Novel vitamin D analogues

Details Novel vitamin D analogues Novel vitamin D analogues

1987-03-18

1989-09-12

Robinson, Douglas W.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

9,10-seco- cyclopentanohydrophenanthrene ring system doai

2603972, A61K 3159, C07J 900

Patent

active

048660485

DESCRIPTION:

BRIEF SUMMARY
This invention relates to a hitherto unknown class of compounds which shows 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 of diseases characterized by abnormal cell differentiation and/or cell proliferation.
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 (and also throughout the remainder of this disclosure) X stands for hydrogen, lower alkyl, halogen or hydroxy; Y stands for hydrogen or hydroxy; R.sup.1 and R.sup.2, which may be the same or different, stand for lower alkyl, optionally substituted with halogen or hydroxy (but with the proviso that R.sup.1 and R.sup.2 cannot both be methyl when X is other than lower alkyl), or, taken together with the carbon atom numbered 25, R.sup.1 and R.sup.2 can form a saturated or unsaturated C.sub.3-C.sub.9 carbocyclic ring (including an aromatic ring) which may optionally by substituted at any possible positions(s) with lower alkyl, halogen or hydroxy; R.sup.3 stands for hydrogen or lower alkyl; R.sup.4 and R.sup.5 represent either each hydrogen, or when taken together constitute a bond, with the result that a double bond connects carbon atoms numbered 22 and 23; and the two undulated bonds to carbon 24 indicate that both R and S forms at this centre are within the scope of the invention. In the context of this invention the expression "lower alkyl" indicates a straight or branched saturated or unsaturated carbon chain with a content of from 1 to 6 atoms.
As it can be seen, the compounds of formula I, depending on the meanings of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5, and/or X, contain one or more additional asymmetric carbon atoms and/or double bonds, and may thus form stereoisomeric forms. The invention covers all these compounds in pure form and also mixtures of them. It should be noted, however, that our investigations indicate a notable difference in activity between the stereoisomeric forms. 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 ("bioreversible derivatives or pro-drugs of I")
Especially preferred are compounds of formula I in which Y is hydroxy and R.sup.3 stands for hydrogen or methyl, and in particular compounds in which R.sup.4 and R.sup.5 taken together represent a bond, especially in such a way that the resulting 22,23-double bond has the trans configuration.
The term "bioreversible derivatives or prodrugs of I" includes, but is not limited to, derivatives of the compounds of formula I in which one or more hydroxy groups have been transformed into --O--acyl or --O--glycosyl groups, such masked groups being hydrolyzable in vivo.
It has recently been shown that certain vitamin D derivatives, in particular 1,25(OH).sub.2 D.sub.3 (1.alpha.,25-dihydroxy-vitamin D.sub.3) are able to stimulate the differentiation of cells and inhibit excessive cell proliferation, and it has been suggested that these compounds might be useful in the treatment of diseases characterized by abnormal cell proliferation and/or cell differentiation such as leukemia, myelofibrosis and psoriasis. However, the well known potent effects of these compounds on calcium metabolism prohibit the use of higher doses, which will give rise to hypercalcemia. Thus, these compounds are not completely satisfactory for use as drugs in the treatment of e.g. psoriasis or leukemia, which may require continuous administration of the drug in relatively high doses.
It has not surprisingly turned out that the compounds of the invention have a favourable therapeutic index and are particularly useful in the treatment of human and veterinary disorders which are characterized by abnormal cell proliferation and/or cell differentiation,

REFERENCES:
patent: 4225596 (1980-09-01), Deluca
patent: 4335120 (1982-06-01), Holick et al.
patent: 4391802 (1983-07-01), Suda et al.
patent: 4442093 (1984-04-01), Maeda et al.
patent: 4610978 (1986-09-01), Dikstein et al.
patent: 4661294 (1987-04-01), Holick et al.
Chemical Abstracts, vol. 102, No. 14; Apr. 8, 1985, #119659m, Dikstein et al.
Handbook of Nonprescription Drugs; 6th ed. (1979), pp. 397-400.

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