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【结 构 式】 
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【药物名称】 【化学名称】(+)-N-(10-Amino-10-methyl-4-oxo-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-8-yl)-N'-methylurea 【CA登记号】173155-95-8, 173156-03-1 (undefined isomer), 173155-39-0 (undefined isomer, diHCl salt) 【 分 子 式 】C16H16N6O2 【 分 子 量 】324.34492 |
【开发单位】Aventis Pharma (Originator) 【药理作用】Antiepileptic Drugs, NEUROLOGIC DRUGS, AMPA Antagonists |
合成路线1
The tetracyclic imidazoindenopyrazinone (IV) was obtained by condensation of 2-bromoindanone (I) with 1-methylimidazole-2-carboxamide (II), followed by demethylation of the resulting imidazolium salt (III) in molten imidazole at 160 C (1). Reaction of (IV) with isoamyl nitrite in the presence of NaH produced oxime (V), which was reduced with zinc powder in acetic acid to yield acetamide (VI). Regioselective methylation of (VI) using methyl iodide and NaH gave (VII). Subsequent nitration of (VII) by means of KNO3 and H2SO4 afforded the 8-nitro derivative (VIII), which was reduced to amine (IX) by hydrogenation over Pd/C. Condensation of amine (IX) with methyl isocyanate in DMF produced urea (X). Finally, the acetamido group of (X) was hydrolyzed in refluxing 6 M HCl.
| 【1】 Chevé, M.; Jimonet, P.; Bohme, G.A.; et al.; 8-Methylureido-10-amino-10-methyl-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-ones: Highly in vivo potent and selective AMPA receptor antagonists. Bioorg Med Chem 2000, 8, 8, 2211. |
| 【2】 Genevois-Borella, A.; Aloup, J.-C.; Audiau, F.; Barreau, M.; Mignani, S.; Ribeill, Y.; Damour, D.; Jimonet, P. (Aventis Pharma SA); Imidazo (1,2-a)-indeno (1,2-e) pyrazin-4-one derivs. and pharmaceutical compsns. containing same. US 5807859; WO 9526350 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 39723 | 2-bromo-1-indanone | 1775-27-5 | C9H7BrO | 详情 | 详情 |
| (II) | 39724 | 1-methyl-1H-imidazole-2-carboxamide | C5H7N3O | 详情 | 详情 | |
| (III) | 39725 | 3-methyl-4-oxo-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-3-ium bromide | C14H12BrN3O | 详情 | 详情 | |
| (IV) | 39726 | 5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one | C13H9N3O | 详情 | 详情 | |
| (V) | 42829 | 4H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4,10(5H)-dione 10-oxime | C13H8N4O2 | 详情 | 详情 | |
| (VI) | 42830 | N-(4-oxo-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-10-yl)acetamide | C15H12N4O2 | 详情 | 详情 | |
| (VII) | 44100 | N-(10-methyl-4-oxo-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-10-yl)acetamide | C16H14N4O2 | 详情 | 详情 | |
| (VIII) | 44101 | N-(10-methyl-8-nitro-4-oxo-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-10-yl)acetamide | C16H13N5O4 | 详情 | 详情 | |
| (IX) | 44102 | N-(8-amino-10-methyl-4-oxo-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-10-yl)acetamide | C16H15N5O2 | 详情 | 详情 | |
| (X) | 44103 | N-(10-methyl-8-[[(methylamino)carbonyl]amino]-4-oxo-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-10-yl)acetamide | C18H18N6O3 | 详情 | 详情 |