Maytansinoid-based drug delivery systems

Abstract

The present subject matter provides for albumin-binding prodrugs, maytansinoid-based compounds, and uses thereof.

1 . A compound having the structure of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof, 
         wherein: 
         R 1  is selected from —H and C 1 -C 4  alkyl; 
         Spacer is selected from: 
       
       
         
           
           
               
               
           
         
         V is absent or selected from —CH 2 —, —O— and —NR 3 —, wherein R 3  is —H or C 1 -C 4  alkyl; each R 2  is independently selected from —H, halogen (e.g., —F, —Cl, —Br or —I) and C 1 -C 4  alkyl or two R 2 s taken together form a C 3 -C 6 , cycloalkyl; 
         n is 0-3; 
         X is absent or selected from —CH 2 —, —O—, —S—, —Se—, and —NR 4 —, wherein R 4  is —H or C 1 -C 4  alkyl; 
         Y is selected from ═CH— and ═N—; 
         Z 1 , Z 2 , Z 3  and Z 4  are each independently selected from —H, halogen (e.g., —F, —Cl, —Br or —I), —CF 3 , —OCH 3 , —CN, —NO 2 , C 1 -C 4  alkyl and C 2 -C 4  alkoxy; 
         AA is an amino acid selected from glycine, D or L proline, sarcosine, N-ethyl-glycine, D or L alanine, D or L N-methylalanine, β-alanine, N-methyl-β-alanine, α-aminoisobutyric acid, and N-methyl-α-aminoisobutyric acid; 
         R′ is selected from O and 
       
       
         
           
           
               
               
           
         
         Y′ is absent or selected from an optionally substituted C 1 -C 6  alkyl, —NH—C(O)—, and —C(O)—NH—; or Y′ is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
       
       wherein n=0-6;
 R 1′  is absent or selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         wherein M 1  is a pharmaceutically acceptable counter ion (e.g., H + , Na + , K + , Ca 2+ , Mg 2+ , NR 4   + , and NHR 3   + ; wherein R is H or C 1 -C 4  alkyl); 
         R 2′  is optionally substituted C 1 -C 18  alkyl wherein optionally up to six carbon atoms in said C 1 -C 18  alkyl are each independently replaced with —OCH 2 CH 2 —; 
         Z 1′ , Z 2′ , Z 3′  and Z 4′  are each independently selected from —H, halogen (e.g., —F, —Cl, —Br or —I), —CF 3 , —OCH 3 , 
         —CN, —NO 2 , —SO 3 M 2 , and C 1 -C 4  alkyl wherein M 2  is a pharmaceutically acceptable counter ion (e.g., H + , Na + , K + , Ca 2+ , Mg 2+ , NR 4   + , and NHR 3   + ; wherein R is H or C 1 -C 4  alkyl); 
         TBG is a thiol-binding group selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridylthio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group, an optionally substituted acetylene group, and an optionally substituted N-hydroxysuccininide ester group; 
         wherein said TBG is optionally bound to a thiol-bearing macromolecular carrier or thiol-bearing tumor-specific carrier. 
       
     
     
         2 .- 36 . (canceled) 
     
     
         37 . The compound of  claim 1 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate, or isomer thereof. 
       
     
     
         38 . The compound of  claim 37 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, or isomer thereof. 
     
     
         39 . The compound of  claim 37 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, or isomer thereof. 
     
     
         40 . The compound of  claim 37 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, or isomer thereof. 
     
     
         41 . The compound of  claim 37 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, or isomer thereof. 
     
     
         42 . The compound of  claim 37 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, or isomer thereof. 
     
     
         43 . The compound of  claim 37 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, or isomer thereof. 
     
     
         44 . The compound of  claim 37 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, or isomer thereof. 
     
     
         45 . The compound of  claim 37 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, or isomer thereof. 
     
     
         46 . The compound of  claim 37 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, or isomer thereof. 
     
     
         47 . The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, or isomer thereof. 
     
     
         48 . The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, or isomer thereof. 
     
     
         49 . The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, or isomer thereof. 
     
     
         50 . The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, or isomer thereof. 
     
     
         51 . The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, or isomer thereof. 
     
     
         52 . The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, or isomer thereof. 
     
     
         53 . The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, or isomer thereof. 
     
     
         54 . The compound of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, or isomer thereof. 
     
     
         55 . The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, or isomer thereof. 
     
     
         56 . The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, or isomer thereof. 
     
     
         57 . The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, or isomer thereof. 
     
     
         58 . The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, or isomer thereof. 
     
     
         59 . A pharmaceutical composition comprising the compound, of  claim 37 , or pharmaceutically acceptable salt, hydrate, or isomer thereof, and a pharmaceutically acceptable carrier. 
     
     
         60 . A pharmaceutical composition comprising the compound, of any one of claim  claim 47 - 58 , or pharmaceutically acceptable salt, hydrate, or isomer thereof, and a pharmaceutically acceptable carrier. 
     
     
         61 . A method for treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition according to  claim 59 , wherein the cancer is selected from the group consisting of adenocarcinoma, uveal melanoma, acute leukemia, acoustic neuroma, ampullary carcinoma, anal carcinoma, astrocytoma, basalioma, pancreatic cancer, connective tissue tumor, bladder cancer, bronchial carcinoma, non-small cell bronchial carcinoma, breast cancer, Burkitt's lymphoma, corpus carcinoma, CUP syndrome, colon cancer, cancer of the small intestine, ovarian cancer, endometrial carcinoma, gallbladder cancer, gallbladder carcinomas, uterine cancer, cervical cancer, neck, nose and ear tumors, hematological neoplasia, hairy cell leukemia, urethral cancer, skin cancer, gliomas, testicular cancer, Kaposi's sarcoma, laryngeal cancer, bone cancer, colorectal carcinoma, head/neck tumors, colon carcinoma, craniopharyngeoma, liver cancer, leukemia, lung cancer, non-small cell lung cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, stomach cancer, colon cancer, medulloblastoma, melanoma, meningioma, kidney cancer, renal cell carcinomas, oligodendroglioma, esophageal carcinoma, osteolytic carcinomas and osteoplastic carcinomas, osteosarcoma, ovarian carcinoma, pancreatic carcinoma, penile cancer, prostate cancer, tongue cancer, ovary carcinoma, and lymph gland cancer. 
     
     
         62 . A method for treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition according to  claim 60 , wherein the cancer is selected from the group consisting of adenocarcinoma, uveal melanoma, acute leukemia, acoustic neuroma, ampullary carcinoma, anal carcinoma, astrocytoma, basalioma, pancreatic cancer, connective tissue tumor, bladder cancer, bronchial carcinoma, non-small cell bronchial carcinoma, breast cancer, Burkitt's lymphoma, corpus carcinoma, CUP syndrome, colon cancer, cancer of the small intestine, ovarian cancer, endometrial carcinoma, gallbladder cancer, gallbladder carcinomas, uterine cancer, cervical cancer, neck, nose and ear tumors, hematological neoplasia, hairy cell leukemia, urethral cancer, skin cancer, gliomas, testicular cancer, Kaposi's sarcoma, laryngeal cancer, bone cancer, colorectal carcinoma, head/neck tumors, colon carcinoma, craniopharyngeoma, liver cancer, leukemia, lung cancer, non-small cell lung cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, stomach cancer, colon cancer, medulloblastoma, melanoma, meningioma, kidney cancer, renal cell carcinomas, oligodendroglioma, esophageal carcinoma, osteolytic carcinomas and osteoplastic carcinomas, osteosarcoma, ovarian carcinoma, pancreatic carcinoma, penile cancer, prostate cancer, tongue cancer, ovary carcinoma, and lymph gland cancer.