Pyrazine derivatives for the treatment of skin disorders

Abstract

The application relates to the compounds 3,5-Diamino-6-chloro-N- [N-[2-[2-(trifluoromethyl)phenyl]ethyl]carbamimidoyl]pyrazine-2- carboxamide (Formula I), 3,5-Diamino-N-[N-(lH-benzimidazol-2-yl) carbamimidoyl]-6-chloropyrazine-2-carboxamide (Formula II) and 3,5- Diamino-6-chloro-N-[N-(2-cyclopentylethyl)carbamimidoyl]pyrazine-2- carboxamide (Formula III), the medical use thereof and in particular use in treatment of a skin disorder. Additionally, related pharmaceutical and cosmetic compositions are disclosed.

Description

[0001] PYRAZINE DERIVATIVES FOR THE TREATMENT OF SKIN DISORDERS

[0002] Field of the invention

[0003] The present invention relates to the field of pharmaceutical treatment, and in particular pharmaceutical treatment using novel compounds.

[0004] 5

[0005] Background

[0006] The skin is a semi-permeable barrier that is central for maintaining homeostasis, and preventing excess water loss, microbial assaults, thermoregulation and sensation. To maintain these functions, the skin requires close regulation of its function involving0 proliferation, differentiation and epidermal immune interactions. Ion channel flux is central for regulating these functions, and cations such as sodium and calcium are tightly regulated both extra- and intracellularly by ion channel exchangers. Changes in intracellular Na and membrane potential can modulate the activity of basolateral Na / H and Na / Ca exchangers which will affect this cross-talk (Harvey et al., 1995).5 This means that an alteration in one of these channels lead to compensatory mechanisms in others. An example of this is where regulation of all individual conductance need not occur in the correct direction in the homeostatic sense, provided a sufficient subset of remaining conductance are appropriately regulated (O' Leary et al. , 2013). 0

[0007] The regulation of these channels is complex, however it is widely accepted that, for many different electrically excitable cells, voltage-gated calcium channels provide an indirect measure of membrane voltage changes, and that the subsequent influx of calcium ions can trigger changes in ion channel expression. A pharmacologic5 demonstration of this phenomenon is that treatment with the sodium channel blocker mexiletine results in upregulation of sodium channel transcription and expression, and treatment with the calcium channel blocker verapamil produces a similar effect to that seen with sodium channel blockade, suggesting that the response to sodium channel blockade is mediated by changes in calcium ion fluxes0 (Rosati et al, 2004). Another example is how sodium overload can prompt NCX overactivity while sodium depletion can also promote NCX1 mediated responses and production of proinflammatory cytokine release from immune cells (Harvey et al., 1995).

[0008] Amiloride (3,5-diamino-6-chloro-N-(diaminomethylidene)pyrazine-2-carboxamide, CAS registry number 2609-46-3) is commonly used, as the hydrochloride salt, as a potassium-sparing diuretic in the therapy of edema, often in combination with thiazide diuretics. Amiloride is known to interact with the epithelial sodium channel (ENaC) and acid-sensing ion channel proteins, as well as sodium / hydrogen antiporters (NHE) and sodium / calcium exchangers (NCX). Amiloride as the hydrochloride salt has been approved for marketing in Europe since at least the early 1970s. W09009792 suggests amiloride and some derivatives thereof for treatment of inflammatory skin and eye disorders. Side effects of amiloride includes electrolyte abnormalities such as hyperkalemia and hypernatremia as well as other metabolic effects.

[0009] One amiloride derivative is benzamil, or benzyl amiloride (3,5-diamino-N-(N'- benzylcarbamimidoyl)-6-chloropyrazine-2-carboxamide, CAS registry number 2898- 76-2). WO2015168574 suggests the use of epithelial ion channel blockers such as amiloride and its derivative benzamil in the treatment of psoriasis.

[0010] W02020150606 suggests a method for treating a disease of immune dysregulation in a subject, said method comprising administering to the subject a therapeutically effective amount of e.g. benzamil. The disease of immune dysregulation may be an inflammatory disease, which in turn may be a dermatological disorder.

[0011] The inflammatory cytokines IL-8, CXCL1, TNFa and / or I Lla have been proven to underlie the pathogenesis of skin disorders where aberrant epidermal signaling lead to an inflammatory immune response. These conditions include psoriasis (Furue M., et al., 2020), nail psoriasis and psoriatic arthritis (Kokolakis G., et al., 2021), melanoma (Dhawan and Richmond, 2002). acne (Li, X., et al., 2019), atopic dermatitis (Farley, S. M., et al. , 2006) (He, H., et al., 2021), seborrheic dermatitis (Molinero, L. L., et al., Clin Immunol), nummular dermatitis (Farley, S. M., et al. , 2006), periorificial dermatitis (Farley, S. M., et al. , 2006), rosacea (Li, N., et al., 2014), vitiligo (Jimbo, H., et al., 2020), Hidradenitis suppurativa (Gupta and Skinner, 2004), lupus (Norman, R., et al., 2006), morphea (Fett, N., 2013), scleroderma, cutaneous ulcers, inflamed seborrheic keratoses, nevi, fibrous papules, Pityriasis rubra pilaris (Muller, H., et al., 2008), Pemphigus, including pemphigus vulgaris and pemphigus vegetans (Tavakolpour, S., et al., 2020), Bullous pemphigoid (Tabatabaei- Panah, P. S., et al., 2019), IgA pemphigus (Howell, S. M., et al., 2005), Keratosis follicula ris (Mayuzumi, N., et al., 2005), Lamellar ichthyosis (Malik, K., et al., 2019), Epidermolytic ichthyosis (Malik, K., et al., 2019), Netherton's syndrome (Malik, K., et al., 2019), congenital ichthyosiform erythroderma (Malik, K., et al., 2019), Cutaneous vasculitis (Carbone, F. and F. Montecucco, 2015), Behcet's disease (van der Houwen and van Laar, 2020), Cutaneous graft versus host disease (Gupta and Skinner, 2004), SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome (Gupta and Skinner, 2004), Sarcoidosis (Gupta and Skinner, 2004), Panniculitis (Gupta and Skinner, 2004), Stevens Johnson syndrome (Wang, C. W., et al., 2018), Toxic epidermal necrolysis (Gupta and Skinner, 2004), Neutrophilic dermatoses (Ahn, C. et al., 2018), pyoderma gangrenosum (Ahn, C. et al., 2018), Sweet Syndrome (Gupta and Skinner, 2004), Sneddon Wilkinson (Gupta and Skinner, 2004), Acute generalized exanthematous pustulosis (AGEP) (Feldmeyer, L., et al., 2016), dermatitis herpetiformis (Amerio, P., et al., 2000), Dermatomyositis (Alexis and Strober, 2005), Cryoporin-associated periodic syndromes (Luo, X. Y., et al., 2020), Familial mediterreanean Fever (Samuels and Ozen, 2006), Xeroderma pigmentosum (Kunisada, M., et al., 2017), Pruritus (Deftu, A. F., et al., 2018), pain (Deftu, A. F., et al., 2018), UV-induced skin damage (Fukunaga, A., et al., 2021), irritant contact dermatitis (Funch, A. B., et al., 2021), Still's disease (Kadavath, S. and P. Efthimiou, 2015), Lichen planus (Wu, T., et al., 2013), eczema (Farley, S. M., et al. , 2006), wound (Zheng, R., et al., 2019), lesion, ulcer, alopecia (Loh, S. H., et al., 2018), as well as cutaneous neoplasm with inflammation including actinic keratosis (Maru, G. B., et al., 2014), squamous cell carcinoma in situ (Maru, G. B., et al., 2014), squamous cell carcinoma, basal cell carcinoma (Maru, G. B., et al., 2014), extramammary Paget's disease, dermatofibroma protuberans, atypical fibroxanthoma, sebaceous carcinoma; and Merkel cell carcinoma.

[0012] WO 2022 / 159028 discloses that several of the ion channels ENaC, NCX1 and NHE, rather than individual ion channels, are deregulated (up or downregulated) in conditions with skin inflammation, as exemplified for skin disorders with an abnormal cytokine signaling. The publication shows that ENaC and NCX1 are upregulated and NHE is downregulated in persons with acne as compared to control persons without acne. Moreover the publication shows that the cytokines CXCL1 and ILla are upregulated in patients with acne as compared to control persons without acne. Furthermore, in patients with atopic dermatitis NCX1 is upregulated and ENAC 5 is downregulated compared to control persons without atopic dermatitis; and the cytokines CXCL1 and TNFa are upregulated in patients with atopic dermatitis.

[0013] As discussed above, many diseases or disorders of the skin are associated with inflammatory cytokines. Although pharmaceuticals for treatment of various skin0 disorders exist, there is a need in the field to identify further modulators of epidermal signaling.

[0014] Disclosure of the invention

[0015] It is an object of the present invention to provide compounds that reduce or at least5 partly overcome challenges in the prior art. It is an object of the present invention to provide novel benzamil analogues which have improved pharmacokinetic properties compared to analogous compounds known in the art. Another object of the present disclosure is to provide benzamil analogues with increased stability in vivo. Another object of the present disclosure is to provide benzamil analogues useful for in vivo0 modulation of at least one cytokine. Yet another object is to provide such compounds which may be useful as medicaments and / or in non-therapeutic (cosmetic) applications. These and other objects are achieved in full, or at least in part, by aspects of the inventive concepts as disclosed herein. 5 The present inventors have identified the novel compounds shown in Formula I, Formula II, and Formula III:

[0016] Formula I

[0017] Formula III

[0018] The inventors show herein that these compounds deregulate the inflammatory cytokines IL-8, CXCL1, TNFa and / or ILla. As such, these compounds may prove useful in therapeutic or non-therapeutic treatment of a disease or conditions associated with one of these cytokines, such as skin inflammation. In addition, the inventors show that the in vivo stability of these compounds is increased compared to benzamil. The inventors demonstrate that these compounds benefit from reduced metabolism into amiloride, compared to benzamil; or essentially no metabolism into amiloride (see Example 4). As such, these compounds may give raise to less side effects resulting from amiloride. Beneficially, a higher dose of the inventive compounds may be tolerated by a subject.

[0019] In a first aspect, there is provided compound selected from the group consisting of Formula I, Formula II, Formula III and a pharmaceutically acceptable salt, hydrate, prodrug, solvate or tautomer thereof. Formula I, Formula II, and Formula III may be considered to be analogues of benzamil.

[0020] In one embodiment, there is provided compound selected from the group consisting of Formula II, Formula III and a pharmaceutically acceptable salt, hydrate, prodrug, solvate or tautomer thereof. In one embodiment, there is provided compound selected from the group consisting of Formula I, Formula II and a pharmaceutically acceptable salt, hydrate, prodrug, solvate or tautomer thereof.

[0021] In one embodiment, said compound is Formula I:

[0022] The IUPAC name of Formula I is:

[0023] 3,5-Diamino-6-chloro-N-[N-[2-[2-

[0024] (trifluoromethyl)phenyl]ethyl]carbamimidoyl]pyrazine-2-carboxamide. Formula I is also denoted MRI001-021, MRI021 and compound 21 herein.

[0025] In one embodiment, said compound is Formula II:

[0026] Formula II

[0027] The IUPAC name of Formula II is:

[0028] 3,5-Diamino-N-[N-(lH-benzimidazol-2-yl)carbamimidoyl]-6-chloropyrazine-2- carboxamide. Formula II is also denoted MR 1001-019, MRI019 and compound 19 herein.

[0029] In one embodiment, said compound is Formula III:

[0030] Formula III

[0031] The IUPAC name of Formula III is: 3,5-Diamino-6-chloro-N-[N-(2-cyclopentylethyl)carbamimidoyl]pyrazine-2- carboxamide. Formula III is also denoted MRI001-029, MRI029 and compound 29 herein.

[0032] Formula I, Formula II and / or Formula III may form salts which are within the scope of the present invention. Salts which are suitable for use in medicine are those wherein a counterion is pharmaceutically acceptable. Salts which are suitable for use in non- therapeutic uses are those wherein a counterion is cosmetically acceptable. The skilled person is aware of suitable salts for use in medicine and cosmetic applications. For example, suitable salts according to the invention include those formed with organic or inorganic acids or bases. In particular, suitable salts formed with acids according to the invention include those formed with mineral acids, strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, such as saturated or unsaturated dicarboxylic acids, such as hydroxycarboxylic acids, such as amino acids, or with organic sulfonic acids, such as (Cl-C4)a I ky I or aryl sulfonic acids which are unsubstituted or substituted, for example by halogen. Pharmaceutically and / or cosmetically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulphuric, nitric, citric, tartaric, acetic, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic, perchloric, fumaric, maleic, glycolic, lactic, salicylic, oxaloacetic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic, isethionic, ascorbic, malic, phthalic, aspartic, and glutamic acids, lysine and arginine. In one embodiment, said pharmaceutically acceptable salt is selected from the group consisting of a hydrochloride salt, a sodium salt, a lactate salt, an acetic salt, a phosphoric salt and a trifluoro acetic acid salt. In one embodiment, said pharmaceutically acceptable salt is a hydrochloride salt. Such salt is exemplified in Example 2. In one embodiment, said pharmaceutically acceptable salt is a sodium salt. In one embodiment, said pharmaceutically acceptable salt is a lactate salt. Examples of lactate salt is found in Example 4. In one embodiment, said pharmaceutically acceptable salt is an acetic salt. In one embodiment, said pharmaceutically acceptable salt is a phosphoric salt. In one embodiment, said pharmaceutically acceptable salt is a trifluoro acetic acid salt. It should be understood that the compounds according to the present disclosure may be useful as a therapeutic agent in its own right. A direct therapeutic effect may for example be accomplished by providing deregulation of an inflammatory cytokine, such as IL-8, CXCL1, TNFa and / or ILla, as shown in Example 3. Thus, in a second aspect there is provided a compound as disclosed herein for use as a medicament. The patient or subject to be treated is envisioned to be a mammal, such as a human.

[0033] Further, in a third aspect of the present disclosure, there is provided a compound as disclosed herein, for use in the prevention, alleviation and / or treatment of a skin disorder. The skin disorder may include skin inflammation.

[0034] For the sake of clarity and avoidance of any doubt, as used herein in the context of therapeutic uses the terms "3,5-Diamino-6-chloro-N-[N-[2-[2- (trifluoromethyl)phenyl]ethyl]carbamimidoyl]pyrazine-2-carboxamide" or "Formula I"; " 3,5-Diamino-N-[N-(lH-benzimidazol-2-yl)carbamimidoyl]-6-chloropyrazine-2- carboxamide" or "Formula II"; and "3,5-Diamino-6-chloro-N-[N-(2- cyclopentylethyl)carbamimidoyl]pyrazine-2-carboxamide" or "Formula III"; "compound" and "compounds" are used interchangeably and are to be interpreted as encompassing 3,5-Diamino-6-chloro-N-[N-[2-[2- (trifluoromethyl)phenyl]ethyl]carbamimidoyl]pyrazine-2-carboxamide (Formula I), 3,5-Diamino-N-[N-(lH-benzimidazol-2-yl)carbamimidoyl]-6-chloropyrazine-2- carboxamide (Formula II), and 3,5-Diamino-6-chloro-N-[N-(2- cyclopentylethyl)carbamimidoyl]pyrazine-2-carboxamide (Formula III) and any pharmaceutically acceptable salt, hydrate, prodrug, solvate and / or tautomer thereof.

[0035] Similarly, for the sake of clarity and avoidance of any doubt, as used herein in the context of non-therapeutic (in other words cosmetic) uses the terms "3,5-Diamino- 6-chloro-N-[N-[2-[2-(trifluoromethyl)phenyl]ethyl]carbamimidoyl]pyrazine-2- carboxamide" or "Formula I"; " 3,5-Diamino-N-[N-(lH-benzimidazol-2- yl)carbamimidoyl]-6-chloropyrazine-2-carboxamide" or "Formula II"; and "3,5- Diamino-6-chloro-N-[N-(2-cyclopentylethyl)carbamimidoyl]pyrazine-2-carboxamide" or "Formula III"; "compound" and "compounds" are used interchangeably and are to be interpreted as encompassing 3,5-Diamino-6-chloro-N-[N-[2-[2- (trifluoromethyl)phenyl]ethyl]carbamimidoyl]pyrazine-2-carboxamide (Formula l),3,5-Diamino-N-[N-(lH-benzimidazol-2-yl)carbamimidoyl]-6-chloropyrazine-2- carboxamide (Formula II), and 3,5-Diamino-6-chloro-N-[N-(2- cyclopentylethyl)carbamimidoyl]pyrazine-2-carboxamide (Formula III) and any cosmetically acceptable salt, hydrate, prodrug, solvate and / or tautomer thereof. As used herein, the term "treatment" is used in the context of therapeutic treatment and relates to the treatment, such as causative or symptomatic treatment, of a disease or disorder, the alleviation of symptoms thereof and / or prevention of said disease or disorder.

[0036] A disorder of the skin, or an inflammation of the skin, may include deregulation of an inflammatory cytokine. Which inflammatory cytokines that are involved is apparent to a person of skill in the art. Non-limiting examples of inflammatory cytokines are IL-8, CXCL1, TNFa and ILla. In one embodiment the skin disorder is a skin disorder wherein IL-8, CXCL1, TNFa and / or ILla are deregulated. In one embodiment the skin disorder is a skin disorder wherein CXCL1, TNFa and / or ILla are deregulated. In one embodiment the skin disorder is a skin disorder wherein IL-8 is deregulated. In one embodiment the skin disorder is a skin disorder wherein CXCL1 is deregulated. In one embodiment the skin disorder is a skin disorder wherein TNFa is deregulated. In one embodiment the skin disorder is a skin disorder wherein ILla is deregulated.

[0037] Non-limiting examples of the skin disorder are as follows: psoriasis; nail psoriasis; psoriatic arthritis; acne; atopic dermatitis; seborrheic dermatitis; nummular dermatitis; periorificial dermatitis; rosacea; vitiligo; hidradenitis suppurativa, such as hidradenitis; lupus; morphea; scleroderma; cutaneous ulcers; inflamed seborrheic keratoses; nevi; fibrous papules; pityriasis rubra pilaris; pemphigus, such as pemphigus vulgaris and pemphigus vegetans; bullous pemphigoid; IgA pemphigus; keratosis fol licula ris; lamellar ichthyosis; epidermolytic ichthyosis; Netherton's syndrome; congenital ichthyosiform erythroderma; cutaneous vasculitis; Behcet's disease; cutaneous graft versus host disease; SAPHO (synovitis; acne; pustulosis; hyperostosis and osteitis) syndrome; sarcoidosis; panniculitis; Stevens Johnson syndrome; toxic epidermal necrolysis; neutrophilic dermatoses; pyoderma gangrenosum; sweet syndrome; Sneddon Wilkinson; acute generalized exanthematous pustulosis (AGEP); dermatitis herpetiformis; dermatomyositis; cryoporin-associated periodic syndromes; familial Mediterranean fever; xeroderma pigmentosum; pruritus; pain; UV-induced skin damage; irritant contact dermatitis; Still's disease; Lichen planus; eczema; alopecia; a disorder associated with delayed wound healing, such as diabetic wounds, radiation wounds, wounds related to bullous diseases such as epidermolysis bullosa; cutaneous neoplasm with inflammation such as actinic keratosis, squamous cell carcinoma such as squamous cell carcinoma in situ (Bowen's disease), basal cell carcinoma, extramammary Paget's disease, dermatofibroma protuberans, atypical fibroxanthoma, sebaceous carcinoma; Merkel cell carcinoma; and melanoma. It is also envisioned that wounds, lesions, and / or ulcers can be treated using the inventive compounds.

[0038] As discussed above, CXCL1 may be deregulated in a disorder of the skin. In one embodiment, the skin disorder is selected from the group consisting of psoriasis; nail psoriasis; psoriatic arthritis, acne, xeroderma pigmentosum, pruritus, pain, irritant contact dermatitis, Lichen planus and atopic dermatitis.

[0039] As discussed above, ILla may be deregulated in a disorder of the skin. In one embodiment, the skin disorder is selected from the group consisting of Bullous pemphigoid, keratosis follicularis, cutaneous vasculitis, cryoporin-associated periodic syndrome, familial mediterreanean fever, UV-induced skin damage, Still's disease, Lichen planus, seborrheic dermatitis, and alopecia.

[0040] As discussed above, TNFa may be deregulated in a disorder of the skin. In one embodiment, the skin disorder is selected from the group consisting of pityriasis rubra pilaris, pemphigus, such as pemphigus vulgaris and pemphigus vegetans, bullous pemphigoid, IgA pemphigus, keratosis follicularis, lamellar ichthyosis, epidermolytic ichthyosis, Netherton's syndrome, congenital ichthyosiform erythroderma, cutaneous vasculitis, Behcet's disease, cutaneous graft versus host disease, SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome, sarcoidosis, panniculitis, Stevens Johnson syndrome, toxic epidermal necrolysis, neutrophilic dermatoses, pyoderma gangrenosum, sweet syndrome, Sneddon Wilkinson, acute generalized exanthematous pustulosis (AGEP), dermatitis herpetiformis, scleroderma, morphea, dermatomyositis, cryoporin-associated periodic syndromes, familial mediterreanean fever, UV-induced skin damage, Still's disease, hidradenitis suppurativa, such as hidradenitis, alopecia, vitiligo, basal cell carcinoma, actinic keratosis, and squamous cell carcinoma such as squamous cell carcinoma in situ (Bowen's disease).

[0041] As discussed above, IL-8 may be deregulated in a disorder of the skin. In one embodiment, the skin disorder is selected from the group consisting of psoriasis, atopic dermatitis, neutrophilic dermatitis, palmoplantar pustulosis, keloids, erythema elevatum diutinum, bullous pemphigoid, acne, rosacea, chronic wounds, hidradenitis suppurativa, lichen planus, cutaneous lupus erythematosus, scleroderma, dermatomyositis, urticaria, and UV-induced skin inflammation.

[0042] In one embodiment, the skin disorder is selected from the group consisting of cutaneous neoplasm with inflammation such as actinic keratosis, squamous cell carcinoma such as squamous cell carcinoma in situ (Bowen's disease), basal cell carcinoma, extramammary Paget's disease, dermatofibroma protuberans, atypical fibroxanthoma, sebaceous carcinoma; Merkel cell carcinoma; and melanoma.

[0043] In one embodiment, the skin disorder is a cutaneous neoplasm with inflammation. In one embodiment, the skin disorder is actinic keratosis. In one embodiment, the skin disorder is squamous cell carcinoma. In one embodiment, the skin disorder is squamous cell carcinoma in situ (Bowen's disease). In one embodiment, the skin disorder is basal cell carcinoma. In one embodiment, the skin disorder is extramammary Paget's disease. In one embodiment, the skin disorder is dermatofibroma protuberans. In one embodiment, the skin disorder is atypical fibroxanthoma. In one embodiment, the skin disorder is sebaceous carcinoma. In one embodiment, the skin disorder is Merkel cell carcinoma.

[0044] In one embodiment, the skin disorder is selected from the group consisting of psoriasis, acne, eczema, hidradenitis and melanoma.

[0045] In one embodiment, the skin disorder is selected from the group consisting of psoriasis, acne, eczema, and hidradenitis.

[0046] In one embodiment, the skin disorder is melanoma. In one embodiment, the skin disorder is psoriasis. In one embodiment, the skin disorder is acne. In one embodiment, the skin disorder is eczema. In one embodiment, the skin disorder is hidradenitis.

[0047] According to the present disclosure, the compound of Formula I, Formula II and / or Formula III may be administered topically or systemically. In one embodiment, the compound of Formula I and Formula II are administrated topically or systemically. In one embodiment, the compound of Formula II and Formula III are administrated topically or systemically. In one embodiment, the compound of Formula I and Formula III are administrated topically or systemically.

[0048] According to the present disclosure, the compound of Formula I, Formula II and / or Formula III may be administered by one of the following routes of administration: intravenously, intraperitoneally, nasally, per rectum, intravaginally, percutaneously, intradermally, subcutaneously, intramuscularly or orally. In one embodiment, the compound of Formula I and Formula II are administrated by such route. In one embodiment, the compound of Formula II and Formula III are administrated by such route. In one embodiment, the compound of Formula I and Formula III are administrated by such route.

[0049] In one embodiment, the compound is administrated intradermally or subcutaneously.

[0050] The skilled person will appreciate that the suitable dose will naturally vary depending on the mode of administration, the particular condition to be treated or the effect desired, gender, age, weight and health of the patient, as well as possibly other factors, evaluated by the treating physician. In one embodiment, the compound is administrated in a dose of from about 0.001 to about 0.1 mg per kg body weight, such as 0.01 to about 0.1 mg per kg body weight, or from about 0.1 to about 300 mg per kg body weight, such as from about 0.2 to about 200 mg per kg body weight, such as from about 0.3 to about 150 mg per kg body weight, such as about 0.4 to about 150 mg per kg bodyweight, such as about 0.5 to about 120 mg per kg bodyweight, such as from about 1 to about 100 mg per kg body weight, such as from about 1 to about 50 mg per kg body weight, such from about 1 to about 5 mg per kg body weight, such as about 1 mg per kg body weight. In one embodiment, the compound is administrated in a mixed dose of about 0.1 mg, or of about 0.5 mg, or of about 1 mg, or of about 1.5 mg.

[0051] In one embodiment, the compound is administrated in an amount effective to achieve a serum concentration of from about 1 to about 50 ng / ml in a subject, such as from about 5 to about 50 ng / mL in a subject, such as from about 5 ng to about 50 ng / ml in a subject.

[0052] In any of these or other routes of administration, the formulation of the composition may be adapted or adjusted according to normal pharmacological procedures, comprising the effective pharmaceutical in a chemical form, suitable for the chosen route, together with suitable excipients, such as adjuvants, carriers, diluents and vehicles, conventionally used and well-known to a person skilled in the art. Conventionally used adjuvants and vehicles as known to a person of skill in the art. As used herein, the term "adjuvant" relates to a compound which potentiates the effect of the pharmaceutically active compound.

[0053] It will be appreciated that the compounds described herein may form part of a pharmaceutical composition. Thus, in a fourth aspect, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting of a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt, hydrate, prodrug, solvate or tautomer thereof; and at least one pharmaceutically acceptable diluent, carrier and / or excipient. In one embodiment, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting of a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt, hydrate, prodrug, solvate or tautomer thereof; and at least one pharmaceutically acceptable diluent, carrier and / or excipient. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound selected from the group consisting of a compound of Formula I, a compound of Formula II, and a pharmaceutically acceptable salt, hydrate, prodrug, solvate or tautomer thereof; and at least one pharmaceutically acceptable diluent, carrier and / or excipient. As used herein, the term "excipient" encompasses adjuvants, carriers, diluents, and vehicles. The skilled person appreciates that any adjuvants, carriers, diluents and vehicles mentioned in connection with the first aspect as disclosed herein are suitable in said pharmaceutical composition and it is within the knowledge of the skilled person to make the appropriate choice thereof. The skilled person appreciates that the pharmaceutical composition may be adapted to be suitable for the selected administration route as well as desired administered dose. Relevant doses and administration routes are disclosed in connection to the third aspect above.

[0054] In one embodiment, the composition further comprises at least one additional therapeutic agent.

[0055] In one embodiment, the at least one additional therapeutic agent is selected from the group consisting of corticosteroids, such as betamethasone, clobetasol, cortisone, corticosterone, deflazacort, desonide, desoximethasone, dexamethasone, prednisone, flunisolide, fluocinolone, hydrocortisone, loteprednol, mometasone, triamcinolone acetonide; vitamin D analogs such as calcipotriol, calcitriol, cholecalciferol, taca Icitol, paricalcitol, alfacalcidol, doxercalciferol, falecalcitriol; retinoids such as tretinoin, isotretinoin, adapalene, tazarotene, trifarotene; UV protection such as titanium dioxide, zinc oxide, avobenzone, octinoxate oxybenzone, benzophenone, benzotriazoles, and cinnamates; and hydroquinone; and / or topical chemotherapy such as 5-fluorouracil; and topical immunotherapy such as imiquimod.

[0056] In one embodiment, the at least one additional therapeutic agent is selected from the group consisting of betamethasone, clobetasol, cortisone, corticosterone, deflazacort, desonide, desoximethasone, dexamethasone, prednisone, flunisolide, fluocinolone, hydrocortisone, loteprednol, mometasone, triamcinolone acetonide, calcipotriol, calcitriol, cholecalciferol, tacalcitol, paricalcitol, alfacalcidol, doxercalciferol, falecalcitriol, tretinoin, isotretinoin, adapalene, tazarotene, trifarotene, titanium dioxide, zinc oxide, avobenzone, octinoxate oxybenzone, benzophenone, benzotriazoles, cinnamates and hydroquinone. In a related embodiment, the at least one additional agent is at least two additional agent, optionally wherein the two agents are selected from the list consisting of betamethasone, clobetasol, cortisone, corticosterone, deflazacort, desonide, desoximethasone, dexamethasone, prednisone, flunisolide, fluocinolone, hydrocortisone, loteprednol, mometasone, triamcinolone acetonide, calcipotriol, calcitriol, cholecalciferol, tacalcitol, paricalcitol, alfacalcidol, doxercalciferol, falecalcitriol, tretinoin, isotretinoin, adapalene, tazarotene, trifarotene, titanium dioxide, zinc oxide, avobenzone, octinoxate oxybenzone, benzophenone, benzotriazoles, cinnamates and hydroquinone.

[0057] The pharmaceutical compositions of the present invention may be formulated for administration topical application, for example, as a lotion, cream, ointment, spray, patch, microneedle array, etc. applied to the skin; in solid, liquid or semi-liquid form, including those adapted for the following: oral administration, for example, tablets, capsules, powders, granules, pastes for application to the tongue, aqueous or nonaqueous solutions or suspensions, drenches, or syrups. In one embodiment, the composition is a topical composition.

[0058] In one embodiment, the composition is for use as a medicament. In one embodiment, the composition is for a use according to the third aspect of the present disclosure.

[0059] It will be appreciated that the compounds described herein may form part of a cosmetic composition. Cosmetic compositions may be useful in improving appearance or feel of the skin of a subject, while not having an effect on the skin that is considered therapeutic. Thus, in a fifth aspect, there is provided a cosmetic composition comprising a cosmetically effective amount of a compound selected from the group consisting of a compound of Formula I, a compound of Formula II, a compound of Formula III, and a cosmetically acceptable salt, hydrate, solvate or tautomer thereof; as well as at least one cosmetically acceptable diluent, carrier and / or excipient. In one embodiment, there is provided a cosmetic composition comprising a cosmetically effective amount of a compound selected from the group consisting of a compound of Formula II, a compound of Formula III, and a cosmetically acceptable salt, hydrate, solvate or tautomer thereof; as well as at least one cosmetically acceptable diluent, carrier and / or excipient.

[0060] As used herein, the term "excipient" encompasses adjuvants, carriers, diluents, and vehicles. The skilled person appreciates that any adjuvants, carriers, diluents and vehicles mentioned in connection with the fifth aspect as disclosed herein are suitable in said cosmetic composition and it is within the knowledge of the skilled person to make the appropriate choice thereof. The skilled person appreciates that the cosmetic composition may be adapted to be suitable for the selected administration route as well as desired administered dose. Relevant doses and administration routes are disclosed in connection to the third aspect above.

[0061] In one embodiment, the composition further comprises at least one additional cosmetic agent. In one embodiment, the cosmetic agent is selected from the group consisting of hydroquinone; benzoyl peroxide; clindamycin; metronidazole; tacrolimus; niacin amide; kojic acid; vitamin C; and UV protection such as titanium dioxide, zinc oxide, avobenzone, octinoxate oxybenzone, benzophenone, benzotriazoles, and a cinnamate.

[0062] The cosmetic compositions of the present invention may be formulated for administration topical application, for example, as a lotion, cream, ointment, spray, patch, microneedle array, etc. applied to the skin; in solid, liquid or semi-liquid form, including those adapted for the following: oral administration, for example, tablets, capsules, powders, granules, pastes for application to the tongue, aqueous or nonaqueous solutions or suspensions, drenches, or syrups.

[0063] In one embodiment, the cosmetic composition is a topical composition.

[0064] The compounds as disclosed herein may also be useful for cosmetic applications. Thus, in a sixth aspect of the present disclosure, there is provided a use of a compound selected from the group consisting of a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt, hydrate, prodrug, solvate or tautomer thereof; and at least one cosmetically acceptable diluent, carrier and / or excipient as a cosmetic. In one embodiment, there is provided a use of a compound selected from the group consisting of a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt, hydrate, prodrug, solvate or tautomer thereof; and at least one cosmetically acceptable diluent, carrier and / or excipient as a cosmetic. In addition, there is provided a use of a composition according to the fifth aspect as a cosmetic.

[0065] In a seventh aspect, there is provided a method of deregulating IL-8, CXCL1, TNFa and / or ILla, such as deregulating CXCL1, TNFa and / or ILla. The method comprises administration of an effective dose of the compound according to the first aspect, or a composition according to the fourth or the fifth aspect, to a subject in need thereof.

[0066] In an eighth aspect, there is provided a method of treating, alleviating and / or preventing a skin disorder. The method comprises administration of an effective dose of the compound according to the first aspect, or a composition according to the fourth aspect, to a subject in need thereof.

[0067] In one embodiment, the skin disorder is selected from the group consisting of psoriasis; nail psoriasis; psoriatic arthritis; acne; atopic dermatitis; seborrheic dermatitis; nummular dermatitis; periorificial dermatitis; rosacea; vitiligo; hidradenitis suppurativa, such as hidradenitis; lupus; morphea; scleroderma; cutaneous ulcers; inflamed seborrheic keratoses; nevi; fibrous papules; pityriasis rubra pilaris; pemphigus, such as pemphigus vulgaris and pemphigus vegetans; bullous pemphigoid; IgA pemphigus; keratosis follicu la ris; lamellar ichthyosis; epidermolytic ichthyosis; Netherton's syndrome; congenital ichthyosiform erythroderma; cutaneous vasculitis; Behcet's disease; cutaneous graft versus host disease; SAPHO (synovitis; acne; pustulosis; hyperostosis and osteitis) syndrome; sarcoidosis; panniculitis; Stevens Johnson syndrome; toxic epidermal necrolysis; neutrophilic dermatoses; pyoderma gangrenosum; sweet syndrome; Sneddon Wilkinson; acute generalized exanthematous pustulosis (AGEP); dermatitis herpetiformis; dermatomyositis; cryoporin-associated periodic syndromes; familial Mediterranean fever; xeroderma pigmentosum; pruritus; pain; UV-induced skin damage; irritant contact dermatitis; Still's disease; Lichen planus; eczema; alopecia; cutaneous neoplasm with inflammation such as actinic keratosis, squamous cell carcinoma such as squamous cell carcinoma in situ (Bowen's disease), basal cell carcinoma, extramammary Paget's disease, dermatofibroma protuberans, atypical fibroxanthoma, sebaceous carcinoma; Merkel cell carcinoma; and melanoma.

[0068] In one embodiment, the skin disorder is selected from the group consisting of acne, xeroderma pigmentosum, pruritus, pain, irritant contact dermatitis, Lichen planus and atopic dermatitis.

[0069] In one embodiment, the skin disorder is selected from the group consisting of pityriasis rubra pilaris, pemphigus, such as pemphigus vulgaris and pemphigus vegetans, bullous pemphigoid, IgA pemphigus, keratosis follicularis, lamellar ichthyosis, epidermolytic ichthyosis, Netherton's syndrome, congenital ichthyosiform erythroderma, cutaneous vasculitis, Behcet's disease, cutaneous graft versus host disease, SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome, sarcoidosis, panniculitis, Stevens Johnson syndrome, toxic epidermal necrolysis, neutrophilic dermatoses, pyoderma gangrenosum, sweet syndrome, Sneddon Wilkinson, acute generalized exanthematous pustulosis (AGEP), dermatitis herpetiformis, scleroderma, morphea, dermatomyositis, cryoporin-associated periodic syndromes, familial mediterreanean fever, UV-induced skin damage, Still's disease, hidradenitis suppurativa such as hidradenitis, alopecia, vitiligo, basal cell carcinoma, actinic keratosis, and squamous cell carcinoma such as squamous cell carcinoma in situ (Bowen's disease).

[0070] In one embodiment, the skin disorder is selected from the group consisting of Bullous pemphigoid, keratosis follicularis, cutaneous vasculitis, cryoporin-associated periodic syndrome, familial mediterreanean fever, UV-induced skin damage, Still's disease, Lichen planus, seborrheic dermatitis, and alopecia.

[0071] In one embodiment, the skin disorder is selected from the group consisting of cutaneous neoplasm with inflammation such as actinic keratosis, squamous cell carcinoma such as squamous cell carcinoma in situ (Bowen's disease), basal cell carcinoma, extramammary Paget's disease, dermatofibroma protuberans, atypical fibroxanthoma, sebaceous carcinoma; Merkel cell carcinoma; and melanoma.

[0072] In one embodiment, the disorder is selected from the group consisting of psoriasis, acne, eczema, hidradenitis and melanoma. In one embodiment, the skin disorder is selected from the group consisting of psoriasis, acne, eczema, and hidradenitis. In one embodiment, the skin disorder is melanoma. In one embodiment, the skin disorder is psoriasis. In one embodiment, the skin disorder is acne. In one embodiment, the skin disorder is echemza. In one embodiment, the skin disorder is hidradenitis.

[0073] 5 Cosmetic treatment may be treatment of an non-pathological condition of the skin. Cosmetic treatment may be treatment of healthy skin. Typically, cosmetic compositions are sold "over the counter" and do not require any medical prescription or do not require prescription by a medical professional. Thus, in a ninth aspect, there is provided a method for cosmetic treatment. The method comprises0 administration of an effective dose of the compound according to the first aspect, or a composition according to the fifth aspect, to a subject.

[0074] In a tenth aspect, there is provided use of a compound or pharmaceutically 5 acceptable salt, hydrate, solvate, tautomer or combination thereof according to the first aspect or a composition according to the fourth aspect, for the manufacture of a medicament.

[0075] In a eleventh aspect, there is provided use of a compound or pharmaceutically acceptable salt, hydrate, solvate, tautomer or combination thereof according to the0 second or third aspect or a composition according to the fourth aspect, for the manufacture of a medicament for use in the treatment of a skin disorder.

[0076] Definitions 5 Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention belongs.

[0077] As used herein, and unless otherwise specified, the term "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in0 the treatment or management of a skin disorder, or to delay or minimize one or more symptoms associated with the skin disorder. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment or management of the skin disorder. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the skin disorder, or enhances the therapeutic efficacy of another therapeutic agent.

[0078] The term "combination" as in the phrase "a first agent in combination with a second agent" includes co-administration of a first agent and a second agent, which for example may be dissolved or intermixed in the same pharmaceutically acceptable carrier, or administration of a first agent, followed by the second agent, or administration of the second agent, followed by the first agent. The present invention, therefore, includes methods of combination therapeutic treatment and combination pharmaceutical compositions. This is relevant for example in the fourth and / or fifth aspect as disclosed herein, wherein the composition comprises an additional active agent.

[0079] As used herein, and unless otherwise specified, the terms "treat," "treating" and "treatment" refer to an action that occurs while a patient is suffering from a skin disorder, which reduces the severity of the skin disorder, or retards or slows the progression of the skin disorder, or achieves or maintains a therapeutic objective. An "effective patient response" refers to any increase in the therapeutic benefit to the patient. An "effective patient psoriasis response" can be, for example, a 5%, 10%, 25%, 50%, or 100% decrease in the physical symptoms of the skin disorder.

[0080] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject with toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio. Compounds, materials, compositions, and / or dosage forms that are pharmaceutically acceptable are also considered cosmetically acceptable.

[0081] The phrase "pharmaceutically acceptable excipient" as used herein refers to an acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, carrier, manufacturing aid (e.g., lubricant, talc, magnesium, calcium or zinc stearate, or steric acid), solvent or encapsulating material, involved in carrying or transporting the, optionally therapeutic, compound for administration to the subject. Each excipient should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject. Some examples of materials which can serve as pharmaceutically excipients include: ethanol, sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; gelatin; talc; waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as ethylene glycol and propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents; water; isotonic saline; pH buffered solutions; and other nontoxic compatible substances employed in pharmaceutical formulations. If desired, certain sweetening and / or flavoring and / or coloring agents may be added. Pharmaceutically acceptable excipients are also considered cosmetically acceptable excipients.The term "compound" as used herein includes compounds in free base from as well as in salt forms.

[0082] As used herein, the term "patient" refers to an individual who is exhibits or is at risk of exhibiting symptom(s) of a disorder relating to the skin.

[0083] The skilled person appreciates that a precursor is a compound that participates in a chemical reaction that produces another compound; and that a prodrug is a compound that, after intake, is metabolized (i.e. participates in a chemical reaction) within the body into a pharmacologically active drug (i.e. another compound). The terms "precursor" or "prodrug" is used herein to describe a compound that participates in a chemical reaction to form Formula 1 or Formula II.

[0084] Formula 1 or Formula II may be protected, thus forming a precursor or a prodrug. The skilled person appreciates that the prodrug or precursor may for example be activated intracellularly (for example via metabolic enzymes) and / or extracellularly (for example in the milieu of gastrointestinal fluids, within the systemic circulation and / or other extracellular fluid compartments or near therapeutic target tissues / cells, relying on common enzymes such as esterases and phosphatases or target directed enzymes). While the invention has been described with reference to various exemplary aspects and embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. Therefore, it is intended that the 5 invention is not limited to any particular embodiment contemplated, but that the invention will include all embodiments falling within the scope of the appended claims. The invention will be further illustrated by the following non-limiting Examples. 0

[0085] References

[0086] Ahn, C. et al. (2018). Pyoderma gangrenosum: a review of pathogenesis and treatment. Expert Rev Clin Immunol, 14(3), 225-233.

[0087] Alexis and Strober. (2005). Off-label dermatologic uses of anti-TNF-a therapies. J Cutan Med5 Surg, 9(6), 296-302.

[0088] Amerio, P., et al. (2000). Expression of eotaxin, interleukin 13 and tumour necrosis factoralpha in dermatitis herpetiformis. Br J Dermatol, 143(5), 974-978.

[0089] Carbone, F. and F. Montecucco. (2015). Inflammation in arterial diseases. IUBMB Life, 67(1), 18-28. 0 Deftu, A. F., et al. (2018). CXCL1 activates TRPV1 via Gi / o protein and actin filaments. Life Sci, 193, 282-291.

[0090] Dhawan, P., and Richmond, A. (2002). Role of CXCL1 in tumorigenesis of melanoma. J Leukoc Biol, 72(1).

[0091] Farley, S. M., et al. . (2006). Fas ligand elicits a caspase-independent proinflammatory5 response in human keratinocytes: implications for dermatitis. J Invest Dermatol,

[0092] 126(11), 2438-2451.

[0093] Feldmeyer, L., et al. (2016). Acute Generalized Exanthematous Pustulosis: Pathogenesis, Genetic Background, Clinical Variants and Therapy. IntJ Mol Sci, 17(8).

[0094] Fett, N. (2013). Scleroderma: nomenclature, etiology, pathogenesis, prognosis, and 0 treatments: facts and controversies. Clin Dermatol, 31(4), 432-437.

[0095] Fukunaga, A., et al. (2021). Bioactive substances in the stratum corneum of the epidermis found as indicators of skin damage due to sun exposure. Photodermatol Photoimmunol Photomed.

[0096] Funch, A. B., et al. (2021). CD8(+) tissue-resident memory T cells recruit neutrophils that are5 essential for flare-ups in contact dermatitis. Allergy. Furue, M., et al. (2020). Interleukin-17A and Keratinocytes in Psoriasis. Int J Mol Sci, 21(4):1275.

[0097] Gupta and Skinner. (2004). A review of the use of infliximab to manage cutaneous dermatoses. J Cutan Med Surg, 8(2), 77-89.

[0098] Harvey et al. (1995). Cross-talk between sodium and potassium channels in tight epithelia. Kidney International, 48, 1191-199.

[0099] He, H., et al. (2021). Mild atopic dermatitis lacks systemic inflammation and shows reduced nonlesional skin abnormalities. J Allergy Clin Immunol, 147(4), 1369-1380.

[0100] Herkenne et al. (2008). In Vivo Methods for the Assessment of Topical Drug Bioavailability. 25(1), 87-103.

[0101] Howell, S. M., et al. (2005). Rapid response of IgA pemphigus of the subcorneal pustular dermatosis subtype to treatment with adalimumab and mycophenolate mofetil. J Am Acad Dermatol, 53(3), 541-543.

[0102] Jimbo, H., et al. (2020). Fas-FasL interaction in cytotoxic T cell-mediated vitiligo: The role of lesional expression of tumor necrosis factor-alpha and interferon-gamma in Fas- mediated melanocyte apoptosis. Exp Dermatol, 29(1), 61-70.

[0103] Kadavath, S. and P. Efthimiou. (2015). Adult-onset Still's disease-pathogenesis, clinical manifestations, and new treatment options. aNN mED, 47(1), 6-14.

[0104] Kokolakis, G., et al. (2021). The Effect of TNF-a Inhibitors on Nail Psoriasis and Psoriatic Arthritis-Real-World Data from Dermatology Practice. J Pers Med, ll(ll):1083.

[0105] Kunisada, M., et al. (2017). CXCL1 Inhibition Regulates UVB-lnduced Skin Inflammation and Tumorigenesis in Xpa-Deficient Mice. J Invest Dermatol, 137(9), 1975-1983.

[0106] Li, N., et al. (2014). Alarmin function of cathelicidin antimicrobial peptide LL37 through IL- 36gamma induction in human epidermal keratinocytes. J Immunol, 193(10), 5140- 5148.

[0107] Li, X., et al. (2019). Identification of Genes and Pathways Associated with Acne Using Integrated Bioinformatics Methods. Dermatology, 235(6), 445-455.

[0108] Loh, S. H., et al. (2018). Role of T helper 17 cells and T regulatory cells in alopecia areata: comparison of lesion and serum cytokine between controls and patients. J EurAcad Dermatol Venereal, 32(6), 1028-1033.

[0109] Luo, X. Y., et al. (2020). Tumor necrosis factor-alpha blockade ameliorates inflammatory response in two children with chronic infantile neurological, cutaneous and articular syndrome. J Dermatol, 47(8), 903-906.

[0110] Malik, K., et al. (2019). Ichthyosis molecular fingerprinting shows profound TH17 skewing and a unique barrier genomic signature. J Allergy Clin Immunol, 143(2), 604-618.

[0111] Maru, G. B., et al. (2014). The role of inflammation in skin cancer. Adv Exp Med Biol, 816, 437-469. Mayuzumi, N., et al. (2005). Effects of ultraviolet B irradiation, proinflammatory cytokines and raised extracellular calcium concentration on the expression of ATP2A2 and ATP2C1. Br J Dermatol, 152(4), 697-701.

[0112] Molinero, L. L., et al. (Clin Immunol). Up-regulated expression of MICA and proinflammatory 5 cytokines in skin biopsies from patients with seborrhoeic dermatitis. 106(1), 50-54.

[0113] Muller, H., et al. (2008). Infliximab monotherapy as first-line treatment for adult-onset pityriasis rubra pilaris: case report and review of the literature on biologic therapy. J Am Acad Dermatol, 59(5 Suppl), S65-70.

[0114] Norman, R., et al. (2006). Case reports of etanercept in inflammatory dermatoses. J Am0 Acad Dermatol, 54(3 Suppl 2), S139-142.

[0115] O' Leary et al. . (2013). . Correlations in ion channel expression emerge from homeostatic tuning rules. Proceedings of the National Academy of Sciences, 110(28), E2645-E265.

[0116] Rosati et al. (2004). Regulation of Ion Channel Expression . Circ Res. , 94, 874-883.

[0117] Samuels and Ozen. (2006). Familial Mediterranean fever and the other autoinflammatory5 syndromes: evaluation of the patient with recurrent fever. Curr Opin Rheumatol,

[0118] 18(1), 108-117.

[0119] Tabatabaei-Panah, P. S., et al. (2019). Proinflammatory Cytokine Gene Polymorphisms in Bullous Pemphigoid. Front Immunol, 10, 636.

[0120] Tavakolpour, S., et al. (2020). Pathogenic and protective roles of cytokines in pemphigus: A0 systematic review. Cytokine, 129, 155026. van der Houwen and van Laar. (2020). Behcet's Disease, and the Role of TNF-alpha and TNF- alpha Blockers. IntJ Mol Sci, 21(9).

[0121] Wang, C. W., et al. (2018). Randomized, controlled trial of TNF-alpha antagonist in CTL- mediated severe cutaneous adverse reactions. J Clin Invest, 128(3), 985-996. 5 Wu, T., et al. (2013). IL-1 alpha regulates CXCL1, CXCL10 and ICAM1 in network form in oral keratinocytes. Clin Lab, 59(9-10), 1105-1111.

[0122] Zheng, R., et al. (2019). Keratinocyte Integrin alpha3betal Promotes Secretion of I L-lalpha to Effect Paracrine Regulation of Fibroblast Gene Expression and Differentiation. J Invest Dermatol, 139(9), 2029-2038 e2023. 0

[0123] Examples

[0124] Example 1: Design of benza mil analogues

[0125] A hit expansion of analogues based on Benzamil (1) was performed. The design of5 novel benzamil analogues was done based on these hits by evaluating their physicochemical properties (Table 1).

[0126] Benzamil (1) Results

[0127] Benzamil analogues 19, 21 and 29 were selected:

[0128] Formula I: MRI001-021 (MRI021, compound 21)

[0129] Formula III: MRI001-029 (MRI029, compound 29) Table 1. Physicochemical properties

[0130] Example 2: Synthesis of benzamil analogues

[0131] Materials

[0132] Methyl 3,5-diamino-6-chloro-pyrazine-2-carboxylate (31), was purchased from AmBeed (Cas:1458-01-l), Lot no: A144498-004. All other reagents and starting materials were ordered from standard vendors.

[0133] General methods

[0134] Flash chromatography was performed with Carlo Erba 60 A, 40-63 pm silica gel or on a Teledyne ISCO Flash Rf+ Lumen instrument with SiliCycle pre-packed columns 230- 400 mesh, 40-63 pm. Preparative HPLC was performed on a Gilson system equipped with a UV detector using an ACE 5 C8 100 x 21.2 mm column. Analytical HPLC-MS was performed using an Agilent 1100 series Liquid Chromatograph / Mass Selective Detector (MSD) (Single Quadrupole) equipped with an electrospray interface and a UV diode array detector. Analyses were performed by two methods using either an ACE 3 C8 (3. Ox 50 mm) column with a gradient of acetonitrile in 0.1% aqueous TFA over 3 min and a flow of 1 mL / min, or an Xbridge C18 (3.0 x 50 mm) column with a gradient of acetonitrile in 10 mM ammonium bicarbonate over 3 min and a flow of 1 mL / min. 1H NMR spectra were recorded on a Bruker AVANCE-III HD 400 MHz NMR instrument at 252C. The prepared compounds were given IUPAC names generated from Biovia Draw. In addition, the commercial names or trivial names were used for the commercial starting materials and reagents. Physicochemical properties were calculated using Osiris DataWarrior, version 4.7.3.

[0135] Synthesis of benzamil analogues

[0136] Benzamil analogues MRI019 (Formula II, "19"), MRI021 (Formula I, "21"), and MRI029 (Formula III, "29") were prepared as outlined in Scheme 1:

[0137] Hydrolysing methyl ester 31 with sodium hydroxide in a methanol / water solvent mixture gave carboxylic acid 32.

[0138] Treating intermediate 32 with oxazole 33 in the presence of triflic acid in t-BuOH gave intermediate 34, which in turn was treated with S-methylisothiourea hemisulfate salt (35) and sodium hydroxide to afford key intermediate 36.

[0139] The final compounds 19, 21 and 29 were then obtained by treating intermediate 36 with the desired amines and triethylamine in THF at elevated temperature to achieve compounds denoted 12-29 in Scheme 1.

[0140] Scheme 1. Reagents and conditions: a) NaOH. MeOH, water, rt, 43 h; b) Tnf x acid, t-BuOH; c) NaOH (aq), TBME, THF; d) EbN, THF, 70CC.

[0141] Details regarding the synthesis can be found below: Preparation of intermediates

[0142] 3.5-Diamino-6-chloro-pyrazine-2-carboxylic acid (32)

[0143] Methyl 3,5-diamino-6-chloro-pyrazine-2-carboxylate (31) (4.70 g, 23.2 mmol), methanol (47 mL) and NaOH (2.78 g in 11.3 mL water) was refluxed for 1.5 h. The mixture was allowed to cool to room temperature (rt) and then neutralised by addition of HCI (4 M, 5 mL). The precipitate was collected by filtration, washed with water and dried under vacuum to give 5.0 g of the product. MS (ESI+) m / z 189 [M+H]+.

[0144] (E)-3-(tert-Butylamino)-l-methyl-3-oxo-prop-l-enyl] 3,5-diamino-6-chloro- pyrazine-2- carboxylate (34)

[0145] A mixture of tert-butanol (0.65 g) and 5-methylisoxazole (33) (0.713 mL, 8.75 mmol) was cooled in an ice bath. Trifluoromethanesulfonic acid (0.774 mL, 8.75 mmol) was added dropwise and the resulting mixture was stirred for 1 h at rt. A solution of 3,5- diamino-6-chloro-pyrazine-2-carboxylic acid (32) (0.550 g, 2.92 mmol) and N,N- diethylethanamine (1.22 mL, 8.75 mmol) in DMF (5 mL) was added to the above prepared mixture. The reaction mixture was stirred for 4 h at rt. Ice-water (20 mL) was added and the resulting precipitate was collected by filtration, washed with water and dried under vacuum to afford 0.520 g (54%) of the title compound. MS (ESI+) m / z 328 [M+H]+.

[0146] 3.5-Diamino-6-chloro-N- (methylsulfanylcarbonimidoyl)pyrazine-2- carboxamide (36)

[0147] To 1 M NaOH (2 mL) was added 2-methylisothiourea;sulfuric acid (35) (0.318 g, 2.29 mmol) and the mixture stirred at rt. MTBE:THF (1:1) (4.00 mL) was added followed by [(E)-3-(tert-butylamino)- l-methyl-3-oxo-prop-l-enyl] 3,5-diamino-6-chloro- pyrazine-2-carboxylate (34) (0.250 g, 0.763 mmol) and the reaction mixture was stirred overnight at rt. Water (4 mL) was added, and the formed precipitate was collected by filtration, washed with water, diethyl ether, and dried under vacuum to furnish 160 mg (80%) of the product. MS (ESI+) m / z 261 [M+H]+. Preparation of final Compounds 19 (Formula II), 21 (Formula I) and 29 (Formula III)

[0148] 3,5-Diamino-6-chloro-N-(methylsulfanylcarbonimidoyl)pyrazine-2-carboxamide (36) (50.0 mg, 0.192 mmol) and amine "d" (2-Aminobenzimidazole in the case of compound 19 and 2-cyclopentylethanamine in the case of compound 21, ca 58.7 mg, 0.288 mmol) were mixed in THF (2 mL) and triethylamine (53.5pL, 0.384 mmol) was added. The reaction mixture was heated at 70 °C overnight. The mixture was allowed to reach rt and the volatiles were removed under vacuum. The residue was purified by acidic preparative HPLC using 2-30% acetonitrile in water (containing 0.1% TFA). The pure fractions were collected and 2 N HCI (5-10 mL) was added. The resulting mixture was lyophilised to afford the title compound as a light-yellow solid.

[0149] Results

[0150] Formula II: Compound MRI001-019, HCI salt: 3,5-Diamino-N-[N-(lH-benzimidazol- 2-yl)carbamimidoyl]-6-chloropyrazine-2-carboxamide dihydrochloride

[0151] Yield = 10 mg (13 % ) m / z [M + H]+346TH NMR (400 MHz, DMSO-d6) 6 7.57- 7.10 (m, 4H), 3.98-3.33 (bs, 7H)

[0152] Formula I: Compound MRI001-021, HCI salt: 3,5-Diamino-6-chloro-N-[N-[2-[2- (trifluoromethyl)phenyl]ethyl]carbamimidoyl]pyrazine-2-carboxamide hydrochloride Yield = 11 mg (14 % ) m / z [M + H]+402

[0153] TH NMR (400 MHz, DMSO-d6) 6 10.54 (s, 1H), 9.42 (t, J = 5.9 Hz, 1H), 9.05 (s, 1H), 8.26 (s, 1H), 7.76 - 7.67 (m, 4H), 7.65 (s, 1H), 7.58 - 7.45 (m, 3H), 7.43 (s, 1H), 3.97 (s, 4H), 3.70 - 3.60 (m, 2H), 3.13 - 2.98 (m, 4H).

[0154] Formula III: Compound MRI001-029, HCI salt: 3,5-Diamino-6- chloro-N-[N-(2- cyclopentylethyl)carbamimidoyl]pyrazine-2- carboxamide hydrochloride 10 mg (20 %) m / z [M + H]+326XH NMR (400 MHz, DMSO-d6) 6 10.57 (s, 1H), 9.32 (t, J = 5.6 Hz, 1H), 8.98 (s, 1H), 8.87 (s, 1H), 7.42 (s,lH), 3.31 (dt, J =7.8, 6.0 Hz, 2H), 1.91 - 1.80 (m,lH), 1.75 (tdd, J = 10.7, 5.6, 2.7 Hz, 2H), 1.66 -1.53 (m, 4H), 1.53 - 1.42 (m, 2H), 1.20 - 1.05 (m,2H).

[0155] Example 3: In vitro study using human keratinocytes

[0156] The aim of the study was to study the effect of Compounds 19 (Formula II), 21 (Formula I) and 29 (Formula III) on human primary keratinocytes. Cells were treated with inventive compounds, whereafter cells were stimulated with TNF-a and IL-17. After incubation, cell viability and cytokine release were investigated.

[0157] Materials and methods

[0158] Reagents

[0159] • Live / Dead fixable violet (Thermo Fisher, L34955)

[0160] • DMSO (Sigma, D5879)

[0161] • DermaLife K medium (Cellsystems, LL0007)

[0162] • Keratinocytes, NHEK-c adult single donor (PromoCell, C-12003)

[0163] • Luminex 2-plex (Bio-Rad, IL-6, CXCL1)

[0164] • ELISA duoset IL-8 (RnD, DY208)

[0165] • PBS (Gibco, Life Technologies, 14190, Lot number: 2241129)

[0166] • Recombinant human TNF-a (R&D Systems, 210-TA / CF)

[0167] • Recombinant human IL-17 (Thermo Fisher, PHC9174)

[0168] • Test items (provided by Sponsor)

[0169] • TrypLE Express solution (Gibco, 2604013)

[0170] • Trypsin Neutralizer solution (Gibco, R007100)

[0171] Equipment

[0172] • Attune flow cytometer (Thermo Fisher, Waltham, MA, USA)

[0173] • Luminex 200 (Bio-Rad, Soina, Sweden)

[0174] • TPP cell culture plate 96-well flat bottom (Thermo Fisher, 92696) V-bottom plates (Nunc, 732-0191)

[0175] Procedures

[0176] Keratinocyte culture protocol

[0177] Human primary keratinocytes (HEKa) from PromoCell were cultured in DermaLife K medium with all supplements, i.e. recombinant human Insulin, LGIutamine, Epinephrine, Apo-Transferrin, recombinant human TGF-a and Extract P LifeFactor. Hydrocortisone was not added to medium.

[0178] Initiating Cultures from Cryopreserved HEK Cells

[0179] • Vial with frozen HEKa was thawed in a 37°C water / bead bath.

[0180] • Cell suspension was transferred to a T75 cell culture flask with 30ml medium.

[0181] • 15 ml from the first culture flask was then transferred to a new T75 flask (2 T75 flasks with 15ml culture in each flask).

[0182] • Cells were cultured for 5-6 days before they were subcultured or used for assay.

[0183] Maintenance of HEKa culture

[0184] • Culture medium was refreshed 24 to 36 hours after cells were thawed.

[0185] • For an established HEKa culture, the media was changed every 48-72 hours.

[0186] • Cells were only used for assay up to passage 5.

[0187] In vitro assay Day 0

[0188] Cells were visualized under microscope and 80% confluence was confirmed. Culture medium was removed from the flask. 3 ml TrypLE Express solution was added. Flask was rocked to ensure that the entire surface was covered. The TrypLE Express solution was immediately removed, and 1.5 ml fresh TrypLE Express solution was added to the flask. Cells were left in room temperature until cells were completely round (approximately 10 minutes). Flask was carefully tapped to detach the cells from the flask and 4 ml Trypsin Neutralizer solution / T75 flask was added. Cells were transferred to a sterile conical tube, counted, and centrifuged at 170xg for 10 minutes. Cells were resuspended in PBS at lxlO6cells / ml and strained trough a 35 pm cell strainer. Cells were resuspended in DermaLife K medium including supplements at 6*105cells / ml and 200 pl was added to wells in a 96-well flat bottom cell culture plate. Cells were incubated overnight at 37°C, 5% CO2.

[0189] In vitro assay Day 1

[0190] Old medium was removed. Cells were treated with compounds 19, 21 or 29 at six different concentrations (10 pM, 5 pM, 1 pM, 100 nM, 10 nM and 1 nM) and stimulated with TNF-a (10 ng / ml) and IL-17 (10 ng / ml), and incubated for 48 hours at 37°C, 5% CO2.

[0191] Analysis of cells and supernatants

[0192] Following incubation with compounds 19 (Formula II), 21 (Formula I) or 29 (Formula III) and subsequent stimulation with TNF-a and IL-17 for 48 hours, cytokine release was analysed using Luminex. Cells were analysed for viability using flow cytometry.

[0193] Analysis of proliferation using flow cytometry

[0194] HEKa cells were detached, washed, and resuspended in Live / Dead fixable violet. Cells were incubated dark at room temperature for 30 minutes. After incubation, cells were washed and resuspended in FACS buffer (1% FBS in PBS) and analysed for viability using flow cytometry.

[0195] Cytokine analysis using Luminex

[0196] All reagents, standard and samples were prepared according to manufacturer's instruction. Briefly, microparticles were added to the plates and washed 2x in 50 pl of standard or sample was added to wells and samples were incubated for 30 minutes at room temperature on a horizontal orbital shaker at 800 rpm. Plate was washed 3x in washing buffer using a magnetic plate. Biotin-antibody was added and incubated in the dark for 30 minutes at room temperature on a horizontal orbital shaker at 800 rpm. Plates were washed 3x in washing buffer using a magnetic plate. Streptavidin-PE was added to each well and incubated in the dark at room temperature on a horizontal orbital shaker (800rpm) for 10 minutes. Plates were washed 3x in washing buffer using a magnetic plate. Microparticles were resuspended in 125 pl assay buffer and incubated for 30 seconds on a horizontal orbital shaker (800rpm). Samples were analyzed on a Bio-Rad Luminex 200 analyzer.

[0197] Cytokine analysis using ELISA

[0198] One day before analysis, ELISA plates were coated with 50 pl human IL-8 capture antibody per well. Plates were incubated overnight at room temperature. Supernatants and cytokine standard were thawed at room temperature and ELISA plates were washed 3x with ELISA washing buffer. 100 pl blocking solution (1% BSA in PBS) was added to each well and incubated for 1 hour at room temperature. ELISA plates were washed 3x with ELISA washing buffer and 50 pl supernatant and standard was added to wells and incubated for 2 hours at room temperature. Plates were washed with ELISA washing buffer 3x and 50 pl detection antibody was thereafter added to each well. Plates were incubated at room temperature for 2 hours. Plates were washed with ELISA washing buffer 3x and 50 pl Streptavidin-HRP solution was thereafter added to each well and incubated for 20 minutes at room temperature. ELISA plates were washed 3x with ELISA washing buffer. 50 pl TMB substrate solution was added to each well and incubated dark at room temperature until the desired color was developed. Absorbance was measured at 650 nm. The control was vehicle treated and cytokine stimulated.

[0199] Acquisition and analysis

[0200] Graphs were performed using Prism 9 for Mac OS X (GraphPad Software, San Diego, CA, USA). Results are presented as mean values ± SEM, if not otherwise stated.

[0201] Results - cell viability

[0202] Table 2: Cell viability : % viable cells vs control (act Ctrl)

[0203] Conclusion - cell viability

[0204] The inventive compounds were well tolerated by the cells. As such, cytokine release in cells treated by 5 uM or less of MRI019, MRI021 or MRI029 would not be explained by a marked decrease in cell viability

[0205] Results -cytokine release

[0206] Table 3. Cytokine release - IL-8 release after 48 hours of incubation with inventive compounds at six different concentrations.

[0207] Unstim = unstimulated. Act Ctrl =activity control (The control was vehicle treated and cytokine stimulated). Ref cpd=betamethasone

[0208] Table 4. Cytokine release - CXCL1 release after 48 hours of incubation with inventive compounds at six different concentrations.

[0209]

[0210] Unstim = unstimulated. Act Ctrl =activity control (The control was vehicle treated and cytokine stimulated). Ref cpd=betamethasone Table 5. Cytokine release - CXCL1 release after 48 hours of incubation with inventive compounds at six different concentrations.

[0211] Unstim = unstimulated. Ref cpd=betamethasone

[0212] Conclusion - cytokine release

[0213] An effect between the inventive compounds and the vehicle control was seen. The effect was considered to be the result of properties of inventive compounds. A decrease of IL-8 and CXCL1 release was seen for the cells treated with inventive compounds. The decrease was dose dependent; the higher the concentration of Formula I, Formula II, or Formula III, the lower the amount of IL-8 and / or CXCL1 in the supernatant. Since the inventive compounds were well tolerated by the cells and the cells were viable during treatment as confirmed above, it can be concluded that the decrease of IL-8 release did not correlate to any decrease in cell viability. In addition, it can be concluded that the decrease of CXCL1 release did not correlate to any decrease in cell viability. Instead, decrease of IL-8 and CXCL1 was considered to be the result of treatment of inventive compounds. Example 4: in vivo studies: pharmacokinetics

[0214] The purpose of this experiment was to obtain pharmacokinetic parameters for the inventive compounds Formula I and Formula II. The purpose was also to investigate the amount of compound metabolized to amiloride. Side effects of amiloride include electrolyte abnormalities such as hyperkalemia, and hypotension. Therefore, avoidance of amiloride as an metabolite is desirable.

[0215] Materials and methods

[0216] The pharmacokinetics (PK) of MRI001 (Benzamil), MRI019 (Formula II) and MRI021 (Formula I) was investigated in female BALB / c mice following intraperitoneal (i.p) injections. Three mice were administered 1.4 mg / kg MRI001 lactate and another three mice were administered 1.4 mg / kg MRI019 lactate (solutions, dose volumes 10 mL / kg). Blood samples were collected from each mouse at 5 minutes, 20 minutes, 1 hour, 3 hours, 6 hours, and 24 hours after dose administration.

[0217] The collected blood samples were kept on ice prior to centrifugation (2000g, 10 min, 4°C). The plasma samples were immediately frozen and stored at -80°C until bioanalysis. Plasma concentrations of MRI001 and MRI019 and their potential metabolite amiloride were measured by ultra-performance liquid chromatographytandem mass spectrometry.

[0218] Non-compartmental analysis (NCA) using the software Phoenix WinNonlin, version 8.3 (Certara, U.S.A.) was used for calculations of plasma PK parameters. Nominal plasma sampling timepoints and nominal doses were used for the NCA analysis. Plasma concentrations below the limit of quantification occurring after Cmax were omitted from the analysis. Cmax, Tmax and Tiast were derived from the observed plasma concentration data. AUC was assessed by integration of the plasma concentration vs. time curve using linear interpolation for increasing plasma levels and logarithmic interpolation for decreasing plasma levels. The apparent terminal plasma half-life (T%) was calculated by In2 / lambdaz. Lambdaz, the first order rate constant associated with the terminal portion of the curve was based on at least 2 terminal concentration values (not including Cmax). If this could not be achieved, its dependent PK parameter Ti / 2was not reported. Mean plasma concentration versus time curves for MRI001, MRI019 and MRI021 are shown in figure 1 to 3 below. The lower limit of quantification for MRI001 and amiloride was 0.5 ng / mL, and 3 ng / mL for MRI019 and MRI021.

[0219] Results

[0220] Calculated PK parameters are shown in Table 6 below. Analysis of amiloride after administration of MRI019 to female BALB / c mice only showed one single plasma sample (out of 18) with concentration above 0.5 ng / mL (1.18 ng / mL in a sample collected at 1 hour after dose administration), and subsequently PK parameters for amiloride could not be calculated for mice dosed with MRI019.

[0221] Table 6. Calculated PK parameter

[0222] Tmax values represent median and range, whereas other PK parameters represent mean and standard deviations. NC, not calculated. *Calculated by sparse settings

[0223] Following administration of 1.4 mg / kg MRI001 to female BALB / c mice, the estimated plasma AUCiast for MRI001 and amiloride was 214 h*ng / mL and 154 h*ng / mL, respectively. Considering the differences in molecular weight between MRI001 (319.75 g / mol) and Amiloride (229.63 g / mol), the estimated AUCiast for both MRI001 and amiloride is approximately 670 h*nmol / L. Following administration of 1.4 mg / kg MRI019 to female BALB / c mice, the estimated plasma AUCiast for MRI019 was 101 h*ng / mL (equals to 292 h*nmol / L).

[0224] Following administration of 1.4 mg / kg MRI021 to female BALB / c mice, the estimated plasma AUCiast for MRI021 was 79.9 h*ng / mL.

[0225] Conclusion

[0226] In conclusion, the PK in female BALB / c mice differs considerably between MRI001, MRI019 and MRI021 in respect of the formation of amiloride. The plasma exposure to MR019 and MRI021 was lower than the plasma exposure to MRI001 in female BALB / c mice. The results indicate that MRI1019 as well as MRI021 are less prone to form amiloride in vivo, compared to Benzamil.

[0227] Itemized list of embodiments

[0228] 1. A compound, which is selected from the group consisting of:

[0229] Formula III and a pharmaceutically acceptable salt, hydrate, prodrug or solvate thereof. 0

[0230] 2. The compound according to item 1, wherein said compound is Formula III.

[0231] 3. The compound according to item 1, wherein said compound is Formula II.

[0232] 4. The compound according to any one of items 1 to 3, wherein said pharmaceutically acceptable salt is selected from the group consisting of a hydrochloride salt, a sodium salt, a lactate salt, an acetic salt, a phosphoric salt and a trifluoro acetic acid salt. 0 5. The compound according to any one of items 1 to 4 for use as a medicament.

[0233] 6. The compound for use according to item 5, for use in the prevention, alleviation and / or treatment of a skin disorder. 7. The compound for use according to item 6, wherein said skin disorder is a skin disorder wherein CXCL1, TNFa and / or ILla are deregulated.

[0234] 8. The compound for use according to any one of items 6 to 7, wherein said skin disorder is selected from the group consisting of psoriasis; nail psoriasis; psoriatic arthritis; acne; atopic dermatitis; seborrheic dermatitis; nummular dermatitis; periorificial dermatitis; rosacea; vitiligo; hidradenitis suppurativa, such as hidradenitis; lupus; morphea; scleroderma; cutaneous ulcers; inflamed seborrheic keratoses; nevi; fibrous papules; pityriasis rubra pilaris; pemphigus, such as pemphigus vulgaris and pemphigus vegetans; bullous pemphigoid; IgA pemphigus; keratosis follicula ris; lamellar ichthyosis; epidermolytic ichthyosis; Netherton's syndrome; congenital ichthyosiform erythroderma; cutaneous vasculitis; Behcet's disease; cutaneous graft versus host disease; SAPHO (synovitis; acne; pustulosis; hyperostosis and osteitis) syndrome; sarcoidosis; panniculitis; Stevens Johnson syndrome; toxic epidermal necrolysis; neutrophilic dermatoses; pyoderma gangrenosum; sweet syndrome; Sneddon Wilkinson; acute generalized exanthematous pustulosis (AGEP); dermatitis herpetiformis; dermatomyositis; cryoporin-associated periodic syndromes; familial Mediterranean fever; xeroderma pigmentosum; pruritus; pain; UV-induced skin damage; irritant contact dermatitis; Still's disease; Lichen planus; eczema; alopecia; a disorder associated with delayed wound healing, such as diabetic wounds, radiation wounds, wounds related to bullous diseases such as epidermolysis bullosa; cutaneous neoplasms with inflammation such as actinic keratosis, squamous cell carcinoma such as squamous cell carcinoma in situ (Bowen's disease), basal cell carcinoma, extramammary Paget's disease, dermatofibroma protuberans, atypical fibroxanthoma, sebaceous carcinoma; Merkel cell carcinoma; and melanoma.

[0235] 9. The compound for use according to any one of items 6 to 8, wherein said skin disorder is selected from the group consisting of psoriasis; nail psoriasis; psoriatic arthritis, acne, xeroderma pigmentosum, pruritus, pain, irritant contact dermatitis, Lichen planus and atopic dermatitis. 10. The compound for use according to any one of items 6 to 8, wherein said skin disorder is selected from the group consisting of cutaneous neoplasms with inflammation such as actinic keratosis, squamous cell carcinoma such as squamous cell carcinoma in situ (Bowen's disease), basal cell carcinoma, extramammary Paget's disease, dermatofibroma protuberans, atypical fibroxanthoma, sebaceous carcinoma; Merkel cell carcinoma; and melanoma.

[0236] 11. The compound for use according to any one of items 6 to 8, wherein said skin disorder is selected from the group consisting of psoriasis, acne, eczema, hidradenitis and melanoma.

[0237] 12. A pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in any one of items 1 to 3, or a pharmaceutically acceptable salt, hydrate, prodrug or solvate thereof, and at least one pharmaceutically acceptable diluent, carrier and / or excipient.

[0238] 13. The pharmaceutical composition according to item 12, further comprising at least one additional therapeutic agent.

[0239] 14. A cosmetical composition comprising a cosmetically effective amount of a compound as defined in any one of items 1 to 3, or a cosmetically acceptable salt, hydrate, prodrug or solvate thereof, and at least one cosmetically acceptable diluent, carrier and / or excipient.

[0240] 15. Use of compound according to any one of items 1 to 3 or a composition according to item 14 as a cosmetic.

Claims

Claims1. A compound, which is selected from the group consisting of:Formula III 0 and a pharmaceutically acceptable salt, hydrate, prodrug, solvate or tautomer thereof.

2. The compound according to claim 1, wherein said compound is selected from the group consisting of Formula II, Formula III and a pharmaceutically acceptable salt, hydrate, prodrug, solvate or tautomer thereof.

3. The compound according to claim 1, wherein said compound is selected from the group consisting of Formula I, Formula II and a pharmaceutically acceptable salt,0 hydrate, prodrug, solvate or tautomer thereof.

4. The compound according to claim 1, wherein said compound is Formula I.

5. The compound according to claim 1, wherein said compound is Formula II.

6. The compound according to claim 1, wherein said compound is Formula III.

7. The compound according to any one of claims 1 to 6, wherein said pharmaceutically acceptable salt is selected from the group consisting of a hydrochloride salt, a sodium salt, a lactate salt, an acetic salt, a phosphoric salt and a trifluoro acetic acid salt.

8. A compound according to any one of claims 1 to 7 for use as a medicament.

9. A compound according to any one of claims 1-7 for use in the prevention, alleviation and / or treatment of a skin disorder.

10. The compound for use according to claim 9, wherein said skin disorder is a skin disorder wherein IL-8, CXCL1, TNFa and / or ILla are deregulated.

11. The compound for use according to claim 9, wherein said skin disorder is a skin disorder wherein CXCL1, TNFa and / or ILla are deregulated.

12. The compound for use according to any one of claims 9 to 11, wherein said skin disorder is selected from the group consisting of psoriasis; nail psoriasis; psoriatic arthritis; acne; atopic dermatitis; seborrheic dermatitis; nummular dermatitis; periorificial dermatitis; rosacea; vitiligo; hidradenitis suppurativa, such as hidradenitis; lupus; morphea; scleroderma; cutaneous ulcers; inflamed seborrheic keratoses; nevi; fibrous papules; pityriasis rubra pilaris; pemphigus, such as pemphigus vulgaris and pemphigus vegetans; bullous pemphigoid; IgA pemphigus; keratosis follicula ris; lamellar ichthyosis; epidermolytic ichthyosis; Netherton's syndrome; congenital ichthyosiform erythroderma; cutaneous vasculitis; Behcet's disease; cutaneous graft versus host disease; SAPHO (synovitis; acne; pustulosis; hyperostosis and osteitis) syndrome; sarcoidosis; panniculitis; Stevens Johnsonsyndrome; toxic epidermal necrolysis; neutrophilic dermatoses; pyoderma gangrenosum; sweet syndrome; Sneddon Wilkinson; acute generalized exanthematous pustulosis (AGEP); dermatitis herpetiformis; dermatomyositis; cryoporin-associated periodic syndromes; familial Mediterranean fever; xeroderma pigmentosum; pruritus; pain; UV-induced skin damage; irritant contact dermatitis; Still's disease; Lichen planus; eczema; alopecia; a disorder associated with delayed wound healing, such as diabetic wounds, radiation wounds, wounds related to bullous diseases such as epidermolysis bullosa; cutaneous neoplasm with inflammation such as actinic keratosis, squamous cell carcinoma such as squamous cell carcinoma in situ (Bowen's disease), basal cell carcinoma, extramammary Paget's disease, dermatofibroma protuberans, atypical fibroxanthoma, sebaceous carcinoma; Merkel cell carcinoma; and melanoma.

13. The compound for use according to any one of claims 9 to 12, wherein said skin disorder is selected from the group consisting of psoriasis; nail psoriasis; psoriatic arthritis, acne, xeroderma pigmentosum, pruritus, pain, irritant contact dermatitis, Lichen planus and atopic dermatitis.

14. The compound for use according to any one of claims 9 to 12, wherein said skin disorder is selected from the group consisting of pityriasis rubra pilaris, pemphigus, such as pemphigus vulgaris and pemphigus vegetans, bullous pemphigoid, IgA pemphigus, keratosis follicula ris, lamellar ichthyosis, epidermolytic ichthyosis, Netherton's syndrome, congenital ichthyosiform erythroderma, cutaneous vasculitis, Behcet's disease, cutaneous graft versus host disease, SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome, sarcoidosis, panniculitis, Stevens Johnson syndrome, toxic epidermal necrolysis, neutrophilic dermatoses, pyoderma gangrenosum, sweet syndrome, Sneddon Wilkinson, acute generalized exanthematous pustulosis (AGEP), dermatitis herpetiformis, scleroderma, morphea, dermatomyositis, cryoporin-associated periodic syndromes, familial mediterreanean fever, UV-induced skin damage, Still's disease, hidradenitis suppurativa, such as hidradenitis, alopecia, vitiligo, basal cell carcinoma, actinic keratosis, and squamous cell carcinoma such as squamous cell carcinoma in situ (Bowen's disease).

15. The compound for use according to any one of claims 9 to 12, wherein said skin disorder is selected from the group consisting of Bullous pemphigoid, keratosis follicula ris, cutaneous vasculitis, cryoporin-associated periodic syndrome, familial mediterreanean fever, UV-induced skin damage, Still's disease, Lichen planus, seborrheic dermatitis, and alopecia.

16. The compound for use according to any one of claims 9 to 12, wherein said skin disorder is selected from the group consisting of cutaneous neoplasm with inflammation such as actinic keratosis, squamous cell carcinoma such as squamous cell carcinoma in situ (Bowen's disease), basal cell carcinoma, extramammary Paget's disease, dermatofibroma protuberans, atypical fibroxanthoma, sebaceous carcinoma; Merkel cell carcinoma; and melanoma.

17. The compound for use according to any one of claims 9 to 12, wherein said skin disorder is selected from the group consisting of psoriasis, acne, eczema, hidradenitis and melanoma.

18. The compound for use according to any one of claims 9 to 12, wherein said skin disorder is selected from the group consisting of psoriasis, acne, eczema, and hidradenitis.

19. The compound for use according to any one of claims 9 to 12, wherein said skin disorder is melanoma.

20. The compound for use according to any one of claims 8 to 19, wherein said compound is administrated topically or systemically.

21. The compound for use according to any one of claims 8 to 20, wherein said compound is administrated intravenously, intraperitoneally, nasally, per rectum, intravaginally, percutaneously, intradermally, subcutaneously, intramuscularly or orally.

22. The compound for use according to any one of claims 8 to 19, wherein said compound is administrated intradermally or subcutaneously.

23. The compound for use according to any one of claims 8 to 22, wherein said compound is administrated in a dose of from about 0.001 to about 0.1 mg per kg body weight, such as 0.01 to about 0.1 mg per kg body weight, or from about 0.1 to about 300 mg per kg body weight, such as from about 0.2 to about 200 mg per kg body weight, such as from about 0.3 to about 150 mg per kg body weight, such as about 0.4 to about 150 mg per kg bodyweight, such as about 0.5 to about 120 mg per kg bodyweight, such as from about 1 to about 100 mg per kg body weight, such as from about 1 to about 50 mg per kg body weight, such from about 1 to about 5 mg per kg body weight, such as about 1 mg per kg body weight.

24. The compound for use according to any one of claims 9 to 22, wherein said compound is administrated in a mixed dose of about 0.1 mg, or of about 0.5 mg, or of about 1 mg, or of about 1.5 mg.

25. The compound for use according to any one of claims 9 to 24, wherein said compound is administrated in an amount effective to achieve a serum concentration of from about 1 to about 50 ng / ml in a subject, such as from about 5 to about 50 ng / mL in a subject, such as from about 5 ng to about 50 ng / ml in a subject.

26. A pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in any one of claims 1 to 6, or a pharmaceutically acceptable salt, hydrate, prodrug, solvate or tautomer thereof, and at least one pharmaceutically acceptable diluent, carrier and / or excipient.

27. The pharmaceutical composition according to claim 26, further comprising at least one additional therapeutic agent.

28. The pharmaceutical composition according to claim 27, wherein said additional therapeutic agent is selected from the group consisting ofcorticosteroids, such as betamethasone, clobetasol, cortisone, corticosterone, deflazacort, desonide, desoximethasone, dexamethasone, prednisone, flunisolide, fluocinolone, hydrocortisone, loteprednol, mometasone, triamcinolone acetonide; vitamin D analogs such as calcipotriol, calcitriol, cholecalciferol, taca Icitol, paricalcitol, alfacalcidol, doxercalciferol, falecalcitriol; retinoids such as tretinoin, isotretinoin, adapalene, tazarotene, trifarotene; UV protection such as titanium dioxide, zinc oxide, avobenzone, octinoxate oxybenzone, benzophenone, benzotriazoles, and cinnamates; and hydroquinone; topical chemotherapy such as 5-fluorouracil; and topical immunotherapy such as imiquimod.

29. The pharmaceutical composition according to any one of claims 26 to 28 wherein said composition is a topical composition.

30. The pharmaceutical composition according to any one of claims 26 to 29 for use as a medicament, optionally for a use as defined in any one of claims 8 to 25.

31. A cosmetical composition comprising a cosmetically effective amount of a compound as defined in any one of claims 1 to 6, or a cosmetically acceptable salt, hydrate, prodrug, solvate or tautomer thereof, and at least one cosmetically acceptable diluent, carrier and / or excipient.

32. The cosmetic composition according to claim 31, further comprising at least one cosmetic agent.

33. The cosmetic composition according to claim 32, wherein said cosmetic agent is selected from the group consisting of hydroquinone; benzoyl peroxide; clindamycin; metronidazole; tacrolimus; niacin amide; kojic acid; vitamin C; and UV protection such as titanium dioxide, zinc oxide, avobenzone, octinoxate oxybenzone, benzophenone, benzotriazoles, and cinnamates.

34. The cosmetic composition according to any one of claims 31 to 33, wherein said composition is a topical composition.

35. Cosmetic use of compound according to any one of claims 1 to 6 or a composition according to any one of claims 31 to 34.

36. A method of deregulating IL-8, CXCL1, TNFa and / or ILla, such as deregulating CXCL1, TNFa and / or ILla or such as deregulating IL-8, the method comprising administration of an effective dose of the compound according to any one of claims 1 to 6 to a subject in need thereof.

37. The method according to claim 36, intended for treating, alleviating and / or preventing a skin disorder in a subject in need thereof.

38. The method of treatment according to claim 37, wherein said skin disorder is selected from the group consisting of psoriasis; nail psoriasis; psoriatic arthritis; acne; atopic dermatitis; seborrheic dermatitis; nummular dermatitis; periorificial dermatitis; rosacea; vitiligo; hidradenitis suppurativa, such as hidradenitis; lupus; morphea; scleroderma; cutaneous ulcers; inflamed seborrheic keratoses; nevi; fibrous papules; pityriasis rubra pilaris; pemphigus, such as pemphigus vulgaris and pemphigus vegetans; bullous pemphigoid; IgA pemphigus; keratosis follicularis; lamellar ichthyosis; epidermolytic ichthyosis; Netherton's syndrome; congenital ichthyosiform erythroderma; cutaneous vasculitis; Behcet's disease; cutaneous graft versus host disease; SAPHO (synovitis; acne; pustulosis; hyperostosis and osteitis) syndrome; sarcoidosis; panniculitis; Stevens Johnson syndrome; toxic epidermal necrolysis; neutrophilic dermatoses; pyoderma gangrenosum; sweet syndrome;Sneddon Wilkinson; acute generalized exanthematous pustulosis (AGEP); dermatitis herpetiformis; dermatomyositis; cryoporin-associated periodic syndromes; familial Mediterranean fever; xeroderma pigmentosum; pruritus; pain; UV-induced skin damage; irritant contact dermatitis; Still's disease; Lichen planus; eczema; alopecia; a disorder associated with delayed wound healing, such as diabetic wounds, radiation wounds, wounds related to bullous diseases such as epidermolysis bullosa; xcutaneous neoplasm with inflammation such as actinic keratosis, squamous cellcarcinoma such as squamous cell carcinoma in situ (Bowen's disease), basal cell carcinoma, extramammary Paget's disease, dermatofibroma protuberans, atypical fibroxanthoma, sebaceous carcinoma; Merkel cell carcinoma; and melanoma.

39. The method of treatment according to any one of claims 37 to 38, wherein said skin disorder is selected from the group consisting of psoriasis; nail psoriasis; psoriatic arthritis, acne, xeroderma pigmentosum, pruritus, pain, irritant contact dermatitis, Lichen planus and atopic dermatitis.

40. The method of treatment according to any one of claims 37 to 38, wherein said skin disorder is selected from the group consisting of pityriasis rubra pilaris, pemphigus, such as pemphigus vulgaris and pemphigus vegetans, bullous pemphigoid, IgA pemphigus, keratosis follicula ris, lamellar ichthyosis, epidermolytic ichthyosis, Netherton's syndrome, congenital ichthyosiform erythroderma, cutaneous vasculitis, Behcet's disease, cutaneous graft versus host disease, SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome, sarcoidosis, panniculitis, Stevens Johnson syndrome, toxic epidermal necrolysis, neutrophilic dermatoses, pyoderma gangrenosum, sweet syndrome, Sneddon Wilkinson, acute generalized exanthematous pustulosis (AGEP), dermatitis herpetiformis, scleroderma, morphea, dermatomyositis, cryoporin-associated periodic syndromes, familial mediterreanean fever, UV-induced skin damage, Still's disease, hidradenitis suppurativa such as hidradenitis, alopecia, vitiligo, basal cell carcinoma, actinic keratosis, and squamous cell carcinoma such as squamous cell carcinoma in situ (Bowen's disease).

41. The method of treatment according to any one of claims 37 to 38, wherein said skin disorder is selected from the group consisting of Bullous pemphigoid, keratosis follicula ris, cutaneous vasculitis, cryoporin-associated periodic syndrome, familial mediterreanean fever, UV-induced skin damage, Still's disease, Lichen planus, seborrheic dermatitis, and alopecia.

42. The method of treatment according to any one of claims 37 to 38, wherein said skin disorder is selected from the group consisting of cutaneous neoplasm withinflammation such as actinic keratosis, squamous cell carcinoma such as squamous cell carcinoma in situ (Bowen's disease), basal cell carcinoma, extramammary Paget's disease, dermatofibroma protuberans, atypical fibroxanthoma, sebaceous carcinoma; Merkel cell carcinoma; and melanoma.

43. The method of treatment according to any one of claims 37 to 38, wherein said skin disorder is selected from the group consisting of psoriasis, acne, eczema, hidradenitis and melanoma.

44. The method of treatment according to any one of claims 37 to 38, wherein said skin disorder is selected from the group consisting of psoriasis, acne, eczema, and hidradenitis.

45. The method of treatment according to any one of claims 37 to 38, wherein said skin disorder is melanoma .

46. Use of a compound or pharmaceutically acceptable salt, hydrate, solvate, tautomer or combination thereof according to any one of claims 1 to 25 or a composition according to any one of claims 26 to 30 for the manufacture of a medicament.

47. Use of a compound or pharmaceutically acceptable salt, hydrate, solvate, tautomer or combination thereof according to any one of claims 1 to 25 or a composition according to any one of claims 26 to 30 for the manufacture of a medicament for use in the treatment of a skin disorder.

Images