Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or...
Patent
1998-05-22
1999-11-02
Leary, Louise N.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
514167, 514310, C12Q 100, A01N 4500
Patent
active
059767847
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to biologically active vitamin D compounds, and more particularly to vitamin D compounds with hydrolyzable groups at one or more of the 1, 3 and 25 carbon positions, such as esters of 1.alpha., 25-dihydroxyvitamin D.sub.3 or esters of 1,25-dihydroxyvitamin D.sub.3 analogs, and their use to regulate over time the function of 1,25(OH).sub.2 D.sub.3 (or of 1,25(OH).sub.2 D.sub.3 analogs) during the treatment of a variety of diseases such as osteoporosis, renal osteodystrophy, hypoparathyroidism or proliferative skin disorders.
The 1.alpha.-hydroxylated metabolites of vitamin D--most importantly 1.alpha.,25-dihydroxyvitamin D.sub.3 and 1(25-dihydroxyvitamin D.sub.2 --are known as highly potent regulators of calcium homeostasis in animals and humans. With the discovery of 1.alpha.,25-dihydroxyvitamin D.sub.3 as the active form of the vitamin has come an intense investigation of analogs of this hormonal form of vitamin D with the intent of finding analogs that have selective biological activity. As a consequence, many structural analogs of these metabolites, such as compounds with different side chain structures, different hydroxylation patterns, or different stereochemistry, have been prepared and tested. Important examples of such analogs are 1.alpha.-hydroxyvitamin D.sub.3, 1.alpha.-hydroxyvitamin D.sub.2, various side chain fluorinated derivatives of 1.alpha.,25-dihydroxyvitamin D.sub.3, 19-nor-vitamin D compounds, and side chain homologated analogs. Several of these known compounds exhibit highly potent activity in vivo or in vitro, and some of these have been found to exhibit an interesting separation of activities in cell differentiation and calcium regulation. This difference in activity provides these compounds increased incidence of fractures and gastrointestinal reaction to the large amounts of fluoride administered. Another suggested method is to block bone resportion by injecting calcitonin or providing phosphonates.
U.S. Pat. No. 4,255,596 suggest the use of various metabolites of vitamin D.sub.3 for increasing calcium absorption and retention within the body of mammals displaying evidence of or with advantageous therapeutic activity profiles and thus some of these compounds are in use, or have been proposed for use, in the treatment of variety of diseases such as renal osteodystrophy, vitamin D-resistant rickets, osteoporosis, psoriasis, and certain malignancies.
Various forms of osteoporosis are known, e.g., postmenopausal, senile and steroid-induced osteoporosis, one of the characteristics of which is the loss of bone mass. Females at the time of menopause suffer a marked loss of bone mass giving rise ultimately to osteopenia, which in turn gives rise to spontaneous crush fractures of the vertebrae and fractures of the long bones. This disease is generally known as postmenopausal osteoporosis and presents a major medical problem, both in the United States and most other countries where the life-span of females reaches ages of at least 60 and 70 years. Generally, the disease which is often accompanied by bone pain and decreased physical activity, is diagnosed by one or two vertebral crush fractures with evidence of diminished bone mass. It is known that this disease is accompanied by diminished ability to absorb calcium, decreased levels of sex hormones, especially estrogen and androgen, and a negative calcium balance.
Similar symptoms of bone loss characterize senile osteoporosis and steroid-induced osteoporosis, the latter being a recognized result of long term glucocorticoid (cortico-steroid) therapy for certain disease states.
Methods of treating osteoporosis have varied considerably but to date no totally satisfactory treatment is yet known. A conventional treatment is to administer a calcium supplement to the patient. However, calcium supplementation by itself has not been successful in preventing or curing the disease. Another conventional treatment is the injection of sex hormones, especially estrogen, which has been reported to be effec
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Cai Zu Y.
DeLuca Hector F.
Phelps Mary E.
Schnoes Heinrich K.
Smith Connie M.
Leary Louise N.
Wisconsin Alumni Research Foundation
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