US2010324064A1PendingUtilityA1
Novel analogs of choline for neuroprotection and cognitive enhancement in neurodegenerative disorders
Assignee: MED COLLEGE GEORGIA RES INSTPriority: Jul 19, 2001Filed: Jul 22, 2010Published: Dec 23, 2010
Est. expiryJul 19, 2021(expired)· nominal 20-yr term from priority
C07D 401/06C07C 215/08C07C 219/06A61P 25/28C07D 295/088C07D 213/38C07D 213/74A61P 25/00
47
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Claims
Abstract
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.
Claims
exact text as granted — not AI-modified1 . A compound according to the chemical structure:
Where each of R 1 , R 2 and R 4 is independently selected from H, a C 1 to C 12 straight, branch-chained or cyclic saturated or unsaturated hydrocarbon, a (CH 2 ) n OR 5 group or an R 6 group; R 3 is H, a C 1 to C 12 alkyl or alkene group or a (CH 2 ) n OR 5 group with the proviso that R 3 and R 4 are not both H;
R A and R B are independently selected from H, a C 1 to C 12 alkyl or alkenyl group or a (CH 2 ) m OR 5 group, preferably with the proviso that when one of R A or R B is a (CH 2 ) m OR 5 group, the other of R A or R B is not a (CH 2 ) m OR 5 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:
Z is
n is 0 to 12;
m is 1 to 8; and
X 1 , X 2 and X 3 are each independently selected from H, OH, F, Cl, Br, R 4 , OR 4 , CF 3 or OCF 3 ;
or a pharmaceutically acceptable salt thereof.
2 . The compound according to claim 1 wherein n is 1 to 8.
3 . The compound according to claim 1 wherein said compound has the structure:
R A and R B are independently selected from H, a C 1 to C 3 alkyl group or a (CH 2 ) m OR 5 group, with the proviso that when one of R A or R B is a (CH 2 ) m OR 5 group, the other of R A or R B is not a (CH 2 ) m OR 5 group;
R 5 is H or a C 1 to C 4 alkyl or alkylene ester group;
R 6 is a group according to the structure:
Z is □(CH 2 ) n —;
X 1 , X 2 and X 3 are selected from H, F, CL, Br, NO 2 or CF 3 ;
n is 1-4
and m is 1-4
or a pharmaceutically acceptable salt thereof.
4 . The compound according to claim 3 where one of X 1 , X 2 and X 3 is F and the other of X 1 , X 2 and X 3 is H.
5 . The compound according to claim 4 wherein R 6 is
6 . The compound according to claim 5 wherein m is 1-2, n is 1-2, R A is CH 3 and R B is CH 2 CH 2 OH.
7 . The compound according to claim 6 wherein m is 1 and n is 2.
8 . The compound according to claim 3 wherein R 6 is
and n is 1-2, m is 1-2.
9 . The compound according to claim 8 wherein R A is CH 3 and R B is CH 2 CH 2 OH.
10 . The compound according to claim 3 wherein R 6 is
X 1 , X 2 and X 3 are selected from H, F, Cl, Br, NO 2 or CF 3 ;
m is 1-2, n is 1-2, R A is CH 3 and R B is CH 2 CH 2 OR.
11 . The compound according to claim 10 wherein R is a C 3 -C 6 alkylene ester group.
12 . The compound according to claim 11 wherein X 1 , X 2 and X 3 are H.
13 . The compound according to claim 1 wherein said chemical structure is
where R′ and R 2 are H;
R 3 is a (CH 2 ) n OR 5 group;
and R 4 is H or a group according to the structure:
Z is □(CH 2 ) n — and
n is 1-2.
14 . The compound according to claim 13 wherein R 5 is H.
15 . A pharmaceutical composition comprising an effective amount of a compound according to the chemical structure:
Where each of R′, R 2 and R 4 is independently selected from H, a C 1 to C 12 straight, branch-chained or cyclic saturated or unsaturated hydrocarbon, a (CH 2 ) n OR 5 group or an R 6 group;
R 3 is H, a C 1 to C 12 alkyl or alkene group or a (CH 2 ) nOR 5 group with the proviso that R 3 and R 4 are not both H;
R A and R B are independently selected from H, a C 1 to C 12 alkyl or alkenyl group or a (CH 2 ) m OR 5 group, preferably with the proviso that when one of R A or R B is a (CH 2 ) m OR 5 group, the other of R A or R B is not a (CH 2 ) m OR 5 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:
Z is
n is 0 to 12;
m is 1 to 8; and
X 1 , X 2 and X 3 are each independently selected from H, OH, F, Cl, Br, R 4 , OR 4 , CF 3 or OCF 3 ;
or a pharmaceutically acceptable salt thereof,
optionally in combination with a pharmaceutically acceptable additive, carrier or excipient.
16 . The composition according to claim 15 wherein n is 1 to 8.
17 . The composition according to claim 15 wherein said compound has the structure:
R A and R B are independently selected from H, a C 1 to C 3 alkyl group or a (CH 2 ) m OR 5 group, with the proviso that when one of R A or R B is a (CH 2 ) m OR 5 group, the other of R A or R B is not a (CH 2 ) m OR 5 group;
R 5 is H or a C 1 to C 4 alkyl or alkylene ester group;
R 6 is a group according to the structure:
Z is □(CH 2 ) n —;
X 1 , X 2 and X 3 are selected from H, F, Cl, Br, NO 2 or CF 3 ;
n is 1-4
and m is 1-4
or a pharmaceutically acceptable salt thereof.
18 . The composition according to claim 17 where one of X 1 , X 2 and X 3 is F and the other of X i , X 2 and X 3 is H.
19 . The composition according to claim 18 wherein R 6 is
20 . The composition according to claim 19 wherein m is 1-2, n is 1-2, R A is CH 3 and R B is CH 2 CH 2 OH.
21 . The composition according to claim 20 wherein m is 1 and n is 2.
22 . The composition according to claim 17 wherein R 6 is
and n is 1-2, m is 1-2.
23 . The composition according to claim 22 wherein R A is CH 3 and R B is CH 2 CH 2 OH.
24 . The composition according to claim 17 wherein R 6 is
X 1 , X 2 and X 3 are selected from H, F, Cl, Br, NO 2 or CF 3 ; m is 1-2, n is 1-2, R A is CH 3 and R B is CH 2 CH 2 OR.
25 . The composition according to claim 24 wherein R is a C 3 -C 6 alkylene ester group.
26 . The composition according to claim 25 wherein X 1 , X 2 and X 3 are H.
27 . The composition according to claim 15 wherein said chemical structure is
where R′ and R 2 are H;
R 3 is a (CH 2 ) n OR 5 group;
and R 4 is H or a group according to the structure:
Z is □(CH 2 ) n — and
n is 1-2.
28 . The composition according to claim 27 wherein R 5 is H.
29 . A method of treating a patient having a neurodegenerative condition or other neurological condition where acetylcholine transmission neurons and their target cells are affected comprising administering to said patient an effective amount of a compound according to the chemical structure:
Where each of R′, R 2 and R 4 is independently selected from H, a C 1 to C 12 straight, branch-chained or cyclic saturated or unsaturated hydrocarbon, a (CH 2 ) n OR 5 group or an R 6 group;
R 3 is H, a C 1 to C 12 alkyl or alkene group or a (CH 2 ) nOR 5 group with the proviso that R 3 and R 4 are not both H;
R A and R B are independently selected from H, a C 1 to C 12 alkyl or alkenyl group or a (CH 2 ) m OR 5 group, preferably with the proviso that when one of R A or R B is a (CH 2 ) m OR 5 group, the other of R A or R B is not a (CH 2 ) m OR 5 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:
Z is
n is 0 to 12;
m is 1 to 8; and
X 1 , X 2 and X 3 are each independently selected from H, OH, F, Cl, Br, R 4 , OR 4 , CF 3 or OCF 3 ;
or a pharmaceutically acceptable salt thereof.
30 . The method according to claim 29 wherein n is 1 to 8.
31 . The method according to claim 29 wherein said compound has the structure:
R A and R B are independently selected from H, a C 1 to C 3 alkyl group or a (CH 2 ) m OR 5 group, with the proviso that when one of R A or R B is a (CH 2 ) m OR 5 group, the other of R A or R B is not a (CH 2 ) m OR 5 group;
R 5 is H or a C 1 to C 4 alkyl or alkylene ester group;
R 6 is a group according to the structure:
Z is □(CH 2 ) n —;
X 1 , X 2 and X 3 are selected from H, F, Cl, Br, NO 2 or CF 3 ;
n is 1-4
and m is 1-4
or a pharmaceutically acceptable salt thereof.
32 . The method according to claim 31 where one of X i , X 2 and X 3 is F and the other of X 1 , X 2 and X 3 is H.
33 . The method according to claim 32 wherein R 6 is
34 . The method according to claim 33 wherein m is 1-2, n is 1-2, R A is CH 3 and R B is CH 2 CH 2 OH.
35 . The method according to claim 34 wherein m is 1 and n is 2.
36 . The method according to claim 31 wherein R 6 is
and n is 1-2, m is 1-2.
37 . The method according to claim 36 wherein R A is CH 3 and R B is CH 2 CH 2 OH.
38 . The method according to claim 31 wherein R 6 is
X 1 , X 2 and X 3 are selected from H, F, Cl, Br, NO 2 or CF 3 ;
m is 1-2, n is 1-2, R A is CH 3 and R B is CH 2 CH 2 OR.
39 . The method according to claim 38 wherein R is a C 3 -C 6 alkylene ester group.
40 . The method according to claim 39 wherein X 1 , X 2 and X 3 are H.
41 . The method according to claim 28 wherein said chemical structure is
where R 1 and R 2 are H;
R 3 is a (CH 2 ) n OR 5 group;
and R 4 is H or a group according to the structure:
Z is □(CH 2 ) n — and
n is 1-2.
42 . The method according to claim 41 wherein R 5 is H.
43 . The method according to claim 29 wherein said condition is selected from the group consisting of Parkinson's disease, Huntington disease, Alzheimer's disease, 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, dementia with Lewy bodies, schizophrenia, paraneoplastic cerebellar degeneration and neurodegenerative conditions caused by stroke.
44 . The method according to claim 31 wherein said condition is selected from the group consisting of Parkinson's disease, Huntington disease, Alzheimer's disease, 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, dementia with Lewy bodies, schizophrenia, paraneoplastic cerebellar degeneration and neurodegenerative conditions caused by stroke.
45 . The method according to claim 34 wherein said condition is selected from the group consisting of Parkinson's disease, Huntington disease, Alzheimer's disease, 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, dementia with Lewy bodies, schizophrenia, paraneoplastic cerebellar degeneration and neurodegenerative conditions caused by stroke.
46 . The method according to claim 38 wherein said condition is selected from the group consisting of Parkinson's disease, Huntington disease, Alzheimer's disease, 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, dementia with Lewy bodies, schizophrenia, paraneoplastic cerebellar degeneration and neurodegenerative conditions caused by stroke.
47 . The method according to claim 39 wherein said condition is selected from the group consisting of Parkinson's disease, Huntington disease, Alzheimer's disease, 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, dementia with Lewy bodies, schizophrenia, paraneoplastic cerebellar degeneration and neurodegenerative conditions caused by stroke.Cited by (0)
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