2-ethyl and 2-ethylidene-19-nor-vitamin D compounds

Details 2-ethyl and 2-ethylidene-19-nor-vitamin D compounds 2-ethyl and 2-ethylidene-19-nor-vitamin D compounds

2001-05-31

2004-10-19

Badio, Barbara P. (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

06806262

ABSTRACT:

BACKGROUND OF THE INVENTION
This 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. U.S.A., 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.
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.
SUMMARY OF THE INVENTION
The discovery of the hormonally active form of vitamin D
3
, 1&agr;,25-dihydroxyvitamin D
3
(1&agr;,25—(OH)
2
D
3
, calcitriol, 1; FIG.
1
), has greatly stimulated research into its physiology and chemistry. As previously noted, it has been established that 1 not only regulates the mineral metabolism in animals and humans, but also exerts potent effects upon cell proliferation and cellular differentiation. Therefore, the chemistry of vitamin D has been recently focused on the design and synthesis of analogs that can exert selective biological actions.
In a previous investigation of the structure-activity relationship of the vitamin D molecule, an analog of the natural hormone 1, 1&agr;,25-dihydroxy-2-methylene-19-nor-vitamin D
3
(2), was prepared in which the exocyclic methylene group is transposed, in comparison with 1, from C-10 to C-2. Also, 2&agr;-methyl analog 3 was obtained by selective hydrogenation of 2. Both analogs were characterized by significant biological potency, enhanced especially in their isomers in the 20S-series.
In a continuing search for biologically active vitamin D compounds novel 19-nor analogs of 1, substituted at C-2 with ethylidene (4a,b and 5a,b) and ethyl (6a,b and 7a,b) groups, have now been synthesized and tested. Structurally the novel 2-ethylidene analogs belong to a class of 19-nor vitamin D compounds 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, and where the group R represents any of the typical side chains known for vitamin D type compounds.
Structurally the novel 2-ethyl analogs belong to a class of 19-nor vitamin D compounds characterized by the general formula II 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, 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 lines, e.g. to the substituents at C-2 and at C-20 indicate that those substituents 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 20S (also referred to as the 20-epi) configuration are the structures presented by formulas (f), (g), (h), (i) and (j) below:
The above novel compounds exhibit a desired, and highly advantageous, pattern of biological activity. The synthesized vitamins were tested for their ability to bind the porcine intestinal vitamin D receptor. The presented results (
FIG. 5
) indicate that 2-ethylidene-19-norvitamins, possessing methyl group from ethylidene moiety directed toward C-3, i.e., trans in relation to C(6)—C(7) bond (isomers E), are more active than 1&agr;,25—(OH)
2
D
3

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