Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1990-12-12
1993-03-16
Bond, Robert T.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
540 30, 540 31, 540 36, 540 38, 540 94, 540 96, 540 97, 552510, 552515, 552519, 552528, 552530, 552562, 552582, 552600, 552601, C07J 1300, C07J 4100, C07J 500
Patent
active
051946025
DESCRIPTION:
BRIEF SUMMARY
The invention relates to new 9.alpha.-hydroxy-17-methylene steroids with a substituted 17-methylene group, to their preparation and to their use in the preparation of corticosteroids.
Nearly all steroids which are currently used as pharmaceuticals originate either directly or indirectly from steroid raw materials found in nature. Originally diosgenin formed the main supply of a raw material. In order to become less dependent of this specific compound investigations have been made to see if other steroids which are abundantly available, e.g. cholesterol, sitosterol, stigmasterol or campesterol could also be used as a starting substance. Microbiological processes were developed to convert in one step said substances into 17-oxo steroids, especially into androst-4-ene-3,17-dione. From the latter compound it was possible to obtain 9.alpha.-hydroxyandrost-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 No. GB-A-1530730, or Mycobacterium species, CBS 482.86, see European patent application No. 87202619.0.
For several syntheses which lead to pharmacologically active steroids 9.alpha.-hydroxyandrost-4-ene-3,17-dione is a very 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 corticosteroids, on the D-ring characterised by the 17.beta.-hydroxyacetyl and 17.alpha.-hydroxy substituents (which both may be esterified), are particularly important representatives of this class. Many corticosteroids possess on the C16-position also a .alpha.-hydroxyl or a methyl group which is either .alpha.- or .beta.-oriented. 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. 1979, 44, 1582 or by Bull. Chem. Soc. Jpn. 1985, 58, 981 and by its references cited under 3) or Chem. Soc. Rev. 1983, 12, 75 or by U.S. Pat. No. 4,500,461 and by its references cited in its introduction. An important group of syntheses of corticosteroids makes use of steroids with an (optionally substituted) 17-methylene group as starting compounds. These may be prepared from the corresponding 17-oxo steroids by well known methods. In case the starting steroid contains also a 9.alpha.-hydroxyl group, the first step is without exception a dehydration to a 9(11)-dehydro steroid. The reason is that the presence of the tertiary 9.alpha.-hydroxyl function is assumed to cause undesired rearrangements, especially in the steroid A-ring, as reported by C. G. Bergstrom and R. M. Dodson, Chemistry and Industry 1961, 1530 and L. J. Chinn & R. M. Dodson, J. Org. Chem. 1959, 24, 879. Because 9(11)-dehydro steroids are believed up to now to be more stable, the dehydration of 9.alpha.-hydroxy steroids seemed to be an obvious reaction to begin, previous to building a side chain of a corticosteroid. No corticosteroid syntheses are known which take along the 9.alpha.-hydroxyl group.
The object of the present invention is to provide starting compounds not earlier used for established routes to the above-said corticosteroids These compounds are 9.alpha.-hydroxy-17-methylene steroids of formula I, which has characteristic cyclopentanopolyhydrophenantrene structure possessing angular methyl groups at C10 and C13. ##STR1## where R.sub.1 is hydrogen, halogen, cyano, isocyano, formamido, (1-6C)alkoxy, (1-6C)alkylcarbonyloxymethyl, methylene, 3,3-alkylenedioxy, 3,3-alkylenedithio or 3,3-alkyleneoxythio group, the alkylene group preferably containing 2 or 3 carbon atoms, methylene, 3,3-alkylenedioxy, 3,3-alkylenedithio or 3,3-alkyleneoxythio group, the alkylene group preferably containing 2 or 3 carbon atoms, alkoxyalkoxy, tetrahydropyranyloxy, amino, 3-alkylamino containing 1 through 4 carbon atoms, 3-dialkylamino wherein the a
REFERENCES:
patent: 3445907 (1969-07-01), Dryden et al.
patent: 3461145 (1969-08-01), Haede et al.
patent: 4462302 (1984-08-01), Nedelec et al.
patent: 4501701 (1985-02-01), Barton et al.
Greene Protective Groups in Organic Synthesis (New York, J. Wiley and Sons, 1981) pp. 133, 144, and 145.
Batisi Jacobus N. M.
Marx Arthur F.
Bond Robert T.
Gist-Brocades N.V.
Ward E. C.
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