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

[0017] Effector macrophage expresses chemokine receptors or O2 integrin receptors, etc. corresponding to the lesion inherent to the tissues after the organic damage via either T-lymphocyte-independent or T-lymphocyte-dependent response and is selectively induced to and activated in lesion being mediated by them whereby said effector macrophage causes a progressive lesion after the tissue damage. An object of the present invention is to provide a pharmaceutical in which expression and function of chemokine receptors such as CCR2, CCR3 or CCR8, β2 integrin receptors such as CD11b / CD18 or other receptors are suppressed to selectively suppress the induction of the above-mentioned effector macrophages whereby progressive lesion after organic damage is prevented and / or treated without inhibiting the function of the organ and the regeneration function and also to provide a therapeutic method using the same. Since the pharmaceutical according to the present invention is able to suppress the induction of effector macrophages causing the progressive lesion after organic damage in a more lesion-selectively manner, it is possible to use in a high dose and, due to the selectivity of the said pharmaceutical, undesirable side effect can be avoided even when it is used in a high dose. Therapy for a long period using the said pharmaceutical is now possible as well. Further, when the lesions are different resulting in progressive lesion after the organic damage in plural tissues, it is possible to carry out more selective and more effective therapy by combination use of the above pharmaceuticals showing different selectivity. That is an advantage which is not noted in the conventional steroidal agents and known γ-lactone immunosuppressants having no selectivity. The present invention also aims to provide useful and novel γ-lactone derivatives.
[0023] Accordingly, if induction of effector macrophage in the damaged organ tissues can be selectively suppressed by way of suppression of expression and function of chemokine receptor such as CCR2, CCR3 and CCR8, β2 integrin receptors such as CD11b / CD18 and other receptors, action of the effector macrophage in a cytotoxic manner to the damaged organ tissues can be prevented and, in addition, induction of the macrophage participating in the tissue regeneration is not suppressed so that lowering of the defense ability of the organism is not noted whereby it has been found that progressive lesion after organic damage can be prevented, mitigated or treated.
[0024] When a compound which is able to selectively suppress the induction of effector macrophage as such is used as a pharmaceutical, there is reduced the side effect such as that defense of organism is unnecessarily lowered or new tissue damage is induced. In addition, it is possible to result in recovery and regeneration of the tissue without an unnecessary lowering of defense of organism and, therefore, it is now possible to continuously carry out the therapy for a long period.
[0027] Here, when lesion of islets of Langerhans of pancreas progresses, diabetes mellitus is able to occur. When diabetes mellitus occurs, diabetic nephropathy which is a glomerular lesion is able to occur as a complication thereof. Ishibashi who is one of the inventors of the present invention has further obtained an unexpected finding that a compound which suppresses the induction of effector macrophage caused by contact of human PBMC with lipopolysaccharide is also able to prevent and / or treat the onset of diabetic glomerular lesion (another name: diabetic nephropathy) together with the onset of diabetes mellitus.
[0028] Ishibashi who is one of the inventors of the present invention has furthermore obtained an unexpected finding that a compound which suppresses the induction of effector macrophage caused by contact of human PBMC with mitomycin-treated human PBMC is also able to prevent and / or treat the onset of lesion of tubulointerstitial tissues which is a complication of pancreatitis together with onset of pancreatitis which is lesion of exocrine, acinar and ductal interstitial tissues of pancreas.

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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