Xanthurenic acid derivative pharmaceutical compositions and methods related thereto

Abstract

The present invention relates to diuretic pharmaceutical compositions and methods and in particular to certain derivatives of the formula I: or a prodrug or pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

1 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I:  
     
       
         
         
             
             
         
       
       wherein R 1 , R 2 , R 3 , R 5 , R 6  and R 7  are independently X 3 R where R is selected from the group consisting of H, halo; optionally substituted saccharide, aliphatic, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; —P(O)(OR a )(OR b ) and —NR a R b , where R a  and R b  are independently H, optionally substituted aliphatic, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;  
       X 1 , X 2  and X 3  are independently —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —OC(O)NH—, —NHC(O)O—, —OS(O) y —, —S(O) y —, —O—, —NHC(O)—, —NHC(O)O—, —S(O) 2 NH—, a bond or absent; where y is an integer from 0 to 3; and  
       R 4  and R 8  are independently H, (═O); hydroxy; or optionally substituted saccharide, aliphatic, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or  
       —P(O)(OR a )(OR b ) or —NR a R b , where R a  and R b  are independently H, or optionally substituted aliphatic, cycloalkyl or heterocycloalkyl, aryl or heteroaryl; or  
       a prodrug or pharmaceutically acceptable salt thereof; and  
       a pharmaceutically acceptable carrier.  
     
   
   
       2 . The pharmaceutical composition of  claim 1  wherein R 1 , R 3 , R 5 , R 6  and R 7  are independently H or halogen.  
   
   
       3 . The pharmaceutical composition of  claim 2  wherein X 1  is absent or a bond and R 4  is hydroxy or (═O).  
   
   
       4 . The pharmaceutical composition of  claim 3  wherein R 2  is —C(O)OR.  
   
   
       5 . The pharmaceutical composition of  claim 4  wherein R 2  is —C(O)OH.  
   
   
       6 . The pharmaceutical composition of  claim 1  wherein R 8  is an optionally substituted saccharide.  
   
   
       7 . The pharmaceutical composition of  claim 6  wherein X 2  is —O— and R 8  is an optionally substituted monosaccharide.  
   
   
       8 . The pharmaceutical composition of  claim 7  wherein R 8  is an aldohexopyranose, aldopentopyranose, aldopentofuranose or ketose.  
   
   
       9 . The pharmaceutical composition of  claim 8  wherein R 8  is a glucoside.  
   
   
       10 . The pharmaceutical composition of  claim 1  wherein the compound of formula I is xanthurenic acid 8-O-β-D-glucoside.  
   
   
       11 . The pharmaceutical composition of  claim 1  wherein X 3  is —OS(O) y —.  
   
   
       12 . The pharmaceutical composition of  claim 1  wherein the compound of formula I is xanthurenic acid 8-O-sulfate.  
   
   
       13 . A pharmaceutical composition comprising: (1) a therapeutically effective amount of a compound of formula I:  
     
       
         
         
             
             
         
       
       wherein R 1 , R 2 , R 3 , R 5 , R 6  and R 7  are independently X 3 R where R is selected from the group consisting of H, halo; optionally substituted saccharide, aliphatic, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; —P(O)(OR a )(OR b ) and —NR a R b , where R a  and R b  are independently H, optionally substituted aliphatic, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;  
       X 1 , X 2  and X 3  are independently —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —OC(O)NH—, —NHC(O)O—, —OS(O) y —, —S(O) y —, —O—, —NHC(O)—, —NHC(O)O—, —S(O) 2 NH—, a bond or absent; where y is an integer from 0 to 3; and  
       R 4  and R 8  are independently H, (═O); hydroxy; or optionally substituted saccharide, aliphatic, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or —P(O)(OR a )(OR b ) or —NR a R b , where R a  and R b  are independently H, or optionally substituted aliphatic, cycloalkyl or heterocycloalkyl, aryl or heteroaryl; or  
       a prodrug or pharmaceutically acceptable salt thereof; and  
       (2) one or more additional diuretic compounds or cardiovascular compounds; and  
       a pharmaceutically acceptable carrier.  
     
   
   
       14 . The pharmaceutical composition of  claim 13 , wherein the additional diuretic compound is selected from the group consisting of a loop diuretic, thiazide diuretic, potassium-sparing diuretic, carbonic anhydrase inhibitor and osmotic diuretic.  
   
   
       15 . The pharmaceutical composition of  claim 14 , wherein the additional diuretic compound is selected from furosemide, bumetamide, torsemide, ethacrynic acid, chlorothiazide, hydrochlorothiazide, spironolactone, amiloride, triamterene, acetazolamide, methazolamide, dichlorphenamide, hydroflumethiazide, methyclothiazide, indapamide, metolazone, polythiazide, chlorthalidone, dorzolamide, brinzolamide, glycerol, mannose and urea.  
   
   
       16 . The pharmaceutical composition of  claim 14 , wherein the additional diuretic compound is furosemide.  
   
   
       17 . The pharmaceutical composition of  claim 13 , wherein the additional cardiovascular agent is selected from the group consisting of an angiotensin converting enzyme inhibitor, angiotensin II receptor antagonist and beta-adrenergic blocker.  
   
   
       18 . The pharmaceutical composition of  claim 17 , wherein the additional cardiovascular agent is lisinopril, moexipril, enalapril, irbesartan, valsartan, losartan, nadolol, propranolol, atenolol, timolol or bisoprolol.  
   
   
       19 . A method of treating, controlling or preventing hypertension, edema, acute renal failure, congestive heart failure, chronic renal failure, ascites, increased intra-ocular pressure, nephrotic syndrome or other disease state involving irregularities in fluid/sodium balance in a mammal comprising administering a pharmaceutically effective amount of a pharmaceutical composition of  claim 1 .  
   
   
       20 . A method of treating, controlling or preventing hypertension, edema, acute renal failure, congestive heart failure, chronic renal failure, ascites, increased intra-ocular pressure, nephrotic syndrome or other disease state involving irregularities in fluid/sodium balance in a mammal comprising administering a pharmaceutically effective amount of a pharmaceutical composition of  claim 13 .  
   
   
       21 . A method for effecting diuresis in a patient in need thereof, comprising administering a pharmaceutically effective amount of a pharmaceutical composition of  claim 1 .  
   
   
       22 . The method of  claim 21 , where said patient has one or more of the following conditions: hypertension, edema, acute renal failure, congestive heart failure, chronic renal failure, ascites, increased intra-ocular pressure or nephrotic syndrome.  
   
   
       23 . A method for effecting diuresis in a patient in need thereof, comprising administering a pharmaceutically effective amount of a pharmaceutical composition of  claim 13 .  
   
   
       24 . The method of  claim 23 , where said patient has one or more of the following conditions: hypertension, edema, acute renal failure, congestive heart failure, chronic renal failure, ascites, increased intra-ocular pressure or nephrotic syndrome.  
   
   
       25 . An isolated antibody that specifically binds to xanthurenic acid-8-O-β-D-glucoside.  
   
   
       26 . The antibody of  claim 25  which is a monoclonal antibody.  
   
   
       27 . The antibody of  claim 25  which is a polyclonal antibody.  
   
   
       28 . A diagnostic kit for assaying xanthurenic acid-8-O-β-D-glucoside in a serum sample, comprising one or more monoclonal antibodies directed against xanthurenic acid-8-O-β-D-glucoside.  
   
   
       29 . A method for determining xanthurenic acid-8-O-β-D-glucoside present in a human serum sample, comprising: 
 a. obtaining a human serum sample;    b. exposing the human serum sample to one or more antibodies that specifically recognizes xanthurenic acid-8-O-β-D-glucoside, the one or more antibodies being present in a predetermined amount so that a portion of the one or more antibodies remain uncomplexed to the human xanthurenic acid-8-O-β-D-glucoside present in the sample; and    c. measuring the amount of uncomplexed one or more antibodies so as to determine the xanthurenic acid-8-O-β-D-glucoside in the human serum sample.    
   
   
       30 . A process for monitoring or detecting a disease associated with an abnormal level of xanthurenic acid-8-O-β-D-glucoside; the process comprising: 
 a. exposing a biological sample to a monoclonal antibody directed against xanthurenic acid-8-O-β-D-glucoside; and    b. detecting a level of xanthurenic acid-8-O-β-D-glucoside in said biological sample using the monoclonal antibody, wherein an elevated level of xanthurenic acid-8-O-β-D-glucoside in said biological sample is associated with the disease.    
   
   
       31 . The process of  claim 30 , wherein said disease is selected from the group consisting of hypertension, edema, acute renal failure, congestive heart failure, chronic renal failure, ascites, increased intra-ocular pressure, nephrotic syndrome or other disease state involving irregularities in fluid/sodium balance.  
   
   
       32 . The process of  claim 30 , wherein said biological sample is a urine sample.  
   
   
       33 . The process of  claim 30 , wherein said biological sample is a serum sample.  
   
   
       34 . A method for the chromatographic quantification of xanthurenic acid-8-O-β-D-glucoside in a biological sample, the method comprising: 
 a. obtaining a biological sample;    b. injecting a known volume of the biological sample into the column of an HPLC unit; and    c. determining the quantity of xanthurenic acid-8-O-β-D-glucoside in the biological sample relative to a standard of xanthurenic acid-8-O-β-D-glucoside.    
   
   
       35 . A method for treating a disease associated with an abnormal level of xanthurenic acid-8-O-β-D-glucoside, the method comprising: 
 administering a pharmaceutically effective dose of the composition of  claim 1  on the basis of the detected level of xanthurenic acid-8-O-β-D-glucoside in the human biological sample.    
   
   
       36 . The method of  claim 35 , wherein the disease is selected from the group consisting of hypertension, edema, acute renal failure, congestive heart failure, chronic renal failure, ascites, increased intra-ocular pressure, nephrotic syndrome or other disease state involving irregularities in fluid/sodium balance.  
   
   
       37 . A method of treatment of a disease or condition associated with decreased sodium reabsorption, the method comprising administering a therapeutically effective amount of a xanthurenic acid-8-O-β-D-glucoside antagonist.