US 2002/0161049 A1 · USE OF CREATINE OR CREATINE ANALOGS FOR THE TREATMENT OF DISEASES OF THE NERVOUS SYSYEM

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 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.

Claims18

Dependent claims

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.

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:
34
and pharmaceutically acceptable salts thereof, wherein:
a) Y is selected from the group consisting of:
—CO2H, —NHOH, —NO2, —SO3H, —C(═O)NHSO2J and —P(═O)(OH)(OJ), wherein J is selected from the group consisting of:
hydrogen, C1-C6 straight chain alkyl, C3-C6 branched alkyl, C2-C6 alkenyl, C3-C6 branched alkenyl, and aryl;
b) A is selected from the group consisting of:
C, CH, C1-C5alkyl, C2-C5alkenyl, C2-C5alkynyl, and C1-C5 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:
C1-C6 straight alkyl, C2-C6 straight alkenyl, C1-C6 straight alkoyl, C3-C6 branched alkyl, C3-C6 branched alkenyl, and C4-C6 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:
—CH2L and —COCH2L 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, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoyl, C3-C4 branched alky, C3-C4 branched alkenyl, and C4 branched alkoyl;
c) X is selected from the group consisting of NR1, CHR1, CR1, O and S, wherein R1 is selected from the group consisting of:
1) hydrogen;
2) K where K is selected from the group consisting of:
C1-C6 straight alkyl, C2-C6 straight alkenyl, C1-C6 straight alkoyl, C3-C6 branched alkyl, C3-C6 branched alkenyl, and C4-C6 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:
—CH2L and —COCH2L where L is independently selected from the group consisting of:
bromo, chloro, epoxy and acetoxy;
4) a C5-C9 a-amino-w-methyl-w-adenosylcarboxylic acid attached via the w-methyl carbon;
5) a C5-C9 a-amino-w-aza-w-methyl-w-adenosylcarboxylic acid attached via the w-methyl carbon;
and
6) a C5-C9 a-amino-w-thia-w-methyl-w-adenosylcarboxylic acid attached via the w-methyl carbon;
d) Z1 and Z2 are chosen independently from the group consisting of:
═O, —NHR2, —CH2R2, —NR2OH;
wherein Z1 and Z2 may not both be ═O and wherein R2 is selected from the group consisting of:
1) hydrogen;
2) K, where K is selected from the group consisting of:
C1-C6 straight alkyl;
C2-C6 straight alkenyl, C1-C6 straight alkoyl, C3-C6 branched alkyl, C3-C6 branched alkenyl, and C4-C6 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:
—CH2L and —COCH2L where L is independently selected from the group consisting of:
bromo, chloro, epoxy and acetoxy;
4) a C4-C8 a-amino-carboxylic acid attached via the w-carbon;
5) B, wherein B is selected from the group consisting of:
—CO2H, —NHOH, —SO3H, —NO2, OP(═O)(OH)(OJ) and —P(—O)(OH)(OJ), wherein J is selected from the group consisting of:
hydrogen, C1-C6 straight alkyl, C3-C6 branched alkyl, C2-C6 alkenyl, C3-C6 branched alkenyl, and aryl, wherein B is optionally connected to the nitrogen via a linker selected from the group consisting of:
C1-C2 alkyl, C2 alkenyl, and C1-C2 alkoyl;
6) —D—E, wherein D is selected from the group consisting of:
C1-C3 straight alkyl, C3 branched alkyl, C2-C3 straight alkenyl, C3 branched alkenyl, C1-C3 straight alkoyl, aryl and aroyl;
and E is selected from the group consisting of:
—(PO3)nNMP, 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)(OCH3)(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)(CH2)]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 —CO2G, where G is independently selected from the group consisting of:
C1-C6 straight alkyl, C2-C6 straight alkenyl, C1-C6 straight alkoyl, C3-C6 branched alkyl, C3-C6 branched alkenyl, C4-C6 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 —(PO3)nNMP, 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)(OCH3)(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)(CH2)]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 —CO2G, where G is independently selected from the group consisting of:
C1-C6 straight alkyl, C2-C6 straight alkenyl, C1-C6 straight alkoyl, C3-C6 branched alkyl, C3-C6 branched alkenyl, C4-C6 branched alkoyl;
and if E is aryl, E may be connected by an amide linkage;
e) if R1 and at least one R2 group are present, R1 may be connected by a single or double bond to an R2 group to form a cycle of 5 to 7 members;
f) if two R2 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 R1 is present and Z1 or Z2 is selected from the group consisting of —NHR2, —CH2R2 and —NR2OH, then R1 may be connected by a single or double bond to the carbon or nitrogen of either Z1 or Z2 to form a cycle of 4 to 7 members.

64 more elements

Dependencies are inferred from the claim text.

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

Life of this patent

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

Life of this patent

Abstract

Claims18