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:
where each of R 1 , and R 2 is independently selected from 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
R 3 is a (CH 2 ) k OR 5 group;
R 4 is selected from a C 1 to C 12 straight, branch-chained or cyclic saturated or unsaturated hydrocarbon, a (CH 2 ) k OR 5 group or a
R A is selected from a C 1 to C 12 alkyl or alkenyl group or a (CH 2 ) p R 5 group;
R B is a a C 1 to C 12 alkyl or alkenyl group;
R 5 is H or a C 1 to C 12 alkyl, 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;
R 6 is a group according to the structure:
k or n is 1 to 12;
m or p is 1 to 8; and
X 1 , X 2 and X 3 are each independently selected from H, OH, F, Cl, Br, NO 2 , R 4 , OR 4 , CF 3 or OCF 3 ;
or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 wherein n or k is 1 to 8.
3. The compound according to claim 1 wherein R 4 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. A pharmaceutical composition comprising an effective amount of a compound according to the chemical structure:
where each of R 1 , and R 2 is independently selected from 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
R 3 is a (CH 2 ) k OR 5 group;
R 4 is selected from a C 1 to C 12 straight, branch-chained or cyclic saturated or unsaturated hydrocarbon, a (CH 2 ) k OR 5 group or a
R A is selected from a C 1 to C 12 alkyl or alkenyl group or a (CH 2 ) p R 5 group;
R B is a a C 1 to C 12 alkyl or alkenyl group;
R 5 is H or a C 1 to C 12 alkyl, 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;
R 6 is a group according to the structure:
k or n is 1 to 12;
m or p is 1 to 8; and
X 1 , X 2 and X 3 are each independently selected from H, OH, F, Cl, Br, NO 2 , R 4 , OR 4 , CF 3 or OCF 3 ; or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient.
8. The compound according to claim 1 wherein n is 1 to 8.
9. The compound according to claim 1 wherein R 4 is a (CH 2 ) k OR 5 group.
10. The compound according to claim 1 wherein R 5 is H.
11. The compound according to claim 3 wherein R 5 is H and k is 1 to 8.
12. The compound according to claim 5 wherein k is 1 to 3.
13. A method of treating a patient for a neurological or neurodegenerative condition selected from the group consisting of Alzheimer's disease, spinal muscular atrophy, Cruetzfelt-Jacob syndrome, dementia with Lewy bodies, and schizophrenia comprising administering an effective amount of a compound according to the chemical structure:
where each of R 1 and R 2 is independently selected from 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
R 3 is a (CH 2 ) k OR 5 group;
R 4 is selected from a C 1 to C 12 straight, branch-chained or cyclic saturated or unsaturated hydrocarbon, a (CH 2 ) k OR 5 group or a
R A is selected from a C 1 to C 12 alkyl or alkenyl group or a (CH 2 ) p R 5 group;
R B is a a C 1 to C 12 alkyl or alkenyl group;
R 5 is H or a C 1 to C 12 alkyl, 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;
R 6 is a group according to the structure:
k or n is 1 to 12;
m or p is 1 to 8; and
X 1 , X 2 and X 3 are each independently selected from H, OH, F, Cl, Br, NO 2 , R 4 , OR 4 , CF 3 or OCF 3 ; or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient.
14. The method according to claim 13 wherein n is 1 to 8.
15. The method according to claim 13 wherein R 4 is a (CH 2 ) k OR 5 group.
16. The method according to claim 13 wherein R 5 is H.
17. The method compound according to claim 15 wherein R 5 is H and k is 1 to 8.
18. The compound according to claim 17 wherein k is 1 to 3.
19. A compound according to the chemical structure:
where each of R 1 and R 2 is independently selected from 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
R 3 is a C 1 to C 12 alkyl or alkene group or a (CH 2 ) k OR 5 group;
R 4 is selected from a (CH 2 ) k OR 5 group or a
R A is selected from a C 1 to C 12 alkyl or alkenyl group or a (CH 2 ) p R 5 group;
R B is a C 1 to C 12 alkyl or alkenyl group;
R 5 is H or a C 1 to C 12 alkyl, 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;
R 6 is a group according to the structure:
k or n is 1 to 12;
m or p is 1 to 8; and
X 1 , X 2 and X 3 are each independently selected from H, OH, F, Cl, Br, NO 2 , R 4 , OR 4 , CF 3 or OCF 3 ;
or a pharmaceutically acceptable salt thereof.
20. The compound according to claim 19 wherein n or k is 1 to 8.
21. The compound according to claim 19 wherein R 3 is a (CH 2 ) k OR 5 group.
22. The compound according to claim 19 wherein R 5 is H.
23. The compound according to claim 21 wherein R 5 is H and k 1 to 8.
24. The compound according to claim 23 wherein k is 1 to 3.
25. A pharmaceutical composition comprising an effective amount of a compound according to the chemical structure:
where each of R 1 and R 2 is independently selected from 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
R 3 is a C 1 to C 12 alkyl or alkene group or a (CH 2 ) k OR 5 group;
R 4 is selected from a (CH 2 ) k OR 5 group or a
R A is selected from a C 1 to C 12 alkyl or alkenyl group or a (CH 2 ) p R 5 group;
R B is a C 1 to C 12 alkyl or alkenyl group;
R 5 is H or a C 1 to C 12 alkyl, 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;
R 6 is a group according to the structure:
k or n is 1 to 12;
m or p is 1 to 8; and
X 1 , X 2 and X 3 are each independently selected from H, OH, F, Cl, Br, NO 2 , R 4 , OR 4 , CF 3 or OCF 3 ; or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient.
26. The compound according to claim 25 wherein n is 1 to 8.
27. The compound according to claim 25 wherein R 3 is a (CH 2 ) k OR 5 group.
28. The compound according to claim 25 wherein R 5 is H.
29. The compound according to claim 27 wherein R 5 is H and k is 1 to 8.
30. The compound according to claim 29 wherein k is 1 to 3.