8-oxoprotoberberine derivative or pharmaceutically acceptable salt thereof, preparation method therefor and pharmaceutical composition for preventing or treating diseases associated with activity of NFAT5, containing same as active ingredient

Patent metadata

Field	Value
Publication number	US-9650389-B2
Application number	US-201415029075-A
Country	US
Kind code	B2
Filing date	Dec 30, 2014
Priority date	Dec 31, 2013
Publication date	May 16, 2017
Grant date	May 16, 2017

Abstract

The preset invention relates to a novel 8-oxoprotoberberine derivative or a pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical composition for preventing or treating diseases associated with the activity of NFAT5 containing the same as an active ingredient. The novel 8-oxoproteoberberine derivative or the pharmaceutically acceptable salt thereof according to the present invention can be useful in a pharmaceutical composition for preventing or treating diseases associated with the activity of NFAT5, particularly rheumatoid arthritis or inflammatory diseases, since it is ascertained that the derivative or a pharmaceutically acceptable salt thereof has remarkably increased oral absorption compared with known protoberberine due to an improvement in the properties thereof, and inhibits the activity of NFAT5 and the secretion of inflammatory cytokines and reduces the expression of NAFT5 in mice with rheumatoid arthritis by directly inhibiting the transcription of NFT5.

First claim

What is claimed is:

1. An 8-oxoprotoberberine derivative represented by formula 1 or a pharmaceutically acceptable salt thereof

wherein A is —C(═O)— or —NHC(═O)—; and
when A is —C(═O)—, R is hydroxyl, amino, straight or branched C1-2 alkoxy, or phenyl unsubstituted or substituted with one or more halogens; and
when A is —NHC(═O)—, R is phenyl unsubstituted or substituted with one or more halogens, and
wherein said 8-oxoprotoberberine derivative or pharmaceutically acceptable salt thereof inhibits NFAT5.

2. The 8-oxoprotoberberine derivative according to claim 1 , wherein the 8-oxoprotoberberine derivative is selected from the group consisting of:
13-ethyl-9,10-dimethoxy-8-oxo-6,8-dihydro-5H -[1,3]dioxolo[4,5-g]isoquinolino[3,2-a]isoquinoline-13-carboxylate;
9,10-dimethoxy-8-oxo-6,8-dihydro-5H-[1,3]dioxolo[4,5-g]isoquinolino[3,2-a]isoquinoline-13-carboxylic acid;
9,10-dimethoxy-8-oxo-6,8-dihydro-5H-[1,3]dioxolo[4,5-g]isoquinolino[3,2-a]isoquinoline-13-carboxamide; and
N-(2-fluorophenyl)-9,10-dimethoxy-8-oxo-6,8-dihydro-5H-[1,3]dioxolo[4,5-g]isoquinolino[3,2-a]isoquinoline-13-carboxamide.

3. A method for preparing the 8-oxoprotoberberine derivative of claim 1 represented by formula 1 comprising the following steps as shown in reaction formula 1:
preparing the compound represented by formula 4 by reacting the compound represented by formula 2 with the compound represented by formula 3 (step 1); and
preparing the compound represented by formula 1 by reacting the compound represented by formula 4 obtained in step 1) under basic condition (step 2):

wherein in reaction formula 1, A and R are independently defined in claim 1 ;
and X 1 and X 2 are halogens.

4. The method of claim 3 , wherein step 2 is composed of the following steps as shown in reaction formula 2:
preparing the compound represented by formula 5 via reduction reaction of the compound represented by formula 4 (step A); and
preparing the compound represented by formula 1 via oxidation reaction of the compound represented by formula 5 obtained in step A (step B):

5. A method for treating diseases associated with the activity of NFAT5 comprising the step of administering an effective dose of the 8-oxoprotoberberine derivative or the pharmaceutically acceptable salt thereof of claim 1 to a subject,
wherein the disease is arthritis or an auto-immune disease selected from the group consisting of systemic scleroderma, lupus erythematosus, atopic dermatitis, Behcet's disease, Sjogren's syndrome, multiple sclerosis, and Graces' hyperthyroidism.

6. The method of claim 5 wherein the 8-oxoprotoberbeing derivative is one or more compounds selected from the group consisting of:
—-ethyl-9,10-dimethoxy-8-oxo-6,8-dihydro-5H-[1,3]dioxolo[4,5-g]isoquinolino[3,2-a]isoquinoline-13-carboxylate;
9,10-dimethoxy-8-oxo-6,8-dihydro-5H-[1,3]dioxolo[4,5-g]isoquinolino[3,2-a]isoquinoline-13 -carboxylic acid;
9,10-dimethoxy-8-oxo-6,8-dihydro-5H-[1,3]dioxolo[4,5-g]isoquinolino[3,2-a]isoquinoline-13 -carboxamide; and
N-(2-fluorophenyl)-9,10-dimethoxy-8-oxo-6,8-dihydro-5H-[1,3]dioxolo [4,5-g]isoquinolino[3,2-a]isoquinoline-13-carboxamide.

7. The method of claim 5 wherein the arthritis is rheumatoid arthritis.

Assignees

• Korea Res Inst Chemical Tech
• The Catholic Univ Of Korea Industry-Academic Coop Found

Inventors

• Cho Heeyeong
• Lim Hee-Jong
• Lee Ge Hyeong
• Park Woo Kyu
• Kim Hyeon Young
• Jeong Dae Young
• Kim Wan Uk
• Cho Chul Soo
• Park Su Jung
• Han Eun Jin

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61K31/4745

  condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48) · CPC title

• C07D491/153 Primary

  the condensed system containing two rings with oxygen as ring hetero atom and one ring with nitrogen as ring hetero atom · CPC title

• A61K31/4355

  the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom · CPC title