Azacytosine analogs and derivatives

Abstract

Compounds and compositions of azacytosine analogs and derivatives are provided. In one aspect of the invention, analogs or derivatives of decitabine and azacitidine are provided with modification at the 2-, 4-, or 6-position of the triazine ring, at the 1′-6′position of the ribose ring, or combinations thereof. Methods of using, synthesizing and manufacturing these analogs and derivatives are also provided. These compounds can be formulated into pharmaceutical compositions that can be used for treating any disease associated with aberrant DNA methylation, or a disease or condition that is sensitive to the treatment with decitabine or azacitidine, such as hematological disorders, tumors and cancers.

1 . A compound of Formula I,  
     
       
         
         
             
             
         
       
     
     or its pharmaceutically acceptable salt, wherein 
 Rx is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, halogen-substituted alkyl or aryl, phenyl, benzyl, hydroxyl, thiol, substituted or unsubstituted amino, —O-alkyl, —S-alkyl, —O-aryl or —S-aryl;  
 R y  is hydrogen, alkyl, or sugar;  
 R z  is a hydrogen, alkyl, aryl, arylalkyl, amino, alkylamino, dialkylamino, alkylarylamino, hydrazine, hydroxylalkylamino, —O-alkyl, —S-alkyl, —O-aryl or —S-aryl; and  
 Q is oxygen, sulfur, methylene, imine, or alkylimine;  
 provided that when R x  is hydrogen, methyl, chloromethyl, phenyl or benzyl, R y  is hydrogen or glycosyl, and Q is oxygen, R z  is not amino.  
 
   
   
       2 . The compound or its pharmaceutically acceptable salt according to  claim 1 , wherein R x  is mono-, di- or trifluoromethyl.  
   
   
       3 . The compound or its pharmaceutically acceptable salt according to  claim 1 , wherein R x  is a straight or branched chain C 1-6  alkyl.  
   
   
       4 . The compound or its pharmaceutically acceptable salt according to  claim 1 , wherein R x  is selected from the group consisting of methyl, ethyl, propyl, butyl and phenyl.  
   
   
       5 . The compound or its pharmaceutically acceptable salt according to  claim 1 , wherein R x  is fluoride.  
   
   
       6 . The compound or its pharmaceutically acceptable salt according to  claim 1 , wherein R x  is chloride or bromide.  
   
   
       7 . The compound or its pharmaceutically acceptable salt according to  claim 1 , wherein R x  is primary or secondary amino.  
   
   
       8 . The compound or its pharmaceutically acceptable salt according to  claim 1 , wherein R y  is a substituted or unsubstituted ribose.  
   
   
       9 . The compound or its pharmaceutically acceptable salt according to  claim 1 , wherein R y  is 2′-deoxyribose or ribose.  
   
   
       10 . The compound or its pharmaceutically acceptable salt according to  claim 9 , wherein R x  is halogen, and R z  is amino.  
   
   
       11 . The compound or its pharmaceutically acceptable salt according to  claim 9 , wherein R x  is fluoride, and R z  is amino.  
   
   
       12 . The compound or its pharmaceutically acceptable salt according to  claim 9 , wherein the R x  is alkyl, and R z  is OCH 3  or O-alkyl.  
   
   
       13 . The compound or its pharmaceutically acceptable salt according to  claim 9 , wherein the R x  is alkyl, R y  is 2′-deoxyribose and R z  is dimethylamino.  
   
   
       14 . The compound or its pharmaceutically acceptable salt according to  claim 1 , wherein Q is sulfur, and R z  is hydrogen, amino, alkylamino, dialkylamino, or O-alkyl.  
   
   
       15 . The compound or its pharmaceutically acceptable salt according to  claim 14 , wherein R x  is alkyl, or halogen.  
   
   
       16 . The compound or its pharmaceutically acceptable salt according to  claim 1 , wherein the salt is selected from the group consisting of hydrochloride, mesylate, EDTA, sulfite, L-Aspartate, maleate, phosphate, L-Glutamate, (+)-L-Tartrate, citrate, L-Lactate, succinate, acetate, hexanoate, butyrate, and propionate salt.  
   
   
       17 . A compound of Formula II  
     
       
         
         
             
             
         
       
     
     or its pharmaceutically acceptable salt, wherein 
 R x  is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, halogen-substituted alkyl or aryl, phenyl, benzyl, hydroxyl, thiol, substituted or unsubstituted amino, —O-alkyl, —S-alkyl, —O-aryl or —S-aryl;  
 R z  is a hydrogen, amino, alkyl, aryl, arylalkyl, alkylamino, dialkylamino, alkylarylamino, hydrazine, hydroxylalkylamino, —O-alkyl, —S-alkyl, —O-aryl or —S-aryl; and Q is oxygen, sulfur, methylene, imine, or alkylimine;  
 Q is oxygen, sulfur, methylene, imine, or alkylimine;  
 provided that when R x  is hydrogen, methyl, chloromethyl, phenyl, or benzyl, and Q is oxygen, R z  is not amino.  
 
   
   
       18 . The compound or its pharmaceutically acceptable salt according to  claim 17 , wherein the salt is selected from the group consisting of hydrochloride, mesylate, EDTA, sulfite, L-Aspartate, maleate, phosphate, L-Glutamate, (+)-L-Tartrate, citrate, L-Lactate, succinate, acetate, hexanoate, butyrate, and propionate salt.  
   
   
       19 . A compound of Formula III  
     
       
         
         
             
             
         
       
     
     or its pharmaceutically acceptable salt, wherein 
 R x  is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, halogen-substituted alkyl or aryl, phenyl, benzyl, hydroxyl, thiol, substituted or unsubstituted amino, —O-alkyl, —S-alkyl, —O-aryl or —S-aryl;  
 R z  is a hydrogen, amino, alkyl, aryl, arylalkyl, alkylamino, dialkylamino, alkylarylamino, hydrazine, hydroxylalkylamino, —O-alkyl, —S-alkyl, —O-aryl or —S-aryl; and Q is oxygen, sulfur, methylene, imine, or alkylimine; and  
 Q is oxygen, sulfur, methylene, imine, or alkylimine;  
 provided that when R x  is hydrogen, methyl, chloromethyl, phenyl, or benzyl, Q is oxygen, R z  is not amino.  
 
   
   
       20 . The compound or its pharmaceutically acceptable salt according to  claim 19 , wherein the salt is selected from the group consisting of hydrochloride, mesylate, EDTA, sulfite, L-Aspartate, maleate, phosphate, L-Glutamate, (+)-L-Tartrate, citrate, L-Lactate, succinate, acetate, hexanoate, butyrate, and propionate salt.  
   
   
       21 . A compound of Formula IV  
     
       
         
         
             
             
         
       
     
     or its pharmaceutically acceptable salt, wherein 
 R x  is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, halogen-substituted alkyl or aryl, phenyl, benzyl, hydroxyl, thiol, substituted or unsubstituted amino, —O-alkyl, —S-alkyl, —O-aryl or —S-aryl; and  
 R z  is a hydrogen, amino, alkyl, aryl, arylalkyl, alkylamino, dialkylamino, alkylarylamino, hydrazine, hydroxylalkylamino, —O-alkyl, —S-alkyl, —O-aryl or —S-aryl;  
 each of R 1 ′, R 2 ′, R 3 ′, R 4 ′, R 5 ′, and R 6 ′ is independently selected from the group consisting of hydrogen, hydroxyl, fluoride, choloride, bromide, iodide, CF 3 , —O-alkyl, —O-acyl, —O-aryl, —S-alkyl, and —S-aryl; and  
 Q is oxygen, sulfur, methylene, imine, or alkylimine,  
 provided that when R x  is hydrogen and R z  is amino, R 4 ′ is not hydroxyl.  
 
   
   
       22 . The compound or its pharmaceutically acceptable salt according to  claim 21 , wherein R 4 ′ is hydrogen; and each of R 1 ′, R 2 ′, R 3 ′, R 5 ′, and R 6 ′ is independently selected from the group consisting of hydrogen, hydroxyl, fluoride, chloride, bromide, iodide, CF 3 , —O-alkyl, —O-acyl, —O-aryl, —S-alkyl, and —S-aryl.  
   
   
       23 . The compound or its pharmaceutically acceptable salt according to  claim 21 , wherein the salt is selected from the group consisting of hydrochloride, mesylate, EDTA, sulfite, L-Aspartate, maleate, phosphate, L-Glutamate, (+)-L-Tartrate, citrate, L-Lactate, succinate, acetate, hexanoate, butyrate, and propionate salt.  
   
   
       24 . Salt of a compound of Formula I,  
     
       
         
         
             
             
         
       
     
     wherein 
 R x  is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, halogen-substituted alkyl or aryl, phenyl, benzyl, hydroxyl, thiol, substituted or unsubstituted amino, —O-alkyl, —S-alkyl, —O-aryl or —S-aryl;  
 R y  is hydrogen, alkyl, or sugar;  
 R z  is a hydrogen, amino, alkyl, aryl, arylalkyl, alkylamino, dialkylamino, alkylarylamino, hydrazine, hydroxylalkylamino, —O-alkyl, —S-alkyl, —O-aryl or —S-aryl; and  
 Q is oxygen, sulfur, methylene, imine, or alkylimine,  
 provided that when R y  is 2′-deoxy-D-ribose or D-ribose, R x  is not hydrogen and R z  is not amino.  
 
   
   
       25 . The salt of  claim 24 , wherein Q is sulfur, and R z  is hydrogen, amino, alkylamino, dialkylamino, or O-alkyl.  
   
   
       26 . The salt of  claim 25 , wherein R x  is alkyl, or halogen.  
   
   
       27 . The salt of  claim 24 , wherein said salt is synthesized with an acid.  
   
   
       28 . The salt of  claim 27 , wherein said acid is selected from the group consisting of hydrochloric, L-lactic, acetic, phosphoric, (+)-L-tartaric, citric, propionic, butyric, hexanoic, L-aspartic, L-glutamic, succinic, EDTA, maleic, and methanesulfonic acid.  
   
   
       29 . The salt of  claim 27 , wherein said acid is selected from the group consisting of HBr, HF, HI, nitric, nitrous, sulfuric, sulfurous, phosphorous, perchloric, chloric, and chlorous acid.  
   
   
       30 . The salt of  claim 27 , wherein said acid is a carboxylic acid or a sulfonic acid.  
   
   
       31 . The salt of  claim 30 , wherein said carboxylic acid is selected from the group consisting of ascorbic, carbonic, and fumaric acid.  
   
   
       32 . The salt of  claim 30 , wherein said sulfonic acid is selected from the group consisting of ethanesulfonic, 2-hydroxyethanesulfonic, and toluenesulfonic acid.  
   
   
       33 . The salt of  claim 24 , wherein said salt is a hydrochloride, mesylate, EDTA, sulfite, L-Aspartate, maleate, phosphate, L-Glutamate, (+)-L-Tartrate, citrate, L-Lactate, succinate, acetate, hexanoate, butyrate, or propionate salt.  
   
   
       34 . A pharmaceutical composition comprising a therapeutically-effective amount of an active compound and a pharmaceutically-acceptable carrier, said active compound being a compound of formula I, II, III, or IV above, or its pharmaceutically acceptable salt.  
   
   
       35 . The pharmaceutical composition according to  claim 34 , wherein the pharmaceutically-acceptable carrier is an aqueous solution.  
   
   
       36 . The pharmaceutical composition according to  claim 35 , wherein the aqueous solution comprises a water miscible non-aqueous solvent selected from the group consisting of glycerin, propylene glycol, polyethylene glycol, and combinations thereof.  
   
   
       37 . The pharmaceutical composition according to  claim 35 , wherein the amount of the active compound in the composition is between 0.1 and 200 mg per ml of the aqueous solution.  
   
   
       38 . The pharmaceutical composition according to  claim 34 , wherein the pharmaceutical carrier is a solution comprising less than 40% water and a water miscible non-aqueous solvent.  
   
   
       39 . The pharmaceutical composition according to  claim 38 , wherein the non-aqueous solvent is selected from the group consisting of glycerin, propylene glycol, polyethylene glycol, and combinations thereof.  
   
   
       40 . The pharmaceutical composition according to  claim 34 , wherein the pharmaceutical carrier is a solution comprising less than 20% water and a water miscible non-aqueous solvent.  
   
   
       41 . The pharmaceutical composition according to  claim 34 , being in a form of lyophilized powder.  
   
   
       42 . The pharmaceutical composition according to  claim 34 , further comprising an acidifying agent added to the composition in a proportion such that the composition has a resulting pH between about 4 and 8.  
   
   
       43 . The pharmaceutical composition according to  claim 42 , wherein the acidifying agent is an inorganic or organic acid.  
   
   
       44 . The pharmaceutical composition according to  claim 43 , wherein the organic acid is selected from the group consisting of ascorbic acid, citric acid, tartaric acid, lactic acid, oxalic acid, formic acid, benzene sulphonic acid, benzoic acid, maleic acid, glutamic acid, succinic acid, aspartic acid, diatrizoic acid, and acetic acid.  
   
   
       45 . The pharmaceutical composition according to  claim 43 , wherein the inorganic acid is selected from the group consisting of hydrochloric acid, sulphuric acid, phosphoric acid, and nitric acid.  
   
   
       46 . The pharmaceutical composition according to  claim 43 , wherein the acidifying agent is ascorbic acid.  
   
   
       47 . The pharmaceutical composition according to  claim 34 , further comprising a pharmaceutically acceptable excipient.  
   
   
       48 . The pharmaceutical composition according to  claim 47 , wherein the excipient is selected from the group consisting of mannitol, sorbitol, lactose, dextrox, and cyclodextrin.  
   
   
       49 . The pharmaceutical composition according to  claim 48 , wherein the cyclodextrin is α-, β-, or γ-cyclodextrin.  
   
   
       50 . The pharmaceutical composition according to  claim 48 , the cyclodextrin is a modified, amorphous cyclodextrin selected from the group consisting of hydroxypropyl-, hydroxyethyl-, glucosyl-, maltosyl-, maltotriosyl-, carboxyamidomethyl-, carboxymethyl-, sulfobutylether-, and diethylamino-substituted α-, β- and γ-cyclodextrin.  
   
   
       51 . The pharmaceutical composition according to  claim 34 , wherein at least 80% of the active compound remains in active form after storage at 25° C. for 7 days.  
   
   
       52 . The pharmaceutical composition according to  claim 34 , wherein at least 80% of the active compound remains in active form after storage at 25° C. for 14 days.  
   
   
       53 . The pharmaceutical composition according to  claim 34 , wherein at least 80% of the active compound remains in active form after storage at 40° C. for 7 days.  
   
   
       54 . The pharmaceutical composition according to  claim 34 , further comprising: a therapeutic agent selected from the group consisting of anti-neoplastic agents, alkylating agents, agents that are members of the retinoids superfamily, hormonal agents, plant-derived agents, biologic agents, interleukins, interferons, cytokines, immuno-modulating agents, and monoclonal antibodies.  
   
   
       55 . A kit, comprising: 
 a first vessel containing a compound of formula I, II, III, or IV above, or its pharmaceutically acceptable salt in a solid form.    
   
   
       56 . The kit according to  claim 55 , wherein the active compound is in a form of lyophilized powder.  
   
   
       57 . The kit according to  claim 56 , further comprising: 
 a second vessel containing a diluent comprising glycerin, propylene glycol, polyethylene glycol or combinations thereof.    
   
   
       58 . The kit according to  claim 57 , wherein the diluent comprises less than 40% water in volume.  
   
   
       59 . The kit according to  claim 55 , where the amount of active compound in the first vessel is between 0.1 and 200 mg.  
   
   
       60 . The kit according to  claim 55 , wherein the diluent further comprises an acidifying agent.  
   
   
       61 . The kit according to  claim 55 , further comprising: a written instruction describing how to administer the active compound as a pharmaceutical to a patient.  
   
   
       62 . A method for treating a patient suffering from a disease associated with aberrant DNA methylation, comprising: 
 administering to the patient a pharmaceutical composition comprising a therapeutically-effective amount of an active compound and a pharmaceutically-acceptable carrier, said active compound being a compound of formula I, II, III, or IV above, or its pharmaceutically acceptable salt.    
   
   
       63 . The method according to  claim 62 , wherein the pharmaceutical composition is administered orally, parenterally, topically, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery, subcutaneously, intraadiposally, intraarticularly, or intrathecally.  
   
   
       64 . The method according to  claim 62 , wherein the pharmaceutical composition is administered intravenously.  
   
   
       65 . The method according to  claim 62 , wherein the pharmaceutical composition is administered subcutaneously.  
   
   
       66 . The method according to  claim 62 , further comprising: 
 administering to the patient a second therapeutic agent in combination with the pharmaceutical composition.    
   
   
       67 . The method according to  claim 66 , wherein the second therapeutic agent is selected from the group consisting of antibiotic agents, alkylating agents, retinoids, hormonal agents, plant-derived agents, biologic agents, interleukins, interferons, cytokines, immuno-modulating agents, and monoclonal antibodies.  
   
   
       68 . The method according to  claim 62 , wherein the disease associated with aberrant DNA methylation is selected from the group consisting of hematological disorders, benign tumor and cancer.  
   
   
       69 . The method according to  claim 68 , wherein the hematological disorder is selected from the group consisting of acute myeloid leukemia, acute promyelocytic leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, the myelodysplastic syndromes, and sickle cell anemia.