Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 9,10-seco- cyclopentanohydrophenanthrene ring system doai
Patent
1995-01-03
1997-03-18
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
056123256
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/DK93/00305 filed Sep. 23, 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, 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 R stands for a straight or branched, saturated or unsaturated alkyl group containing from 4 to 12 carbon atoms optionally substituted with a hydroxy group, and possibly containing a ring structure, and in which at least one of the carbon atoms not bearing a hydroxyl group is substituted with one or more halogen atoms or an azido group.
Preferably R is a group of formula II ##STR3## where q is 0 or 1, and n and m are independently 0 or integers running from 1 to 6; Y.sup.1 and Y.sup.2 are independently hydrogen, halogen or azido; R.sup.1 and R.sup.2 which may be the same or different, stand for hydrogen, lower alkyl, lower cycloalkyl, or, taken together with the carbon atom (starred in formula II) bearing the group X, R.sup.1 and R.sup.2 can form a C.sub.3 -C.sub.8 carbocyclic ring; R.sup.1 and R.sup.2 may optionally be substituted with an azido group or one or more halogen atoms; X stands for hydrogen or hydroxy.
In the context of this invention, the expression "lower alkyl" indicates a straight or branched saturated or unsaturated carbon chain containing from 1 to 5 carbon atoms, and the expression "lower cyclo-alkyl" indicates a saturated or unsaturated C.sub.3 -C.sub.7 carbocyclic ring. Halogen stands for fluorine, chlorine, bromine or iodine.
In particular, R.sup.1 and R.sup.2 are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2-fluoropropyl-2, 3-fluoropentyl-3, chloromethyl, trichloromethyl, 2-chloropropyl-2, 3-chloropentyl-3, bromomethyl, 2-bromopropyl-2, 3-bromopentyl-3, iodomethyl, 2-iodopropyl-2, 3-iodopentyl-3-azidomethyl, 2-azidopropyl-2, and 3-azidopentyl-3.
As can be seen from formula I and II, depending on the meanings of R, Y.sup.1, Y.sup.2, X, R.sup.1 and R.sup.2 the compounds of the invention comprise several diastereoisomeric forms. The invention covers all these diastereoisomers in pure form and also mixtures of such diastereoisomers. 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 R is not substituted with hydroxy 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 condit
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Kubodera, et al: "Synthetic Studies of Vitamin D Analogues, XI. Synthesis and Differentiation-Inducing Activity of 1alpha, 25-Dihydroxy-22-oxavitamin D3 Analogues", Chemical Parmaceutical Bull., vol. 40, No. 6, Jun. 1, 1992-pp. 1494-1499.
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Hansen Kai
Pedersen Henrik
Leo Pharmaceutical Products Ltd. A/S (L.o slashed.vens Kemiske F
Prior Kimberly J.
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