Vitamin D3 mimics

Details Vitamin D3 mimics Vitamin D3 mimics

1998-08-24

2001-04-17

Padmanabhan, Sreeni (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S741000, C548S961000, C549S516000, C549S545000, C568S715000

Reexamination Certificate

active

06218430

ABSTRACT:

FIELD OF THE INVENTION
In one aspect, the present invention relates to the synthesis of non-secosteroidal compounds having vitamin D
3
receptor (VDR) modulating activity. In another aspect, the invention relates to non-secosteroidal compounds, their pharmacologically acceptable salts, and pharmacologically acceptable compositions thereof which display VDR modulating activity in vitro and in vivo in mammals. In yet another aspect, the invention relates to methods of treating and preventing disease states in mammals with abnormal calcium regulatory, abnormal immune responsive, hyperproliferative, and/or neurodegenerative characteristics.
BACKGROUND AND PRIOR ART
The active form of vitamin D
3
, 1,25-dihydroxyvitamin D
3
[1,25(OH)
2
D
3
], is a secosteroid long recognized as a major regulator of calcium homeostasis, and bone development and remodeling (M. R. Haussler et al.
N. Engl. J. Med.
1977, 297, 974-983; H. F. DeLuca
FASEB J
. 1988, 2, 224-236). Work begun in the early 1980's has found that 1,25(OH)
2
D
3
is a potent differentiator of leukemic cells (E. Abe et al.
Proc. Natl. Acad. Sci
. 1981, 76, 4990-4994; S. Dokoh et al.
Cancer Res
. 1984, 44, 2103-2109; D. J. Mangelsdorf et al.
J. Cell. Biol.
1984, 98, 391-398), as well as a growth inhibitor for cells of cancers such as prostate, breast, and colon (K. Colston et al. Endocrinology 1981, 108, 1083-1086; D. Bar-Shavitz et al.
Proc. Natl. Acad. Sci
. 1983, 80, 5907-591 1; R. J. Skowronski et al.
Endocrinology
1993, 13Z 1952-1960). Immunosuppressive effects of 1,25(OH)
2
D
3
have been observed in vitro (D. D. Tsoukas et al.
Science
1984, 224, 1438-1440; S. C. Manolagas et al.
Mol. Cell. Endocrinol
. 1985, 43, 113-122), and in animal models of lupus, diabetes, multiple sclerosis and rheumatoid arthritis (C. Mathieu et al.
Endocrinology
1995, 136, 866-872; J. M. Lemire et al.
Autoimmunity
1992, 12, 143-148; M. T. Cantora et al.
Proc. Natl. Acad. Sci
. 1996, 93, 7861-7864; M. T. Cantora et al.
J. Nutrition
1998, 128, 68-72).
Declining levels of nerve growth factor (NGF) in old age is hypothesized to have a role in neurodegeneration and Alzheimer's disease. VDR is located in the areas of the brain where NGF is produced and where neurodegeneration is thought to occur (hippocampus and basal forebrain). 1,25(OH)
2
D
3
induces NGF in vitro in cell culture (M. S. Saporito et al.
Brain Res
. 1994, 633, 189-196; I. Neveu et al. Brain Res.
Mol. Brain Res
. 1994, 24, 70-76) and in vivo in the rat hippocampus and cortex (Saporito et al. 1994; M. S. Saporito et al.
Exp. Neurol
. 1993, 123, 295-302). Additionally, there has been a report that a 1,25(OH)
2
D
3
analogue has efficacy in a rodent model of Alzheimer's Disease (S. Carswell, abstract,
IBC Conference
, “The Potential of Vitamin D Analogs for the Treatment of Alzheimer's Disease”, Philadelphia, Pa., 1997).
1,25(OH)
2
D
3
binds to its intracellular receptor, the VDR, with high affinity and specificity resulting in transcriptional activation of vitamin D target genes such as those for the bone proteins osteocalcin and osteopontin. The 1,25(OH)
2
D
3
-VDR complex also regulates a key metabolic enzyme of 25(OH)D
3
and 1,25(OH)
2
D
3
, 25-hydroxyvitamin D
3
-24-hydroxylase. Activation in these cases occurs through receptor binding to discrete regulatory regions within the promoters of these genes. VDR has been shown to form a heterodimer with the retinoid X receptor (RXR); this heterodimer binds with high affinity to vitamin D responsive elements (VDRE's) in the regulatory regions of the target genes (M. R. Haussler
Ann. Rev. Nutr
. 1986, 6, 527-562; K. Ozono
J. Bone Min. Res
. 1991, 6, 1021-1027).
Because in vitro (G. Zugmaier et al. Br.
J. Cancer
1996, 73, 1341-1346; Y. Higashimoto et al.
Anticancer Res
. 1996, 16, 2653-2660; S. E. Blutt et al.
Endocrinology
1997, 138, 1491-1497) and animal model (Y. Honma et al.
Cell Biol.
1983, 80, 201-204; G. K. Potter et al.
Exp. Hematol
. 1985, 13, 722-732; K. W. Colston et al.
Biochem. Pharmacol
. 1992, 44, 693-702; J. A. Eisman et al.
Cancer Res
. 1987,47, 21-25; A. Belleli et al.
Carcinogenesis
1992, 13, 2293-2298) studies show 1,25(OH)
2
D
3
an effective agent in inhibiting growth and inducing differentiation of a variety of cancer types, this compound is a potential drug for treatment of these conditions in humans. 1,25(OH)
2
D
3
analogs also have shown effectiveness in animal models of humoral hypercalcemia of malignancy (HHM) (M. Haq et al.
J. Clin. Invest
. 1993, 91, 2416-2422; K. Endo et al.
J. Biol. Chem
. 1994, 269, 32693-32699).
1,25(OH)
2
D
3
has demonstrated efficacy in the treatment of dermatological conditions. Analogs of 1,25(OH)
2
D
3
are effective treatments for psoriasis, a condition with both hyperproliferative and autoimmune components (E. L. Smith et al.
J. Amer. Acad. Dermatol
. 1988, 19, 516-528) and may also be effective in the treatment of other skin disorders including acne and wrinkles (E. T. Binderup et al. U.S. Pat. No. 5,190,935). 1,25(OH)
2
D
3
has also shown efficacy in the prevention of chemotherapy-induced hair-loss (alopecia) (J. J. Jimenez et al.
Cancer Res
. 1992, 52, 5123; J. J. Jimenez et al.
Clin. Res
. 1994, 42, 128A; J. J. Jimenez et al.
Am. J. Med. Sci
. 1995, 310, 43).
Known activities of vitamin D
3
are not limited to the treatment and cure of disease states, but also includes chemoprevention: the prophylactic use for the prevention of said disease states (Prostate cancer: M. S. Lucia
Cancer Res
. 1995, 55, 5621-5627. Breast cancer: M. A. Anzano et al.
Cancer Res
. 1994, 54, 1653-1656. Autoimmune disease models: Mathieu et al. 1995; Lemire et al. 1992).
Currently, 1,25(OH)
2
D
3
, as Rocaltrol® (Hoffinann-La Roche), is administered to kidney failure patients undergoing chronic kidney dialysis to treat hypocalcemia and the resultant metabolic bone disease. Although many patients experience no side effects from this treatment, its usefulness is limited because the normal calcium mobilization function of 1,25(OH)
2
D
3
increases with dosage resulting in hypercalcemia (elevated serum calcium) in animals and humans. This only known side effect of 1,25(OH)
2
D
3
may cause soft tissue calcification which can be life threatening. Recently, chemical modifications of 1,25(OH)
2
D
3
have yielded analogs with attenuated calcium mobilization effects (R. Bouillon et aL
Endocrine Rev
. 1995, 16, 200-257). One such analog, MC903 or Dovonex® (Bristol-Meyers Squibb), is currently used in Europe and the United States as a topical treatment for mild to moderate psoriasis (K. Kragballe et al.
Br. J. Dermatol
. 1988, 119, 223-230).
The therapeutic potential of 1,25(OH)
2
D
3
has spurred the development of secosteroidal analogs of 1,25(OH)
2
D
3
with reduced calcemic effects and that retain desirable properties, and in fact, all compounds previously known to activate the VDR are secosteroidal analogs of the parent 1,25(OH)
2
D
3
. Although some degree of separation between the beneficial and calcium raising (calcemic) effects has been achieved in these analogs, to date the separation has been insufficient to allow for oral administration to treat conditions such as cancers, leukemias, and severe psoriasis.
Thus, the development of compounds in which the VDR modulating activity is more fully divorced from calcium mobilization activity might lead to effective treatments for disease states responsive to vitamin D
3
and its analogs including those with abnormal calcium regulatory, abnormal immune responsive, hyperproliferative, and/or neurodegenerative characteristics such as leukemia, cancers, psoriasis, renal osteodystrophy, renal failure, osteoporosis, humoral hypercalcemia of malignancy, acne, alopecia, host-graft rejection, lupus, multiple sclerosis, autoimmune induced diabetes, scleroderma, rheumatoid arthritis, acne, wrinkles, insufficient sebum secretion, insufficient dermal hydration, insufficient dermal firmness, and Alzheimer's disease.
BISPHENOLS
Bisphenols are a well-known family of compounds consisting of tw

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