Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 9,10-seco- cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2001-04-16
2002-11-19
Pryor, Alton (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
06482812
ABSTRACT:
BACKGROUND AND SUMMARY OF THE INVENTION
The present invention relates to vitamin D compounds, and more particularly, to a method of presenting the 1&agr;-OH of vitamin D compounds in an axial orientation and the compounds made thereby.
The two diastereomeric forms of monosubstituted cyclohexanes (Scheme I) are differently populated, the equilibrium constant K being given by the equation
&Dgr;G°=−RT1nK
where K=[equatorial conformer]/[axial conformer]. &Dgr;G° (usually negative) is the difference of free energy between the equatorial and axial conformers and −&Dgr;G° is known as conformational free energy of the substituent R [defined as it's A value, Winstein et al., J. Am. Chem. Soc. 77, 5562 (1955)]. Thus, the greater the A value of the substituent R, the greater a driving force to adopt the R-equatorial form. A value can be, therefore, considered as
destabilization energy imparted to a monosubstituted six-membered chair by an axial substituent. Thus, for example, the A value of methyl substituent equals ca. 1.7 kcal/mol [Hirsch, Top. Stereochem. 1, 199 (1967)] that corresponds to 95% of population of equatorial conformer of methylcyclohexane at room temperature. The conformational free energies of substituents in cyclohexanes under ideal conditions are expected to be additive. It is usually assumed that all conformational effects are additive, i.e. various destabilizing interactions identified within a six-membered ring system operate independently of each other. In di-, tri- and polysubstituted cyclohexanes mutual interactions among the substituents have to be considered. Such interactions can destabilize one chair conformation raising its energy to favor an alternate inverted chair form, or even favor some other, distorted (rigid or flexible) cyclohexane geometries. The most important interactions that influence the equilibrium between the respective chair conformations include interaction of a pair of substituents in 1,2-trans-diequatorial and 1,3-cis-diaxial relationship. Thus, total destabilization energy (E
D
) can be described as a sum of the substituents' A values, representing monoaxial interactions, G values for 1,2-diequatorial interactions and U values for 1,3-diaxial interactions [Corey, et al., J. Org. Chem. 45, 765 (1980)].
E
D
=&Sgr;(
A+G+U
)
In the case of alkylidenecyclohexanes, additional interactions are involved, especially in 2-substituted derivatives. The most important interaction (designated A
1,3
-strain, Johnson, Chem. Rev. 68, 375 (1968)] exists in the allylic segment between equatorial R
1
and substituent R
2
of the exomethylene unit (Scheme II). When both
R
1
and R
2
are medium or large groups, the axial conformer is preferred over the equatorial (Malhotra et al., J. Am. Chem. Soc. 87, 5492 (1965)]. Thus, for example, when R
1
=R
2
=Me the difference in energy between both forms is approximately 4.5 kcal/mol, in favor of the axial conformer. In the case when R
1
=Me and R
2
=H, a 1:3 peri interaction exists which increases by ca. 1.25 kcal/mol the destabilization energy of the system (Duraisamy et al., J. Am. Chem. Soc. 105, 3264 (1983)].
Conformational behavior of vitamin D has attracted considerable attention over the past 25 years. It has been suggested long ago [Havinga, Experientia 29, 1181 (1973)] that vitamin D compounds can exist as a mixture of two rapidly equilibrating A-ring chair conformers. These two conformations were abbreviated as &agr;- and &bgr;- forms (Scheme III).
1
H NMR studies of vitamin D
2
and D
3
in chloroform solutions confirmed the existence of the dynamic equilibrium between the two chair forms [La Mar et al., J. Am. Chem. Soc. 96, 7317 (1974); Wing et al., J. Am. Chem. Soc. 97, 4980 (1975)] of these B-ring secosteroids. A similar conformational equilibrium has also been found for 25-hydroxyvitamin D
3
(25-OH-D
3
), 1&agr;-hydroxyvitamin D
3
(1&agr;-OH-D
3
) and the natural hormone 1&agr;,25-dihydroxyvitamin D
3
(1&agr;,25-(OH)
2
D
3
) as well as some other A-ring substituted vitamin D derivatives [see for example Helmer et al., Arch. Biochem. Biophys. 241, 608 (1985); Sheves et al., J. Org. Chem. 42, 3597 (1977); Berman et al., J. Org. Chem. 42, 3325 (1977); Sheves et al., J. Chem. Soc. Chem. Commun. 643 (1975); Okamura et al., J. Org. Chem. 43, 574 (1978)]. In the &agr;-chair conformer of vitamin D molecule, the hydroxy group is equatorial whereas in the &bgr;-chair conformer the hydroxy group is axially oriented.
NMR studies of various vitamin D compounds in solutions have also shown that the ratio of the respective A-ring conformers depends significantly on the solvent used [Helmer et al., Arch. Biochem. Biophys. 241, 608 (1985)]. Unfortunately, due to solubility problems, it is impossible to study these conformer populations in an aqueous medium. X-Ray diffraction studies of vitamin D
2
and D
3
confirmed that their A-rings also occur in the solid phase as an equimolar mixture of such extreme &agr;- and &bgr;-chair conformations [Hull et al., Acta Cryst., Sect. B, 32, 2374 (1976); Trinh et al., J. Org. Chem. 41, 3476 (1976)]. Interestingly, 25-OH-D
3
exists in the solid state exclusively in the &agr;-form whereas the natural hormone 1&agr;,25-(OH)
2
D
3
in the A-ring &bgr;-form [Trinh et al., J. Chem. Soc., Perkin Trans. II, 393 (1977); Suwinska et al., Acta Cryst., Sect. B, 52, 550 (1996)]. X-Ray studies have also shown that the C(5)═C(6)—C(7)═C(8) diene part of the molecule is nearly planar, whereas the exocyclic C(10)═C(19) bond, because of steric strain, is twisted out of plane by about 55°. This exomethylene group is situated below the mean A-ring plane in the &agr;-chair form and above it in the alternate &bgr;-chair form. In the case of vitamin D analogs substituted in the ring A with a 1&agr;-hydroxy group, crucial for biological activity, the orientation of 1&agr;-OH is axial in the &agr; chair form and equatorial in the &bgr;-form (Scheme IV).
It has to be added that molecular mechanics calculations revealed that, similarly as in the case of the model 1,2-dimethylenecyclohexane ([Hofmann et al., J. Org. Chem. 55, 2151 (1990)], an existence of other than low-energy chair conformations of the ring A can be expected for D vitamins, namely, half-chair or twist forms [Mosquera et al., J. Mol. Struct. 168, 125, (1988); Hofer et al., Monatsh. fur Chemie, 124, 185 (1993)].
In 1974, it was proposed [Okamura et al., Proc. Natl. Acad. Sci. USA 71, 4194 (1974); Wing et al., Science 186, 939 (1974)] that calcium regulation ability of vitamin D is limited to the compounds that can assume a ring-A chair conformation in which the 1&agr;-hydroxy group (or pseudo-1&agr;-OH) occupies an equatorial orientation. Such conformation, according to this hypothesis, has the proper geometry for binding to the protein receptor, a step which is necessary to induce the biological response leading to the calcium transport and calcium mobilization in the body. However, recent results of biological testing of 1&agr;,25-dihydroxy-10, 19-dihydroxyvitamin D
3
compounds do not support the idea that the equatorially favored 1-hydroxyl would be the most biologically active. On the contrary, 1&agr;,25-dihydroxy-10(S), 19-dihydrovitamin D
3
, the analog strongly biased toward the A-ring chair conformer possessing 1&agr;-axial orientation, provided the greatest in vivo biological response and showed very significant activity on intestinal calcium transport. Moreover, more recent studies on 19-norvitamins, especially those substituted at C-2, demonstrate that pronounced biological activity is provided by compounds having an axial 1&agr;-hydroxyl. Thus, it is believed that axial orientation of the 1&agr;-hydroxyl group in the vitamin D molecule is of crucial importance for its biological activity and, the prediction of its biological response can be made by evaluation of the conf
DeLuca Hector F.
Sicinski Rafal R.
Andrus Sceales Starke & Sawall LLP
Pryor Alton
Wisconsin Alumni Research Foundation
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