Creatine, its derivatives, compositions and methods of use thereof

Abstract

The application describes creatine or its derivatives, compositions comprising the same, and uses thereof for topical or systemic administration to treat pain, itch, or eczema, or inflammation associated with a cosmetic or medical condition, disorder or disease in a human subject, wherein the inflammation causes the pain, itch, or eczema. In addition, the application describes clinical use of these compounds and compositions which can reduce or eliminate erythema, edema and tissue distortions associated with inflammation.

1 . A method for treating pain in a human subject in need thereof, the method comprising administering to the human subject a composition comprising a creatine derivative of Formula (2):
   H 2 NC(═NR 1 )N(CH 3 )CH 2 COR 2    Formula (2)
   
       or a pharmaceutically acceptable salt thereof or a solvate thereof, and optionally a pharmaceutically or cosmetically acceptable carrier,
 wherein, R 1  is H or an acyl radical having up to 29 carbon atoms; R 2  is H, OR 3 , NHR 4 , or any other amino group containing radical having up to 10 carbon atoms; R 3  is H, an alkyl, aralkyl or aryl radical, wherein the alkyl, aralkyl or aryl radical has up to 19 carbon atoms; and R 4  is H, OH, an alkyl, aralkyl, aryl or acyl radical, wherein the alkyl, arakyl, aryl or acyl radical has up to 19 carbon atoms, with a proviso that R 2  is not OH when R 1  is H. 
 
     
     
         2 . The method of  claim 1 , wherein R 1  is H or an acyl radical having up to 19 carbon atoms, and the acyl radical is selected from the group consisting of acetyl, butanoyl, benzyloxycarbonyl, benzoyl, formyl, hexadecanoyl, hexanoyl, heptanoyl, linoleic, linolenic, nonanoyl, octanoyl, propanoyl, phenylacetyl, pentanoyl, and pyroglutamyl. 
     
     
         3 . The method of  claim 1 , wherein R 2  is H, OH, OEt, OC 3 H 7 , NHOH, or NH 2 . 
     
     
         4 . The method of  claim 1 , wherein R 2  is NHNH 2 , NHNHAc, NHCONH 2 , NH(C═NH)NH 2 , NH(C═NH)NHNH 2 , NHNH(C═NH)NH 2 , NH(C═NH)NHNHAc, NHNH(C═NH)NHAc, or (H 3 C) 2 N(C═N)N(CH 3 ). 
     
     
         5 . The method of  claim 1 , wherein the creatine derivative is selected from the group consisting of:
 H 2 NC(═NH)N(CH 3 )CH 2 CONH 2 ,   H 2 NC(═NH)N(CH 3 )CH 2 COOC 2 H 5 ,   H 2  NC(═NAc)N(CH 3 )CH 2 COOH,   H 2  NC(═NAc)N(CH 3 )CH 2 CONH 2 ,   H 2 NC(═NAc)N(CH 3 )CH 2 COOC 2 H 5 ,   H 2 NC(═NH)N(CH 3 )CH 2 CHO,   H 2 NC(═NAc)N(CH 3 )CH 2 CHO,   H 2  NC(═NBz)N(CH 3 )CH 2 COOH,   H 2  NC(═NBz)N(CH 3 )CH 2 CONH 2 ,   H 2 NC(═NBz)N(CH 3 )CH 2 COOC 2 H 5 ,   H 2 NC(═NBz)N(CH 3 )CH 2 CHO,   H 2 NC(═NH)N(CH 3 )CH 2 CONH(C═NH)NH 2 ,   H 2 NC(═NAc)N(CH 3 )CH 2 CONH(C═NH)NH 2 ,   H 2 NC(═NH)N(CH 3 )CH 2 CONHNH(C═NH)NH 2      H 2 NC(═NAc)N(CH 3 )CH 2 CONHNH(C═NH)NH 2 ,   H 2 NC(═NAb)N(CH 3 )CH 2 COOC 2 H 5 ,   H 2 NC(═NAb)N(CH 3 )CH 2 COOH,   H 2 NC(═NAb)N(CH 3 )CH 2 CONH 2 ,   H 2 NC(═NAc)N(CH 3 )CH 2 COOC 3 H 7 ,   H 2 NC(═NAb)N(CH 3 )CH 2 COOC 3 H 7 , and   H 2 NC(═NPc)N(CH 3 )CH 2 COOH.   
     
     
         6 .- 8 . (canceled) 
     
     
         9 . The method of  claim 1 , wherein the composition comprises at least 1% by weight or volume, based on a total weight or volume of the composition, of the creatine derivative of Formula (2) or a pharmaceutically acceptable salt thereof or a solvate thereof. 
     
     
         10 . (canceled) 
     
     
         11 . The method of  claim 1 , wherein the composition is topically administered or systemically administered. 
     
     
         12 .- 14 . (canceled) 
     
     
         15 . The method of  claim 1 , wherein the method further comprises administering another pharmacological agent to provide synergetic or synergestic effect. 
     
     
         16 . (canceled) 
     
     
         17 . The method of  claim 1 , wherein the pain is associated with a medical condition, disorder or disease, and the medical condition, disorder or disease is selected from the group consisting of arthritis, headache, dental pain, eczema, lipoma, muscle pain, pharyngitis, sprain, trauma, sunburn, mosquito bite, and thermal burns. 
     
     
         18 .- 19 . (canceled) 
     
     
         20 . A method for treating itch in a human subject in need thereof, the method comprising administering to the human subject a composition comprising a creatine derivative of Formula (2):
   H 2 NC(═NR 1 )N(CH 3 )CH 2 COR 2    Formula (2)
   
       or a pharmaceutically acceptable salt thereof or a solvate thereof, and optionally a pharmaceutically or cosmetically acceptable carrier,
 wherein, R 1  is H or an acyl radical having up to 29 carbon atoms; R 2  is H, OR 3 , NHR 4 , or any other amino group containing radical having up to 10 carbon atoms; R 3  is H, an alkyl, aralkyl or aryl radical, wherein the alkyl, aralkyl or aryl radical has up to 19 carbon atoms; and R 4  is H, OH, an alkyl, aralkyl, aryl or acyl radical, wherein the alkyl, arakyl, aryl or acyl radical has up to 19 carbon atoms, with a proviso that R 2  is not OH when R 1  is H. 
 
     
     
         21 . The method of  claim 20 , wherein R 1  is H or an acyl radical having up to 19 carbon atoms, and the acyl radical is selected from the group consisting of acetyl, butanoyl, benzyloxycarbonyl, benzoyl, formyl, hexadecanoyl, hexanoyl, heptanoyl, linoleic, linolenic, nonanoyl, octanoyl, propanoyl, phenylacetyl, pentanoyl, and pyroglutamyl. 
     
     
         22 . The method of  claim 20 , wherein R 2  is H, OH, OEt, OC 3 H 7 , NHOH, or NH 2 . 
     
     
         23 . The method of  claim 20 , wherein R 2  is NHNH 2 , NHNHAc, NHCONH 2 , NH(C═NH)NH 2 , NH(C═NH)NHNH 2 , NHNH(C═NH)NH 2 , NH(C═NH)NHNHAc, NHNH(C═NH)NHAc, or (H 3 C) 2 N(C═N)N(CH 3 ). 
     
     
         24 . The method of  claim 20 , wherein the creatine derivative is selected from the group consisting of:
 H 2 NC(═NH)N(CH 3 )CH 2 CONH 2 ,   H 2 NC(═NH)N(CH 3 )CH 2 COOC 2 H 5 ,   H 2  NC(═NAc)N(CH 3 )CH 2 COOH,   H 2  NC(═NAc)N(CH 3 )CH 2 CONH 2 ,   H 2 NC(═NAc)N(CH 3 )CH 2 COOC 2 H 5 ,   H 2 NC(═NH)N(CH 3 )CH 2 CHO,   H 2 NC(═NAc)N(CH 3 )CH 2 CHO,   H 2  NC(═NBz)N(CH 3 )CH 2 COOH,   H 2  NC(═NBz)N(CH 3 )CH 2 CONH 2 ,   H 2 NC(═NBz)N(CH 3 )CH 2 COOC 2 H 5 ,   H 2 NC(═NBz)N(CH 3 )CH 2 CHO,   H 2 NC(═NH)N(CH 3 )CH 2 CONH(C═NH)NH 2 ,   H 2 NC(═NAc)N(CH 3 )CH 2 CONH(C═NH)NH 2 ,   H 2 NC(═NH)N(CH 3 )CH 2 CONHNH(C═NH)NH 2      H 2 NC(═NAc)N(CH 3 )CH 2 CONHNH(C═NH)NH 2 ,   H 2 NC(═NAb)N(CH 3 )CH 2 COOC 2 H 5 ,   H 2 NC(═NAb)N(CH 3 )CH 2 COOH,   H 2 NC(═NAb)N(CH 3 )CH 2 CONH 2 ,   H 2 NC(═NAc)N(CH 3 )CH 2 COOC 3 H 7 ,   H 2 NC(═NAb)N(CH 3 )CH 2 COOC 3 H 7 , and   H 2 NC(═NPc)N(CH 3 )CH 2 COOH.   
     
     
         25 . The method of  claim 20 , wherein the composition comprises at least 1% by weight or volume, based on a total weight or volume of the composition, of the creatine derivative of Formula (2) or a pharmaceutically acceptable salt thereof or a solvate thereof. 
     
     
         26 . The method of  claim 20 , wherein the composition is topically administered or systemically administered. 
     
     
         27 . The method of  claim 20 , wherein the method further comprises administering another pharmacological agent to provide synergetic or synergestic effect. 
     
     
         28 . The method of  claim 20 , wherein the itch is associated with a medical condition, disorder or disease, and the medical condition, disorder or disease is selected from the group consisting of eczema, sunburn, mosquito bite, and dermatitis. 
     
     
         29 . A composition for topical administration to treat treating pain or itch or eczema in a human subject in need thereof, the composition comprising a creatine derivative of Formula (2):
   H 2 NC(═NR 1 )N(CH 3 )CH 2 COR 2    Formula (2)
   
       , and optionally a pharmaceutically or cosmetically acceptable carrier, wherein, R 1  is an acyl radical having up to 29 carbon atoms; R 2  is H or OR 3 ; R 3  is H, an alkyl, aralkyl or aryl radical, wherein the alkyl, aralkyl or aryl radical has up to 19 carbon atoms. 
     
     
         30 . The composition of  claim 29 , wherein the creatine derivative is selected from the group consisting of:
 H 2 NC(═NAc)N(CH 3 )CH 2 COOC 2 H 5 ,   H 2  NC(═NAc)N(CH 3 )CH 2 COOCH 3 ,   H 2  NC(═NAc)N(CH 3 )CH 2 COOCH(CH 3 ) 2 ,   H 2 NC(═NAc)N(CH)CH 2 COOC 3 H 7 ,   H 2 NC(═NAc)N(CH 3 )CH 2 CHO,   H 2 NC(═NBz)N(CH 3 )CH 2 COOC 2 H 5 ,   H 2 NC(═NBz)N(CH)CH 2 COOCH 3 ,   H 2  NC(═NBz)N(CH 3 )CH 2 COOCH(CH 3 ) 2 ,   H 2 NC (═NBz)N(CH 3 )CH 2 COOC 3H 7 ,   H 2 NC(═NBz)N(CH 3 )CH 2 CHO,   H 2 NC(═NAb)N(CH 3 )CH 2 COOC 2 H 5 ,   H 2 NC(═NAb)N(CH 3 )CH 2 COOCH 3 ,   H 2 NC(═NAb)N(CH 3 )CH 2 COOCH(CH 3 ) 2 ,   H 2 NC(═NAb)N(CH)CH 2 CHO,   H 2 NC(═NAb)N(CH 3 )CH 2 COOC 3 H 7 ,   H 2 NC(═NPc)N(CH 3 )CH 2 CHO,   H 2 NC(═NPc)N(CH)CH 2 COOCH 3      H 2 NC(═NPc)N(CH 3 )CH 2 COOC 2 H 5 ,
 H 2 NC(═NPc)N(CH 3 )CH 2 COOC 3 H 7 , 
 H 2  NC(═NPc)N(CH 3 )CH 2 COOCH(CH 3 ) 2    
   H 2 NC(═NFm)N(CH 3 )CH 2 COOC 2 H 5 ,   H 2  NC(═NFm)N(CH 3 )CH 2 COOCH 3      H 2  NC(═NFm)N(CH)CH 2 COOCH(CH 3 ) 2      H 2 NC(═NFm)N(CH 3 )CH 2 COOC 3 H 7 , and   H 2 NC(═NFm)N(CH 3 )CH 2 CHO.   
     
     
         31 . A composition for cutaneous injection to treat pain or itch or eczema in a human subject in need thereof, the composition comprising a creatine derivative of Formula (2):
   H 2 NC(═NR 1 )N(CH 3 )CH 2 COR 2    Formula (2)
   
       optionally a pharmaceutically or cosmetically acceptable carrier, wherein, R 1  is an acyl radical having up to 29 carbon atoms; R 2  is H, OR 3;  R 3  is H, an alkyl, aralkyl or aryl radical, wherein the alkyl, aralkyl or aryl radical has up to 19 carbon atoms; 
     
     
         32 . The composition of  claim 31 , wherein the creatine derivative is selected from the group consisting of:
 H 2 NC(═NAc)N(CH 3 )CH 2 COOC 2 H 5 ,   H 2  NC(═NAc)N(CH 3 )CH 2 COOCH 3      H 2  NC(═NAc)N(CH 3 )CH 2 COOCH(CH 3 ) 2      H 2 NC(═NAc)N(CH 3 )CH 2 COOC 3 H 7      H 2 NC(═NAc)N(CH 3 )CH 2 CHO
 H 2 NC(═NBz)N(CH 3 )CH 2 COOC 2 H 5 , 
 H 2 NC(═NBz)N(CH 3 )CH 2 COOCH 3    
 H 2 NC(═NBz)N(CH 3 )CH 2 COOCH(CH 3 ) 2    
 H 2 NC(═NBz)N(CH 3 )CH 2 COOC 3 H 7    
 H 2 NC(═NBz)N(CH 3 )CH 2 CHO
 H 2  NC(═NAb)N(CH 3 )CH 2 COOCH 3    
 H 2  NC(═NAb)N(CH 3 )CH 2 COOCH(CH 3 ) 2    
 H 2 NC(═NAb)N(CH 3 )CH 2 COOC 3 H 7    
 H 2 NC(═NAb)N(CH 3 )CH 2 CHO 
 
 H 2 NC(═NAb)N(CH 3 )CH 2 COOC 2  H 5    
   H 2 NC(═NPc)N(CH 3 )CH 2 CHO,   H 2 NC(═NPc)N(CH 3 )CH 2 COOCH 3      H 2 NC(═NPc)N(CH 3 )CH 2 COOC 2 H 5 ,
 H 2 NC(═NPc)N(CH 3 )CH 2 COOC 3 H 7 , 
 H 2 NC(═NPc)N(CH 3 )CH 2 COOCH(CH 3 ) 2    
   H 2 NC(═NFm)N(CH 3 )CH 2 COOC 2 H 5 ,   H 2 NC(═NFm)N(CH 3 )CH 2 COOCH 3      H 2 NC(═NFm)N(CH 3 )CH 2 COOCH(CH 3 ) 2      H 2 NC(═NFm)N(CH 3 )CH 2 COOC 3 H 7      H 2 NC(═NFm)N(CH 3 )CH 2 CHO