141664-12-2Relevant articles and documents
PROCESS AND INTERMEDIATES TO PREPARE l7?-hydroxy-7alpha-methyl-19-nor-17alpha-pregn-5(10)-en-20-yn-3-one
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Page 25-27, (2010/02/06)
The present invention is a process for the preparation of l7?-hydroxy-7alpha-methyl-19-nor-17alpha-pregn-5(10)-en-20-yn-3-one (17alpha-ethynyl-l7?-hydroxy-7alpha-methyl-5(10)-estren-3-one, tibolone) of formula 1, which comprises hydrolysis of 17alpha-ethynyl-l7?-hydroxy-7alpha-methyl-5(10)-estrene 3,3-cyclic ketals of formula 2, where groups R1, R2, R3 and R4 are hydrogen atoms or alkyl groups, or R1 and R3, taken together with the carbon atoms within the dioxolane ring to which they are attached, form an alicyclic ring fused to the dioxolane ring, with R2 and R4 being hydrogen atoms, or R1 and R3 together with the carbon atoms to which they are attached form an aromatic ring fused to the dioxolane ring, where R2 and R4, taken together, form a chemical bond within said aromatic ring. In addition, the present invention includes an intermediate, compound of formula 2 and two processes to prepare 17alpha-ethynyl-17(3-hydroxy-7alpha-methyl-5(10)-estrene 3,3-cyclic ketals of formula 2: (a) by contacting 17alpha-ethynyl-l7?hydroxy-7alpha-methyl-4-estren-3-one with vicinal diols in the presence of a protic acid, and (b) by contacting 7alpha-methyl-5(10)-estrene-17-one 3,3-cyclic ketals of formula 4, where R1-R4 are defined as above, with metal acetylides, in inert solvents.
7α-Methy-17α-(E-2′[ 125l]iodvinyl)-19-nortestosterone: A new radioligand for the detection of androgen receptor
Hoyte, Robert M.,Brown, Theodore J.,MacLusky, Neil J.,Hochberg, Richard B.
, p. 13 - 23 (2007/10/02)
We have synthesized two γ-emitting, 125I-labeled steroids, E- and Z-7α-methyl-17α-((2′-[ 125I]iodovinyl)-19-nortestosterone [125I](E- and Z-MIVNT) for specific labeling of androgen receptors. [125I]E- and [125I]Z-MIVNTwere synthesized stereospecifically from E- and Z-7α-methyl- 17α-(2′-tri-n-butylstannylvinyl)-19-nortestosterone. The tin adducts were prepared by addition of tri-n-butyltin hydride to 7α-methyl-17α-ethynyl-19-nortestosterone, and after purification they were converted in high yield to the [125I]MIVNT isomers by reaction with 125I (generated in situ by oxidation of [125I] iodide with chloramine T). The 125I-labeledproducts were purified by high-performance liquid chromatography, and their mass determined with an ultraviolet detector (specific activity of both, approximately 2,200 Ci/mmol). In rat prostate cytosol, [125I]E-MIVNT bound with high affinity to a single class of binding sites. Nonspecific binding in the presence of 5α-dihydrotestosterone was relatively low, and compared favorably with that obtained in parallel studies with [3H]methyltrienolone (R1881). The E-isomer bound prostate cytosol with at least twice the affinity of the Z-isomer; therefore, the interaction of the E-isomer with the androgen receptor as well as other steroid receptors was studied in greater detail. Complexes of the androgen receptor with [125I]E-MIVNT as well as [3H]R1881 dissociate very slowly at 4C (kdiss for BOTH = 0.04 h-1). Displacement studies showed that the interaction of[125I]E-MIVNTwith the androgen receptor is highly specific. Competition studies showed that unlabeled E-MIVNT binds poorly to other steroid receptors in rat tissue cytosols. These binding properties make [125I]E-MIVNT a promising ligand for study of the androgen receptor, and [1325I]E-MIVNT a potential imaging agent for the detection of androgen-dependent tumors, such as prostate cancer. (Steroids 58:13-23, 1993).
Synthesis of high affinity fluorine-substituted ligands for the androgen receptor. Potential agents for imaging prostatic cancer by positron emission tomography
Liu,Carlson,Katzenellenbogen
, p. 2113 - 2129 (2007/10/02)
We have prepared nine androgens substituted with fluorine at C-16 or C-20 to evaluate their potential, as positron emission tomographic (PET) imaging agents for prostatic cancer when labeled with the positron emitting radionuclide fluorine-18 (t( 1/2 ) = 110 min). These compounds represent members from the following classes of androgens: testosterone (T), 5α- dihydrotestosterone (DHT), 7α-methyl-19-nortestosterone (MNT), mibolerone (Mib), and metribolone (R1881). All of these compounds were prepared by functionalization of suitable androgen precursors, and the synthetic routes were developed to allow the introduction of fluorine by a fluoride ion displacement reaction late in the synthesis, as is required for the preparation of these compounds in fluorine-18 labeled form. We have also prepared four androgens in which the C-3 carbonyl or 17β-hydroxyl groups are replaced by fluorine. Most of the fluorine-substituted androgens show high affinity for the androgen receptor (AR), although fluorine substitution lowers their affinity by a small factor. None of the androgens where fluorine replaces oxygen functions at C-3 or C-17 have substantial affinity for AR. Derivatives of the natural androgens (T and DHT) as well as MNT have little affinity for other steroid hormone receptors (progesterone and mineralocorticoid receptors), whereas the Mib and R1881 derivatives have somewhat greater heterologous binding. With sex steroid binding protein, a human serum binding protein, the pattern of binding affinities is nearly the reverse, with derivatives of Mib, R1881 and MNT having low affinity, and DHT and T, high affinity. From these fluorine-substituted compounds, we can select several whose preparation in fluorine-18 labeled form for further tissue distribution studies is merited.
