Vitamin D analogues

Details Vitamin D analogues Vitamin D analogues

1995-05-02

1998-01-20

Prior, Kimberly J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

9,10-seco- cyclopentanohydrophenanthrene ring system doai

552653, A61K 3159, C07C40100

Patent

active

057101426

DESCRIPTION:

BRIEF SUMMARY
The application is a 371 of international application PCT/DK93/00351, filed Nov. 1, 1993.
This invention relates to a hitherto unknown class of compounds which shows antiinflammatory and immunomodulating effects as well as strong activity in inducing differentiation and inhibiting undesirable proliferation of certain cells, including cancer cells and skin cells, to pharmaceutical preparations containing these compounds, to dosage units of such preparations, and to their use in the treatment and prophylaxis of hyperparathyroidism, particularly secondary hyperparathyroidism associated with renal failure, of a number of disease states including diabetes mellitus, hypertension, ache, alopecia, skin ageing, imbalance in the immune system, of inflammatory diseases such as rheumatoid arthritis and asthma, of diseases characterized by abnormal cell differentiation and/or cell proliferation such as e.g. psoriasis and cancer, for prevention and/or treatment of steroid induced skin atrophy, and for promoting osteogenesis and treating osteoporosis.
The compounds of the present invention are derivatives of 1.alpha.,25-dihydroxy-20-epi-vitamin D.sub.3 as represented by the general formula I ##STR2## in which formula the ".sunburst." indicates that this carbon may be modified, and the moiety U, substituting the 24-methylene of 1.alpha.,25-dihydroxy-20-epi-vitamin D.sub.3, stands for (CH.sub.2).sub.n --Y--(CH.sub.2).sub.m, where n is 0, 1 or 2, m is 1 or 2, and Y is oxygen or sulphur; and derivatives formed by replacing either the 22-methylene or the 23-methylene by an oxygen or by replacing 22- and 23-methylene with --CH.dbd.CH--; R' is methyl or ethyl; and in which one or more carbon atoms directly bonded to C-25 may optionally be substituted with one or more fluorine atoms.
Depending on the nature of the chain linking C-20 and C-25, the compounds of the invention can comprise several isomeric forms (e.g. R or S configuration at asymmetric carbon atoms, E or Z configuration of double bonds). The invention covers all these diastereoisomers in pure form or as diastereomeric mixtures. In addition, derivatives of I in which one or more of the hydroxy groups are masked as groups which can be reconverted to hydroxy groups in vivo are also within the scope of the invention.
The compounds I in which the hydroxyl group on carbon-25 is replaced by hydrogen are another type of prodrug. 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 shown that 1.alpha.,25-dihydroxy-vitamin D.sub.3 (1,25(OH).sub.2 D.sub.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).sub.2 D.sub.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).sub.2 D.sub.3, or its pro-drug 1.alpha.-OH-D.sub.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).sub.2 D.sub.3 is suggested by the recent observation of an association between hereditary vitamin D resistance and alopecia: treatment with 1,25(OH).sub.2 D.sub.3 may promote hair growth (Editorial, Lancet, Mar. 4, 1989, p. 478). Also, t

REFERENCES:
patent: 4594432 (1986-06-01), Baggiolini et al.
patent: 4612308 (1986-09-01), Baggiolini et al.
patent: 4617297 (1986-10-01), Boris et al.
patent: 4711881 (1987-12-01), Ikekawa
patent: 4719205 (1988-01-01), DeLuca et al.
patent: 4804502 (1989-02-01), Baggiolini et al.
patent: 4832875 (1989-05-01), Ikekawa
patent: 4851401 (1989-07-01), DeLuca et al.
patent: 4868165 (1989-09-01), Ikekawa
patent: 5190935 (1993-03-01), Binderup et al.
patent: 5194431 (1993-03-01), DeLuca et al.
patent: 5200536 (1993-04-01), Ikekawa et al.
patent: 5260290 (1993-11-01), DeLuca et al.
patent: 5292728 (1994-03-01), Neef et al.
Kobayashi, et al: "Production oand specificity of anti-22-oxacalcitriol antisera", Chemical and Pharmaceutical Bulletin, vol. 40, No. 6, Jun. 1992, pp. 1520-1522, see the whole document.
Calverley: "Synthesis of MC 903, a biologically active vitamin D metabolite analogue", Tetrahedron, vol. 43, No. 20, 1987, pp. 4609-4619, see the whole document.

Affiliated with

Also associated with

Rating

Vitamin D analogues does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Vitamin D analogues, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Vitamin D analogues will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-725465