Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 9,10-seco- cyclopentanohydrophenanthrene ring system doai
Patent
1994-09-01
1996-08-13
Prior, Kimberly J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
9,10-seco- cyclopentanohydrophenanthrene ring system doai
552653, 204166, A61K 3159, C07C40100
Patent
active
055456332
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/DK93/00196.
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, acne, 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 invention constitute a novel class of vitamin D analogues and are represented by the general formula I ##STR2## in which formula X is hydrogen or hydroxy; R.sup.1 and R.sup.2, which may be the same or different, stand for hydrogen or a C.sub.1 -C.sub.6 hydrocarbyl radical; or R.sup.1 and R.sup.2, taken together with the carbon atom (starred in formula I) bearing the group X, can form a C.sub.3 -C.sub.8 carbocyclic ring; Q is a single bond or a C.sub.1 -C.sub.8 hydrocarbylene diradical. R.sup.1, R.sup.2, and/or Q may be optionally substituted with one or more deuterium or fluorine atoms.
In the context of this invention, the expression hydrocarbyl radical (hydrocarbylene diradical) indicates the residue after removal of 1 (2) hydrogen atom(s) from a straight, branched or cyclic saturated or unsaturated hydrocarbon.
Examples of R.sup.1 and R.sup.2 when taken separately include (apart from hydrogen), but are not limited to, methyl, trifluoromethyl, ethyl, vinyl, normal-, iso- and cyclo-propyl, and 1-methylvinyl.
Examples of R.sup.1 and R.sup.2 when taken together include di-, tri-, tetra- and penta-methylene.
Examples of Q include a single bond, methylene, di-, tri- and tetra-methylene, --CH.sub.2 --CH.dbd.CH--, --CH.sub.2 --C.tbd.C--, --CH.dbd.CH--CH.sub.2 --, --C.tbd.C--CH.sub.2 --, phenylene (C.sub.6 H.sub.4 ; ortho, meta, para), --CH.sub.2 --(C.sub.6 H.sub.4)--, and --(C.sub.6 H.sub.4)--CH.sub.2 --.
The configuration about the 17, 20-double bond can be either E or Z. As can be seen from formula I, depending on the meanings of R.sup.1, R.sup.2, Q and X the compounds of the invention can comprise several diastereoisomeric forms (e.g. R or S configuration at the starred carbon atom). The invention covers all these diastereoisomers in pure form as well as mixtures of diastereoisomers.
In particular, both diastereoisomers having the two possible configurations about the 17, 20-double bond are included.
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 are also within the scope of the invention.
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 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 prolife
REFERENCES:
Chaudhuri et al: "Acid-catalysed rearrangement of 20alpha-e thynylpregn-5-ene-3beta-diol 3-acetate", Journal of the American Chemical Society, vol. 87, No. 16, Aug. 20, 1965, cited in the application.
Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske / Fabrik
Prior Kimberly J.
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