Nitroderviatives as drugs for diseases having an inflammatory basis

Abstract

Use for the treatment of diseases having an inflammatory basis of compounds or salts thereof, having the following general formula (I): A-X 1 -L-(W) p -NO 2 wherein A contains the radical of a drug, X 1 and W are bivalent radicals, L is a covalent bond or oxygen, sulphur, NR 1c wherein R 1c is H or a C 1 -C 5 linear or branched alkyl.

1 . A method for treating pre-cancer or cancer diseases on an inflammatory basis in a patient in need thereof comprising administering to the patient in need thereof an effective amount of a nitroderivative or salts thereof having the following general formula (I):
   A-X 1 -L-(W) p -NO 2   (I)   
     wherein:
 p is an integer equal to 1 or 0; 
 A=R-T 1 -, wherein 
 R is the radical of a precursor drug and it has the following formula: 
 
     
       
         
         
             
             
         
       
       s is 0 
       R 1  is OCOR 3  being R 3a  C 1 -C 5  linear or branched radical; 
       R 6  is H; 
       T 1 =(CO), 
       X 1 =-T B -Y-T BI - wherein 
       T B =X, wherein X=O, S, NR 1C , wherein R 1C  is H or a linear or branched alkyl, having from 1 to 5 carbon atoms; 
       T BI =(CO) tx  or (X) txx , wherein tx and txx have the value of 0 or 1; with the proviso that tx=1 when txx=0; and tx=0 when txx=1; X is as above; 
       Y is a bivalent linking group selected from the following: 
     
     
       
         
         
             
             
         
       
     
     wherein:
 nIX is an integer in the range 0-3; 
 nIIX is an integer in the range 1-3; 
 R TIX , R TIX′ , R TIIX , R TIIX′ , equal to or different from each other are H or a C 1 -C 4  linear or branched alkyl; 
 Y 3  is a saturated, unsaturated or aromatic heterocyclic ring, having 5 or 6 atoms, containing one or two nitrogen atoms, 
 an alkylene group R′ wherein R′ is a C 1 -C 20  linear or branched, optionally substituted with one or more of the following groups: —NHCOR 3 , wherein R 3  is as above, —NH 2  or —OH; 
 a cycloalkylene having from 5 to 7 carbon atoms, optionally substituted with R′, R′ being as above, one or more carbon atoms of the cycloalkylene ring can optionally be replaced by heteroatoms; 
 
     
       
         
         
             
             
         
       
     
     wherein n3 is an integer from 0 to 3 and n3′ is an integer from 1 to 3; 
     
       
         
         
             
             
         
       
     
     wherein n3 and n3′ have the above meaning, 
     
       
         
         
             
             
         
       
     
     wherein
 R 4  is hydroxy, hydrogen or R 5 O— alkoxy, wherein R 5  is a C 1 -C 10  linear, branched or cyclic alkyl group; 
 R 2  is a C 2 -C 10  linear or branched alkenylene group which can contain one or more double bonds; 
 
     
       
         
         
             
             
         
       
     
     wherein R 1f =H, CH 3  and nf is an integer from 0 a 6;
 L=covalent bond, CO or X, X being as defined above; 
 W=Y T O wherein Y T  has the same meaning of Y as defined above and Y T  is equal or different from Y. 
 
   
   
       2 . The method according to  claim 1 , wherein in formula (AI), R 1  is an acetyloxy group in position 2 of the ring and the free valence of the radical R is saturated with the —COOH group and the compound is known as Acetylsalicylic acid. 
   
   
       3 . The method according to  claim 1 , wherein Y 3  in formula (II) of the linking group Y of X 1  in formula (I) is selected from the following bivalent radicals: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       4 . The method according to  claim 3 , wherein Y 3  is an aromatic ring having 6 atoms, containing one nitrogen atom, said aromatic ring having two free valences respectively in the positions 2 and 6, or 2 and 3 or 2 and 5 with respect to the heteroatom. 
   
   
       5 . The method according to  claim 4 , wherein Y 3  is Y12 (pyridyl). 
   
   
       6 . The method according to  claim 1 , wherein the compounds are selected from the following: 
     2-(acetyloxy)benzoic acid 3-(nitrooxymethyl)phenyl ester, 
     2-(acetyloxy)benzoic acid 4-(nitrooxymethyl)phenyl ester, 
     2-(acetyloxy)benzoic acid 2-(nitrooxymethyl)phenyl ester, 
     2-(acetyloxy)benzoic acid 6-(nitrooxymethyl)-2-methylpyridinyl ester hydrochloride, or nitrate, 
     2-(acetyloxy)benzoic acid 5-(nitrooxymethyl)-2-methylpyridinyl ester hydrochloride, or nitrate, 
     2-(acetyloxy)benzoic acid 3-(nitrooxymethyl)-2-methylpyridinyl ester hydrochloride, or nitrate, 
     trans-3-[4-[2-acetyloxybenzoyloxy]-3-methoxyphenyl]-2-propenoic acid 4-(nitrooxy)butyl ester. 
   
   
       7 . The method according to  claim 1  wherein the pre-cancer diseases on an inflammatory basis are those affecting the digestive or intestinal tract. 
   
   
       8 . Method according to  claim 7  wherein the pre-cancer diseases are colitis, gastritis, duodenitis, enteritis, hepatopathies. 
   
   
       9 . The method according to  claim 1  wherein the pre-cancer diseases on an inflammatory basis are those affecting urogenital, respiratory apparatus or skin districts. 
   
   
       10 . The method according to  claim 1  wherein the cancer diseases on an inflammatory basis are those affecting urogenital, respiratory apparatus, skin or digestive systems. 
   
   
       11 . The method according to  claim 10  wherein the cancer disease is colon cancer. 
   
   
       12 . The method according to  claim 10  wherein the cancer disease is bladder cancer. 
   
   
       13 . The method according to  claim 10  wherein the cancer disease is prostate cancer. 
   
   
       14 . The method according to  claim 1  wherein compounds of the invention are used in combination with chemotherapeutic drugs or in the radiotherapeutic treatment.