Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 9,10-seco- cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2002-02-18
2003-05-20
Qazi, Sabiha (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
9,10-seco- cyclopentanohydrophenanthrene ring system doai
C552S653000
Reexamination Certificate
active
06566352
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to vitamin D compounds, and more particularly to 1&agr;-hydroxy-2-methylene-19-nor-pregnacalciferol and its pharmaceutical uses.
The natural hormone, 1&agr;,25-dihydroxyvitamin D
3
and its analog in ergosterol series, i.e. 1&agr;,25-dihydroxyvitamin D
2
are known to be highly potent regulators of calcium homeostasis in animals and humans, and their activity in cellular differentiation has also been established, Ostrem et al., Proc. Natl. Acad. Sci. USA, 84, 2610 (1987). Many structural analogs of these metabolites have been prepared and tested, including 1&agr;-hydroxyvitamin D
3
, 1&agr;-hydroxyvitamin D
2
, various side chain homologated vitamins and fluorinated analogs. Some of these compounds exhibit an interesting separation of activities in cell differentiation and calcium regulation. This difference in activity may be useful in the treatment of a variety of diseases as renal osteodystrophy, vitamin D-resistant rickets, osteoporosis, psoriasis, and certain malignancies.
Recently, a new class of vitamin D analogs has been discovered, i.e. the so called 19-nor-vitamin D compounds, which are characterized by the replacement of the A-ring exocyclic methylene group (carbon 19), typical of the vitamin D system, by two hydrogen atoms. Biological testing of such 19-nor-analogs (e.g., 1&agr;,25-dihydroxy-19-nor-vitamin D
3
) revealed a selective activity profile with high potency in inducing cellular differentiation, and very low calcium mobilizing activity. Thus, these compounds are potentially useful as therapeutic agents for the treatment of malignancies, or the treatment of various skin disorders. Two different methods of synthesis of such 19-nor-vitamin D analogs have been described (Perlman et al., Tetrahedron Lett. 31, 1823 (1990); Perlman et al., Tetrahedron Lett. 32, 7663 (1991), and DeLuca et al., U.S. Pat. No. 5,086,191).
In U.S. Pat. No. 4,666,634, 2&bgr;-hydroxy and alkoxy (e.g., ED-71) analogs of 1&agr;,25-dihydroxyvitamin D
3
have been described and examined by Chugai group as potential drugs for osteoporosis and as antitumor agents. See also Okano et al., Biochem. Biophys. Res. Commun. 163, 1444 (1989). Other 2-substituted (with hydroxyalkyl, e.g., ED-120, and fluoroalkyl groups) A-ring analogs of 1&agr;,25-dihydroxyvitamin D
3
have also been prepared and tested (Miyamoto et al., Chem. Pharm. Bull. 41, 1111 (1993); Nishii et al., Osteoporosis Int. Suppl. 1, 190 (1993); Posner et al., J. Org. Chem. 59, 7855 (1994), and J. Org. Chem. 60, 4617 (1995)).
Recently, 2-substituted analogs of 1&agr;,25-dihydroxy-19-nor-vitamin D
3
have also been synthesized, i.e. compounds substituted at 2-position with hydroxy or alkoxy groups (DeLuca et al., U.S. Pat. No. 5,536,713), with 2-alkyl groups (DeLuca et al U.S. Pat. No. 5,945,410), and with 2-alkylidene groups (DeLuca et al U.S. Pat. No. 5,843,928), which exhibit interesting and selective activity profiles. All these studies indicate that binding sites in vitamin D receptors can accommodate different substituents at C-2 in the synthesized vitamin D analogs.
In a continuing effort to explore the 19-nor class of pharmacologically important vitamin D compounds, an analog which is characterized by the presence of a methylene substituent at the carbon 2 (C-2) has been synthesized and tested. Of particular interest is the analog which is characterized by a hydroxyl group at carbon 1 and a shortened side chain attached to carbon 20, i.e. 1&agr;-hydroxy-2-methylene-19-nor-pregnacalciferol. This vitamin D analog seemed an interesting target because the relatively small methylene group at C-2 should not interfere with the vitamin D receptor. Moreover, molecular mechanics studies performed on the model 1&agr;a-hydroxy-2-methylene-19-nor-vitamins indicate that such molecular modification does not change substantially the conformation of the cyclohexanediol ring A. However, introduction of the 2-methylene group into 19-nor-vitamin D carbon skeleton changes the character of its 1&agr;- and 3&bgr;- A-ring hydroxyls. They are both now in the allylic positions, similarly, as 1&agr;-hydroxyl group (crucial for biological activity) in the molecule of the natural hormone, 1&agr;,25-(OH)
2
D
3
.
SUMMARY OF THE INVENTION
The present invention is directed toward 1&agr;-hydroxy-2-methylene-19-nor-pregnacalciferol, its biological activity, and various pharmaceutical uses for this compound.
Structurally this 19-nor analog is characterized by the general formula I shown below:
The above compound exhibits a desired, and highly advantageous, pattern of biological activity. This compound is characterized by relatively high binding to vitamin D receptors, but very low intestinal calcium transport activity, as compared to that of 1&agr;,25-dihydroxyvitamin D
3
, and has very low ability to mobilize calcium from bone, as compared to 1&agr;,25-dihydroxyvitamin D
3
. Hence, this compound can be characterized as having little, if any, calcemic activity. Thus, it may be useful as a therapeutic agent for suppression of secondary hyperparathyroidism of renal osteodystrophy.
The compound of the invention has also been discovered to be especially suited for treatment and prophylaxis of human disorders which are characterized by an imbalance in the immune system, e.g. in autoimmune diseases, including multiple sclerosis, lupis, diabetes mellitus, host versus graft reaction, and rejection of organ transplants; and additionally for the treatment of inflammatory diseases, such as rheumatoid arthritis, asthma, and inflammatory bowel diseases such as celiac disease and croans disease, as well as the improvement of bone fracture healing and improved bone grafts. Acne, alopecia and hypertension are other conditions which may be treated with the compound of the invention.
The above compound is also characterized by relatively high cell differentiation activity. Thus, this compound also provides a therapeutic agent for the treatment of psoriasis, or as an anti-cancer agent, especially against leukemia, colon cancer, breast cancer and prostate cancer. In addition, due to its relatively high cell differentiation activity, this compound provides a therapeutic agent for the treatment of various skin conditions including wrinkles, lack of adequate dermal hydration, i.e. dry skin, lack of adequate skin firmness, i.e. slack skin, and insufficient sebum secretion. Use of this compound thus not only results in moisturizing of skin but also improves the barrier function of skin.
The compound may be present in a composition to treat the above-noted diseases and disorders in an amount from about 0.01 &mgr;g/gm to about 100 &mgr;g/gm of the composition, and may be administered topically, transdermally, orally or parenterally in dosages of from about 0.01 &mgr;g/day to about 100 &mgr;g/day.
REFERENCES:
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patent: 5089641 (1992-02-01), DeLuca et al.
patent: 5536713 (1996-07-01), DeLuca et al.
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patent: 5840718 (1998-11-01), Hennessy et al.
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patent: 5945410 (1999-08-01), DeLuca et al.
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Brown et al, “New Active Analogues of Vitamin D with Low Calcemic Activity” Kidney International, vol. 38, Suppl. 29 (1990) pp. S-22-S-27.
Hareau et al, “Asymmetric Synthesis of 1&agr;,25-Dihydroxyvitamin D3A-Ring Precursor Starting with 5-Tert-Butyldimethylsiloxy-2-Cyclohexenone” Tetrahedron Letters, 41 (2000) pp. 2385-2388.
Sicinski et al, “New 1&agr;,25-Dihydroxy-19-Norvitamin D3Compounds of High Biological Activity: Synthesis and Biological Evaluation of 2-Hydroxymethyl, 2-Methyl, and 2-Methylene Analogues” J. Med. Chem., 41 (1998) pp. 4662-4674.
Posner et al, “2-Fluoroalkyl A-Ring Analogs of 1,25-Dihydroxyvitamin D3•Stereocontrolled Total Synthesis via Intramolecular and Intermolecular Diels-Alder Cycloaddit
Clagett-Dame Margaret
DeLuca Hector F.
Plum Lori A.
Andrus Sceales Starke & Sawall LLP
Qazi Sabiha
Wisconsin Alumni Research Foudation
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