3-Desoxy-vitamin D3 analog esters

Details 3-Desoxy-vitamin D3 analog esters 3-Desoxy-vitamin D3 analog esters

2002-09-18

2003-05-06

Qazi, Sabiha (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

06559138

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to 3-desoxy-20-desmethyl-20-cyclopropyl vitamin D
3
analog esters and methods for producing and using the same.
BACKGROUND OF THE INVENTION
Osteoporosis
Osteoporosis is the most common form of metabolic bone disease and may be considered the symptomatic, fracture stage of bone loss (osteopenia). Although osteoporosis may occur secondary to a number of underlying diseases, 90% of all cases appear to be idiopathic. Postmenopausal women are at risk for idiopathic osteoporosis (postmenopausal or Type I osteoporosis); another particularly high risk group for idiopathic osteoporosis is the elderly of either sex (senile or Type II osteoporosis). Osteoporosis has also been related to corticosteroid use, immobilization or extended bed rest, alcoholism, diabetes, gonadotoxic chemo-therapy, hyperprolactinemia, anorexia nervosa, primary and secondary amenorrhea, transplant immunosuppression, and oophorectomy. Postmenopausal osteoporosis is characterized by fractures of the spine, while femoral neck fractures are the dominant features of senile osteoporosis.
The mechanism by which bone is lost in osteoporotics is believed to involve an imbalance in the process by which the skeleton renews itself. This process has been termed bone remodeling. It occurs in a series of discrete pockets of activity. These pockets appear spontaneously within the bone matrix on a given bone surface; as a site of bone resorption. Osteoclasts (bone dissolving or resorbing cells) are responsible for the resorption of a portion of bone of generally constant dimension. This resorption process is followed by the appearance of osteoblasts (bone forming cells) which then refill with new bone the cavity left by the osteoclasts.
In a healthy adult subject, osteoclasts and osteoblasts function so that bone formation and bone resorption are in balance. However, in osteoporotics an imbalance in the bone remodeling process develops which results in bone being replaced at a slower rate than it is being lost. Although this imbalance occurs to some extent in most individuals as they age, it is much more severe and occurs at a younger age in postmenopausal osteoporotics, following oophorectomy, or in iatrogenic situations such as those resulting from corticosteroid therapy or the immunosuppression practiced in organ transplantation.
Various approaches have been suggested for increasing bone mass in humans afflicted with osteoporosis, including administration of androgens, fluoride salts, and parathyroid hormone and modified versions of parathyroid hormone. It has also been suggested that bisphosphonates, calcitonin, calcium, 1,25-dihydroxy vitamin D
3
and some of its analogs, and/or estrogens, alone or in combination, may be useful for preserving existing bone mass.
Vitamin D
3
is a critical element in the metabolism of calcium, promoting intestinal absorption of calcium and phosphorus, maintaining adequate serum levels of calcium and phosphorus, and stimulating flux of calcium into and out of bone. Vitamin D
3
is hydroxylated in vivo, with the resulting 1&agr;,25-dihydroxy metabolite being the active material. Animal studies with 1,25-(OH)
2
vitamin D
3
have suggested bone anabolic activity. Aerssens et al. in
Calcif Tissue Int
, 55:443-450 (1994) reported upon the effect of 1&agr;-hydroxy Vitamin D
3
on bone strength and composition in growing rats with and without corticosteroid treatment. However, human usage is restricted to antiresorption due to the poor therapeutic ratio (hypercalciuria and hypercalcemia as well as nephrotoxicity).
Dechant and Goa, in “Calcitriol. A review of its use in the treatment of postmenopausal osteoporosis and its potential in corticosteroid-induced osteoporosis,” Drugs Aging [NEW ZEALAND 5 (4): 300-17 (1994)], reported that 1,25-dihydroxyvitamin D
3
(calcitriol) has shown efficacy in the treatment of postmenopausal osteoporosis (and promise in corticosteroid-induced osteoporosis) based upon a clinical trial in 622 women with postmenopausal osteoporosis. Patients with mild to moderate disease (but not those with more severe disease) who received calcitriol (0.25 microgram twice daily) had a significant 3-fold lower rate of new vertebral fractures after 3 years of treatment compared with patients receiving elemental calcium 1000 mg/day. In patients commencing long term treatment with prednisone or prednisolone, calcitriol 0.5 to 1.0 micrograms/day plus calcium 1000 mg/day, administered with or without intranasal calcitonin 400 IU/day, prevented steroid-induced bone loss. Overall, calcitriol was well tolerated. At recommended dosages hypercalcaemia was infrequent and mild, generally responding to reductions in calcium intake and/or calcitriol dosage. However, the narrow therapeutic window of calcitriol required that its use be adequately supervised, with periodic monitoring of serum calcium and creatinine levels. This study clearly identifies the key limitation of calcitriol therapy as the close proximity of therapeutic and toxic doses.
Certain 3-desoxy-20-cyclopropyl vitamin D3 analogs are disclosed as inhibiting cellular proliferation in vitro in prostate cancer lines (“20-Cyclopropyl-Cholecalciferol Vitamin D3 Analogs,” M. Koike et. al.,
Anticancer Research
, 19:1689-1698 (1999))
Hyperparathyroidism
Secondary hyperparathyroidism is a common finding in patients with chronic renal failure. It is established that the reduction of renal 1,25(OH)
2
vitamin D
3
(calcitriol) synthesis is one of the principal mechanisms leading to the secondary hyperparathyroidism in these patients and it has been shown that calcitriol possesses direct suppressive action on PTH synthesis. Therefore, administration of calcitriol has been recommended for the treatment of secondary hyperparathyroidism in these patients. However, as described above, calcitriol has potent hypercalcemic effects giving it a narrow therapeutic window which limits its usage, especially at high doses. It would therefore be desirable to have an alternative means of treating hyperparathyroidism without incurring these undesirable hypercalcemic effects.
While a variety of compounds are available for treating these and other diseases, many of these compounds have undesirable side-effects and/or are relatively unstable, i.e., have short storage period. Therefore, there is a continuing needs for other compounds which are useful in treating these diseases.
BRIEF SUMMARY OF THE INVENTION
One aspect of the present invention provides a 3-desoxy vitamin D
3
analog ester of the formula:
or a salt thereof, and methods for using and producing the same, where
dotted line is optionally a double bond;
L is a linker selected from the group consisting of:
—CH
2
—CH
2
—CH
2
—,
—CH
2
—CH═CH—,
—CH
2
—C≡C—,
—CH
2
—CH
2
—C(═O)—, and
—CH═CH—CH═CH—;
each of R
2
and R
3
is independently alkyl or haloalkyl; or R
2
and R
3
and together with the carbon atom to which they are attached to form a cycloalkyl; and
each of R
1
and R
4
is independently hydrogen, alkyl, acyl group or other hydroxy protecting group,
provided at least one of R
1
and R
4
is an acyl group.
DEFINITIONS
“Acetate” or “Ac” are used interchangeably herein and refer to a moiety of the formula —C(═O)CH
3
.
“Acyl” refers to a moiety of the formula —C(O)R′, where R′ is alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl.
“Alkyl” means a linear fully-saturated hydrocarbon moiety having one to six, preferably one to four, carbon atoms or a branched fully saturated hydrocarbon moiety having three or six carbon atoms.
“Aralkyl” means a moiety of the formula —R
a
—R
b
, where R
a
is alkyl and R
b
is aryl as defined herein.
“Aryl” means a monocyclic or bicyclic aroma tic hydrocarbon moiety. In addition, one or more, preferably one, two or three, hydrogen atoms of the aryl moiety can be replaced by halo, nitro, cyano, hydroxy, amino, alkyl or alkoxy. Exemplary aryl groups include phenyl and naphthalenyl which can be substituted with one or more substituents listed above. Prefer

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