Nitric Oxide Releasing Produgs of Therapeutic Agents

Abstract

The present invention relates to nitric oxide releasing prodrugs of known drugs or therapeutic agents wherein the drug or therapeutic agents contain at least one carboxylic acid group. The invention also relates to processes for the preparation of these nitric oxide releasing prodrugs, to pharmaceutical compositions containing them and to methods of using these prodrugs.

1 . The compounds of the invention that are covered within the scope of the formula (II), which are nitric oxide releasing prodrugs of known carboxyl-containing drugs or therapeutic agents useful in the treatment of diseases or disorders that are characteristic of the drugs from which the prodrugs of the present invention are derived, all their geometrical and stereoisomeric forms and also pharmaceutically acceptable salts thereof: 
       
         
           
           
               
               
           
         
         Wherein, 
         (X) n -Dx-C(═O)O represents a drug or therapeutic agent containing at least one carboxylic acid group, which is covalently bonded to the specified linker “C(H)(Ry)” via a bio-cleavable ester linkage; wherein, Ry is an alkyl C 1 -C 6  or cycloalkyl C 3 -C 7 ; n is an integer 0-11; X independently at each occurrence represents OH, O— h PG, SH, S— s PG, CO 2 H or C(═O)O— c PG, NH 2 , NH, HN— a PG, N— a PG, P(═O)(OH) 2 , P(═O)(O— p PG) 2 , an aldehyde group or keto group or their bio-cleavable derivatives acetal, oxime, hydrazone or semcarbazone, or a mixture of one or more types of these functional groups, wherein  h PG is a hydroxyl protecting group selected from a group consisting of acetate, methoxyacetate, benzoate, phenylacetate, pivalate, phenoxyacetate, nitrate, ethyl carbonate, or methoxymethyl carbonate;  s PG is a sulfhydryl protecting group selected from a group consisting of acetyl group, benzoyl group or disulfide bond;  c PG is a carboxyl protecting group selected from lower (C 1 -C 6 ) alkyl esters;  a PG is an amino protecting group selected from a group consisting of acetyl, methoxyacetyl, ethoxycarbonyl, tert-butoxycarbonyl, 2-acetylthioethoxycarbonyl or 2-(2-aminoethyl)dithioethoxy-carbonyl groups;  p PG is a phosphate protecting group selected from a group consisting of 2-(S-acetylthio)ethyl (SATE), 3-pivaloyloxy-1,3-dihydroxypropyl derivative, dithiodiethanol derivative, 4-acyloxybenzyl phosphate mono or diester derivative; Dx is a D1-D115; wherein, D1 is aspirin or a part thereof; D2 is naproxen or a part thereof; D3 is chlorambucil or a part thereof; D4 is flurbiprofen or a part thereof; D5 is ketoprofen or a part thereof; D6 is indomethacin or a part thereof; D7 is ibuprofen or a part thereof; D8 is ketorolac or a part thereof; D9 is diclofenac or a part thereof; D10 is mesalamine or a part thereof; D11 is valproic acid or a part thereof; D12 is gabapentin or a part thereof; D13 is pregabalin or a part thereof; D14 is vigabatrin or a part thereof; D15 is tiagabine or a part thereof; D16 is atorvastatin or a part thereof; D17 is cerivastatin or a part thereof; D18 is fluvastatin or a part thereof; D19 is pitavastatin or a part thereof; D20 is pravastatin or a part thereof; D21 is rosuvastatin or a part thereof; D22 is bezafibrate or a part thereof; D23 is ciprofibrate or a part thereof; D24 is gemfibrozil or a part thereof; D25 is enalapril or a part thereof; D26 is lisinopril or a part thereof; D27 is captopril or a part thereof; D28 is candesartan or a part thereof; D29 is valsartan or a part thereof; D30 is losartan acid (EXP-3174) or a part thereof; D31 is iloprost or a part thereof; D32 is melagastran or a part thereof; D33 is ridogrel or a part thereof; D34 is tirpfiban or a part thereof; D35 is triflusal or a part thereof; D36 is limaprost or a part thereof; D37 is capobenic acid or a part thereof; D38 is etacrynic acid or a part thereof; D39 is ticrynafen or a part thereof; D40 is cetirizine or a part thereof; D41 is fexofenadine or a part thereof; D42 is melphalan or a part thereof; D43 is methotrexate or a part thereof; D44 is amineptine or a part thereof; D45 is tianeptine or a part thereof; D46 is amoxicillin or a part thereof; D47 is ampicillin or a part thereof; D48 is ciprofloxacin or a part thereof; D49 is amphotericin B or a part thereof; D50 is candicidin or a part thereof; D51 is folic acid or a part thereof; D52 is biotin or a part thereof; D53 is artesunate or a part thereof; D54 is zanamivir or a part thereof; D55 is oseltamivir (Tamiflu) or a part thereof; D56 is zanamivir or a part thereof; D57 is mitiglinide or a part thereof; D58 is repaglinide or a part thereof; D59 is acetoxolone or a part thereof; D60 is rebamipide or a part thereof; D61 is trimoprostil or a part thereof; D62 is alfa-lipoic acid or a part thereof; D63 is acetylcarnosine or a part thereof; D64 is rexofelast or a part thereof; D65 is prostaglandin E 2  or a part thereof; D66 is ecgonidine or a part thereof; D67 is ecgonine or a part thereof; D68 is kainic acid or a part thereof; D69 is adapalene or a part thereof; D70 is all-trans-retinoic acid or a part thereof; D71 is thiocarbamizine or a part thereof; D72 is thiocarbarsone or a part thereof; D73 is actarit or a part thereof; D74 is diacerein or a part thereof; D75 is penicillamine or a part thereof; D76 is amlexanox or a part thereof; D77 is montelukast or a part thereof; D78 is seratrodast or a part thereof; D79 is carprofen or a part thereof; D80 is probenecid or a part thereof; D81 is orotic acid or a part thereof; D82 is oxycinchophen or a part thereof; D83 is unoprostone or a part thereof; D84 is epristeride or a part thereof; D85 is tiratricol or a part thereof; D86 is thyroxine or a part thereof; D87 is R-eflornithine or a part thereof; D88 is S-eflornithine or a part thereof; D89 is fumagillin or a part thereof; D90 is acitretin or a part thereof; D91 is mandelic acid or a part thereof; D92 is clorazepate or a part thereof; D93 is Sennoside or a part thereof; D94 is cholic acid or a part thereof; D95 is cyclobutyrol or a part thereof; D96 is trepibutone or a part thereof; D97 is methallenestril or a part thereof; D98 is alvimopan or a part thereof; D99 is loxiglumide or a part thereof; D100 is ε-aminocaproic acid or a part thereof; D101 is a tranexamic acid or a part thereof; D102 is S-adenosyl methionine or a part thereof; D103 is tiopronin or a part thereof; D104 is bucillamine or a part thereof; D105 is pidotimod or a part thereof; D106 is thymopentin or a part thereof; D107 is brequinar or a part thereof; D108 is mycophenolic acid or a part thereof; D109 is baclofen or a part thereof; D110 is acetylcarnitine or a part thereof; D111 is carbocysteine or a part thereof; D112 is isbogrel or a part thereof; D113 is ozagrel or a part thereof; D114 is carmoxirole or a part thereof; D115 is domitroban or a part thereof; D116 is ramatroban or a part thereof; or a geometrical form, stereoisomeric form, or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . A compound according to  claim 1  is selected from the group comprising of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         Wherein, Ry,  a PG,  c PG,  h PG,  s PG,  p PG are as defined in  claim 1 . 
       
     
     
         3 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of  claim 1 , or a pharmaceutically acceptable salt thereof; and one or more of pharmaceutically acceptable carriers, vehicles, or diluents. 
     
     
         4 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of  claim 2 , or a pharmaceutically acceptable salt thereof; and one or more of pharmaceutically acceptable carriers, vehicles, or diluents. 
     
     
         5 . A method of treating a disease or disorder in a human or mammal where a chronic, sustained and selective release of the constituent drug, therapeutic agent, and/or nitric oxide from a compound of formula (II) is beneficial; comprising administering to a mammal or a human in need of the treatment a therapeutically effective amount of the pharmaceutical composition as claimed in  claim 3 . 
     
     
         6 . A method of treating a disease or disorder in a human or mammal where a chronic, sustained and selective release of the constituent drug, therapeutic agent, or nitric oxide is beneficial; comprising administering to a mammal or a human in need of treatment a therapeutically effective amount of the pharmaceutical composition as claimed in  claim 4 .