Diazepan derivatives or salts thereof

Abstract

To provide a compound which has an anticoagulation action based upon inhibition of activated blood coagulation factor X and is useful as an anticoagulant or an agent for prevention and treatment of diseases caused by thrombus or embolus. A diazepan derivative such as 4-[(3-carbamimidoylphenylamino)methyl]-3-[4-(4-methyl-1,4-diazepan-1-yl)benzoylamino]benzoic acid and 3-hydroxy-4′-methoxy-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}benzanilide or a salt thereof is an effective ingredient.

1. A diazepan compound represented by the following formula (I) or a pharmaceutically acceptable isomer or salt thereof: 
       
         
           
           
               
               
           
         
       
       symbols in the above formula have the following meanings:
 rings A and B: they are the same or different and are each aryl or heteroaryl which may have 1 to 3 substituents;
 X 1 : —C(═O)—NR 4 —, —NR 4 —C(═O)—, —NR 4 —CH 2 —, —O—CH 2 —, —CH 2 —CH 2 — or —CH═CH—; 
 X 2 : —C(═O)—NR 5 — or —NR 5 —C(═O)—; 
 R 1 : hydrogen atom, lower alkyl, -lower alkylene-O— lower alkyl, C 3-8  cycloalkyl, aryl, heteroaryl, -lower alkylene-C 3-8  cycloalkyl, -lower alkylene-aryl, -lower alkylene-heteroaryl or —C(═NR 6 )-lower alkyl; 
 R 2 : —OH; 
 R 3 : hydrogen atom, halogen atom or lower alkyl; and 
 R 4 , R 5  and R 6 : they are the same or different and are each hydrogen atom or lower alkyl. 
 
 
     
     
       2. The diazepan compound or a salt thereof according to  claim 1 , wherein the ring A and the ring B are the same or different and are each benzene ring, pyridine ring, naphthalene ring, thiophene ring, benzofuran ring or quinoline ring which may have 1 to 3 substituents. 
     
     
       3. The diazepan compound or a salt thereof according to  claim 1 , wherein the substituent of the aryl or heteroaryl which may have 1 to 3 substituents is a substituent selected from optionally substituted lower alkyl, lower alkenyl, lower alkynyl, C 3-8  cycloalkyl, optionally O-substituted lower alkyl, halogen atom, —NH 2 , —NH-lower alkyl, —N-(lower alkyl) 2 , —C(═NH)—NH 2 , —C(═N—OH)—NH 2 , —C(═NH)—NH—OH, —C(═NH)—NH—C(═O)—O-lower alkyl, —COOH, optionally —C(═O)—O-substituted lower alkyl, optionally —C(═O)—O-substituted C 6-14  aryl, optionally —C(═O)—O-substituted heteroaryl, —CN, —NO 2 , —OH, optionally —O—CO-substituted lower alkyl, —O—CO—NH 2 , —O—CO—NH-lower alkyl, —O—CO—N-(lower alkyl) 2 , —SH, —C(═O)—NH 2 , —C(═O)—NH-(lower alkyl) and —C(═O)—N-(lower alkyl) 2 . 
     
     
       4. The diazepan compound or a salt thereof according to  claim 1  selected from 3-hydroxy-4′-methoxy-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}benzanilide, 3-hydroxy-N 1 -(4-methoxybenzoyl)-N 2 -[4-(4-methyl-1,4-diazapan-1-yl)benzoyl]-1,2-phenylenediamine, 5-chloro-N-(5-chloro-2-pyridyl)-3-hydroxy-2-{[4-(4-methyl-1,4-diazepan-1-yl)-benzoyl]amino}benzamide, 5-chloro-3-hydroxy-4′-methoxy-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}benzanilide and 5-bromo-N-(5-chloro-2-pyridyl)-3-hydroxy-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}benzamide. 
     
     
       5. A pharmaceutical composition containing the diazepan compound or a salt thereof according to  claim 1  as an effective ingredient and a pharmaceutically acceptable carrier. 
     
     
       6. An activated blood coagulation factor X inhibitor in which the diazepan compound or a salt thereof according to  claim 1  as is an effective ingredient. 
     
     
       7. A diazepan compound selected from 3-hydroxy-4′-methoxy-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}benzanilide, 4′-chloro-3-hydroxy-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}benzanilide, 4′-fluoro-3-hydroxy-2-{[4-(4-methyl-1,4-4-diazepan-1yl)benzoyl]amino}benzanilide, 4′-fluoro-3-hydroxy-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}benzanilide, 3-hydroxy-3′-methyl-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}benzanilide, 4′-bromo-3-hydroxy-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}benzanilide, 5-hydroxy-4′-methoxy-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}benzanilide, 4-hydroxy-4′-methoxy-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}benzanilide, N 1 -(4-chlorobenzoyl)-3-hydroxy-N 2 -[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]-1,2-phenylenediamine, N 1 -(4-bromobenzoyl)-3-hydroxy-N 2 -[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]-1,2-phenylenediamine,  3 -hydroxy-N 1 -(3-methylbenzoyl)-N 2 -[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]-1,2-phenylenediamine, 3-hydroxy-N 1 -(3-methylbenzoyl)-N 2 -[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]-1,2-phenylenediamine, N 1 -(3-chloro-4-methoxybenozyl)-3-hydroxy-N 2 -[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]-1,2-phenylenediamine, N 1 -[(5-chloro-2-thienyl)carbonyl]-3-hydroxy-N 2 -[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]-1,2-phenylenediamine, N 1 -(4-fluorobenzoyl)-3-hydroxy-N 2 -[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]-1,2-phenylenediamine, 3-hydroxy-N 2 -[4-(4-methyl-1,4-diazepan-1-yl)-benzoyl]N 1 -(2-naphthoyl)-1,2-phenylenediamine, N 1 -[(5-bromo-2-thienyl)carbonyl]-3-hydroxy-N 2 -[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]-1,2-phenylenediamine, N 1 -(1-benzofuran-2-ylcarbonyl)-3-hydroxy-N 2 -[4-(4-methyl-1,4-diazepan-yl)benzoyl]-1,2-phenylenediamine, 3-hydroxy-N 2 -[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]-N 1 -(quinolin-3-ylcarbonyl)-1,2-phenylenediamine, 3-hydroxy-N 1 -[(5-methoxy-2-thienyl)carbonyl]-N 2 -[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]-1,2-phenylenediamine, N 1 -(3-fluoro-4-methoxybenozyl)-3-hydroxy-N 2 -[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]-1,2-phenylenediamine, 3-hydroxy-N 1 -(4-methoxybenzoyl)-N 2 -{4-[4-(4-pyridyl)-1,4-diazepan-1-yl]benozyl}-1,2-phenylenediamine, 3-hydroxy-N 1 -(4-methoxybenzoyl)-N 2 -(4-{4-[1-(N-methylimino)ethyl]-1,4-diazepan-1-yl}benzoyl)-1,2-phenylenediamine, N 2 -[4-(4-benzyl-1,4-diazepan-1-yl)benzoyl]-3-hydroxy-N 1 -(4-methoxybenzoyl)-1,2-phenylenediamine, 3-[(4-methoxybenzoyl)amino]-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}phenyl sulfate, 3-hydroxy-N 2 -(4-methoxybenzoyl)-N 1 -[4-(4-methyl-1,4-diazepan-1-yl)benozyl]-1,2-phenylenediamine, N 2 -[4-(1,4-diazepan-1-yl)benzoyl]-3-hydroxy-N 1 -(4-methoxybenzoyl)-1,2-phenylenediamine, N 2 -[4-(4-cyclopropylmethyl-1,4-diazepan-1-yl)benozyl]-3-hydroxy-N 1 -(4-methoxybenzoyl)-1,2-phenylenediamine, 3-hydroxy-N 2 -{4-[4-(1-iminoethyl)-1,4-diazepan-1-yl]benzoyl}-N 1 -(4-methoxybenozyl)-1,2-phenylenediamine, N 2 -[4-(4-cyclobutyl-1,4-diazepan-1-yl)benzoyl]-3-hydroxy-N 1 -(4-methoxybenzoyl)-1,2-phenylenediamine, 3-hydroxy-N 1 -(4-methoxybenozyl)-N 2 -{4-[4-(2-methoxyethyl)-1,4-diazepan-1-yl]benozyl}-1,2-phenylenediamine, 5-chloro-N-(5-chloro-2-pyridyl)-3-hydroxy-2-[{4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}benzamide, 5-bromo-N-(5-chloro-2-pyridyl)-3-hydroxy-2-{[4-(4-methyl-1,4-diazapan-1-yl)benzoyl]amino}benzamide 5-chloro-N-(5-chloro-2-pyridyl)-3-hydroxy-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}benzamide, 5-bromo-N-(5-chloro-2-pyridyl)-3-hydroxy-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}benzamide or a salt thereof. 
     
     
       8. A diazepan compound represented by the following formula (I) or a pharmaceutically acceptable isomer or salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is C 1-6  alkyl; 
 B is phenyl or pyridine where the phenyl is attached to the rest of the compound in the 1,4-position and the pyridine is attached to the rest of the compound in the 2,5-position; 
 X 2  is —C(═O)—NH— or —NH—C(═O)—; 
 R 2  is —OH; 
 X 1  is —C(═O)—NH— or —NH—C(═O)—; and 
 A is a phenyl substituted with 0-3 substituents which are independently selected from the group consisting of halo, —OH, —O-lower alkyl, and substituted lower alkyl in which the substituent is —OH.  
 
     
     
       9. The compound of claim 8, wherein A is substituted with a substituent in the 4-position.  
     
     
       10. The compound of claim 9, wherein the substituent is —OCH 3 .  
     
     
       11. The compound of claim 8, wherein lower alkyl is methyl or ethyl.  
     
     
       12. The compound of claim 8, wherein R 1  is methyl.  
     
     
       13. The compound of claim 8, wherein R 1  is methyl and B is a phenyl attached to the rest of the compound in the 1,4-position.  
     
     
       14. The compound of claim 8, wherein X 2  is —C(═O)—NH—.  
     
     
       15. The compound of claim 8, wherein X 1  is —C(═O)—NH—.  
     
     
       16. The compound of claim 8, wherein halo is chloro.  
     
     
       17. The compound of claim 8, wherein X 2  is —N(H)—C(═O)—.  
     
     
       18. The compound of claim 8, wherein X 1  is —N(H)—C(═O)—.  
     
     
       19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 8.  
     
     
       20. The compound of claim 8, wherein R 1  is methyl; B is a phenyl attached to the rest of the compound in the 1,4-position; X 2  is —N(H)—C(═O)—; and A is substituted with a substituent in the 4-position and the substituent is halo or —OCH 3 .