Anti-PCSK9 compounds and methods for the treatment and/or prevention of cardiovascular diseases

Patent metadata

Field	Value
Publication number	US-10131637-B2
Application number	US-201414767126-A
Country	US
Kind code	B2
Filing date	Mar 11, 2014
Priority date	Mar 15, 2013
Publication date	Nov 20, 2018
Grant date	Nov 20, 2018

Abstract

Disclosed are compounds of the class of 2-phenylacetamides that modulate the physiological action of the proprotein convertase subtilisin kexin type 9 (PCSK9), and methods of using these modulators to reduce LDL-cholesterol levels and/or for the treatment and/or prevention of cardiovascular disease (CVD), including treatment of hypercholesterolemia.

First claim

What is claimed is:

1. A composition comprising:
A) a compound represented by the formula:

including the pharmaceutically acceptable salts and all stereoisomers thereof,
wherein X 1 , Y 1 , and Z 1 are the same or different and each represents hydrogen or a substituent selected from the group consisting of hydroxyl, halogen, amino, alkoxy, carboxy, amido, aminocarbonylamino, monoalkylaminocarbonylamino, dialkylaminocarbonylamino, carbamato, carboxamido, monoalkylaminosulfinyl, dialkylaminosulfinyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, hydroxysulfonyloxy, alkoxysulfonyloxy, alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl, alkylsulfonylalkyl, monoalkylaminosulfonylalkyl, dialkylaminosulfonylalkyl, monoalkylaminosulfinylalkyl, dialkylaminosulfinyl and, optionally substituted, lower alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl;
X is O or NR 4 ; R 4 is selected from the group consisting of H and lower alkyl;
A is CO, CONR 5 , or SO 2 ; R 5 is selected from the group consisting of H and lower alkyl, and
B) a low density lipoprotein (LDL) lowering drug.

2. A compound which is N-(3-chloro-4-methylphenyl)-2-[(4-acetamidophenyl)formamido]-2-phenylacetamide.

3. A compound which is [(3-chloro-4-methylphenyl)carbamoyl](phenyl)methyl 4-acetamidobenzoate.

4. The composition of claim 1 , wherein said LDL lowering drug is a statin.

5. The composition of claim 1 , wherein said LDL lowering drug is atorvastatin.

6. The composition of claim 1 , wherein said amido is a formamido, alkylamido, or arylamido.

Assignees

• Shifa Biomedical Corp
• Temple University—Of the Commonwealth System of Higher Education

Inventors

• Abdel-Meguid Sherin Salaheldin
• Abou-Gharbia Magid
• Blass Benjamin
• Childers Wayne
• Elshourbagy Nabil
• Ghidu Victor
• Martinez Rogelio
• Meyers Harold
• Mousa Shaker A

Classifications

• A61K31/235

  having an aromatic ring attached to a carboxyl group · CPC title

• C07D213/68

  attached in position 4 · CPC title

• A61K31/4418

  having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine · CPC title

• C07C2602/02

  the rings having only two atoms in common · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title