Vitamin D amide derivatives

Details Vitamin D amide derivatives Vitamin D amide derivatives

1994-05-31

1996-02-27

Kumar, Shailendra

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

9,10-seco- cyclopentanohydrophenanthrene ring system doai

514169, 514319, 552501, 552544, 552547, 552505, 552653, 564188, 564189, 546205, A61K 3159, C07C40100

Patent

active

054949050

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP92/02577, filed on Nov. 06, 1992.
This invention relates to novel vitamin D analogues, more particularly to 1.alpha.-hydroxy vitamin D.sub.3 analogues having a modified side chain at the 17-position and exhibiting cell modulating activity.
Vitamin D.sub.3, which has the formula ##STR1## is well known to play a vital role in the metabolism of calcium, by promoting intestinal absorption of calcium and phosphorus, maintaining adequate serum levels of calcium and phosphorus and stimulating mobilisation of calcium from the bone fluid compartment in the presence of parathyroid hormone.
About 20 years ago it was learned that the D vitamins undergo hydroxylation in vivo, hydroxylation at the 25-position occurring in the liver and hydroxylation at the 1.alpha.-position occurring in the kidney, the resulting 1.alpha.,25-dihydroxy metabolite being the biologically active material. This discovery led to the synthesis of many analogues of vitamin D, evaluation of which indicated that hydroxyl groups at the 1.alpha.-position and at either the 24R- or the 25-position were essential for a compound or metabolite thereof to exhibit a substantial effect on calcium metabolism. While, as indicated above, such hydroxyl groups will normally ultimately be introduced in vivo, hydroxylation at the 24R- or 25-position occurring rather more readily than at the 1.alpha.-position, the use of vitamin D analogues already so hydroxylated has proved of substantial advantage by virtue of their enhanced levels of activity and their rapidity of action and subsequent elimination from the body. It will be appreciated that 1.alpha.-hydroxylated vitamin D derivatives are of especial benefit to patients suffering from renal failure.
Examples of hydroxylated vitamin D analogues in current use include the natural metabolite 1.alpha.,25-dihydroxy vitamin D.sub.3 and 1.alpha.-hydroxy vitamin D.sub.3 (which is readily 25-hydroxylated in vivo). Other reportedly promising compounds include 1.alpha.,24R-dihydroxy vitamin D.sub.3, D.sub.2 analogues of the above compounds and 1.alpha.,25-dihydroxy analogues carrying fluorine atoms at the 24-, 26- and/or 27- positions (See De Luca and Schnoes, Ann. Rev. Biochem. (1983), 52, pp 411-439 and De Luca et al., Top. Curr. Chem. (1979), 83, pp 1-65).
More recently it has been learned that the natural metabolite 1.alpha.,25-dihydroxy vitamin D.sub.3 has additional effects on cellular metabolism. These cell modulating effects include stimulation of cell maturation and differentiation (Tanaka et al., Biochem. J. (1982), 204, pp 713-719; Amento et al., J. Clin. Invest. (1984), 73, pp 731-739; Colston et al., Endocrinology (1981), 108, pp 1083-1086; Abe et al., Proc. Nat. Acad. Sci. (1981), 78, pp 4990-4994) and immunosuppressive effects (e.g. inhibition of interleukin II production) (Rigby, Immunology Today (1988), 9, pp 54-58). Still more recently, an immunopotentiating effect of 1.alpha.,25-dihydroxy vitamin D.sub.3 has been observed, the compound having been found to stimulate the production of bactericidal oxygen metabolites and the chemotactic response of leukocytes (see, for example, Cohen et al., J. Immunol. (1986), 136, pp 1049-1053). It is well known that leukocytes play a major role in the body's defence against various infections (see, for example, Roitt, Brostoff and Male, "Immunology" 2.sup.nd Ed. (1989), C. V. Mosby, St. Louis, sec 16.10-16.13 and 17.4-17.5), e.g. by adhering to and engulfing invading organisms (chemotactic response) and/or by producing superoxides and/or other toxic oxygen metabolites. It is known that this response may also be stimulated by mitogens such as the co-carcinogenic phorbal esters and .gamma.-interferon, which-are structurally quite different from vitamin D analogues.
By virtue of these effects on cellular metabolism, 1.alpha.,25-dihydroxy vitamin D.sub.3 in principle has therapeutic potential in such diverse areas as treatment of psoriasis, inflammatory and autoimmune diseases, neoplasias and-hyperplasias, as an adjunct in the chemotherapy o

REFERENCES:
patent: 4217288 (1980-08-01), DeLuca et al.
patent: 5206230 (1993-04-01), Ikekawa et al.
Calverly, Tetrahedron, vol. 43, No. 20, pp. 4609-4619, 1987.
Kabakoff et al.; "In Vitro Inhibitor Studies of Vitamin D 25-Hydroxylase in Rat Liver Microsomes"; Archives of Biochemistry and Biophysics, vol. 221, No. 1, 1983, pp. 38-45.

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