Chitosan covalently linked with small molecule integrin antagonist for targeted delivery

Abstract

The invention relates to the chitosan polymer derivatives of formula I: and pharmaceutically acceptable salts and esters thereof, wherein Y, X 1 , X 4 , R 1 , R 2 , and n are defined in the detailed description and claims. The chitosan polymer derivatives of formula I bind to or associate with alpha-4-beta-1 (α4β1) and alpha-V-beta-3 (αVβ3) integrin dimers and can be used in delivery formulations to deliver drugs, nucleic acids, or other therapeutic compounds to tissues or cells expressing such integrins.

1 . A chitosan polymer derivative of formula I: 
       
         
           
           
               
               
           
         
         wherein the monomers of formula I are covalently linked to each other by a single oxygen atom at positions X 1  and X 4  which represent beta-1-4 linkages, except at the terminal ends of the polymer wherein X 1  and X 4  represent hydroxy of any stereochemistry; and wherein: 
         Y is selected from the group consisting of:
 (1) a moiety of the formula: 
 
       
       
         
           
           
               
               
           
         
         
           
             and 
           
           (2) a moiety of the formula: 
         
       
       
         
           
           
               
               
           
         
         R1 is selected from the group consisting of:
 (1) a moiety of the formula: 
 
       
       
         
           
           
               
               
           
         
         
           
             wherein m is 0 or 1; and 
           
           (2) a moiety of the formula: 
         
       
       
         
           
           
               
               
           
         
         
           
             wherein 
           
         
       
       
         
           
           
               
               
           
         
         
           
             is: 
           
         
       
       
         
           
           
               
               
           
         
         R2 is hydrogen or methyl, and n is 8-25. 
       
     
     
         2 . A chitosan polymer derivative according to  claim 1  wherein Y is: 
       
         
           
           
               
               
           
         
       
     
     
         3 . A chitosan polymer derivative according to  claim 1  wherein Y is: 
       
         
           
           
               
               
           
         
       
     
     
         4 . A chitosan polymer derivative according to any one of  claims 1  to  3  wherein R1 is: 
       
         
           
           
               
               
           
         
       
     
     
         5 . A chitosan polymer derivative according to any one of  claims 1  to  3  wherein R1 is: 
       
         
           
           
               
               
           
         
       
     
     
         6 . A chitosan polymer derivative according to  claim 5  wherein: 
       
         
           
           
               
               
           
         
       
     
     
         7 . A chitosan polymer derivative according to  claim 5  wherein: 
       
         
           
           
               
               
           
         
       
     
     
         8 . A chitosan polymer derivative according to  claim 5  wherein: 
       
         
           
           
               
               
           
         
       
     
     
         9 . A chitosan polymer derivative according to  claim 5  wherein: 
       
         
           
           
               
               
           
         
       
     
     
         10 . A chitosan polymer derivative according to  claim 1  which is:
 Cs(AK)-Pr-S-αvβ3 Ligand 2 (Chitosan Derivative A), 2.5% N-acetyl-chitosan loaded with 0.15% of (S)—N-[4-[3-[3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5- dioxo-2,5-dihydro-pyrrol-1-yl)-propionylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-1-oxopropyl]amino]propoxy]-phenyl]-3-[2-[3-[guanidino]-benzoylamino]-acetylamino]-succinamic acid. 
 
     
     
         11 . A chitosan polymer derivative according to  claim 1  which is:
 Cs(AK)-Pr-S-αvβ3 Ligand 2 (Chitosan Derivative B), 2.5% N-acetyl-chitosan loaded with 0.21% of (S)—N-[4-[3-[3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5- dioxo-2,5-dihydro-pyrrol-1-yl)-propionylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-1-oxopropyl]amino]propoxy]-phenyl]-3-[2-[3-[guanidino]-benzoylamino]-acetylamino]-succinamic acid. 
 
     
     
         12 . A chitosan polymer derivative according to  claim 1  which is:
 Cs(AK)-Pr-S-αvβ3 Ligand 2 (Chitosan Derivative C), 2.5% N-acetyl-chitosan loaded with 0.76% of (S)-[N-[4-[3-[3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5- dioxo-2,5-dihydro-pyrrol-1-yl)-propionylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-1-oxopropyl]amino]propoxy]-phenyl]-3-[2-[3-[guanidino]-benzoylamino]-acetylamino]-succinamic acid. 
 
     
     
         13 . A chitosan polymer derivative according to  claim 1  which is:
 Cs(NM)-Pr-S-αvβ3 Ligand 3 (Chitosan Derivative D), 14% N-acetyl-chitosan loaded with 0.3% of (S)—N-[4-[3-[3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5-dioxo- 2,5-dihydro-pyrrol-1-yl)-propionylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-1-oxopropyl]amino]ethoxy]-phenyl]-3-[2-[3-[guanidino]-benzoylamino]-acetylamino]-succinamic acid. 
 
     
     
         14 . A chitosan polymer derivative according to  claim 1  which is:
 Cs(NM)-Pr-S-αvβ3 Ligand 3 (Chitosan Derivative E), 14% N-acetyl-chitosan loaded with 0.6% of (S)—N-[4-[3-[3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5-dioxo- 2,5-dihydro-pyrrol-1-yl)-propionylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-1-oxopropyl]amino]ethoxy]-phenyl]-3-[2-[3-[guanidino]-benzoylamino]-acetylamino]-succinamic acid. 
 
     
     
         15 . A chitosan polymer derivative according to  claim 1  which is:
 Cs(NM)-Pr-S-αvβ3 Ligand 3 (Chitosan Derivative F), 14% N-acetyl-chitosan loaded with 1.9% of (S)—N-[4-[3-[3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5-dioxo- 2,5-dihydro-pyrrol-1-yl)-propionylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-1-oxopropyl]amino]ethoxy]-phenyl]-3-[2-[3-[guanidino]-benzoylamino]-acetylamino]-succinamic acid. 
 
     
     
         16 . A chitosan polymer derivative according to  claim 1  which is:
 Cs(NM)-Pr-S-αvβ3 Ligand 3 (Chitosan Derivative G), 14% N-acetyl-chitosan loaded with 6% of (S)—N-[4-[3-[3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-propionylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-1-oxopropyl]amino]ethoxy]-phenyl]-3-[2-[3-[guanidino]-benzoylamino]-acetylamino]-succinamic acid. 
 
     
     
         17 . A chitosan polymer derivative according to  claim 1  which is:
 Cs(NM)-Pr-S-αvβ3 Ligand 3 (Chitosan Derivative H), 14% N-acetyl-chitosan loaded with 5.0% of (S)—N-[4-[3-[3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5-dioxo- 2,5-dihydro-pyrrol-1-yl)-propionylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-1-oxopropyl]amino]ethoxy]-phenyl]-3-[2-[3-[guanidino]-benzoylamino]-acetylamino]-succinamic acid. 
 
     
     
         18 . A chitosan polymer derivative according to  claim 1  which is:
 Cs(NM)-Pr-S-VLA 4  Ligand 1 (Chitosan Derivative I), 14% N-acetyl-chitosan derivatized with 20% of (S)-3-[4-(2,6-dichlorobenzoylamino)phenyl]-2-[[[1-[2-[3-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5-dioxo-2,5-dihydropyrrol-1-yl)propionylamino]-ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propionylamino]ethyl]cyclopentyl]carbonyl]amino]propionic acid. 
 
     
     
         19 . A chitosan polymer derivative according to  claim 1  which is:
 Cs(NM)-Pr-S-VLA 4  Ligand 3 (Chitosan Derivative J), 14% N-acetyl-chitosan derivatized with 18% of (S)-2-[4-[(3-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5-Dioxo-2,5-dihydropyrrol-1-yl)propionylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propionylamino)methyl]-2,6-difluorobenzoylamino]-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]propionic acid. 
 
     
     
         20 . A chitosan polymer derivative according to  claim 1  which is:
 Cs(NM)-VLA 4  Ligand 2 Acid (4% Loading) (Chitosan Derivative K), 14% N-acetyl-chitosan derivatized with 4% of N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[1-(S)-1-carboxy-2-[4-(2,6-dichlorobenzoylamino)phenyl]ethylcarbamoyl]cyclopentyl]ethylcarbamoyl]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]succinamic acid. 
 
     
     
         21 . A pharmaceutical composition comprising: a compound according  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . (canceled) 
     
     
         26 . A pharmaceutical composition comprising a compound according to  claim 2  and a pharmaceutically acceptable carrier. 
     
     
         27 . A pharmaceutical composition comprising a compound according to  claim 3  and a pharmaceutically acceptable carrier. 
     
     
         28 . A pharmaceutical composition comprising a compound according to  claim 4  and a pharmaceutically acceptable carrier. 
     
     
         29 . A pharmaceutical composition comprising a compound according to  claim 5  and a pharmaceutically acceptable carrier. 
     
     
         30 . A pharmaceutical composition comprising a compound according to  claim 6  and a pharmaceutically acceptable carrier. 
     
     
         31 . A pharmaceutical composition comprising a compound according to  claim 7  and a pharmaceutically acceptable carrier. 
     
     
         32 . A pharmaceutical composition comprising a compound according to  claim 8  and a pharmaceutically acceptable carrier. 
     
     
         33 . A pharmaceutical composition comprising a compound according to  claim 9  and a pharmaceutically acceptable carrier. 
     
     
         34 . A pharmaceutical composition comprising a compound according to  claim 10 , wherein said compound is
 Cs(AK)-Pr-S-αvβ3 Ligand 2 (Chitosan Derivative A), 2.5% N-acetyl-chitosan loaded with 0.15% of (S)—N-[4-[3-[3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5- dioxo-2,5-dihydro-pyrrol-1-yl)-propionylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-1-oxopropyl]amino]propoxy]-phenyl]-3-[2-[3-[guanidino]-benzoylamino]-acetylamino]-succinamic acid;   Cs(AK)-Pr-S-αvβ3 Ligand 2 (Chitosan Derivative B), 2.5% N-acetyl-chitosan loaded with 0.21% of (S)—N-[4-[3-[3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5- dioxo-2,5-dihydro-pyrrol-1-yl)-propionylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-1-oxopropyl]amino]propoxy]-phenyl]-3-[2-[3-[guanidino]-benzoylamino]-acetylamino]-succinamic acid;   Cs(AK)-Pr-S-αvβ3 Ligand 2 (Chitosan Derivative C), 2.5% N-acetyl-chitosan loaded with 0.76% of (S)—N-[4-[3-[3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5- dioxo-2,5-dihydro-pyrrol-1-yl)-propionylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxyl-1-oxopropyl]amino]propoxy]-phenyl]-3-[2-[3-[guanidino]-benzoylamino]-acetylamino]-succinamic acid.   Cs(NM)-Pr-S-αvβ3 Ligand 3 (Chitosan Derivative D), 14% N-acetyl-chitosan loaded with 0.3% of (S)—N-[4-[3-[3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5-dioxo- 2,5-dihydro-pyrrol-1-yl)-propionylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-1-oxopropyl]ainino]ethoxy]-phenyl]-3-[2-[3-[guanidino]-benzoylamino]-acetylamino]-succinamic acid;   Cs(NM)-Pr-S-αvβ3 Ligand 3 (Chitosan Derivative E), 14% N-acetyl-chitosan loaded with 0.6% of (S)—N-[4-[3-[3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5-dioxo- 2,5-dihydro-pyrrol-1-yl)-propionylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-1-oxopropyl]amino]ethoxy]-phenyl]-3-[2-[3-[guanidino]-benzoylamino]-acetylamino]-succinamic acid;   Cs(NM)-Pr-S-αvβ3 Ligand 3 (Chitosan Derivative F), 14% N-acetyl-chitosan loaded with 1.9% of (S)—N-[4-[3-[3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5-dioxo- 2,5-dihydro-pyrrol-1-yl)-propionylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-1-oxopropyl]amino]ethoxy]-phenyl]-3-[2-[3-[guanidino]-benzoylamino]-acetylamino]-succinamic acid;   Cs(NM)-Pr-S-αvβ3 Ligand 3 (Chitosan Derivative G), 14% N-acetyl-chitosan loaded with 6% of (S)—N-[4-[3-[3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-propionylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-1-oxopropyl]amino]ethoxy]-phenyl]-3-[2-[3-[guanidino]-benzoylamino]-acetylamino]-succinamic acid;   Cs(NM)-Pr-S-αvβ3 Ligand 3 (Chitosan Derivative H), 14% N-acetyl-chitosan loaded with 5.0% of (S)—N-[4-[3-[3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5-dioxo- 2,5-dihydro-pyrrol-1-yl)-propionylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-1-oxopropyl]amino]ethoxy]-phenyl]-3-[2-[3-[guanidino]-benzoylamino]-acetylamino]-succinamic acid;   Cs(NM)-Pr-S-VLA 4  Ligand 1 (Chitosan Derivative I), 14% N-acetyl-chitosan derivatized with 20% of (S)-3-[4-(2,6-dichlorobenzoylamino)phenyl]-2-[[[1-[2-[3-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5-dioxo-2,5-dihydropyrrol-1-yl)propionylamino]-ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propionyl amino]ethyl]cyclopentyl]carbonyl]amino]propionic acid;   Cs(NM)-Pr-S-VLA 4  Ligand 3 (Chitosan Derivative J), 14% N-acetyl-chitosan derivatized with 18% of (S)-2-[4-[(3-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5-Dioxo-2,5-dihydropyrrol-1-yl)propionylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propionylamino)methyl]-2,6-difluorobenzoylamino]-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]propionic acid; or   Cs(NM)-VLA 4  Ligand 2 Acid (4% Loading) (Chitosan Derivative K), 14% N-acetyl-chitosan derivatized with 4% of N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[1-(S)-1-carboxy-2-[4-(2,6-dichlorobenzoylamino)phenyl]ethylcarbamoyl]cyclopentyl]ethylcarbamoyl]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]succinamic acid.   
     
     
         35 . A method for the treatment of inflammation, cancer, or a metabolic disease or condition, said method comprising: administering to a patient in need thereof, a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         36 . A method for the treatment of inflammation, cancer, or a metabolic disease or condition, said method comprising: administering to a patient in need thereof, a therapeutically effective amount of a compound according to  claim 2 . 
     
     
         37 . A method for the treatment of inflammation, cancer, or a metabolic disease or condition, said method comprising: administering to a patient in need thereof, a therapeutically effective amount of a compound according to  claim 3 . 
     
     
         38 . A method for the treatment of inflammation, cancer, or a metabolic disease or condition, said method comprising: administering to a patient in need thereof, a therapeutically effective amount of a compound according to  claim 4 . 
     
     
         39 . A method for the treatment of inflammation, cancer, or a metabolic disease or condition, said method comprising: administering to a patient in need thereof, a therapeutically effective amount of a compound according to  claim 5 . 
     
     
         40 . A method for the treatment of inflammation, cancer, or a metabolic disease or condition, said method comprising: administering to a patient in need thereof, a therapeutically effective amount of a compound according to  claim 6 . 
     
     
         41 . A method for the treatment of inflammation, cancer, or a metabolic disease or condition, said method comprising: administering to a patient in need thereof, a therapeutically effective amount of a compound according to  claim 7 . 
     
     
         42 . A method for the treatment of inflammation, cancer, or a metabolic disease or condition, said method comprising: administering to a patient in need thereof, a therapeutically effective amount of a compound according to  claim 8 . 
     
     
         43 . A method for the treatment of inflammation, cancer, or a metabolic disease or condition, said method comprising: administering to a patient in need thereof, a therapeutically effective amount of a compound according to  claim 9 . 
     
     
         44 . A method for the treatment of inflammation, cancer, or a metabolic disease or condition, said method comprising: administering to a patient in need thereof, a therapeutically effective amount of a compound according to  claim 34 .