2-oxo-3,4-dihydropyridine-5-carboxylates and their use

Patent metadata

Field	Value
Publication number	US-9932309-B2
Application number	US-201515326848-A
Country	US
Kind code	B2
Filing date	Jul 28, 2015
Priority date	Jul 29, 2014
Publication date	Apr 3, 2018
Grant date	Apr 3, 2018

Abstract

The present invention is directed to novel compounds of Formula (I), pharmaceutically acceptable salts or solvates thereof, and their use.

First claim

The invention claimed is:

1. A compound of general Formula I:

or pharmaceutically acceptable salts or solvates thereof,
wherein
R 1 is C1-C6-alkyl, aryl or heteroaryl, wherein said aryl moiety is independently substituted by one or more groups selected from the group consisting of halo, cyano, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, and 5- or 6-membered aryl, and said heteroaryl moiety is optionally independently substituted by one or more groups selected from the group consisting of halo, cyano, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, and 5- or 6-membered aryl;
L 1 is a single bond or (CH 2 ) n , wherein n is 1, 2 or 3;
R 2 is C1-C4 alkyl, alkynyl, alkoxy, hydroxy, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonylamino, cyano, B alkylsulfonyl, aralkyl, cycloalkyl, heterocyclyl or heteroaryl, wherein said heterocyclyl moiety is optionally substituted by one or more substituents independently selected from the group consisting of alkyl and alkoxycarbonyl, and said heteroaryl moiety is optionally substituted by one or more C1-C2-alkyl;
L 2 is a single bond or (CH 2 ) n , wherein n is 1 or 2;
R 3 is aryl, heteroaryl, cycloalkyl or arylcarbonyl wherein each of said moieties is optionally substituted by one or more substituents independently selected from the group consisting of halo, alkyl, haloalkyl, aryl, cyano, alkoxy, haloalkoxy, alkoxycarbonyl, aminoalkoxy, alkylaminoalkoxy, dialkylaminoalkoxy, HO 3 S-alkoxy,

wherein m is 1 to 500,
[N(R 8 ) 3 -alkoxy] + Q − , wherein R 8 is linear C1-C4-alkyl and Q − is a counter anion, and
a cyclic moiety selected from the group consisting of

wherein R A is H, OH, C0-C4-alkyl-COOH or C1-C6-alkyl, R B is C1-C6-alkyl optionally substituted with —COOH, R C is C1-C6-alkyl, and Q − is a counter anion;
or wherein said cycloalkyl moiety is fused to an aryl, preferably phenyl, moiety;
R 4 is H, C1-C2-alkyl or 5- or 6-membered aryl;
R 5 is H, C1-C4-alkyl, 5- or 6-membered aryl, or alkoxyalkyl; and
X is O or NR′, wherein R′ is H, C1-C2-alkyl or R′ taken together with L 2 and R 3 form a 5- or 6-membered heterocyclyl moiety which is optionally fused to an aryl moiety.

2. The compound according to claim 1 having Formula II

and pharmaceutically acceptable salts and solvates thereof.

3. The compound according to claim 2 having Formula IIa

and pharmaceutically acceptable salts, and solvates thereof, wherein
R 6 is halo, alkyl, haloalkyl, aryl, cyano, alkoxy, haloalkoxy, alkoxycarbonyl, aminoalkoxy, alkylaminoalkoxy, dialkylaminoalkoxy, HO 3 S-alkoxy,

wherein m is 1 to 500,
[N(R 8 ) 3 -alkoxy] + Q − , wherein R 8 is linear C1-C4-alkyl and Q − is a counter anion, or
a cyclic moiety selected from the group consisting of

wherein R A is H, OH, C0-C4-alkyl-COOH or C1-C6-alkyl, R B is C1-C6-alkyl optionally substituted with —COOH, R C is C1-C6-alkyl, and Q − is a counter anion.

4. The compound according to claim 1 having Formula III

and pharmaceutically acceptable salts, and solvates thereof, wherein
R 7 and R 8 are independently selected from the group consisting of H, halo, haloalkyl, and cyano, with the proviso that at least one of R 7 and R 8 is not H.

5. The compound according to claim 1 having Formula IV

and pharmaceutically acceptable salts, and solvates thereof, wherein
R 9 and R 10 are independently selected from the group consisting of H, halo, haloalkyl, and cyano, with the proviso that at least one of R 9 and R 10 is not H.

6. The compound according to claim 1 having Formula V

and pharmaceutically acceptable salts, and solvates thereof.

7. The compound according to claim 1 and pharmaceutically acceptable salts, and solvates thereof, wherein R 5 is methyl.

8. The compound according to claim 1 and pharmaceutically acceptable salts, and solvates thereof, wherein L 1 and R 2 are taken together to form a moiety selected from the group consisting of cycloalkylmethyl, heterocyclylmethyl, heteroarylmethyl, 2-alkoxyeth-1-yl, 3-alkoxyprop-1-yl, and alkoxycarbonylmethyl, said heteroarylmethyl moiety being optionally substituted by one or more C1-C2 alkyl.

9. The compound according to claim 1 and pharmaceutically acceptable salts, and solvates thereof, wherein R 2 is tetrahydrofuranyl.

10. The compound according to claim 9 and pharmaceutically acceptable salts, and solvates thereof, wherein L 1 is CH 2 .

11. The compound according to claim 1 selected from the group consisting of:

Assignees

• Univ Lille Ii Droit & Sante
• Pasteur Institut
• Inst Nat Sante Rech Med
• Inst Nat Sante Rech Med

Inventors

• Charton Julie
• Deprez Benoit
• Leroux Florence
• Staels Bart
• Muhr-Tailleux Anne
• Hennuyer Nathalie
• Lestavel Sophie
• Picon Sylvain
• Aknin Karen
• Boulahjar Rajaa
• Dubanchet Barbara

Classifications

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P3/08

  for glucose homeostasis (pancreatic hormones A61P5/48) · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

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