Analogs of choline for neuroprotection and cognitive enhancement in neurodegenerative disorders
The present invention relates to novel analogs of choline and methods of use or treatment of neurodegenerative disorders and/or conditions such as Parkinson's disease, Huntington disease, Alzheimer's disease and related disorders such as amyotrophic lateral sclerosis, spinal muscular atrophy, Friedrich's ataxia, Pick's disease, Bassen-Kornzweig syndrome, Refsom's disease, retinal degeneration, Cruetzfelt-Jacob syndrome or prion disease (mad cow disease), dementia with Lewy bodies, schizophrenia, paraneoplastic cerebellar degeneration and neurodegenerative conditions caused by stroke. The present compounds are effective to treat any neurological condition where acetylcholine transmission neurons and their target cells are affected. Compounds according to the present invention are effective to alleviate and/or reverse the effects of a neurodegenerative condition, prevent further deterioration and/or enhance cognition and memory in patients suffering from neurodegenerative disorders, especially Alzheimer's disease.
1. A compound according to the chemical structure:
wherein each R 1 is a
R 2 is H, a C 1 to C 12 straight, branch-chained or cyclic saturated or unsaturated hydrocarbon, a (CH 2 ) k OR 5 group or a group R 1 as described above;
R 3 is a H, a C 1 to C 12 alkyl group, a C 2 to C 12 alkenyl, group or a (CH 2 ) k OR 5 group;
R 5 is H, a C 1 to C 12 alkyl, a C 2 to C 12 alkenyl group or carboxylic acid, a C 2 to C 12 acyl or alkyl ester group or a C 3 to C 12 alkylene ester group;
n is 0 to 12; and
k is 1 to 12;
or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 wherein, n is 0 to 8 and or k is 1 to 8.
3. The compound according to claim 1 wherein R 3 is a (CH 2 ) k OR 5 group.
4. The compound according to claim 1 wherein R 5 is H.
5. The compound according to claim 3 wherein R 5 is H and k is 1 to 8.
6. The compound according to claim 5 wherein k is 1 to 3.
7. The compound according to claim 5 wherein k is 2.
8. A pharmaceutical composition, comprising an effective amount of a compound according to the chemical structure:
wherein each R 1 is a
R 2 is H, a C 1 to C 12 straight, branch-chained or cyclic saturated or unsaturated hydrocarbon, a (CH 2 ) k OR 5 group or a group R 1 as described above;
R 3 is a H, C 1 to C 12 alkyl group, a C 2 to C 12 alkenyl group or a (CH 2 ) k OR 5 group;
R 5 is H, a C 1 to C 12 alkyl, a C 2 to C 12 alkenyl group or carboxylic acid, a C 2 to C 12 acyl or alkyl ester group or a C 3 to C 12 alkylene ester group;
n is 0 to 12; and
k is 1 to 12;
or a pharmaceutically acceptable salt thereof,
in combination with a pharmaceutically acceptable carrier, additive or excipient.
9. The composition according to claim 8 wherein n is 0 to 8 and or k is 1 to 8.
10. The composition according to claim 8 wherein R 3 is a (CH 2 ) k OR 5 group.
11. The composition according to claim 8 wherein R 5 is H.
12. The composition, according to claim 10 wherein R 5 is H and k is 1 to 8.
13. The composition according to claim 12 wherein k is 1 to 3.
14. The composition according to claim 13 wherein k is 2.
15. A method of treating a patient having a neurodegenerative condition or other neurological condition selected from the group consisting of Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, Friedrich's ataxia, Pick's disease, Bassen-Kornzweig syndrome, Refsum's disease, retinal degeneration, Cruetzfelt-Jacob syndrome, dementia with Lewy bodies, and schizophrenia comprising administering to said patient an effective amount of a compound according to the chemical structure:
wherein each R 1 is a
R 2 is H, a C 1 to C 12 straight, branch-chained or cyclic saturated or unsaturated hydrocarbon, a (CH 2 ) k OR 5 group or a group R 1 as described above;
R 3 is a H, C 1 to C 12 alkyl group, a C 2 to C 12 alkenyl group or a (CH 2 ) k OR 5 group;
R 5 is H, a C 1 to C 12 alkyl, a C 2 to C 12 alkenyl group or carboxylic acid, a C 2 to C 12 acyl or alkyl ester group or a C 3 to C 12 alkylene ester group;
n is 0 to 12; and
k is 1 to 12;
or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient.
16. The method according to claim 15 wherein n is 0 to 8 and or k is 1 to 8.
17. The method according to claim 15 wherein R 3 is a (CH 2 ) k OR 5 group.
18. The method according to claim 15 wherein R 5 is H.
19. The method according to claim 17 wherein R 5 is H and k is 1 to 8.
20. The method according to claim 19 wherein k is 1 to 3.
21. The method according to claim 20 wherein k is 2.
22. A method of treating a patient having a neurodegenerative or neurological condition selected from the group consisting of Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, Friedrich's ataxia, Pick's disease, Bassen-Kornzweig syndrome, Refsum's disease, retinal degeneration, Cruetzfelt-Jacob syndrome, dementia with Lewy bodies, and schizophrenia comprising administering to said patient an effective amount of a compound according to the chemical structure:
wherein each R 1 is a
R 2 is H, a C 1 to C 12 straight, branch-chained or cyclic saturated or unsaturated hydrocarbon, a (CH 2 ) k OR 5 group or a group R 1 as described above;
R 3 is a H, C 1 to C 12 alkyl group, a C 2 to C 12 alkenyl group or a (CH 2 ) k OR 5 group;
R 5 is H, a C 1 to C 12 alkyl, a C 2 to C 12 alkenyl group or carboxylic acid, a C 2 to C 12 acyl or alkyl ester group or a C 3 to C 12 alkylene ester group;
n is 0 to 12; and
k is 1 to 12;
or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient.
23. The method according to claim 22 wherein it is 0 and k is 1-3.
24. The method according to claim 22 wherein R 1 is a group according to the chemical structure:
25. The method according to claim 22 wherein R 1 is a group according to the chemical structure:
26. The method according to claim 22 wherein k is 1-2.
27. A method of treating a patient for a neurological or neurodegenerative condition selected from the group consisting of Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, Friedrich's ataxia, Pick's disease, Bassen-Kornzweig syndrome, Refsum's disease, retinal degeneration, Cruetzfelt-Jacob syndrome, dementia with Lewy bodies, and schizophrenia, comprising administering an effective amount of a compound according to the chemical structure:
wherein each R 1 is a
R 2 is H, a C 1 to C 12 straight, branch-chained or cyclic saturated or unsaturated hydrocarbon, a (CH 2 ) k OR 5 group or a group R 1 as described above;
R 3 is a H, C 1 to C 12 alkyl group, a C 2 to C 12 alkenyl group or a (CH 2 ) k OR 5 group;
R 5 is H, a C 1 to C 12 alkyl, a C 2 to C 12 alkenyl group or carboxylic acid, a C 2 to C 12 acyl or alkyl ester group or a C 3 to C 12 alkylene ester group;
n is 0 to 12; and
k 1 to 12;
or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient.