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Synthesis and Evaluation of Azole‐substituted 2‐Aryl‐6‐methoxy‐3,4‐dihydronaphthalenes and ‐naphthalenes as Inhibitors of 17α‐Hydroxylase‐C17,20‐Lyase (P450 17
Author(s) -
Zhuang Yan,
Hartmann Rolf W.
Publication year - 1999
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/(sici)1521-4184(19991)332:1<25::aid-ardp25>3.0.co;2-7
Subject(s) - chemistry , azole , aryl , isocyanide , enzyme , biotransformation , microsome , catalysis , reagent , lyase , organic chemistry , stereochemistry , medicinal chemistry , antifungal , alkyl , medicine , dermatology
The synthesis and biological evaluation of azole‐substituted 3,4‐dihydronaphthalenes ( 7a, 7b, 14a, 14b ) and naphthalenes ( 12a, 12b, 16a, 16b ) as nonsteroidal inhibitors of 17α‐hydroxylase‐C17,20‐lyase (P450 17, CYP 17) are described. In the case of the dihydronaphthalenes, introduction of the phenyl substituent into the 2‐position was accomplished by coupling 2‐hydroxy‐3,4‐dihydronaphthalene‐2‐trifluoromethanesulfonate 1 with the corresponding aryl‐Zn‐bromides 4a and 4b in the presence of Pd(PPh 3 ) 4 as catalyst yielding 5a and 5b as key intermediates. In the case of the naphthalenes, 2‐bromonaphthalene 9 was reacted with the corresponding Grignard reagents yielding 10a and 10b . After transformation of the intermediate acetals 5a, 5b, 10a, 10b into the corresponding aldehydes, the latter compounds were reacted with tosylmethyl isocyanide and K 2 CO 3 to give the oxazoles 7a, 7b, 12a , and 12b . The imidazoles 14a, 14b, 16a , and 16b were prepared by heating the corresponding 4‐tosyloxazolines in ammonia, which were prepared by reacting the aldehydes with tosylmethyl isocyanide and NaCN. Using a microsomal fraction of human testicular enzyme, the title compounds did not inhibit the target enzyme.