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行政院國家科學委員會補助專題研究計畫成果報告
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※ 含間苯血栓素抗拮劑的設計與合成
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計畫類別：■個別型計畫 □整合型計畫
計畫編號：NSC89－2113－M－006－006－
執行期間：89 年 7 月 31 日至 89 年 10 月 31 日
計畫主持人：簡偉明
執行單位：國立成功大學藥理研究所
中 華 民 國 89 年 10 月 31 日
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含間苯血栓素抗拮劑的設計與合成
Design and Synthesis of Inter phenylene Thr omboxane
Antagonists
計畫編號：NSC89－2113－M－006－006
執行期限：88 年 8 月 1 日至 89 年 7 月 31 日
主持人：簡偉明 國立成功大學藥理研究所
一、中文摘要 設計及合成兼具血栓素抗拮劑及前列腺環素 致效作用的血小板抑制劑，將可防止因血小板過度 敏感而引起的不正常血小板凝集及血栓的生成。本 報告描述此類抗拮劑 7-oxabicyclo[2.2.1]heptane 衍 生物的合成及初步藥理研究結果。 關鍵詞：血栓素抗拮劑、前列腺環素致效劑、血小 板抑制劑 AbstractDesign and synthesis of platelet inhibitors that contain both thromboxane antagonist and prostacyclin agonist activity should be beneficial for the prevention of abnormal platelet aggregation and thrombus formation by hyperactive platelets. Here we reported the synthesis of a
7-oxabicyclo[2.2.1]-Heptane derivative and its preliminary pharmacological properties.
Keywords: Thromboxane antagonist, Prostacyclin
agonist, Platelet inhibitor
二、緣由與目的
Platelet abnormality may result in various blood clotting disorders, which may be fatal. The
regulation of platelet functions, especially aggregation is related to second messengers such adenosine diphosphate and thromboxane A2. These molecules
generate a positive feedback leading to an irreversible platelet aggregation and thrombi formation. Of the two amplifiers, thromboxane A2 is more potent and its
effects irreversible. On the other hand, prostacyclin desensitizes platelets by increase of intracellular camp level which prevents the aggregation process.
In the past, thromboxane antagonists were proposed to be used as anti-platelet agents that may prevent platelet activation and aggregation.
Previously, attempts have been made to produce either pure thromboxane antagonist and prostacyclin agonists. However, the results were significant but far from satisfactory. It is possible that a single mechanism is not sufficient to prevent multi-cause platelet hyper-reactivity. Nevertheless, if the same moiety contains
both thromboxane antagonistic prostacyclin agonistic activities, it not only stabilizes the platelets and increases the threshold to activate them, but also prevents the secondary positive feedback event of activation.
As a result, we planned to design and synthesize thromboxane receptor antagonists that also process prostacyclin agonistic activities.
三、結果與討論
Since we have some experience in the design of thromboxane antagonists, we used 7-oxabicyclo[2.2.1]heptane as the backbone which has been shown to process strong thromboxane antagonistic activity. By variation of the lower portion of the molecule, we hope to come up with an useful anti-platelet agent. Here we would like to report the synthesis of an interesting dual thromboxane antagonist and prostacyclin agonist, 1-[4-(2- carboxyethyl)-benzyl]-2-{(4-isopropoxyl)phenyl-1,2,4-diazolyl}-7-oxabicyclo[2.2.1]heptane.
The synthesis started with the known, 1-[4-(2-carboxyethyl)-benzyl]-
7-oxabicyclo[2.2.1]-heptane-2-carboxylic acid. Conjugation of which with 2-isopropoxylphenylamidine results in the formation 3 in excellent yield. Heating of the resulting compound affords 4 quantitatively. Hydrolysis of the methyl ester 4 in alcoholic potassium hydroxide yielded the target compound in 84%.
2-isopropoxylphenylamidine was synthesized from 2-cycanophenol. After isopropoxyl ether formation with isopropyl bromide, resulted 6 in good yield. Addition of hydroxylamine to 6, afforded the desired compound.
Preliminary pharmacological studies indicated that some derivatives of 5 are potent thromboxane antagonists that inhibit the thromboxane agonist; U46, 619 induced platelet aggregation and ADP induced aggregation. They also act on the prostacyclin receptor with moderate activities.
3 COOH O COOCH3 COOH O COOCH3 CONH O COOCH3 N O OH O COOCH3 O N N O O COOH O N N O 3 4. 5. 6. 1 2 3 4 5 OH CN O CN O NH NHOH 1. 2. 6 7
Figur e One. Synthesis of Anti-platelet Agent 5.
1, Isopropyl bromide; 2. Hydroxylamine; 3. Epimerisation; 4. Amide formation with 7; 5.
heating; 6, Hydrolysis.
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四、計畫成果自評
Dual thromboxane antagonist and prostacyclin agonist,
1-[4-(2-carboxyethyl)-benzyl]-2-
{(4-isopropoxyl)phenyl-1,2,4-diazolyl}-7-oxabicyclo[2.2.1]heptane is a good lead for the discovery of even more potent anti-platelet agents. Progress has been made recently and will be reported in due course.
五、參考文獻
1. Bergstrom, S; Carlson, LA; and Weeks, JR. (1968) Pharmacol. Rev. 20, 1-48.
2. Armstrong, RA; Jones, RL; Peesapati, V; Will, SG. (1985) Br. J. Pharmacol. 84 595-607. 3. Jones, RL. (1999) Pharmacology in the next
millennium. The Eighth IUPHAR SEAWP meeting, Taipei. Abstract S089.
