Vitamin D analogues containing a hydroxy or alkylated hydroxy gr

Details Vitamin D analogues containing a hydroxy or alkylated hydroxy gr Vitamin D analogues containing a hydroxy or alkylated hydroxy gr

1995-01-03

1996-12-31

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

055894712

DESCRIPTION:

BRIEF SUMMARY
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 present invention are represented by the general formula I ##STR2## in which formula Q is a --CH.sub.2 --, --CH.dbd.CH-- or --C.tbd.C--; U is a C.sub.1 -C.sub.6 alkylene, R.sup.1 is hydrogen, a C.sub.1 -C.sub.4 alkyl or YR' in which Y stands for the radicals --SO-- or --SO.sub.2 -- and R' stands for a C.sub.1 -C.sub.4 alkyl.
R.sup.2 and R.sup.3 are independently hydrogen or C.sub.1 -C.sub.4 alkyl, additionally R.sup.2 and R.sup.3, when taken together with the starred carbon atom, may form a C.sub.3 -C.sub.6 carbocyclic ring; Z is hydrogen or hydroxy.
R.sup.2, R.sup.3, and U may optionally and independently be substituted with one or more fluorine atoms.
Examples of R.sup.2 and R.sup.3 when taken separately include, but are not limited to hydrogen, methyl, ethyl, normal and isopropyl.
Examples of R.sup.2 and R.sup.3 when taken together include ethylene, tri-, tetra-, and pentamethylene.
Examples of U include methylene, ethylene, tri-, tetra-, and pentamethylene.
Particularly preferred compounds include such in which Q is --CH.sub.2 --, U is --(CH.sub.2).sub.2 --, R.sup.1 is hydrogen, methyl or ethyl, R.sup.2 and R.sup.3 are ethyl and Z is hydroxy.
As can be seen from formula I, the compounds of the invention comprise several diastereoisomeric forms (e.g. R or S configuration at C-20 or at the starred carbon atom, E or Z configuration of a side chain double bond). The invention covers all these diastereoisomers in pure form as well as mixtures of such diastereoisomers.
Particularly preferred compounds are compounds containing a saturated side chain with the S-configuration at C-20.
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.
The compounds I in which Z is hydrogen are actually another type of prodrug. These compounds are relatively inactive in vitro, but are converted to active compounds of formula I by enzymatic side chain 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

REFERENCES:
patent: 5403940 (1995-04-01), Vall os et al.
Kubodera, et al.; "Synthetic Studies of Vitamin D Analogues, XI. Synthesis nd Differentiation-Inducing Activity of 1alpha,25-Dihydroxy-22-oxavitamin D3 Analogues", Chemical Parmaceutical Bull., vol. 40, No. 6, Jun. 1, 1992-pp. 1494-1499.
Brown, et al.: "New Active analogues of vitamin D with low calcemic activity", Kidney International, vol. 38, No. 29, 1990, pp. S-22-S-27.

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