Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Patent
1988-02-24
1990-04-03
Robinson, Douglas W.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
514174, 514176, 514180, 514181, 540 67, 540108, 540111, 552523, 552529, 552565, 552566, 552564, 552580, 552581, 552572, 552573, 552574, 552575, 552588, 552589, 552590, 552594, 552595, 552596, 552597, 552598, 552601, 552602, 552604, 552605, 552607, 552608, C07S 900, A61K 3156
Patent
active
049138529
DESCRIPTION:
BRIEF SUMMARY
The invention has as an object novel compounds obtained from the associative synthesis of sulfur-containing or sulfur-free amino acids with derivatives of .DELTA.-4-pregnene-3,20-dione or with derivatives of .DELTA.-1,4-pregnadiene-3,20-dione, as well as their addition salts with mineral or organic acids in the presence of the amino group or their mineral salts in the presence of the carboxylic group, processes for their preparation, their pharmacological activity and pharmaceutical compositions containing them.
At present, anti-inflammatory steroids having hydrosolubility have already been described, especially as regards their use by injectable means. To this end, synthesis of esters at the 21 and/or 17 position of steroids with polybasic acids or amino acids has already been described.
On the other hand, anti-inflammatory steroids obtained from the associative synthesis between amino acids and steroids having an ester function at the 21 position and sulfur-containing at the level of the side chain, but not having a salifiable free amino group have also already been described.
The present invention concerns anti-inflammatory steroid compounds resulting from an associative synthesis between steroid and amino acids and having a reservoir effect associated with a cutaneous tropism where a hydrosoluble group in the form of a mineral or organic salt is favorable.
To obtain this conjoint double activity, the claimed novel structures respond to the three general formulas I, II and III, and have:
Either an ester bond at position 21 but comprising a sulfur-containing amino acid structure with a free amino group (general formula I).
Or an amino group at position 21 obtained from sulfur-containing or sulfur-free amino acid (formula II),
Or a sulfur-containing group at position 21 and a terminal amino acid structure (formula III), ##STR2## in which: for the three general formulas I, II, and III the C.sub.1 -C.sub.2 bond may be a saturated bond (hydrocortisone derivatives for example), or may be an ethylenic bond (dexamethasone derivatives for example); R.sub.5 may also be methylene; --O--C(Y).sub.2 --O--, 4 carbon atoms; for protecting the thiol function; formula I with formation of a disulfur bridge; especially methyl obtained from alanine, or a branched chain alkyl group, obtained from valine, leucine, isoleucine, or a linear hydroxyalkyl group, obtained from serine, threonine, or a thioalkyl group obtained from methionine, or a thioalkyl group obtained from cysteine, or an arylalkyl group for example either benzyl obtained from phenylalanine, or hydroxybenzyl obtained from tyrosine, or indolylalkyl obtained from tryptophan, or imidazolylalkyl obtained from histidine, or an amidoalkyl group obtained from asparagine, glutamine, or a carboxylic alkyl group in free form or salified with sodium, obtained for example from aspartic acid, glutamic acid or cyclicized in the form of pyroglutaminic acid, or an alkyl amino group obtained from lysine, or a guanidinoalkyl group obtained from arginine, or also a dithiodimethyl group obtained from cystine, symmetrically fixing two glucocorticoids; pyrrolidine type obtained from proline; calcium; having 1 to 4 carbon atoms, or an arylalkyl group of the benzyl or heterocyclic type; or n=2 obtained from homocysteine; chain alkyl group preferably having 1 to 3 carbon atoms, in the form of an ammonium or amino-containing structure; or branched chain alkyl group, or arylalkyl.
The invention also has an object processes for preparing derivatives as defined by formulas I, II and III above.
For the derivatives of formula I, the process consists of successive transformations of the steroid to mesylate then to an iodine-containing derivative, this latter reacting with the carboxylic function of an amino acid whose amine function is protected by tert-butyloxycarbonyl. Thereafter, the protective group of the amine function is eliminated. The steroid may be hydrocortisone, or dexamethasone or any other glucocorticoid steroid having the --CO--CH.sub.2 OH chain, the amino acid is especially cys
REFERENCES:
"Solution Kinetics of a Water-Soluble Hydrocortisone Prodrug: Hydrocortisone-21-Lysinate", Journal of Pharmaceutical Sciences, vol. 74, No. 1, By K. Johnson et al., Jan. 1985, pp. 87-89.
Efthyimiopoulos Constantin
Jung Jean
Jung Louis
Koch Bernard
Milioni Catherine
Henley III Raymond J.
Robinson Douglas W.
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