Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 9,10-seco- cyclopentanohydrophenanthrene ring system doai
Patent
1993-01-08
1994-12-27
Prescott, Arthur C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
9,10-seco- cyclopentanohydrophenanthrene ring system doai
514 35, 514410, A61K 3159, C07J 900
Patent
active
053766512
DESCRIPTION:
BRIEF SUMMARY
This invention relates to the use of 20(R)-22-oxavitamin D analogues for treatment or prevention of skin ageing, and to the use of such compounds for preparation of pharmaceutical compositions for treatment and/or prevention of skin ageing.
Ageing of the skin involves the intrinsic process of senescense and extrinsic damage induced by chronic exposure to UV radiation (photoageing).
Clinically, the ageing process is characterized by skin changes such as thinning, loss of elasticity and wrinkling. The main histologic features of aged skin include epidermal athrophy and dysplasia as well as dermal damage with marked elastosis and loss of collagen.
It has recently been demonstrated that topical tretinoin can improve the features of photodamaged skin by daily continuous application (1). However, because of the irritant properties of tretinoin the use of this drug is associated with unpleasant side effects, and therefore there is a need for better tolerated and more active products for prevention and reversal of skin ageing.
We have now found that certain analogues of vitamin D are active in the prevention and treatment of skin ageing and at the same time are free of the irritant effects characteristic of retinoids.
It is well known that a number of vitamin D metabolites and analogues inhibit the proliferation of keratinocytes (2)(3)(4). As a result of this, a thinning of the epidermal layer is seen in guinea pigs in areas treated with a petrolatum ointment containing such an analogue compared to areas treated with petrolatum alone (4). A similar reduction of epidermal thickness is seen in psoriatic lesions treated with 1,25-dihydroxyvitamin D.sub.3 (3).
However, in contrast to this, we have now surprisingly seen a profound thickening of epidermis in rats treated with an ointment containing a member of a series of new 20(R)-22-oxa-vitamin D analogues e.g. those described in our copending international application PCT/DK90/00036, indicating the usefulness of such preparations for treatment or profylaxis of skin ageing, including photo-ageing.
The compounds described in PCT/DK90/00036 are represented by the general formula I ##STR1## in which formula R stands for an alkyl group containing from 4 to 12 carbon atoms optionally substituted with a hydroxy group.
Preferably R is a group of formula II ##STR2## where n is an integer from 1 to 7; 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; 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.
As can be seen from formula I and II, depending on the meanings of R, X, R.sup.1 and R.sup.2, 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 and also mixtures of diastereoisomers.
Among compounds of particular interest are the compounds of formula I in which n (in formula II) is 3 or 4 and R.sup.1 and R.sup.2 represent methyl, ethyl or n-propyl groups.
Most preferred are the compounds in which n is 3 or 4 and R.sup.1 and R.sup.2 represents ethyl groups.
The compounds are formulated in pharmaceutical compositions which are suitable for topical treatment, and in which the active ingredient comprises from 0.01 ppm to 10 ppm.
The formulations include liquid or semi-liquid preparations such as liniments, lotions, applicants, oil-in-water or water-in-oil emulsions such a creams, ointments or pastes.
In addition to the pharmaceutical carrier the formulations may include one or more additional ingredients such as diluents, buffers, flavouring agents, binders, surface active agents
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T. Okano et al, "Vitamin D Molecular, Cellular and Clinical Endocrinology", Proceedings of the Seventh Workshop on Vitamin D, Apr. 1988, pp. 462-463.
S. Morimoto et al, "Comparison of the Inhibitions of Proliferation of Normal and Psoriatic Fibroblasts by Lalpha, 25-dihydroxyvitamin D3 and Synthetic Analigues of Vitamin De with an Oxygen Atom in their side chain":, Biochemistry International, vol. 19, No. 5, Nov. 1989, pp. 1143-1144.
T. Valaja et al, "Affinity of 22-oxa-1,25(OH)2D3 for 1,25-dihydroxyvitamin D receptor and its effects on the Synthesis of Osteoclacin in Human Osterosarcoma Cells", Biochemical and Biophysical Research Communications, Vil 169, No. 2, Jun. 1990, pp. 629-635.
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T. Oikawa et al, "Inhibition of Angiogenesis by Vitamin D3 Analogues", European Journal of Pharmacology, vol. 178, No. 2, Jan. 1990, pp. 257-250.
Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske / Fabrik
Prescott Arthur C.
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