Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-07-17
2002-11-12
Solola, T. A. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S460000, C549S423000, C424S562000, C424S573000, C424S577000
Reexamination Certificate
active
06479538
ABSTRACT:
BACKGROUND OF THE INVENTION
The importance of the vitamin D in the biological systems of higher animals has been recognized since its discovery by Mellanby in 1920 (Mellanby, E. (1921)
Spec. Rep. Ser. Med Res. Council
(GB) SRS 61:4). It was in the interval of 1920-1930 that vitamin D officially became classified as a “vitamin” that was essential for the normal development of the skeleton and maintenance of calcium and phosphorous homeostasis.
Studies involving the metabolism of vitamin D
3
(cholecalciferol) were initiated with the discovery and chemical characterization of the plasma metabolite, 25-hydroxyvitamin D
3
[25(OH)D
3
] (Blunt, J. W. et al. (1968)
Biochemistry
6:3317-3322) and the hormonally active form, 1&agr;,25(OH)
2
D
3
(Myrtle, J. F. et al. (1970)
J. Biol. Chem
. 245:1190-1196; Norman, A. W. et al. (1971)
Science
173:51-54; Lawson, D. E. M. et al (1971)
Nature
230:228-230; Holick, M. F. (1971)
Proc. Natl. Acad. Sci. USA
68:803-804). The formulation of the concept of a vitamin D endocrine system was dependent both upon appreciation of the key role of the kidney in producing 1&agr;, 25(OH)
2
D
3
in a carefully regulated fashion (Fraser, D. R. and Kodicek, E (1970)
Nature
288:764-766; Wong, R. G. et al. (1972)
J. Clin. Invest
. 51:1287-1291), and the discovery of a nuclear receptor for 1&agr;,25(OH)
2
D
3
(VD
3
R) in the intestine (Haussler, M. R. et al. (1969)
Exp. Cell Res
. 58:234-242; Tsai, H. C. and Norman, A. W. (1972)
J. Biol. Chem
. 248:5967-5975). The operation of the vitamin D endocrine system depends on the following: first, on the presence of cytochrome P450 enzymes in the liver (Bergman, T. and Postlind, H. (1991)
Biochem. J
. 276:427-432; Ohyama, Y and Okuda, K. (1991)
J. Biol. Chem
. 266:8690-8695) and kidney (Henry, H. L. and Norman, A. W. (1974)
J. Biol. Chem
. 249:7529-7535; Gray, R. W. and Ghazarian, J. G. (1989)
Biochem. J
. 259:561-568), and in a variety of other tissues to effect the conversion of vitamin D
3
into biologically active metabolites such as 1&agr;,25(OH)
2
D
3
and 24R,25(OH)
2
D
3
; second, on the existence of the plasma vitamin D binding protein (DBP) to effect the selective transport and delivery of these hydrophobic molecules to the various tissue components of the vitamin D endocrine system (Van Baelen, H. et al. (1988)
Ann NY Acad. Sci
. 538:60-68; Cooke, N. E. and Haddad, J. G. (1989)
Endocr. Rev
. 10:294-307; Bikle, D. D. et al. (1986)
J. Clin. Endocrinol. Metab
. 63:954-959); and third, upon the existence of stereoselective receptors in a wide variety of target tissues that interact with the agonist 1&agr;,25(OH)
2
D
3
to generate the requisite specific biological responses for this secosteroid hormone (Pike, J. W. (1991)
Annu. Rev. Nutr
. 11:189-216). To date, there is evidence that nuclear receptors for 1&agr;,25(OH)
2
D
3
(VD
3
R) exist in more than 30 tissues and cancer cell lines (Reichel, H. and Norman, A. W. (1989)
Annu. Rev. Med
. 40:71-78).
Vitamin D
3
and its hormonally active forms are well-known regulators of calcium and phosphorous homeostasis. These compounds are known to stimulate, at least one of, intestinal absorption of calcium and phosphate, mobilization of bone mineral, and retention of calcium in the kidneys. Furthermore, the discovery of the presence of specific vitamin D receptors in more than 30 tissues has led to the identification of vitamin D
3
as a pluripotent regulator outside its classical role in calcium/bone homeostasis. A paracrine role for 1&agr;,25(OH)
2
D
3
has been suggested by the combined presence of enzymes capable of oxidizing vitamin D
3
into its active forms, e.g., 25-OHD-1&agr;-hydroxylase, and specific receptors in several tissues such as bone, keratinocytes, placenta, and immune cells. Moreover, vitamin D
3
hormone and active metabolites have been found to be capable of regulating cell proliferation and differentiation of both normal and malignant cells (Reichel, H. et al. (1989)
Ann. Rev. Med
. 40: 71-78).
Given the pluripotent activities of vitamin D
3
and its metabolites, much attention has focused on the development of synthetic analogs of these compounds. However, clinical applications of vitamin D
3
and its structural analogs have been limited by the undesired side effects elicited by these compounds after administration to a subject, such as the deregulation of calcium and phosphorous homeostasis in vivo that results in hypercalcemia.
SUMMARY OF THE INVENTION
The present invention is based, at least in part, on the discovery of vitamin D3 compounds having a cyclic ether side chain, referred to hereinafter as “cyclic ether vitamin D3 compounds”, and which are represented by the formula I. This invention also describes 3-epi forms of 1&agr;-hydroxy-vitamin D3 compounds, which are represented by the formula II. The cyclic ether and 1&agr;-hydroxy-vitamin D3 compounds of formulas I and II, respectively, referred to hereinafter as “vitamin D3 compounds of formulas I and II” can be produced in vivo via a pathway which catalyzes the epimerization 3-&bgr;-hydroxy-vitamin D3 in certain tissues, e.g., keratinocytes, bone cells. The vitamin D3 compounds of the present invention can be used as substitutes for natural and synthetic forms of vitamin D3.
Accordingly, the present invention pertains to cyclic ether vitamin D3 compounds having the formula (I) as follows:
wherein A
1
, A
2
and A
3
represent a single or a double bond; X, R
1
, R
2
, R
3
, R
4
and R
5
can, e.g., be chosen individually from the group of: a hydrogen, a halogen, a haloalkyl, a hydroxy, a hydroxy-protecting group, an alkyl, e.g., a lower alky, an alkenyl, an alkynyl, an alkoxy, an aryl group and a heterocyclic group. The orientation of the X group can be in either an &agr;- or a &bgr;-configuration.
In a preferred embodiment, the cyclic ether vitamin D3 compound is in its 3-epi configuration, wherein the orientation of the X group on the A-ring is in an &agr;-configuration.
The present invention also pertains to 3-epi forms of 1&agr;-hydroxy-vitamin D3 compounds having the formula II as follows:
wherein A
1
represents a single, a double, e.g., a trans-double, a cis-double, or a triple bond; A
2
, A
3
and A
4
represent a single or a double bond; R
2
, R
3
, R
4
, R
7
, R
8
and R
9
can, e.g., be chosen individually from the group of: a hydrogen, a deuterium, a deuteroalkyl, a hydroxy, an alkyl, e.g., a lower alkyl, e.g., a C
1
-C
4
alkyl, an alkoxide, an O-acyl, a halogen, e.g., a fluoride, a haloalkyl (e.g., a fluoroalkyl, —CF
3
), a hydroxyalkyl, e.g., a hydroxyalkyl wherein the alkyl group is a C
4
-C
10
alkyl, an amine or a thiol group, and wherein the pairs of R
2
and R
3
, or R
4
and R
7
taken together can be an oxygen atom, e.g., as in a carbonyl moiety
and R
5
and R
6
can, e.g., each be chosen individually from the group of: a hydrogen, a deuterium, a halogen, e.g., a fluoride, an alkyl, e.g., a lower alkyl, e.g., a C
1
-C
4
alkyl, a hydroxyalkyl, a haloalkyl, e.g., a fluoroalkyl, and a deuteroalkyl. The amine or thiol group of R
2
, R
3
, R
4
, R
7
, R
8
and R
9
can be substituted to form, e.g., a primary or a secondary amine, or a primary or secondary thiol, wherein the substituents can be an alkyl or an aryl group, e.g., a substituent having 2- to 10-carbon atoms.
In another aspect, the present invention further pertains to a pharmaceutical composition comprising, a therapeutically effective amount of a vitamin D3 compound having the formulas I or II, and a pharmaceutically acceptable carrier.
In yet another aspect, this invention provides a method of modulating a biological activity of a vitamin D3-responsive cell. This method comprising contacting the cell with an effective amount of an isolated vitamin D3 compound of formulas I and II such that modulation of the activity of the cell occurs.
Another aspect of the invention provides a method of treating in a subject, a disorder characterized by aberrant growth or activity of a cell, comprising administering to the subject an effective amount of a pharmaceutical composition of a
Hanley, Esq. Elizabeth A.
Lahive & Cockfield LLP
Lauro, Esq. Peter C.
Solola T. A.
Women and Infants Hospital
LandOfFree
Cyclic ether vitamin D3 compounds, 1&agr;(OH)3-EPI-vitamin... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Cyclic ether vitamin D3 compounds, 1&agr;(OH)3-EPI-vitamin..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Cyclic ether vitamin D3 compounds, 1&agr;(OH)3-EPI-vitamin... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2982571