Novel heterocyclic systems and pharmaceutical compositions thereof

Abstract

Novel heterocyclic systems are herein disclosed, which possess many biological activities, including but not limited to anticancer activity. The disclosed compounds are useful in the treatment of many disease states related to cell proliferation. In particular, new pyran derivatives are provided along with processes for their preparations and methods for their pharmaceutical applications, for example, as anticancer agents. These compounds were found to have antiproliferative effects against multiple cancer cell lines and showed low toxicity to normal fibroblasts. The disclosed compounds also exhibited anticancer properties by inducing caspase-mediated cell death mechanisms and arresting cancer cell progression. Further, these novel compounds were able to target multiple key proteins/enzymes, including thioredoxin reductase, glutathione reductase, transferrin receptors, inisitol-3-phosphate synthase, cystolic aminopeptidase, and transketolase, which are over-expressed in tumor cells.

1 . A compound having the following general formula: 
       
         
           
           
               
               
           
         
       
       wherein: 
       
         
           
           
               
               
           
         
       
       is an aryl, heteroaryl, alicyclic, or heteroalicyclic ring, which may be unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of: a halogen atom, CN, R 3 , OR 3 , SR 3 , N(R 3 ) 2 , C(O)R 3 , C(O)OR 3 , NR 3 C(O)R 3 , C(O)NR 3 , SO 2 R 3 , NR 3 SO 2 R 3 , and SO 2 N(R 3 ) 2 ;
 X is —O, —NR 4 , —NSO 2 R 4 , —CH 2 , —CHR 4 , or —C(R 4 ) 2 ; 
 H a  and H b  are each hydrogen atoms; and 
 R 1  and R 2  are:
 each independently selected from the group consisting of: a hydrogen, halogen atom, CN, R 3 , OR 3 , SR 3 , N(R 3 ) 2 , C(O)R 3 , C(O)OR 3 , NR 3 C(O)R 3 , C(O)NR 3 , SO 2 R 3 , NR 3 SO 2 R 3 , and SO 2 N(R 3 ) 2 ; or 
 connected to form a 5 or 6 membered ring which is fused to ring D, wherein the 5 or 6 membered ring is either unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of: a halogen atom, CN, R 3 , OR 3 , SR 3 , N(R 3 ) 2 , C(O)R 3 , C(O)OR 3 , NR 3 C(O)R 3 , C(O)NR 3 , SO 2 R 3 , NR 3 SO 2 R 3 , and SO 2 N(R 3 ) 2 , 
 
 or a pharmaceutically acceptable salt, pro-drug, or derivative thereof: 
 
     
     
         2 . The compound of  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       is either a mono, bi, poly, or fused ring system. 
     
     
         3 . The compound of  claim 1 , wherein R 3  is independently hydrogen or a substituted group selected from the group consisting of: a C 1-6  aliphatic group; a monocyclic 3-8 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and a bicyclic 8-10 membered saturated, partially unsaturated, or aryl ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     
     
         4 . The compound of  claim 1 , wherein R 4  is hydrogen or an unsubstituted or a substituted alkyl, aryl or heteroaryl group. 
     
     
         5 . The compound of  claim 1 , wherein R 3  is selected from the group consisting of: —CX 3 , —CHX 2 , and —CH 2 X, wherein X is chlorine, fluorine, bromine or iodine. 
     
     
         6 . The compound of  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       is a phenyl group or a substituted phenyl group. 
     
     
         7 . The compound of  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       is a napthyl group or a substituted napthyl group. 
     
     
         8 . The compound of  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       is tetrahydropyridoquinoline. 
     
     
         9 . The compound of  claim 1 , wherein R 1  and R 2  are each independently selected from the group consisting of: a hydrogen, halogen atom, CN, R 3 , OR 3 , SR 3 , N(R 3 ) 2 , C(O)R 3 , C(O)OR 3 , NR 3 C(O)R 3 , C(O)NR 3 , SO 2 R 3 , NR 3 SO 2 R 3 , and SO 2 N(R 3 ) 2 . 
     
     
         10 . The compound of  claim 1 , wherein R 1  and R 2  are connected to form a 5 or 6 membered ring which is fused to ring D and the 5 or 6 membered ring is either unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of: a halogen atom, CN, R 3 , OR 3 , SR 3 , N(R 3 ) 2 , C(O)R 3 , C(O)OR 3 , NR 3 C(O)R 3 , C(O)NR 3 , SO 2 R 3 , NR 3 SO 2 R 3 , and SO 2 N(R 3 ) 2 . 
     
     
         11 . A process for preparing the compound of  claim 1 . 
     
     
         12 . The process of  claim 11 , wherein compounds of a general formula I and a general formula II are used, wherein the general formula I is as follows: 
       
         
           
           
               
               
           
         
         and the general formula II is as follows: 
       
       
         
           
           
               
               
           
         
       
       wherein: 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of: a phenyl group, a napthyl group, tetrahydropyridoquinoline, and an unsubstituted or substituted ring with 1, 2, 3, or 4 substituents independently selected from the group consisting of: a halogen atom, CN, R 3 , OR 3 , SR 3 , N(R 3 ) 2 , C(O)R 3 , C(O)OR 3 , NR 3 C(O)R 3 , C(O)NR 3 , SO 2 R 3 , NR 3 SO 2 R 3 , and SO 2 N(R 3 ) 2 ;
 X is selected from the group consisting of: —O, —NR 4 , —NSO 2 R 4 , —CH 2 , —CHR 4 , and —C(R 4 ) 2 ; and 
 R 1  and R 2  are:
 each independently a hydrogen, halogen atom, CN, R 3 , OR 3 , SR 3 , N(R 3 ) 2 , C(O)R 3 , C(O)OR 3 , NR 3 C(O)R 3 , C(O)NR 3 , SO 2 R 3 , NR 3 SO 2 R 3 , SO 2 N(R 3 ) 2 ; or 
 connected to form a 5 or 6 membered ring which is fused to ring D, wherein the 5 or 6 membered ring is either unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of: a halogen atom, CN, R 3 , OR 3 , SR 3 , N(R 3 ) 2 , C(O)R 3 , C(O)OR 3 , NR 3 C(O)R 3 , C(O)NR 3 , SO 2 R 3 , NR 3 SO 2 R 3 , and SO 2 N(R 3 ) 2 . 
 
 
     
     
         13 . The process of  claim 12 , wherein the compound of the general formula I and the compound of the general formula II are mixed in acetonitrile and, thereafter, trifluoroacetic acid is added and refluxed until the acetonitrile and excess trifluoroacetic acid are removed. 
     
     
         14 . The process of  claim 12 , wherein the compound of the general formula I and the compound of the general formula II are mixed in 1,4-dioxane and, thereafter, scandium triflate is added and a resulting mixture is stirred and heated until the 1,4-dioxane is removed. 
     
     
         15 . A compound having the following general formula: 
       
         
           
           
               
               
           
         
       
       wherein: 
       
         
           
           
               
               
           
         
       
       is an aryl, heteroaryl, alicyclic, or heteroalicyclic ring, which may be unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of: a halogen atom, CN, R 1 , OR 1 , SR 1 , N(R 1 ) 2 , C(O)R 1 , C(O)OR 1 , NR 1 C(O)R 1 , C(O)NR 1 , SO 2 R 1 , NR 1 SO 2 R 1 , and SO 2 N(R 1 ) 2 ;
 X is —O, —NR 2 , —NSO 2 R 2 , —CH 2 , —CHR 2 , or —C(R 2 ) 2 ; 
 H a  and H b  are each hydrogen atoms; and 
 n=1, 2, or 3 and B has a ring size of 6, 7, or 8; and 
 
       
         
           
           
               
               
           
         
       
       is a 5, 6, or 7 membered heterocyclic ring that is either unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of: a halogen atom, CN, R 1 , OR 1 , SR 1 , N(R) 2 , C(O)R 1 , C(O)OR 1 , NR 1 C(O)R 1 , C(O)NR 1 , SO 2 R 1 , NR 1 SO 2 R 1 , and SO 2 N(R 1 ) 2 ,
 or a pharmaceutically acceptable salt, pro-drug, or derivative thereof. 
 
     
     
         16 . The compound of  claim 15 , wherein, R 1  is independently hydrogen or a substituted group selected from the group consisting of: a C 1-6  aliphatic group; a monocyclic 3-8 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and a bicyclic 8-10 membered saturated, partially unsaturated, or aryl ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     
     
         17 . The compound of  claim 15 , wherein R 2  is hydrogen or an unsubstituted or a substituted alkyl, aryl, or heteroaryl group. 
     
     
         18 . The compound of  claim 15 , wherein R 2  is selected from the group consisting of: —CX 3 , —CHX 2 , and —CH 2 X, wherein X is chlorine, fluorine, bromine, or iodine. 
     
     
         19 . The compound of  claim 15 , wherein 
       
         
           
           
               
               
           
         
       
       is phenyl or a substituted phenyl. 
     
     
         20 . The compound of  claim 15 , wherein 
       
         
           
           
               
               
           
         
       
       is napthyl or a substituted napthyl. 
     
     
         21 . The compound of  claim 15 , wherein 
       
         
           
           
               
               
           
         
       
       is an unsubstituted or substituted indole, pyrrole, or imidazole. 
     
     
         22 . The compound of  claim 15 , wherein n is 1 or 2. 
     
     
         23 . The compound of  claim 15 , wherein 
       
         
           
           
               
               
           
         
       
       is pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, thiazole, or benzothiazole. 
     
     
         24 . The compound of  claim 15 , wherein 
       
         
           
           
               
               
           
         
       
       is an unsubstituted ring or a ring with 1, 2, 3, or 4 substituents independently selected from the group consisting of: a halogen atom, CN, R 1 , OR 1 , SR 1 , N(R 1 ) 2 , C(O)R 1 , C(O)OR 1 , NR 1 C(O)R 1 , C(O)NR 1 , SO 2 R 1 , NR 1 SO 2 R 1 , and SO 2 N(R 1 ) 2 . 
     
     
         25 . A process for the preparation of the compound of  claim 15 . 
     
     
         26 . The process in  claim 25  comprising using compounds of a general formula III and a general formula IV, wherein the general formula III is: 
       
         
           
           
               
               
           
         
       
       and the general formula IV is as follows: 
       
         
           
           
               
               
           
         
       
       and wherein: 
       
         
           
           
               
               
           
         
       
       is an aryl, heteroaryl, alicyclic, or heteroalicyclic ring, which may be unsubstituted or substituted with 1, 2, 3, or 4 substituents that may independently be selected from the group consisting of: a halogen atom, CN, R 1 , OR 1 , SR 1 , N(R 1 ) 2 , C(O)R 1 , C(O)OR 1 , NR 1 C(O)R 1 , C(O)NR 1 , SO 2 R 1 , NR 1 SO 2 R 1 , and SO 2 N(R 1 ) 2 ;
 X is —O, —NR 2 , —NSO 2 R 2 , —CH 2 , —CHR 2 , or —C(R 2 ) 2 ; 
 n is 1 or 2; and 
 
       
         
           
           
               
               
           
         
       
       is pyridine, pyrazine, quinolone, isoquinoline, thiazole, or benzothiazole. 
     
     
         27 . The process of  claim 26 , wherein the compound of the general formula III and the compound of the general formula IV are mixed in acetonitrile and, thereafter, trifluoroacetic acid is added and refluxed until the acetonitrile and excess trifluoroacetic acid are removed. 
     
     
         28 . The process of  claim 26 , wherein the compound of the general formula III and the compound of the general formula II are mixed in acetonitrile and, thereafter, trifluoroacetic acid is added and refluxed until the acetonitrile and excess trifluoroacetic acid are removed. 
     
     
         29 . A compound according to one of the following chemical structures, including enantiomers, diastereoisomers, and derivatives thereof: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         30 . A pharmaceutical composition comprising one or more compounds of  claim 29  as an active ingredient. 
     
     
         31 . A method of using one or more compounds of  claim 29  for the treatment of diseases states including the cancer by modulating the functions of thioredoxin/thioredoxin reductase, transketolase, cytosol aminopeptidase, glutathione reductase, inositol-3-phosphate synthase and transferrin receptors. 
     
     
         32 . A method of inhibiting thioredoxin/thioredoxin reductase, in vitro or in vivo, comprising contacting a cell with an effective amount of one or more compounds of  claim 29 . 
     
     
         33 . A method of regulating cell proliferation, in vitro or in vivo, comprising contacting a cell with an effective amount of one or more compounds of  claim 29 . 
     
     
         34 . A method of: (a) inhibiting cell proliferation; (b) inhibiting cell cycle progression; (c) promoting apoptosis; or (d) a combination of one or more of these, in vitro or in vivo, comprising contacting a cell with one or more compounds of  claim 29 . 
     
     
         35 . A method for the treatment of a proliferative condition or a condition mediated by thioredoxin/thioredoxin reductase comprising administering to a subject suffering from said condition a therapeutically-effective amount of one or more compounds of  claim 29 . 
     
     
         36 . A method of using one or more compounds of  claim 29  in a medicament for use in the treatment of a condition mediated by transketolase. 
     
     
         37 . A method of using one or more compounds of  claim 29  in a medicament for use in the treatment of a condition mediated by cytosol aminopeptidase. 
     
     
         38 . A method of using one or more compounds of  claim 29  in a medicament for use in the treatment of a condition mediated by glutathione reductase. 
     
     
         39 . A method of using one or more compounds of  claim 29  in a medicament for use in the treatment of a condition mediated by inositol-3-phosphate synthase. 
     
     
         40 . A method of using one or more compounds of  claim 29  in a medicament for use in the treatment of a condition mediated by transferrin receptors.