Silstatin compounds

Abstract

The present disclosure relates to Silstatin compounds, pharmaceutical compositions comprising such compounds, kits, and methods for using such compounds or pharmaceutical compositions.

1 . A compound of formula (I), 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10  and R 11  are independently selected from —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl and —(C 2 -C 6 )alkynyl,
 wherein the alkyl, alkenyl or alkynyl are unsubstituted or substituted with a substituent selected from —OH, —NH 2 , —NHR′, —NHR′R″, —SH, —SR′, —C(O)OH, —C(O)NH 2 , —C(O)NHR′, —C(O)NR′R″, —NHC(═NH)NH 2 , —(C 6 -C 14 )aryl, —(C 6 -C 14 )aryl substituted with OH, -(5- or 6-membered monocyclic heteroaryl), -(9- or 10-membered bicyclic heteroaryl) and —(C 3 -C 7 )cycloalkyl, wherein R′ and R″ are independently selected from —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl and (C 2 -C 6 )alkynyl; or 
 wherein the alkyl, taken together with an adjacent N, forms a (5- or 6-membered)heterocyclyl; 
 X 1 , X 2 , X 3 , X 4 , X 5  and X 6  are independently selected from —H, (C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl and —(C 2 -C 6 )alkynyl; and 
 aa 1  is an amino acid, wherein the amino acid is unsubstituted or substituted with a protecting group or a Linking Unit. 
 
       
     
     
         2 . A compound of formula (II), 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10  and R 11  are independently selected from —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl and —(C 2 -C 6 )alkynyl,
 wherein the alkyl, alkenyl or alkynyl are unsubstituted or substituted with a substituent selected from —OH, —NH 2 , —NHR′, —NHR′R″, —SH, —SR′, —C(O)OH, —C(O)NH 2 , 
 
         —C(O)NHR′, —C(O)NR′R″, —NHC(═NH)NH 2 , —(C 6 -C 14 )aryl, —(C 6 -C 14 )aryl substituted with OH, -(5- or 6-membered monocyclic heteroaryl), -(9- or 10-membered bicyclic heteroaryl) and —(C 3 -C 7 )cycloalkyl, wherein R′ and R″ are independently selected from 
         —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl and (C 2 -C 6 )alkynyl; or
 wherein the alkyl, taken together with an adjacent N, forms a (5- or 6-membered)heterocyclyl; 
 
         X 1 , X 2 , X 3 , X 4 , X 5  and X 6  are independently selected from —H, (C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl and —(C 2 -C 6 )alkynyl; 
         aa 2  is an amino acid, wherein the amino acid is unsubstituted or substituted with a protecting group or a Linking Unit. 
       
     
     
         3 . The compound of  claim 1  or  2 , wherein at least one of R 1 , R 4 , and R 8  is (C 1 -C 6 )alkyl. 
     
     
         4 .- 11 . (canceled) 
     
     
         12 . The compound of  claim 1  or  2 , wherein at least one of R 1 , R 4 , and R 8  is (C 1 -C 6 )alkyl substituted with (C 3 -C 7 )cycloalkyl. 
     
     
         13 .- 29 . (canceled) 
     
     
         30 . The compound of  claim 1  or  2 , wherein each of R 2 , R 3 , R 5 , R 6 , R 7 , R 9 , R 10  and R 11  is independently (C 1 -C 3 )alkyl. 
     
     
         31 . The compound of  claim 1  or  2 , wherein each of X 1 , X 2 , X 3 , X 4 , X 5  and X 6  is independently H or (C 1 -C 6 )alkyl. 
     
     
         32 . (canceled) 
     
     
         33 . The compound of  claim 1  or  2 , wherein one of aa 1  or aa 2  is valine. 
     
     
         34 . The compound of  claim 1  or  2 , wherein one of aa 1  or aa 2  is threonine optionally substituted with a protecting group or a Linking Unit. 
     
     
         35 . The compound of  claim 1  or  2 , wherein one of aa 1  or aa 2  is tyrosine optionally substituted with a protecting group or a Linking Unit. 
     
     
         36 .- 44 . (canceled) 
     
     
         45 . The compound of  claim 1 , wherein the compound has formula (Ia): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         aa 1  is valine, threonine optionally substituted with a protecting group or a Linking Unit, or tyrosine optionally substituted with a protecting group or a Linking Unit. 
       
     
     
         46 .- 57 . (canceled) 
     
     
         58 . The compound of  claim 1 , wherein the compound has formula (Ib): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         aa 1  is valine, threonine optionally substituted with a protecting group or a Linking Unit, or tyrosine optionally substituted with a protecting group or a Linking Unit. 
       
     
     
         59 .- 70 . (canceled) 
     
     
         71 . The compound of  claim 1 , wherein the compound has formula (Ic): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         aa 1  is valine, threonine optionally substituted with a protecting group or a Linking Unit, or tyrosine optionally substituted with a protecting group or a Linking Unit. 
       
     
     
         72 .- 83 . (canceled) 
     
     
         84 . The compound of  claim 2 , wherein the compound has formula (IIa): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         aa 2  is valine, threonine optionally substituted with a protecting group or a Linking Unit, or tyrosine optionally substituted with a protecting group or a Linking Unit. 
       
     
     
         85 .- 96 . (canceled) 
     
     
         97 . The compound of  claim 1 , wherein the compound has formula (IIb): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         aa 2  is valine, threonine optionally substituted with a protecting group or a Linking Unit, or tyrosine optionally substituted with a protecting group or a Linking Unit. 
       
     
     
         98 .- 109 . (canceled) 
     
     
         110 . The compound of  claim 2 , wherein the compound has formula (IIc): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         aa 2  is valine, threonine optionally substituted with a protecting group or a Linking Unit, or tyrosine optionally substituted with a protecting group or a Linking Unit. 
       
     
     
         111 .- 122 . (canceled) 
     
     
         123 . A compound selected from the group consisting of:
 Cyclo-[Val-D-Hica-D-Val-Lac] 3 ;   Cyclo-{Thr-D-Hica-D-Val-Lac-[Val-D-Hica-D-Val-Lac] 2 };   Cyclo-{Tyr-D-Hica-D-Val-Lac-[Val-D-Hica-D-Val-Lac] 2 };   Cyclo-[Val-D-Hcha-D-Val-Lac] 3 ;   Cyclo-{Thr-D-Hcha-D-Val-Lac-[Val-D-Hcha-D-Val-Lac] 2 };   Cyclo-{Tyr-D-Hcha-D-Val-Lac-[Val-D-Hcha-D-Val-Lac] 2 };   Cyclo-{Thr-D-Hcha-D-Val-Lac-[Val-D-Hica-D-Val-Lac] 2 };   Cyclo-{Tyr-D-Hcha-D-Val-Lac-[Val-D-Hica-D-Val-Lac]2}; and   
       pharmaceutically acceptable salts thereof. 
     
     
         124 . A compound, which is 
       
         
           
           
               
               
           
         
       
       and a pharmaceutically acceptable salt thereof. 
     
     
         125 . A pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         126 .- 127 . (canceled) 
     
     
         128 . A method for killing or inhibiting the proliferation of tumor cells or cancer cells comprising treating tumor cells or cancer cells with a compound of  claim 1  in an amount effective to kill or inhibit the proliferation of the tumor cells or cancer cells. 
     
     
         129 . A method for treating cancer in a patient in need thereof comprising administering to the patient a compound of  claim 1 , wherein the compound is administered in an amount effective to treat cancer. 
     
     
         130 . (canceled) 
     
     
         131 . A method of determining inhibition of cellular proliferation by a compound, comprising contacting cells in a cell culture medium with the compound of  claim 1  and measuring the cytotoxic activity of the compound, whereby proliferation of the cells is inhibited. 
     
     
         132 . A method of inhibiting the growth of tumor cells that overexpress a tumor-associated antigen comprising administering to a patient the compound of  claim 1  conjugated to an antibody that is specific for said tumor-associated antigen, and optionally a second therapeutic agent wherein the compound and said second therapeutic agent are each administered in amounts effective to inhibit growth of tumor cells in the patient. 
     
     
         133 .- 139 . (canceled) 
     
     
         140 . A method of inhibiting bacterial or fungal growth in a sample, comprising exposing the sample to a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         141 . A method for treating a bacterial or fungal infection in a patient in need thereof comprising administering to the patient a compound of  claim 1 , wherein the compound is administered in an amount effective to treat the infection. 
     
     
         142 .- 145 . (canceled)