Use of cis-or transurocamic acid for the treatment of photodermatoses and immunogenic skin diseases

A compound of the general formula (I): Q--R--X wherein Q is a substituted or unsubstituted furanyl, imidazolyl, pyrrolyl 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, an alkyl or an aryl group and pharmaceutically acceptable salts thereof, are described for use in topical treatments of skin conditions which involve an overactive immune response, or which are responsive to UV irradiation. Pharmaceutical compositions of the compound of general formula (I) are also described.

DESCRIPTION 
The present invention relates to compounds of general formula I: 
EQU Q--R--X (I) 
wherein Q is a substituted or unsubstituted furanyl, imidazolyl, pyrrolyl 
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 
EQU Q--R--X (I) 
wherein Q, R and X are as hereinbefore defined, or a pharmaceutically 
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 (primary and 
secondary), seleromyxoedema, subcorneal pustular dermatoses, transient 
acantholytic dermatoses, psoriasis and atopic eczema. The invention, 
preferably, can relate to just one or a selection of the aforementioned 
conditions. 
The invention further extends to a method of treating a skin condition 
considered to involve an over active immune response, or a condition 
responsive to UV irradiation, inclusive of the specific conditions listed 
above, or just one or a selection of these conditions. 
In a third aspect, the invention provides the use of a compound of general 
formula (I), as hereinbefore defined, for the manufacture of a medicament 
for use in the treatment of any one, a selection, or all of the conditions 
defined, or listed above. 
In a further aspect, the present invention provides a pharmaceutical 
composition, comprising a compound of general formula (I), as hereinbefore 
defined, in admixture with a pharmaceutically acceptable excipient or 
carrier and suitable for topical use. Preferably, said composition is for 
use in treating a condition as hereinbefore defined or listed above. 
In embodiments of any aspect of the invention, Q, in general formula (I), 
can be substituted with F, Cl, Br or --CH.sub.3 but, preferably, is 
unsubstituted; R.sup.1 -R.sup.4 each, independently, can be H, a lower 
alkyl group (preferably C.sub.1 -C.sub.4) or a phenyl group but, 
preferably, are H; and R, preferably, is (cis)CR.sup.1 .dbd.CR.sup.2. 
In all aspects and embodiments of the invention, the preferred compound 
general formula (I) is cis-UCA. However, the invention encompasses the 
topical application of trans-UCA and its conversion, in situ, to cis-UCA 
by irradiation with UV light. The necessary UV light can be provided from 
an artificial source or by exposure to sunlight. Preferably, the UV is 
provided using an artificial source. 
Preferred pharmaceutical compositions, in accordance with the present 
invention, comprise ointments, gels, aerosols, wipes, creams, lotions or 
emulsions which include a compound of general formula I, in admixture with 
a suitable carrier, mixture of carriers or emulsion thereof. 
Cis-UCA can be prepared from the trans-isomer which is available from Sigma 
UK Ltd. (Poole, Dorset, UK). To prepare the cis-isomer, a solution of 
trans-UCA at a concentration of 10 mg/ml in dimethyl sulphoxide (or 
methanol) is spread thinly and irradiated under two Phillips TL20W/L UV 
lamps for three hours, which provide a total dose of 864 mj/cm2 in the 
range 270-350 nm. The conversion rate of trans-UCA to cis-UCA is in the 
order of 70%. Thus, all compositions and preparations, in accordance with 
the invention, which include cis-UCA can also include trans-UCA and, where 
quantities of cis-UCA are mentioned, a proportion thereof can be 
trans-UCA. 
Methods of synthesizing other compounds of formula I are set out in M. 
Norval et al., Photochemistry and Photobiology Vol. 49. No. 5. pp 633-639. 
1989. 
Pharmaceutical compositions may be prepared by incorporating cis-UCA, 
prepared in the manner discussed above, into a conventional pharmaceutical 
cream or other suitable base, using conventional techniques known in the 
art.

The following examples are provided by way of illustrative embodiments and 
are not intended in any way to limit the scope of the invention. 
EXAMPLE 1 
Gel Composition 
100 g of a gel composition, suitable for topical application to the skin, 
were prepared from the following quantities of the following substances; 
______________________________________ 
cis-UCA 1.0 g 
Hydroxyethyl cellulose 2.0 g 
Nipasept Sodium 0.15 g 
Glycerol l0 g 
Water to l00 g. 
______________________________________ 
The hydroxyethyl cellulose used was Cellosize QP52, OOOH and was employed 
as a viscosity enhancer, as well as to provide the composition with the 
required gel characteristics. 
The cis-UCA was prepared from trans-UCA by irradiating a thinly spread 
solution of 1.0 g of trans-UCA, in dimethyl sulphoxide (10 mg/ml), with 
two Phillips TL 20 w/l UV lamps for three hours. The conversion rate of 
trans-UCA to cis-UCA was approximately 70% and, therefore, the cis-UCA 
used contained up to about 30% trans-UCA. After irradiation, the remaining 
solvent was removed by evaporation and the cis-UCA was dissolved in a 
portion of the water. The remaining components were then mixed into the 
resulting solution and the rest of the water was added to form the final 
gel. 
EXAMPLE 2 
Cis-UCA, formed by the irradiation method set out in Example 1, was mixed 
into a jelly formed from 50% white soft paraffin and 50% liquid paraffin 
at a concentration of about 2% w/w. The resulting composition was suitable 
for topical application to the skin. 
EXAMPLE 3 
Non-aqueous Spray 
Non-aqueous sprays in accordance with the invention can be prepared using 
the following materials in the proportions set out below: 
______________________________________ 
% w/v 
______________________________________ 
cis-UCA 0.1-5 
isopropyl isostearate 10-40 
cyclomethicone 10-40 
Azone 0-20 
oil (preferably coconut) to 100 
______________________________________ 
The preferred composition for such a spray is 2% cis-UCA, 30% isopropyl 
isostearate, 30% cyclomethicone, 5% azone and 33% coconut oil (all %/w/v). 
EXAMPLE 4 
Gel Composition 
Further gels in accordance with the invention can be prepared using the 
following materials in the proportions set out below: 
______________________________________ 
% w/w 
______________________________________ 
cis-UCA 0.1-10 
Sodium carboxymethy 1.5-2.5 
cellulose 
Sorbic acid 0.75 
Propylene glycol 2.0-25 
Buffering agent 0.01-1 
Purified Water to 100 
______________________________________ 
The preferred composition for such a gel is 5% cis-UCA, 2% sodium 
carboxymethyl cellulose, 0.75% sorbic acid 10% propylene glycol, 0.1% 
buffering agent and purified water to 100% (all %w/w). 
EXAMPLE 5 
Cream Composition 
Creams in accordance with the invention can be prepared using the following 
materials in the proportions set out below: 
______________________________________ 
cis-U 0.1-10 
Cosmowax 10-25 
Oleyl Alcohol 0.1-10 
Oleic Acid 0.1-10 
Liquid Paraffin 5-25 
Polysorbate 20 0.1-5 
Phenonip 0.1-1 
Buffering Agent 0.1-1 
Sorbic Acid 0.075 
Purified Water to 100 
______________________________________ 
The preferred composition for such a cream is 5% cis-UCA, 15% cosmowax, 3% 
oleyl alcohol, 2% olecic acid, 15% liquid paraffin, 1% polysorbate 20, 
0.5% phenonip, 0.1% buffering agent, 0.075% sorbic acid and water to 100%. 
EXAMPLE 6 
Paint Composition 
Paints in accordance with the invention can be prepared using the following 
materials in the proportions set out below: 
______________________________________ 
% w/v 
______________________________________ 
cis-UCA 0.1-10 
Purified Water 0-60 
Dimethyl Sulphoxide To 100 
______________________________________ 
The preferred composition for such a paint is 5% cis-UCA, 20% purified 
water and 75% dimethyl sulphoxide.