Toshiya Morie

Synthesis and resolution of (±)-N-[1-methyl-4-(3-methylbenzyl)hexahydro-1H-1,4-diazepin-6-yl]-1H-indazole-3-carboxamide by preferential crystallization

Abstract (±)- N -[1-Methyl-4-(3-methylbenzyl)hexahydro-1 H -1,4-diazepin-6-yl]-1 H -indazole-3-carboxamide (±)- 1 was prepared from N -methyl- N ′-(3-methylbenzyl)-ethylenediamine 5 and 2-(1-benzyloxycarbonyl-1 H -indazole-3-carbonylamino)propenal 4 and was found to exist as a racemic mixture based on the melting point, solubility, infrared spectrum, and X-ray diffraction pattern. Resolution by a preferential crystallization of (±)- 1 and successive recrystallization from acetone gave the enantiomerically pure ( R )-isomer, which showed a potent and selective 5-HT 3 receptor antagonistic activity.

Ring expansion of nitrogen-containing chloromethylheteroalicycles via aziridinium intermediates

The nucleophilic reaction of NaN3 with the chloromethylheteroalicycles, 4-benzyl-3chloromethyl-morpholine 5a, -tetrahydro-4H-1,4-thiazine 5b, -1-methylpiperazine 5c and 1-benzyl-2-chloromethylpiperidine 5d, gave the ring-expanded compounds 6-azido-4-benzylhexahydro-1,4-oxazepine 11a and its analogues 11b–d along with the normally substituted compounds 3-azidomethyl-4-benzylmorpholine 10a and its analogues 10b–d in varying ratios. LUMO frontier electron densities of the reaction centres indicated that the reaction proceeded via the aziridinium intermediate 9 and accounted for the predominance of the reaction product 10 or 11.

A Novel αvβ3 Integrin Antagonist Suppresses Neointima Formation for More Than 4 Weeks After Balloon Injury in Rats

Objectives—We performed a detailed kinetic analysis in a rat balloon injury model to clarify the essential roles of αvβ3 integrin and endothelial cell (EC) regeneration in neointima formation. Using this model, we evaluated the antistenotic effect of Dainippon compound BS-1417, a novel αvβ3 integrin antagonist. Methods and ResultsKinetic analysis using RT-PCR showed that αvβ3 integrin-related genes are upregulated before neointima formation. Morphological and functional analyses revealed that EC regeneration requires >4 weeks after injury, and that recovery of EC normal function coincides with the arrest of neointima formation. Subcutaneous infusion of BS-1417 for 2, 4, 7, or 12 weeks after injury potently inhibited neointima formation without affecting EC regeneration. Although withdrawal of treatment with BS-1417 after short-term administration after injury resulted in catch-up growth of neointima, a long-term study suggested that this catch-up growth can be prevented by continuous administration of BS-1417 until EC regeneration. ConclusionWe clarified that αvβ3 integrin and EC regeneration play an essential role in neointima formation, and that continuous administration of BS-1417 potently and stably inhibits neointima formation without affecting EC regeneration. These findings suggest that BS-1417 might be useful as a novel systemic drug for the treatment of restenosis.

Convenient Synthesis of N-(2, 2-Dimethyl-1, 3-dioxan-5-yl)-1H-indazole-3-carboxamide, the Intermediate of 5-HT3 Receptor Antagonist

Abstract The convenient large-scale synthesis of the title compound, which is the intermediate of potent 5-HT3 receptor antagonist, N-(1-benzyl-4-memylhexahydro-1H-1,4-diazepin-6-yl)-1H-indazole-3-carboxamide (1), is described.

A novel series of N-(hexahydr-1,4-diazepin-6-yl) and N-(hexahydroazepin-3-yl)benzamides with high affinity for 5-HT3 and dopamine D2 receptors

A novel series of benzamides with a hexahydro-1,4-diazepine or hexahydroazepine ring in the amine moiety were prepared, and their binding affinities for 5-HT3 and dopamine D2 receptors were evaluated. The R isomer of the 1-ethyl-4-methylhexahydro-1,4-diazepinylbenzamide (R)-22 had potent affinity for both receptors. The R-enantiomer of the corresponding 1-ethylhexahydroazepinylbenzamide 28 showed potent affinity for dopamine D2 receptors with reduced affinity for 5-HT3 receptors, while the S isomer was found to be a potent and selective 5-HT3 receptor antagonist.

Asymmetric synthesis of the enantiomers of 2-aminomethyl-4-(4-fluorobenzyl)morpholine, an intermediate of mosapride, a gastroprokinetic agent

An efficient asymmetric synthesis of the enantiomers of 2- aminomethyl-4-(4-fluorobenzyl)morpholine (3) which has served as an intermediate of mosapride (1), a potential gastroprokinetic agent, was achieved by the conversion of enantiomeric 3-chloro-1-(4-fluorobenzylamino)-2-propanol (8) to the oxomorpholine (10) followed by reduction and amination, in approximately 35% overall yield with > 98% ee. This synthetic route comprises the regioselective opening of homochiral epichlorohydrin (4) with 4- fluorobenzylamine, with retention of the configuration

EFFICIENT SYNTHESIS OF (R)-6-BENZYLOXYCARBONYLAMINO-1-METHYL-4-(3-METHYL BENZYL)HEXAHYDRO-1,4-DIAZEPINE. 2. NOVEL FORMATION OF HEXAHYDRO-1,4-DIAZEPINE RING USING 1,2,3-TRISUBSTITUTED AMINOPROPANE DERIVATIVE AND GLYOXAL

Abstract An efficient and practical method for synthesis of the optically active hexahydro-1,4-diazepine 2 , which is a key intermediate of DAT-582, a potent and selective serotonin-3 receptor antagonist, is described. Treatment of the ( R )-1,2,3-trisubstituted aminopropane dihydrochloride 5b prepared from methyl ( S )-1-tritylaziridine-2-carboxylate ( 4 ) via the ( S )-1-benzyloxycarbonylaziridine-2-carboxamide 8 with glyoxal in the presence of NaBH 3 CN or boran-triethylamine complex directly gave 2 in good yield without racemization.

Efficient synthesis of (6R)-6-amino-1-methyl-4-(3-methylbenzyl)hexahydro-1H-1,4-diazepine from methyl (2R)- and (2S)-1-benzyloxycarbonylaziridine-2-carboxylates

An efficient and practical method for the synthesis of (6R)-6-amino-1-methyl-4-(3-methylbenzyl)hexahydro-1H-1,4-diazepine 2, which serves as the amine part of DAT-582, a potent and selective 5-HT3 receptor antagonist, is described. The key intermediates, the chiral 2,3-diaminopropionic esters 20 and 26, are prepared by treatment of the optically active aziridines (R)-13 and (S)-13, obtained from D- and L-serine methyl ester hydrochlorides (R)-9 and (S)-9, with the ethylenediamine 19 and its protected derivative 18, respectively. Intramolecular reductive cyclization of 20 gives the chiral 6-benzyloxycarbonylaminohexahydro-1H-1,4-diazepine 22 with high optical purity via the corresponding iminium salt. Deprotection of 22 affords the desired chiral amine 2. As an alternative method, intramolecular amidation of the 2,3-diaminopropionic acids 23 and 28, which are prepared from 20 and 26, gives the 6-benzyloxycarbonylaminohexahydro-1H-1,4-diazepin-5-one 24 and the 7-oxo analogue 29. After removal of the benzyloxycarbonyl group, the resultant compounds 25 and 30 are reduced with diisobutylaluminium hydride to produce the optically active amine 2.

Stereoselective synthesis of the B/C/D ring systmes of aphidicolane and stemodane diterpenes

Diastereoisomeric tricyclo[6.3.1.01,6]dodecane derivatives (3) and (4), which correspond to the B/C/D ring systems of aphidicolane and stemodane diterpenes, were selectively prepared from the common spirodienone (5) by means of facile regioselective C–C bond formation mediated by the neighbouring hydroxy group participation.