Vitamin D analogues and their pharmaceutical use

Details Vitamin D analogues and their pharmaceutical use Vitamin D analogues and their pharmaceutical use

2001-10-23

2003-03-25

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

06537980

ABSTRACT:

This invention relates to hitherto unknown vitamin D compounds which shows strong activity in inducing differentiation and inhibiting undesirable proliferation of certain cells, including skin cells and cancer cells, as well as anti-inflammatory and 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 characterised by abnormal cell differentiation and/or cell proliferation such as cancer, leukemia, myelofibrosis, and psoriasis, of a number of disease states including hyperparathyroidism, particularly secondary hyperparathyroidism associated with renal failure, diabetes mellitus, hypertension, acne, alopecia, skin ageing, AIDS, neurodegenerative disorders such as Alzheimer's disease, host versus graft reactions, rejection of transplants, inflammatory diseases such as rheumatoid arthritis and asthma, for prevention and/or treatment of steroid induced skin atrophy, and for promoting osteogenesis and treating osteoporosis.
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 characterised by a dysfunction of the immune system, e.g. autoimmune diseases, AIDS, host versus graft reactions, and rejection of transplants or other conditions characterised 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 characterised 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 safely 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 recognised world-wide 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)).
There is a continuing need for new vitamin D analogues with an acceptable combination of desired therapeutic activity and minimum toxic effects. Compounds having a structure similar to the compounds of the present invention are disclosed in EP 522 013. However, said compounds exhibit considerable skin irritation, and are therefore less suitable for topic administration or local treatment of skin diseases.
The compounds of the present invention provide hitherto undisclosed vitamin D analogues with immunosuppressive and cell proliferation inhibitory activities without the undesired side effects of increased serum calcium levels and skin irritation.
The present invention relates to compounds of the general formula I
wherein R
1
and R
2
, which may be the same or different, represent (C
1
-C
4
)alkyl, and R
3
represents hydrogen, halogen, (C
1
-C
4
)alkyl, or O—(C
1
-C
4
)alkyl, and in-vivo hydrolysable esters thereof with pharmaceutically acceptable acids.
The configuration at the tentative chiral carbon atom (starred in formula I and Ia (below)) may be R or S. In preferred compounds of the invention the starred carbon atom is substituted with identical alkyl groups (R
1
=R
2
) and is thus achiral.
More particularly, the invention relates to compounds of the general formula Ia:
wherein R
1
, R
2
, and R
3
have the meanings defined above.
Preferred are compounds of formula Ia wherein R
1
and R
2
independently represent methyl or ethyl and wherein R
3
represents hydrogen, F, Cl, methyl, ethyl, or methoxy. Furthermore, preferred compounds of formula Ia are compounds wherein the group R
3
is in the 4-position or in the 5-position. Further preferred compounds of formula Ia are compounds wherein R
1
and R
2
both represent methyl and R
3
represents hydrogen, F, or methyl. Most preferred compounds of formula Ia are compounds wherein R
3
represents hydrogen, 5-methyl, or 4-fluoro, and R
1
and R
2
both represent methyl.
The invention also includes diastereoisomers of the compounds of formula I in pure form or as a mixture of such diastereoisomers.
Specifically preferred compounds of the invention are selected from the group consisting of:
1(S),3(R)-Dihydroxy-20(R)-[((3-(2-hydroxy-2-propyl)-phenyl)-methoxy)-methyl]-9,10-secopregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-[((3-(2-hydroxy-2-propyl)-5-methyl-phenyl)-methoxy)-methyl]-9,10-secopregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-[((3-(2-hydroxy-2-propyl)-5-methoxy-phenyl)-methoxy)-methyl]-9,10-seco-pregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-[((3-(2-hydroxy-2-propyl)-4-fluoro-phenyl)-methoxy)-methyl]-9,10-seco-pregna-5(Z),7(E),10(19)-triene,
and in-vivo hydrolysable 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 any carbon atom, and includes the subclasses of normal alkyl (n-alkyl), and primary, secondary and tertiary alkyl groups respectively, and having the number of carbon atoms specified, including for example (C
1
-C
4
)alkyl, e.g. methyl, ethyl, n-propyl, and isobutyl. Alkane refers to an acyclic branched or unbranched hydrocarbon having the general formula C
n
H
2n+2
, and therefore consisting entirely of hydrogen atoms and saturated carbon atoms.
The compounds of formula Ia may conveniently be prepared from the vitamin D derivative 1 described in Tetrahedron 43 4609 (1987) by the route outlined in Scheme I. The corresponding ortho and para substituted analogues of formula I may

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