Darglitazone

Darglitazone
Legal status
Legal status	In general: uncontrolled;
Identifiers
	IUPAC name 5-[(4-[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propanoyl]phenyl)methyl]-1,3-thiazolidine-2,4-dione;
CAS Number	141200-24-0 ;
PubChem CID	60870;
ChemSpider	54854 ;
UNII	AVP9C03Z3K;
ChEMBL	ChEMBL55624 ;
CompTox Dashboard (EPA)	DTXSID3057644 ;
Chemical and physical data
Formula	C23H20N2O4S
Molar mass	420.481 g/mol g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CC1=C(N=C(O1)C2=CC=CC=C2)CCC(=O)C3=CC=C(C=C3)CC4C(=O)NC(=O)S4;
	InChI InChI=1S/C23H20N2O4S/c1-14-18(24-22(29-14)17-5-3-2-4-6-17)11-12-19(26)16-9-7-15(8-10-16)13-20-21(27)25-23(28)30-20/h2-10,20H,11-13H2,1H3,(H,25,27,28) ; Key:QQKNSPHAFATFNQ-UHFFFAOYSA-N ;
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Darglitazone is a member of the thiazolidinedione class of drugs and an agonist of peroxisome proliferator-activated receptor-γ (PPAR-γ), an orphan member of the nuclear receptor superfamily of transcription factors. It has a variety of insulin-sensitizing effects, such as improving glycemic and lipidemic control, and is used in the treatment of metabolic disorders such as type II diabetes.

Synthesis

The first step in the construction of the terminal side chain in the first glitazones comprises a reaction of benzaldehyde with the mono-oxime from diacetyl to afford the corresponding benzoxazole N-oxide. Reaction of that intermediate with phosphorus oxychloride leads to the chlorination of the adjacent methyl group in a version of the Polonovski reaction to afford the choromethyl derivative. This is then used to alkylate the carbanion from the substituted acetoacetate. Heating the first-obtained product in a strong acid leads to the hydrolysis of the ester. The resulting β-ketoacid loses carbon dioxide under reaction conditions; the acetal hydrolyses also to reveal the free aldehyde. Aldol condensation of this last intermediate in the presence of a base with readily available thiazolidinedione links the two fragments. The double bond in the first-formed product is then reduced catalytically to afford darglitazone.

References

Hulin, Bernard; Clark, David A.; Goldstein, Steven W.; McDermott, Ruth E.; Dambek, Paul J.; Kappeler, Werner H.; Lamphere, Charles H.; Lewis, Diana M.; Rizzi, James P. (1992). "Novel thiazolidine-2,4-diones as potent euglycemic agents". Journal of Medicinal Chemistry. 35 (10): 1853–64. doi:10.1021/jm00088a022. PMID 1588563.