Epidithiodioxopiperazine compound or its derivatives, and the use thereof

Patent metadata

Field	Value
Publication number	US-10045995-B2
Application number	US-201715440655-A
Country	US
Kind code	B2
Filing date	Feb 23, 2017
Priority date	Nov 25, 2011
Publication date	Aug 14, 2018
Grant date	Aug 14, 2018

Abstract

The present invention relates to an epidithiodioxopiperazine derivative represented by the following Chemical Formula 1 or its reduced derivative; a method for preparing a compound represented by Chemical Formula 1 having improved intracellular permeability and mimicking the activity of 2-Cys-Prx in its reduced form in the cells; a pharmaceutical composition for preventing or treating vascular diseases comprising an epidithiodioxopiperazine compound or its derivatives or pharmaceutically acceptable salts thereof as an active ingredient; a drug delivery device for local administration including the pharmaceutical composition; and a pharmaceutical composition for inhibiting melanoma metastasis comprising the epidithiodioxopiperazine compound or its derivatives or pharmaceutically acceptable salts thereof as an active ingredient.

First claim

What is claimed is:

1. A method for treating vascular diseases, induced by PrxII deficiency or inactivation, comprising administering a pharmaceutical composition comprising an epidithiodioxopiperazine derivative represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient into a subject suspected of having vascular diseases:

wherein, R1 to R4 are each independently hydrogen, a halogen atom, a hydroxyl group, linear or branched C1 to C6 alkyl, alkenyl or alkynyl, linear or branched C1 to C6 alkoxy, linear or branched C1 to C6 hydroxyalkyl, substituted or unsubstituted benzyl, linear or branched C1 to C6 alkylaryl, a linear or branched C1 to C6 perfluoroalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted perfluoroaryl group, a substituted or unsubstituted heteroaryl group comprising an oxygen, nitrogen or sulfur atom in a ring as a heteroatom, or a substituted or unsubstituted epidithiodioxopiperazine group; or
R1 and R2, and/or R3 and R4 each independently form a substituted or unsubstituted C3 to C6 cycloalkyl group with a carbon atom to which these are attached; or form a substituted or unsubstituted heterocyclic ring having 5 to 8 ring atoms with a carbon atom to which these are attached, and additional carbon or heteroatoms, and herein, 1 or 2 ring atoms of the heterocyclic ring are selected from nitrogen (N), oxygen (O) or sulfur (S), wherein the alkyl and the aryl group may optionally include a heteroatom of oxygen, nitrogen, or sulfur in the middle of the chain, and each of the substituted epidithiodioxopiperazine groups may independently optionally include the substituents defined above and have a structure identical to or different from the mother nucleus epidithiodioxopiperzine; and
the derivative represented by Chemical Formula 1 does not include a compound represented by the following Chemical Formula 16

2. The method of claim 1 , wherein the epidithiodioxopiperazine compound is any one of compounds represented by the following Chemical Formulae 7 to 15 and 17 to 31:

wherein, A and B are each independently hydrogen; methoxy; or a hydroxyl group,

3. The method of claim 1 , wherein the vascular disease is selected from the group consisting of hypertension, an ischemic coronary artery disease, cerebral artery occlusion, artherosclerosis, a peripheral arterial occlusive disease, thromboembolism, diabetic foot lesion, venous ulcer, deep vein thrombosis, carotidal artherosclerosis, vasospasm, arteritis and vascular restenosis.

4. The method of claim 3 , wherein the vascular restenosis is caused by vascular graft, vascular cutting, artherosclerosis, intravascular lipid accumulation, hypertension, arteritis or angioplasty.

5. The method of claim 1 , wherein the composition promotes proliferation or migration of endothelial cells while inhibiting proliferation or migration of vascular smooth muscle cells.

6. The method of claim 3 , wherein the ischemic coronary artery disease is unstable angina pectoris, angina pectoris, or myocardial infarction.

7. The method of claim 3 , wherein the cerebral artery occlusion is stroke.

8. The method of claim 3 , wherein the peripheral arterial occlusive disease is a bergers disease.

9. A method for inhibiting melanoma metastasis comprising administering a pharmaceutical composition comprising an epidithioxopiperazine derivative represented by the following Chemical Formulae 20 or 21, or a pharmaceutically acceptable salt thereof as an active ingredient into a subject suspected of melanoma metastasis;

10. The method of claim 9 , wherein the composition inhibits the metastasis of melanoma through mimicking an intracellular PrxII activity.

11. A method for inhibiting melanoma metastasis, comprising a pharmaceutical composition comprising an epidithiodioxopiperazine derivative represented by the following Chemical Formula 1 or pharmaceutically acceptable salt, wherein R1 to R4 are each independently hydrogen, linear or branched C1 to C6 alkyl or alkenyl, alkoxybenzyl, alkoxyalkyl or benzhydryl,

12. The method of claim 11 , wherein R1 to R4 are each independently hydrogen, methyl, n-butyl, allyl, 4-methoxypropyl, 3-methoxypropyl or bezhydryl.

13. The method of claim 11 , wherein the epidithiodioxopiperazine derivative is any one of compounds represented by the following chemical formulae 7 to 15.

14. The method of claim 11 , wherein the composition inhibits metastasis of melanoma mimicking an intracellular PrxII activity.

Assignees

• Univ Ewha Ind Collaboration
• Univ Ewha Ind Collaboration

Inventors

• Kang Sang Won
• Kang Dong Hoon
• Lee Doo Jae

Classifications

• C12Q1/26

  involving oxidoreductase · CPC title

• G01N2333/90212

  acting on a sulfur group of donors (1.8) · CPC title

• G01N2500/02

  Screening involving studying the effect of compounds C on the interaction between interacting molecules A and B (e.g. A = enzyme and B = substrate for A, or A = receptor and B = ligand for the receptor) · CPC title

• A61K31/00

  Medicinal preparations containing organic active ingredients · CPC title

• C07D513/08 Primary

  Bridged systems · CPC title