Vitamin D analogues

Details Vitamin D analogues Vitamin D analogues

2001-03-20

2003-11-11

Qazi, Sabiha (Department: 1616)

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

Organic compounds

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

C552S653000, C514S167000

Reexamination Certificate

active

06646143

ABSTRACT:

This invention relates to novel vitamin D analogues which show strong activity in inducing differentiation and inhibiting undesirable proliferation of certain cells, including skin cells and cancer cells, as well as immunomodulating effects, to pharmaceutical preparations containing these compounds, to dosage units of such preparations, and to their use in the treatment and prophylaxis of diseases characterized by abnormal cell differentiation and/or cell proliferation.
BACKGROUND OF THE INVENTION
It has been shown that 1&agr;,25-dihydroxy-vitamin D
3
(1,25(OH)
2
D
3
) influences the effects and/or production of interleukins (Muller, K. et al.,
Immunol. Lett.,
17 361-366 (1988)), indicating the potential use of this compound in the treatment of diseases characterized by a dysfunction of the immune system, e.g. autoimmune diseases, AIDS, host versus graft reactions, and rejection of transplants or other conditions characterized by an abnormal interleukin-1 production, e.g. inflammatory diseases such as rheumatoid arthritis and asthma.
It has also been shown that 1,25(OH)
2
D
3
is able to stimulate the differentiation of cells and inhibit excessive cell proliferation (Abe, E. et al.,
Proc. Natl. Acad. Sci
., U.S.A., 78, 4990-4994 (1981)), and it has been suggested that this compound might be useful in the treatment of diseases characterized by abnormal cell proliferation and/or cell differentiation such as leukemia, myelofibrosis and psoriasis.
Also, the use of 1,25(OH)
2
D
3
, or its pro-drug 1&agr;-OH-D
3
, for the treatment of hypertension (Lind, L. et al.,
Acta Med. Scand.,
222, 423-427 (1987)) and diabetes mellitus (Inomata, S. et al.,
Bone Mineral.,
1, 187-192 (1986)) has been suggested. Another indication for 1,25(OH)
2
D
3
is suggested by the recent observation of an association between hereditary vitamin D resistance and alopecia: treatment with 1,25(OH)
2
D
3
may promote hair growth (Editorial, Lancet, March 4, p. 478 (1989)). Also, the fact that topical application of 1,25(OH)
2
D
3
reduces the size of sebaceous glands in the ears of male Syrian hamsters suggests that this compound might be useful for the treatment of acne (Malloy V. L. et al., The Tricontinental Meeting for Investigative Dermatology, Washington, (1989)).
However, the therapeutic possibilities in such indications are severely limited by the well known potent effect of 1,25(OH)
2
D
3
on calcium metabolism; elevated blood concentrations will rapidly give rise to hypercalcemia. Thus, this compound and some of its potent synthetic analogues are not satisfactory for use as drugs in the treatment of e.g. psoriasis, leukemia or immune diseases which may require continuous administration of the drug in relatively high doses.
A number of vitamin D analogues have recently been described that show some degree of selectivity in favour of the cell differentiation inducing/cell proliferation inhibiting activity in vitro as compared with the effects on calcium metabolism in vivo (as measured in increased serum calcium concentration and/or increased urinary calcium excretion), which adversely limit the dosage that can safety be administered. One of the first of these to appear, calcipotriol (INN) or calcipotriene (USAN), has been developed on the basis of this selectivity and is now recognized worldwide as an effective and safe drug for the topical treatment of psoriasis.
A study with another vitamin D analogue, Seocalcitol [1(S), 3(R)-dihydroxy20(R)-(5′-ethyl-5′-hydroxy-hepta-1 ′(E), 3 ′(E)-diene-1′-yl)-9,10-secopregna-5(Z), 7(E), 10(19)-triene], selected on this basis supports the concept that systemically administered vitamin D analogues may inhibit breast cancer cell proliferation in vivo at sub-toxic doses (Colston, K. W. et al.,
Biochem. Pharmacol.
44, 2273-2280 (1992) and Mathiasen, I. S. et al.,
J. Steroid Biochem. Molec. Biol.,
46, 365-371 (1993)).
Related compounds having the following formula are disclosed in WO 98/47866:
wherein A is a single or double bond, T is CH
2
or CH
2
CH
2
; B is CH
2
CH
2
, CH═CH or C≡C, R
1
and R
3
are H or OH, C(R,R) is CH
2
or C═CH
2
, R
2
is CH
3
and R
4
is H, or R
2
is H and R
4
is CH
3
, L is phenyl and R
5
is OH or C(C
1-4
-alkyl)
2
OH, or L—R
5
is 2-furyl which is 5-substituted by C(C
1-4
-alkyl)
2
OH, with the proviso that when L is phenyl, A is a single bond, B is C≡C, T is CH
2
, each R
1
and R
3
are OH, C(R,R) is C═CH
2
, R
2
is CH
3
, R
4
is H, and R
5
is C)CH
3
)
2
OH, then R
5
must be in position ortho or para. These compounds are described in WO 98/47866 as useful in the treatment or prevention of vitamin D dependent disorders, particularly psoriasis, basal cell carcinomas, disorders of keratinization and keratosis, leukemia, osteoporosis, hyperparathyroidism accompanying renal failure, transplant rejection and graft vs. host disease.
The stereochemistry of the compounds described in WO 98/47866 is not given at the double bond (position 22) when B is CH═CH. However, from the exemplification and the syntheses which are disclosed, it is evident that only 22-trans compounds are envisaged.
Notwithstanding the extensive prior art efforts to provide therapeutically effective products, there is a continuing need for new vitamin D analogues with an acceptable combination of desired therapeutic activity and minimum toxic effects. The compounds of the present invention provide hitherto undisclosed vitamin D analogues with cell proliferation inhibitory and cell differentiating promoting activities without the undesired side effects of increased serum calcium levels and skin irritation.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the general formula I
wherein X represents hydrogen or hydroxy; R
1
and R
2
, which may be the same or different, represent hydrogen, (C
1
-C
4
)alkyl optionally substituted with one hydroxyl group or one or more fluorine atoms, or, together with the carbon atom to which they are attached, R
1
and R
2
form a (C
3
-C
5
)carbocyclic ring. R
3
represents hydrogen, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, or a halogen atom, such as fluorine, chlorine, bromine, or iodine.
The configuration of the carbon atoms marked with an asterisk may be both S or R.
The present invention also relates to in vivo hydrolyzable esters of the compounds of general formula I with pharmaceutically acceptable acids.
As will be evident, the compounds of formula I have the cis-configuration at the double bond at position 22. According to the invention, it has been found that the 22-cis compounds are much more active in stimulating cell differentiation and inhibiting undesirable cell proliferation.
DETAILED DESCRIPTION OF THE INVENTION
Preferred Embodiments
In compounds of the invention it is preferred that X represents hydroxy; R
1
and R
2
are the same and preferably represent (C
1
-C
2
)alkyl optionally substituted with one hydroxyl group or one or more fluorine atoms; and R
3
represents hydrogen,(C
1
-C
2
)alkyl, fluorine or chlorine. Preferred positions of the C(R
1
)(R
2
)(X) group are meta and para. Even more preferred are compounds of formula I wherein R
1
and R
2
both represent methyl, trifluoromethyl, or ethyl, and R
3
represents hydrogen.
The invention also includes diastereoisomers of the compounds of formula I in pure form or as a mixture of diastereoisomers of a compound of formula I.
Preferred compounds of the invention are selected from the group consisting of:
1(S), 3(R)-Dihydroxy-20(R)-[2(Z)-(3-(2-hydroxy-2-propyl)-phenyl)-vinyl]-9, 10-secopregna-5(Z), 7(E), 10(19)-triene.
1(S), 3(R)-Dihydroxy-20(S)-[2(Z)-(4-(2-hydroxy-2-propyl)-phenyl)-vinyl]-9,10-secopregna-5(Z), 7(E), 10(19)-triene.
1(S), 3(R)-Dihydroxy-20(R)-[2(Z)-(4-(2-hydroxy-2-propyl)-phenyl)-vinyl]-9,10-secopregna-5(Z), 7(E), 10(19)-triene,
and in-vivo hydrolyzable esters thereof with pharmaceutically acceptable acids.
The term “alkyl” as used herein refers to any univalent group derived from an alkane by removal of a hydrogen atom from

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