Use of creatine or creatine compounds for skin preservation

Abstract

The present invention relates to the use of creatine compounds such as, for example, creatine, creatine phosphate or analogs of creatine, such as creatine-pyruvate, creatine-ascorbate, cyclocreatine, 3 guanidinopropionic acid, guanidinoacetate, homocyclocreatine, guanidino benzoates as energy generating systems and antioxidants for preservation of skin against adverse aging effects and damage secondary to insults such as harmful sun radiations, stress and fatigue. The creatine compounds which can be used in the present method include (1) creatine, creatine phosphate and analogs of these compounds which can act as substrates or substrate analogs for creatine kinase; (2) molecules that mimic the biological activity of creatine (3) molecules that modulate the creatine kinase system.

1 . A method for treating a subject for a skin disorder comprising administering to said subject an effective amount of creatine, creatine, creatine phosphate, a creatine compound or a salt thereof, such that said skin disorder is treated. 
     
     
         2 - 5 . (canceled) 
     
     
         6 . The method of  claim 1 , wherein said skin disorder is associated with free radicals, aging, sun radiation, stress or fatigue. 
     
     
         7 - 9 . (canceled) 
     
     
         10 . The method of  claim 1 , wherein said subject is afflicted with skin wrinkles or is at risk for a skin disorder. 
     
     
         11 . (canceled) 
     
     
         12 . The method of  claim 1 , wherein the creatine compound is of the general formula: 
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof, wherein:
 a) Y is selected from the group consisting of: —CO 2 H, —NHOH, —NO 2 , —SO 3 H, —C(═O)NHSO 2 J and —P(═O)(OH)(OJ), wherein J is selected from the group consisting of: hydrogen, C 1 -C 6  straight chain alkyl, C 3 -C 6  branched alkyl, C 2 -C 6  alkenyl, C 3 -C 6  branched alkenyl, and aryl; 
 b) A is selected from the group consisting of: C, CH, C 1 -C 5  alkyl, C 2 -C 5  alkenyl, C 2 -C 5  alkynyl, and C 1 -C 5  alkoyl chain, each having 0-2 substituents which are selected independently from the group consisting of:
 1) K, where K is selected from the group consisting of: C 1 -C 6  straight alkyl, C 2 -C 6  straight alkenyl, C 1 -C 6  straight alkoyl, C 3 -C 6  branched alkyl, C 3 -C 6  branched alkenyl, and C 3 -C 6  branched alkoyl, K having 0-2 substituents independently selected from the group consisting of: bromo, chloro, epoxy and acetoxy; 
 2) an aryl group selected from the group consisting of: a 1-2 ring carbocycle and a 1-2 ring heterocycle, wherein the aryl group contains 0-2 substituents independently selected from the group consisting of: —CH 2 L and —COCH 2 L where L is independently selected from the group consisting of: bromo, chloro, epoxy and acetoxy; and 
 3) —NH-M, wherein M is selected from the group consisting of: hydrogen, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 1 -C 4  alkoyl, C 3 -C 4  branched alkyl, C 3 -C 4  branched alkenyl, and C 4  branched alkoyl; 
 
 c) X is selected from the group consisting of NR 1 , CHR 1 , CR 1 , O and S, wherein R 1  is selected from the group consisting of:
 1) hydrogen; 
 2) K where K is selected from the group consisting of: C 1 -C 6  straight alkyl, C 2 -C 6  straight alkenyl, C 1 -C 6  straight alkoyl, C 3 -C 6  branched alkyl, C 3 -C 6  branched alkenyl, and C 4 -C 6  branched alkoyl, K having 0-2 substituents independently selected from the group consisting of: bromo, chloro, epoxy and acetoxy; 
 3) an aryl group selected from the group consisting of a 1-2 ring carbocycle and a 1-2 ring heterocycle, wherein the aryl group contains 0-2 substituents independently selected from the group consisting of: —CH 2 L and —COCH 2 L where L is independently selected from the group consisting of: bromo, chloro, epoxy and acetoxy; 
 4) a C 5 -C 9  a-amino-w-methyl-w-adenosylcarboxylic acid attached via the w-methyl carbon; 
 5) a C 5 -C 9  a-amino-w-aza-w-methyl-w-adenosylcarboxylic acid attached via the w-methyl carbon; and 
 6) a C 5 -C 9  a-amino-w-thia-w-methyl-w-adenosylcarboxylic acid attached via the w-methyl carbon; 
 
 d) Z 1  and Z 2  are chosen independently from the group consisting of: ═O, —NHR 2 , —CH 2 R 2 , —NR 2 OH; wherein Z 1  and Z 2  may not both be ═O and wherein R 2  is selected from the group consisting of:
 1) hydrogen; 
 2) K, where K is selected from the group consisting of: C 1 -C 6  straight alkyl; C 2 -C 6  straight alkenyl, C 1 -C 6  straight alkoyl, C 3 -C 6  branched alkyl, C 3 -C 6  branched alkenyl, and C 4 -C 6  branched alkoyl, K having 0-2 substituents independently selected from the group consisting of: bromo, chloro, epoxy and acetoxy; 
 3) an aryl group selected from the group consisting of a 1-2 ring carbocycle and a 1-2 ring heterocycle, wherein the aryl group contains 0-2 substituents independently selected from the group consisting of: —CH 2 L and —COCH 2 L where L is independently selected from the group consisting of: bromo, chloro, epoxy and acetoxy; 
 4) a C 4 -C 8  a-amino-carboxylic acid attached via the w-carbon; 
 5) B, wherein B is selected from the group consisting of: —CO 2 H, —NHOH, —SO 3 H, —NO 2 , OP(═O)(OH)(OJ) and —P(═O)(OH)(OJ), wherein J is selected from the group consisting of: hydrogen, C 1 -C 6  straight alkyl, C 3 -C 6  branched alkyl, C 2 -C 6  alkenyl, C 2 -C 6  branched alkenyl, and aryl, wherein B is optionally connected to the nitrogen via a linker selected from the group consisting of: C 1 -C 2  alkyl, C 2  alkenyl, and C 1 -C 2  alkoyl; 
 6) -D-E, wherein D is selected from the group consisting of: C 1 -C 3  straight alkyl, C 3  branched alkyl, C 2 -C 3  straight alkenyl, C 3  branched alkenyl, C 1 -C 3  straight alkoyl, aryl and aroyl; and E is selected from the group consisting of: —(PO 3 ) n NMP, where n is 0-2 and NMP is ribonucleotide monophosphate connected via the 5′-phosphate, 3′-phosphate or the aromatic ring of the base; —[P(═O)(OCH 3 )(O)] m -Q, where m is 0-3 and Q is a ribonucleoside connected via the ribose or the aromatic ring of the base; —[P(═O)(OH)(CH 2 )] m -Q, where m is 0-3 and Q is a ribonucleoside connected via the ribose or the aromatic ring of the base; and an aryl group containing 0-3 substituents chosen independently from the group consisting of: Cl, Br, epoxy, acetoxy, —OG, —C(═O)G, and —CO 2 G, where G is independently selected from the group consisting of: C 1 -C 6  straight alkyl, C 2 -C 6  straight alkenyl, C 1 -C 6  straight alkoyl, C 3 -C 6  branched alkyl, C 3 -C 6  branched alkenyl, C 4 -C 6  branched alkoyl, wherein E may be attached to any point to D, and if D is alkyl or alkenyl, D may be connected at either or both ends by an amide linkage; and 
 7) -E, wherein E is selected from the group consisting of —(PO 3 ) n NMP, where n is 0-2 and NMP is a ribonucleotide monophosphate connected via the 5′-phosphate, 3′-phosphate or the aromatic ring of the base; —[P(═O)(OCH 3 )(O)] m -Q, where m is 0-3 and Q is a ribonucleoside connected via the ribose or the aromatic ring of the base; —[P(═O)(OH)(CH 2 )] m -Q, where m is 0-3 and Q is a ribonucleoside connected via the ribose or the aromatic ring of the base; and an aryl group containing 0-3 substituents chose independently from the group consisting of: Cl, Br, epoxy, acetoxy, —OG, —C(═O)G, and —CO 2 G, where G is independently selected from the group consisting of: C 1 -C 6  straight alkyl, C 2 -C 6  straight alkenyl, C 1 -C 6  straight alkoyl, C 3 -C 6  branched alkyl, C 3 -C 6  branched alkenyl, C 4 -C 6  branched alkoyl; and if E is aryl, E may be connected by an amide linkage; 
 
 e) if R 1  and at least one R 2  group are present, R 1  may be connected by a single or double bond to an R 2  group to form a cycle of 5 to 7 members; 
 f) if two R 2  groups are present, they may be connected by a single or a double bond to form a cycle of 4 to 7 members; and 
 g) if R 1  is present and Z 1  or Z 2  is selected from the group consisting of —NHR 2 , —CH 2 R 2  and —NR 2 OH, then R 1  may be connected by a single or double bond to the carbon or nitrogen of either Z 1  or Z 2  to form a cycle of 4 to 7 members. 
 
     
     
         13 . The method of  claim 1 , wherein said treatment of said skin disorder reduces or eliminates at least one preexisting symptom of skin disorder or prevents said skin disorder. 
     
     
         14 - 17 . (canceled) 
     
     
         18 . The method of  claim 1 , wherein said creatine compound is cyclocreatine, cyclocreatine phosphate, creatine-pyruvate, creatine-ascorbate, homocyclocreatine, 3-guanidinopropionic acid, guanidinoacetate or a guanidino benzoic acid. 
     
     
         19 - 25 . (canceled) 
     
     
         26 . The method of  claim 1 , further comprising co-administering to said subject an effective amount of a skin preserving agent. 
     
     
         27 - 32 . (canceled) 
     
     
         33 . The method of  claim 1 , further comprising the coadministration of a pharmaceutical carrier suitable for topical administration. 
     
     
         34 . (canceled) 
     
     
         35 . The method of  claim 1 , further comprising the coadministration of a sunscreen or sunblock. 
     
     
         36 . (canceled) 
     
     
         37 . A composition for the treatment of the skin of a subject, comprising an effective amount of creatine, creatine phosphate, a creatine compound or a salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         38 . The composition of  claim 37 , wherein said composition is suitable for topical administration. 
     
     
         39 . (canceled) 
     
     
         40 . The composition of  claim 37 , wherein said composition further comprises a sunblock or sunscreen. 
     
     
         41 . (canceled) 
     
     
         42 . The composition of  claim 37 , wherein said composition is formulated as a cosmetic foundation or a skin cleansing agent. 
     
     
         43 . The composition of  claim 37 , further comprising a penetration agent, hydroxyacids, retinols, aloe, chamomile or mixtures thereof. 
     
     
         44 . (canceled) 
     
     
         45 . (canceled) 
     
     
         46 . The composition of  claim 37 , wherein said effective amount is effective to treat or prevent a skin disorder. 
     
     
         47 - 51 . (canceled) 
     
     
         52 . The composition of  claim 37 , wherein said creatine compound is cyclocreatine, cyclocreatine phosphate, creatine-pyruvate, creatine-ascorbate, homocyclocreatine, 3-guanidinopropionic acid, guanidinoacetate or a guanidino benzoic acid. 
     
     
         53 - 59 . (canceled) 
     
     
         60 . The composition of  claim 37 , further comprising co-administering to said subject an effective amount of a skin preserving agent. 
     
     
         61 . The composition of  claim 60 , wherein said skin preserving agent is an antioxidant, an energy-enhancing agent, a vitamin or a vitamin precursor. 
     
     
         62 - 66 . (canceled) 
     
     
         67 . The composition of  claim 37 , wherein said creatine compound is of the general formula: 
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof, wherein:
 a) Y is selected from the group consisting of: —CO 2 H, —NHOH, —NO 2 , —SO 3 H, —C(═O)NHSO 2 J and —P(═O)(OH)(OJ), wherein J is selected from the group consisting of: hydrogen, C 1 -C 6  straight chain alkyl, C 3 -C 6  branched alkyl, C 2 -C 6  alkenyl, C 3 -C 6  branched alkenyl, and aryl; 
 b) A is selected from the group consisting of: C, CH, C 1 -C 5  alkyl, C 2 -C 5  alkenyl, C 2 -C 5  alkynyl, and C 1 -C 5  alkoyl chain, each having 0-2 substituents which are selected independently from the group consisting of:
 1) K, where K is selected from the group consisting of: C 1 -C 6  straight alkyl, C 2 -C 6  straight alkenyl, C 1 -C 6  straight alkoyl, C 3 -C 6  branched alkyl, C 3 -C 6  branched alkenyl, and C 3 -C 6  branched alkoyl, K having 0-2 substituents independently selected from the group consisting of: bromo, chloro, epoxy and acetoxy; 
 2) an aryl group selected from the group consisting of: a 1-2 ring carbocycle and a 1-2 ring heterocycle, wherein the aryl group contains 0-2 substituents independently selected from the group consisting of: —CH 2 L and —COCH 2 L where L is independently selected from the group consisting of: bromo, chloro, epoxy and acetoxy; and 
 3) —NH-M, wherein M is selected from the group consisting of: hydrogen, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 1 -C 4  alkoyl, C 3 -C 4  branched alkyl, C 3 -C 4  branched alkenyl, and C 4  branched alkoyl; 
 
 c) X is selected from the group consisting of NR 1 , CHR 1 , CR 1 , O and S, wherein R 1  is selected from the group consisting of:
 1) hydrogen; 
 2) K where K is selected from the group consisting of: C 1 -C 6  straight alkyl, C 2 -C 6  straight alkenyl, C 1 -C 6  straight alkoyl, C 3 -C 6  branched alkyl, C 3 -C 6  branched alkenyl, and C 4 -C 6  branched alkoyl, K having 0-2 substituents independently selected from the group consisting of: bromo, chloro, epoxy and acetoxy; 
 3) an aryl group selected from the group consisting of a 1-2 ring carbocycle and a 1-2 ring heterocycle, wherein the aryl group contains 0-2 substituents independently selected from the group consisting of: —CH 2 L and —COCH 2 L where L is independently selected from the group consisting of: bromo, chloro, epoxy and acetoxy; 
 4) a C 5 -C 9  a-amino-w-methyl-w-adenosylcarboxylic acid attached via the w-methyl carbon; 
 5) a C 5 -C 9  a-amino-w-aza-w-methyl-w-adenosylcarboxylic acid attached via the w-methyl carbon; and 
 6) a C 5 -C 9  a-amino-w-thia-w-methyl-w-adenosylcarboxylic acid attached via the w-methyl carbon; 
 
 d) Z 1  and Z 2  are chosen independently from the group consisting of: ═O, —NHR 2 , —CH 2 R 2 , —NR 2 OH; wherein Z 1  and Z 2  may not both be ═O and wherein R 2  is selected from the group consisting of:
 1) hydrogen; 
 2) K, where K is selected from the group consisting of: C 1 -C 6  straight alkyl; C 2 -C 6  straight alkenyl, C 1 -C 6  straight alkoyl, C 3 -C 6  branched alkyl, C 3 -C 6  branched alkenyl, and C 4 -C 6  branched alkoyl, K having 0-2 substituents independently selected from the group consisting of: bromo, chloro, epoxy and acetoxy; 
 3) an aryl group selected from the group consisting of a 1-2 ring carbocycle and a 1-2 ring heterocycle, wherein the aryl group contains 0-2 substituents independently selected from the group consisting of: —CH 2 L and —COCH 2 L where L is independently selected from the group consisting of: bromo, chloro, epoxy and acetoxy; 
 4) a C 4 -C 8  a-amino-carboxylic acid attached via the w-carbon; 
 5) B, wherein B is selected from the group consisting of: —CO 2 H, —NHOH, —SO 3 H, —NO 2 , OP(═O)(OH)(OJ) and —P(═O)(OH)(OJ), wherein J is selected from the group consisting of: hydrogen, C 1 -C 6  straight alkyl, C 3 -C 6  branched alkyl, C 2 -C 6  alkenyl, C 2 -C 6  branched alkenyl, and aryl, wherein B is optionally connected to the nitrogen via a linker selected from the group consisting of: C 1 -C 2  alkyl, C 2  alkenyl, and C 1 -C 2  alkoyl; 
 6) -D-E, wherein D is selected from the group consisting of: C 1 -C 3  straight alkyl, C 3  branched alkyl, C 2 -C 3  straight alkenyl, C 3  branched alkenyl, C 1 -C 3  straight alkoyl, aryl and aroyl; and E is selected from the group consisting of: —(PO 3 ) n NMP, where n is 0-2 and NMP is ribonucleotide monophosphate connected via the 5′-phosphate, 3′-phosphate or the aromatic ring of the base; —[P(═O)(OCH 3 )(O)] m -Q, where m is 0-3 and Q is a ribonucleoside connected via the ribose or the aromatic ring of the base; —[P(═O)(OH)(CH 2 )] m -Q, where m is 0-3 and Q is a ribonucleoside connected via the ribose or the aromatic ring of the base; and an aryl group containing 0-3 substituents chosen independently from the group consisting of: Cl, Br, epoxy, acetoxy, —OG, —C(═O)G, and —CO 2 G, where G is independently selected from the group consisting of: C 1 -C 6  straight alkyl, C 2 -C 6  straight alkenyl, C 1 -C 6  straight alkoyl, C 3 -C 6  branched alkyl, C 3 -C 6  branched alkenyl, C 4 -C 6  branched alkoyl, wherein E may be attached to any point to D, and if D is alkyl or alkenyl, D may be connected at either or both ends by an amide linkage; and 
 7) -E, wherein E is selected from the group consisting of —(PO 3 ) n NMP, where n is 0-2 and NMP is a ribonucleotide monophosphate connected via the 5′-phosphate, 3′-phosphate or the aromatic ring of the base; —[P(═O)(OCH 3 )(O)] m -Q, where m is 0-3 and Q is a ribonucleoside connected via the ribose or the aromatic ring of the base; —[P(═O)(OH)(CH 2 )] m -Q, where m is 0-3 and Q is a ribonucleoside connected via the ribose or the aromatic ring of the base; and an aryl group containing 0-3 substituents chose independently from the group consisting of: Cl, Br, epoxy, acetoxy, —OG, —C(═O)G, and —CO 2 G, where G is independently selected from the group consisting of: C 1 -C 6  straight alkyl, C 2 -C 6  straight alkenyl, C 1 -C 6  straight alkoyl, C 3 -C 6  branched alkyl, C 3 -C 6  branched alkenyl, C 4 -C 6  branched alkoyl; and if E is aryl, E may be connected by an amide linkage; 
 
 e) if R 1  and at least one R 2  group are present, R 1  may be connected by a single or double bond to an R 2  group to form a cycle of 5 to 7 members; 
 f) if two R 2  groups are present, they may be connected by a single or a double bond to form a cycle of 4 to 7 members; and 
 g) if R 1  is present and Z 1  or Z 2  is selected from the group consisting of —NHR 2 , —CH 2 R 2  and —NR 2 OH, then R 1  may be connected by a single or double bond to the carbon or nitrogen of either Z 1  or Z 2  to form a cycle of 4 to 7 members.