8-azaprostaglandin derivatives and medical use thereof

Abstract

The pharmaceutical composition comprising the compound of the invention having 8-azaprostaglandin skeleton represented by formula (I) (wherein, all the symbols have the same meanings as that of the specification.) a salt thereof, a solvate thereof or a cyclodextrin clathrate thereof, or a prodrug thereof and them as active ingredient have EP 4 agonistic action and thus are considered useful for the prevention and/or treatment of immunological diseases, asthma, neuronal cell death, arthritis, lung failure, pulmonary fibrosis, pulmonary emphysema, bronchitis, chronic obstructive pulmonary disease, liver damage, acute hepatitis, nephritis, renal insufficiency, hypertension, myocardial ischemia, systemic inflammatory response syndrome, sepsis, hemophagous syndrome, macrophage activation syndrome, Still's disease, Kawasaki disease, burn, systemic granulomatosis, ulcerative colitis, Crohn's disease, hypercytokinemia at dialysis, multiple organ failure, shock and glaucoma, etc. Furthermore, the compounds also have an action of accelerating bone formation, so it is expected to be useful for the prevention and/or treatment of diseases associated with loss in bone mass, for example, primary osteoporosis, secondary osteoporosis, bone metastasis of cancer, hypercalcemia, Paget's disease, bone loss, osteonecrosis, bone formation after bone operation, alternative treatment for bone grafting.

1 . A compound represented by formula (I)  
     
       
         
         
             
             
         
       
       wherein   is a single bond or double bond,  
          is α-configuration, β-configuration or a voluntary mixture of α-configuration and β-configuration,  
       D is —COOR 1  or tetrazoryl,  
       R 1  is hydrogen or C1-4 alkyl,  
       G is ringA or C1-4 alkylene,  
       ringA is  
       
         
           
           
               
               
           
         
       
       R 2  is a halogen atom, C1-4 alkyl or C1-4 alkoxy,  
       p is 0 or an integer of 1-4,  
       when p is 2 or more, plural R 2 's are the same or different,  
       Y is a single bond or —S—,  
       T is oxygen or sulfur,  
       X is —CH 2 —, —O— or —S—,  
       ringB is C3-7 cycloalkyl optionally substituted,  
       
         
           
           
               
               
           
         
       
       wherein R 3  is (1) a halogen atom, (2) C1-4 alkyl optionally substituted with 1-5 of halogen atom(s), (3) C1-4 alkoxy optionally substituted with 1-5 of halogen atom(s), (4) C1-4 alkyl substituted with C1-4 alkoxy, (5) phenyl or (6) 3- to 15-membered mono-, bi- or tri-heterocyclic aryl containing 1 to 4 hetero atom(s) selected from oxygen, nitrogen and sulfur atom(s) which may be partially or fully saturated, and (5) phenyl or (6) heterocyclic aryl in R 3  is optionally substituted with 1-3 of (a) halogen atom(s), (b) C1-4 alkyl, (c) C1-4 alkoxy and/or (d) nitro,  
       q is 0 or an integer of 1-5,  
       when q is 2 or more, plural R 3 's are the same or different,  
       n is an integer of 1-4,  
       a salt thereof, a solvate thereof, a cyclodextrin clathrate thereof, or a prodrug thereof.  
     
   
   
       2 . The compound according to  claim 1 , which is selected from the group consisting of: 
 (1) 4-[(2-{(4S)-4-[(1E,3S)-4-(3-ethylphenyl)-3-hydroxybut-1-enyl]-2-oxo-1,3-thiazolidine-3-yl]ethyl)sulfanyl]butanoic acid,    (2) 4-[(2-{(4S)-4-[(1E,3S)-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-thiazolidine-3-yl}ethyl)sulfanyl]butanoic acid,    (3) 4-{[2-((4S)-4-{(1E,3S)-4-[4-fuloro-3-(trifluoromethyl)phenyl]-3-hydroxybut-1-enyl}-2-oxo-1,3-thiazolidine-3-yl)ethyl]sulfanyl}butanoic acid,    (4) 4-[(2-{(4S)-4-[(1E,3S)-4-(3,5-difluorophenyl)-3-hydroxybut-1-enyl]-2-oxo-1,3-thiazolidine-3-yl}ethyl)sulfanyl]butanoic acid,    (5) 4-[(2-{(4S)-4-[(1E,3S)-3-hydroxy-4-(3-propylphenyl)but-1-enyl]-2-oxo-1,3-thiazolidine-3-yl]ethyl)sulfanyl]butanoic acid,    (6) 4-[(2-{(4S)-4-[(1E,3S)-4-(3-ethyl-4-fulorophenyl)-3-hydroxybut-1-enyl]-2-oxo-1,3-thiazolidine-3-yl}ethyl)sulfanyl]butanoic acid,    (7) 4-[(2-{(4S)-4-[(1E,3S)-4-(3,4-difluorophenyl)-3-hydroxybut-1-enyl]-2-oxo-1,3-thiazolidine-3-yl}ethyl)sulfanyl)butanoic acid.    (8) 4-{[2-((4S)-4-{(1E,3S)-3-hydroxy-4-[3-(trifluoromethyl)phenyl]but-1-enyl]-2-oxo-1,3-thiazolidine-3-yl}ethyl)sulfanyl]butanoic acid,    (9) 4-[2-{(4S)-4-[(1E,3S)-4-(4-fuloro-3-methylphenyl)-3-hydroxybut-1-enyl]-2-oxo-1,3-thiazolidine-3-yl}ethyl)sulfanyl]butanoic acid,    (10) 4-[(2-{(4S)-4-[(1E,3S)-4-(3-fulorophenyl)-3-hydroxybut-1-enyl]-2-oxo-1,3-thiazolidine-3-yl}ethyl)sulfanyl]butanoic acid,    (11) 4-[(2-{(4S)-4-[(1E,3S)-4-(3-chloro-4-fulorophenyl)-3-hydroxybut-1-enyl]-2-oxo-1,3-thiazolidine-3-yl}ethyl)sulfanyl]butanoic acid,    (12) 4-{[2-((4S)-4-{(1E,3S)-3-hydroxy-4-[3-(methoxymethyl)phenyl]but-1-enyl}-2-oxo-1,3-thiazolidine-3-yl)ethyl]sulfanyl}butanoic acid,    (13) 7-{(2R)-2-[(1E,3S)-4-(4-fulorophenyl)-3-hydroxybut-1-enyl]-5-thioxopyrrolidine-1-yl}heptanoic acid,    (14) 7-{(2R)-2-[(1E,3S)-4-(3,5-difluorophenyl)-3-hydroxybut-1-enyl]-5-thioxopyrrolidine-1-yl}heptanoic acid,    (15) 7-((2R)-2-{(1E,3S)-4-[4-fuloro-3-(trifluoromethyl)phenyl]-3-hydroxybut-1-enyl}-5-thioxopyrrolidine-1-yl)heptanoic acid,    (16) 7-{(2R)-2-[(1E,3S)-4-(4-fuloro-3-methylphenyl)-3-hydroxybut-1-enyl]-5-thioxopyrrolidine-1-yl}heptanoic acid,    (17) 7-{(2R)-2-[(1E,3S)-4-(3-ethyl-4-fulorophenyl)-3-hydroxybut-1-enyl]-5-thioxopyrrolidine-1-yl}heptanoic acid,    (18) 7-((2R)-2-{(1E,3S)-3-hydroxy-4-[3-(trifluoromethyl)phenyl]but-1-enyl}-5-thioxopyrrolidine-1-yl)heptanoic acid,    (19) 7-{(2R)-2-[(1E,3S)-4-(3-fulorophenyl)-3-hydroxybut-1-enyl]-5-thioxopyrrolidine-1-yl}heptanoic acid,    (20) 7-{(2R)-2-[(1E,3S)-3-hydroxy-4-phenylbut-1-enyl]-5-thioxopyrrolidine-1-yl}heptanoic acid,    (21) 7-{(2R)-2-[(1E,3S)-4-(3,4-difluorophenyl)-3-hydoroxybut-1-enyl]-5-thioxopyrrolidine-1-yl}heptanoic acid,    (22) 7-{(2R)-2-[(1E,3S)-4-(3-chloro-4-fulorophenyl)-3-hydroxybut-1-enyl]-5-thioxopyrrolidine-1-yl}heptanoic acid,    (23) 7-{(2R)-2-[(1E,3S)-4-(3-ethylphenyl)-3-hydroxybut-1-enyl]-5-thioxopyrrolidine-1-yl}heptanoic acid,    (24) 7-{(2R)-2-[(1E,3S)-3-hydroxy-4-(3-propylphenyl)but-1-enyl]-5-thioxopyrrolidine-1-yl}heptanoic acid.    
   
   
       3 . The compound according to  claim 1 , which is represented by formula (I-1):  
     
       
         
         
             
             
         
       
       wherein G 1  is ringA 1  or C1-4 alkylene,  
       ringA 1  is  
       
         
           
           
               
               
           
         
       
       wherein left-pointing arrow represents binding to S, and right-pointing arrow represents binding to COOR 1 ,  
       ringB 1  is C3-7 cycloalkyl,  
       
         
           
           
               
               
           
         
       
       ringB 1  may be substituted with a halogen atom, C1-4 alkyl, phenyl, methoxymethyl, trifluoromethyl and/or trifluoromethoxy,  
       other symbols have the same meanings as described in  claim 1 , and  
       wherein when T is oxygen, X is —CH 2 —, and  
       when n is an integer of 2-4, G 1  is ringA 1 .  
     
   
   
       4 . The compound according to  claim 3 , which is selected from the group consisting of: 
 (1) (15α,13E)-9-oxo-15-hydroxy-16-(3-phenylphenyl)-17,18,19,20-tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid,    (2) (15α,13E)-9-oxo-15-hydroxy-16-(3-ethylphenyl)-17,18,19,20-tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid,    (3) (15α,13E)-9-oxo-15-hydroxy-16-(3-chloro-4-fulorophenyl)-17,18,19,20-tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid,    (4) (15α,13E)-9-oxo-15-hydroxy-16-(naphthalene-2-yl)-17,18,19,20-tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid,    (5) (15α,13E)-9-oxo-15-hydroxy-16-(3-trifluoromethoxyphenyl)-17,18,19,20-tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid,    (6) (15α,13E)-9-oxo-15-hydroxy-16-(4-fuloro-3-phenylphenyl)-17,18,19,20-tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid,    (7) (15α,13E)-9-oxo-15-hydroxy-16-(4-fuloro-3-methylphenyl)-17,18,19,20-tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid,    (8) (15α,13E)-9-oxo-15-hydroxy-16-(3,5-difulorophenyl)-17,18,19,20-tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid,    (9) (15α,13E)-9-oxo-15-hydroxy-16-(3-fulorophenyl)-17,18,19,20-tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid,    (10) (15α,13E)-9-oxo-15-hydroxy-16-(4-fuloro-3-trifuloromethylphenyl)-17,18,19,20-tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid,    (11) (15α,13E)-9-oxo-15-hydroxy-16-(3-trifuloromethylphenyl)-17,18,19,20-tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid,    (12) (15α,13E)-9-oxo-15-hydroxy-16-(3,4-difulorophenyl)-17,18,19,20-tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid,    (13) (15α,13E)-9-oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid,    (14) (15α,13E)-9-oxo-15-hydroxy-16-(3-propylphenyl)-17,18,19,20-tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid,    (15) (15α,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid,    (16) (15α,13E)-9-oxo-15-hydroxy-16-(3-ethyl-4-fulorophenyl)-17,18,19,20-tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid,    (17) (15α,13E)-9-oxo-15-hydroxy-16-phenyl-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-aza-10-oxaprost-13-ene,    (18) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-aza-10-oxaprost-13-ene,    (19) (15α,13E)-9-oxo-15-hydroxy-16-(4-fulorophenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-aza-10-oxaprost-13-ene,    (20) (15α,13E)-9-oxo-15-hydroxy-16-(naphthalene-2-yl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-aza-10-oxaprost-13-ene,    (21) (15α,13E)-9-oxo-15-hydroxy-16-(3-phenylphenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-aza-10-oxaprost-13-ene,    (22) (15α,13E)-9-oxo-15-hydroxy-16-(3-phenylphenyl)-5-(5-carboxythiophene-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,    (23) (15α,13E)-9-oxo-15-hydroxy-16-(naphthalene-2-yl)-5-(5-carboxythiophene-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,    (24) (15α,13E)-9-oxo-15-hydroxy-16-(4-fuloro-3-phenylphenyl)-5-(5-carboxythiophene-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,    (25) (15α,13E)-9-oxo-15-hydroxy-16-(3-ethylphenyl)-5-(5-carboxythiophene-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,    (26) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-5-(5-carboxythiophene-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,    (27) (15α,13E)-9-oxo-15-hydroxy-16-(3-trifluoromethoxyphenyl)-5-(5-carboxythiophene-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,    (28) (15α,13E)-9-oxo-15-hydroxy-16-(4-fuloro-3-phenylphenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,    (29) (15α,13E)-9-oxo-15-hydroxy-16-(3-ethylphenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,    (30) (15α,13E)-9-oxo-15-hydroxy-16-(naphthalene-2-yl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,    (31) (15α,13E)-9-oxo-15-hydroxy-16-(3-trifluoromethoxyphenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,    (32) (15α,13E)-9-oxo-15-hydroxy-16-(3-chloro-4-fulorophenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,    (33) (15α,13E)-9-oxo-15-hydroxy-16-cyclopropyl-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,    (34) (15α,13E)-9-oxo-15-hydroxy-16-cyclohexyl-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,    (35) (15α,13E)-9-oxo-15-hydroxy-16-(4-fulorophenyl)-5-(5-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,    (36) (15α,13E)-9-oxo-15-hydroxy-16-cyclobutyl-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,    (37) (15α,13E)-9-oxo-15-hydroxy-16-(4-chlorophenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,    (38) (15α,13E)-9-oxo-15-hydroxy-16-cycloheptyl-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,    (39) (15α,13E)-9-oxo-15-hydroxy-16-(indane-2-yl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,    (40) (15α,13E)-9-oxo-15-hydroxy-16-(tetrahydropyran-4-yl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,    (41) (15α,13E)-9-oxo-15-hydroxy-16-(7-methylnaphthalene-2-yl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,    (42) (15α,13E)-9-oxo-15-hydroxy-16-(4-fulorophenyl)-17,18,19,20-tetranol-5,10-dithia-8-azaprost-13-enoic acid,    (43) (15α,13E)-9-oxo-15-hydroxy-16-(4-fulorophenyl)-17,18,19,20-tetranol-6-thia-8-azaprost-13-enoic acid,    (44) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranol-6-thia-8-azaprost-13-enoic acid, and    (45) (15α,13E)-9-thioxo-15-hydroxy-16-(4-fulorophenyl)-17,18,19,20-tetranol-5-thia-8-azaprost-13-enoic acid.    
   
   
       5 . The compound according to  claim 1 , which is represented by formula (I-2):  
     
       
         
         
             
             
         
       
       wherein G 2  is  
       
         
           
           
               
               
           
         
       
       wherein left-pointing arrow represents binding to —(CH 2 ) 2 —, and right-pointing arrow represents binding to D,  
       R 4  is (1) a halogen atom, (2) C1-4 alkyl (3) C1-4 alkoxy, (4) C1-4 alkyl optionally substituted with 1-5 of halogen atom(s), (5) C1-4 alkoxy optionally substituted with 1-5 of halogen atom(s), (6) phenyl or (7) 3- to 15-membered mono-, bi- or tri-heterocyclic aryl containing 1 to 4 hetero atom(s) selected from oxygen, nitrogen and sulfur atom(s) which may be partially or fully saturated, and (6) phenyl or (7) heterocyclic in the R 4  may be substituted with 1-3 of (a) a halogen atom(s), (b) C1-4 alkyl (c) C1-4 alkoxy and/or (d) nitro,  
       r is an integer 1 to 5, and  
       other symbols have the same meanings as described in  claim 1 .  
     
   
   
       6 . The compound according to  claim 5 , which is selected from the group consisting of: 
 (1) (15α,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3,5-dimethylphenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic acid,    (2) (15α,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(benzothiazol-2-yl)phenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic acid,    (3) (15α,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(4-fulorophenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic acid,    (4) (15α,13E)-9-oxo-15-hydroxy-16-(3-(5-methylbenzothiazol-2-yl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,    (5) (15α,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(5-methylbenzoxazol-2-yl)phenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic acid,    (6) (15α,13E)-9-oxo-15-hydroxy-16-(3-(6-methylbenzoxazol-2-yl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,    (7) (15α,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(6-methylbenzoxazol-2-yl)phenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic acid,    (8) (15α,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(4-methylbenzothiazol-2-yl)phenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic acid,    (9) (15α,13E)-9-oxo-15-hydroxy-16-(3-(4-methylbenzothiazol-2-yl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,    (10) (15α,13E)-1,6-(2-fuloro-1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-methylphenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic acid,    (11) (15α,13E)-1,6-(3-methyl-1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-methylphenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic acid,    (12) (15α,13E)-9-oxo-15-hydroxy-16-(3-(5,7-dimethylbenzoxazol-2-yl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,    (13) (15α,13E)-9-oxo-15-hydroxy-16-(3-(5-chlorobenzothiazol-2-yl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,    (14) (15α,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(5-chlorobenzothiazol-2-yl)phenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic acid,    (15) (15α)-9-oxo-15-hydroxy-16-(3-(2,4-dimethylphenyl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,    (16) (15α,13E)-9-oxo-15-hydroxy-16-(3-(3,4-dimethylphenyl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,    (17) (15α,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3,4-difluorophenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic acid,    (18) (15α,13E)-1,6-(2-methyl-1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-methylphenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic acid,    (19) (15α,13E)-9-oxo-15-hydroxy-16-(3-(5-chlorobenzoxazol-2-yl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,    (20) (15α,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-methyl-4-fulorophenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic acid,    (21) (15α,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-chloro-4-fulorophenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic acid,    (22) (15α,13E)-1,6-(3-methoxy-1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-methylphenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic acid,    (23) (15α,13E)-9-oxo-15-hydroxy-16-(3-trifluoromethoxyphenyl)-17,18,19,20-tetranol-5-thia-8-azaprost-13-enoic acid,    (24) (15α,13E)-9-oxo-15-hydroxy-16-(3,5-difluorophenyl)-17,18,19,20-tetranol-5-thia-8-azaprost-13-enoic acid,    (25) (15α,13E)-9-oxo-15-hydroxy-16-(3-(phenyl)phenyl)-17,18,19,20-tetranol-5-thia-8-azaprost-13-enoic acid,    (26) (15α,13E)-9-oxo-15-hydroxy-16-(3-(4-fulorophenyl)phenyl)-17,18,19,20-tetranol-5-thia-8-azaprost-13-enoic acid, and    (27) (15α,13E)-9-oxo-15-hydroxy-16-(3-phenyl-4-fulorophenyl)-17,18,19,20-tetranol-5-thia-8-azaprost-13-enoic acid.    
   
   
       7 . A pharmaceutical composition comprising the compound represented by formula (I) according to  claim 1 , a salt thereof, a solvate thereof, a cyclodextrin clathlate thereof, or a prodrug thereof, and a pharmaceutically acceptable carrier.  
   
   
       8 . An EP4 agonist comprising the compound represented by formula (I) according to  claim 1 , a salt thereof, a solvate thereof or a cyclodextrin clathlate thereof, or a prodrug thereof, and a pharmaceutically acceptable carrier.  
   
   
       9 . A method for preventing and/or treating EP4-mediated disease, which comprises administrating to a mammal an effective amount of the compound represented by formula (I) according to  claim 1 , a salt thereof, a solvate thereof or a cyclodextrin clathrate thereof, or a prodrug thereof.