Compounds with super-aspirin effects

Abstract

A compound having the structural formula (I) and pharmaceutically acceptable salt and/or hydrates thereof, (I) wherein Y is an arylester or an C 1 -C 8 alkylaryl ester, selected from the group consisting of: benzene, toluene, xylene, benzoic acid, benzoate, nicotinate, isonicotinate and halobenzene, which can be unsubstituted or substituted with at least one nitric oxide releasing group; and/or at least one of hydroxide, —Cl, —Br, a C 1 -C 8 alkyl, benzyl, a C 1 -C 8 alkoxy, benzyloxy, —NHC(O)R, —NH 2 , —NO 2 —ONO 2 , —(CH 2 ) n ONO 2 , —OC(O)[(CH 2 ) n ] cyclic ONO 2 , —OCOArONO 2 , —OCOAr(CH 2 ) n ONO 2 or a C 1 -C 5 haloalkyl ester, wherein R is a C 1 -C 8 alkyl or a C 1 -C 8 alkoxy group, n=1-8 and m=3-10, to produce a super-aspirin effect.

1 . A method for the treatment or prevention of cancer metastasis involving tumor cell induced platelet aggregation (TCIPA) or for the treatment or prevention of cardiovascular disease (CVD) in conjunction with the treatment or prevention of cancer metastasis involving tumor cell induced platelet aggregation (TCIPA), comprising administering to a subject in need thereof an effective amount of a compound having the structural formula (I) and pharmaceutically acceptable salt and/or hydrates thereof, 
       
         
           
           
               
               
           
         
         wherein Y is an arylester or an C 1 -C 8  alkylaryl ester, selected from the group consisting of: 
         benzene, toluene, xylene, benzoic acid, benzoate, nicotinate, isonicotinate and halobenzene, which can be unsubstituted or substituted with
 at least one nitric oxide releasing group; and/or 
 at least one of hydroxide, —Cl, —Br, a C 1 -C 8  alkyl, benzyl, a C 1 -C 8  alkoxy, 
 benzyloxy, —NHC(O)R, —NH 2 , —NO 2 , —ONO 2 , —(CH 2 ) n ONO 2 , —OC(O)[(CH 2 ) m ] cyclic ONO 2 , —OCOArONO 2 , —OCOAr(CH 2 ) n ONO 2  or a C 1 -C 5  haloalkyl ester, wherein R is a C 1 -C 8  alkyl or a C 1 -C 8  alkoxy group, n=1-8 and m=3-10. 
 
       
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1 , wherein the cancer metastasis involving tumor cell induced platelet aggregation (TCIPA) is associated with malignant mesothelioma, gynecological malignancies, lung, renal, gastric, ovarian, colon, colorectal, breast tumors or other solid tumor types. 
     
     
         4 . The method of  claim 1 , wherein the CVD is coronary heart disease, cardiomyopathy, cardiovascular disease, ischaemic heart disease, heart failure, hypertensive heart disease, inflammatory heart disease, valvular heart disease, myocardial Infarction or other associated conditions caused by these CVD types. 
     
     
         5 . (canceled) 
     
     
         6 . The method of  claim 1 , wherein the nitric oxide release group of the compound is a nitrate ester, a C 1  to C 8  alkyl nitrate ester, a C 3 -C 10  cycloalkyl nitrate ester or a C 1 -C 8  alkyl nitrate ester. 
     
     
         7 . The method of  claim 6  wherein the nitric oxide release group is selected from the group consisting of: —NO 2 , —ONO 2 , —(CH 2 ) n ONO 2 , —OC(O)[(CH 2 ) m ] cyclic ONO 2 , —OCOArONO 2 , —OCOAr(CH 2 ) n ONO 2 . 
     
     
         8 . The method of  claim 1 , wherein the arylester or the alkylaryl ester of the compound is substituted at the 2- or 3-position of the aryl ring. 
     
     
         9 . The method of  claim 8 , wherein the aryl ester is substituted at the 2-position of the aryl ring. 
     
     
         10 . The method of  claim 9 , wherein the aryl ester is selected from benzoate or nicotinate, preferably nicotinate. 
     
     
         11 . The method of  claim 1 , wherein the Y group of the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The method of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         13 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The method of  claim 1 , wherein the compound having the general structure (I) is metabolised to aspirin, nicotinic acid and a compound having structure: 
       
         
           
           
               
               
           
         
       
     
     
         15 . (canceled) 
     
     
         16 . A method for producing an aspirin effect in a subject in need thereof, comprising administering to the subject an effective amount of a compound having the structural formula (I) and pharmaceutically acceptable salt and/or hydrates thereof, 
       
         
           
           
               
               
           
         
         wherein Y is an arylester or an C 1 -C 8  alkylaryl ester, selected from the group consisting of: 
         benzene, toluene, xylene, benzoic acid, benzoate, nicotinate, isonicotinate and halobenzene, which can be unsubstituted or substituted with 
         at least one nitric oxide releasing group; and/or 
         at least one of hydroxide, —Cl, —Br, a C 1 -C 8  alkyl, benzyl, a C 1 -C 8  alkoxy, 
         benzyloxy, —NHC(O)R, —NH 2 , —NO 2 , —ONO 2 , —(CH 2 ) n ONO 2 , —OC(O)[(CH 2 ) m ] cyclic ONO 2 , —OCOArONO 2 , —OCOAr(CH 2 ) n ONO 2  or a C 1 -C 5  haloalkyl ester, wherein R is a C 1 -C 8  alkyl or a C 1 -C 8  alkoxy group, n=1-8 and m=3-10, 
       
       to produce a super aspirin effect by releasing at least aspirin and a further compound having structure (II) 
       
         
           
           
               
               
           
         
         wherein Y is an arylester, selected from the group consisting of: benzene, toluene, xylene, benzoic acid, benzoate, nicotinate and halobenzene, which can be unsubstituted or substituted with
 at least one nitric oxide releasing group; and/or 
 at least one of hydroxide, —Cl, —Br, a C 1 -C 8  alkyl, benzyl, a C 1 -C 8  alkoxy, 
 benzyloxy, —NHC(O)R, —NH 2 , —NO 2 , —ONO 2 , —(CH 2 ) n ONO 2 , —OC(O)[(CH 2 ) m ] cyclic ONO 2 , —OCOArONO 2 , —OCOAr(CH 2 ) n ONO 2  or a C 1 -C 5  haloalkyl ester, wherein R is a C 1 -C 8  alkyl or a C 1 -C 8  alkoxy group, n=1-8 and m=3-10. 
 
       
     
     
         17 . The method according to  claim 16  wherein the compound (I) is 
       
         
           
           
               
               
           
         
         and the compound (II) is 
       
       
         
           
           
               
               
           
         
       
     
     
         18 . A compound having general structure (II), 
       
         
           
           
               
               
           
         
         wherein Y is an arylester or a C 1 -C 8  aryl ester, selected from the group consisting of: 
         benzene, toluene, xylene, benzoic acid, benzoate, nicotinate, isonicotinate and halobenzene, which can be unsubstituted or substituted with 
         at least one nitric oxide releasing group; and/or 
         at least one of —Cl, —Br, a C 1 -C 8  alkyl, benzyl, a C 1 -C 8  alkoxy, 
         benzyloxy, —NHC(O)R, —NH 2 , —NO 2 , —ONO 2 , —(CH 2 ) n ONO 2 , —OC(O)[(CH 2 ) m ] cyclic ONO 2 , —OCOArONO 2 , —OCOAr(CH 2 ) n ONO 2  or a C 1 -C 5  haloalkyl ester, wherein R is a C 1 -C 8  alkyl or a C 1 -C 8  alkoxy group, n=1-8 and m=3-10. 
       
     
     
         19 . A compound according to  claim 18  having structure (Ill) and pharmaceutically acceptable salt and/or hydrates thereof, 
       
         
           
           
               
               
           
         
       
     
     
         20 . A method for producing a super aspirin effect in a subject in need thereof, comprising administering to the subject an effective amount of a compound having the structural formula (I) and pharmaceutically acceptable salt and/or hydrates thereof, 
       
         
           
           
               
               
           
         
         wherein Y is an arylester or a C 1 -C 8  aryl ester, selected from the group consisting of: benzene, toluene, xylene, benzoic acid, benzoate, nicotinate, isonicotinate and halobenzene, which can be unsubstituted or substituted with 
         at least one nitric oxide releasing group; and/or 
         at least one of —Cl, —Br, a C 1 -C 8  alkyl, benzyl, a C 1 -C 8  alkoxy, 
         benzyloxy, —NHC(O)R, —NH 2 , —NO 2 , —ONO 2 , —(CH 2 ) n ONO 2 , —OC(O)[(CH 2 ) n ] cyclic ONO 2 , —OCOArONO 2 , —OCOAr(CH 2 ) n ONO 2  or a C 1 -C 5  haloalkyl ester, wherein R is a C 1 -C 8  alkyl or a C 1 -C 8  alkoxy group, n=1-8 and m=3-10. 
       
     
     
         21 . (canceled)