153463-20-8

As part of a program to prepare Δ8(14)-15-ketosterols that cannot readily be metabolized to cholesterol or side-chain oxygenated species, we have prepared 3β-hydroxy-7α-fluoro-5α-cholest-8(14)-en-15-one (VII) and the 9α-hydroxy (IV), 9α-fluoro (VI) and 7α-fluoro (VIII) derivatives of 3β-hydroxy-25,26,26,26,27,27,27-heptafluoro-5α-cholest-8(14)-en-15- one (II). Sterol IV was prepared by oxidation of the Δ8,14 dienol ethyl ether of the 3β-acetate of II with m-chloroperbenzoic acid, followed by mild alkaline hydrolysis of the 3β-acetate derivative of IV. Treatment of IV with hydrogen fluoride-pyridine gave VI. The 7α-fluoro-15-ketosterols VII and VIII were synthesized by treating the 3β,15-bis-trimethylsilyl Δ7,14-dienol ether derivative of the appropriate Δ8(14)-15-ketosterol with N-fluoropyridinium triflate, followed by hydrolysis of residual trimethylsilyl ethers and purification by high-performance liquid chromatography. The combined results of 1H and 13C nuclear magnetic resonance (NMR) chemical shifts, 1H-1H coupling constants, 1H-19F long-range coupling constants and molecular modeling indicated that a 7α-fluoro, 9α-fluoro or 9α-hydroxy substituent has negligible effect on the conformation of the 15-ketosterols. 1H and 13C-NMR data are also given for Δ6,8(14)- and δ8(14),9(11)-15-ketosterols, synthetic byproducts that could not be detected readily in samples of the fluoro-15-ketosterols by chromatographic methods. Mass spectra of VI and of previously reported 9α-fluoro and 9α-hydroxy-Δ8(14)-15-ketosterols showed abundant M-62 or M-60 ions that appear to correspond to loss of ketene and HF or H2O. The 9α-hydroxy-F7-15-ketosterol IV, the 7α-fluoro-15-ketosterol VII and the 7α-fluoro-F7-15-ketosterol VIII were of equivalent potency to the parent 3β-hydroxy-5α-cholest-8(14)-en-15-one (I) in lowering the levels of 3- hydrox-3-methylglutaryl coenzyme A reductase activity in CHO-K1 cells. The 9α-fluoro-F7-15-ketosterol VI showed high potency but appeared to be slightly less active than I.

3β-Hydroxy-25,26,26,26,27,27,27-heptafluor 5α-cholestan-15-one (4) has been prepared as part of a program to synthesize 15-ketosterols that are not readily metabolized to cholesterol or side-chain oxygenated species. Saponification of 3β -acetoxy-5α-chola-8(14),23-dien-15-one (5) followed by lithium-ammonia reduction with a bromobenzene quench gave 3β-hydroxy-5α-chol-23-en-15-one (6). Addition of (CF3)2CFI to 6 in the presence of triethylborane gave an iodide preparation, which was reduced to 4 with tributyltin hydride (71% overall yield of 4 from 5). The 23-iodide preparations consisted of 6:1 mixtures of (23R)-3β -hydroxy-23-iodo-25,26,26,26,27,27,27-heptafluoro 15-one (9a) and its C-23 epimer 9b with variable amounts of 4. Compound 4 was also prepared by lithium-ammonia reduction of the Δ814 analogs of 4 and iodides 9a and 9b. The presence of small amounts of 6 in the latter product suggested a side reaction involving cleavage of the C24-C25 bond with loss of a (CF3)2 CF· radical. Also prepared were 25,26,26,26,27,27,27-heptafluoro-5α-cholestane-3β,15α-diol, its 15β epimer, the 7α-methyl analog of 4, 3β-hydroxy-7α-methyl-5α-cholestan-15-one (16), and (25R)-3β,26-dihydroxy-5α-cholestan-15-one. Full 1H and 13C-NMR data of high precision with complete signal assignments are given for all new compounds. Definitive 1H-NMR stereochemical assignments of the C-24 protons were established for most sterols with a C8H17 side chain based on analysis of the downfield H-24 resonance in a 750-MHz spectrum of 16. Detailed electron-impact mass spectral data are presented together with a summary of major fragmentation patterns for 15-hydroxy-and 15-ketosteroids with and without a Δ814 bond.

Pharmaceutical compositions are provided for lowering the activity of HMG-CoA reductase and/or lowering serum cholesterol, comprising an amount effective to lower the activity of HMG-CoA reductase and/or lower serum cholesterol of a side chain derivatized