Synthesis of 3-hydroxy-3-cyclohexylbutyric acid derivatives. 1. Cyclic homologues of 3-hydroxy-3-methylglutaric acid

Z and E isomers of 3-methyl-3-(carboxymethyl)hexahydro-1 (3H)-isobenzofuranones (I), lactones of 3-hydroxy-3-(2-carboxycyclohexyl) butyric acids (II), were prepared and tested on cholesterol biosynthesis in vitro. Compound I of the Z series was prepared through its ethyl ester by hydrogenation, over Rh/Al2O3 catalyst, of the phenyl ring of 3-methyl-3-[(ethoxycarbonyl)methyl]-1(3H)-isobenzofuranone. Compound I of the E series was prepared, through its ethyl ester, by Reformatsky reaction from ethyl (E)-2-acetylcyclohexanecarboxylate. 3-Methyl-3-(carboxymethyl)-5,6,7,8-tetrahydro-1(3H)-isobenzofuranone, 3-methyl-3-ethyl-5,6,7,8-tetrahydro-1(3H)-isobenzofuranone, and 3-methyl-3-(carboxymethyl)-1(3H)-isobenzofuranone were also prepared and tested. The above compounds inhibited acetate incorporation in cholesterol and fatty acids in rat liver slices at 5 X 10(-3) M but lack specific inhibitory activity on HMG-CoA reductase.     

Lactone, 10. Mitt. Zur Synthese N-heterocyclisch substituierter γ,γ-Diphenyl-γ-butyrolactone

Lactones, X: Synthesis of γ,γ-Diphenyl-γ-butyrolactones Substituted by N-Heterocycles Starting from 3 and 16 , syntheses of γ,γ-diphenyl-γ-butyrolactones with N-heterocycles at the α-position are described. Scope and limitation of the syntheses, tautomerism and stereochemistry of the products as well as spectroscopic results which are inconsistent with data from the literature are discussed.     

Synthesis of 3-hydroxy-3-phenacyloxindole analogs.

Substituted isatins and substituted acetophenones were condensed to give analogs of 3-hydroxy-3-phenacyloxindole. These alcohols were dehydrated, and the alkene was reduced. None of the products had the level of anticonvulsant activity exhibited by the parent compound.     

CMT-3. CollaGenex

CMT-3 is an orally active matrix metalloprotease inhibitor, and one of a series of inhibitors of multiple proteases and cytokines, under development by CollaGenex. The compound is currently undergoing phase II trials for the potential treatment of cancer, in particular metastatic cancer and HIV-related Kaposi's sarcoma.     

Antiarrhythmic activity of 3-amino-3-methyloxindoles.

A series of 3-amino-3-methyloxindoles was synthesized from indoles by modification of previously described procedures. All compounds showed activity against chloroform-induced arrhythmias in mice. One member of the series, 3-methyl-3-piperidinooxindole, displayed activity equal to that of lidocaine while showing only one-third the acute toxicity.