Materials and Methods for Treating Coagulation Disorders

Abstract

This invention is drawn to compounds which are more easily metabolized by the metabolic drug detoxification systems. Particularly, warfarin analogs which have been designed to include esters within the structure of the compounds are taught. The invention teaches methods of reducing the toxicity of drugs comprising the introduction of ester groups into drugs during the synthesis of the drug. This invention is also drawn to methods of treating coagulation disorders comprising the administration of compounds which have been designed to be metabolized by serum or intracellular hydrolases and esterases. Pharmaceutical compositions of the ester containing warfarin, analogs are also taught.

1 .- 3 . (canceled) 
     
     
         4 . A method for providing anticoagulant activity to a patient in need of such treatment, the method comprising administering a compound or pharmaceutically acceptable salt thereof, where the compound is 
       3-(1-Hydroxy-3-oxo-3,4-dihydro-naphthalen-2-yl)-3H-isobenzofuran-1-one; 
       3-Cyclohexyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid; 
       3-Cyclohexyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid methyl ester; 
       3-Cyclohexyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid ethyl ester; 
       3-Cyclohexyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid n-propyl ester; 
       3-Cyclopentyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid; 
       3-Cyclopentyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid methyl ester; 
       3-Cyclopentyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid ethyl ester; 
       3-Cyclopentyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid n-propyl ester; 
       3-Propyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid; 
       3-Propyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid methyl ester; 
       3-Propyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid ethyl ester; 
       3-Propyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid n-propyl ester; 
       (4-Hydroxy-2-oxo-2H-chromen-3-yl)-phenyl-acetic acid; 
       (4-Hydroxy-2-oxo-2H-chromen-3-yl)-phenyl-acetic acid methyl ester; 
       (4-Hydroxy-2-oxo-2H-chromen-3-yl)-phenyl-acetic acid ethyl ester; 
       (4-Hydroxy-2-oxo-2H-chromen-3-yl)-phenyl-acetic acid n-propyl ester; 
       (4-Hydroxy-2-oxo-2H-chromen-3-yl)-phenyl-acetic acid 2-propyl ester; 
       (4-Hydroxy-2-oxo-2H-chromen-3-yl)-phenyl-acetic acid n-butyl ester; 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-butyric acid; 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-butyric acid methyl ester; 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-butyric acid ethyl ester; 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-butyric acid n-propyl ester; 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-butyric acid isopropyl ester; 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-butyric acid n-butyl ester; 
       4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid; 
       4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid methyl ester; 
       4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid ethyl ester; 
       4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid n-propyl ester; 
       4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid n-butyl ester; 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid; 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid methyl ester; 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid ethyl ester; 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid n-propyl ester; 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid n-butyl ester; 
       3-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid; 
       3-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid methyl ester; 
       3-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid ethyl ester; 
       3-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid n-propyl ester; 
       3-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid n-butyl ester; 
       2-Benzyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid; 
       2-Benzyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid methyl ester; 
       2-Benzyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid ethyl ester; 
       2-Benzyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid n-propyl ester; 
       2-Benzyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid n-butyl ester; 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-butyric acid; 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-butyric acid methyl ester; 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-butyric acid ethyl ester; 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-butyric acid n-propyl ester; 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-butyric acid n-butyl ester; 
       4-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H-isochromen-3-yl)-methyl]-benzoic acid methyl ester; 
       4-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H-isochromen-3-yl)-methyl]-benzoic acid ethyl ester; 
       4-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H-isochromen-3-yl)-methyl]-benzoic acid n-propyl ester; 
       4-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H-isochromen-3-yl)-methyl]-benzoic acid n-butyl ester; 
       3-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H-isochromen-3-yl)-methyl]-benzoic acid; 
       3-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H-isochromen-3-yl)-methyl]-benzoic acid methyl ester; 
       3-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H-isochromen-3-yl)-methyl]-benzoic acid ethyl ester; 
       3-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H-isochromen-3-yl)-methyl]-benzoic acid n-propyl ester; 
       3-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H-isochromen-3-yl)-methyl]-benzoic acid n-butyl ester; 
       2-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H-isochromen-3-yl)-methyl]-benzoic acid; 
       2-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H-isochromen-3-yl)-methyl]-benzoic acid methyl ester; 
       2-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H-isochromen-3-yl)-methyl]-benzoic acid ethyl ester; 
       2-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H-isochromen-3-yl)-methyl]-benzoic acid n-propyl ester; or 
       2-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H-isochromen-3-yl)-methyl]-benzoic acid n-butyl ester. 
     
     
         5 . A method according to  claim 4 , wherein the compound is 
       3-(1-Hydroxy-3-oxo-3,4-dihydro-naphthalen-2-yl)-3H-isobenzofuran-1-one, or pharmaceutically acceptable salts thereof. 
     
     
         6 . A method according to  claim 4 , wherein the compound is 
       3-Cyclohexyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid; 
       3-Cyclohexyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid methyl ester; 
       3-Cyclohexyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid ethyl ester; 
       3-Cyclohexyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid n-propyl ester; 
       3-Cyclopentyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid; or pharmaceutically acceptable salts thereof. 
     
     
         7 . A method according to  claim 4 , wherein the compound is 
       3-Cyclopentyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid methyl ester; 
       3-Cyclopentyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid ethyl ester; 
       3-Cyclopentyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid n-propyl ester; 
       3-Propyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid; 
       3-Propyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid methyl ester; or pharmaceutically acceptable salts thereof. 
     
     
         8 . A method according to  claim 4 , wherein the compound is 
       3-Propyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid ethyl ester; 
       3-Propyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid n-propyl ester; 
       (4-Hydroxy-2-oxo-2H-chromen-3-yl)-phenyl-acetic acid; 
       (4-Hydroxy-2-oxo-2H-chromen-3-yl)-phenyl-acetic acid methyl ester; 
       (4-Hydroxy-2-oxo-2H-chromen-3-yl)-phenyl-acetic acid ethyl ester; or pharmaceutically acceptable salts thereof. 
     
     
         9 . A method according to  claim 4 , wherein the compound is 
       (4-Hydroxy-2-oxo-2H-chromen-3-yl)-phenyl-acetic acid n-propyl ester; 
       (4-Hydroxy-2-oxo-2H-chromen-3-yl)-phenyl-acetic acid 2-propyl ester; 
       (4-Hydroxy-2-oxo-2H-chromen-3-yl)-phenyl-acetic acid n-butyl ester; 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-butyric acid; 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-butyric acid methyl ester; 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-butyric acid ethyl ester; or pharmaceutically acceptable salts thereof. 
     
     
         10 . A method according to  claim 4 , wherein the compound is 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-butyric acid n-propyl ester; 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-butyric acid isopropyl ester; 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-butyric acid n-butyl ester; 
       4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid; 
       4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid methyl ester; 
       4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid ethyl ester; or pharmaceutically acceptable salts thereof. 
     
     
         11 . A method according to  claim 4 , wherein the compound is 2-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-butyric acid n-propyl ester; 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-butyric acid isopropyl ester; 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-butyric acid n-butyl ester; 
       4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid; 
       4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid methyl ester; 
       4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid ethyl ester; or pharmaceutically acceptable salts thereof. 
     
     
         12 . A method according to  claim 4 , wherein the compound is 
       4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid n-propyl ester; 
       4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid n-butyl ester; 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid; 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid methyl ester; 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid ethyl ester; 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid n-propyl ester; 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid n-butyl ester; 
       3-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid; 
       3-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid methyl ester; 
       3-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid ethyl ester; or pharmaceutically acceptable salts thereof. 
     
     
         13 . A method according to  claim 4 , wherein the compound is 
       3-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid n-propyl ester; 
       3-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid n-butyl ester; 
       2-Benzyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid; 
       2-Benzyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid methyl ester; 
       2-Benzyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid ethyl ester; 
       2-Benzyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid n-propyl ester; 
       2-Benzyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid n-butyl ester; 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-butyric acid; 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-butyric acid methyl ester; or pharmaceutically acceptable salts thereof. 
     
     
         14 . A method according to  claim 4 , wherein the compound is 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-butyric acid ethyl ester; 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-butyric acid n-propyl ester; 
       2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-butyric acid n-butyl ester; 
       4-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H-isochromen-3-yl)-methyl]-benzoic acid methyl ester; 
       4-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H-isochromen-3-yl)-methyl]-benzoic acid ethyl ester; 
       4-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H-isochromen-3-yl)-methyl]-benzoic acid n-propyl ester; 
       4-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H-isochromen-3-yl)-methyl]-benzoic acid n-butyl ester; 
       3-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H-isochromen-3-yl)-methyl]-benzoic acid; or pharmaceutically acceptable salts thereof. 
     
     
         15 . A method according to  claim 4 , wherein the compound is 
       3-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H-isochromen-3-yl)-methyl]-benzoic acid methyl ester; 
       3-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H-isochromen-3-yl)-methyl]-benzoic acid ethyl ester; 
       3-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H-isochromen-3-yl)-methyl]-benzoic acid n-propyl ester; 
       3-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H-isochromen-3-yl)-methyl]-benzoic acid n-butyl ester; 
       2-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H-isochromen-3-yl)-methyl]-benzoic acid; 
       2-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H-isochromen-3-yl)-methyl]-benzoic acid methyl ester; 
       2-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H-isochromen-3-yl)-methyl]-benzoic acid ethyl ester; 
       2-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H-isochromen-3-yl)-methyl]-benzoic acid n-propyl ester; 
       2-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)-(4-hydroxy-1-oxo-1H-isochromen-3-yl)-methyl]-benzoic acid n-butyl ester; or pharmaceutically acceptable salts thereof.