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Indole and indazole derivatives having a cell-, tissue- and organ-preserving effect

Inactive Publication Date: 2010-11-18
LG LIFE SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0006]The inventors of the present invention carried out intensive and extensive researches to develop compounds which can inhibit necrosis of various animal cells in preserving various tissues, organs or blood and thus can provide an extended preservation period, enhanced protection effect and improved organ function after transplantation. As a result, we have now found out that the indole and indazole derivatives represented by the following formula (1) show remarkable effects as described below. Indole and indazole compounds according to the present invention have been already disclosed and claimed in Korean Patent Application Nos. 10-2007-0082687, 10-2008-0080519 and 10-2008-0080537, which were filed by the present applicant.
[0396]In addition, the indole or indazole compound according to the present invention can be used by further adding it in a conventional solution for preserving organs. If the indole or indazole compound according to the present invention is added in the conventional solution for preserving organs, the preservation period of the above-mentioned organs for transplantation can be greatly extended and organ damage after transplantation can be effectively prevented or treated.
[0398]Together with the active ingredient, the “pharmaceutical composition” according to the present invention may comprise a pharmaceutically acceptable carrier, diluent, excipient or combination thereof, if needed. Such a pharmaceutical composition facilitates the administration of the compound into a living organism. There are many administration techniques including oral, injection, aerosol, parenteral and topical administrations, but not limited thereto.
[0404]If needed, the compound of the present invention or the pharmaceutical compositions containing the same can also be administered in combination with other active agents, for example, other materials that can prevent injury of organs, isolated cell systems or tissues caused by cold storage, transplant operation or post-transplantation reperfusion

Problems solved by technology

A number of patients are in need of transplants but many organs are not kept in a proper condition for use and thus discarded.
However, many transplant surgeries are not done immediately as such.
Therefore, the extended time of storage and improved quality of organs to be transplanted by improving storage method remain as urgent technical problems.

Method used

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  • Indole and indazole derivatives having a cell-, tissue- and organ-preserving effect
  • Indole and indazole derivatives having a cell-, tissue- and organ-preserving effect
  • Indole and indazole derivatives having a cell-, tissue- and organ-preserving effect

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of cyclopentyl-[2-(4,5-dihydro-1,3-thiazol-2-yl)-1H-indol-7-yl]-amine

[0521]

Cyclopentyl-[2-(4,5-dihydro-thiazol-2-yl)-1H-indol-7-yl]-amine

[0522]The compound obtained in Preparation 28 (15 mg, 0.07 mmol) was dissolved in 1,2-dichloroethane (10 ml). Cyclopentanone (12 mg, 0.14 mmol) and sodium triacetoxyborohydride (29 mg, 0.14 mmol) were added, and the mixture was stirred for 3 h at room temperature. After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and the residue was purified by column chromatography to give the title compound (6.7 mg, Yield 34%).

[0523]1H-NMR (400 HMz, CDCl3); δ 10.27 (s, 1H), 7.06 (d, J=8.0 Hz, 1H), 7.00 (t, J=7.6 Hz, 1H), 6.92 (s, 1H), 6.52 (d, J=7.2 Hz, 1H), 4.42 (m, 2H), 4.38 (m, 1H), 4.35 (m, 2H), 2.00 (m, 2H), 1.64 (m, 4H), 1.46 (m, 2H)

[0524]Mass spectrum (ESI, m / z): Calculated: 285.13, Found: 285.41

example 2

Synthesis of [2-(4,5-dihydro-thiazol-2-yl)-1H-indol-7-yl]-(4-methyl-cyclohexyl)-amine

[0525]

[2-(4,5-Dihydro-thiazol-2-yl)-1H-in dol-7-yl]-(4-methyl-cyclohexyl)-ami ne

[0526]The compound obtained in Preparation 28 (19 mg, 0.09 mmol) and 4-methyl-cyclohexanone were reacted according to the same procedure as Example 1 to give the two diastereomers in the amount of 9.1 mg and 7.4 mg (total Yield 60%), respectively.

[0527]1H-NMR (400 HMz, CDCl3);

[0528]Compound 1: δ 10.26 (s, 1H), 7.05˜6.97 (m, 2H), 6.92 (s, 1H), 6.51 (d, J=7.6 Hz, 1H), 4.40 (m, 2H), 3.65 (m, 1H), 3.46 (m, 2H), 1.72 (m, 3H), 1.52 (m, 3H), 1.22 (m, 3H), 0.82 (d, J=8.0 Hz, 3H)

[0529]Compound 2: δ 10.24 (s, 1H), 7.05˜6.96 (m, 2H), 6.92 (s, 1H), 6.50 (d, J=6.8 Hz, 1H), 4.44 (m, 2H), 3.47 (m, 2H), 3.25 (m, 1H), 2.11 (m, 2H), 1.74 (m, 2H), 1.36 (m, 1H), 1.10 (m, 4H), 0.90 (d, J=6.4 Hz, 1H)

[0530]Mass spectrum (ESI, m / z): Calculated: 313.16, Found: 313.47

example 3

Synthesis of [2-(4,5-dihydro-thiazol-2-yl)-1H-indol-7-yl]-piperidin-4-yl-amine

[0531]

[2-(4,5-Dihydro-thiazol-2-yl)-1H-in dol-7-yl]-piperidin-4-yl-amine

[0532]To the compound prepared from the compound of Preparation 28 (20 mg, 0.09 mmol) and 1-(t-butylcarbonyl)-4-piperidone according to the same procedure as Example 1 were added dichloromethane and trifluorocarboxylic acid solution (5:1, v / v, 5 ml). The mixture was stirred for 1 h at room temperature and distilled under reduced pressure. Saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and purified by column chromatography to give the title compound (4.9 mg, Yield 18%).

[0533]1H-NMR (400 HMz, CDCl3, MeOH-d4); δ 7.39 (s, 1H), 7.07 (d, J=8.0 Hz, 1H), 6.99 (t, J=8.0 Hz, 1H), 6.93 (s, 1H), 6.47 (d, J=7.6 Hz, 1H), 4.41 (m, 2H), 3.77 (m, 1H), 3.48 (m, 4H), 3.11 (m, 2H), 2.29 (m, 2H), 1.87 (m...

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Abstract

The present invention relates to a composition for preserving cells, tissues and organs, comprising as an active ingredient indole and indazole compounds of formula (1), or a pharmaceutically acceptable salt or isomer thereof, which are effective for preventing injury of organs, isolated cell systems or tissues caused by cold storage, transplant operation or post-transplantation reperfusion; a preservation method; and a preparation method of the composition.

Description

TECHNICAL FIELD[0001]The present invention relates to a composition for preserving cells, tissues or organs of animals comprising an indole or indazole compound of formula (1) or a pharmaceutically acceptable salt or isomer thereof as an effective ingredient, a preservation method by using the same and a method for preparing the same. Specifically, the indole and indazole compounds according to the present invention are effective in protecting cells, tissues and organs of animals to be transplanted and preventing their injury caused during transportation or storage. Furthermore, the indole and indazole compounds according to the present invention protect organs from injury of tissues or organs caused by reperfusion after transplantation.BACKGROUND ART[0002]Recently, cases of organ transplantation have increased according to the development of surgical operation technique and medicines such as immunosuppressant. A number of patients are in need of transplants but many organs are not ...

Claims

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Application Information

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IPC IPC(8): A01N1/02C12N5/071C12N5/02
CPCC07D209/08C07D231/54C07D401/04C07D401/14C07D417/14C07D405/12C07D405/14C07D413/14C07D417/04C07D403/04A61P39/06A61P43/00A61K31/404
Inventor KIM, SOON HAKIM, HYOUNG JINCHUNG, CHUL WOONGPARK, HEUI SULKWAK, HYO SHINKIM, SUNG HOPARK, JIN GU
Owner LG LIFE SCI
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