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【结 构 式】 
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【药物名称】Perphenazine 4-Aminobutyrate Mesylate;CYP-1020;BL-1020 (free base);AN-168 (hydrochloride) 【化学名称】4-Aminobutyric acid 2-[4-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]piperidin-1-yl]ethyl ester (tris)methanesulfonate 【CA登记号】503537-33-5 (monohydrochloride);751477-01-7 (free base);916898-60-7 (maleate);916898-61-8 (methanesulfonate);916898-62-9 (p-tolu 【 分 子 式 】C28H45ClN4O11S4 【 分 子 量 】777.39 |
【开发单位】BioLineRx, Inc. (IS) 【药理作用】Dopamine D2 Receptor Antagonist；Treatment of Schizophrenia；GABAA Receptor Agonist； |
合成路线1
N-Protection of 4-aminobutyric acid with Boc2O gives N-Boc-4-aminobutyric acid (II) , which by esterification with perphenazine (III) by means of either CDI in DMF or DCC and DMAP in CH2Cl2 affords the N-Boc-amino ester (IV). Alternatively, treatment of N-Boc-GABA (II) with t-BuCOCl in the presence of of Et3N in THF gives the mixed anhydride (V), which by reaction with perphenazine (III) in THF yields amino ester (IV) . Finally, compound (IV) is deprotected by means of MsOH in acetonitrile .
| 【1】 Nudelman, A., Gil-Ad, I., Shpaisman, N. et al. A mutual prodrug ester of GABA and perphenazine exhibits antischizophrenic efficacy with diminished extrapyramidal effects. J Med Chem 2008, 51(9): 2858-62. |
| 【2】 Nudelman, A., Weizman, A., Rephaeli, A., Gil-Ad, I. (Ramot at Tel Aviv University, Ltd.; Bar-Ilan University). Conjugated anti-psychotic drugs and uses thereof. CA 2461663, EP 1429844, EP 2275143, JP 2005503423, JP 2010090170, KR 201009724, WO 2003026563. |
| 【3】 Nudelman, A., Rephaeli, A., Gil-Ad, I., Weizman, A., Halachmi, S., Benjamin, E.J. (Ramot at Tel Aviv University, Ltd.; Bar-Ilan University; BioLineRx, Ltd.). Novel salts of conjugated psychotropic drugs and processes of preparing same. EP 1888120, EP 2272537, JP 2008545777, US 2009298814, WO 2006131923. |
| 【4】 Gil-Ad, I., Rephaeli, A., Weizman, A., Nudelman, A. (Bar-Ilan University; Ramot at Tel Aviv University, Ltd.). Conjugated psychotropic drugs and uses thereof. CA 2560905, EP 1727566, JP 200753029, JP 2011121971, US 2004242570, US 7544681, WO 2005092392. |
| 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) | 13620 | 4-Amino-n-butyric acid; 4-Aminobutyric acid;Piperidinic acid;Piperidic acid | 56-12-2 | C4H9NO2 | 详情 | 详情 |
| (II) | 39226 | 4-[(tert-butoxycarbonyl)amino]butyric acid;4-((tert-butoxycarbonyl)amino)butanoic acid | 57294-38-9 | C9H17NO4 | 详情 | 详情 |
| (III) | 68568 | 2-(4-(3-(2-chloro-10H-phenothiazin-10-yl)propyl)piperazin-1-yl)ethanol | 58-39-9 | C21H26ClN3OS | 详情 | 详情 |
| (IV) | 68569 | 2-(4-(3-(2-chloro-10H-phenothiazin-10-yl)propyl)piperazin-1-yl)ethyl 4-((tert-butoxycarbonyl)amino)butanoate | C30H41ClN4O4S | 详情 | 详情 | |
| (V) | 68570 | 4-((tert-butoxycarbonyl)amino)butanoic pivalic anhydride | C14H25NO5 | 详情 | 详情 |