Use of creatine or creatine analogs for the treatment of diseases of the nervous system

Abstract

The present invention relates to the use of creatine compounds including creatine, creatine phosphate or analogs of creatine, such as cyclocreatine, for treating diseases of the nervous system. Creatine compounds can be used as therapeutically effective agents against a variety of diseases of the nervous system such as diabetic and toxic neuropathies, peripheral nervous system diseases, Alzheimer's disease, Parkinson's disease, stroke, Huntington's disease, amyotropic lateral sclerosis, motor neuron disease, traumatic nerve injury, multiple sclerosis, dysmyelination and demyelination disorders, and mitochondrial diseases. 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) bisubstrate inhibitors of creatine kinase comprising covalently linked structural analogs of adenosine triphosphate (ATP) and creatine; (3) creatine analogs which can act as reversible or irreversible inhibitors of creatine kinase; and (4) N-phosphorocreatine analogs bearing non-transferable moieties which mimic the N-phosphoryl group.

1 . A method for treating a subject afflicted with a nervous system disease comprising
 administering to the subject an amount of creatine, creatine phosphate or a creatine analog or a salt thereof compound sufficient to prevent, reduce, ameliorate or eliminate said disease.   
     
     
         2 . The method of  claim 1  wherein the subject is a mammal. 
     
     
         3 . The method of  claim 1  wherein the subject is human. 
     
     
         4 . A method for treating a subject for diseases of the nervous system comprising:
 administering an effective amount of a creatine compound to a subject such that the subject is treated for diseases of the nervous system, 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 4 -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 O-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 8  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 O-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 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 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. 
       
     
     
         5 . The method of  claim 4  wherein the treatment comprises reducing or eliminating symptoms associated with a preexisting disease of the nervous system. 
     
     
         6 . The method of  claim 4  wherein the treatment comprises preventing the occurrence of diseases of the nervous system within the subject. 
     
     
         7 . The method of  claim 4  wherein the creatine compound is creatine. 
     
     
         8 . The method of  claim 4  wherein the creatine compound is creatine phosphate. 
     
     
         9 . The method of  claim 4  wherein the creatine compound is cyclocreatine. 
     
     
         10 . The method of  claim 4  wherein the creatine compound is cyclocreatine phosphate. 
     
     
         11 . The method of  claim 4  wherein the creatine compound is homocyclocreatine. 
     
     
         12 . The method of  claim 4  wherein the disease of the nervous system is selected from the groups consisting of neuropathies; Alzheimer disease, Parkinson's disease, Huntington's disease, motor neuron disease, traumatic nerve injury, multiple sclerosis, acute disseminated encephalomyelitis, acute necrotizing hemorrhagic leukoencephalitis, dysmyelination disease, mitochondrial disease, migrainous disorder, bacterial infection, fungal infection, stroke, aging, dementia, peripheral nervous system diseases and mental disorders such as depression and schizophrenia. 
     
     
         13 . The method of  claim 12  wherein the creatine compound is selected from the group consisting of creatine, creatine phosphate, cyclocreatine and cyclocreatine phosphate. 
     
     
         14 . The method of  claim 4  further comprising coadministering to the subject a neurotransmitter, a neurotransmitter analog, a steroid, an immunomodulating agent, or an immune suppressive agent. 
     
     
         15 . The method of  claim 4  wherein the subject is treated for diseases of the nervous system by reducing or eliminating symptoms associated with a preexisting diseases of the nervous system. 
     
     
         16 . The method of  claim 4  wherein the subject is treated for diseases of the nervous system by preventing the occurrence of a disease of the nervous system within the subject. 
     
     
         17 . A method for alleviating in a subject being treated for a nervous system disease toxic side effects of drugs used to treat the nervous system diseases, comprising administering to the subject an amount of a creatine, creatine phosphate or a creatine analog, or a salt thereof, sufficient to prevent, reduce, ameliorate or alleviate said toxic side effects. 
     
     
         18 . The method of  claim 17  wherein the creatine analog is cyclocreatine or cyclocreatine phosphate.