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【结 构 式】 
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【药物名称】 【化学名称】6-[3-[19-Amino-14(S)-carboxy-19-imino-8,12-dioxo-2,9,13,18-tetraazanonadecanoyl]phenyl]-3,8-diamino-5-methylphenanthridinium chloride 【CA登记号】 【 分 子 式 】C36H46ClN9O5 【 分 子 量 】720.27832 |
【开发单位】INSERM (Originator) 【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY |
合成路线1
Acylation of amino derivative (I) with 3-cyanobenzoyl chloride (II) provides amide (III) which is then cyclized to give phenanthridine (IV) by refluxing with phosphoryl chloride in nitrobenzene and catalysis of SnCl4. Hydrolysis of the nitrile derivative (IV) in H2SO4 gives carboxylic acid derivative (V). Quaternization of (V) is carried out using dimethyl sulfate and after refluxing in a HCl solution, derivative (VI) is obtained. Reduction of (VI) using iron powder in a mixture of HCl-ethanol yields the ethidium chloride derivative (VII) which is coupled to the protected arginine-linking chain (VIII) (see below) in presence of DCC and HOBt. Last step is the deprotection of the arginine moiety with TFA and separation of the obtained products.
| 【1】 Guedj, R.; Peytou, V.; Aubertin, A.-M.; Terreux, R.; Bailly, C.; Patino, N.; Condom, R.; Cabrol-Bass, D.; Gelus, N.; Synthesis and antiviral activity of ethidium - Arginine conjugates directed against the TAR RNA of HIV-1. J Med Chem 1999, 42, 20, 4042. |
| 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) | 41160 | 4,4'-dinitro[1,1'-biphenyl]-2-amine; 4,4'-dinitro[1,1'-biphenyl]-2-ylamine | C12H9N3O4 | 详情 | 详情 | |
| (II) | 34921 | 3-cyanobenzoyl chloride | 1711-11-1 | C8H4ClNO | 详情 | 详情 |
| (III) | 41161 | 3-cyano-N-(4,4'-dinitro[1,1'-biphenyl]-2-yl)benzamide | C20H12N4O5 | 详情 | 详情 | |
| (IV) | 41162 | 3-(3,8-dinitro-6-phenanthridinyl)benzonitrile | C20H10N4O4 | 详情 | 详情 | |
| (V) | 41163 | 3-(3,8-dinitro-6-phenanthridinyl)benzoic acid | C20H11N3O6 | 详情 | 详情 | |
| (VI) | 41164 | 6-(3-carboxyphenyl)-5-methyl-3,8-dinitrophenanthridinium chloride | C21H14ClN3O6 | 详情 | 详情 | |
| (VII) | 41165 | 3,8-diamino-6-(3-carboxyphenyl)-5-methylphenanthridinium chloride | C21H18ClN3O2 | 详情 | 详情 | |
| (VIII) | 41166 | methyl (2S)-2-([3-[(6-aminohexanoyl)amino]propanoyl]amino)-5-[(imino[[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino]methyl)amino]pentanoate | C30H52N6O7S | 详情 | 详情 |
合成路线2
Derivative (VIII) is obtained as follows: Activation of protected aminoacid (IX) with DCC/HOSu and coupling with H-Arg(Pmc)-OH (A) yields carboxylic acid derivative (X) which is converted to methyl ester (XI). Catalytic hydrogenation of (XI) and coupling with the protected caproic acid (XII) in presence of DCC and HOSu provides derivative (XIII) which is finally catalytically hydrogenated yielding intermediate (VIII).
| 【1】 Guedj, R.; Peytou, V.; Aubertin, A.-M.; Terreux, R.; Bailly, C.; Patino, N.; Condom, R.; Cabrol-Bass, D.; Gelus, N.; Synthesis and antiviral activity of ethidium - Arginine conjugates directed against the TAR RNA of HIV-1. J Med Chem 1999, 42, 20, 4042. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII),(VIII) | 41166 | methyl (2S)-2-([3-[(6-aminohexanoyl)amino]propanoyl]amino)-5-[(imino[[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino]methyl)amino]pentanoate | C30H52N6O7S | 详情 | 详情 | |
| (A) | 41167 | (2S)-2-amino-4-[(imino[[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino]methyl)amino]butyric acid | C19H32N4O5S | 详情 | 详情 | |
| (IX) | 17022 | beta-Alanine; 3-aminopropionic acid | 107-95-9 | C3H7NO2 | 详情 | 详情 |
| (X) | 41168 | (2S)-2-[(3-aminopropanoyl)amino]-5-[(imino[[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino]methyl)amino]pentanoic acid | C23H39N5O6S | 详情 | 详情 | |
| (XI) | 41169 | methyl (2S)-2-[(3-aminopropanoyl)amino]-5-[(imino[[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino]methyl)amino]pentanoate | C24H41N5O6S | 详情 | 详情 | |
| (XII) | 41170 | 6-aminohexanoic acid | 60-32-2 | C6H13NO2 | 详情 | 详情 |