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WO 2012/084978 Al 28 June 2012 (28.06.2012) P O P C T

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WO 2012/084978 Al 28 June 2012 (28.06.2012) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2012/084978 Al 28 June 2012 (28.06.2012) P O P C T (51) International Patent Classification: (74) Agent: UEXKULL & STOLBERG; Beselerstr. 4, 22607 A61K 31/192 (2006.01) A61P 17/04 (2006.01) Hamburg (DE). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/EP20 11/073444 kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (22) Date: International Filing CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, 20 December 201 1 (20. 12.201 1) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (25) Filing Language: English HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (26) Publication Language: English MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (30) Priority Data: OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, 10196271 .0 2 1 December 2010 (21. 12.2010) EP SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicant (for all designated States except US) : GALEN- PHARMA GMBH [DE/DE]; Wittland 13, 24109 Kiel (84) Designated States (unless otherwise indicated, for every (DE). kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (72) Inventors; and UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, (75) Inventors/Applicants (for US only): MEHNERT, Jorg TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, [DE/DE]; c/o GALENpharma GmbH, Wittland 13, 24109 DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Kiel (DE). SOBLIK, Hanns [DE/DE]; c/o GALENpharma LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, GmbH, Wittland 13, 24109 Kiel (DE). PIOTROWIAK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Ralf [DE/DE]; c/o GALENpharma GmbH, Wittland 13, GW, ML, MR, NE, SN, TD, TG). 24109 Kiel (DE). [Continued on nextpage] (54) Title: (i?)-2-(3-FLUORO-4-PHENYLPHENYL)PROPIONIC ACID FOR USE IN THE TREATMENT OF SKIN DISEASES (57) Abstract: The present invention = Figure 1 relates to (i?)-2-(3-fluoro-4- phenylphenyl)propionic acid (tarenflurbil) or a pharmaceutically acceptable salt, solv 7000 ate or ester thereof for use in the treatment of inflammation of the skin as well as a pharmaceutical composition comprising 6000 tarenflurbil. 5000 Donor A S 4000 Donor B Donor C 3000 2000 1000 .39|l .56|6.25| 25 | 100 | 00 o Tarenflurbil [ g/ l] w o 2012/084978 Al II 11 II I 1 Illlll I III I III! Ill I III II I II Published: (R) -2- (3- luoro-4-phenylphenyl) propionic acid for use in the treatment of skin diseases The present invention relates to (R) -2- (3-f luoro-4- phenylphenyl )propionic acid (tarenf lurbil ) for use in the treatment of skin diseases and pharmaceutical compositions comprising tarenf lurbil . Skin diseases and, in particular, inflammatory skin dis eases today represent a widespread and unsolved problem. The most frequent non-infectious, inflammatory skin dis eases include atopic dermatitis and psoriasis. In Germany alone, between 3.5 and 5 million people suffer from atopic dermatitis (syn. neurodermatitis, asthma- eczema, atopic eczema, chronic constitutional eczema, en dogenous eczema, prurigo Besnier, neurodermatitis diffusa, intrinsic eczema, infantile eczema, allergic eczema) . Fre- quency has increased significantly during the last few decades. Atopic dermatitis is one of the most frequent childhood diseases (10-20%) (Dermatologie und Venerologie, Ed. Braun-Falco et al ., 5th edition, 2005, p . 381) . The incidence of psoriasis (syn. psora, arthritis psoriatica, psoriatic osteoarthropathy, arthropathia psoriatica, rhu- matisme psoriasique, chronic arthritis psoriatica, psoria- ris vulgaris, psoriasis nummularis, generalized psoriasis pustulosa, impetigo herpetiformis, psoriasis pustulosa of the Zumbusch type, acrodermatitis continua suppurativa (acrodermatitis continua suppurativa of Hallopeau) , pso riasis pustulosa palmoplantaris, guttate psoriasis, psori atic arthropathy, psoriasis inversa) is reported to be ap proximately 2% in Europe and the USA (Dermatologie und Venerologie, Ed. Braun-Falco et al ., 5th edition, 2005, p . 476) . Chronic inflammatory skin diseases such as psoriasis or atopic dermatitis represent a severe physical and emo tional burden on those affected. Thus far it has not been possible to cure such skin diseases, which means that therapy has been restricted to alleviating the symptoms. Today there are no medicinal products or non-medicamentous measures for treating atopic dermatitis which make possi ble a long-term cure of the disease (Dermatologie und Ven- erologie, Ed. Braun-Falco et al ., 5th edition, 2005, p . 391) . The pharmacotherapy of chronic, inflammatory skin diseases can be carried out systemically (e.g. by oral administra tion or injection o f a medicinal product) or topically (i.e. applied externally to the skin in targeted manner), wherein the topical therapy is preferred because of the lower risk of side effects. With such a targeted, topical therapy, the active ingredient is transported to its site of action in the tissue affected preferably without no- ticeably burdening other tissues or organs that are not involved . The commonly used topical standard therapy often reaches its limits in patients suffering from severe forms of pso- riasis or atopic dermatitis and side effects can occur during long-term treatment. Today the following topical therapeutic agents are com monly used for the treatment of inflammatory skin dis- eases. Corticosteroid-containing ointments are used for acute in flammatory skin diseases because of their strongly anti inflammatory effect. However, Cortisol is at the same time a hormone occurring naturally in the body which performs many regulatory functions in the metabolism and in the im mune system. Thus, during more prolonged topical treat ments, undesired side effects can occur on the skin, such as e.g. teleangiectasias, striae, steroid acne, changes in skin pigmentation, bacterial infections and hypertricho sis. Furthermore, corticoids can lead to epidermal atrophy and thinning of the epidermis making it easy for the lat- ter to be damaged. Systemic side effects in the case of particularly high doses of strong and very strong corti coids include inter alia water retention in the tissue (edema) and thus weight increase, weakening of the immune defence, promotion of the development of stomach ulcers, promotion of the development of and exacerbation of exist ing diabetes mellitus, promotion of the development and exacerbation of an existing bone atrophy (osteoporosis) . Following the abrupt discontinuation of a local glucocor ticoid therapy, a rebound effect may occur, in which the skin symptoms in question return with greater severity than before the treatment and then not infrequently also respond more poorly than previously to glucocorticoids. Children in particular are more susceptible than are adult patients to a glucocorticoid-induced suppressive effect on the hypothalamus-hypophyseal-adrenal axis and to Cushing' s syndrome, because the ratio of skin surface to body weight is greater in children. This extensive list of side ef fects, some of which are also very serious, has given rise to a "cortisone phobia" in most patients and in some mem- bers of the medical profession. Immune modulators and calcineurin inhibitors, e.g. tac rolimus and pimecrolimus , are two anti-inflammatory m e dicaments whose therapeutic efficacy can be compared with that of the likewise anti-inflammatory cortisone topical agents, but which do not cause skin atrophy. The active ingredient tacrolimus is known from transplantation m edi cine, where it is used to inhibit the immune system. How ever, this group of medicaments has proved to have the ma- jor disadvantage that it is clearly less effective com pared with the corticoids which are usually applied topi cally. Furthermore, there has been discussion of carcino genicity in connection with exposure to light. This group of medicaments has thus become established more as a rem edy of second choice, particularly as the high price of the products limits application over a large area. Systemic administration of anti-inflammatory medicinal products is considered only in rare cases when symptoms are particularly severe, e.g. glucocorticoids as an ini tial short-term treatment, furthermore immunosuppressants such as cyclosporin A , azathioprine or mycophenolate mofetil. The side effects are numerous and affect the most diverse organs such as e.g. kidneys, liver and gastro intestinal tract; skin, musculature, haematopoietic sys tem, immune system, cardiovascular system, nervous system and sensory organs. More recent observations indicate that the systemic ad ministration of biologies such as e.g. omalizumab and in fliximab can also lead to an improvement in symptoms. How ever, these are to be used with care, as serious side ef- fects can occur and they therefore require further re search (Bieber, Th., Atopic Dermatitis, Ann. Dermatol. Vol. 22, No. 2 , 2010, pp. 125-135) . When administered systemically, antihistamines alleviate itching in skin diseases. They block the action of the histamine released from the mast cells which is involved in causing itching. However, the antipruriginous action of these substances is highly controversial in the case of topical administration having regard to eczematous itch- ing. (Dermatologie und Venerologie, Ed. Braun-Falco et al., 5th edition, 2005, p . 393) . Antibiotics are used if bacterial infections of the skin occur, especially following scratch injuries. Such a bac- terial infection is rapidly controlled by short-term treatment with antibiotics. However, this successfully controls only the effects accompanying a skin disease, and not the skin disease as such.
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