Method and compositions for treating persistent pulmonary hypertension using aralkyl ester soft drugs

Abstract

A method and compositions for treating persistent pulmonary hypertension in human newborns that deploys an intravenous infusion of a modified drug formed by adding one or more of a predetermined chemical arrangement to an efficacious parent drug compound so as to retain efficacy while re-directing a preferred route and rate of the parent drug compound's metabolism to an inactive or very weakly active and non-toxic metabolite are disclosed. The chemical arrangement is φ-R—X—R′; wherein φ is a phenyl, substituted aryl or heteroaryl system that is already present in the parent drug compound or is specifically added to the parent drug compound via a metabolically stable connection; R is an alkyl or alkene containing chain either branched or unbranched from 0 to 10 carbons that is already present in the parent drug compound or is added to the parent drug compound via a metabolically stable connection to φ; X is a carboxyl, sulfoxyl or phosphatyl function that is specifically added to the parent drug compound via a metabolically stable connection to R; and, R′ is an added alkyl, alkenyl or aralkyl group either branched or unbranched containing from 1 to 10 carbons, or is a structural element already present as an inherent portion of the parent drug compound.

1 . A method for treating persistent pulmonary hypertension in human newborns comprising deploying an intravenous infusion of a modified drug formed by adding one or more of a predetermined chemical arrangement to an efficacious parent drug compound so as to retain efficacy while re-directing a preferred route and rate of the parent drug compound's metabolism to an inactive or very weakly active and non-toxic metabolite, the chemical arrangement comprising:  
       φ-R—X—R′ wherein φ is a phenyl, substituted aryl or heteroaryl system that is already present in the parent drug compound or is specifically added to the parent drug compound via a metabolically stable connection;    R is an alkyl or alkene containing chain either branched or unbranched from 0 to 10 carbons that is already present in the parent drug compound or is added to the parent drug compound via a metabolically stable connection to φ;    X is a carboxyl, sulfoxyl or phosphatyl function that is specifically added to the parent drug compound via a metabolically stable connection to R; and    R′ is an added alkyl, alkenyl or aralkyl group either branched or unbranched containing from 1 to 10 carbons, or is a structural element already present as an inherent portion of the parent drug compound.    
     
     
         2 . The method of  claim 1 , in which the parent compound comprises an alpha-adrenergic receptor ligand.  
     
     
         3 . The method of  claim 2 , in which the alpha-adrenergic receptor ligand has an inherent phenyl ring system and comprises tolazoline or is a derivative of tolazoline wherein the inherent phenyl system is also substituted with one or more methyl, hydroxy or methoxy groups in any combination of attachments to any of ortho-, meta-, or para-positions on the inherent phenyl ring system.  
     
     
         4 . A composition comprising at least one of tolazoline or its derivatives having one or more methyl, hydroxy or methoxy groups attached to an inherent phenyl ring system therein, the composition being modified by one or more of a predetermined chemical arrangement connected to the inherent phenyl ring system, the chemical arrangement comprising:  
       R—X—R′ wherein R is an alkyl or alkene containing chain either branched or unbranched from 0 to 10 carbons that is directly connected to any un-substituted carbon atom within the inherent phenyl ring system;    X is a carboxyl, sulfoxyl or phosphatyl function that is connected to R via a metabolically stable linkage; and    R′ is an alkyl, alkenyl or aralkyl group either branched or unbranched containing from 1 to 10 carbons that is connected to X via a linkage that is labile toward metabolism by humans,    said chemical arrangement not being a methyl or ethyl ester of a carboxylic acid moiety attached to the inherent phenyl ring system via an alkyl chain having from 0 to 2 carbons.    
     
     
         5 . cancelled  
     
     
         6 . A composition comprising at least one of tolazoline or its derivatives having one or more methyl, hydroxy or methoxy groups attached to an inherent phenyl ring system, the composition being modified by one or more of a predetermined chemical arrangement connected to an inherent dihydro-imidazole ring system therein, the chemical arrangement comprising:  
       φ-R—X—R′ wherein φ is a phenyl, substituted aryl or heteroaryl system that is directly connected to any un-substituted carbon atom within the inherent dihydro-imidazole ring system;    R is an alkyl, or alkenyl containing chain either branched or unbranched from 0 to 10 carbons that is connected to φ via a metabolically stable linkage;    X is a carboxyl, sulfoxyl or phosphatyl function that is connected to R via a metabolically stable linkage; and,    R′ is an alkyl, alkenyl or aralkyl group either branched or unbranched containing from 1 to 10 carbons connected to X via a linkage that is labile toward metabolism by humans.    
     
     
         7 . The composition of  claim 6 , wherein at least one predetermined chemical arrangement is added and wherein φ is a phenyl ring, R is an ethyl chain, X is a carboxyl function, and R′ is a methyl group.  
     
     
         8 . A composition comprising at least one of tolazoline or its derivatives having one or more methyl, hydroxy or methoxy groups attached to an inherent phenyl ring therein, the composition being modified by one predetermined chemical arrangement incorporated between an inherent phenyl ring system and an inherent dihydro-imidazole ring system therein, the chemical arrangement comprising:  
       X—R′ wherein X is a carboxyl, sulfoxyl or phosphatyl function that is directly connected to the inherent phenyl ring system via respective carbon, sulfur or phosphorous atoms; and,    R′ is the inherent dihydro-imidazole ring system that is connected to one of oxygen atoms present in X via a 2-position carbon atom.    
     
     
         9 . The composition in  claim 8 , wherein X is a carboxy group.  
     
     
         10 . A composition comprising at least one of tolazoline or its derivatives having one or more methyl, hydroxy or methoxy groups attached to an inherent phenyl ring system, the composition being modified by a first chemical arrangement connected to the inherent phenyl ring system and by a second chemical arrangement connected to an inherent dihydro-imidazole ring system, the chemical arrangements comprising:  
       φ-R—X—R′ wherein φ is the inherent phenyl ring system in the first chemical arrangement, and is an added phenyl, substituted aryl or heteroaryl system that is directly connected to any un-substituted carbon atom within the dihydro-imidazole ring system in the second chemical arrangement;    R is an alkyl or alkene containing chain either branched or unbranched from 0 to 10 carbons that is directly connected to any un-substituted carbon atom within the inherent phenyl ring system in the first chemical arrangement and within the phenyl, substituted aryl or heteroaryl system of the added φ in the second chemical arrangement;    X is a carboxyl, sulfoxyl or phosphatyl function that is connected to R via a metabolically stable linkage; and,    R′ is an alkyl, alkenyl or aralkyl group either branched or unbranched containing from 1 to 10 carbons that is connected to X via a linkage that is labile toward metabolism by humans.    
     
     
         11 . The composition in  claim 10 , wherein φ is a phenyl ring for the dihydro-imidazole connection in the second chemical arrangement, R is an ethyl group in both the first and the second chemical arrangements, X is a carboxyl function in both the first and the second chemical arrangements, and R′ is a methyl group in both the first and the second chemical arrangements.  
     
     
         12 . A composition comprising at least one of tolazoline or its derivatives having one or more methyl, hydroxy or methoxy groups attached to an inherent phenyl ring system, the composition being modified by a first chemical arrangement connected to the inherent phenyl ring system and by a second chemical arrangement incorporated between the inherent phenyl ring system and an inherent dihydro-imidazole ring, the chemical arrangements comprising:  
       R—X—R′ wherein R is absent for the incorporation between the inherent phenyl ring system and the inherent dihydro-imidazole ring in the second chemical arrangement, and is an alkyl or alkene containing chain either branched or unbranched from 0 to 10 carbons that is directly attached to any un-substituted carbon within the inherent phenyl ring system in the first chemical arrangement;    X is a carboxyl, sulfoxyl or phosphatyl function that is directly connected to the inherent phenyl ring system via respective carbon, sulfur or phosphorous atoms for the incorporation between the inherent phenyl ring system and the inherent dihydro-imidazole ring in the second chemical arrangement, and is connected to R via a metabolically stable linkage;    R′ is the inherent dihydro-imidazole system that is connected to one of oxygen atoms present in X via a 2-position carbon atom for the incorporation between the phenyl ring and the dihydro-imidazole ring in the second chemical arrangement, and is an alkyl, alkenyl or aralkyl group either branched or unbranched containing from 1 to 10 carbons that is connected to X via a linkage that is labile toward metabolism by humans for the connection of the first chemical arrangement to the phenyl ring system.    
     
     
         13 . The composition in  claim 12 , wherein R is an ethyl group and R′ is a methyl group for the inherent phenyl ring system in the first chemical arrangement, and X is a carboxyl function in both the first and the second chemical arrangements.  
     
     
         14 . The composition comprising at least one of tolazoline or its derivatives having one or more methyl, hydroxy or methoxy groups attached to an inherent phenyl ring system, the composition being modified by a first chemical arrangement connected to an inherent dihydro-imidazole ring system and by a second chemical arrangement incorporated between the inherent phenyl ring system and the inherent dihydro-imidazole ring, the first and second chemical arrangements comprising:  
       φ-R—X—R′ wherein φ is the inherent phenyl for the incorporation between the phenyl ring and the dihydro-imidazole ring in the second chemical arrangement, and is a phenyl, substituted aryl or heteroaryl system that is directly connected to any un-substituted carbon atom within the dihydro-imidazole ring system in the first chemical arrangement;    R is absent for the incorporation between the phenyl ring and the dihydro-imidazole ring in the second chemical arrangement, and is an alkyl or alkylene containing chain either branched or unbranched from 0 to 10 carbons that is directly attached to any un-substituted carbon within the added φ system in the first chemical arrangement;    X is a carboxyl, sulfoxyl or phosphatyl function that is directly connected to the inherent phenyl ring via respective carbon, sulfur or phosphorous atoms for the incorporation between the phenyl ring system and the dihydro-imidazole ring system, and is connected to R via a metabolically stable linkage;    R′ is the inherent dihydro-imidazole ring system that is connected to one of oxygen atoms present in X via a 2-position carbon for the incorporation between the phenyl ring and the dihydro-imidazole ring in the second chemical arrangement, and is an alkyl, alkenyl or aralkyl group either branched or unbranched containing from 1 to 10 carbons connected to X via a linkage that is labile toward metabolism by humans for the connection of the predetermined chemical arrangement to the dihydro-imidazole ring system in the first chemical arrangement.    
     
     
         15 . The composition in  claim 14 , wherein φ is a phenyl ring, R is an ethyl and R′ is a methyl for the connection to the dihydro-imidazole ring system in the first chemical arrangement, and X is a carboxyl function in both in the first and the second chemical arrangements.  
     
     
         16 . A composition comprising at least one of tolazoline or its derivatives and having one or more methyl, hydroxy or methoxy groups attached to an inherent phenyl ring system, the composition being modified by a first predetermined chemical arrangement connected to the inherent phenyl ring system, a second predetermined chemical arrangement connected to an inherent dihydro-imidazole ring system, and a third chemical arrangement incorporated between the inherent phenyl ring system and the inherent dihydro-imidazole ring system, the first, second and third chemical arrangements comprising:  
       φ-R—X—R′ wherein φ is the inherent phenyl in the first chemical arrangement and for incorporation between the phenyl ring and the dihydro-imidazole ring in the third chemical arrangement, and is either an added phenyl, substituted aryl or heteroaryl system that is directly connected to any un-substituted carbon atom within the inherent dihydro-imidazole ring system in the second chemical arrangement;    R is absent for incorporation between the phenyl ring and the dihydro-imidazole ring in the third chemical arrangement, and is an alkyl or alkene containing chain either branched or unbranched from 0 to 10 carbons that is directly attached to an un-substituted carbon within the inherent phenyl ring system in the first chemical arrangement and is separately attached to an un-substituted carbon within the added phenyl ring system in the second chemical arrangement;    X is a carboxyl, sulfoxyl or phosphatyl function that is directly connected to the inherent phenyl ring via the respective carbon, sulfur or phosphorous atoms for the incorporation between the phenyl ring and the dihydro-imidazole ring in the third chemical arrangement, and is connected to R via a metabolically stable linkage for both the first and the second chemical arrangements;    R′ is the inherent dihydro-imidazole ring system that is connected to one of the oxygen atoms present in X via a 2-position carbon atom for the incorporation between the phenyl ring and the dihydro-imidazole ring in the third chemical arrangement, and is an alkyl, alkenyl or aralkyl group either branched or unbranched containing from 1 to 10 carbons connected to X via a linkage that is labile toward metabolism by humans for both the first and second chemical arrangements.    
     
     
         17 . The composition in  claim 16 , wherein φ is a phenyl for the dihydro-imidazole connection in the second chemical arrangement, R is an ethyl group for the connection to both the inherent and the added phenyl rings in the first and the second chemical arrangements, respectively, X is a carboxyl function for the first, the second, and the third chemical arrangements, and R′ is a methyl group for the first and the second chemical arrangements.  
     
     
         18 . The method of  claim 1 , in which the programmed metabolism of the added chemical arrangement circumvents one or more toxic metabolic pathways.  
     
     
         19 . The method of  claim 1 , in which a programmed rate of metabolism for the added chemical arrangement is adjusted so as to produce a shorter duration of action for the modified drug as compared to the parent drug.  
     
     
         20 . The method of  claim 19 , in which the shorter duration allows the modified drug to be under moment-to-moment control by adjustment of an infusion rate of the modified drug when administered intravenously.  
     
     
         21 . The method of  claim 20 , in which the intravenous administration is used to treat critical care neonates.