Organic compounds -- part of the class 532-570 series – Organic compounds – 9,10-seco-cyclopentanohydrophenanthrene ring system or...
Reexamination Certificate
2003-03-26
2004-08-10
Qazi, Sabiha (Department: 1616)
Organic compounds -- part of the class 532-570 series
Organic compounds
9,10-seco-cyclopentanohydrophenanthrene ring system or...
C514S167000
Reexamination Certificate
active
06774251
ABSTRACT:
BACKGROUND OF THE INVENTION
The natural hormone, 1&agr;,25-dihydroxyvitamin D
3
and its analog in the 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 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 such 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, similar analogs of 1&agr;,25-dihydroxy-19-norvitamin 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.
Recently analogs which are characterized by the transposition of the ring A exocyclic methylene group, present in the normal vitamin D skeleton, from carbon 10 (C-10) to carbon 2 (C-2), i.e., 2-methylene-19-nor-vitamin D compounds, were synthesized and tested. Molecular mechanics studies 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;-hydroxy group (crucial for biological activity) in the molecule of the natural hormone, 1&agr;,25-(OH)
2
D
3
. These analogs have exhibited similar rate of binding to the receptor as 1&agr;,25-dihydroxyvitamin D
3
and were also characterized by high cell differentiation activity. These compounds were characterized by little, if any intestinal calcium transport activity, as compared to that of 1&agr;,25-dihydroxyvitamin D
3
, while exhibiting relatively high activity, as compared to that of 1&agr;,25-dihydroxyvitamin D
3
in their ability to mobilize calcium from bone.
More than ten years ago an interesting 1&agr;-hydroxyvitamin D analog was synthesized, namely, 1&agr;-hydroxy-20-methyl-pregnacalciferol (also sometimes referred to as 1&agr;-hydroxy-homopregnacalciferol) which was essentially devoid of calcemic activity, showed some HL-60 cell differentiation ability but unexpectedly exhibited comparable binding to the receptor as 1&agr;,25-dihydroxyvitamin D
3
[Lau, W. F. (1986) Ph.D. Thesis, University of Wisconsin-Madison]. In a: continuing effort to explore the 19-nor class of pharmacologically important vitamin D compounds, a 1&agr;-hydroxy-19-nor-vitamin D analog, which is characterized by the presence of methylene substituent at the carbon 2 (C-2) and 17&bgr;-isopropyl side chain has now been synthesized and tested.
SUMMARY OF THE INVENTION
The present invention is directed toward a method of making 1&agr;-hydroxy-2-methylene-19-nor-homopregnacalcifeol having the structure
comprising the steps of:
condensing a bicyclic ketone having the structure
with an allylic phosphine oxide having the structure
where Y
1
, Y
2
and R, which may be the same or different, are each a hydroxy-protecting group, to produce a protected 19-nor-vitamin D analog having the structure
thereafter cleaving the protecting group R to form an alcohol having the structure
converting said alcohol to an ester having the structure
where R
1
is a tosyl group or a mesyl group;
reducing said ester to obtain 17&bgr;-isopropyl vitamin D derivative having the structure
and deprotecting said 17&bgr;-isopropyl vitamin D derivative to form 1&agr;-hydroxy-2-methylene-19-nor-homopregnacalciferol.
REFERENCES:
patent: 4666634 (1987-05-01), Miyamoto et al.
patent: 4800198 (1989-01-01), DeLuca et al.
patent: 5089641 (1992-02-01), DeLuca et al.
patent: 5536713 (1996-07-01), DeLuca et al.
patent: 5578587 (1996-11-01), DeLuca et al.
patent: 5587497 (1996-12-01), DeLuca et al.
patent: 5843928 (1998-12-01), Deluca et al.
patent: 5877168 (1999-03-01), Miyamoto et al.
patent: 5936105 (1999-08-01), Paaren
patent: 5936133 (1999-08-01), DeLuca et al.
patent: 5945410 (1999-08-01), DeLuca et al.
patent: 5972917 (1999-10-01), Bishop et al.
patent: 6277837 (2001-08-01), DeLuca et al.
patent: 6306844 (2001-10-01), DeLuca et al.
patent: WO 02/20021 (2002-03-01), None
Pearlman et al., 1alpha, 25-dihydroxy-19-nor-vitamin D3, A Novel Vitamin D-Related Compound with Potential Therapeautic Activity, Feb. 1, 1990, Pergamon Press, Tetrahedron Letters, vol. 31, No. 13, pp 1823-1824.*
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.
DeLuca Hector F.
Gowlugari Sumithra
Sicinski Rafal R.
Andrus Sceales Starke & Sawall LLP
Qazi Sabiha
Wisconsin Alumni Research Foundation
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