GB2437429A

GB2437429A - Urocanic acid derivatives

Info

Publication number: GB2437429A
Application number: GB0711234A
Authority: GB
Inventors: Arthur Kammeijer
Original assignee: VALLETTA HEALTH BV
Current assignee: VALLETTA HEALTH BV
Priority date: 2007-06-11
Filing date: 2007-06-11
Publication date: 2007-10-24
Also published as: GB0711234D0

Abstract

Derivatives of urocanic acid of formulae 1-3: <EMI ID=1.1 HE=32 WI=100 LX=515 LY=765 TI=CF> <PC>wherein W is absent or selected from (CH2)y and CH=CH, where y is 1 or 2; R1 is selected from OR2 and NR3R4; R2 is a branched, unbranched, saturated or unsaturated C1-8 hydrocarbon chain; and R3 and R4 are hydrogen or a branched, unbranched, saturated or unsaturated C1-8 hydrocarbon chain; have improved efficacy and/or tissue penetration properties. These compounds may be useful in the treatment of immune related diseases particularly dermatological conditions such as psoriasis and eczema. Compositions and pharmaceutical compositions are also outlined.

Description

Title: Urocanic acid derivatives The invention relates to derivatives

of urocanic acid that have improved efficacy and/or tissue penetration properties. The invention further provides use of these derivatives in a medicament for modulating an immunerelated disease in an individual.

Ultraviolet radiation (UV), in particular the UVB range, is able to suppress the immune system. An explanation for the phenomenon of UV-mediated immunosuppression is that it prevents the recognition of molecules that are altered upon exposure to UV radiation as "nowself' neoantigens, which otherwise would result in chronically inflamed skin. However, a drawback of UV-mediated immunosuppression is that it enhances a risk of acquiring an infectious disease and of developing skin cancer Urocanic acid (UCA) is a major UVabsorbing chromophore in the epidermis and is one of the initiators of UV-induced immunosuppression. TransUCA is present in a non-exposed epidermis and can be photoisomerized by UV-exposure of the skin into ci.sUCA (Norval et at. 1995. Photochem Photobiol. 62: 209-217; Noonan and De Fabo. 1002. Immunol Today 13: 250-254). In general, modulation or suppression of immune responses is provided by oxidation products of urocanic acid (UOPs), not cis-urocanic acid per se, comprising at' least 3 UOPs: imidazole-4-carboxyaldehyde, imidazote-4-acetic acid or iniidazole -4-carboxylic acid.

lmidazo1e4-acetic acid (ImAc) can be formed from both trans-and cis-UCA isomers by photooxidation in the epidermis and in vitro (Kammeyer et al. 2001. Biochim. Biophys. Acta 1526: 277-285). ImAc has recently been shown to suppress the contact hypersensitivity (CHS) response in mice (Kammeyer et al. 2004. Photochem Photobiol. 80: 72-77), as was shown for cis-UCA by others (Norval et at. 1995. Photochem Photobiol. 62: 209-217; Noonan and De Fabo.

1992. Immunol Today 13: 250-254).

The present invention provides a new class of imidazole derivates with improved efficacy. The compounds are all imidazole derivatives, including iznidazolones, with a modification at the C4 position of the imidazole ring, when compared to the imidazoles of WO 01/00145. The present invention therefore provides an imidazole derivative, or a salt thereof, selected from the group consisting of:

I

W-C-O-Rl (formula i); 0 11,,W-C-0-R1 and I-IN NH (formula 2); W-C-o-R I and HN N (formula 3); wherein: W is either absent, or selected from (CH2)y and CHCH, wherein y = 1 or 2; and Ri is selected from R2 and N(R3,R4), wherein R2 is a branched or unbranched, saturated or unsaturated, CrCs hydrocarbon chain; and wherein R3 and R4 independently represent hydrogen, or a branched or unbranched, saturated or unsaturated, C1-Ca hydrocarbon chain.

Imidazole derivatives, including imidazolone derivatives, of the invention show enhanced efficacy and/or tissue distribution upon administration, in particular when the imidazole derivative of the invention is compared with a derivative having the same backbone but a different Ri group, such as an oxidation product of urocanic acid. Furthermore, imidazole derivatives of the invention exhibit enhanced tissue penetration. Without being bound by theory, it is believed that the estimated pKoiw (J. Garst, J. Pharm. Sci. 73 (1984) 1623 1629) of these imidazole derivatives is between zero and two, and that it is this property that enables enhanced efficacy and/or tissue penetration compared to ImAc and other oxidation products of urocanic acid. The imidazole derivatives of the invention more effectively reach and/or penetrate their cellular targets and show enhanced immunosuppressive behaviour. It is to be expected that longer hydrocarbon chains at the C4 position will increase the pKo/w value of the resuLting compounds. Surprisingly, the modifications leave the immune suppressive quality of the compounds intact. Preferred imidazole derivatives, including imidazolone derivatives, according to the invention are presented in

Table 1.

In particular preferred imidazole derivatives according to the invention are imidazole derivatives whereby said imidazole derivative comprises an imidazole ring structure according to formula 1. Imidazole derivatives comprising this imidazole ring structure have been identified as natural oxidation products of urocanic acid (UOP8) in the skin.

In one aspect of the invention, it is preferred that an imidazole derivative according to the invention is a compound according to formula 1, whereby W is absent.

Preferred examples of these imidazole derivatives are methyl imidazole4 carboxylate, ethyl imidazole-4carboxylate, propyl imidazole -4carboxylate, isopropyl iinidazole4-carboxylate, butyl imidazole-4-carboxylate, sec butyl imidazole-4carboxylate, tert butyl imidazole-4-carboxylate, pentyl imidazole 4carboxylate, hexyl imidazole 4carboxylate, heptyl imidazole -4-carboxylate, octyl imidazole 4-carboxylate, 2,3-diinethylpentyl imidazole -4-carboxylate, 2,3 dimethylpentyl imidazole -4carboxylate, N-methyl imidazole -4-carboxylamide, N, N -dimethyl imidazole -4-carboxylamide, N-ethyl imidazole 4-carboxylamide, N, N diethyl irnidazole -4-carboxylamide, N-propyl imidazole -4-carboxylamide, N,N-dipropyl imidazole -4-carboxylamide, N-isopropyl imidazole -4-carboxylamide, N,N-diisopropyl imidazole -4-carboxylamide, N-butyl imidazole - 4-carboxylamide, N,N-dibutyl imidazole-4-carboxylarnide, N-secbutyl imidazole -4-carboxylamide, N,N-di secbutyl imidazole -4-carboxylamide, N tert- butyl imidazole-4carboxylamide, N,N-di tert-butyl imidazole-4- carboxylarnide, Npentyl imidazole -4-carboxylamide, N,N-dipentyl im idazole4-carboxylamide, N-hexy imidazole4carboxylamide, N,N-dihexyl imidazole4 carboxylamide, N-heptyl imidazole-4-carboxylamide, N, Ndiheptyl imidazole 4-carboxylamide, N-octyl imidazole -4carboxylamide, N, N- dioctyl imidazole 4 carboxylamide, N -(2, 3-dimethylpentyl)imidazole -4-carboxylamide, N,Ndi (2, 3-dimethylpentyl)imidazole -4-carboxylamide, N -(2.3 dimethylhexyl)imidazole-4-carboxylamide, and N, N di-(2, 3 dimethylhexyl)imidazole-4carboxylamide.

A particularly preferred compound according to this aspect of the invention is ethyl imidazole-4-carboxylate. This compound has particularly advantageous efficacy, tissue penetration, tissue distribution and/or immune suppressive properties In another aspect of the invention, a preferred imidazole derivative of the invention comprises a compound according to formula 1, whereby W is CH2. -Preferred examples of these imidazole derivatives according to this aspect of the invention are methyl imidazole-4-acetate, ethyl imidazole-4-acetate, propyl imidazole -4-acetate, isopropyl imidazole-4-acetate, butyl imidazole 4 acetate, sec butyl imidazole4acetate, tert butyl imidazole4'acetate, pentyl imidazole-4-acetate, hexyl imidazole -4acetate, heptyl imidazole -4-acetate, octyl iniidazole -4-acetate, 2,3-dimethylpentyl imidazole-4-acetate, 2,3-dimethylpentyl imidazole -4-acetate, N-methyl imidazolè-4-acetamide, N, N dimethyl imidazole4-acetamide, N-ethyl imidazole -4-acetamide, N,Ndiethyl imidazole -4-acetamide, N-propyl imidazole -4-acetamide, N,Ndipropyl imidazole -4-acetamide, N-isopropyl imidazole -4-acetarnide, N, N-diisopropyl imidazole 4-acetamide, N-butyl imidazole-4-acetamide, N,N-dibutyl irnidazole- 4-acetamide, N-sec-butyl imidazole-4-acetamide, N,N-di sec-butyl imidazole- 4-acetarnide, N-tertbutyl imidazo]e-4-acetamide, N,N-di-tert-butyl imidazole 4-acetamide, N-pentyl imidazole 4-acetarnide, N, Ndipentyl imidazole-4-acetamide, N-hexy imidazole-4-acetamide, N,N-dihexyl imidazole-4-acetamide, N-heptyl imidazole -4-acetamide, N, N-diheptyl imidazole-4-acetamide, N-octyl imidazole -4-acetamide, N,N-dioctyl imidazole-4-acetamide, and branched and/or saturated and unsaturated derivatives thereof such as N (2,3-dimethylpentyl)imidazole 4-acetamide, N,N-di-(2, 3 -dimethylpentyl)imidazole 4-acetamide, N -(2,3dimethylhexyl)imidazole-4-acetamide, and N,N-di-(2,3-dimethylhexyl)imidazole -4-acetamide.

A particularly preferred compound according to this aspect of the invention is ethyl imidazole-4-acetate. This compound has particularly advantageous efficacy, tissue penetration, tissue distribution and/or immune suppressive properties.

Without being bound by theory, it is to be expected that tissue penetration, distribution and immunosuppressive effects increase upon introduction of enlarged hydrocarbon chains from Cz to C8. Therefore, preferred compounds of the invention comprise compounds according to formula 1, whereby Ri is selected from R2 and N(.R3,R4), wherein R2, R3, and R4 are independently selected from a branched or unbranched, saturated or unsaturated, C2C8 hydrocarbon chain, more preferred a branched or unbranched, saturated or unsaturated C3C hydrocarbon chain, more preferred a branched or unbranched, saturated or unsaturated C4C8 hydrocarbon chain, more preferred a branched or unbranched, saturated or unsaturated C5Cs hydrocarbon chain, more preferred a branched or unbranched, saturated or unsaturated CrC8 hydrocarbon chain, more preferred a branched or unbranched, saturated or unsaturated C7C8 hydrocarbon chain, more preferred a branched or unbranched, saturated or unsaturated C8 hydrocarbon chain.

Particularly preferred is an imidazole derivative according to formula 1, whereby Ri is selected from -R2 and N-(R3,R4), wherein R2, R3, and R4 are independently selected from more preferred a branched or unbranched saturated or unsaturated C4C8 hydrocarbon chain.

Preferred imidazole derivatives of the invention are saturated, branched or unbranched, imidazole derivatives due to their improved skin penetration properties and increased pKo/w's over unsaturated chains. Unsaturated, branched or unbranched, imidazole derivatives, however, have an improved resistance to microbial degradation, compared to saturated imidazole derivatives. Therefore, unsaturated imidazole derivatives are preferred if enhanced stability of the imidazole derivatives is required.

In another aspect, the invention provides a use of an imidazole derivative according to the invention as a medicament.

The invention further provides the use of an imidazole derivative according to the invention in the preparation of a medicament for the treatment of an immunerelated disease. The imidazole derivatives of the invention have anti inflammatory properties and may thus be used as topical agents in dermatology, ophthalmology and earnosethroat medicine. They may also be developed as systemic agents and then be used orally in a wide variety of inflammatory diseases.

An imidazole derivative of the invention was found to have immunosuppressive properties. Many immune re]ated diseases are known, including 1mm unemediated inflammatory diseases, infectious diseases, immunodeficiency diseases, and cancer. Patients with immune related diseases that benefit from suppressing the immune response by an imidazole derivative of the invention, are patients suffering from especially immUne mediated and inflammatory diseases. Preferred examples of such immune-mediated and inflammatory diseases comprise systemic lupus erythematosis, arthritis, scieroderma, idiopathic inflammatory niyopathies, including dermatomyositis and polymyositis, Crohn's disease, and dermatological diseases such as eczema, and psoriasis. A further beneficial application is suppression of the immune response in transplantations and degenerative neurological disorders like multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS).

A preferred use according to the invention is a medicament for the treatment of an immunerelated or inflammatory dermatological disease, including but not limited to eczema and psoriasis.

Preferred examples of eczema that might be treated with a medicament of the invention comprise contact eczema such as allergic contact eczema and irritant contact eczema, perioral dermatitis, Poison Ivy dermatitis, dermatitis herpetiformis, Grover's disease; atopic eczema or atopiform eczema, discoid eczema, seborrhoeic eczema, and varicose eczema. Examples of psoriasis that might be treated with a medicament of the invention are plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, scalp psoriasis, genital psoriasis, and psoriasis of the nails.

Other preferred inflammatory diseases of the skin that can be treated with a compound andlor medicament of the invention include lupus erythematodes, lichen planus, and other popular and plaque type dermatological conditions.

In a further preferred embodiment, the invention provides a composition comprising an imidazole derivative according to the invention and carrier, diluent or excipient therefore.

A typical carrier for an imidazole derivative of the invention is an aqueous carrier such as water, and including a buffered aqueous solution comprising but not limited to phosphate buffered saline, and an aqueous alcoholic solution. An auxiliary agent such as a detergent can be added to the aqueous carrier to enhance the solubility of an imidazole derivative of the invention.

A typical diluent or excipient for an imidazole derivative of the invention comprises a binder such as starch or a cellulose derivative. Said diluent may also comprise a colored additive or a flavor enhancer.

The invention further provides a pharmaceutical composition comprising an imidazole derivative according to the invention and a pharmaceutically acceptable carrier, diluent or excipient therefore.

In formulating said imidazole derivative the imidazole derivative is adjusted to an appropriate concentration and formulated in a pharmaceutically and/or veterinarally acceptable carrier, diluent, excipient. Typical pharmaceutically acceptable carriers are known in the art and comprise phosphate buffered saline, oil including but not limited to mineral and vegetal oil, and aqueous solutions of, for example, sodium caroboxymethyl cellulose, magnesium stearate and polyvinyippyrrolidone.

The invention further provides the use of the pharmaceutical composition according to the invention for suppressing an immune response from an individual.

In a preferred embodiment, a pharmaceutical composition comprising an imidazole derivative of the invention is applied onto the skin. Said pharmaceutical composition can be an ointment, paste, cream, lotion, liquid, aerosol (spray), film or laminate, comprising said imidazole derivative.

Thus in a further aspect the invention provides an ointment, paste, cream, lotion, liquid, aerosol (spray), film and/or laminate, comprising an imidazole derivative of the invention.

in a preferred embodiment, said pharmaceutical composition further comprises other ingredients, such as beeswax, zinc oxide, allantoin, and/or vitamin A, vitamin D and vitamin E, which may help to protect the skin.

In a preferred embodiment, said pharmaceutical composition further comprises solvents such as alcohol and propylene glycol, which are known to increase the solubility of drugs in the skin layers, and may function as a penetration enhancer for transdermal therapeutic systems. Other penetration enhancers that are known in the art can be added to said pharmaceutical composition, including but not limited to laurocapram, methol, and vitamin E. In a further preferred embodiment, said pharmaceutical composition further comprises ingredients that enhance the immune suppressing activity of said imidazole derivative. Suitable immune suppressor enhancers comprise corticosteroids, methotrexate, azathioprine, cyclophosphamide, chiorambucil cyclosporine and tacrolimus and derivatives thereof such as rapamycin.

In a particularly preferred embodiment, said pharmaceutical composition further comprises corticosteroids. Suitable corticosteroids comprise prednisone, prednisolone, methyiprednisolone, cortisone, hycirocortisone, fludrocortisone, dexamethasone, triamcinolone, budesonide and betamethasone.

The invention also provides a method of mod ulating an immune response in an individual in need of such treatment, said method comprising treating said individual with an effective amount of a pharmaceutical composition according to the invention.

The term "effective amount" refers to a concentration or amount of an imidazole derivative which results in achieving a particular stated purpose. An "effective amount" of an imidazole derivative may be determined empirically.

Examples

Example 1

Synthesis of ethyl imidazole4acetate Compounds.

Jmidazole4acetic acid (ImAc) was synthesized by SynCom (sample code 42583) and supplied by Chemsbop, Weert.

Acetyl chloride was derived from Fluka (puriss.) as a colorless liquid.

Ethanol absolute (Lichrosolve, purity (>99.9 % by GC) was purchased from VWRIMerck (nr. 1.00983) Procedure.

ImAc (6.3 g, 50 mmol) was dissolved in 80 ml ethanol. Acetyl chloride (ii g, mmol, 10 ml) was dropwise added through a dripping funnel. The mixture was allowed to react for 5 h. During the first 30 minutes solid (starting) material completely dissolved. After cooling, the ethanol was evaporated on a RotavaporTM -device until 20 ml was left. Acidity was neutralized to pH 5 with sodium bicarbonate 8.4 % and to --8 with NaOH 1 M or Na2CO3 10 %.

Ethyl acetate (3 x 15 ml) was used to extract the waterphase under vigorously stirring. The EtOAc layer was separated with a separation funnel and the combined fractions were dried over anhydrous Na2SO4 while the solution was stirred. After 2 hours EtOAc was evaporated on a RotavaporTM -device. The crude product (-6 g) was a yellow oily liquid that was treated for 3 hours in a Speedvacdevice, set to 60 C. The final product was referred to as: ImCH2COOEt batch 2. ( Et-ImAc)

Product specifications

Yield: 5. 94 g M.p.: <room temp.Appearance brownish clear oil. IR:

UV: A. 211 nm (H20), no abs. beyond 240 nm.

Mass: M/Z = 154 confirmed.

HPLC: RPcolumn Phenomenex Aqua 250 x 4.6 mm, eluent: ammonium formate 20 mM pH 5.1, CHSCN 5 %, D: 226 nm, F: 0.8 mI/mm. RT of product 11.98 miii., 61807 AU I nmol. 0.2 % imidawle4acetic acid as detected impurity.

Example 2

Suppression of prolonged contact hypersensitivity (PCHS) by ethyl imidazole 4-acetate in BALB/c mice.

Topical test compounds.

Ethyl imidazole4acetate was dissolved in ethanol/water 1:1 in a concentration of 5 %. The topical application of ethanol/water 1:1 alone served as full-response control. Ethanol/water test solutions were topically applied with a pipette in aliquots of 20 jiL/ear.

Prolonged con tact hypersensitivity.

Mice were sensitized with 10 p1 1 % oxazolone in acetone on day -6 in all experiments on the outside of both ears. On day 0 mice were challenged with 10 pl 0.5 % oxazolone in acetone on both ears. Repeated elicitations were applied on day 2, 4, 7, 9. Applied oxazolone concentrations in acetone were 0.5 %, 0.25 %, 0.25 %, 0.25 %, respectively. From day 1 up to one day before the final day of the experiment, twice daily doses of test solutions were topically given at approximately 11 AM and 16 PM. Duplicate ear thickness measurements were made on day 0, 1, 3, 5, 8, 10 and 11 prior to any daily topical application. Mice.

The use of mice was allowed by the Comittee of Experimental Animal handling of the Academic Medical Center Amsterdam. Female BALB/c mice (8 -10 weeks of age) were purchased from Charles River (L'Arbresle, France) and kept in light, humidity and temperature-controlled rooms in the animal facility, l2 weeks before the experiment. They were fed adlibitum with water and CRM-E food van Special Diets services (SDS, Witham, Essex, UK).

Statistical analyses Data points, obtained with test compound administration, were compared to the data, obtained with vehicle (ethanol/water 1:1) administration and were statistically processed using Welch's unpaired ttest.

Results The averaged suppressive effects of imidazole4carboxylic acid, sodium salt (ImCOO.Na), EtImAc and prednisolone on PCHS response, derived from 2 3 experiments are shown in Fig. 3 and compared to placebo (100 % ear swelling; straight line). A comparison between the compounds can be made and a sequence from high to low effectiveness can be assigned as follows: prednisolone > ethyl imidazole-4acetate (Et-ImAc)> imidazole4acetic acid (ImAc) imidazole4carboxylic acid.

Therefore, we conclude that Et-ImAc is a new immunosuppressant. The immunosuppressive, e.g. anti-inflammatory properties of Et-ImAc are stronger than that of ImAc. This is likely due to the improved skin penetration of Et linAc, by which a similar molecular entity may reach immune target cells in higher concentrations than by topical application of 1mM. The efficacy seems to be between that of ImAc, a weak to moderate immunosuppressant, and prednisolone, a classical strong suppressant, but might require further optimization.

Table 1 __________________________ _________________________ ethyl idazoe4acetate ethyl imidazole-4carboxylate ethyl imidazcie-4propionic acid ethyl imidazo[e4propenoic acid propyl imidazole 4acetate propyl irnidazole4-carboxylate propyl imidazole4propionic acid propyl irnidazole4propenoiC acid isopropyl imidazole4-propiothc isopropyl imidazole4acetate isopropyl irnidazole-4carboxy1ate acid isopropyl imidazole4propenoic acid -butyl imidazole4acetate butyl imidaiole4tarboxylate butyl imidazole4propionic acid butyl imidawle4propenoic acid sec butyl iinidaaole4propioniC sac butyl iinidazole4acetate sec butyl imidazole-4carboxylate acid sec butyl imidazole4propenoiC acid tart butyl imidazole4propionic tert butyl iniidazole4acetate tert butyl imidazole4carboxylate acid tert butyl iznidazole4propenoiC acid pentyl imidazole4acetate pentyl imidazole4carboxylate pentyl imidazole4propwnic acid pentyl imidazole-4-propenoiC acid hexyl inüdazoje4-acetate hexyl ixnidazole4carboxylate hexyl iuudazole-4-propiothc acid rl iinidazole4propenoiC acid heptyl iniidazole-4acetate heptyl imidazole4carboxylate heptyl ijnidazole*propioniC acid heptyl imidazole4propenoic acid octyl imidawle4acetate octyl imidazole4-carboxylate octyl iniid.azole4propioniC acid octyl imidazole4propenoiC acid 2,3diinethylpentyl imidawle4 2,Sdinethy1penty1 imidazole4 2,3-dimethylpentyl imidazole4 23-dimethylpentyl inudazole4propenoiC acetate carboxylate propionic acid acid 2.3-dimethylpentyl ixnidazole-4 Z3-dixnethylpentyl imidazole-4-2,3-diinethylpeutyl imidazole4 2,S-dijnethylpentYl imidazole*propenOiC acetate carboicylate propionic acid acid N-methyl imidazole4 N-methyl unidazole4 N-methyl iznidazole4acetamide carboxylamide propionylauiide N-methyl jj4azole4propenoYlaZZUde N.N-dimethyl imidazole4 N.N-dimethyl imidazole4 N,N-dimethyl imidazole4acetamide carboxylatnide propionylamide NN-thmetbyl idazo1e4propeflOylamide N-ethy' imidazole-C N-ethyl imidazole4acetaxnide N-ethyl imidazo1e4carboxyamide propionylatnide N-ethyl imidazole4propenoyiamide N,Ndiethyl imidazole-4-NN-diethyl midazo1e4 N,N-diethyl imidazole4'acetainide carboxylamide propionylainide N1N-diethy] unidazole4-propenoylamide N-propyl iinidazole-4 N-propyl imidazole4-acetamide N-propyl iniidazole4carboxylamide propionylamide Npropyl ixidazole4-propenoylami&e N,N-dipropyl imidazole-4 N,N-thpropyl ixrndawle* N,N-dipropyl iznidazole4acetaxnide carboxylaniide propionylanaide N,Ndipropyl ixnidazole4proyenoylainide N-isopropyl imidazole-4' N-isopropyl imidazole4 Nisopropyl unidazole-4acetamide carboxylamide pionylamide Nisopropyl imidazole4propenoylamide N,N-diisopz-opyl iniidazole-4-N,N-diisopropyl iinidazole-4 NNdiieopropyl imidazole-4 NN-diisopropyl imidazole4 acetamide carboxylaznide propionylamide propenoylamide N-butyl imidazole4- N-butyl imidazole4acetamide N-butyl imidawle4-carboxylamide propionylainide Nbutyl irnidazole-4-propexaoylamide -N,Ndibutyl waidazole-4-N,Ndibutyl inaidazole-4 6' N,Ndibutyl imidazole4acetarnide carboxylainide propionylamide NN-dibutyl jmidazole-tpropenoylamida N-sec-butyl imidazole4 N-secbutyl iidazole4 N sec-butyl irnidazole+acetamide carboxylamide propionylamide N-sec-butyl imidazole-4propenoylalalide N,N-di-sec-butyl inudazole-4 N,N-di-sec-butyl imidazole4 N,N-di secbuty[ imidazole4 N,N-di sec-butyl iniidazole4 acetamide carboxylamide propionylainide propenoylainide N-tert-butyl ünidazole-4 N-tert-butyl iinidazole4' N-tert-butyl imidazole-4acetaniide carboxylainide propionylainide N-tert-butyl inaidazole4propeaoyla1zaide N.Ndi tertbutyl iinidazole-4-N,N-di tertbutyl imidazole4 N,N-di tert-butyl imidazole4 N,N-di tert-butyl inidazole4 acetainide carboxylarnide propionylainide propenoylamide N-pentyl imidazole4 -N-pentyl imidazoledacetamide N,entyl imidazole4-carboxylanhide propionylamide N-pentyl ixnidazole-4propenOYLamlde N,N-dipentyl, iznidazole4 N,N-dipentyl imidazole+ -N,Ndipentyl imidazole-4acetaniide carboxylamide propionylanaide NNdipentyl iidazole-4prOPenOYlamIde N-hexy iinidazole-4 1 Nhexy imidazole 4acetande N-hexy iniidazole4carboxylamide propionylamide Nhexy imidazole4propenoyLaDzde N.N-dihexyl imidazole4 N,Ndihexyl imidazole4 NNdihexyl imidazole4-acetamide carboxylamide propionylamide N,N-dihexyl ixnidazole*propenoylamide N-heptyl imidazole4-IsFheptyl imidazole-4acetamide N-heptyl imidazole4-carboxylamide propionylamide Nheptyl iidazole4propenoylamide N,N-diheptyl imidazole4' N.Ndiheptyl imidazole4 N,Ndiheptyl imidazole-4acetamide carboxylamide propionylamide N,N-diheptyl imidazole-4ipropenoylanhide Noctyl imidazole-4- !+octy) imidazole4acet.amide Noctyl midazole4carboxylamide propionylamide Noctyl imidazole4propenoylamide N,Ndioctyl imidazole-4 N,Ndioctyl imidazole4 N.Ndioctyl irwdazole4'acetamide carboxylaoiide propionylaTnide N,Ndioctyl iniidazole4propeuoylamide N (2,3dimethypentyOiinidazole4 N (2,3d.inietbylpentyl)ixnidazole4 N (2,3dimethylpentyDimidazole N (2,adimethylpentyl)ixuidazole4 4 acetarnide carboxylainide 4propionylamide propenoylamide N,N-di(2.3-N,N-di(2,3-N.N-di(2.3 dimethylpentyDiniidazole- 4 diniethylpentyl)iznidazola4 dimethylpentyDimidazole4 N,Ndi(2.3dinisthylpentyl)iwidazole4 acetamde carboxylamide propionylaznide propenoylamide N -(2.3-dinethylhexy)iInidaZOle4 N 3-diuiethyThexyI)imidazole4 N (2,3-diinethythexyDixnidazole N (2,adimethy[hexyJ)imidaZOle4 acetanjide carhoxylamide 4propionylamide propenoylaniide N,Ndi(2,3 N.Ndi(2,3 N,N-di'(2.3-diinetbylhexyl)irnidazole-dimethylbexyl)imidazole4 diinethylhexyDimidazole+ N,Ndi(2,SdmethylhaXYOüflidaZole+ 4-acetamide carboxylainide propionylainide propenoylamide ethyl iinidazo[-2-one4propiofllc ethyl imidazol2one-4acetate ethyl imidazoF2one4carboxylate acid ethyl I idazol2one4propenoic acid propyl iidazI2one-4propionic propyl imidazol2-one4-acetate propyl imidazol-2one4carboxylate acid propyl imidazol-2-one4propenoic acid isopropyl imidaaol-2one-4 isopropyl imidazol-2-one4-isopropyl imidazol-2one-4-acetate carboxylate propionic acid isopropyl imidazol2-one-4-propenoic acid butyl iidazol-2-one4-propionic butyl imidazl-2-one-4-acetate -butyl imidazol-2-one4-carboxyJate acid butyl imidaz F2one-4propenoic acid sec butyl imidazol-2-one-4 sec butyl imidazol2one4-Sec butyl imidazoF2-one-4-acetate carboxylat.e propioaic acid sec butyl imidazol-2-one-4-propeuoic acid tert butyl iniidazol-2one4 tert butyl imidaaol2-one4 tert butyl iniidazol2one-4acetate carboxylatepropionic acid tart butyl imidazol-2one-4--propenoic acid pentyl imidazol-2-one-4-propiomc pentyl ixnidazol-2one4-acetate pentyl imidazol-2-one-4-carboxylate acid pentyl iaiidazoi2-oae-4propenoic acid hexyl imidazol-2-one4-propionic -hexyl imidazol-2-one4acetath hexyl imidazol-2-one-4-carboxylate acid hexyl imidazol2one4 oropenoic acid heptyl imidazoi-2one4propionic heptyl imidazol2-one-4-acetate heptyl imidazol-2one4carboxylate acid heptyL imidazol-2one-4propenoic acid octyl midazo)-2-one4-propionic octyl imidazol-2-one-4-acetate octyl imidazoL-2-one-4-carboxylate acid octyl imidazol-2one4-propenoic acid 2,3-dimetbylpentyl iinidazol-2-ooe-4-2,Sdimethylpentylimidazol-2-one-2,3-dimethylpeEltyl inudazol-2 2.3-dimethylpentyl unidazol-2-oce-4-acetate 4carboxylate one-4-propionic acid propenoic acid 2,3dimethytpentyl iinidazol-2-one-4-2,3-cliniethylpentyl imidazol-2-one 2,3dimethylpentyl imidazol-2' 2,3dimethylpentyl imidazol2-one4-acetate 4-carboxylate one-*propionic acid propenoic acid N-methyl imidazoL-2--one-4-Nniethyl imidazol-2-one-4-N-methyl imidazol-2-one-4acetamide carboxylaniide propionylamide N-methy' imidazol2-one4propenoylamtde N,N-dimethyl iidazol-2one-4 N,N-dimethyl imidazol-2-one-4-N,N-dimethyl imidazol-2one-4-N,N-dirnethyl imiazol-2one4 acetamide carboxylanjide propionylamide propenoylamide N-ethyl iznidazol-2-one4-N-ethyl imidazol2-one-4-N-ethyl imidazol-2one4-acetamide carboxylaniide propionyla nide N-ethyl imidazol-2-one4-propenoylamjde N,N-diethyl imidazo-2-one4-N,N-diethyl iniidazol-2-one4-NN-diethyl imidazol2-one-4-N,N-diethyl unidazol-2one-4-acetamide carboxylamjde propionylamide pz-openoylarnide N-propyl iinidazot-2-one-4-N-propyl iznidazol2-one-4-N-propyl imidazol-2-one-4-acetamjde cathoxylamide propionylamide Npropyl iinidazo12-one-4-propenoyIaijde N,N-dipropyl imidazol-2-one4-N,Ndipropyl imidazo]-2-one-4-N.Ndipropyl imidazol-2-one-4-N,N-dipropy imidazoF2-one-4 acetamide carboxylamide propionylaznide propenoylamide N-isopropyl imidazol2-one-4-N-isopropyl imidazol-2one-4-N-isopropyl imidazol-2-one-4-N-isopropyl imidazol-2-oae-4 acetamide carboxylamide propionylamide propenoylamide N,Ndiisopropyl iinidazol-2-one-4-N.N-diisopropyl imidazol-2-one-4-N.N-diisopropyl imidazol-2-one-4-N,N-diisopropyl iniidazol2one4-acetamide carboxylainide propionylaniide propenoylainide Nbutyl iidazol-2-one4-N-butyl imidazol-2-one-4-N-butyl imidazol-2-one-4-acetaniide carboxylamide propionylamide N-butyl imidazol-2-one-4propenoylaniide N,N-dibutyl imidazol-2-one-4 N.N-dibutyl ünidazol-2-one-4-N,N-dibutyl imidazol-2-one-4-N,N-dibutyl imidazol-2-one-4-acetamide carboxylamide propionylamide propenoylamide N-sec-butyl imidazol-2-one-4-N-sec-butyl imidazol-2-one-4-N-sec-butyl ünidazol-2-one-4-N-sec-butyl imidazol-2-one-4-acetainide carboxylamide propionylaniide propenoylamide N.N-di-sec-butyl imidazol-2-one-4-N.N-di sec-butyl imidazol-2-one4-N.N-di-sec-butyl iniidazol-2-one-N,N-di-sec-butyl imidazol-2-one4-acetaniide carboxylamide 4-propionylamide propenoylamide N-tert-butyl imidazol-2-one-4-N-tert-butyl iinidazol-2-one-4-N-tert-butyl imidazol-2-one-4-N tert-butyl imidazol2-one-4-acetainide carboxylamide popionylamrde propenoylamide N,N-di-' tert-butyl imidazol-2-one-4-N,N-di-tert-butyl imidazoF2-one-4-N,Ndi tert-butyl tmidazol-2-one N.N-di-terti,utyl iinidazol-2-one-4-acetamide carboxylanaide 4-propionylarnide propenoylamide N-pentyl imidazol-2-one-4-N-pentyl imidazol-2-one-4-N-pentyl imidazol-2one-4-acetaniide carboxylamide propionylaniide N-pentyl unidazol-2-one-4-propenoylanude N,N-dipentyl imidazol-2-one-4-N.Ndipentyl imidaz.ol-2-one-4 N,N-dipeiityl iniidazol-2-one-4-N.N-dipentyl imidazol-2-one-4-acetaznide carboxylarnide propionylamide propenoylamide Nhexy imidazol-2-one -4 N-hexy imid.azol-2-one-4-Nhexy imidazol -2-one -4acetamide carboxylamide propionylaniide N-hexy imidazol-2-one-4-propenoylamjde N,N-dihexyl imidazol-2-one-4-N,N-dihexyl imidazol-2one-4-N,N-dihexyl imidazol-2one-4-N,Ndihexyl imidazol-2-one4-acetamide carboxylatmde propionylaniide openoylamide N-heptyl imidazol-2-one-4-Nheptyl iniidazol-2-one-4-N-heptyl imidazol-2-one-4-acetamjde carboxylamide propionylamide N-heptyl iinidazol-2-one-4-propenoylamide N,N-diheptyl imidazol-2-one-4-N.N-diheptyl imidazol-2-one-4-N,Ndiheptyl imidazol-2-one-4-N,Ndiheptyl iniidazol-2-ozie-4-acetamide carboxylanilde propionylamide propenoylamide N-octyl imidazol-2-one-4-N-octyl iinidazol-2one-4 imidazol-2-one4-acetamide carboxyl.amide propionylamide N-octyl imidazol-2-one-4-propenoylamide N,N-dioctyl imidazol-2-one-4-N,N-dioctyl iniidazol-2one-4-N,N-thoctyl imidazol-2-one-4-N.N-dioctyl unidazoi-2-one4-acetamide carboxylamide propionylamide propenoylamide N -(2.3-dimethylpentyDimidazol-2-N (2.3-dimethylpeotyl)imidazol-2-N -(2,3-dimethylperatyl)iuüdazol-N -(2,3-diznethylpentyOimidazol-2-one-4-one-4-acetamide one-4-cazboxylamide 2-one-4propionylamide propenoylamide N,N-di-(2,3-N,N-di-(2.3-N,N-di(2,3-dimethylpeiityl) imidazol-dimetbylpentyDünidazol-2-one-4-dimethylpentyOimidazol-2oue-4-N. N-di-(2,3dimethylpentyl)imidazol-2-one- 2-one-4-acetamjde carboxylanaide pi-opionylamade 4-pi-openoylamide N -(2,3-dimethythexyl)imidawl-2-N -(Z3-dimethylhexyl)iniidazol-2-N -(2,3-d.imethylhexyOimidazol-2-N -(2,3-diinethylhexy)iithdazol-2-one-4-one4-acetamide one-4carboxylamide one-4-propionylamide propenoylamide N,N-di(2,3--N.N-di-(2,3-dimethyl.hexyDimidazol-N,N-di-(2.3-dimethylhexyDi. midazol-diznethy]hexyl)üuidazol-2-one-4-N.N-di-(2,3-diinethylhexyl) imidazol2-one- 2-one-4-acetaniide 2-one-4-carboxylamide pz-opionylaniide 4-propenoylauiide ethyl imidazol-5-one-4-propionic -ethyl imidazol5one-4-acetate ethyl imidazol-5-one-4-carboxylate acid ethyl imidazol-5-one-4-propenoac acid propyl imidazol5-one-4-propionic propyl lm2dazol-5-one-4acetate propyl imidazol5-one4carboxylate acid propyl imidazo15one4propenoic acid isopropyl imidazo5one4 isopropyl imidaz15one4 isopropyl imidazol-5one4-acetate carboxylate propionic acid isopropyl imidazol5one-4propenoic acid butyl imidazol-5-one-4propionic butyl imidazol5-one-4-acetate butyl imidazol-5-one4-carboxylate acid butyl i idazol5one4-propenoic acid sec butyl imidazol-5one4-sec butyl imidazol--one-4 sec butyl iLnidazol5-one-4-acetate carboxylate propionic acid sec butyl imidazol5one4propenoic acid tart butyl imidazol-5one-4tert buty) imidazol5one-4-tert butyt imidazl-5one-4acetate carboxylate propionic acid tert butyl I idazo[-5one4propenoic acid pentyl imidazol-5-one-4propionic pentyl imidazl-5-one4-acetate peny iinidazol'5-one-4-carboxylate acid pentyl imidazolSone4propenoic acid hexyl imidazo]-5-one4-propionic hexyl iidazol5one4acetate hexyl imidazl5one4cathoxylate acid hexyl imidazoi-5one4propeaoic acid heptyl iniidazoF5-one4propionic heptyl iidazol5one-4-acetate heptyl uxidazol5-one-4carboxylate acid heptyl ixnidazol-5-one4-propenoic acid octyl imidazol-5-one-4propionic octyl iidazol-5-one4acetate octyl midazol5one4carboxylate acid octyl imidazol-5one4propenoic acid 2,3-dimethylpentyl imidazol-5one4 2,3-diinethylpentyl imidazol5-one 2,3-dimethylpentyl ImidazolS 23-dimethylpentyl imidazol5-one4 acetate 4carboxylate one4propionic acid propenoic acid 2,3-dimethylpentyl imidazol-5-one4-2,3dimethylpentyl iniidazol-5-one-2,3-dixnethylpentyl imidazol-5 2,3dimethylpentyl irnidazol5one4 acetate 4-carboxylate one-4propioniv acid propenoic acid Ninethyl imidazol5-one4 N-methyl imidazol-5one4 N-methyl imidazoi5one4acetamide carboxylamide propionylaui2de N-methyl idzoL5one*propenoylamide N,N-din2ethyl imidazol-5-one-4 NNdimethyl imidazol-5oae4 N,N-dimethyl midazl5one4 N,N-dimethyl imidazot-5-one4 acatamide carboxylamide propionylaniide propenoylamide Nethyl irnidazol-5-one-4-N-ethyl imidazol6-one -4-N-ethyl imidazl-5-one-4-acetamide carboxylainide propioiiylamide N-ethyl iniidazol-5-one -4propenoylaznide NN-dietbyl imidazol-5-one-4-N.N-diethyl iidazl-5one4-N,N-diethyl iznidazol-5-one-4-N,N-diethyl imidazol-S-one-4-acetamide carboxylamide propioxiylarnide propenoylamide N-propyl imidazol-5-one-4-N-propyl imidazol-5-one-4-N-yropyl imidazol5one-4acetamide carboxylamide propionylaznide Npropyl imidzol-5-oDe-4-propenoylainide N.Ndipropyl ixnidazol-5-one4 NN-dipropyl imidazol-5-one-4-N,N-dipropyl inaidazol-5one-4-N,Ndipropyl iidazol-5-oae-4-acetamide carboxylacnde propionylaniide propenoylamide N-isopropyl imidazol-5one4 N-isopropyl iinidazol-5-one-4-N-isopropyl imidazol-5one-4 N-isopropyl ünidazol5one4 acetamide carboxylarnide propionylamide propenoylamide N,N-diisopropyl iznidazol-5-one-4-N,N-diisopropyl imidazol5-one4-N,N-diisopropyl imidazot-5-one4 N,Ndiisopropyl imidazol-5-one-4-acetamide carboxylamide propionylamide propenoylaniide N-butyl imidaol-5-one-4-N-butyl imidazol5-one-4- -N-butyl imidazol-5-one-4-acetamide carboxylamide propionylanilde N-butyl imidazol-5one-4-propenoylaznide N,N-dibutyl unidazol-5one-4-N.N-dibutyl imidazol-5-one-4-N,N-dibutyl imidazol-5-one4-N,Ndibutyl iuiidazol'5-one-4-acetaniide carboxylamide propionylamide propenoylamide N-secbutyl imidazol-5-one-4 N-secbutyl iniidazol-5-one-4-N-sec-btLtyl imidazol-5-one-4 N-sec-butyl iidazol-5-one-4-acetawide carboxylainide propionylamide propenoylamide N,N-di-sec-butyl imidazol-5-one-4-N,Ndi sec-butyl imidazol-5-one-4-N,N-di-sec-butyl imidazol-5-one-N,N-di-sec-butyl imidazol'5one-4 acatamide carboxylamide 4-propionylamide propenoylanude N-tert-butyl iidazol-5-one4 N-tert-butyl iniidazol-5-one4-N-tert-butyl imidazol-5one-4-N-tert-butyl iidazol-5-one4-ace tamide carboxylamide propicnylaniide propenoylairnde N.N-th-tert-butyl ixnidazol-5-one-4-N,N-di-tei-t-butyl imidazol-5-one-4-N,N-di tert-butyl imidazol-5-one-N.N-di-tert-butyl imidazol-5-oce-4-acetamide carboxylamide 4-propionylamide propenoylamide N-pentyl imidazol5-one4 N-pentyl iniidazol-5-one-4-N-pentyl imidazol-5one-4-acetamide carboxylarnide propionylamide N-pentyl iidazol5one4-propeEzoylamide NN-dipentyl imidazol-5-one-4-NN-dipenty1 iinidazol-5-one* N,N-dipentyl jxnidazol-5one4-N,N-thpentyl iinidazoF5-one-4-acetarnide carboxylarnide propionylaznide propenoylamide Nhexyl imidazol5one-4-N-hexy imidazoL5one4 N-hexyl imida zol-5one-4 acetamide carboxylauiide propionyla,mde N-hexy iidazo15one4propenoy1amjde N.Ndihexyl idazo15one4 N,N-thhexyl inixdazol-5-one-4 N,Ndihexyl imidazo[5one4 N.N-dihexyl ünidazol5-one-4-acecaxxiide carboxytamide propiony1axthde propenoylamide N-heptyl imidazol-5one-4 -Nbeptyl imidazo1-5-one-4 Nheptyl imidazo1-5one4acetamjde carboxylamide propionylainjde Nheptyl ünidazo15-one4propenoy1anijde N,Ndiheptyl imidazol-5-one4-N,Ndiheptyl imidazo1-5one-4 1'I,Ndiheptyl imidazoI-5one4 N,Ndiheptyl imidazol5-one* acetarnide carboxylamide propionylarnide propenoylainide Noctyl uuidazol-5-one-4 N-octyl imidazl5one4 Noctyl imidazo-5-one4acetamide carboxylaniide propionylamide Noctyl inidazoF5one-4propenoyIaxnjde N.Ndioctyl imidazol-5-one'4-N,Ndioctyl imidazol-5-one4-N,tsFdioctyl iidazol-5-one4 N,Ndioccyl idazol-5one4 acetainide carboxylarnide propionylaznide propenoylamide N -(2,3dixnethylpentyl)imidazol-5-N -(2,3diinethylpentyflixnidazol5* N -(2,3-dimethylpentyl)imidazol N (2,3dimethylpentyl)imidazol5-one4 one-4acetamide ooe-4-carboxy]amide 5-one4-propionylamtde propenoylamide N.N-di(2.3 N,Ndi-(2.3 N.N-di(2,3-diniethylpentyDimidazol-diznethy1peniidazo1-5-one-4 diinetbylpentyl)imidazol-5one4 N,Ndi(2,3dimethy1pentyt)imidazo15one' 5one4-acetamide carboçy1aniide propionylamide 4propenoylamide N -(23dimethylhezyl)imidazol-5-N -(2,3diwethylhexyDixuidazol-5-N (2,3-dimethylhexyDimidazoi5-N (2,3-diniethythexyl)imidazol5one4-one-4acetamide one-4-carboxytamide one-4propionylamide propenoylainide N.Ndi(2,3 N,N-di-(2,3dimethylbexyDimidazoF N.Ndi(23dimethythexyDimidazo1-diniethylhexyl)iidazol-Sone4 N,Nli(2.3dimehylhexDimidazoFSone 5-one-4acetamide 5one+carboxylamide propionylamide 4propenoylaxnide au-

Claims

Claims 1. imidazole derivative, or a salt thereof, selected from

W-C-O-R I

H.ç,J.4 (formula 1); _ç_WCORl and HNNH (formula 2); W-C-O-Rl And HN N (formula 3) wrein * W is either absent, or selected from (CH2)y and CH=CH, wherein y = 1 or 2; and * Ri is selected from R2 and N(R3,R4), wherein R2 is a branched or unbranched, saturated or unsaturated CrCs hydrocarbon chain; and wherein R3 and R4 independently represent hydrogen, or a branched or unbranched, saturated or unsaturated C1C8 hydrocarbon chain.

2. An ixnidazole derivative selected from the derivatives presented in

Table 1.

3. Imidazole derivative according to claim 1 or claim 2, whereby said imidazole derivative comprises an imidazole ring structure according to formula 1.

4. Imidazole derivative according to claim 3, whereby W is absent.

5. Imidazole derivative according to claim 3, whereby W is CH2.

6. Imidazole derivative according to claim 5, whereby said derivative is ethyl imidazole-4acetate.

7. Imidazole derivative according to formula 1, whereby R2, R3, arid R4 are independently selected from a branched or unbranched, saturated or unsaturated C4-C8 hydrocarbon chain.

8. Imidazole derivative according to any of claims F5 or claim 7, whereby said R2, R3, and R4 each comprises a saturated, branched or unbranched hydrocarbon chain.

9. Use of an imidazole derivative according to any of the previous claims, or a pharmaceutically acceptable salt thereof, as a medicament.

10. Use of an imidazole derivative according to any of claims 1-8 in the preparation of a medicament for modulating an immunere1ated disease.

11. Use according to claim 9 or claim 10, whereby said immune-related disease is a dermatological disease. 2G

12. Use according to claim 11, whereby said dermatological disease is psoriasis or eczema.

13. A composition comprising an imidazole derivative according to any of claims 1-8 and a carrier, diluent or excipient therefore.

14. A pharmaceutical composition comprising an imidazole derivative according to any of claims 18 and a pharmaceutically acceptable carrier, diluent or excipient therefore.

15. Use of the pharmaceutical composition of claim 14 for modulating an immune-related disease of an individual.

16. Method of modulating an immune-related disease of an individual in need of such treatment, said method comprising treating said individual with an effective amount of the pharmaceutical composition of claim 14.