Wnt protein signalling inhibitors

Abstract

The present invention generally relates to protein signalling. In particular, compounds that inhibit the Wnt protein signalling pathway are disclosed. Such compounds may be used in the treatment of Wnt protein signalling-related diseases and conditions such as cancer, degenerative diseases, type II diabetes and osteopetrosis.

1 . A method of inhibiting Wnt protein signalling in a cell comprising administering to the cell an effective amount of a compound of formula (A): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is 
 
       
         
           
           
               
               
           
         
          wherein
 R 11  is selected from the group consisting of hydrogen, halogen, alkyl (C≦4) , substituted alkyl (C≦4) , alkoxy (C≦4) , substituted alkoxy (C≦4)  and 
 
       
       
         
           
           
               
               
           
         
         R 2  is selected from the group consisting of hydrogen, alkyl (C≦4) , substituted alkyl (C≦4) , alkoxy (C≦4)  and substituted alkoxy (C≦4) ; and 
         R 3  is selected from the group consisting of hydrogen, halogen, alkyl (C≦4) , substituted alkyl (C≦4) , alkoxy (C≦4) , substituted alkoxy (C≦4) , 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The method of  claim 1 , wherein the compound is further defined by formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is 
 
       
         
           
           
               
               
           
         
          wherein
 R 11  is selected from the group consisting of hydrogen, halogen, alkyl (C≦4) , substituted alkyl (C≦4) , alkoxy (C≦4) , substituted alkoxy (C≦4)  and 
 
       
       
         
           
           
               
               
           
         
         R 2  is selected from the group consisting of hydrogen, alkyl (C≦4) , substituted alkyl (C≦4) , alkoxy (C≦4)  and substituted alkoxy (C≦4) ; and 
         R 3  is selected from the group consisting of hydrogen, halogen, alkyl (C≦4) , substituted alkyl (C≦4) , alkoxy (C≦4) , substituted alkoxy (C≦4) , 
       
       
         
           
           
               
               
           
         
       
     
     
         3 . The method of  claim 2 , wherein the cell is in vitro. 
     
     
         4 . The method of  claim 2 , wherein the cell is in vivo. 
     
     
         5 . The method of  claim 2 , wherein the method of inhibiting Wnt protein signalling is further defined as a method of inhibiting Wnt response. 
     
     
         6 - 8 . (canceled) 
     
     
         9 . The method of  claim 2 , wherein the method of inhibiting Wnt protein signalling is further defined as a method of inhibiting Wnt protein production. 
     
     
         10 . The method of  claim 9 , wherein the compound of formula (I) is further defined as a compound of formula (III): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 25  is alkyl (C≦4) , substituted alkyl (C≦4) , alkoxy (C≦4) , or substituted alkoxy (C≦4) ; and 
 R 26  is selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         
           wherein R 29  are each independently selected from the group consisting of hydrogen, halogen, alkyl (C≦4) , substituted alkyl (C≦4) , alkoxy (C≦4) , substituted alkoxy (C≦4)  and 
         
       
       
         
           
           
               
               
           
         
       
     
     
         11 . The method of  claim 10 , wherein the compound of formula (III) is further defined as any one or more of the following: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The method of  claim 2 , wherein the compound of formula (I) is further defined as a compound of formula (IV): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 31  is selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         
           wherein R 34  and R 35  are selected from the group consisting of hydrogen, halogen, alkyl (C≦4) , substituted alkyl (C≦4) , alkoxy (C≦4) , substituted alkoxy (C≦4)  and 
         
       
       
         
           
           
               
               
           
         
         
            and 
         
         R 32  is 
       
       
         
           
           
               
               
           
         
         
           wherein R 38  is selected from the group consisting of hydrogen, halogen, alkyl (C≦4) , substituted alkyl (C≦4) , alkoxy (C≦4)  and substituted alkoxy (C≦4) . 
         
       
     
     
         13 . (canceled) 
     
     
         14 . A method of treating cancer in a patient comprising administering to the patient an effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is 
 
       
         
           
           
               
               
           
         
          wherein
 R 11  is selected from the group consisting of hydrogen, halogen, alkyl (C≦4) , substituted alkyl (C≦4) , alkoxy (C≦4) , substituted alkoxy (C≦4)  and 
 
       
       
         
           
           
               
               
           
         
         R 2  is selected from the group consisting of hydrogen, alkyl (C≦4) , substituted alkyl (C≦4) , alkoxy (C≦4)  and substituted alkoxy (C≦4) ; and 
         R 3  is selected from the group consisting of hydrogen, halogen, alkyl (C≦4) , substituted alkyl (C≦4) , alkoxy (C≦4) , substituted alkoxy (C≦4) , 
       
       
         
           
           
               
               
           
         
       
     
     
         15 . The method of  claim 14 , wherein the compound of formula (I) is further defined as any one or more of the following compounds: 
       
         
           
           
               
               
           
         
       
     
     
         16 . The method of  claim 14 , wherein the compound of formula (I) is comprised with a pharmaceutically acceptable carrier, diluent, and/or excipient in a pharmaceutical composition. 
     
     
         17 . The method of  claim 14 , wherein the cancer is colorectal cancer, breast cancer, liver cancer, lung cancer, or prostate cancer. 
     
     
         18 . The method of  claim 14 , further comprising administration of a chemotherapeutic, radiation therapy, immunotherapy, hormone therapy, toxin therapy, or gene therapy. 
     
     
         19 . The method of  claim 14 , wherein the method of administration is selected from the group consisting of intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostaticaly, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, intramuscularly, subcutaneously, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularally, orally, locally, via inhalation, via injection, via infusion, via continuous infusion, via localized perfusion bathing target cells directly, via a catheter, via a lavage, in cremes, in lipid compositions, or any combination thereof. 
     
     
         20 . The method of  claim 14 , wherein the dose of the compound of formula (I) that is administered is about 1 μg/kg to about 100 mg/kg. 
     
     
         21 . A method of treating or preventing osteopetrosis in a patient comprising administering to the patient an effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is 
 
       
         
           
           
               
               
           
         
          wherein
 R 11  is selected from the group consisting of hydrogen, halogen, alkyl (C≦4) , substituted alkyl (C≦4) , alkoxy (C≦4) , substituted alkoxy (C≦4)  and 
 
       
       
         
           
           
               
               
           
         
         R 2  is selected from the group consisting of hydrogen, alkyl (C≦4) , substituted alkyl (C≦4) , alkoxy (C≦4)  and substituted alkoxy (C≦4) ; and 
         R 3  is selected from the group consisting of hydrogen, halogen, alkyl (C≦4) , substituted alkyl (C≦4) , alkoxy (C≦4) , substituted alkoxy (C≦4) , 
       
       
         
           
           
               
               
           
         
       
     
     
         22 . The method of  claim 21 , further comprising administration of a second osteopetrosis-treating agent or a second osteopetrosis-preventing agent. 
     
     
         23 . The method of  claim 21 , wherein the method of administration is selected from the group consisting of intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intranasally, topically, intramuscularly, subcutaneously, intraumbilically, orally, locally, via inhalation, via injection, via infusion, via continuous infusion, via localized perfusion bathing target cells directly, via a catheter, in cremes, in lipid compositions, or any combination thereof. 
     
     
         24 . The method of  claim 14 , wherein the dose of the compound of formula (I) that is administered is about 1 μg/kg to about 100 mg/kg. 
     
     
         25 . A method of treating a degenerative disease in a patient comprising administering to the patient an effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is 
 
       
         
           
           
               
               
           
         
          wherein
 R 11  is selected from the group consisting of hydrogen, halogen, alkyl (C≦4) , substituted alkyl (C≦4) , alkoxy (C≦4) , substituted alkoxy (C≦4)  and 
 
       
       
         
           
           
               
               
           
         
         R 2  is selected from the group consisting of hydrogen, alkyl (C≦4) , substituted alkyl (C≦4) , alkoxy (C≦4)  and substituted alkoxy (C≦4) ; and 
         R 3  is selected from the group consisting of hydrogen, halogen, alkyl (C≦4) , substituted alkyl (C≦4) , alkoxy (C≦4) , substituted alkoxy (C≦4) , 
       
       
         
           
           
               
               
           
         
       
     
     
         26 . The method of  claim 25 , wherein the degenerative disease is type II diabetes or age-related impairment of tissue repair. 
     
     
         27 . The method of  claim 25 , further comprising administration of a second agent to treat a degenerative disease. 
     
     
         28 . The method of  claim 25 , wherein the method of administration is selected from the group consisting of intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostaticaly, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intramuscularly, subcutaneously, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularally, orally, locally, via inhalation, via injection, via infusion, via continuous infusion, via localized perfusion bathing target cells directly, via a catheter, via a lavage, in cremes, in lipid compositions, or any combination thereof. 
     
     
         29 . The method of  claim 25 , wherein the dose of the compound of formula (I) that is administered is about 1 μg/kg to about 100 mg/kg. 
     
     
         30 . A method of treating type II diabetes in a patient comprising administering to the patient an effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is selected from the group consisting of 
 
       
         
           
           
               
               
           
         
          wherein
 r and t are each independently 0 or 1, 
 R 11  is selected from the group consisting of hydrogen, halogen, alkyl (C≦4) , substituted alkyl (C≦4) , alkoxy (C≦4) , substituted alkoxy (C≦4)  and 
 
       
       
         
           
           
               
               
           
         
         R 2  is selected from the group consisting of hydrogen, alkyl (C≦4) , substituted alkyl (C≦4) , alkoxy (C≦4)  and substituted alkoxy (C≦4) ; and 
         R 3  is selected from the group consisting of hydrogen, halogen, alkyl (C≦4) , substituted alkyl (C≦4) , alkoxy (C≦4) , substituted alkoxy (C≦4) , 
       
       
         
           
           
               
               
           
         
       
     
     
         31 . The method of  claim 30 , further comprising administration of a second agent to treat diabetes. 
     
     
         32 . The method of  claim 30 , wherein the method of administration is selected from the group consisting of intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostaticaly, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intramuscularly, subcutaneously, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularally, orally, locally, via inhalation, via injection, via infusion, via continuous infusion, via localized perfusion bathing target cells directly, via a catheter, via a lavage, in cremes, in lipid compositions, or any combination thereof. 
     
     
         33 . The method of  claim 30 , wherein the dose of the compound of formula (I) that is administered is about 1 μg/kg to about 100 mg/kg. 
     
     
         34 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent, and/or excipient and any one or more of the following compounds: 
       
         
           
           
               
               
           
         
       
     
     
         35 - 60 . (canceled)