Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-02-09
2000-02-22
Powers, Fiona T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514861, 514863, 514885, 514887, 548561, 548562, A61K 3140
Patent
active
060280980
DESCRIPTION:
BRIEF SUMMARY
DESCRIPTION
The present invention relates to compounds of general formula I: or thiopheneyl group, R is CR.sup.1.sub.2 --CR.sup.2.sub.2, (cis)CR.sup.1 .dbd.CR.sup.2, or (trans)CR.sup.1 .dbd.CR.sup.2, X is COOR.sup.3 or NR.sup.1 R.sup.4, and R.sup.1 -R.sup.4 are each, independently, H, or an alkyl or an aryl group and to pharmaceutically acceptable salts thereof. The invention also relates to the use of such compounds in the topical treatment of skin conditions considered to involve an over-active immune response, or which are responsive to ultraviolet (UV) radiation.
Trans-urocanic acid (UCA) is a naturally occurring compound found in the upper layers of the epidermis, where it is synthesized through deamination of histidine by histidase. When the skin is irradiated with ultraviolet light, up to 60 or 70% of the trans-UCA present is converted into the cis-isomer and it is thought that cis-UCA, once so generated, functions as a mediator in both systemic and local UV induced immune system suppression. See the review article by M. Norval et al. in Photochemistry and Photobiology Vol. 50. No. 2, pp 267-275, 1989 (1).
Support for the proposition that cis-UCA is a mediator in UV induced suppression of the immune system is provided by the work reported by M. Norval et al. in Photochemistry and Photobiology Vol. 49. No. 5, pp 633-639, 1989 and that of V. E. Reeve et al., reported in Photodermatol Photoimmunol Photoreed 1991: 8: pp 176-180. The former authors found that cis-UCA was able to induce suppression of normal delayed type hypersensitivity response to herepes simplex virus type 1 in mice and the latter found that cis-UCA, generated by applying trans-UCA (in a cosmetic cream) to murine skin and then irradiating the treated skin, systemically suppressed normal contact hyper-sensitivity. Reeve et al. suggested that this activity is potentially harmful, since it could result in tumour development and, therefore, concluded that urocanic acid was potentially hazardous and should not be used as a cosmetic ingredient. Indeed, Reeve et al., in Photochemistry and Photobiology Vol. 49. No. 4. pp 459-464. 1989., reported that topically applied trans-UCA significantly increased the tumour load induced in hairless mice, on exposure to Erythema inducing doses of UV light or sunlight.
Thus, rather than being confirmed as therapeutically useful, investigation of their metabolic roles has led to the removal of trans-UCA from various commercially available cosmetic creams (see Concar in the New Scientist, May 16, 1992), to obviate the risk of it being transformed into the apparently harmful cis-isomer, and to cis-UCA being considered of potential use only in the treatment of serious or life-threatening conditions, such as those involving transplant surgery, etc. For example, cis-UCA has been suggested as a possible immuno-suppressive agent for use in transplant surgery, particularly in skin grafting.
However, contrary to the indications discussed above, it has now been found that certain UCA isomers, derivatives and analogues can be therapeutically useful. Accordingly, the present invention provides a compound of general formula I acceptable salt thereof, for use in a topical treatment of a skin condition which involves an over active immune response or which is responsive to UV radiation.
In preferred embodiments of the invention, a compound of general formula (I) can be for use in a method of treating photodermatoses including polymorphic light eruption, photosensitivity, dermatitis/actinic reticuloid syndrome, actinic prurigo and solar urticaria; general urticarias of allergic and non-allergic type; contact sensitivity and skin diseases that respond to UV radiation including, acne vulgaris, alopecia areata, dermatitis herpetiformis, eosinophilic pustular folliculitis, erythrokeratoderma (symmetrical and progressive), chronic lichenoid GVH disease, granuloma annulare, histiocytosis X, ichthyosis linearis circumflexa, lichen planus, pityriasis lichenoides, pityriasis rosea, pityriasis rubra pilaris, pressure sores, pruritis
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Ferguson James
Goodman Michael
Bioglan Ireland (R&D) Limited
Powers Fiona T.
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