Use of creatine analogues and creatine kinase modulators for the prevention and treatment of obesity and its related disorders

Abstract

The present invention relates to the use of creatine compounds for treating or preventing a metabolic disorder related to body weight control such as obesity, and it's associated diseases in a patient experiencing said disorder. The creatine compounds which can be used in the present method include (1) analogues of creatine which can act as substrates or substrate analogues for the enzyme creatine kinase; (2) compounds which can act as inhibitors of creatine kinase; (3) compounds which can modulate the creatine transporter (4) N-phosphocreatine analogues bearing transferable or non-transferable moieties which mimic the N-phosphoryl group. (5) compounds which modify the association of creatine kinase with other cellular components.

What is claimed is:  
     
         1 . A method of treating or preventing a body disorder related to weight gain or loss in a subject afflicted with said disorder, comprising administering to the subject an amount of a creatine compound, or a pharmaceutically acceptable salt thereof, effective to treat, reduce, or prevent said disorder.  
     
     
         2 . A method of  claim 1  wherein said disorder is obesity.  
     
     
         3 . A method of  claim 1  wherein said disorder is cachexia.  
     
     
         4 . A method of  claim 1  wherein said disorder is obesity associated disorders such as cardiovascular disease, hypertension, hyperlipidaemia osteoporosis and osteoarthritis.  
     
     
         5 . A method of  claim 1  wherein the subject is a human.  
     
     
         6 . A method for treating a metabolic disorder consisting of obesity and it's associated diseases, in a subject experiencing said disorder, comprising administering to the subject a therapeutic amount of a creatine analogue having 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(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 4 -C 6  branched alkoyl, K having 0-2 substituents independently selected from the group consisting of rromo, 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) 2 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) 2 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 3 -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 12 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.  
 Currently preferred compounds include cyclocreatine, creatine phosphate and those included in Tables 1 and 2 hereinabove.  
 
     
     
         7 . A method of  claim 6  wherein the creatine compound is used in combination with standard therapies used to treat body weight disorders.  
     
     
         8 . A method for treating obesity in a patient experiencing said disorder comprising the use of a creatine kinase inhibitor.  
     
     
         9 . A method for treating obesity in a subject experiencing said disorder comprising administering to the subject an effective amount of a creatine kinase transporter regulator.  
     
     
         10 . A method for treating obesity in a patient experiencing said disorder comprising the use of compounds which modify energy generation through the creatine kinase system.  
     
     
         11 . A method for treating a body weight disorder in a patient experiencing said disorder comprising the use of creatine and creatine phosphate analogues.  
     
     
         12 . The use of the creatine kinase structural coordinates to design compounds for the treatment of diseases related to body weight disorders.  
     
     
         13 . The use of the creatine kinase system as a target for the design of therapeutics for the treatment of body weight disorders.