Vitamin D analogues

Details Vitamin D analogues Vitamin D analogues

1998-12-04

2001-03-06

Qazi, Sabiha N. (Department: 1616)

Organic compounds -- part of the class 532-570 series

Organic compounds

9,10-seco-cyclopentanohydrophenanthrene ring system or...

C514S167000, C552S653000

Reexamination Certificate

active

06197982

ABSTRACT:

This invention relates to a hitherto unknown class of compounds which shows strong activity in inducing differentiation and inhibiting undesirable proliferation of certain cells, including skin cells and cancer cells, as well as immunomodulating and antiinflammatory effects, to pharmaceutical preparations containing these compounds, to dosage units of such preparations, and to their use in the treatment and/or prophylaxis of diseases characterized by abnormal cell differentiation and/or cell proliferation such as e.g. psoriasis and other disturbances of keratinization, HIV-associated dermatoses, wound healing, cancer, including skin cancer, and of diseases of, or imbalance in, the immune system, such as host versus graft and graft versus host reaction and transplant rejection, and autoimmune diseases, such as discoid and systemic lupus erythematosus, diabetes mellitus and chronic dermatoses of autoimmune type, e.g. scleroderma and pemphigus vulgaris, and inflammatory diseases, such as rheumatoid arthritis and asthma, as well as a number of other disease states including hyperparathyroidism, particularly secondary hyperparathyroidism associated with renal failure, cognitive impairment or senile dementia (Alzheimers disease) and other neurodegenerative diseases, hypertension, acne, alopecia, skin atrophy, e.g. steroid induced skin atrophy, skin ageing, including photo-ageing, and to their use for promoting osteogenesis and treating/preventing osteoporosis and osteomalacia.
The compounds of the invention constitute a novel class of vitamin D analogues and are represented by the general formula I
in which formula X is hydrogen or hydroxy; R
1
and R
2
, which may be the same or different, stand for hydrogen or a C
1
-C
3
alkyl radical; or R
1
and R
2
, taken together with the carbon atom bearing the group X, can form a C
3
-C
6
carbocyclic ring; R
3
stands for a C
1
-C
3
alkyl radical, an aryl or an aralkyl radical, or for YR
4
, in which Y stands for the radicals —CO—S—, —CS—O— or —CS—S—, and R
4
stands for a C
1
-C
3
alkyl radical or an aryl or an aralkyl radical; Q is (CH
2
)
n
, n being 1-4. R
1
, R
2
and Q independently may optionally be substituted with one or more fluorine atoms.
Examples of R
1
and R
2
when taken separately include (apart from hydrogen), but are not limited to, methyl, trifluoromethyl, ethyl, pentafluoroethyl, and normal-, iso- and cyclo-propyl.
Examples of R
1
and R
2
when taken together include di-, tri-, tetra- and pentamethylene.
Examples of R
3
and R
4
include, but are not limited to, methyl, ethyl, propyl, normal-, iso- and cyclopropyl, phenyl and benzyl.
Most preferred examples of Q include di- and trimethylene.
As can be seen from formula I, depending on the meanings of R
1
, R
2
, R
3
, Q and X the compounds of the invention can comprise several diastereoisomeric forms (e.g. R or S configuration at the carbon atom bearing the radicals R
1
, R
2
, and X). The invention covers all these diastereoisomers in pure form as well as mixtures thereof.
In particular, both diastereoisomers having the two possible configurations (in the following designated “A” and “B”) at the carbon atom marked “22” are included. A is the preferred one.
In addition, prodrugs of I in which one or more of the hydroxy groups are masked as groups which can be reconverted to hydroxy groups in vivo can also be envisaged.
Compounds of formula I in which X is hydrogen also may act as prodrugs, as these compounds are relatively inactive in vitro but are converted to active compounds of formula I by enzymatic hydroxylation after administration to the patient.
It has been known for more than two decades that vitamin D (D
3
/D
2
) is a pro-hormone which is hydroxylated in vivo to the active hormone 1&agr;,25-dihydroxy-vitamin D
3
(1,25(OH)
2
D
3
or calcitriol). Vitamin D
2
is metabolized in the same way as D
3
and is bioequivalent with D
3
in humans. 1,25(OH)
2
D
3
is responsible for maintaining calcium (and phosphate) homeostasis by regulation of the intestinal calcium absorption, the renal calcium excretion and the bone mineralization/resorption. Other hormones such as parathyroid hormone (PTH) and calcitonin function as positive and negative feedback calcium regulators respectively in concert with 1,25(OH)
2
D
3
[1],[2].
This knowledge has led to the use of 1,25(OH)
2
D
3
and its prodrug 1&agr;-hydroxy-D
3
(alfacalcidol, INN) in the treatment of patients with kidney failure, where the important renal 1&agr;-hydroxylation of 25-hydroxy vitamin D is impaired, leading to hypocalcemia, secondary hyperparathyroidism and bone demineralization (renal osteodystrophy) [1].
It has since been shown that the (nuclear) receptor for 1,25(OH)
2
D
3
(VDR) is present, not only in the intestine, bone and kidney, but in a large number of other locations, such as e.g. parathyroid glands, islets of the pancreas, mammary gland cells, keratinocytes and fibroblasts of the skin, circulating monocytes and (activated) lymphocytes, and many other normal cell types and tissue; in addition the VDR is also present in several cancer cell lines [2],[3],[4].
In accordance with this widespread occurrence of the VDR, it has been experimentally demonstrated that 1,25(OH)
2
D
3
has biological effects over and beyond the “classical” effects on calcium regulation.
It was shown that 1,25(OH)
2
D
3
is able to stimulate the differentiation of cells and inhibit excessive cell proliferation [5], suggesting potential use in the treatment of e.g. psoriasis and cancer. It was also shown that 1,25(OH)
2
D
3
influences the effects and/or production of interleukins [6], indicating the potential use of this compound in the treatment of immunological disorders, such as e.g. autoimmune diseases and rejection of transplants.
The use of 1,25(OH)
2
D
3
, or its pro-drug 1&agr;(—OH—D
3
, for the treatment of several other disease states has also been suggested: hypertension [7], diabetes mellitus [8], alopecia [9], acne [10], osteoporosis [11] and neurodegenerative disorders [121.
The inhibition of angiogenesis by 1,25(OH)
2
D
3
[13] indicates a possible inhibition of tumour growth via reduction of the growth of new blood vessels into the tumour.
However, the therapeutic possibilities of 1,25(OH)
2
D
3
in several of these indications are severely limited by the potent effect of this hormone on calcium metabolism, because serious side effects due to hypercalcemia will result from the high doses necessary to obtain a therapeutic effect on e.g. psoriasis or cancer or immunological disorders.
In order to overcome this problem a large number of vitamin D analogues have been described, and some of these show selectivity in favour of the cell differentiation inducing/cell proliferation inhibiting activity as compared with the effect on calcium metabolism [3],[4],[14].
This work has resulted in therapeutically useful, or potentially useful, vitamin D analogues. Thus, the vitamin D
3
analogue, MC
903
(calcipotriol, calcipotriene, INN, cf. table 1), is a potent inducer of cell differentiation and inhibitor of cell proliferation which shows only moderate activity on calcium metabolism in vivo [15].
Calcipotriol is on the market as a safe and effective drug for the treatment of the hyperproliferative disease of the skin, psoriasis. Calcipotriol renders improvement, without hypercalcemia, in 70-80% of the patients ([6],[17]. However, this selectivity is not paralleled by in vitro studies, which show that calcipotriol binds equally well as 1,25(OH)
2
D
3
to the intestinal vitamin D receptor. The low in vivo activity on calcium metabolism of calcipotriol is due to a rapid metabolism of the compound, thus limiting the potential of this compound for systemic use [16].
The efficacy of several vitamin D analogues in inducing differentiation and inhibiting proliferation of cancer cells has been demonstrated, both in

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