Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 9,10-seco- cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2003-01-28
2004-02-24
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
06696431
ABSTRACT:
BACKGROUND OF THE INVENTION
This patent invention relates to vitamin D compounds, and more particularly to vitamin D derivatives substituted at the carbon 2 position.
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 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, 2-substituted 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.
In a continuing effort to explore the 19-nor class of pharmacologically important vitamin D compounds, their analogs which are characterized by the presence of an alkylidene (particularly methylene) substituent at the carbon 2 (C-2), i.e. 2-alkylidene-19-nor-vitamin D compounds, have now been synthesized and tested. Of particular interest are the 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. Such vitamin D analogs seemed interesting targets because the relatively small alkylidene (particularly methylene) group at C-2 should not interfere with vitamin D receptor. Moreover, molecular mechanics studies performed on the model 1&agr;-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
A class of 1&agr;-hydroxylated vitamin D compounds not known heretofore are the 19-nor-vitamin D analogs having an alkylidene (particularly methylene) group at the 2-position, i.e. 2-alkylidene-19-nor-vitamin D compounds, particularly 2-methylene-19-nor-vitamin D compounds. These latter compounds are those in which the A-ring exocyclic methylene group typical of all vitamin D system has been transposed to the carbon 2, i.e. 19-nor-vitamin D analogs having a methylene group at the 2-position.
Structurally these novel analogs are characterized by the general formula I shown below:
where Y
1
and Y
2
, which may be the same or different, are each selected from the group consisting of hydrogen and a hydroxy-protecting group, R
6
and R
8
, which may be the same or different, are each selected from the group consisting of hydrogen, alkyl, hydroxyalkyl and fluoroalkyl, or, when taken together represent the group —(CH
2
)
x
— where X is an integer from 2 to 5, and where the group R represents any of the typical side chains known for vitamin D type compounds.
More specifically R can represent a saturated or unsaturated hydrocarbon radical of 1 to 35 carbons, that may be straight-chain, branched or cyclic and that may contain one or more additional substituents, such as hydroxy- or protected-hydroxy groups, fluoro, carbonyl, ester, epoxy, amino or other heteroatomic groups. Preferred side chains of this type are represented by the structure below
where the stereochemical center (corresponding to C-20 in steroid numbering) may have the R or S configuration, (i.e. either the natural configuration about carbon 20 or the 20-epi configuration), and where Z is selected from Y, —OY, —CH
2
OY, —C≡CY, CH═CHY, and —CH
2
CH
2
CH═CR
3
R
4
, where the double bond may have the cis or trans geometry, and where Y is selected from hydrogen, methyl, —COR
5
and a radical of the structure:
where m and n, independently, represent the integers from 0 to 5, where R
1
is selected from hydrogen, deuterium, hydroxy, protected hydroxy, fluoro, trifluoromethyl, and C
1-5
-alkyl, which may be straight chain or branched and, optionally, bear a hydroxy or protected-hydroxy substituent, and where each of R
2
, R
3
, and R
4
, independently, is selected from deuterium, deuteroalkyl, hydrogen, fluoro, trifluoromethyl and C
1-5
alkyl, which may be straight-chain or branched, and optionally, bear a hydroxy or protected-hydroxy substituent, and where R
1
and R
2
, taken together, represent an oxo group, or an alkylidene group, ═CR
2
R
3
, or the group —(CH
2
)
p
—, where p is an integer from 2 to 5, and where R
3
and R
4
, taken together, represent an oxo group, or the group —(CH
2
)
q
—, where q is an integer from 2 to 5, and where R
5
represents hydrogen, hydroxy, protected hydroxy, C
1-5
alkyl or —OR
7
where R
7
represents C
1-5
alkyl, and wherein any of the CH-groups at positions 20, 22, or 23 in the side chain may be replaced by a nitrogen atom, or where any of the groups —CH(CH
3
)—, —CH(R
3
)—, or —CH(R
2
)— at positions 20, 22, and 23, respectively, may be replaced by an oxygen or sulfur atom.
The wavy line to the methyl substituent at C-20 indicates that carbon 20 may have either the R or S configuration.
Specific important examples of side chains with natural 20R-configuration are the structures represented by formulas (a), b), (c), (d) and (e) below. i.e. the side chain as it occurs in 25-hydroxyvitamin D
3
(a); vitamin D
3
(b); 25-hydroxyvitamin D
2
(c); vitamin D
2
(d); and the C-24 epimer of 25-hydroxyvitamin D
2
(e):
Specific important examples of side chains with the unnatural 20(S) (also referred to as the 20-epi) configuration are the structures represented by formulas (f), (g), (h), and (i) below:
The above novel compounds exhibit a des
DeLuca Hector F.
Sicinski Rafal R.
Andrus Sceales Starke & Sawall LLP
Qazi Sabiha
Wisconsin Alumni Research Foundation
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