N-substituted-5-substituted phthalamic acids as sortilin inhibitors
The present invention is directed to N-substituted-5-substituted phthalamic acids which of formula (A). The compounds are considered useful for the treatment of diseases treatment of a neurodegenerative disease, psychiatric disease, motorneuron disease, peripheral neuropathies, pain, neuroinflammation or atherosclerosis such as Alzheimer's disease and Parkinson's disease.
1. A compound of Formula [A]:
wherein:
R1 represents H or F,
R2 represents halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 1 -C 6 halogenated alkyl,
R3 represents halogen, H, C 1 -C 6 alkyl or C 1 -C 6 halogenated alkyl,
L is a direct bond or represents CH 2 ,
R 4 represents:
wherein X represents C or N, wherein N is present at 1 or 2 positions, and
* denotes the attachment point,
or
wherein:
M represents C, N or CC≡N,
A and B each independently represents H, C 1 -C 3 alkyl, or
A and B form a 5, 6 or 7 membered carbocyclic saturated or unsaturated ring together with the carbon atom they are attached to, and * denotes the attachment point,
or
wherein * denotes the attachment point;
that may be substituted with C≡N, 1 or 2 C 1 -C 3 alkyl, 1 or 2 halogenated alkyl, 1 or 2 C 1 -C 3 alkoxy or 1 or 2 halogen(s),
or a pharmaceutically acceptable salt or prodrug thereof,
with the proviso that the compound is not 5-methyl-2-[[(4-methyl-2-thiazolyl)amino]carbonyl].
2. The compound according to claim 1 , wherein the halogenated alkyl is CF 3 .
3. The compound according to claim 1 , wherein R2 is Cl, Br or CF 3 and R3 is H or Cl.
4. The compound according to claim 1 , wherein said compound is selected from the group consisting of:
N-(6-Methyl-pyridin-2-yl)-5-trifluoromethyl-phthalamic acid;
5-Bromo-N-(6-methyl-pyridin-2-yl)-phthalamic acid;
5-Methyl-N-(6-methyl-pyridin-2-yl)-phthalamic acid;
5-Chloro-N-(6-methyl-pyridin-2-yl)-phthalamic acid;
4,5-Dichloro-N-(6-methyl-pyridin-2-yl)-phthalamic acid;
5-Bromo-N-(3-methyl-4,5,6,7-tetrahydro-benzo[b]thiophen-2yl)-phthalamic acid;
N-(5,6-Dimethyl-pyridin-2-yl)-5-trifluoromethyl-phthalamic acid;
N-(4-methyl-pyridin-2-yl)-5-trifluoromethyl-phthalamic acid;
N-(2-methyl-pyridin-4-yl)-5-trifluoromethyl-phthalamic acid;
4,5-Dichloro-N-(4-methyl-pyridin-2-yl)-phthalamic acid;
4,5-Dichloro-N-(5,6-Dimethyl-pyridin-2-yl)-phthalamic acid;
4,5-Dichloro-N-(2-methyl-pyridin-4-yl)-phthalamic acid;
4,5-Dichloro-N-(2-methyl-pyrimidin-4-yl)-phthalamic acid;
5-Chloro-6-fluoro-N-(6-methyl-pyridin-2-yl)-phthalamic acid;
4,5-Dimethyl-N-(6-methyl-pyridin-2-yl)-phthalamic acid;
2-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)carbamoyl)-5-(trifluoromethyl)benzoic acid;
2-(4-methylpyrimidin-2-yl)carbamoyl)-5-(trifluoromethyl)benzoic acid;
2-((5,6-dimethylpyrazin-2-yl)carbamoyl)-5-(trifluoromethyl)benzoic acid;
5-Bromo-N-(5-methyl-pyridin-2-yl)-phthalamic acid;
5-Bromo-N-(5-chloro-pyridin-2-yl)-phthalamic acid;
5-Bromo-N-pyridin-2-yl-phthalamic acid;
5-Bromo-N-(6-chloro-pyridin-2-yl)-phthalamic acid;
5-Bromo-N-(5,6-dimethyl-pyridin-2-yl)-phthalamic acid;
5-Bromo-N-(4-methyl-pyridin-2-yl)-phthalamic acid;
5-Bromo-N-(2-methyl-pyridin-4-yl)-phthalamic acid;
5-Bromo-N-pyridin-3-yl)-phthalamic acid;
5-Bromo-N-(3-methyl-pyridin-2-yl)-phthalamic acid;
5-Bromo-N-(4-methyl-thiazol-2-yl)-phthalamic acid;
5-Bromo-N-quinolin-2-yl-phthalamic acid;
5-Bromo-N-(5,6-dichloro-pyridin-2-yl)-phthalamic acid;
5-Bromo-N-(6-methyl-pyridin-3-yl)-phthalamic acid;
5-Bromo-N-(6-methyl-pyridazin-3-yl)-phthalamic acid;
5-Bromo-N-(4,6-dimethyl-pyridin-2-yl)-phthalamic acid;
5-Bromo-N-(2-methyl-pyrimidin-4-yl)-phthalamic acid;
5-Bromo-N-(6-methyl-pyrimidin-4-yl)-phthalamic acid;
N-(2-Methoxy-pyridin-4-yl)-5-trifluoromethyl-phthalamic acid;
N-(6-Methoxy-pyridin-2-yl)-5-trifluoromethyl-phthalamic acid;
N-Pyridin-2-ylmethyl-5-trifluoromethyl-phthalamic acid;
N-Pyridin-4-ylmethyl-5-trifluoromethyl-phthalamic acid;
N-Pyridin-3-ylmethyl-5-trifluoromethyl-phthalamic acid;
N-(6-Methyl-pyridin-2-yl)-5-propyl-phthalamic acid;
N 5-Isopropenyl-N-(6-methyl-pyridin-2-yl)-phthalamic acid;
N 5-Isopropyl-N-(6-methyl-pyridin-2-yl)-phthalamic acid;
2-(2-methylpyrimidin-4-yl)carbamoyl)-5-(trifluoromethyl)benzoic acid;
2-(4,5-dimethylpyrimidin-2-yl)carbamoyl)-5-(trifluoromethyl)benzoic acid;
2-(5,6,7,8-tetrahydroquinolin-2-yl)carbamoyl)-5-(trifluoromethyl)benzoic acid;
2-((6-methylpyridin-2-yl)carbamoyl)-4, 5-bis(trifluoromethyl)benzoic acid;
24(5,6,7,8-tetrahydroquinolin-2-yl)carbamoyl)-4,5-bis(trifluoromethyl)benzoic acid;
2-((5,6-dimethylpyridin-2-yl)carbamoyl)-4, 5-bis(trifluoromethyl)benzoic acid;
2-((2-methylpyrimidin-4-yl)carbamoyl)-4, 5-bis(trifluoromethyl)benzoic acid; and
2-((2, 6-dimethylpyridin-4-yl)carbamoyl)-5-(trifluoromethyl)benzoic acid;
or is a pharmaceutically acceptable salt or prodrug thereof.
5. A pharmaceutical composition comprising a compound according to claim 1 and one or more pharmaceutically acceptable carriers or diluents.
6. A pharmaceutical composition comprising a prodrug according to claim 1 and one or more pharmaceutically acceptable carriers or diluents.
7. The compound according to claim 4 , wherein said compound is N-(6-Methyl-pyridin-2-yl)-5-trifluoromethyl-phthalamic acid or a pharmaceutically acceptable salt or prodrug thereof.
8. The pharmaceutical composition according to claim 5 , wherein said compound is N-(6-Methyl-pyridin-2-yl)-5-trifluoromethyl-phthalamic acid or a pharmaceutically acceptable salt or prodrug thereof.