Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclopentanohydrophenanthrene ring system containing
Patent
1989-09-25
1994-10-04
Ford, John M.
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclopentanohydrophenanthrene ring system containing
552612, C07J 100
Patent
active
053528093
DESCRIPTION:
BRIEF SUMMARY
The invention relates to new 9-alpha-hydroxy steroids with a substituted D-ring, to their preparation and to the subsequent dehydration to 9,11-dehydro steroids.
Nearly all steroids which are currently used as pharmaceuticals originate either directly or indirectly from steroid raw materials found in nature. Originally diosgenin constituted the main supply of this raw material. In order to become less dependent of this specific compound one has investigated whether other steroids which are abundantly available, viz. cholesterol, sitosterol, stigmasterol and campesterol could also be used as starting material. Microbiological syntheses were developed to prepare in one step from said materials 17-oxo steroids, especially androst-4-ene-3,17-dione. From the latter compound it was possible to obtain 9-alpha-hydroxy-androst-4-ene-3,17-dione using a second microbiological step. This compound can be prepared even directly from the above-mentioned sterols, for example by using a specific Mycobacterium fortuitum strain, see British patent GB 1530730.
9-Alpha-hydroxyandrost-4-ene-3,17-dione is for several syntheses which lead to pharmacologically active steroids a suitable starting compound, because it is apt to functionalisation in the D-ring, as well as in the C-ring of the steroid nucleus. An important class of steroids containing many pharmacologically active compounds are the pregnanes. The corticostoroids, on the D-ring characterized by the (optionally esterified) 17-beta-hydroxyacetyl, 17-alpha-hydroxy substituents are particularly important representatives of this class. Many possess also a methyl or hydroxyl group on C.sup.16. Multi-step chemical syntheses of pregnanes starting from the readily available above-mentioned 17-oxo steroids are well known in the art as illustrated by J. Org. Chem., Vol. 44, no. 9 (1979), 1582-1584 or by Bull. Chem. Soc. Jpn., Vol. 58, 981-986 (19,35) and by its references cited under 3) or by U.S. Pat. No. 4,500,461 and by its references cited in its introduction. In case the starting compound is a 9-alpha-hydroxy steroid, the first step is without exception a dehydration to a 9,11-dehydro steroid. The reason probably is that the presence of the tertiary 9-alpha-hydroxyl function is assumed to cause undesired rearrangements, especially in the steroid A-ring. See e.g. C. G. Bergstrom and R. M. Dodson, Chemistry and Industry, 1530 (1961) and L. J. Chinn & R. M. Dodson, J. Org. Chem. 24 (1959), 879. Because 9,11-dehydro steroids are believed to be more stable and a good starting point for the introduction of substituents on C.sup.9 and C.sup.11 the dehydration of 9-alpha-hydroxy steroids seemed to be an obvious reaction to begin every synthesis.
The object of the present invention is to provide new routes to tile above-said corticosteroids, which routes are characterized by the use of a common type of new intermediates, The invented intermediates belong to a novel class of 9-alpha-hydroxy steroids, characterised by a D-ring according to formula I ##STR1## where R.sub.2 is --C.tbd.CY (provided, when R.sub.4 and Y both are hydrogen, R.sub.5 is not acetyloxy), Y is hydrogen or halogen, optionally protected hydroxy, cyano, 1'-( 1-6C)alkoxy-ethenyl, 1'-(1-6C) alkylthio-ethenyl, 1'-aryloxy-ethenyl, 1'-arylthioethenyl, 1',1'-trimethylenedithio-ethyl, haloethynyl, sulfonate, sulfite, trialkylsilyloxy, optionally halogenated (1-6C)carboxylic acyloxy, --C(.dbd.NR.sub.80)--CH.sub.3, --C(NHR.sub.82).dbd.CH.sub.2, --C(.dbd.NR.sub.80)--CH.sub.2 X, X is halogen, chlorine atoms, methyl or nitro groups, R.sub.4 is not hydrogen), hydroxy, optionally halogenated (t-6C)carboxylic acyloxy, hydrogen,
More particularly the novel 9-alpha-hydroxy steroids are characterized by the general formula II ##STR2## where R.sub.2 -R.sub.5 are as defined above while the rings A, B, C and D may contain one or more double bonds, these double bonds being preferably present between C.sup.1 and C.sup.2, C.sup.3 and C.sup.4, C.sup.4 and C.sup.5, C.sup.5 and C.sup.6, C.sup.6 and C.sup.7, and/or C.sup.11 and C.sup.12, more p
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Eppstein, et al, JACS 80(7) 1958 pp. 3382 to 3389.
Batist Jacobus N. M.
Kapur Jagdish C.
Marx Arthur F.
Van Zoest Willem J.
Ford John M.
Gist-Brocades N.V.
Sripada P. K.
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