새로운 베타-락탐 抗生物質의 合成과 生物活性에 關한 硏究 = Study on the synthesis & antibacterial activity of new β-lactam antibiotics

국문 초록 (Abstract)

본 硏究는 좋은 抗菌活性이 期待되는 經口用 베타-락탐 抗生物質들을 開發하기 爲한 것으로서, 새로운 化合物들을 合成하고 그 化合物들의 生物活性을 試驗管內에서 試驗하였다.
6-아미노페니실란酸 및 7-아미노세팔로스포란酸誘導體의 아미노基에 ---經口用에서 그램陽性菌에 對해 强한 活性을 나타내는 ---D(-)-α-페닐글리신類을 아실化 反應시켜 6-[D(-)-α-아미노페닐아세트아미도]페니실린酸 및 7-[D(-)--아미노페닐아세트아미도]세팔로스포란 酸類를 製造하고, 다시 이들의 아미노基에 ---세팔로스포린系에서 그램陰性菌에 對해 强한 抗菌力을 나타내는 ---(Z)-2-알콕시이미노-2-(2-아미노티아졸-4-일) 아세트그룹을 導入하여 6-[D(-)-α-[(Z)-2-알콜시이미노-2-(2-아미노티아졸-4-일) 아세트아미노]페닐아세트아미도]페니실란酸 및 7-[(D)-α-[(Z)-2-알콕시이미노-2-(2-아미노티아졸-4-일)아세트아미노]페닐아세트아미도]세팔로스포란酸類의 新規化合物들을 合成하였다.
또 이 (Z)-2-알콕시이미노-2-(2-아미노티아졸-4-일)아세트酸의 티아졸環을 피리딘, 피리미딘 및 피롤環 等으로 變化시킨 化合物들을 合成하고 이 誘導體를 7-아미노세팔로스포란酸誘導體와 아실化 反應시켜 새로운 物質의 合成을 試圖하였다. 그러나 이들은 아직까지 目的化合物을 얻지 못하였으나 繼續 硏究中에 있다.
이들 合成된 24個의 新規合成物들의 抗菌活性을 試驗管內에서 試驗하였다. 그 結果, 大部分 좋은 抗菌活性을 나타냈으며 一部는 그램陽性菌에 對하여, 一部는 그램陰性菌에 對하여 旣存의 比較 抗生物質보다 優秀하였다. 特히 7-[D(-)-α-{(Z)-2-(2-아미노티아졸-4-일)-2-메톡시이미노아세트아미도}(p-히드록시페닐)아세트아미도]-3-[(1-메틸-1H-테트라졸-5-일)티오메틸]-3-세펨-4-카르복시酸(K11)은 Sa. lutea, B. subtilis에 强한 抗菌力을 나타내었다.

다국어 초록 (Multilingual Abstract)

To develope oral antibiotics having good antibacterial activity, several new β-lactam antibiotic compounds were synthesized and their antibacterial activities were tested in vitro.
6-[D(-)-α-Aminophenylacetamido]penicillanic and 7-[D(-)-α-aminophenylacetamido]cephalosporanic acid derivatives were prepared by acylation of the amino group of 6-APA and 7-ACA derivatives with D(-)-α-phenylglycine and [D(-)-α-(p-hydroxyphenyl)]glycine, which consist of the oral antibiotics having the strong activity against Gram-positive bacteria. In further pursuit, new compounds of 6-[D(-)-α-[(Z)-2-alkoxyimino-2-(2-aminothiazol-4-yl)acetamido]phenylacetamido] penicillanic and 7-[D(-)-α-[(Z)-2-alkoxyimino-2-(2-aminothiazol-4-yl)acetamido]phenylacetamido]cephalosporanic acid derivatives were synthesized by introducing (Z)-2-alkoxyimino-2-(2-aminothizol-4-yl) acetyl group--constituent which represents the potent antibacterial activity against Gram-negative bacteria among the cephalosporin antibiotics--into the amino group of the above compounds.
It was also attempted to synthesize another new β-lactams having pyrrole, pyridine and pyrimidine ring in place of thiazole ring of (Z)-2-alkoxyimino-2-(2-aminothiazol-4-yl)acetyl group, but the compounds were not obtained yet.
The antibacterial activities of new 24 compounds were tested in vitro. As the results, most of them showed a good activity. Especially, 7-[D(-)-α-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido](p-hydroxyphenyl)acetamido]-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid(K11) was very active in vitro against strains of Sa. lutea and B. subtilis.

목차 (Table of Contents)

• 目次 = V
• 要約 = I
• 略語 = III
• 1. 緖論 = 1
• 2. 結果 및 考察 = 4
• 3. 結論 = 23
• 4. 實驗 = 24
• 實驗 1. = 24
• 實驗 2. = 25
• 實驗 3. = 27
• 實驗 4. = 27
• 實驗 5. = 28
• 實驗 6. = 28
• 實驗 7. = 29
• 實驗 8. = 31
• 實驗 9. = 31
• 實驗 10. = 33
• 實驗 11. = 34
• 實驗 12. = 35
• 實驗 13. = 35
• 實驗 14. = 37
• 實驗 15. = 38
• 實驗 16. = 38
• 實驗 17. = 38
• 實驗 18. = 40
• 實驗 19. = 41
• 實驗 20. = 42
• 實驗 21. = 42
• 實驗 22. = 43
• 實驗 23. = 44
• 實驗 24. = 44
• 實驗 25. pyrrole誘導體의 合成. = 45
• 實驗 26. pyrimidine誘導體의 合成. = 46
• 實驗 27. Minimum Inhibition Concentration (MIC. in vitro)의 測定. = 52
• 參考 文獻 = 53
• Abstract = 105