Imidazothiazole Derivatives Having Proline Ring Structure

Abstract

Compounds that inhibit interaction between murine double minute 2 (Mdm2) protein and p53 protein and that exhibit anti-tumor activity are provided. Compounds provided by the present disclosure include imidazothiazole derivatives that inhibit interaction between Mdm2 protein and p53 protein and exhibit anti-tumor activity.

1 - 19 . (canceled) 
     
     
         20 . A method of treating cancer, comprising administering a compound according to formula (1): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, to a patient, 
       wherein
 Ar 1  represents a phenyl group optionally substituted with one or more substituents each independently selected from a halogen atom, a cyano group, and a C 1 -C 6  alkyl group; 
 Ar 2  represents a phenyl group optionally substituted with one or more substituents each independently selected from a halogen atom, a C 1 -C 6  alkyl group, and a cyano group; or a pyridyl group optionally substituted with one or more substituents each independently selected from a halogen atom, a C 1 -C 6  alkyl group, and a cyano group; 
 R 1  represents a C 1 -C 6  alkyl group optionally substituted with one or more substituents each independently selected from a halogen atom, a hydroxy group, a C 1 -C 6  alkoxy group, a carbamoyl group, an amino group, a C 1 -C 6  alkanoyl group, and a cyano group; or a C 1 -C 6  alkanoyl group optionally substituted with one or more substituents each independently selected from a halogen atom, a hydroxy group, a C 1 -C 6  alkoxy group, a carbamoyl group, an amino group, and a cyano group; a hydrogen atom; or a hydroxy group; 
 R 2  and R 3  each independently represent a C 1 -C 6  alkyl group optionally substituted with one or more substituents each independently selected from a halogen atom, a hydroxy group, a C 1 -C 6  alkoxy group, a carbamoyl group, an amino group, a C 1 -C 6  alkanoyl group, and a cyano group; a carboxy group; or a hydrogen atom; or R 2  and R 3  may together form an oxo group; or R 2  and R 3  together with the carbon atoms to which R 2  and R 3  are respectively bonded may form a 3- to 5-membered saturated hydrocarbon ring in a spiro form; 
 R 4  represents a C 1 -C 6  alkyl group optionally substituted with one or more substituents each independently selected from a halogen atom, a hydroxy group, a C 1 -C 6  alkoxy group, a carbamoyl group, an amino group, a C 1 -C 6  alkanoyl group, and a cyano group; 
 R 5  represents a C 1 -C 6  alkyl group optionally substituted with one or more substituents each independently selected from a halogen atom, a hydroxy group, a C 1 -C 6  alkoxy group, a carbamoyl group, an amino group, a C 1 -C 6  alkanoyl group, and a cyano group; 
 R 6  represents a halogen atom or a hydrogen atom; and 
 R 7  represents a halogen atom. 
 
     
     
         21 . The method according to  claim 20 , wherein the cancer is selected from lung cancer, breast cancer, prostate cancer, colon cancer, acute myeloid leukemia, malignant lymphoma, retinoblastoma, neuroblastoma, and sarcoma. 
     
     
         22 . The method according to  claim 20 , wherein the cancer is selected from lung cancer, prostate cancer, colon cancer, acute myeloid leukemia, malignant lymphoma, and osteosarcoma. 
     
     
         23 . The method according to  claim 20 , wherein the compound inhibits suppression of p53 transcription. 
     
     
         24 . The method according to  claim 20 , wherein the compound prevents degradation of p53. 
     
     
         25 . The method according to  claim 20 , wherein the compound inhibits Mdm2-p53 binding and ubiquitination of p53 by Mdm2. 
     
     
         26 . The method according to  claim 20 , wherein the patient is a human. 
     
     
         27 . The method according to  claim 26 , wherein the compound is administered in an amount of 0.01 to 500 mg/kg body weight per day. 
     
     
         28 . The method according to  claim 26 , wherein the compound is administered in an amount of 0.1 to 100 mg/kg body weight per day. 
     
     
         29 . The method according to  claim 26 , wherein the compound is administered at least once per day. 
     
     
         30 . The method according to  claim 26 , wherein the compound is administered at least twice per day. 
     
     
         31 . The method according to  claim 26 , wherein the compound is administered at least four times per day. 
     
     
         32 . The method according to  claim 20 , wherein the compound is represented by general formula (2): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7  are as defined in  claim 20 . 
     
     
         33 . The method according to  claim 20 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; and 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         34 . A method of inhibiting cell growth, comprising administering a compound according to formula (1): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, to a patient, 
       wherein
 Ar 1  represents a phenyl group optionally substituted with one or more substituents each independently selected from a halogen atom, a cyano group, and a C 1 -C 6  alkyl group; 
 Ar 2  represents a phenyl group optionally substituted with one or more substituents each independently selected from a halogen atom, a C 1 -C 6  alkyl group, and a cyano group; or a pyridyl group optionally substituted with one or more substituents each independently selected from a halogen atom, a C 1 -C 6  alkyl group, and a cyano group; 
 R 1  represents a C 1 -C 6  alkyl group optionally substituted with one or more substituents each independently selected from a halogen atom, a hydroxy group, a C 1 -C 6  alkoxy group, a carbamoyl group, an amino group, a C 1 -C 6  alkanoyl group, and a cyano group; or a C 1 -C 6  alkanoyl group optionally substituted with one or more substituents each independently selected from a halogen atom, a hydroxy group, a C 1 -C 6  alkoxy group, a carbamoyl group, an amino group, and a cyano group; a hydrogen atom; or a hydroxy group; 
 R 2  and R 3  each independently represent a C 1 -C 6  alkyl group optionally substituted with one or more substituents each independently selected from a halogen atom, a hydroxy group, a C 1 -C 6  alkoxy group, a carbamoyl group, an amino group, a C 1 -C 6  alkanoyl group, and a cyano group; a carboxy group; or a hydrogen atom; or R 2  and R 3  may together form an oxo group; or R 2  and R 3  together with the carbon atoms to which R 2  and R 3  are respectively bonded may form a 3- to 5-membered saturated hydrocarbon ring in a spiro form; 
 R 4  represents a C 1 -C 6  alkyl group optionally substituted with one or more substituents each independently selected from a halogen atom, a hydroxy group, a C 1 -C 6  alkoxy group, a carbamoyl group, an amino group, a C 1 -C 6  alkanoyl group, and a cyano group; 
 R 5  represents a C 1 -C 6  alkyl group optionally substituted with one or more substituents each independently selected from a halogen atom, a hydroxy group, a C 1 -C 6  alkoxy group, a carbamoyl group, an amino group, a C 1 -C 6  alkanoyl group, and a cyano group; 
 R 6  represents a halogen atom or a hydrogen atom; and 
 R 7  represents a halogen atom. 
 
     
     
         35 . The method according to  claim 34 , wherein the compound inhibits suppression of p53 transcription. 
     
     
         36 . The method according to  claim 34 , wherein the compound prevents degradation of p53. 
     
     
         37 . The method according to  claim 34 , wherein the compound inhibits Mdm2-p53 binding and ubiquitination of p53 by Mdm2. 
     
     
         38 . The method according to  claim 37 , wherein the compound is administered in an amount selected from 0.01 to 500 mg/kg body weight per day and 0.1 to 100 mg/kg body weight per day. 
     
     
         39 . The method according to  claim 37 , wherein the compound is administered at least once per day, at least twice per day, or at least four times per day.