N-substituted-5-substituted phthalamic acids as sortilin inhibitors

Patent metadata

Field	Value
Publication number	US-9682967-B2
Application number	US-201414763544-A
Country	US
Kind code	B2
Filing date	Jan 27, 2014
Priority date	Jan 28, 2013
Publication date	Jun 20, 2017
Grant date	Jun 20, 2017

Abstract

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.

First claim

The invention claimed is:

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.

Assignees

• H Lundbeck As

Inventors

• Maltas Philip James
• Watson Stephen
• Langg{Hacek Over (A)}Rd Morten
• David Laurent

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P25/02

  for peripheral neuropathies · CPC title