Tricyclo compounds, a process for their production and 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 reproduction, 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 hndroxy or protected hydroxy, and  
 R 3  is methyl, ethyl, propyl or allyl.  
 
     
     
         3 . A compound of  claim 2 , wherein 
 R 2  is allyl.    
     
     
         4 . A compound of  claim 3 , wherein 
 R 1  is hydroxy, 1-(lower alkythio)(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-mrethoxycyclohexyl)-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 4,9 ]heptacos-17-ene-2,3,9,15-tetraone.    
     
     
         14 . A process for production 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 no 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  
 (c) reducing 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,  
 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,  
 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.  vakushimaensis  No. 7238.