【结 构 式】 |
【药物名称】Elacridar, GW-120918, GF-120918A(HCl), GW-918, GG-918, GF-120918 【化学名称】N-[4-[2-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]phenyl]-5-methoxy-9-oxo-9,10-dihydroacridine-4-carboxamide 【CA登记号】143664-11-3, 143851-84-7 (maleate salt(1:1)), 143851-98-3 (monoHCl) 【 分 子 式 】C34H33N3O5 【 分 子 量 】563.65921 |
【开发单位】GlaxoSmithKline (Originator) 【药理作用】Modulators of the Therapeutic Activity of Antineoplastic Agents, Multidrug Resistance Modulators, ONCOLYTIC DRUGS, P-Glycoprotein (MDR-1) Inhibitors |
合成路线1
The condensation of 2-(4-nitrophenyl)ethyl bromide (I) with 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (II) by means of K2CO3 and KI in DMF at 100 C gives 6,7-dimethoxy-2-[2-(4-nitrophenyl)ethyl]-1,2,3,4-tetrahydroisoquinoline (III), which is reduced with H2 over Pd/C in ethanol to yield the corresponding amine (IV). Finally, this compound is condensed with 5-methoxy-9-oxo-9,10-dihydroacridine-4-carboxylic acid (V) by means of DCC and HOBt in DMF to afford the target carboxamide. The intermediate 5-methoxy-9-oxo-9,10-dihydroacridine-4-carboxylic acid (V) has been obtained as follows: The condensation of 2-amino-3-methoxybenzoic acid (VI) with 2-bromobenzoic acid (VII) by means of K2CO3 and copper dust give the diphenylamine (VIII), which is cyclized to the target acridine (V) by means of POCl3 in refluxing acetonitrile.
【1】 Dodic, N.; et al.; Synthesis and activity against multidrug resistance in Chinese hamster ovary cells of new acridone-4-carboxamides. J Med Chem 1995, 38, 13, 2418. |
【2】 Dumaitre, B.A.; Dodic, N. (GlaxoSmithKline plc); Acridine derivs.. EP 0494623; EP 0569380; JP 1994506440; US 5604237; WO 9212132 . |
【3】 Sharp, M.J.; Mader, C.J.; Strachan, C. (GlaxoSmithKline plc); Synthesis of acridine deriv. multidrug-resistant inhibitors. WO 9852923 . |
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) | 19191 | 1-(2-bromoethyl)-4-nitrobenzene | 5339-26-4 | C8H8BrNO2 | 详情 | 详情 |
(II) | 25859 | 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline; 6-methoxy-1,2,3,4-tetrahydro-7-isoquinolinyl methyl ether | C11H15NO2 | 详情 | 详情 | |
(III) | 19193 | 6,7-dimethoxy-2-(4-nitrophenethyl)-1,2,3,4-tetrahydroisoquinoline; 6-methoxy-2-(4-nitrophenethyl)-1,2,3,4-tetrahydro-7-isoquinolinyl methyl ether | C19H22N2O4 | 详情 | 详情 | |
(IV) | 19194 | 4-[2-[6,7-dimethoxy-3,4-dihydro-2(1H)-isoquinolinyl]ethyl]aniline; 4-[2-[6,7-dimethoxy-3,4-dihydro-2(1H)-isoquinolinyl]ethyl]phenylamine | C19H24N2O2 | 详情 | 详情 | |
(V) | 53881 | 5-methoxy-9-oxo-9,10-dihydro-4-acridinecarboxylic acid | n/a | C15H11NO4 | 详情 | 详情 |
(VI) | 53879 | 2-Amino-3-methoxybenzoic acid; 2-Amino-m-anisic acid; 3-Methoxyanthranilic acid | 3177-80-8 | C8H9NO3 | 详情 | 详情 |
(VII) | 15546 | 2-bromobenzoic acid; o-bromobenzoic acid | 88-65-3 | C7H5BrO2 | 详情 | 详情 |
(VIII) | 53880 | 2-(2-carboxyanilino)-3-methoxybenzoic acid | n/a | C15H13NO5 | 详情 | 详情 |