Compositions and Methods for Treating Conditions That Affect Epidermis

Abstract

The present invention relates to the compositions and methods for treating or alleviating conditions that affect the epidermis (e.g., wrinkles, sun damaged skin, symptoms of aged skin, or the like).

1 .- 40 . (canceled) 
     
     
         41 . A method for treating or alleviating a patient experiencing skin conditions, or for improving the mitochondrial activities, enhancing collagen expressions in the skin, increasing endurance and strength in an individual, or for treating or preventing age related macular degeneration in an individual wherein the compound of Formula I is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof wherein 
         Z is —C(═O)NR 5 —, —OC(═O)NR 5 —, —NR 7 C(═O)O—, or —NR 5 C(═O)NR 5 —, wherein each R 5  is independently hydrogen, alkyl, aryl, or heterocyclic; 
         Y is a phosphonium group; 
         Each R 1  is independently hydrogen, or a phosphate group; 
         R 2  is absent, alkyl, cycloalkyl, heterocycloalkyl, alkylaryl, alkylarylalkyl, or aryl; 
         R 3  is alkyl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, alkylaryl, or alkylarylalkyl; 
         R 4  is hydrogen, alkyl, or aryl; or 
         R 4  and a R 1  groups together with the nitrogen atoms to which they are attached form a heterocyclic ring containing at least five atoms; or 
         R 4  and R 3  groups together with the nitrogen atom to which they are attached forming a heterocyclic ring containing at least five atoms; 
         at each occurrence, an alkyl is optionally substituted with 1-3 substituents independently selected from halo, haloalkyl, hydroxyl, amino, thio, ether, ester, carboxy, oxo, aldehyde, cycloalkyl, nitrile, urea, amide, carbamate and aryl; or at each occurrence, an aryl is optionally substituted with 1-5 substituents independently selected from halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, and CN; and W is hydrogen or alkyl. 
       
     
     
         42 . The method of  claim 41 , wherein
 Z is —C(═O)NR 5 —, —OC(═O)NR 5 —, —NR 5 C(═O)O—, or —NR 5 C(═O)NR 5 —; wherein each R 5  is independently hydrogen, or C 1-6 alkyl;   Y is a phosphonium group;   each R 1  is independently hydrogen, or alkyl;   R 2  is alkyl, cycloalkyl, heterocycloalkyl, or alkylaryl;   R 3  is alkyl, cycloalkyl, alkylcycloalkyl;   R 4  is hydrogen, or C 1-6  alkyl; and W is hydrogen.   
     
     
         43 . The method of  claim 42 , wherein Z is —C(═O)NR 5 —, and R 5  is hydrogen, or C 1-6  alkyl. 
     
     
         44 . The method of  claim 42 , wherein Z is —C(═O)NH—. 
     
     
         45 . The method of  claim 42 , wherein the phosphonium group is selected from —P + (R′) 3 X − , wherein R′ is alkyl or aryl; and X −  is a pharmaceutically acceptable anion. 
     
     
         46 . The use of  claim 45 , wherein R′ is phenyl; and X −  is chloride, or trifluoroacetate. 
     
     
         47 . The method of  claim 42 , wherein
 Z is —C(═O)NR 5 —, wherein R 5  is hydrogen, or methyl;   Y is —P + (R′) 3 X − , wherein R′ is alkyl or aryl; X −  is chloride, or trifluoroacetate;   each R 1  is hydrogen;   R 2  is C 1-8  alkyl;   R 3  is alkyl,   R 4  is hydrogen or C 1-4  alkyl; and W is hydrogen, or a pharmaceutically acceptable salt thereof.   
     
     
         48 . The method of  claim 42 , wherein Z is —C(═O)NH, each R 1  is hydrogen, R 2  is C 1-8  alkyl; R 3  is C 1-8 alkyl; and R 4  is methyl. 
     
     
         49 . The method of  claim 42 , wherein the compound of Formula I is selected from:
 N 2 -[amino(imino)methyl]-N 2 -methyl-N-[3-(triphenylphosphonio)propyl]glycinamide chloride;   N 2- [ammonio(imino)methyl]-N,N 2 -dimethyl-N-[3-(triphenylphosphonio)propyl]glycinamide bis(trifluoroacetate);   N 2 -[ammonio(imino)methyl]-N 2 -methyl-N-[3-(triphenylphosphonio)propyl]glycinamide bis(trifluoroacetate);   N 2 -[ammonio(imino)methyl]-N 2 -methyl-N-[3-(triphenylphosphonio)propyl]glycinamide dichloride;   N 3 -[amino(imino)methyl]-N 3 -methyl-N-[4-(triphenylphosphonio)butyl]-β-alaninamide trifluoroacetate-trifluoroacetic acid;   {4-[(4-{[amino(imino) methyl](methyl)amino}butanoyl)amino] butyl}(triphenyl)phosphonium trifluoroacetate-trifluoroacetic acid;   {4-[(4-{[amino (imino)methyl](methyl)amino}-2,2-dimethylbutanoyl)amino]butyl} (triphenyl)phosphonium trifluoroacetate-trifluoroacetic acid;   [3-({[1-({[amino(imino)methyl](methyl)amino}methyl)cyclopropyl]carbonyl}amino)propyl] (triphenyl)phosphonium trifluoroacetate-trifluoroacetic acid; or   [3-({[4-({[amino(imino)methyl](methyl)amino}methyl)tetrahydro-2H-pyran-4-yl]carbonyl}amino)propyl](triphenyl)phosphonium trifluoroacetate-trifluoroacetic acid.   
     
     
         50 . The method of  claim 41 , wherein the compound of Formula I is: N 2 -[amino(imino)methyl]-N 2 -methyl-N-[3-(triphenylphosphonio)propyl]glycinamide chloride. 
     
     
         51 . The method of  claim 41 , wherein the skin condition is sun damaged skin, skin rash, acne, symptoms of aged skin, unwanted side effects of medical treatments of human skin, or risk of contracting melanoma. 
     
     
         52 . The method of  claim 51 , wherein the symptom of aging is greater susceptibility to solar radiation or caused by greater susceptibility to solar radiation, or caused by increased cellular senescence, loss of elasticity or caused by the loss of elasticity, decreased tensile strength or caused by the loss of tensile strength, fragile or thin skin or caused by fragile or thin skin, delayed or impaired collagen remodeling or caused by delayed or impaired collagen remodeling, reduced epidermal hydration or caused by reduced epidermal hydration;
 wherein the unwanted side effects are caused by a cancer therapy on human skin or caused by administering a corticosteroid or a non-steroidal drug that binds to the glucocorticosteroidal receptor on human skin systemically or topically, or the unwanted side effect is a rash, acne form blistering, skin atrophy, thin skin, fragile skin, telangiectasia, or striae.   
     
     
         53 . The method of  claim 52 , wherein the cancer therapy comprises the use of an Epidermal growth factor receptor (EGFR) inhibitor or a chemotherapeutic agent. 
     
     
         54 . The method of  claim 53 , wherein the Epidermal growth factor receptor (EGFR) inhibitor is cetuximab. 
     
     
         55 . The method of  claim 53 , wherein the chemotherapeutic agent is Gemcitabine or Temozolomide. 
     
     
         56 . The method of  claim 41 , wherein the mitochondrial activity is increased in the dermis or the epidermis, or both. 
     
     
         57 . The method of  claim 41 , wherein the enhancement of collagen expression is to reduce wrinkles, or to strengthen fragile skin, or to increase thickness of thin skin. 
     
     
         58 . The method of  claim 57 , wherein the enhancement of collagen expression is in elderly population. 
     
     
         59 . The method of  claim 51 , wherein alleviating unwanted side effects of medical treatments of human skin comprises co-administering a corticosteroid or a non-steroidal drug to a patient in need thereof with a compound of Formula (I) or a pharmaceutically acceptable salt thereof. 
     
     
         60 . The method of  claim 59 , wherein the corticosteroid comprises Dexamethasone, Betamethasone or Clobetasol.