Wildonger K J, Ratcliffe R W
Department of Synthetic Chemical Research, Merck Research Laboratories, Rahway, New Jersey 07065.
J Antibiot (Tokyo). 1993 Dec;46(12):1866-82. doi: 10.7164/antibiotics.46.1866.
The syntheses of five thiols, including three dihydropyrrolotriazoliumthiol salts, 1,4-dimethyl-5-mercaptomethyl-1,2,4-triazolium trifluoromethanesulfonate, and 6-mercapto-6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazolium chloride; and the addition of these thiols to 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphono)oxy-6-[1(R)-hydroxyethyl]-1-met hylcarbapen-2-em-3-carboxylate and the subsequent hydrogenolysis of the addition products is described. The latter thiol provides a new route towards the preparation of L-627 (LJC 10,627). The compounds were evaluated in vitro against a panel of Gram-positive and Gram-negative bacteria and their antibacterial activities compared with imipenem. The compounds were measured for their hydrolytic stability to dehydropeptidase I (DHP-I) relative to imipenem. The five compounds generally had poorer Gram-positive and Pseudomonas activity than imipenem, although their Gram-negative activity was variably improved. The monocyclic triazolium analog was nearly comparable in overall activity to the four bicyclic heterarylium analogs evaluated, including L-627 (LJC 10,627). All compounds were more stable to DHP-I than imipenem, although minor differences existed among them.
描述了五种硫醇的合成，包括三种二氢吡咯并三唑硫醇盐、1,4 - 二甲基 - 5 - 巯基甲基 - 1,2,4 - 三唑三氟甲磺酸盐以及6 - 巯基 - 6,7 - 二氢 - 5H - 吡唑并[1,2 - a][1,2,4]三唑氯化物；还描述了将这些硫醇加成到4 - 硝基苄基(1R,5R,6S)-2-(二苯基膦酰基)氧基 - 6 - [1(R)-羟乙基]-1 - 甲基碳青霉烯 - 2 - 烯 - 3 - 羧酸盐上以及随后对加成产物进行氢解的过程。后一种硫醇为制备L - 627（LJC 10,627）提供了一条新途径。对这些化合物进行了体外抗一组革兰氏阳性和革兰氏阴性细菌的评估，并将它们的抗菌活性与亚胺培南进行了比较。还测定了这些化合物相对于亚胺培南对脱氢肽酶I（DHP - I）的水解稳定性。这五种化合物的革兰氏阳性菌和假单胞菌活性通常比亚胺培南差，不过它们的革兰氏阴性菌活性有不同程度的提高。单环三唑类似物的总体活性与所评估的四种双环杂芳基类似物（包括L - 627（LJC 10,627））几乎相当。所有化合物对DHP - I的稳定性都比亚胺培南好，尽管它们之间存在细微差异。
