利用 HPLC 在各種不同 PH 值的磷酸 緩衝溶液中,評估化合物 1-11 的安定性

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Atenolol 前驅藥之製備研究

Preparation of Potential Prodrugs for Atenolol

中文摘要

Atenolol 是心血管選擇性的交感乙型受體之體之拮抗劑( cardioselective β-receptor antagonist), 在臨床上用來治療高血壓(hypertension)、心絞痛 (angina) 、心律不整 (arrhythmia)和急性的心肌梗塞 (acute phase of myocardial infarction)。在所有的交感 乙型受體之拮抗劑中, atenolol 具有最高的親水性;由於這個原因使得 atenolol 在通過小腸 壁不良,造成其口服時的生體可用率僅有 50% 。本研究目的為了提高其親脂性行為

(lipophilicity) ,增加服吸收及生體可用率;進而合成一系列的 atenolol 前驅藥 (prodrugs)。

本實驗中利用三氯醋酸 (trichloroacetic acid) 在 atenolol 的胺基上做成離子對 (ion pair)保護基,可選擇性的在 atenolol 的羥基上製備其酯類衍生物 (O-acylatenolol);利用 acyl anhydride 或 acyl chloride 合成 acetyl、 propionyl、 butyryl 和 benzoyl 之 atenolol 酯類衍生物 (1-4)。此外我們也直接加入 acyl anhydride 或 acyl chloride 在 atenolol 的胺 基上製備醯胺類的衍生物( N-acylatenolol) (5,6),進而加入過量的 acyl anhydride 或 acyl chloride 合成 N,O-diacylatenolol (7,8),另一方面,我們分別利用 acetone 和

benzaldehyde 製備 2,2-dimethyloxazolidine (9)和 2-phenyloxazolidine (10) 的衍生 物。並且也以 atenolol 與 ethyl chloroformate 和 triethylamine 合成 oxazolidone 的衍 生物 (11)。

為了評估前驅藥的可用性,進行安定性方面之試驗。利用 HPLC 在各種不同 PH 值的磷酸 緩衝溶液中,評估化合物 1-11 的安定性。 我們發現在 PH≦7 時,所有的酯類化合物 1-4 皆會 造成分子內的 N-O acyl migration 產生 N-acylatenolo;而在咸性的溶液中,會同時產生 N-acylatenolol 和 atenolol。酯類化合物 1-4 在 PH4 的磷酸緩衝溶液中測得之降解半衰期,

其中以化合物 1 最短 (18min),而化合物 4 最長 (32min)。然而 oxazolidine 的衍生物在磷 酸緩衝溶液中,完全水解成 atenolol;其降解半衰期約為 66min。至於化合物 5-8 和 ll,在 任何 pH 值下皆相當安定。在分配係數方面,利用 n-octanol 和 pH7.4 的磷酸緩衡溶液評估 其親脂性;由結果發現其分配係數增為 atenolol 的 9-68 倍。由以上的結果希望能增加 atenolol 的親脂性,來克服 atenolol 低親脂性的載遞問題;另外我們也可以利用高親脂性的前驅藥做為 穿皮劑型之可能性。

英文摘要

Atenolol is well known as a cardioselective β-receptor antagonist and it has clearly demonstrated its efficacy in the treatment of hypertension, angina, arrhythmia and myocardial infarction. Among all the blocking agents, it was found that atenolol is more hydrophilic than the others. The low oral bioavailibility of atenolol(50%)is dued to the polar nature of this drug. The aim of this study is to take the advantages of the concept of bioreversible prodrug to syntheze more lipophilic atenolol

derivatives and thus the oral bioavailiaility will be enchanced.

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In order to prepare the ester derivatives of atenolol on the hydroxyl group selectively, the amino function was first protected by formation of an ion-pair with trichloroacetic acid in nonpolar slovent. A series of ester derivatives of atenolol were prepared by incorporating substituents such as acetyl, propionyl, butyryl and benzoyl (1-4) into the β-hydroxy by acyl anhydride or acyl chloride, N-acyl(5,6)and N,O-diacyl (7,8)derivatives were also prepared.On the other hand,the preparation of 2,2-dimethyloxazolidine(9)and 2-phenyloxazolidine(10)derivatives were

accomplished by reaction of atenolol with acetone and benzaldehyde respectively 5,6. The oxazolidone derivative (11)was prepared by ethyl chloroformate and triethylamine with atenolol.7.

The stability of atenolo prodrugs were evaluated in various pH phosphate buffer solutions by HPLC. All O-acylatenoloesters (1-4) produced N-acylated at pH≦7 by imtramolecular N→O acyl migration whereas in alkaline solutions they underwent simultaneous hydrolysis to atenolo and N-acyl derivatives. The half-lives of degradation of the estersranged from 18 min for compound 1 to 32 min for

compound 4 in PH 4 buffer solution. 8,9 In contrast to the esters, all the oxazolidine derivatives of atenolol (9,10) were hydrolyzed to atenolol in buffer solutions. The half-lives of the oxazolidines were about 66 min. 10,11 However, amide compounds 5-8 and oxazolidone compound 11 were found that there is no significant change in any PH conditions. Furthermore, the lipophilicity of the compounds prepared were evaluated in a n-octanol/PH7.4 phosphate buffer system. The partition coefficient of the compounds prepared were 9-68 times more lipophilic than that of atenolol. The enhancement in lipophilicity may be desirable in situations where delivery problem for atenolol are due to its low lipophilicity. The lipophilic atenololo prodrugs may also be useful for design of transdermal delivery preparation.

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