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Title:  Use of kinase inhibitors for treating neurodegenerative diseases

United States Patent:  6,288,089

Inventors:  Zawada; Michael (10162 E. Exposition Ave., Denver, CO 80231); Heidenreich; Kim (215 Locust La., Denver, CO 80220); Freed; Curt (9080 E. Jewell Cir., Denver, CO 80231)

Appl. No.:  469980

Filed:  December 21, 1999
Abstract

The present invention relates to methods of treating neurodegenerative diseases, including but not limited to Parkinson's disease. In particular, the present invention provides methods utilizing the administration of pyridyl imidazoles having simultaneous inhibitory activity towards p38 mitogen-activated protein (MAP) kinase and c-jun-N-terminal kinase (JNK). The present invention also provides methods for preventing apoptosis of dopamine neurons using pyridyl imidazoles. The present invention also provides methods for the treatment of neurodegenerative diseases, including but not limited to Parkinson's disease.

SUMMARY OF THE INVENTION

The present invention relates to methods for treating neurodegenerative diseases. In particular, the present invention relates to methods for treating neurodegenerative diseases, comprising the steps of: a) providing a subject suffering from a neurodegenerative disease and a composition comprising a pyridyl imidazole; and b) administering the composition to the subject suffering from neurodegenerative disease under conditions such that neurodegeneration is ameliorated in the subject. In one embodiment, the neurodegenerative disease is selected from the group consisting of Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. In a preferred embodiment, the neurodegenerative disease is Parkinson's disease. It is not intended that the present invention be limited to any particular stage of the disease (e.g., early or advanced stages).

In one embodiment, the composition is administered to the subject orally. In another embodiment, the composition is a therapeutic composition. In yet another embodiment, the subject is human. In one particularly preferred embodiment, the human is a recipient of transplant cells (i.e., has undergone neuronal cell transplant). In an alternative preferred embodiment, the subject will undergo transplantation of neuronal cells. In yet another preferred embodiment, the composition is administered to a human subject who has transplanted cells, under conditions such that the survival and/or function of the transplanted cells in the subject is improved. In a further preferred embodiment, the composition is a therapeutic composition. In yet another embodiment, the subject is a non-human animal.

In one embodiment, the pyridyl imidazole is selected from the group consisting of PD 169316, isomeric PD 169316, SB 203580, SB 202190, SB 220025, and RWJ 67657. In a preferred embodiment, the pyridyl imidazole is selected from the group consisting of PD 169316 and isomeric PD 169316.

The present invention also provides methods for inhibiting p38 MAP kinase and c-jun-N-terminal kinases, comprising the steps of: a) providing a sample comprising c-jun-N-terminal kinase and p38 kinase and a compound; and b) exposing the sample to the compound under conditions such that the activities of p38 and c-jun-N-terminal kinase are inhibited. In one embodiment, the compound is a pyridyl imidazole. In yet another embodiment, the pyridyl imidazole is selected from the group consisting of PD 169316, isomeric PD 169316, SB 203580, SB 202190, SB 220026, and RWJ 67657. In a preferred embodiment, the pyridyl imidazole is selected from the group consisting of PD 169316 and isomeric PD 169316.

Furthermore, the present invention provides methods of preventing apoptosis of dopamine neurons, comprising the steps of: a) providing dopamine neurons and a composition comprising a pyridyl imidazole; and b) exposing the composition to the dopamine neurons under conditions such that apoptosis of the dopamine neurons is prevented. In a preferred embodiment, the pyridyl imidazole is selected from the group consisting of PD 169316, isomeric PD 169316, SB 203580, SB 202190, SB 220026, and RWJ 67657. In a preferred embodiment, the pyridyl imidazole is selected from the group consisting of PD 169316 and isomeric PD 169316. In one embodiment, the neurons are from an in vitro culture system. In another embodiment, the neurons comprise primary cells. In another embodiment, the neurons are transplanted neurons. In another embodiment, the dopamine neurons are endogenous neurons.

In one embodiment, the methods of the present invention further comprise the step of implanting dopamine neurons to a subject, and wherein the exposing step occurs after the implanting step. In another embodiment, the methods of the present invention further comprise the step of implanting dopamine neurons to a subject, and wherein the exposing step occurs before the implanting step. In yet another embodiment, the methods of the present invention further comprise the step of implanting dopamine neurons to a subject, and wherein the exposing step occurs before and after the implanting step.

Claim 1 of 15 Claims

What is claimed is:

1. A method for treating a subject, comprising the steps of:

a) providing:

i) a subject, wherein said subject has a neurodegenerative disease, and

ii) a composition comprising at least one pyridyl imidazole compound, wherein said pyridyl imidazole compound is selected from the group consisting of

PD 169316; isomeric PD 169316; SB 203580; SB 202190; SB 220025; RWJ 67657;

2-(4-Cyanophenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole;

1-Methyl-2-(4-methoxyphenyl)-4-phenyl-5-(4-pyridyl)-imidazole;

2-(4-Cyanophenyl)-1-methyl-4-phenyl-5(4-pyridyl)imidazole;

2-(4-Aminomethylphenyl)-1-methyl-4-phenyl-5-(4-pyridyl)-imidazole;

4-[1-Methyl-4-phenyl-5(4-pyridyl)-imidazol-2-yl]benzoic acid, sodium salt;

2-(4-Acetamidomethyphenyl)-1-methyl-4-phenyl-5-(4-pyridyl)imidazole;

Methyl-4-[1-methyl-4-phenyl-5-(4-pyridyl)-imidazol-2-yl]benzoate;

4-(4-Fluorophenyl)-N-1-hydroxy-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole;

4-(4-Fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole;

4-[4-(4-Fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]benzoic acid;

2-(4-Cyanophenyl)-4-(4-fluorophenyl)-1-N-hydroxy-5-(4-pyridyl)imidazole;

2-(4-Aminomethylphenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole;

2-(4-Cyanophenyl)-4-(4-fluorophenyl)-N-1-hydroxy-5-(4-quinolyl)imidazole;

2-(4-Cyanophenyl)-4-(4-fluorophenyl)-5-(4-quinolyl)-1H-imidazole;

2-(3,5-Dibromo-4-hydroxyphenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazo le; Ethyl

4-[4-(4-Fluorophenyl)-5-(4-pyridyl)]-1H-imidazol-2-yl]-benzoate;

2-[3,5-Dimethyl-4-hydroxy(phenyl)]-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imid azole;

4-(4-Fluorophenyl-2-(2-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole;

4-(4-Fluorophenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-imidazole; Methyl

4-[4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]-benzoate;

4-(4-Fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl)-1H-imidazole;

4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole;

N,N-Dimethyl-4-[4-(4-fluorophenyl-5-(4-pyridyl)-1H-imidazol-2-yl]-benzamide ;

2-[(4-N,N-Dimethyl)aminomethylphenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-i midazole;

2-[4-(Dimethylamino)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole;

4-(4-Fluorophenyl)-2-phenyl-5-(4-pyridyl)-1H-imidazole;

2-[4-(3-Dimethylaminopropoxy)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-im idazole;

4-(4-Fluorophenyl)-2-(4-nitrophenyl)-5-(4-pyridyl)-1H-imidazole;

N,N-Dimethyl-4-[2-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]-benzoylo xyacetamnide;

2-(4-Aminophenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole;

4-(4-Fluorophenyl)-2-(4-methanesulfonamidophenyl)-5-(4-pyridyl)-1H-imidazol e;

4-[4-(4-Fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]phenyl-sulfonamide;

N'-Cyano-N-4-[4-(fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]benzylguanidi ne;

2-[4-(Methanesulfonamido)methylphenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)-1H- imidazole;

4-(4-Fluorophenyl)-2-(4-methoxyphenyl)-5-(4-pyridyl)-1H-imidazole;

2-(4-Amino-3-iodophenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole;

N-Benzyl-N-methyl-4-[4-(4-fluorophenyl-5-(4-pyridyl)-1H-imidazol-2-yl]benza mide;

2-[4-(N-Benzyl-N-methyl)aminomethylphenyl]-4-(4-fluorophenyl)-5-(4-pyridyl) -1H-imidazole;

4-(4-Fluorophenyl)-N-1-hydroxy-2-(4-methylthiophenyl)-5-(4-quinolyl)imidazo le;

4-(4-Fluorophenyl)-2-(4-methylthiophenyl)-5-(4-quinolyl)-1H-imidazole;

4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-quinolyl) 1H-imidazole;

4-(3-Chlorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole;

4-(3-Chlorophenyl)-N-1-hydroxy-2-(4-methylthio-phenyl)-5-(4-pyridyl)-1H-imi dazole;

4-(3-Chlorophenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-imidazole;

4-(4-Fluorophenyl)-2-(4-formamidomethylphenyl)-5-(4-pyridyl)-1H-imidazole;

4-[4-(4-Fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]-benzohydroxamic acid;

O-Benzyl-4-[4-(4-Fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]-benzohydroxa mic acid;

4-[4-(4-Fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]benzamidoxime;

N"-Methyl-N'-cyano-N-[4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]-be nzylguanidine;

N-1-Hydroxy-4-(3-methoxyphenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-imi dazole;4-(3-ethoxyphenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)imidazole;

4-(3-Methoxyphenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole;

Morpholino-4-[4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]benzamide;

4-(4-Fluorophenyl)-5-[4-(2-methylpyridyl)]-2-(4-methylthiophenyl)-1H-imidaz ole;

4-(4-Fluorophenyl)-5-[4-(2-methylpyridyl)]-2-(4-methylsulfinylphenyl)-1H-im idazole;

4-(4-Fluorophenyl)-N-1-hydroxy-5-(4-pyrimidinyl)-imidazole;

4-(4-Fluorophenyl)-2-(4-methylthiophenyl)-5-(4-pyrimidinyl)-1H-imidazole;

4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyrimidinyl)-1H-imidazol e;

4-(4-Fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyrimidinyl)-1H-imidazol e;

4-(4-Fluorophenyl)-2-(4-Morpholinomethylphenyl)-5-(4-pyridyl)-1H-imidazole;

4-(4-Fluorophenyl)-2-(4-hydroxymethyl)-5-(4-pyridyl)-1H-imidazole;

4-[4-(4-Fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]-benzaldehyde;

4-(2-Methoxyphenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole;

N-1-Hydroxy-4-(2-methoxyphenyl)-2-(4-methylthio-phenyl)-5-(4-pyridyl)imidaz ole;

4-(2-Methoxyphenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-imidazole;

3-[4-(4-Fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]phenyl-5-methyl-4,5-di hydro-1,2,4-oxadiazole; 3-[4-(4-Fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]phenyl-5-methyl-1,2,4 -oxadiazole;

4-(3-Aminophenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-imidazole;

N-1-Hydroxy-2-(4-methylthiophenyl)-4-(3-nitrophenyl)-5-(4-pyridyl)imidazole ;

2-(4-Methylthiophenyl)-4-(3-nitrophenyl)-5-(4-pyridyl)-1H-imidazole;

4-(3-Methanesulfonamidophenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-imid azole;

3-[4-(4-Fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]phenyl-1,2,4-oxadiazol -5(4H)-one;

4-(3-Acetamidophenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-imidazole;

4-(4-Fluorophenyl)-1-N-hydroxy-5-[4-(2-methylpyridyl)]-2-(4-methylthiopheny l)-imidazole;

3-[4-(4-Fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]-phenyl-5,5-dimethyl-4 ,5-dihydro-1,2,4-oxadiazole;

N-Hydroxy-N-1-[4-[4-(4-fluorophenyl)5-(4-pyridyl)-1H-imidazol-2-yl]phenyl]- ethyl]urea; N-Hydroxy-N-[4-[4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]phenyl]- methyl urea; 4-(3-Methylthiophenyl)-2-(4-morpholinomethylphenyl)-5-(4-pyridyl)-1H-imida zole;

4-(3-Methylsulfinylphenyl)-2-(4-morpholinomethylphenyl)-5-(4-pyridyl)-1H-im idazole;

4-(3-Methanesulfonamidophenyl)-2-(4-methylsulfinylpheny )-5-(4-pyridyl)-1H-imidazole 2-(4-Ethylthiophenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole;

4-(4-Fluorophenyl)-2-[(4-(4-methyl-1-piperzinyl)-sulfonyl-phenyl]-5-(4-pyri dyl) 1H-imidazole;

4-(4-Fluorophenyl)-2-[4-(N-methylmethanesulfonamido)-methylphenyl]-5-(4-pyr idyl)-1H-imidazole; Diethyl-[1-methyl-4-phenyl-5-(4-pyridyl)-imidazol-2-yl]-methoxy methylphosphonate;

4-(4-Fluorophenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-imidazole;

4-(4-Fluorophenyl)-2-(3-methylthiophenyl)-5-(4-pyridyl)-1H-imidazole;

4-(4-Fluorophenyl)-2-(3-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole;

4-(4-Fluorophenyl)-2-(4-methoxyphenyl)-5-(4-pyridyl)imidazole;

4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-1-(N-morpholinopropyl)-5-(4-p yridyl)-imidazole; 4-(4-Fluorophenyl)-2-(4-methylthiophenyl)-1-(N-morpholinopropyl)-5-(4-pyri dyl)-imidazole; 4-(4-Fluorophenyl)-2-(4-methylsulfonylphenyl)-1-(N-morpholinopropyl)-5-(4- pyridyl)imidazole; 4-(4-Fluorophenyl)-1-(methylthio-1-propyl)-2-([4-N-morpholinomethyl]phenyl )-5-(4-pyridyl)imidazole;

4-(4-Fluorophenyl)-1-(methylsulfinyl-1-propyl)-2-([4N-morpholinomethyl]phen yl)-5-(4-pyridyl)imidazole; 4-(4-Fluorophenyl)-1-(methylsulfonyl-1-propyl)-2-([4-N-morpholinomethyl]ph enyl)-5-(4-pyridyl)imidazole; and pharmaceutically acceptable salts thereof; and

b) administering said composition to said subject under conditions such that said neurodegenerative disease in said subject is ameliorated.


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