Use of agonists of formyl peptide receptor 2 for treating dermatological diseases

Abstract

The present invention relates to a method for treating dermal inflammation and dermal diseases by local or systemic delivery, in a subject in need of such treatment, which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of at least one agonist of Formyl peptide receptor 2 (FPR2).

What is claimed is: 
     
         1 . A method of treating dermal inflammation or a dermal disease in a subject in need of such treatment, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a formyl peptide receptor 2 (FPR2) agonist of Formula III: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is halogen, hydrogen, optionally substituted C 1-8  alkyl, OR 9 , C(O)R 10 , NO 2 , NR 13 R 14 , CN, SR 15  or SO 2 R 16 ; 
 R 2  is halogen, optionally substituted C 1-8  alkyl, CF 3 , OR 9 , C(O)R 10 , NO 2 , NR 13 R 14 , CN, SR 15  or SO 2 R 16 ; 
 R 3  is hydrogen, optionally substituted C 1-8  alkyl, optionally substituted C 3-8  cycloalkyl, optionally substituted C 3-8  cycloalkenyl, optionally substituted C 6-10  aryl, optionally substituted heterocycle, or together with R 5  forms a 10- or 11-membered polycyclic ring which is optionally substituted; 
 R 4  is hydrogen, optionally substituted C 1-8  alkyl, 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       optionally substituted C 3-8  cycloalkyl, optionally substituted C 3-8  cycloalkenyl, optionally substituted C 6-10  aryl, optionally substituted heterocycle, or together with R 5  forms a spiro monocyclic or polycyclic, carbocyclic or heterocyclic, saturated or unsaturated 5 to 10 member ring which is optionally substituted;
 R 5  is hydrogen, optionally substituted C 1-8  alkyl, optionally substituted C 3-8  cycloalkyl, optionally substituted C 3-8  cycloalkenyl, optionally substituted C 6-10  aryl, optionally substituted heterocycle, or together with R 4  forms a spiro monocyclic or polycyclic carbocyclic or heterocyclic, saturated or unsaturated 5 to 10 member ring which is optionally substituted or together with R 3  forms a 5 or 6 member ring which is optionally substituted; 
 R 6  is halogen, hydrogen, optionally substituted C 1-8  alkyl, OR 9 , C(O)R 10 , NO 2 , NR 13 R 14 , CN, SR 15  or SO 2 R 16 ; 
 R 7  is halogen, hydrogen, optionally substituted C 1-8  alkyl, OR 9 , C(O)R 10 , NO 2 , NR 13 R 14 , CN, SR 15  or SO 2 R 16 ; 
 R 8  is halogen, hydrogen, optionally substituted C 1-8  alkyl, OR 9 , C(O)R 10 , NO 2 , NR 13 R 14 , CN, SR 15  or SO 2 R 16 ; 
 R 9  is hydrogen, C(O)(C 1-8  alkyl) or optionally substituted C 1-8  alkyl; 
 R 10  is hydrogen, optionally substituted C 1-8  alkyl, O(C 1-8  alkyl), NR 11 R 12  or OH; 
 R 11  is hydrogen, optionally substituted C 6-10  aryl or optionally substituted C 1-8  alkyl; 
 R 12  is hydrogen, optionally substituted C 6-10  aryl or optionally substituted C 1-8  alkyl; 
 R 13  is hydrogen, optionally substituted C 6-10  aryl or optionally substituted C 1-8  alkyl; 
 R 14  is hydrogen, optionally substituted C 6-10  aryl, optionally substituted C 1-8  alkyl, C(O)(C 1-8  alkyl) or SO 2 (C 1-8  alkyl); 
 R 15  is hydrogen, optionally substituted C 1-8  alkyl or O(C 1-8  alkyl); 
 R 16  is OH, O(C 1-8  alkyl), (C 1-8  alkyl) or NR 11 R 12 ; 
 R 17  is hydrogen, optionally substituted C 6-10  aryl or optionally substituted C 1-8  alkyl; 
 R 18  is hydrogen, C(O)(C 1-8  alkyl), optionally substituted C 6-10  aryl, or optionally substituted C 1-8  alkyl; 
 R 19  is hydrogen, C(O)(C 1-8  alkyl), optionally substituted C 6-10  aryl or optionally substituted C 1-8  alkyl; 
 R 20  is hydrogen, optionally substituted C 6-10  aryl or optionally substituted C 1-8  alkyl; 
 R 21  is hydrogen, optionally substituted C 6-10  aryl or optionally substituted C 1-8  alkyl; 
 n is 1, 2, 3, 4, or 5; and 
 m is 1, 2, 3, 4, or 5, 
 
       or a pharmaceutically acceptable salt thereof, 
       and wherein the dermal inflammation or dermal disease is selected from the group consisting of dermal wound healing, hypertrophic scars, keloids, burns, rosacea, atopic dermatitis, acne, psoriasis, seborrheic dermatitis, actinic keratoses, basal cell carcinoma, squamous cell carcinoma, melanoma, viral warts, photoaging, photodamage, melasma, post-inflammatory hyperpigmentation, disorders of pigmentation and alopecia, scarring and non-scarring forms; 
       and wherein the administration is by local delivery. 
     
     
         2 . The method according to  claim 1 , wherein the FPR2 agonist is a compound selected from:
 1-(4-bromophenyl)-3-[4-ethyl-2,5-dioxo-4-(2-phenylethyl)imidazolidin-1-yl]urea;   1-(4-bromophenyl)-3-[4-ethyl-2,5-dioxo-4-(propan-2-yl)imidazolidin-1-yl]urea;   1-(4-bromophenyl)-3-(4,4-diethyl-2,5-dioxoimidazolidin-1-yl)urea;   1-(4-bromo-2-fluorophenyl)-3-(4,4-diethyl-2,5-dioxoimidazolidin-1-yl)urea;   1-(4-bromophenyl)-3-(2,4-dioxo-1,3-diazaspiro[4.5]dec-3-yl)urea;   1-(4-bromophenyl)-3-[4-methyl-2,5-dioxo-4-(2-phenylethyl)imidazolidin-1-yl]urea;   1-(4-bromophenyl)-3-[4-methyl-2,5-dioxo-4-(2-phenylethyl)imidazolidin-1-yl]urea;   1-(4-bromo-2-fluorophenyl)-3-[4-ethyl-2,5-dioxo-4-(propan-2-yl)imidazolidin-1-yl]urea;   1-(4-bromophenyl)-3-[2,5-dioxo-4,4-di(propan-2-yl)imidazolidin-1-yl]urea;   1-(4-bromophenyl)-3-(4,4-dicyclopropyl-2,5-dioxoimidazolidin-1-yl)urea;   1-(4-bromophenyl)-3-[4-ethyl-2,5-dioxo-4-(propan-2-yl)imidazolidin-1-yl]urea;   1-(4-bromophenyl)-3-[4-ethyl-2,5-dioxo-4-(propan-2-yl)imidazolidin-1-yl]urea;   1-(4-bromo-2-fluorophenyl)-3-[4-ethyl-2,5-dioxo-4-(2-phenylethyl)imidazolidin-1-yl]urea;   1-(4-bromophenyl)-3-{4-[2-(furan-2-yl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea;   1-(4-bromophenyl)-3-{4-[2-(4-fluorophenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea;   1-(4-bromophenyl)-3-{4-[2-(3-fluorophenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea;   1-(4-bromophenyl)-3-{4-[2-(4-hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea;   1-(4-bromophenyl)-3-{4-methyl-2,5-dioxo-4-[2-(thiophen-2-yl)ethyl]imidazolidin-1-yl}urea;   1-(4-bromo-2-fluorophenyl)-3-{4-[2-(4-hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea;   1-(4-bromophenyl)-3-{4-methyl-4-[2-(5-methylfuran-2-yl)ethyl]-2,5-dioxoimidazolidin-1-yl}urea;   1-(4-bromo-2-fluorophenyl)-3-{4-[2-(3-fluoro-4-hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea;   1-(4-bromophenyl)-3-{4-[2-(3-fluoro-4-hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea;   1-(4-bromo-2-fluorophenyl)-3-{4-[2-(2-hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea;   1-(4-bromo-2-fluorophenyl)-3-{4-[2-(3-hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea;   1-(4-bromophenyl)-3-{4-[2-(3-hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea;   1-(4-bromophenyl)-3-{4-[2-(2-hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea;   1-(4-bromophenyl)-3-[4-(hydroxymethyl)-2,5-dioxo-4-(propan-2-yl)imidazolidin-1-yl]urea;   2-[1-{[(4-bromophenyl)carbamoyl]amino}-2,5-dioxo-4-(propan-2-yl)imidazolidin-4-yl]-N-(2-hydroxyethyl)acetamide;   methyl 2-[2-(1-{[(4-bromophenyl)carbamoyl]amino}-4-ethyl-2,5-dioxoimidazolidin-4-yl)ethyl]benzoate;   2-[1-{[(4-bromophenyl)carbamoyl]amino}-2,5-dioxo-4-(propan-2-yl)imidazolidin-4-yl]-N-(1,3-dihydroxypropan-2-yl)acetamide;   2-[2-(1-{[(4-bromophenyl)carbamoyl]amino}-4-ethyl-2,5-dioxoimidazolidin-4-yl)ethyl]benzoic acid;   2-[2-(1-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-ethyl-2,5-dioxoimidazolidin-4-yl)ethyl]benzoic acid;   3-({[1-{[(4-bromophenyl)carbamoyl]amino}-2,5-dioxo-4-(propan-2-yl)imidazolidin-4-yl]acetyl}amino)propanoic acid;   2-[1-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-2,5-dioxo-4-(propan-2-yl)imidazolidin-4-yl]-N-(2-hydroxyethyl)acetamide;   2-{2-[1-{[(4-bromophenyl)carbamoyl]amino}-2,5-dioxo-4-(propan-2-yl)imidazolidin-4-yl]ethyl}benzoic acid;   diethyl [2-({[1-{[(4-bromophenyl)carbamoyl]amino}-2,5-dioxo-4-(propan-2-yl)imidazolidin-4-yl]acetyl}amino)ethyl]phosphonate;   1-(4-bromophenyl)-3-{4-[2-(2-fluorophenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea; and   3-({[1-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-2,5-dioxo-4-(propan-2-yl)imidazolidin-4-yl]acetyl}amino)propanoic acid.   
     
     
         3 . The method according to  claim 1 , wherein the FPR2 agonist is a compound is selected from:
 1-(4-bromophenyl)-3-[4-ethyl-2,5-dioxo-4-(2-phenylethyl)imidazolidin-1-yl]urea;   1-(4-bromophenyl)-3-[4-ethyl-2,5-dioxo-4-(propan-2-yl)imidazolidin-1-yl]urea;   1-(4-bromophenyl)-3-(4,4-diethyl-2,5-dioxoimidazolidin-1-yl)urea;   1-(4-bromo-2-fluorophenyl)-3-(4,4-diethyl-2,5-dioxoimidazolidin-1-yl)urea;   1-(4-bromophenyl)-3-(2,4-dioxo-1,3-diazaspiro[4.5]dec-3-yl)urea;   1-(4-bromophenyl)-3-[4-methyl-2,5-dioxo-4-(2-phenylethyl)imidazolidin-1-yl]urea;   1-(4-bromo-2-fluorophenyl)-3-[4-ethyl-2,5-dioxo-4-(propan-2-yl)imidazolidin-1-yl]urea;   1-(4-bromophenyl)-3-[2,5-dioxo-4,4-di(propan-2-yl)imidazolidin-1-yl]urea; and   1-(4-bromophenyl)-3-(4,4-dicyclopropyl-2,5-dioxoimidazolidin-1-yl)urea.   
     
     
         4 . The method of  claim 1 , wherein the FPR2 agonist is 1-(4-bromophenyl)-3-[4-ethyl-2,5-dioxo-4-(2-phenylethyl)imidazolidin-1-yl]urea. 
     
     
         5 . The method of  claim 1 , wherein the FPR2 agonist is 1-(4-bromophenyl)-3-[4-ethyl-2,5-dioxo-4-(propan-2-yl)imidazolidin-1-yl]urea. 
     
     
         6 . The method of  claim 1 , wherein the FPR2 agonist is 1-(4-bromophenyl)-3-(4,4-diethyl-2,5-dioxoimidazolidin-1-yl)urea. 
     
     
         7 . The method of  claim 1 , wherein the FPR2 agonist is 1-(4-bromo-2-fluorophenyl)-3-(4,4-diethyl-2,5-dioxoimidazolidin-1-yl)urea. 
     
     
         8 . The method of  claim 1 , wherein the FPR2 agonist is 1-(4-bromophenyl)-3-(2,4-dioxo-1,3-diazaspiro[4.5]dec-3-yl)urea. 
     
     
         9 . The method of  claim 1 , wherein the FPR2 agonist is 1-(4-bromophenyl)-3-[4-methyl-2,5-dioxo-4-(2-phenylethyl)imidazolidin-1-yl]urea. 
     
     
         10 . The method of  claim 1 , wherein the FPR2 agonist is 1-(4-bromo-2-fluorophenyl)-3-[4-ethyl-2,5-dioxo-4-(propan-2-yl)imidazolidin-1-yl]urea. 
     
     
         11 . The method of  claim 1 , wherein the FPR2 agonist is 1-(4-bromophenyl)-3-[2,5-dioxo-4,4-di(propan-2-yl)imidazolidin-1-yl]urea. 
     
     
         12 . The method of  claim 1 , wherein the FPR2 agonist is 1-(4-bromophenyl)-3-(4,4-dicyclopropyl-2,5-dioxoimidazolidin-1-yl)urea. 
     
     
         13 . The method according to  claim 1 , wherein the FPR2 agonist is a compound selected from:
 1-(4-chlorophenyl)-3-(2,4-dioxo-1,3-diazaspiro[4,5]decan-3-yl) urea;   1-(4-chlorophenyl)-3-(4-ethyl-4-methyl-2,5-dioxoimidazolidin-1-yl)urea; and   1-(8-methyl-2,4-dioxo-1,3-diazaspiro[4,5]decan-3-yl)-3-(p-tolyl)urea.   
     
     
         14 . The method according to  claim 1 , wherein the FPR2 agonist is a compound selected from:
 (+) 1-(4-bromophenyl)-3-[4-methyl-2,5-dioxo-4-(2-phenylethyl)imidazolidin-1-yl]urea;   (+) 1-(4-bromophenyl)-3-[4-ethyl-2,5-dioxo-4-(propan-2-yl)imidazolidin-1-yl]urea;   (−) 1-(4-bromophenyl)-3-[4-ethyl-2,5-dioxo-4-(propan-2-yl)imidazolidin-1-yl]urea; and   ethyl 3-[1-{[(4-bromophenyl)carbamoyl]amino}-2,5-dioxo-4-(propan-2-yl)imidazolidin-4-yl]propanoate.   
     
     
         15 . A method of treating dermal inflammation or a dermal disease in a subject in need of such treatment, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound is selected from the group consisting of:
 ethyl 3-{[(4-bromophenyl)carbamoyl]amino}-2,4-dioxo-1,3-diazaspiro[4.5]decane-8-carboxylate;   1-[4-methyl-2,5-dioxo-4-(2-phenylethyl)imidazolidin-1-yl]-3-phenylurea; and   1-(2-fluorophenyl)-3-[4-methyl-2,5-dioxo-4-(2-phenylethyl)imidazolidin-1-yl]urea;   
       and wherein the dermal inflammation or dermal disease is selected from the group consisting of dermal wound healing, hypertrophic scars, keloids, burns, rosacea, atopic dermatitis, acne, psoriasis, seborrheic dermatitis, actinic keratoses, basal cell carcinoma, squamous cell carcinoma, melanoma, viral warts, photoaging, photodamage, melasma, post-inflammatory hyperpigmentation, disorders of pigmentation and alopecia, scarring and non-scarring forms; 
       and wherein the administration is by local delivery. 
     
     
         16 . The method of  claim 1 , wherein the local delivery is topical dermal delivery. 
     
     
         17 . The method of  claim 15 , wherein the local delivery is topical dermal delivery. 
     
     
         18 . The method of  claim 16 , wherein the pharmaceutical composition is in a form selected from the group consisting of a cream, a lotion, a gel, a solution, a spray, a foam, a suspension and an emulsion. 
     
     
         19 . The method of  claim 17 , wherein the pharmaceutical composition is in a form selected from the group consisting of a cream, a lotion, a gel, a solution, a spray, a foam, a suspension and an emulsion.