Prodrugs of Substituted 1,3-Dioxanes and Their Uses

Abstract

The present invention relates to prodrugs of compounds containing 1,3-dioxane moiety, pharmaceutical compositions thereof, and the use of the compounds and compositions for the modulation of thromboxane A2 or a peroxisome proliferator-activated receptor. The prodrugs of the compounds, analogs, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions can be used in the treatment and prevention of cancer.

1 . A compound of formula (III) 
       
         
           
           
               
               
           
         
       
       where X is hydrogen, halogen, cyano, nitro, hydroxyl, haloalkyl, alkyl, or O—R where R is a lower alkyl group,
 n is 0, 1, 2, 3, 4, or 5; 
 Z 1  and Z 2  are independently selected to be O, N, or S, and R p  and R p′  are independently selected from H, lower alkyl, or a progroup. 
 
     
     
         2 - 9 . (canceled) 
     
     
         10 . A method of inhibiting a thromboxane A2 or a peroxisome proliferator-activated receptor, the method comprising contacting the receptor with a compound of formula (III) 
       
         
           
           
               
               
           
         
         where X is hydrogen, halogen, cyano, nitro, hydroxyl, haloalkyl, alkyl, or O—R where R is a lower alkyl group, 
         n is 0, 1, 2, 3, 4, or 5; 
         Z 1  and Z 2  are independently selected to be O, N, or S, and R p  and R p′  are independently selected from H, lower alkyl, or a progroup. 
       
     
     
         11 - 15 . (canceled) 
     
     
         16 . A method for treating or preventing a disorder associated with a thromboxane A2 or peroxisome proliferator-activated receptors, the method comprising: administering to a subject an effective amount of a compound of  claim 1  or acceptable salts, N-oxides, hydrates, or solvates thereof; and pharmaceutically-acceptable carrier or diluent. 
     
     
         17 . The method of  claim 16 , wherein the disorder is selected from the group consisting of diabetes, cancer, inflammation, AIDS, metabolic syndrome, obesity, pre-diabetes, hypertension and dyslipidemia. 
     
     
         18 . The method of  claim 17 , wherein the subject is a human. 
     
     
         19 - 23 . (canceled) 
     
     
         24 . The method of  claim 16 , wherein the disorder is selected from the group consisting of myocardial infarction, thrombosis, thrombotic disorders, pulmonary hypertension, atherosclerosis, diabetic nephropathy, retinopathy, peripheral arterial disease, lower limb circulation, pulmonary embolism, thrombus formation, stent-triggered thrombus formation, stent-triggered hyperplasia, septic shock, preeclampsia, asthma, allergic rhinitis, tumour angiogenesis and metastasis. 
     
     
         25 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         26 . (canceled) 
     
     
         27 . The composition according to  claim 25 , wherein the composition is for delayed-, modified-, sustained-, or controlled-release of the compound. 
     
     
         28 . The composition according to  claim 27  comprising at least one release rate modifier. 
     
     
         29 . The composition according to  claim 28 , wherein said release rate modifier is selected from the group consisting of hydroxypropylmethyl cellulose, methyl cellulose, sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate, polyethylene oxide, cremophor, corn oil glyceride and propylene glycol, Xanthan gum, Carbomer, ammonio methacrylate copolymer, hydrogenated castor oil, carnauba wax, paraffin wax, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, methacrylic acid copolymer and mixtures thereof.