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 selective vasopressin Vla receptor antagonists to the host animal, wherein at least one of the antagonists is a compound of the formula:
or a salt thereof, wherein
A is a carboxylic acid, an ester, or an amide;
B is a carboxylic acid, an ester, or an amide; or B is an alcohol or thiol, or a derivative thereof;
R 1 is hydrogen or C 1 -C 6 alkyl;
R 2 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halo, haloalkyl, cyano, formyl, alkylcarbonyl, or a substituent selected from the group consisting
of —CO 2 R 8 , —CONR 8 R 8′ , and —NR 8 (COR 9 ); where R 8 and R 8′ are each independently selected from hydrogen, alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted arylalkyl; or R 8 and R 8′ are taken together with the attached nitrogen atom to form a heterocyclyl group; and where R 9 is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and R 8 R 8′ N—(C 1 -C 4 alkyl);
R 3 is an amino, amido, acylamido, or ureido group, which is optionally substituted; or R 3 is a nitrogen-containing heterocyclyl group attached at a nitrogen atom; and
R 4 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkylcarbonyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylhaloalkyl, optionally substituted arylalkoxyalkyl, optionally substituted arylalkenyl, optionally substituted arylhaloalkenyl or optionally substituted arylalkynyl.
2. The method of claim 1 wherein at least one of the antagonists is a compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein
A and A′ are each independently selected from —CO 2 H, or an ester or amide derivative thereof;
n is an integer selected from 0 to about 3;
R 1 is hydrogen or C 1 -C 6 alkyl;
R 2 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halo, haloalkyl, cyano, formyl, alkylcarbonyl, or a substituent selected from the group consisting of —CO 2 R 8 , —CONR 8 R 8′ , and —NR 8 (COR 9 ); where R 8 and R 8′ are each independently selected from hydrogen, alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted arylalkyl; or R 8 and R 8′ are taken together with the attached nitrogen atom to form an heterocycle; and where R 9 is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and R 8 R 8′ N—(C 1 -C 4 alkyl);
R 3 is an amino, amido, acylamido, or ureido group, which is optionally substituted; or R 3 is a nitrogen-containing heterocyclyl group attached at a nitrogen atom; and
R 4 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkylcarbonyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylhaloalkyl, optionally substituted arylalkoxyalkyl, optionally substituted arylalkenyl, optionally substituted arylhaloalkenyl, or optionally substituted arylalkynyl.
3. The method of claim 1 wherein at least one of the antagonists is a compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein
A is —CO 2 H, or an ester or amide derivative thereof;
Q is oxygen; or Q is sulfur or disulfide, or an oxidized derivative thereof;
n is an integer from 1 to 3;
R 1 , R 2 , R 3 , and R 4 are as defined in formula I; and
R 5″ is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, and optionally substituted aminoalkyl.
4. The method of claim 2 wherein A is of the formula
where R N is hydrogen or optionally substituted alkyl, or an amide prodrug forming group; R a is hydrogen or optionally substituted alkyl; and R Ar is hydrogen or one or more aryl substituents.
5. The method of claim 2 wherein n is 1 or 2.
6. The method of claim 2 wherein R 1 is hydrogen; and R 2 is hydrogen or alkyl.
7. The method of claim 2 wherein R 3 is of the formulae:
wherein R 10 and R 11 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, alkoxycarbonyl, alkylcarbonyloxy, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkyloxy, optionally substituted aryl alkylcarbonyloxy, diphenylmethoxy, and triphenylmethoxy; and R 12 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted arylalkyl, and optionally substituted aryloyl.
8. The method of claim 1 for treating one or more neuropsychiatric symptoms of Huntington's Disease.
9. The method of claim 8 wherein the compound is selected from the group consisting of
and salts thereof, and combinations thereof.
10. A pharmaceutical composition adapted for or capable of treating a neurodegenerative disease or disorder in a host animal, the composition comprising one or more compounds of the formula of claim 1 , and optionally, one or more carriers, diluents, or adjuvants, or a combination thereof.
11. The method of claim 2 wherein one or both of A and A′ is an independently selected amido of the formula C(O)NHX or C(O)NR 14 X, where R 14 is selected from the group consisting of hydroxy, alkyl, alkoxycarbonyl, and benzyl; and X is selected from the group consisting of alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl-(C 1 -C 4 alkyl), R 6 R 7 N—, and R 6 R 7 N—(C 2 -C 4 alkyl), where each heterocyclyl is independently selected.
12. The method of claim 2 wherein one or both of A and A′ is an amide of an independently selected optionally substituted nitrogen-containing heterocycle attached at a nitrogen, and selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, triazolidinyl, triazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,3-oxazinyl, morpholinyl, oxadiazolidinyl, and thiadiazolidinyl.
13. The method of claim 2 wherein one or both of A and A′ is an amide of an optionally substituted 1,2,3,4-tetrahydroisoquinolin-2-yl.
14. The method of claim 2 wherein one or both of A and A′ is an independently selected amide of a substituted piperidine or piperazine.
15. The method of claim 2 wherein R 4 is of the formulae:
wherein Y is an electron withdrawing group, and Y 1 is hydrogen or one or more aryl substituents.
16. The method of claim 3 wherein Q is oxygen or sulfur.
17. The method of claim 3 wherein R 5″ is optionally substituted aryl(C 2 -C 4 alkyl).
18. The method of claim 3 wherein n is 1 or 2.
19. The method of claim 3 wherein A is of the formula C(O)NHX or C(O)NR 14 X, where R 14 is selected from the group consisting of hydroxy, alkyl, alkoxycarbonyl, and benzyl; and X is selected from the group consisting of alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl-(C 1 -C 4 alkyl), R 6 R 7 N—, and R 6 R 7 N—(C 2 -C 4 alkyl).
20. The method of claim 3 wherein A is an amide of an optionally substituted nitrogen-containing heterocycle attached at a nitrogen, and selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, triazolidinyl, triazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,3-oxazinyl, morpholinyl, oxadiazolidinyl, and thiadiazolidinyl.
21. The method of claim 7 wherein R 3 is
22. The method of claim 3 wherein R 3 is
where R 10 and R 11 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, alkoxycarbonyl, alkylcarbonyloxy, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkyloxy, optionally substituted aryl alkylcarbonyloxy, diphenylmethoxy, and triphenylmethoxy.
23. The method of claim 9 wherein the neuropsychiatric symptoms comprise aggression, irritability, or anger, or a combination thereof.
24. The method of claim 23 wherein the compound is
or a salt thereof.
25. The method of claim 1 for treating one or more neuropsychiatric symptoms of Parkinson's Disease.
26. The method of claim 25 wherein the compound is selected from the group consisting of
and salts thereof, and combinations thereof.
27. The method of claim 26 wherein the neuropsychiatric symptoms comprise aggression, irritability, or anger, or a combination thereof.
28. The method of claim 27 wherein the compound is
or a salt thereof.
29. The method of claim 1 for treating one or more neuropsychiatric symptoms of Alzheimer's Disease.
30. The method of claim 29 wherein the compound is selected from the group consisting of
and salts thereof, and combinations thereof.
31. The method of claim 30 wherein the neuropsychiatric symptoms comprise aggression, irritability, or anger, or a combination thereof.
32. The method of claim 31 wherein the compound is
or a salt thereof.