One class of pyrazolone compounds and use thereof

Patent metadata

Field	Value
Publication number	US-10196389-B2
Application number	US-201515326310-A
Country	US
Kind code	B2
Filing date	Jul 14, 2015
Priority date	Jul 14, 2014
Publication date	Feb 5, 2019
Grant date	Feb 5, 2019

Abstract

Provided are a class of pyrazolone compounds and a use thereof. In particular, a compound represented by formula I is provided, wherein the definition of each variable group is as described in the description. The compounds of formula (I) have a direct AMPK-activating activity and can significantly promote the phosphorylation of AMPK and ACC of L6 myocytes and HepG2 cells in a dose-dependent manner.

First claim

The invention claimed is:

1. A compound of formula I, or a pharmaceutically acceptable salt thereof:

wherein the structure is:

R 1 is selected from the group consisting of 6- to 12-membered aryl group and 5-10 membered heteroaryl in which hydrogen atoms on the group are optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 halogen substituted alkyl, adamantyl, hydroxyl, amino, nitro, substituted or unsubstituted acetoxy group (AcO), carboxyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, substituted or unsubstituted phenyl, and —SO 2 —NH 2 ; wherein the term “substituted” as used with respect to the C1-C4 halogen substituted alkyl, substituted or unsubstituted acetoxygroup (AcO), and substituted or unsubstituted phenyl refers to one or more hydrogen atoms on the group being substituted with substituents selected from the group consisting of halogen, trifluoromethyl, hydroxy, amino, C1-C4 alkyl, C1-C4 alkoxy, adamantyl, and cyano;
R 4 is selected from the group consisting of H, C1-C4 alkyl, C1-C4 haloalkyl, halogen, hydroxy, amino, nitro, AcO, carboxyl, C1-C4 alkoxy, and cyano;
R 5 is selected from the group consisting of H, C1-C4 alkyl, C3-C7 cycloalkyl, C1-C4 alkylene-C3-C7 cycloalkyl, phenyl, C1-C4 alkylene phenyl, wherein hydrogen atoms on phenyl or C1-C4 alkylene phenyl are optionally substituted by one or more substituents selected from the group consisting of hydroxy, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein when R 5 is a phenyl-containing group, the hydrogen atoms of two adjacent carbons on the phenyl are optionally substituted by “—O—(CH 2 ) n O—”, wherein n=1, 2 or 3;
n3 is 0, 1, or 2;
X is selected from the group consisting of 0 and NR 8 , wherein R 8 is selected from the group consisting of H, C1-C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl, phenyl, and C1-C4 alkylene phenyl.

2. The compound of claim 1 , wherein:
R 1 is selected from the group consisting of 6- to 12-membered aryl group and 5-10 membered heteroaryl group in which the hydrogen atoms on the group are optionally substituted with one or more substituents selected from the group consisting of halogen, trifluoromethyl, C1-C4 alkyl, adamantyl, hydroxyl, amino, nitro, substituted or unsubstituted acetoxygroup (AcO), carboxyl, C1-C4 alkoxy, cyano, substituted or unsubstituted phenyl, and —SO 2 —NH 2 ;
R 4 is H or methyl;
R 5 is selected from the group consisting of C1-C4 alkyl, C3-C7 cycloalkyl, C1-C4 alkylene-C3-C7 cycloalkyl and benzyl, wherein the hydrogen atoms on benzyl are optionally substituted by one or more substituents selected from the group consisting of hydroxy, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and C2-C4 alkylene; wherein the hydrogen atoms of two adjacent carbons on phenyl are optionally substituted by “—O— (CH 2 ) n O—”, wherein n=1, 2 or 3;
n3 is 1; and
X is O or NR 8 , wherein R 8 is H or methyl.

3. The compound of claim 1 , wherein:
R 1 is aryl or heteroaryl selected from the group consisting of phenyl and benzothiazolyl; in which the hydrogen atoms on the aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, trifluoromethyl, C1-C4 alkyl, hydroxyl, amino, nitro, substituted or unsubstituted acetoxy group (AcO), carboxyl, C1-C4 alkoxy, cyano, substituted or unsubstituted phenyl, and —SO 2 —NH 2 ; and
X is NR B , wherein R 8 is H or methyl.

4. The compound of claim 1 , wherein R 5 is selected from the group consisting of benzyl, wherein the hydrogen atoms on benzyl are optionally substituted by one or more substituents selected from the group consisting of hydroxy, halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, and C2-C4 alkylene; wherein the hydrogen atoms of two adjacent carbons on phenyl structure of benzyl are optionally substituted by “—O— (CH 2 ) n O—”, wherein n=1, 2 or 3.

5. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

6. A preparation method of a compound of formula I of claim 1 , wherein the method comprises:
(1) reacting a compound of formula Ia with a compound of formula Ib in an inert solvent, thereby forming a compound of formula I′;

(b1) optionally dehydrogenating the compound of formula I′ in an inert solvent, thereby forming a compound of formula I″;

(b2) optionally conducting an elimination reaction with the compound of formula I′ and R 2 I in an inert solvent, thereby forming a compound of formula I′″;

wherein R 1 , R 4 , R 5 , X and n3 are defined as in claim 1 ; each of n1 and n2 is 1; and each of R 2 and R 3 is H or methyl.

7. The preparation method of claim 6 , wherein when X in formula I′, I″ or I′″ is O, the method further comprises:
(i) when R 5 is other than H, conducting a hydrolysis reaction of a formula Ic compound in an inert solvent, thereby forming a compound of formula Id;

(ii) reacting the compound of formula Id with R 5 —NH 2 in an inert solvent, thereby forming a compound of formula Ie;

wherein the structure

in the formula Ic, Id, and Ie is:

and
wherein each group is defined as in claim 6 .

8. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula I of claim 1 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

9. A method of activating AMPK activity in vitro, the method comprising contacting AMPK with a compound of formula I of claim 1 , or a pharmaceutically acceptable salt thereof.

10. A method of promoting phosphorylation of at least one of AMPK and ACC in vitro, the method comprising contacting AMPK and/or ACC with a compound of formula I of claim 1 , or a pharmaceutically acceptable salt thereof.

11. A method of treating diabetes or obesity in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 8 .

12. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 5 , or a

Assignees

• Shanghai Inst Materia Medica Cas

Inventors

• Nan Fajun
• Li Jia
• Li Jingya
• Zhang Mei
• Chen Dakai
• Zhang Lina
• Zhang Runtao
• Xie Zhifu

Classifications

• A61P43/00

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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title