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Selective preventing and therapeutic agents for progressive lesion after organic damage

a technology of organic damage and selective prevention, applied in the direction of drugs, instruments, immunological disorders, etc., can solve the problems of severe side effects, prolonged steroid treatment, and further worsening of hereditary lesion, so as to achieve selective and effective therapy, prevent the induction of effector macrophages, and reduce the effect of side effects

Inactive Publication Date: 2005-06-30
ISHIBASHI MICHIO +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention relates to a pharmaceutical and a therapeutic method for preventing and treating damage to organs caused by various factors such as blood flow disorder, ischemia reperfusion injury, hypertension, hyperglycemia, hyperlipemia, pharmaceutical agents, or viral infection. The invention selectively suppresses the induction of effector macrophage, which is a cause of progressive lesion and further damage to the organ. The invention also provides a screening method for identifying compounds that can be used as the pharmaceutical. The invention further relates to a method for preventing and treating rejection in transplantation of allogenic or xenogenic organ cells. The invention uses novel γ-lactone derivatives as the pharmaceutical and immunosuppressant."

Problems solved by technology

However, since steroidal preparations non-selectively suppress the macrophage, they also suppress the response of even the macrophage participating in the reaction for tissue regeneration at the same time whereby organism defensive mechanism including the regeneration is lessened.
In addition, new tissue damage is induced resulting in lesion and, as a result, there is a problem that effector macrophage mediated by the expression of chemokines and cytokines is actively induced whereby the inherent lesion is further worsened.
In addition, there is a difficulty that a continuous therapy by steroids for a long period is accompanied by a severe side effect.

Method used

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  • Selective preventing and therapeutic agents for progressive lesion after organic damage
  • Selective preventing and therapeutic agents for progressive lesion after organic damage
  • Selective preventing and therapeutic agents for progressive lesion after organic damage

Examples

Experimental program
Comparison scheme
Effect test

example 1

Manufacture of (RS)-(−)-α-methyl-2-naphthalene-methyl 2-(4-fluorophenoxy)-5-oxotetrahydrofuran-2-carboxylate

[0257]

[0258] To a solution prepared by dissolving 164 mg (0.6 mmol, 1 equivalent) of 2-(4-fluorophenoxy)-5-oxotetrahydrofuran-2-carboxylic acid manufactured by a method mentioned in paragraph [0018], page 5 of Japanese Patent Laid-Open No. 04 / 338,331 in 2.2 ml of ether at 0° C. were added 240 μl (2.7 mmol, 4 equivalents) of (COCl)2 gradually and then two drops of dimethylformamide (DMF) were added thereto. At that time, discharge of gas was observed.

[0259] The reaction solution was allowed to stand for 1 hour with stirring at 0° C., ether was removed in vacuo and the product was dried in vacuo.

[0260] The product was dissolved in 2.5 ml of ether, then 130 mg (0.75 mmol, 1.1 equivalents) of (S)-(−)-α-methyl-2-naphthalenemethanol and 8 mg (0.07 mmol, 0.1 equivalent) of dimethylaminopyrrolidone (hereinafter, abbreviated as DMAP) were gradually added and, at the same time, 140 μ...

example 2

Manufacture of (±)-2-(4-fluorophenoxy)-5-oxotetrahydrofuran-2-carboxylic Acid

(a) Manufacture of (−)-2-(4-fluorophenoxy)-5-oxotetrahydrofuran-2-carboxylic Acid

[0277]

[0278] C11H9FO5

[0279] Molecular weight 240.1

[0280] White solid

[0281] Tf=128° C.

[0282] To a solution of 98 mg (0.24 mmol, 1 equivalent) of (S)-(−)-α-methyl-2-naphthalenemethyl 2-(4-fluorophenoxy)-5-oxotetrahydrofuran-2-carboxylate represented by the formula (3-1) manufactured in Example 1 dissolved in 4 ml of ethyl acetate and 8 drops of ethanol was added a Pd / C catalyst in an amount of 10 parts by weight to 100 parts by weight of the above solution. The resulting solution was washed with water several times, stirred at room temperature and subjected to a catalytic reduction using hydrogen for 4 hours. The product was dissolved in ethyl acetate, the catalyst was removed by filtering through Celite (manufactured by Johns Manville Sales Co.) and the solvent was removed in vacuo. The product was purified by means of a r...

example 3

Manufacture of Benzyl 2-(4-fluorobenzyl)-5-oxotetrahydrofuran-2-carboxylate

[0294]

[0295] C19H17FO4

[0296] Molecular weight=328.3

[0297] White crystals

[0298] Tf=70° C.

[0299] In the presence of Amberyst resin 15 (manufactured by Rohm & Haas Co.), a solution where 192 mg (0.4 mmol, 1 equivalent) of dibenzyl 2-(4-fluorobenzyl)-2-hydroxypentane-1,5-dicarboxylate were dissolved in 6 ml of anhydrous toluene was heated at 60° C. for 10 hours. This was returned to room temperature and filtered through cotton to remove the Amberyst resin 15. The solvent was removed in vacuo and the product was separated by chromatography (eluent: hexane / ethyl acetate, 8.5:2.5 (v / v)). After purification by recrystallization from ether-hexane twice, the present compound was obtained as thin flaky crystals in an amount of 99 mg (yield: 76%).

[0300] Thin-layer chromatography: Rf=0.24 (hexane / ethyl acetate, 7:3 (v / v))

[0301] RMN 1H (300 MHz; CDCl3) d ppm: 2.15-2.52 (4H, m); 3.1 (1H, d. J=14.4 Hz); 3.3 (1H, d, J=...

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Abstract

An object of the present invention is to provide a pharmaceutical agents for preventing and / or treating the progressive lesion after the organic damage without inhibiting organic function or regeneration function thereof, by selectively suppressing the induction of cytotoxic effector macrophages which are induced into the damaged organs in response to chemokines and cytokines which are expressed depending on the type of damaged organic tissues.

Description

TECHNICAL FIELD [0001] Organs in organism may be damaged, for example, by blood flow disorder, ischemia reperfusion injury, hypertension, hyperglycemia, hyperlipemia, pharmaceutical agent or viral infection. Damaged organ tissues show any of responses of necrosis, natural death or self-regeneration depending upon the degree of the damage. Immune system deeply participates in such a response and some of macrophages which are carriers of such immune participate in self-regeneration of organ tissues while others participate in necrosis or natural death of organ tissues. The latter, i.e. that which shows cytotoxicity in a functional manner among the much differentiated macrophages, is called effector macrophage and such an effector macrophage further worsens the damage after the above-mentioned damage and causes a progressive lesion after the organic damage. [0002] The present invention relates to a pharmaceutical in which induction of effector macrophage which is a cause of progressive...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/341A61K31/343A61K31/365A61P1/18A61P13/12A61P37/06A61P43/00C07D307/33C07D307/68
CPCA61K31/341A61K31/343G01N2500/10C07D307/33C07D307/68A61K31/365A61P1/18A61P13/12A61P37/06A61P43/00
Inventor ISHIBASHI, MICHIOWAGNER, ALAINMIOSKOWSKI, CHARLESSYLVAIN, CATHERINE
Owner ISHIBASHI MICHIO
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