1-substituted 1,2,3,4-tetrahydro-1,7-naphthyridin-8-amine derivatives and their use as ep4 receptor antagonists

Abstract

The present invention provides a compound represented by the formula (I): wherein each symbol is as defined in the specification, or a salt thereof has an EP4 receptor antagonistic action, and is useful as an agent for the prophylaxis or treatment of EP4 receptor associated diseases (e.g., rheumatoid arthritis, aortic aneurysm (e.g. abdominal aortic aneurysm, thoracic aortic aneurysm, thoracoabdominal aortic aneurysm etc.), endometriosis, ankylosing spondylitis, inflammatory breast cancer etc.) and the like.

1 . A compound represented by the formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         G 1  is a carbon atom or a nitrogen atom, 
         G 2  is a carbon atom or a nitrogen atom, 
         Ring A is an optionally further substituted 6-membered nitrogen-containing heterocycle, 
         G 3  is an oxygen atom, an optionally substituted methylene, NR′, a sulfur atom, S(O) or S(O) 2 , 
         R 1  is a hydrogen atom or a substituent, 
         X is an optionally substituted ethylene, 
         R 2  and R 3  are each independently a hydrogen atom or an optionally substituted C 1-6  alkyl group, or R 2  and R 3  are joined together to form a cycloalkane or a heterocycle, each of which is optionally substituted, 
         R 4  is a hydrogen atom or a substituent, 
         Ring B is an optionally further substituted ring, 
         Ring C is an optionally further substituted ring, and 
         W is a bond, or a spacer in which the number of atoms in the main chain is 1 to 4, 
         or a salt thereof. 
       
     
     
         2 . The compound or salt of  claim 1 , wherein
 G 1  is a carbon atom,   G 2  is a carbon atom or a nitrogen atom,   Ring A is pyridine or pyrimidine, each of which is optionally further substituted by 1 to 2 substituents selected from the group consisting of   (a) a halogen atom,   (b) a C 1-6  alkyl group, and   (c) a C 3-10  cycloalkyl group,
 G 3  is an oxygen atom, NR 1  wherein R 1  is a C 1-6  alkyl group, methylene or a sulfur atom, 
 X is ethylene optionally substituted by an oxo group, 
 R 2  and R 3  are each a hydrogen atom or a C 1-6  alkyl group, or R 2  and R 3  are joined together to form a C 3-10  cycloalkane, 
 R 4  is a hydrogen atom, 
 Ring B is 
   
       (1) a C 6-14  aromatic hydrocarbon ring optionally further substituted by 1 to 3 substituents selected from the group consisting of
 (a) a carboxy group, 
 (b) a C 1-6  alkoxy-carbonyl group, 
 (c) a cyano group, 
 (d) a carbamoyl group, 
 (e) a mono- or di-C 1-6  alkyl-carbamoyl group, 
 (f) a mono- or di-C 1-6  alkoxy-carbamoyl group, 
 (g) a mono- or di-C 7-16  aralkyloxy-carbamoyl group, 
 (h) 5-tetrazolyl, and 
 (i) a C 1-6  alkoxy group, 
 
       (2) a C 3-10  cycloalkane, or 
       (3) a 5- to 10-membered aromatic heterocycle optionally further substituted by 1 to 3 C 1-6  alkyl groups,
 Ring C is a C 6-14  aromatic hydrocarbon ring, a C 3-10  cycloalkane or a 5- to 14-membered aromatic heterocycle, each of which is optionally further substituted by 1 to 3 substituents selected from the group consisting of 
 (1) a halogen atom, 
 (2) an optionally halogenated C 1-6  alkyl group, 
 (3) a C 1-6  alkoxy group, and 
 (4) a C 6-14  aryl group, and
 W is 
 
 
       (1) a C 1-4  alkylene group optionally substituted by an oxo group, or 
       (2) —(CH 2 ) m1 —O— wherein m1 is an integer of 0 to 3. 
     
     
         3 . 4-[(1S)-1-[[4-[(3-Chlorophenyl)methyl]-2,3-dihydropyrido[4,3-b][1,4]oxazin-5-yl]amino]ethyl]benzoic acid or a salt thereof. 
     
     
         4 . 4-[1-[[4-[(3,4-Difluorophenyl)methyl]-2,3-dihydropyrido[4,3-b][1,4]oxazin-5-yl]amino]cyclopropyl]benzoic acid or a salt thereof. 
     
     
         5 . 4-[(1S)-1-[[4-[(4-Methoxyphenyl)methyl]-2,3-dihydropyrido[4,3-b][1,4]oxazin-5-yl]amino]ethyl]benzoic acid or a salt thereof. 
     
     
         6 . A medicament comprising the compound or salt according to  claim 1 . 
     
     
         7 . The medicament according to  claim 6 , which is an EP4 receptor antagonist. 
     
     
         8 . The medicament according to  claim 6 , which is an agent for the prophylaxis or treatment of EP4 receptor associated diseases. 
     
     
         9 . The medicament according to  claim 8 , wherein the EP4 receptor associated diseases are selected from rheumatoid arthritis, aortic aneurysm, endometriosis, ankylosing spondylitis and inflammatory breast cancer. 
     
     
         10 . The compound or salt of  claim 1  for use in the prophylaxis or treatment of EP4 receptor associated diseases. 
     
     
         11 . The compound or salt of  claim 10 , wherein the EP4 receptor associated diseases are selected from rheumatoid arthritis, aortic aneurysm, endometriosis, ankylosing spondylitis and inflammatory breast cancer. 
     
     
         12 . A method of inhibiting EP4 receptor in a mammal, which comprises administering an effective amount of the compound or salt of  claim 1  to the mammal. 
     
     
         13 . A method for the prophylaxis or treatment of EP4 receptor associated diseases in a mammal, which comprises administering an effective amount of the compound or salt of  claim 1  to the mammal. 
     
     
         14 . The method of  claim 13 , wherein the EP4 receptor associated diseases are selected from rheumatoid arthritis, aortic aneurysm, endometriosis, ankylosing spondylitis and inflammatory breast cancer. 
     
     
         15 . Use of the compound or salt of  claim 1  for the production of an agent for the prophylaxis or treatment of EP4 receptor associated diseases. 
     
     
         16 . Use of  claim 15 , wherein the EP4 receptor associated diseases are selected from rheumatoid arthritis, aortic aneurysm, endometriosis, ankylosing spondylitis and inflammatory breast cancer.