Synthesis of novel water soluble benzylazolium prodrugs of lipophilic azole antifungals

Bioorganic and Medicinal Chemistry Letters

Volumn 12, Issue 19, 2002, Pages 2775-2780

  Ohwada, Jun ^a   Murasaki, Chikako ^a   Yamazaki, Toshikazu ^a   Ichihara, Shigeyasu ^a   Umeda, Isao ^a   Shimma, Nobuo ^a  

^a NIPPON ROCHE RESEARCH CENTER   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIFUNGAL AGENT; BENZYL DERIVATIVE; IMIDAZOLE DERIVATIVE; PRODRUG; TRIAZOLE DERIVATIVE; WATER;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; ASPERGILLUS FUMIGATUS; CANDIDA ALBICANS; CANDIDIASIS; CONTROLLED STUDY; DRUG DESIGN; DRUG EFFICACY; DRUG RELEASE; DRUG SOLUBILITY; DRUG STABILITY; DRUG SYNTHESIS; LUNG ASPERGILLOSIS; MALE; NONHUMAN; PHYSICAL CHEMISTRY; RAT;

ANIMALS; ANTIFUNGAL AGENTS; ASPERGILLUS FUMIGATUS; AZOLES; CANDIDA ALBICANS; CANDIDIASIS; CHEMISTRY, PHYSICAL; HALF-LIFE; HUMANS; ITRACONAZOLE; KETOCONAZOLE; MICROBIAL SENSITIVITY TESTS; PRODRUGS; RATS; SOLUBILITY; THIAZOLES; TRIAZOLES;

EID: 0037037390     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(02)00557-7     Document Type: Article

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17. Compound 1 was prepared as follows. 3,5-Dimethyl-4-hydroxybenzyl alcohol (2.5 g) in 5 mL of 48% HBr and 45 mL of acetic acid was stirred for 40 min at 15°C and the mixture was poured onto a mixture of chloroform and ice-water. The organic layer was dried and concentrated to give 1 as a white solid, which could be used without further purification.
18. Compound 9 was obtained as a stable powder and quickly released BMS-207147 in an alkaline medium.
19. 2O: C, 51.68; H, 4.76; N, 10.64; S, 4.06. Found: C, 51.64; H, 4.93; N, 10.31; S, 3.94.
20. The compounds were incubated with human plasma at a concentration of 10 μg/mL at 37°C for up to 120 min.
21. In the systemic candidiasis and aspergillosis model in rat, the efficacy of 16 was slightly reduced in spite of its high conversion rate in plasma. The reason is unclear so far.