Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-12-22
2002-03-19
Qazi, Sabiha (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C552S653000, C514S167000
Reexamination Certificate
active
06359012
ABSTRACT:
CROSS-REFERENCE TO RELATED APPLICATIONS
Not Applicable.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not Applicable.
BACKGROUND OF THE INVENTION
This invention relates to a stereospecific synthesis of 24(S)-hydroxyvitamin D
2
which is, in effect, a prodrug for 1&agr;,24(S)-dihydroxyvitamin D
2
, a natural metabolite of vitamin D
2
that has been shown to have highly significant biologic effects, with a large therapeutic index when administered to a subject.
Vitamin D has long been established as having an important biological role in bone and mineral metabolism. For example, vitamin D plays a critical role in stimulating calcium absorption and regulating calcium metabolism. More recently, other roles for vitamin D have come to light. Specific nuclear receptors for 1&agr;,25-dihydroxyvitamin D
3
, the natural hormone form of vitamin D
3
, have been found in cells of diverse organs not involved in calcium homeostasis. For example, Miller et al., 52
Cancer Res
. (1992) 515-520, have demonstrated biologically active, specific receptors for 1&agr;,25-dihydroxyvitamin D
3
in the human prostatic carcinoma cell line, LNCaP.
Still other metabolic conditions in which it has been suggested that vitamin D plays a role are immune response (see, e.g., U.S. Pat. No. 4,749,710 issued to Truitt et al.; U.S. Pat. No. 5,559,107 issued to Gates et al.; U.S. Pat. Nos. 5,540,919, 5,518,725 and 5,562,910 issued to Daynes et al.) and inflammatory response (see, e.g., U.S. Pat. No. 5,589,471 issued to Hansen et al.).
The discovery of active forms of vitamin D (M. F. Holick et al., 68
Proc. Natl. Acad. Sci. USA
, 803-804 (1971); G. Jones et al., 14
Biochemistry
, 1250-1256 (1975)), and active vitamin D analogs (M. F. Holick et al., 180
Science
190-191 (1973); H. Y. Lam et al., 186
Science
1038-1040 (1974)) in the 1970's caused much excitement and speculation about the usefulness of these vitamin D compounds in the treatment of bone depletive disorders, and later in treatment of other disease states such as inhibition of malignant cell proliferation (see, e.g., U.S. Pat. No. 4,391,802 issued to Suda et al.; Skowronski et al., 136
Endocrinology
(1995) 20-26).
However, it has been found that active vitamin D compounds, particularly 1&agr;-hydroxylated vitamin D
3
compounds, can produce dangerously elevated blood calcium levels due to their inherent calcemic activity. Because of this toxicity, 1-hydroxylated vitamin D
3
compounds can only be administered at dosages that are, at best, modestly beneficial, for example, in preventing or treating loss of bone or bone mineral content.
Considering the diverse biological actions of vitamin D and its potential as a therapeutic agent, a need exists for vitamin D compounds with greater specificity of activity and selectivity of action, e.g., vitamin D compounds with antiproliferative and differentiating effects but which have less calcemic activity than therapeutic amounts of the known compounds or analogs of vitamin D
3
.
Interest has grown in the use of so-called prodrugs or compounds which when administered are metabolized to known active vitamin D compounds. With this interest, the need for straightforward, efficient syntheses of vitamin D prodrugs, especially 24-hydroxylated vitamin D compounds, has intensified. Very few methods for 24-hydroxylation of vitamin D compounds have been reported. See, e.g., Jones et al., 202
Arch. Biochem. Biophys
. (1980) 450-457 and Mawer et al., 83
J. Clin. Endo. Metab
. (1998) 2156-2166 which disclose a biologically generated 24-hydroxyvitamin D
2
. Such biological syntheses compared to chemical syntheses are inefficient and require extremely large numbers of animal hosts to produce small amounts of desired compound. The art thus has yet to respond with a straightforward method for the synthesis of 24-hydroxyvitamin D compounds, particularly, 24-hydroxyvitamin D
2
.
BRIEF SUMMARY OF THE INVENTION
The present invention provides a heretofore unmet need by the prior art, and specifically to the inherent inadequacies of prior synthetic processes for preparing 24-hydroxylated vitamin D compounds, specifically 24-hydroxyvitamin D
2
wherein the hydroxyl group at the carbon-24 position is in the (S) configuration. The method of the present invention is distinguished by its simplicity in that it eliminates certain separatory steps of diastereomers characteristic of prior art processes.
The product compound of the method of the present invention is represented by formula (1), shown hereinafter, and is 24(S)-hydroxyvitamin D
2
which has potent biological activity but low calcemic activity relative to the active forms of vitamin D
3
. Preferably, such compound is a 24-hydroxylated prodrug which is hydroxylated in vivo at the C-1 position to form 1,24(S)-dihydroxylated active vitamin D
2
.
The method of the present invention includes coupling of (S)-(+)-2,3-dimethyl-2-triethylsilyloxybutyraldehyde and a vitamin D phosphine oxide derivative to form a C-3 and C-24 diprotected trans-vitamin D
2
which is then deprotected and irradiated to yield the 24(S)-hydroxyvitamin D
2
.
Other advantages and a fuller appreciation of the specific attributes of this invention will be gained upon an examination of the following drawings, detailed description of preferred embodiments, and appended claims. It is expressly understood that the drawings are for the purpose of illustration and description only, and are not intended as a definition of the limits of the invention.
REFERENCES:
patent: 4260549 (1981-04-01), DeLuca et al.
patent: 4391802 (1983-07-01), Suda et al.
patent: 4554106 (1985-11-01), DeLuca et al.
patent: 4749710 (1988-06-01), Truitt et al.
patent: 4758383 (1988-07-01), Tachibana
patent: 5518725 (1996-05-01), Daynes et al.
patent: 5540919 (1996-07-01), Daynes et al.
patent: 5559107 (1996-09-01), Gates et al.
patent: 5562910 (1996-10-01), Daynes et al.
patent: 5589471 (1996-12-01), Hansen et al.
patent: 9824800 (1998-06-01), None
Manchand, Percy S., G. P. Yiannikouros, P. S. Belica and P. Madan, “Nickel-Mediated Conjugate Addition. Elaboration of Calcitriol from Ergocalciferol”,J. Org. Chem.,60, 6674-6581 (1994).
Miller, G. J., G. E. Stapleton, J. A. Ferrara, M. S. Lucia, S. Pfister, T. E. Hedlund and P. Upadhya, “The Human Prostatic Carcinoma Cell Line LNCaP Expresses Biologically Active, Specific Receptors for 1&agr;,25-Dihydroxyvitamin D3”,Cancer Research, 52, 515-520 (Feb. 1, 1992).
Holick, M. F., H. K. Schnoes and H. F. DeLuca, “Identification of 1,25-Dihydroxycholecalciferol, a Form of Vitamin D3Metabolically Active in the Intestine”,Proc. Nat. Acad. Sci. USA, vol. 68, No. 4, pp. 803-804 (Apr. 1971).
Holick, M. F., E. J. Semmler, H. K. Schnoes and H. F. DeLuca, “1&agr;Hydroxy Derivative of Vitamin D3: A Highly Potent Analog of 1&agr;,25-Dihydroxyvitamin D3”,Science, vol. 180, pp. 190-191 (Apr. 1973).
Jones, Glenville, H. K. Schnoes and H. F. DeLuca, “Isoloation and Identification of 1,25-Dihydroxyvitamin D2”,Biochemistry, vol. 14, No. 6, pp. 1250-1256 (1975).
Jones, Glenville, H. K. Schnoes, L. Levan and H. F. DeLuca, “Isolation and Identification of 24-Hydroxyvitamin D2and 24,25-Dihydroxyvitamin D2”,Archives of Biochemistry and Biophysics, vol. 202, No. 2, pp. 450-457 (1980).
Lam, H. Y. Peter, H. K. Schnoes and H. F. DeLuca, “1&agr;-Hydroxyvitamin D2: A Potent Synthetic Analog of Vitamin D2”,Science, vol. 486, No. 4168, pp. 1038-1040 (Dec. 1974).
Skowronski, Roman J., D. M. Peehl and D. Feldman, “Actions of Vitamin D3Analogs on Human Prostate Cancer Cell Lines: Comparison with 1,25-Dihydroxyvitamin D3”,Endocrinology, vol. 136, No. 1, pp. 20-26 (1995).
Mawer, E. Barbara, G. Jones, M. Davies, P. E. Still, V. Byford, N. J. Schroeder, H. L. J. Makin, C. W. Bishop and J. C. Knutson, “Unique 24-Hydroxylated Metabolites Represent a Significant Pathway of Metabolism of Vitamin D2in Humans: 24-Hydroxyvitamin D2and 1,24-Dihydroxyvitamin D2Detectable in Human Serum”,JCE&M, vol. 83, No. 6, pp. 2156-2166 (Jun. 1998).
Seebach, Dieter, R. Naef and G. Calderari, “&agr;-Alkylation of &agr;-Heterosubstituted
Geiss William B.
Gregg Brian T.
Helle Mark A.
Meckler Harold
Bone Care International, Inc.
Michael & Best & Friedrich LLP
Qazi Sabiha
Welch Teresa J.
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