Aminocarboxylic acid derivative and medicinal use thereof

Abstract

The present invention relates to a compound represented by the formula (I), a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof, and a medicament containing the same. The compound represented by the formula (I) has an ability to bind to an S1P receptor (particularly, EDG-1, EDG-6, and/or EDG-8) and is useful for preventing and/or treating for rejection to transplantation, graft-versus-host disease, autoimmune diseases, allergic diseases, neurodegenerating diseases, and the like. wherein all symbols are described in the specification.

1 . A compound represented by a formula (I) 
       
         
           
           
               
               
           
         
         wherein a ring A represents a cyclic group, 
         a ring B represents a cyclic group which may further have a substituent(s), 
         X represents a bond or a spacer which has a main chain having 1 to 8 atoms and one atom of which may be taken together with a substituent of the ring B to form a ring which may have a substituent(s), 
         Y represents a bond or a spacer which has a main chain having 1 to 10 atoms and one atom of which may be taken together with a substituent of the ring B to form a ring which may have a substituent(s), 
         Z represents an acid group which may be protected, and 
         n represents 0 or 1, with proviso that when n is 0, m represents 1 and R 1  represents a hydrogen atom or a substituent, and when n is 1, m represents 0 or an integer of 1 to 7 and R 1  represents a substituent, when m is 2 or more, a plurality of R 1 s may be the same or different, 
         a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof. 
       
     
     
         2 . The compound according to  claim 1 , a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof, wherein Z represents (1) a carboxyl group which may be protected, (2) a hydroxy group which may be protected, (3) a hydroxamic acid group which may be protected, (4) a sulfonic acid group which may be protected, (5) a boronic acid group which may be protected, (6) a carbamoyl group which may be protected, (7) a sulfamoyl group which may be protected, (8) a —P(═O)(OR 2 ) (OR 3 ) group, wherein R 2  and R 3  each independently represent a hydrogen atom and a C1-8 alkyl group, or R 2  and R 3  join together to represent a C2-4 alkylene group, or (9) a tetrazolyl group. 
     
     
         3 . The compound according to  claim 1 , a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof, wherein Y represents 
       
         
           
           
               
               
           
         
         wherein a carbon atom or a nitrogen atom may be substituted by an arbitrary number of substituents on its arbitrary positions where the substituents can be placed, and a right arrow binds to Z. 
       
     
     
         4 . The compound according to  claim 1 , a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof, wherein a ring B is a benzene ring which may have a substituent(s), or a dihydronaphthalene ring which may have a substituent(s). 
     
     
         5 . The compound according to  claim 1 , a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof, wherein 
       
         
           
           
               
               
           
         
         wherein R 4 , R 4-1 , R 5 , R 5-1  and R 5-2  each independently represent a hydrogen atom, a halogen atom, trifluoromethyl, trifluoromethoxy, C1-8 alkoxy, or C1-8 alkyl; p represents an 0 or an integer of 1 to 4, in which when p is 2 or more, a plurality of R 4 's may be the same or different; and a right arrow binds to Z. 
       
     
     
         6 . The compound according to  claim 1 , a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof, wherein 
       
         
           
           
               
               
           
         
         wherein all symbols have the same meanings as described in  claims 1  and  5 . 
       
     
     
         7 . The compound according to  claim 1 , a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof, wherein X represents 
       
         
           
           
               
               
           
         
         wherein R 6  and R 7  each independently represent a hydrogen atom, a halogen atom, hydroxy which may be protected, amino which may be protected, C1-8 alkyl, or C1-8 alkyl substituted by hydroxy which may be protected; or R 6  and R 7  may be taken together with a carbon atom to which they are bound to form a ring which may have a substituent(s); a symbol   represents an α-configuration; a symbol   represents a β-configuration; and a right arrow binds to ring B. 
       
     
     
         8 . The compound according to  claim 7 , a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof, wherein X represents 
       
         
           
           
               
               
           
         
         wherein all symbols have the same meanings as described in  claim 7 . 
       
     
     
         9 . The compound according to  claim 8 , a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof, wherein X represents 
       
         
           
           
               
               
           
         
         wherein all symbols have the same meanings as described in  claim 7 . 
       
     
     
         10 . The compound according to  claim 1 , a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof, wherein ring A is a benzene ring or a pyridine ring. 
     
     
         11 . The compound according to  claim 1 , a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof, wherein R 1  represents a halogen atom, C1-8 alkyl, or C1-8 alkoxy. 
     
     
         12 . The compound according to  claim 5 , a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof, wherein 
       
         
           
           
               
               
           
         
         wherein all symbols have the same meanings as described in  claims 1  and  5 . 
       
     
     
         13 . The compound according to  claim 12 , a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof, wherein Z is carboxyl which may be protected. 
     
     
         14 . The compound according to  claim 12 , a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof, wherein X represents 
       
         
           
           
               
               
           
         
         wherein a right arrow binds to a ring B and the other symbols have the same meanings as described in  claim 7 . 
       
     
     
         15 . The compound according to  claim 12 , a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof, wherein a ring A is a benzene ring or a pyridine ring. 
     
     
         16 . The compound according to  claim 12 , a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof, wherein R 1  represents a halogen atom, C1-8 alkyl which may have a substituent(s), or C1-8 alkoxy which may have a substituent(s). 
     
     
         17 . The compound according to  claim 12 , a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof, which is a compound represented by the formula (IC-2): 
       
         
           
           
               
               
           
         
         wherein all symbols have the same meanings as described in  claims 1  and  5 . 
       
     
     
         18 . The compound according to  claim 1 , a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof, which is 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinecarboxylic acid, 1-({6-[(4-isobutyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinecarboxylic acid, 1-({6-[(4-isobutyl-3-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinecarboxylic acid, 1-({6-[(2-ethoxy-4-isobutylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinecarboxylic acid, 1-[(6-{[4-isopropoxy-2-(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinecarboxylic acid, 1-[(6-{[2,4-bis(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinecarboxylic acid, 1-({1-chloro-6-[(2-methoxy-4-propylbenzyl)oxy]-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinecarboxylic acid, 1-({1-chloro-6-[(4-isobutyl-2-methoxybenzyl)oxy]-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinecarboxylic acid, 1-[(1-chloro-6-{[(2S)-3-(2,4-difluorophenyl)-2-methylpropyl]oxy}-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinecarboxylic acid, 1-[(6-{[4-ethoxy-2-(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinecarboxylic acid, 1-({6-[(4-ethyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinecarboxylic acid, 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1,5-dimethyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinecarboxylic acid, 1-[(6-{[2,4-bis(trifluoromethyl)benzyl]oxy}-1-chloro-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinecarboxylic acid, 1-[(6-{[2-(difluoromethoxy)-4-propylbenzyl]oxy}-1,5-dimethyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinecarboxylic acid, 1-[(6-{[4-ethoxy-3-(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinecarboxylic acid, or 1-({6-[(2-methoxy-6-propyl-3-pyridinyl)methoxy]-1,5-dimethyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinecarboxylic acid. 
     
     
         19 . The compound according to  claim 17 , a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof, which is 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinecarboxylic acid or 1-[(6-{[2,4-bis(trifluoromethyl)benzyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinecarboxylic acid. 
     
     
         20 . A pharmaceutical composition which comprises the compound represented by the formula (I) according to  claim 1 , a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof. 
     
     
         21 . The pharmaceutical composition according to  claim 20 , which is an EDG-1 agonist, EDG-6 agonist and/or EDG-8 agonist. 
     
     
         22 . The pharmaceutical composition according to  claim 21 , which is an EDG-1 agonist. 
     
     
         23 . The pharmaceutical composition according to  claim 20 , which is an agent for preventing and/or treating a disease related to EDG-1, EDG-6 and/or EDG-8. 
     
     
         24 . The pharmaceutical composition according to  claim 23 , wherein the disease related to EDG-1, EDG-6 and/or EDG-8 is rejection in transplantation of an organ, tissues, and/or cells, autoimmune disease, allergic disease, asthma, multiple organ failure, ischemia-reperfusion injury, malignant tumor, and/or neurodegenerative disease. 
     
     
         25 . The pharmaceutical composition according to  claim 24 , wherein the rejection in transplantation of an organ, tissues, and/or cells is a rejection in transplantation of kidney, liver, heart, lung, dermal graft, cornea, vascular, chordae, bone, bone marrow cells, neuronal cells, and/or pancreatic islet cells; the autoimmune disease is collagen disease, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, autoimmune diabetes, lung fibrosis, and/or liver fibrosis, and the allergic disease is atopic dermatitis, pollen disease, and/or food allergy. 
     
     
         26 . The pharmaceutical composition according to  claim 20 , which is an immunosuppressant agent and/or an agent causing lymphopenia. 
     
     
         27 . An agent comprising the compound represented by the formula (I) described in  claim 1 , a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof in combination with one or at least two agent(s) selected from the group consisting of an antimetabolite, an alkylating agent, a T cell activation inhibitor, a calcineurin inhibitor, a proliferation signal inhibitor, a steroid, an immunosuppressant agent, an antibody used in immune suppression, an agent for treating rejection, an antibiotic, an antiviral agent, and an antifungal agent. 
     
     
         28 . A method for prevention and/or treatment of a disease related to EDG-1, EDG-6 and/or EDG-8 in a mammal, which comprises administering to a mammal an effective amount of the compound represented by the formula (I) described in  claim 1 , a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof. 
     
     
         29 . A method for immune suppression and/or lymphopenia in a mammal, which comprises administering to a mammal an effective amount of the compound represented by the formula (I) according to  claim 1 , a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof.