Selective preventing and therapeutic agents for progressive lesion after organic damage

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.

1 - 14 . (canceled)  
     
     
         15 . A kit for screening a compound which is able to prevent, mitigate or treat glomerular lesion of kidney, lesion of islet of Langerhans of pancreas or diabetes mellitus and diabetic glomerular lesion, which comprises (a) human PBMC, (b) lipopolysaccharide, (c) human AB type serum, (d) RPMI 1640 medium and (e) a plate to which monolayered autologous erythrocytes are adhered.  
     
     
         16 . A kit for screening a compound which is able to prevent, mitigate or treat progressive tubulointerstitial lesion after renal damage, lesion of exocrine, acinar or ductal interstitial tissues of pancreas or pancreatitis and lesion of interstitial tissues of urinary tubule, which comprises (a) human PBMC, (b) mitomycin-treated human PBMC, (c) human AB type serum, (d) RPMI 1640 medium and (e) a plate to which monolayered autologous erythrocytes are is adhered.  
     
     
         17 - 27 . (canceled)  
     
     
         28 . A method for prevention and/or therapy of glomerular lesion of kidney, lesion of islets of Langerhans of pancreas or diabetes mellitus and diabetic glomerular lesion, which comprises using a pharmaceutical containing a compound selectively suppressing the induction of effector macrophages caused by contact of human PBMC with lipopolysaccharide.  
     
     
         29 . A method for prevention and/or therapy of progressive tubulointerstitial lesion after renal damage, lesion of exocrine, acinar or ductal interstitial tissues of pancreas or pancreatitis, and lesion of interstitial tissues of urinary tubule, which comprises using a pharmaceutical containing a compound selectively suppressing the induction of effector macrophages caused by contact of human PBMC with mitomycin-treated human PBMC.  
     
     
         30 . A method for screening a compound which is able to prevent, mitigate or treat glomerular lesion of kidney, lesion of islet of Langerhans of pancreas or diabetes mellitus and diabetic glomerular lesion, which comprises measuring a suppressive action of a compound to be tested against the induction of effector macrophage caused by contact of human PBMC with lipopolysaccharide.  
     
     
         31 . The method for screening according to  claim 30 , wherein effector macrophages are induced by incubation of human untreated PBMC in RPMI 1640 medium in the presence of a compound to be tested, lipopolysaccharide and human AB type serum, the said induced effector macrophages are brought into contact with monolayered autologous erythrocytes, and a compound showing less production of SPFC as compared with the absence of the said compound to be tested is screened.  
     
     
         32 . A method for screening a compound which is able to prevent, mitigate or treat progressive tubulointerstitial lesion after renal damage, lesion of exocrine interstitial tissues of pancreas or pancreatitis and lesion of interstitial tissues of urinary tubule, which comprises measuring a suppressive action of a compound to be tested against the induction of effector macrophages caused by contact of human PBMC with mitomycin-treated human PBMC.  
     
     
         33 . The method for screening according to  claim 32 , wherein effector macrophages are induced by a mixed incubation of mitomycin-treated human PBMC and human untreated PBMC in RPMI 1640 medium in the presence of a compound to be tested and human AB type serum, the said induced effector macrophages are brought into contact with monolayered autologous erythrocytes and a compound showing less production of SPFC as compared with the absence of the said compound to be tested is screened.  
     
     
         34 . A method for the induction of effector macrophages which are a cause of glomerular lesion of kidney, lesion of islet of Langerhans of pancreas or diabetes mellitus and diabetic glomerular lesion, which comprises bringing lipopolysaccharide into contact with human PBMC.  
     
     
         35 . A method for the induction of effector macrophages which are a cause of progressive tubulointerstitial lesion after renal damage, lesion of exocrine interstitial tissues of pancreas or pancreatitis and lesion of interstitial tissues of urinary tubule, which comprises bringing human PBMC into contact with mitomycin-treated human PBMC.  
     
     
         36 . The method according to  claim 28  or  29 , wherein the compound suppressing the induction of effector macrophages is selected from the group consisting of: 
 (i) an optical isomer γ-lactone represented by the formula (3):                          or an optical isomer γ-lactone represented by the formula (4):                          wherein,    R 21  is an optionally substituted naphthyl group,    R 22  is an optionally substituted straight or branched hydrocarbon residue having 1 to 6 carbon atoms, or a mixture of said optical isomers represented by the formulae (3) and (4);    (ii) one of said optical isomers represented by the formulae (3) and (4), or a mixture of said optical isomers represented by the formulae (3) and (4) wherein R 21  is naphthyl and R 22  is methyl;    (iii) a compound represented by the formula (5):                          wherein,    (a) R 1  and R 2  may be the same or different and each is hydrogen, an open-chain aliphatic hydrocarbon group which may be substituted or interrupted by an intervening group, an optionally substituted cyclic aliphatic hydrocarbon group, an optionally substituted aryl group, an optionally substituted heterocyclic group or an optionally substituted condensed heterocyclic group;    X 2  is O, S or NR 3  in which R 3  is hydrogen, oxygen, an open-chain aliphatic hydrocarbon group which may be substituted or interrupted by an intervening group, an optionally substituted cyclic aliphatic hydrocarbon group, an optionally substituted aryl group, an optionally substituted heterocyclic group or an optionally substituted condensed heterocyclic group; and    n is an integer from 1 to 5; or    (b) X 2  is O, S or NR 3 ,    R 1 , R 2  and R 3  each is a substituent represented by the formula R 10 -Z-R 11 —, wherein R 10  and R 11  may be the same or different and each is an optionally substituted open-chain or cyclic hydrocarbon group, an optionally substituted aryl group, an optionally substituted heterocyclic group or an optionally substituted condensed heterocyclic group, and Z is an intervening group; and    n is an integer from 1 to 5,    or a pharmacologically acceptable salt thereof;    (iv) a compound represented by the formula (6):                          wherein,    R 1 , X 2  and n have the same meaning as defined above,    X 1  is halogen, cyano group, an optionally substituted mercapto group, an optionally substituted sulfo group, an optionally substituted sulfonyl group, an optionally substituted hydroxyl group, an optionally substituted amino group or an optionally substituted phosphoryl group, or a pharmacologically acceptable salt thereof, and    (v) a compound represented by the formula (7):                          wherein,    R 1 , X 1  and X 2  have the same meaning as defined above,    R 5  and R 6  may be the same or different and each is    (a) hydrogen, a straight or branched aliphatic hydrocarbon group which may be substituted or interrupted by an intervening group, an optionally substituted cyclic aliphatic hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted condensed heterocyclic group;    (b) a substituent represented by the formula R 10 -Z-R 11 —, wherein R 10  and R 11  may be the same or different and each is an optionally substituted open-chain or cyclic hydrocarbon group, an optionally substituted aryl group, an optionally substituted heterocyclic group or an optionally substituted condensed heterocyclic group; and Z is an intervening group; or    (c) R 5  and R 6  together with the carbon atom to which they are attached form an optionally substituted aromatic ring; 
 or a pharmacologically acceptable salt thereof.  
   
     
     
         37 . The method according to  claim 36 , wherein the compound suppressing the induction of effector macrophages is selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
     
     
         38 . The method according to  claim 28  or  29 , wherein the compound suppressing the induction of effector macrophages is a compound represented by the formula (4-2):  
       
         
           
           
               
               
           
         
       
     
     
         39 . The method according to  claim 36 , wherein the compound suppressing the induction of effector macrophages is a compound represented by the formula (6-2):  
       
         
           
           
               
               
           
         
       
       wherein Bn is benzyl.  
     
     
         40 . The method according to  claim 28  or  29 , wherein the compound suppressing the induction of effector macrophages is a compound represented by the formula (7-3):  
       
         
           
           
               
               
           
         
         wherein Bn is benzyl.  
       
     
     
         41 . The method according to 36, wherein the compound suppressing the induction of effector macrophages is a compound represented by the formula (7), wherein R 5  and R 6  together with the carbon atom to which they are attached form an optionally substituted aromatic ring, X 2  is O, X 1  is optionally substituted hydroxyl and R 1  is hydrogen.