Dermatological use of vitamin D derivatives

Details Dermatological use of vitamin D derivatives Dermatological use of vitamin D derivatives

1997-07-21

1998-10-27

Killos, Paul J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

514530, 514550, 560 1, 560121, 560126, 560128, 560184, 560188, A01N 3702, A01N 3708, C07C 6974, C07C 6966

Patent

active

058278834

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to the use of vitamin D derivatives of the formula I ##STR2## wherein X is .dbd.CH.sub.2 or H,H; --CH.sub.2 --CH.sub.2 R.sup.3 ; trifluoromethyl-hydroxy-nieder-alkyl; disorders such as psoriasis, as well as acne and photodamaged skin; and to the use of the compounds of formula I in the manufacture of pharmaceutical compositions for the treatment of the aforementioned conditions.
The invention further relates to novel vitamin D derivatives of the formula I given above, wherein X, Y, A, R.sup.1, R.sup.2, R.sup.3 and n have the above meaning; with the proviso that X is H,H when Y is a moiety the preparation of the compounds of formula I, and to pharmaceutical compositions containing a compound of the formula I wherein X, Y, A, R.sup.1, R.sup.2, R.sup.3 and n have the above meaning; with the proviso that X is H,H when Y is a moiety --CH(CH.sub.3)--CH.sub.2 --OC(O)--C(OH)(CH.sub.3).sub.2 and the dotted bond in the five-membered ring is absent.
The term "lower" as used herein denotes preferably moieties containing 1-5 carbon atoms, such as methyl, ethyl, isopropyl, isobutyl, tert.-butyl and 3-pentyl. Cycloalkyl moieties may be monocyclic such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl or bicyclic such as moieties are 2-hydroxy-2-propyl, 2-hydroxy-2-methyl-butyl and 3-hydroxy-3-methyl-butyl. Examples of hydroxy-cycloalkyl are 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl and 1-hydroxy-cycloheptyl. A trifluoromethyl-hydroxy-lower alkyl moiety is, for example, 2-hydroxy-2-trifluoro-propyl.
In the structural formulas presented herein a broken bond (HO"") denotes that the substituent is below the plane of the paper and a wedged bond (OH) denotes that the substituent is above the plane of the paper. In compounds of formula I wherein the dotted bond in the five-membered ring is absent, Y is above the plane of the paper (Y). In the compounds of formula I wherein Y is a moiety (a) or (b) the carbon atom 20 (the one adjacent to the ring carbon atom) may have R or S configuration.
In accordance with this invention, the novel compounds of formula I can be prepared by a process which comprises removing the hydroxy protecting groups from a compound of the formula II ##STR3## wherein Z is a protecting group and Y' is a moiety Y wherein any hydroxy groups contained therein are protected, .dbd.CH.sub.2 when Y is a moiety --CH(CH.sub.3)--CH.sub.2 --OC(O)--C(OH)(CH.sub.3).sub.2 and the dotted bond in the five-membered ring is absent is excluded,
The protecting groups Z can be any conventional hydroxy protecting group. Examples of such groups are silyl ether protecting groups such as tert.-butyl-dimethylsilanyl. Another example of a hydroxy protecting group is tetrahydropyranyl. The removal of the hydroxy protecting groups Z can be effected in a manner known per se for the removal of such groups. For instance, silylether and tetrahydropyranyl groups can be removed by treatment with acidic reagents, such as hydrogen fluoride or tetrabutyl ammonium fluoride in tetrahydrofuran.
The compounds of formula II can be obtained by reacting a compound of the formula III ##STR4## with a compound of the formula IV ##STR5## or by esterifying a compound of the formula V ##STR6## with an acid of the formula R.sup.2 COOH or a reactive derivative thereof, wherein in the above formulas Ph is phenyl; and Y', X and Z are as defined earlier.
The reaction of a compound of the formula III with a compound of the formula IV can be carried out under the conventional conditions of a Wittig reaction, i.e. in the presence of a base, e.g., butyl lithium, in an inert organic solvent, such as tetrahydrofuran. The esterification of a compound of formula V is suitably carried out by reacting the compound of formula V with the appropriate acid in the presence of a condensation agent such as dicyclohexylcarbodiimide or EDCI or under the conventional conditions of a Mitsunobu reaction. These reactions as well as the preparation of precursors of the compounds of formula II is described in detail in Examples A to S. With an approp

REFERENCES:
K. Allewaert, et al. Bioorg. Med. Chem. Lett. vol. 3, No. 9 pp. 1859-1862 (1993).
M. Chodynski, et al. Steroids, vol. 56, No. 6, pp. 311-315 (1991).
K. Allewaert, et al. Steroids, vol. 59, No. 12 pp. 686-690 (1994).

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