Synthesis of some new testosterone derivatives fused with substituted pyrazoline ring as promising 5alpha-reductase inhibitors.
Condensation of 3beta-hydroxy-16-[(4-chlorophenyl)methylene]androst-5-en-17-one (1) with hydrazine hydrate in acetic acid afforded N-acetyl pyrazoline derivative 2, while condensation of 1 with semicarbazide afforded compound 3. Also, compound 1 was treated with hydrazine hydrate in absolute methanol or ethanol to afford the corresponding alpha-methoxy (4) and alpha-ethoxy (5) derivatives, which were cyclized with etherated boron trifluoride to the pyrazoline derivative 6. The latter could be prepared directly by refluxing 1 with hydrazine hydrate in dioxane. Oxidation of compound 6 with Oppenour or Moffat oxidizing agents yielded 3-oxo-derivatives 7 and 8, respectively. On the other hand, condensation of compound 1 with substituted hydrazines, gave the corresponding 3beta-hydroxyandrostenopyrazolines 9a,b, which were oxidized using the Moffat method to give 3-oxo-androstenopyrazolines 10a,b, which were condensed with ethylene triphenyl-phosphorane in DMSO to yield 3-ethylene androstenopyrazolines 11a,b. Dehydrogenation of 9a,b with Wettestein oxidation afforded Delta4,6-diene-3-one analogues 12a,b, which were treated with chloranil to yield Delta(4,6,8(14))-tri-ene-3-one analogues 13a,b. Oppenour oxidation of 9a,b afforded Delta4-ene-3-one analogues 14a,b, which were treated with dichlorodicyanoquinone (DDQ) in dioxane to give Delta1,4,6-triene-3-one analogues 15a,b. Pharmacological screening showed that many of these compounds inhibit 5alpha-reductase activity.
Amr
Abd El-Galil El-Sayed
Ael-G
Applied Organic Chemistry Department, National Research Centre Dokki, Cairo, Egypt. aamr1963@yahoo.com
Abdel-Latif
Nehad Ahmed
NA
Abdalla
Mohamed Mostafa
MM
D000818:Animals; D042944:Cholestenone 5 alpha-Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013196:Dihydrotestosterone / Q000097:blood; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000633:toxicity; D007279:Injections, Subcutaneous; D007928:Lethal Dose 50; D008297:Male; D011467:Prostate / Q000187:drug effects / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000097:blood; D045165:Testosterone Congeners / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000633:toxicity
D004791:Enzyme Inhibitors; D011720:Pyrazoles; D045165:Testosterone Congeners; D013196:Dihydrotestosterone; D013739:Testosterone; D042944:Cholestenone 5 alpha-Reductase