 3-methyl analogue as inhibitors of phenylethanolamine N-methyltransferase (PNMT)

A regioselective synthesis of 8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine (LY134046, 10 ) and its 3-methyl analogue 26 from 6,7-dichloro-3-hydroxyphthalide ( 16 ) is described. The key step involved 1,4-hydride addition to the α,β-unsaturated nitrile 17 to give the saturated nitrile 18 using sodium borohydride in 2-propanol. In the preparation of LY134046 10 , the COOH group in 18 was first esterified and then the nitrile function was selectively reduced with borane to yield the aminoester 20 . The aminoester 20 was then cyclized to the azepinone 21 which on reduction with borane provided LY134046 10 in an overall yield of 22%. The route is adaptable to the preparation of hitherto unknown 3-substituted-2-benzazepines as demonstrated by the preparation of the 3-methyl analogue 26 . In this case the nitrile 18 was reacted with an excess methylmagnesium iodide to give the ketoacid 22 . Esterification of 22 followed by reductive amination with sodium cyanoborohydride and ammonium acetate provided the aminoester 24 , which was then converted to the target benzazepine 26 as described earlier for the title compound. The reaction conditions and the reagents used throughout the sequence are fairly mild and many functional groups may be tolerated. The only limitation to this procedure is the availability of the corresponding hydroxyphthalide. A variation in the choice of reagent in the Grignard reaction of 18 should provide an access to a variety of 3-substituted-2-benzazepines.     

Analysis of 4-methyl-piperazine-1-carbodithioic acid 3-cyano-3,3-diphenyl-propyl ester hydrochloride and its major metabolites in rat plasma and tissues by LC-MS/MS

4-Methyl-piperazine-1-carbodithioic acid 3-cyano-3,3-diphenylpropyl ester hydrochloride (TM-208) is a newly synthesized compound, which has shown excellent in vivo and in vitro anticancer activity and low toxicity. To investigate the metabolism of TM-208 in rats, in the present study, we administered TM-208 orally to rats and analyzed its metabolites existing in rat plasma and central tissues by LC-MS/MS. Rat plasma and tissue samples were collected before or after a single oral dose (250 mg/kg) of TM-208, then the analytes were extracted from samples by liquid-liquid extraction and analyzed using LC-MS/MS. The structures of proposed metabolites were elucidated according to the rules of drug metabolism and disposition in vivo and the characteristic fragmentation behaviors of TM-208 in ESI-ITMS(n). Five metabolites (M1-M5) were tentatively or assuredly identified: (2-amino-ethyl)-dithiocarbamic acid 3-cyano-3,3-diphenyl-propyl ester (M1), (2-methylamino-ethyl)-dithiocarbamic acid 3-cyano-3,3-diphenyl-propyl ester (M2), 4-methyl-piperazine-1-carbothioic acid S-(3-cyano-3,3-diphenyl-propyl) ester (M3), piperazine-1-carbodithioic acid 3-cyano-3,3-diphenylpropyl ester (M4), and sulfine of (4-methyl-piperazine-1-carbodithioic acid 3-cyano-3,3-diphenylpropyl ester) (M5).