Dipeptoid prodrugs and their use

Abstract

The present application relates to prodrug derivatives of 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)-4-[4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitrile, processes for their preparation, their use for the treatment and/or prophylaxis of diseases, and their use for the manufacture of medicaments for the treatment and/or prophylaxis of diseases, especially of cardiovascular disorders.

1 . A method of treatment of a cardiovascular disorder selected from the group consisting of: hypertension, peripheral and cardiac vascular disorders, coronary heart disease, coronary restenosis, myocardial infarction, acute coronary syndrome, acute coronary syndrome with ST elevation, acute coronary syndrome without ST elevation, stable and unstable angina pectoris, myocardial insufficiency, princemetal angina, persistent ischemic dysfunction, temporary postischemic dysfunction, heart failure, tachycardia, atrial tachycardia, arrhythmias, atrial and ventricular fibrillation, persistent atrial fibrillation, permanent atrial fibrillation, atrial fibrillation with normal left ventricular function, atrial fibrillation with impaired left ventricular function, Wolff-Parkinson-White syndrome, disturbances of peripheral blood flow, elevated levels of fibrinogen and of low density LDL, and elevated concentrations of plasminogen activator inhibitor 1 (PAI-1) comprising administering an effective amount of a compound of the formula (I) 
       
         
           
           
               
               
           
         
         in which 
         R A  is a group of the formula 
       
       
         
           
           
               
               
           
         
         in which 
         * means the point of linkage to the O atom, 
         L 1  and L 2  are independently of one another a bond or —CH 2 —, 
         R 1 , R 2  and R 3  are independently of one another hydrogen or methyl, 
         R 4  and R 6  are identical or different and are independently of one another hydrogen or the side group of a natural α-amino acid or its homologs or isomers, 
         R 5  and R 7  are independently of one another hydrogen or methyl, 
         L 3  is straight-chain or branched (C 2 -C 4 )-alkanediyl which is additionally substituted by amino, 
         R 8 , R 9  and R 10  are independently of one another hydrogen or methyl, 
         m is the number 2, 3, 4, 5 or 6, 
         L 4  is straight-chain or branched (C 2 -C 4 )-alkanediyl, which is additionally substituted by carboxyl, 
         R 11  is hydrogen or methyl, and 
         n is the number 1, 2, 3 or 4, 
         or a salt thereof to a human or animal in need thereof. 
       
     
     
         2 . The method of  claim 1 , wherein in the compound of formula (I)
 R A  is a group of the formula   
       
         
           
           
               
               
           
         
         in which 
         * means the point of linkage to the O atom, 
         L 1  is a bond, 
         L 2  is a bond or —CH 2 —, 
         R 1  and R 3  are independently of one another hydrogen or methyl, 
         R 4  is hydrogen, methyl, propan-2-yl, propan-1-yl, 2-methylpropan-1-yl, 1-methyl-propan-1-yl, butan-1-yl, benzyl, p-hydroxybenzyl, imidazol-4-ylmethyl, hydroxymethyl, 1-hydroxyethyl, carbamoylmethyl or 2-carbamoylethyl, 
         R 6  is hydrogen, imidazol-4-ylmethyl, 4-aminobutan-1-yl, 3-aminopropan-1-yl, 2-aminoethyl, aminomethyl or 3-guanidinopropan-1-yl, 
         L 3  is straight-chain (C 2 -C 4 )-alkanediyl which is additionally substituted by amino, 
         R 8  and R 10  are independently of one another hydrogen or methyl, 
         m is the number 2, 3 or 4, 
         L 4  is straight-chain (C 2 -C 4 )-alkanediyl which is additionally substituted by carboxyl, 
         R 11  is hydrogen or methyl, and 
         n is the number 2, 3 or 4 
         or a salt thereof. 
       
     
     
         3 . The method of  claim 1  wherein in the compound of formula (I):
 R A  is a group of the formula 
 
       
         
           
           
               
               
           
         
         in which 
         * means the point of linkage to the O atom, 
         L 1  and L 2  are each a bond, 
         R 4  is hydrogen, methyl, propan-2-yl, propan-1-yl, 2-methylpropan-1-yl, 1-methyl-propan-1-yl, butan-1-yl, benzyl, p-hydroxybenzyl, imidazol-4-ylmethyl, hydroxymethyl, 1-hydroxyethyl, carbamoylmethyl or 2-carbamoylethyl, 
         R 6  is imidazol-4-ylmethyl, 4-aminobutan-1-yl, 3-aminopropan-1-yl, 2-aminoethyl, aminomethyl or 3-guanidinopropan-1-yl, 
         L 3  is a group of the formula —CH(NH 2 )—CH 2 —, —CH 2 —CH(NH 2 )—, —CH 2 —CH(NH 2 )—CH 2 —, —CH(NH 2 )—CH 2 —CH 2 — or —CH 2 —CH 2 —CH(NH 2 )—, 
         m is the number 2, 3 or 4, 
         L 4  is a group of the formula **—CH 2 —CH(COOH)— or **—CH 2 —CH 2 —CH(COOH)—, in which 
         ** represents the point of linkage to the adjoining carbonyl group, and 
         n is the number 2 or 3, 
         or a salt thereof. 
       
     
     
         4 . The method of  claim 1 , wherein in the compound of formula (I)
 R A  is a group of the formula   
       
         
           
           
               
               
           
         
         in which 
         * means the point of linkage to the O atom, 
         L 1  and L 2  are each a bond, 
         R 4  is hydrogen, methyl, propan-2-yl, 2-methylpropan-1-yl, benzyl, hydroxymethyl or 1-hydroxyethyl, and 
         R 6  is imidazol-4-ylmethyl, 4-aminobutan-1-yl, 3-aminopropan-1-yl, 2-aminoethyl, aminomethyl or 3-guanidinopropan-1-yl, 
         or a salt thereof. 
       
     
     
         5 . The method of  claim 1 , wherein in the compound of formula (I)
 R A  is a group of the formula   
       
         
           
           
               
               
           
         
         in which 
         * means the point of linkage to the O atom, 
         L 3  is a group of the formula —CH(NH 2 )—CH 2 —, —CH 2 —CH(NH 2 )—, —CH(NH 2 )—CH 2 —CH 2 — or —CH 2 —CH 2 —CH(NH 2 )—, and 
         m is the number 2 or 3, 
         or a salt thereof. 
       
     
     
         6 - 12 . (canceled) 
     
     
         13 . The method of  claim 1 , wherein the compound of formula (I) is a compound having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The method of  claim 1 , wherein the compound of formula (I) is a compound having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The method of  claim 1 , wherein the compound of formula (I) is a compound having the formula 
       
         
           
           
               
               
           
         
       
     
     
         16 . The method of  claim 1 , wherein the compound of formula (I) is a compound having the formula 
       
         
           
           
               
               
           
         
       
     
     
         17 . The method of  claim 1 , wherein the compound of formula (I) is a compound having the formula 
       
         
           
           
               
               
           
         
       
     
     
         18 . The method of  claim 1 , wherein the compound of formula (I) is a compound having the formula 
       
         
           
           
               
               
           
         
       
     
     
         19 . The method of  claim 1 , wherein the compound of formula (I) is a compound having the formula 
       
         
           
           
               
               
           
         
       
     
     
         20 . The method of  claim 1 , wherein the cardiovascular disorder is selected from the group consisting of: hypertension, coronary heart disease, acute coronary syndrome, angina pectoris, heart failure, myocardial infarction and atrial fibrillation.