Tricyclo compounds, a process for their production and a pharmaceutical composition containing the same

Abstract

This invention relates to tricyclo compounds useful for treatment and prevention of resistance by transplantation, graft-versus-host diseases by medulla ossium transplantation, autoimmune diseases, infectious diseases, and the like, which can be represented by the following formula: to a process for their production, to a pharmaceutical composition containing the same and to a use thereof.

What we claim is:  
     
         1 . A compound of the formula:  
       
         
           
           
               
               
           
         
         wherein 
 R 1  is hydroxy or protected hydroxy,  
 R 2  is hydrogen, hydroxy or protected hydroxy,  
 R 3  is methyl, ethyl, propyl or allyl,  
 n is an integer of 1 or 2, and  
 the symbol of a line and dotted line is a single bond or a double bond,  
 
         and salt thereof.  
       
     
     
         2 . A compound of  claim 1 , which can be represented by the following formula:  
       
         
           
           
               
               
           
         
         wherein 
 R 1  is hydroxy or protected hydroxy,  
 R 2  is hydroxy or protected hydroxy, and  
 R 3  is methyl, ethyl, propyl or allyl.  
 
       
     
     
         3 . A compound of  claim 2 , wherein 
 R 3  is allyl.    
     
     
         4 . A compound of  claim 3 , wherein 
 R 1  is hydroxy, 1-(lower alkylthio)(lower)alkoxy, trisubstituted silyloxy or acyloxy.    
     
     
         5 . A compound of  claim 4 , wherein 
 R 1  is hydroxy, lower alkylthiomethoxy, tri(lower)alkylsilyloxy, lower alkyl-diarylsilyloxy, lower alkanoyloxy which may have carboxy, cyclo(lower)alkoxy(lower)alkanoyloxy which may have two lower alkyl groups on the cycloalkyl moiety, camphorsulfonyloxy, carboxy(lower)alkylcarbamoyloxy, tri(lower)alkylsilyl(lower)alkoxycarbonyl(lower)-alkylcarbamoyloxy, aroyloxy which may have one or two nitro, arenesulfonyloxy which may have halogen or ar(lower)alkanoyloxy which may have lower alkoxy and trihalo(lower)alkyl, and R 2  is hydroxy or lower alkanoyloxy.    
     
     
         6 . A compound of  claim 5 , which is 
 17-allyl-1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0 4,9 ]octacos-18-ene-2,3,10,16-tetraone.    
     
     
         7 . A compound of  claim 5 , wherein 
 R 1  is lower alkanoyloxy and R 2  is hydroxy or lower alkanoyloxy.    
     
     
         8 . A compound of  claim 7 , which is 
 12-[2-(4-acetoxy-3-methoxycyclohexyl)-1-methylvinyl]-17-allyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 4,9 ]-octacos-18-ene-2,3,10,16-tetraone.    
     
     
         9 . A compound of  claim 7 , which is 
 14-acetoxy-12-[2-(4-acetoxy-3-methoxycyclohexyl)-1-methylvinyl]-17-allyl-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0 4,9 ]octacos-18-ene-2,3,10,16-tetraone.    
     
     
         10 . A compound of  claim 2 , which is 
 17-ethyl-1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0 4,9 ]octacos-18-ene-2,3,10,16-tetraone.    
     
     
         11 . A compound of  claim 2 , which is 
 1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13,19,17,21,27-pentamethyl-11,28-dioxa-4-azatricyclo[22.3.1.0 4,9 ]-octacos-18-ene-2,3,10,16-tetraone.    
     
     
         12 . A compound of  claim 1 , wherein 
 R 1  is hydroxy, lower alkylthiomethoxy, lower alkanoyloxy or arenesulfonyloxy which may have halogen, R 2  is hydrogen or hydroxy, n is an integer of 2 and the symbol of a line and dotted line is a double bond.    
     
     
         13 . A compound of  claim 1 , which is 
 16-allyl-1,13-dihydroxy-11-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-22,24-dimethoxy-12,18,20,26-tetramethyl-10,27-dioxa-4-azatricyclo-[21.3.1.0 4,8 ]heptacos-17-ene-2,3,9,15-tetraone.    
     
     
         14 . A process for production of the compound of the formula:  
       
         
           
           
               
               
           
         
         wherein 
 R 1  is hydroxy or protected hydroxy,  
 R 2  is hydrogen, hydroxy or protected hydroxy,  
 R 3  is methyl, ethyl, propyl or allyl,  
 n is an integer of 1 or 2, and  
 the symbol of a line and dotted line is a single bond or a double bond,  
 
          and salt thereof, which comprises  
         (a) culturing a FR-900506, FR-900520 and/or FR-900525 substance(s)-producing strain belonging to the genus Streptomyces in a nutrient medium and recovering the FR-900506, FR-900520 and/or FR-900525 substance(s) to give the FR-900506, FR-900520 and/or FR-900525 substance(s);  
         (b) culturing a FR-900520 and/or FR-900523 substance(s)-producing strain belonging to the genus Streptomyces in a nutrient medium and recovering the FR-900520 and/or FR-900523 substance(s) to give the FR-900520 and/or FR-900523 substance(s);  
         (c) introducing a hydroxy-protective group into a compound of the formula:  
         
           
             
             
                 
                 
             
           
         
          wherein R 2 , R 3 , n and the symbol of a line and dotted line are each as defined above,  
          to give a compound of the formula:  
         
           
             
             
                 
                 
             
           
         
          wherein R 2 , R 3 , n and the symbol of a line and dotted line are each as defiend above, and R a   1  is protected hydroxy,  
          or a salt thereof;  
         (d) introducing a hydroxy-protective group into a compound of the formula:  
         
           
             
             
                 
                 
             
           
         
          wherein R 1 , R 3 , n and the symbol of a line and the dotted line are each as defined above,  
          or a salt thereof, to give a compound of the formula:  
         
           
             
             
                 
                 
             
           
         
          wherein R 1 , R 3 , n and the symbol of a line and dotted line are each as defined above, and R a   2  is protected hydroxy,  
          or a salt thereof;  
         (e) reacting a compound of the formula:  
         
           
             
             
                 
                 
             
           
         
          wherein R 1 , R 3  and n are each as defined above, and R b   2  is a leaving group,  
          or a salt thereof, with a base, to give a compound of the formula:  
         
           
             
             
                 
                 
             
           
         
          wherein R 1 , R 3  and n are each as defined above,  
          or a salt thereof;  
         (f) oxidizing a compound of the formula:  
         
           
             
             
                 
                 
             
           
         
          wherein R 1 , R 3  and n are each as defined above,  
          or a salt thereof, to give a compound of the formula:  
         
           
             
             
                 
                 
             
           
         
          wherein R 1 , R 3  and n are each as defiend above,  
          or a salt thereof; and  
         (g) reducing a compound of the formula:  
         
           
             
             
                 
                 
             
           
         
          wherein R 1 , R 2 , n and the symbol of a line and dotted line are each as defined above,  
          or a salt thereof, to give a compound of the formula:  
         
           
             
             
                 
                 
             
           
         
          wherein R 1 , R 2 , n and the symbol of a line and dotted line are each as defined above,  
          or a salt thereof, and  
         (h) removing a carboxy-protective group from a compound of the formula:  
         
           
             
             
                 
                 
             
           
         
          wherein R 2 , R 3 , n and the symbol of a line and dotted line are each as defined above, and R b   1  is protected carboxy(lower)alkylcarbamoyloxy,  
          or a salt thereof to give a compound of the formula:  
         
           
             
             
                 
                 
             
           
         
          wherein R 2 , R 3 , n and the symbol of a line and dotted line are each as defined above, and R c   1  is carboxy(lower)alkylcarbamoyloxy,  
          or a salt thereof.  
       
     
     
         15 . A pharmaceutical composition containing tricyclo compounds of  claim 1 , as active ingredients, in association with a pharmaceutically acceptable, substantially non-toxic carrier or excipient.  
     
     
         16 . A use of tricyclo compounds of  claim 1  for manufacture of medicament for treating or preventing resistance by transplantation, autoimmune diseases and infectious diseases.  
     
     
         17 . A method for treating or preventing resistance by transplantation, autoimmune diseases and infectious diseases by administering tricyclo compounds of  claim 1 .  
     
     
         18 . A biologically pure culture of the microorganism  Streptomyces tsukubaensis  No. 9993.  
     
     
         19 . A biologically pure culture of the microorganisms  Streptomyces hygroscopicus  subsp. yakushimaensis No. 7238.