Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 9,10-seco- cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2000-07-14
2001-10-23
Moezie, Minna (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
9,10-seco- cyclopentanohydrophenanthrene ring system doai
C552S653000
Reexamination Certificate
active
06306844
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to vitamin D compounds, and more particularly to pharmaceutical uses for 2&agr;(-methyl-19-nor-20(S)-1&agr;,25-dihydroxyvitamin D
3
.
The natural hormone, 1&agr;,25-dihydroxyvitamin D
3
and its analog in ergocalciferol series, i.e. 1&agr;,25-dihydroxyvitamin D
2
are known to be highly potent regulators of calcium homeostasis in animals and humans, and more recently their activity in cellular differentiation has 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), 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 methyl substituent at the carbon 2 (C-2) has been synthesized and tested. Of particular interest is the analog which is characterized by the unnatural configuration of the methyl group at carbon 20 (C-20), i.e. 2&agr;-methyl-19-nor-20(S)-1&agr;,25-dihydroxyvitamin D
3
. This vitamin D analog seemed an interesting target because the relatively small methyl group at C-2 should not interfere with the vitamin D receptor. Moreover, molecular mechanics studies performed on the model 1&agr;-hydroxy-2-methyl-19-nor-vitamins indicate that such molecular modification does not change substantially the conformation of the cyclohexanediol ring A. However, introduction of the 2-methyl group into 19-nor-vitamin D carbon skeleton changes the character of its 1&agr;- and 3&bgr;- A-ring hydroxyls. Both hydroxyls are allylic to the exocyclic methylene group similar to the 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 2&agr;-methyl-19-nor-20(S)-1&agr;,25-dihydroxyvitamin D
3
, 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 solid wedge-shaped line to the methyl substituent at C-20 indicates that carbon 20 has the S configuration.
The above compound exhibits a desired, and highly advantageous, pattern of biological activity. This compound is characterized by intestinal calcium transport activity equal to that of 1&agr;,25-dihydroxyvitamin D
3
, but exhibiting relatively high activity, as compared to 1&agr;,25-dihydroxyvitamin D
3
, in its ability to mobilize calcium from bone. Hence, this compound is highly specific in its calcemic activity. Its preferential activity on mobilizing calcium from bone allows the in vivo administration of this compound for the treatment of metabolic bone diseases where bone loss is a major concern. Because of its preferential activity on bone, this compound would be a preferred therapeutic agent for the treatment of diseases where bone formation is desired, such as osteoporosis, especially low bone turnover osteoporosis, steroid induced osteoporosis, senile osteoporosis or postmenopausal osteoporosis, as well as osteomalacia and renal osteodystrophy. The treatment may be transdermal, oral or parenteral. The compound may be present in a composition in an amount from about 0.1 &mgr;g/gm to about 50 &mgr;g/gm of the composition, and may be administered in dosages of from about 0.1 &mgr;g/day to about 10 &mgr;g/day.
The compound of the invention is also 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, diabetes mellitus, host versus graft reaction, and rejection of transplants; and additionally for the treatment of inflammatory diseases, such as rheumatoid arthritis and asthma, as well as the improvement of bone fracture healing and improved bone grafts. Acne, alopecia, skin conditions such as dry skin (lack of dermal hydration), undue skin slackness (insufficient skin firmness), insufficient sebum secretion and wrinkles, and hypertension are other conditions which may be treated with the compound of the invention.
The above compound is also characterized by 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. The compound may be present in a composition to treat psoriasis in an amount from about 0.01 &mgr;g/gm to about 50 &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 10 &mgr;g/day.
It has also been discovered that this compound increases breaking strength (cortical strength) as well as crushing strength (trabecular strength) of bones. Thus, this compound could also be used in conjunction with bone replacement procedures such as hip replacements, knee replacements, and the like.
REFERENCES:
patent: 4666634 (1987-05-01), Miyamoto et al.
patent: 5086191 (1992-02-01), DeLuca et al.
patent: 5237110 (1993-08-01), DeLuca et al.
patent: 5246925 (1993-09-01), DeLuca et al.
patent: 5536713 (1996-07-01), DeLuca et al.
patent: 5587497 (1996-12-01), DeLuca et al.
patent: 5945410 (1999-08-01), DeLuca et al.
patent: 6127559 (2000-10-01), DeLuca et al.
patent: 0184206 (1985-12-01), None
patent: 0078704 (1987-04-01), None
patent: 0387077 (1990-09-01), None
patent: 0480572 (1992-04-01), None
patent: 0474517 (1992-11-01), None
patent: 0516410 (1992-12-01), None
patent: WO90/09991 (1990-09-01), None
patent: WO96/01811 (1996-01-01), None
patent: 98/41500 (1998-09-01), None
Chemical Abstracts, XP-002066055, vol. 121, No.
DeLuca Hector F.
Smith Connie M.
Andrus Sceales Starke & Sawall LLP
Hui San-ming
Moezie Minna
Wisconsin Alumni Research Foundation
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