Compositions and methods for treating neurodegenerative diseases
Compounds, and compositions, methods, and uses thereof, are described herein for treating neurodegenerative diseases and disorders. In particular, vasopressin receptor modulators, and compositions, methods and uses thereof, are described herein for treating neuropsychiatric aspects of neurodegenerative diseases such as Huntington's Disease, Parkinson's Disease, and Alzheimer's Disease.
1. A method for treating Huntington's Disease, Parkinson's Disease, or Alzheimer's Disease in a host animal, the method comprising administering a composition comprising one or more compounds selected from the group consisting of the formulae
Example
A′
44
4-(piperidinyl)piperidinyl
63
1-benzylpiperidin-4-ylamino
Example
A
A′
132F
(R)-1-phenylethy-1-
4-
amino
(piperidinyl)piperidinyl
Example
A′
133
4-
(piperidinyl)piperidinyl
Example
A′
35
4-(2-phenylethyl)piperazinyl
88
4-(piperidinyl)piperidinyl
91
4-(pyrrolidinyl)piperazinyl
95
4-benzylpiperazinyl
96
4-(3,4-
methylenedioxybenzyl)piperazinyl
103
4-butylpiperazinyl
104
4-isopropylpiperazinyl
110
4-cyclohexylpiperazinyl
111
4-(2-cyclohexylethyl)piperazinyl
112
4-[2-(morpholin-4-yl)ethyl]piperazinyl
120
4-(cyclohexylmethyl)piperazinyl
120B
4-propyl-piperazinyl
120E
4-(piperidinylmethyl)piperidinyl
120H
4-cyclohexylpiperazinyl
Example
A′
226
4-
cyclohexylpiperazinyl
229
4-n-butylpiperazinyl
Example
A′
172
(3-trifluoromethoxybenzyl)amino
174
(3,5-dichlorobenzyl)amino
175
(2,5-dichlorobenzyl)amino
176
(2,3-dichlorobenzyl)amino
177
(2-fluoro-5-trifluoromethylbenzyl)amino
179
(3-fluoro-5-trifluoromethylbenzyl)amino
180
(2-fluoro-3-trifluoromethylbenzyl)amino
182
(2-trifluoromethylbenzyl)amino
185
(3,5-difluorobenzyl)amino
187
(3-chlorobenzyl)amino
189
(3-nitrobenzyl)amino
190
(3-bromobenzyl)amino
191
benzylamino
193
(3-methylbenzyl)amino
203
(1S)-(3-methoxyphenyl)ethylamino
205
N-methyl-N-(3-
trifluoromethylbenzyl)amino
206
[(S)-α-methylbenzyl]amino
207
(1-phenylcycloprop-1yl)amino
212
[(5-methylfur-2-yl)methyl]amino
213
(thien-2-ylmethyl)amino
214
[(S)-1,2,3,4-tetrahydro-1-naphth-1-yl]amino
215
[(R)-1,2,3,4-tetrahydro-1-naphth-1-yl]amino
216
(indan-1-yl)amino
217
(1-phenylcyclopent-1-yl)amino
219
(2,5-dimethoxybenzyl)amino
221A
N-methyl-3-Me-benzylamide
221B
N-methyl-2,3-Cl-benzylamide
221C
N-methyl-3-Cl-benzylamide
221D
N-methyl-3-Br-benzylamide
221F
(R)-1-(3-trifluorophenyl)ethylamide
221G
1-phenyl-cyclohexylamide
221H
1-(2-fluorophenyl)-cyclopentylamide
221P
indan-2-ylamino
Example
A
A′
221
1-(3-fluorophenyl)-
4-
AM
cyclopentylamino
cyclohexylpiperazinyl
221
1-(4-methylphenyl)-
4-
AP
cyclopropylamino
cyclohexylpiperazinyl
221
(R)-1,2,3,4-tetrahydro-1-
4-ethylpiperazinyl
BD
naphtylamino
Ex-
am-
ple
R 10
Ar 2
n
α
A
A′
241
Ph
Ph
2
L
(R)-1,2,3,4-
4-cyclo-
tetrahydronaphth-1-
pentylpiperazin-
ylamino
1-yl
242
Ph
3-
2
L
(R)-1,2,3,4-
4-cyclo-
MeO—Ph
tetrahydronaphth-1-
hexylpiperazin-
ylamino
1-yl
243
Ph
3-Cl—Ph
2
L
(R)-1,2,3,4-
4-cyclo-
tetrahydronaphth-1-
hexylpiperazin-
ylamino
1-yl
244
Ph
3-Cl—Ph
2
L
1-phenyl-cyclopent-1-
4-cyclo-
ylamino
hexylpiperazin-
1-yl
245
Ph
3-F—Ph
2
L
(R)-1,2,3,4-
4-cyclohexyl-
tetrahydronaphth-1-
piperazin-
ylamino
1-yl
246
Ph
3-CF 3 —Ph
2
L
(R)-1,2,3,4-
4-cyclohexyl-
tetrahydronaphth-1-
piperazin-
ylamino
1-yl
247
Ph
3-Cl—Ph
1
D
N-methyl-3-CF 3 -
4-(1-piperidyl)
benzylamino
piperidin-1-yl
249
Ph
3-
2
L
(R)-1,2,3,4-
4-cyclohexyl-
NO 2 —Ph
tetrahydronaphth-1-
piperazin-
ylamino
1-yl
251
3-
3-Cl—Ph
2
L
(R)-1,2,3,4-
4-cyclohexyl-
Cl—Ph
tetrahydronaphth-1-
piperazin-
ylamino
1-yl
252
Ph
3,5-
2
L
(R)-1,2,3,4-
4-cyclohexyl-
Cl 2 —Ph
tetrahydronaphth-1-
piperazin-
ylamino
1-yl
256
3-
Ph
1
D
(R)-1-Ph-ethylamino
4-(1-pipendyl)
Cl—Ph
piperidin-1-yl
Example
A′
α
232
4-(piperidinyl)piperidinyl
D
232D
4-cyclohexylpiperazinyl
DL
Example
Ar
255
thien-2-yl
Example
Y 1
R N
R a
R Ar
R 1
559
3-Cl
H
(R)—Me
H
H
606
3-Br
H
(R)—Me
H
H
617
3-Br
Me
H
3-CF 3
H
623
H
H
(R)—CF 3
H
H
626
H
H
(S)—CF 3
H
H
677
H
H
H
2-F
H
682
H
H
H
2-Br
H
778
3-Me
H
(R)—Me
H
H
Example
R N
R a
R Ar
R 1
599
Me
H
3-CF 3
H
601
H
(R)—Me
H
H
and
Example
R N
R a
R Ar
R 1
670
Me
H
3-CF 3
H
672
H
(R)—Me
H
H
and pharmaceutically acceptable salts thereof.
2. The method of claim 1 for treating Huntington's Disease.
3. The method of claim 2 for treating one or more neuropsychiatric symptoms of Huntington's Disease.
4. The method of claim 3 wherein the neuropsychiatric symptoms comprise aggression, irritability, or anger, or a combination thereof.
5. The method of claim 1 for treating Parkinson's Disease.
6. The method of claim 5 for treating one or more neuropsychiatric symptoms of Parkinson's Disease.
7. The method of claim 6 wherein the neuropsychiatric symptoms comprise aggression, irritability, or anger, or a combination thereof.
8. The method of claim 1 for treating Alzheimer's Disease.
9. The method of claim 8 for treating one or more neuropsychiatric symptoms of Alzheimer's Disease.
10. The method of claim 9 wherein the neuropsychiatric symptoms comprise aggression, irritability, or anger, or a combination thereof.