3-Carboxy-5-methyl-N-[4-(trifluoromethyl)phenyl]-4-isoxazolecarboxamide, a new prodrug for the antiarthritic agent 2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide.
The title compound 3-carboxyisoxazole 3 was synthesized by cycloaddition of carbethoxyformonitrile oxide to N-[4-(trifluoromethyl)phenyl]-3-pyrrolidino-2-butenamide (6) with spontaneous elimination of pyrrolidine followed by hydrolysis of the ethyl ester. Compound 3 was shown to be absorbed intact after oral administration to rats. Over 24 h, the compound was metabolized to yield plasma concentrations of the antiinflammatory agent 2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide (2), similar to those obtained following an equivalent dose of the established prodrug of 5-methyl-N-[4-(trifluoromethyl)phenyl]isoxazole-4-carboxamide (1).
Patterson
J W
JW
Institute of Organic Chemistry, Syntex Research, Palo Alto, California 94304.
Cheung
P S
PS
Ernest
M J
MJ
D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism*; D001168:Arthritis / Q000188:drug therapy*; D003437:Crotonates; D006885:Hydroxybutyrates / Q000138:chemical synthesis* / Q000378:metabolism*; D008297:Male; D009570:Nitriles; D011355:Prodrugs / Q000138:chemical synthesis* / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D014052:Toluidines
D000814:Aniline Compounds; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003437:Crotonates; D006885:Hydroxybutyrates; D009570:Nitriles; D011355:Prodrugs; D014052:Toluidines; C073586:3-carboxy-5-methyl-N-(4-(trifluoromethyl)phenyl)-4-isoxazolecarboxamide; C527525:teriflunomide