Novel benzodiazepine derivatives

Abstract

The invention relates to novel benzodiazepine derivatives with antiproliferative activity and more specifically to novel benzodiazepines of formula (I) and (II), in which the diazepine ring (B) is fused with a heterocyclic ring (CD), wherein the heterocyclic ring is bicyclic or a compound of formula (III), in which the diazepine ring (B) is fused with a heterocyclic ring (C), wherein the heterocyclic ring is monocyclic. The invention provides cytotoxic dimers of these compounds. The invention also provides conjugates of the monomers and the dimers. The invention further provides compositions and methods useful for inhibiting abnormal cell growth or treating a proliferative disorder in a mammal using the compounds or conjugates of the invention. The invention further relates to methods of using the compounds or conjugates for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, or associated pathological conditions.

1 - 31 . (canceled) 
     
     
         32 . A compound having formula (XII): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 the double line   between N and C represents a single bond or a double bond, provided that when it is a double bond X is absent and Y is —H, and when it is a single bond, X is —H; Y is selected from the group consisting of —OH, —OR, —NR′R″, —SO 3 , and —OSO 3 , wherein R, R′ and R″ are a linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms; 
 one of R 2 , R 3 , R 2 ′ and R 3 ′ is the linking group and the others are —H or —NO 2 ; 
 R 6  is —OR; 
 Z is CH 2 ; 
 A is O or NR 15 ; and 
 R 15  is H, linear, branched or cyclic alkyl having from 1 to 10 carbon atoms, a polyethylene glycol unit (—OCH 2 CH 3 ) n , wherein n is an integer from 1 to 2000. 
 
       
     
     
         33 . The compound of  claim 32 , having formula (XIV): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein
 Y is selected from the group consisting of —OH, —OR, —SO 3 , and —OSO 3 , wherein R is a linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms; 
 nn is 0 or an integer from 1 to 5; and 
 one of R 2 , R 3 , R 2 ′ and R 3 ′ is the linking group and the others are —H or —NO 2 . 
 
       
     
     
         34 . The compound of  claim 32 , wherein one of R 2 , R 3 , R 2 ′, or R 3 ′ is selected from the group consisting of:
 —NR 33 (C═O) p″ (CR 20 R 21 ) m (CR 22 R 23 ) n (OCH 2 CH 2 ) p (CR 40 R 41 ) p″ Y″(CR 24 R 25 ) q (CO) t X″, 
 —NR 33 (C═O) p″ (CR 20 R 21 ) m (CR 26 ═CR 27 ) m′ (CR 22 R 23 ) n (OCH 2 CH 2 ) p (CR 40 R 41 ) p″ Y″(CR 24 R 25 ) q (CO) t X″, 
 —NR 33 (C═O) p″ (CR 20 R 21 ) m (alkynyl) n′ (CR 22 R 23 ) n (OCH 2 CH 2 ) p (CR 40 R 41 ) p″ Y′(CR 24 R 25 ) q (CO) t X″, 
 —NR 33 (C═O) p″ (CR 20 R 21 ) m (piperazino) t′ (CR 22 R 23 ) n (OCH 2 CH 2 ) p (CR 40 R 41 ) p″ Y″(CR 24 R 25 ) q (CO) t X″, 
 —NR 33 (C═O) p″ (CR 20 R 21 ) m (pyrrolo) t′ (CR 22 R 23 ) n (OCH 2 CH 2 ) p (CR 40 R 41 ) p″ Y″(CR 24 R 25 ) q (CO) t X″, and 
 —NR 33 (C═O) p″ (CR 20 R 21 ) m A″ m″ (CR 22 R 23 ) n (OCH 2 CH 2 ) p (CR 40 R 41 ) p″ Y″(CR 24 R 25 ) q (CO) t X″, 
 wherein: 
 m, n, p, q, m′, n′, t′ are integer from 1 to 10, or are optionally 0; 
 m″, n″ and p″ are 0 or 1; 
 X″ is covalently linked to the CBA, and when Y″ is not S—S and t=0, X″ is 
 
       
         
           
           
               
               
           
         
       
       —CH 2 —CO—, or —S—; and when t=1, X″ is —NH—;
 Y″ is absent or is selected from O, S, S—S or NR 32 , wherein R 32  has the same definition as given above for R; 
 A″ is an amino acid selected from glycine, alanine, leucine, valine, lysine, citrulline, glutamate, or a polypeptide containing between 2 to 20 amino acid units; 
 R 20 , R 21 , R 22 , R 23 , R 24 , and R 25  are the same or different and are —H or a linear or branched alkyl having from 1 to 5 carbon atoms; and 
 one of R 40  and R 41  is optionally a negatively or positively charged functional group and the other is —H or an alkyl, alkenyl, alkynyl having 1 to 4 carbon atoms. 
 
     
     
         35 . The compound of  claim 32 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         36 . A conjugate comprising a compound of  claim 32  linked to a cell binding agent. 
     
     
         37 . The conjugate of  claim 36 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein the wavy line represents a linkage to the cell-binding agent. 
       
     
     
         38 . The conjugate of  claim 36 , wherein the cell-binding agent binds to target cells selected from tumor cells, virus infected cells, microorganism infected cells, parasite infected cells, autoimmune cells, activated cells, myeloid cells, activated T-cells, B cells, or melanocytes; cells expressing the CD4, CD6, CD19, CD20, CD22, CD30, CD33, CD37, CD38, CD40, CD44, CD56, EpCAM, CanAg, CALLA, or Her-2 antigens; Her-3 antigens or cells expressing insulin growth factor receptor, epidermal growth factor receptor, and folate receptor. 
     
     
         39 . The conjugate of  claim 38 , wherein the tumor cells are selected from breast cancer cells, prostate cancer cells, ovarian cancer cells, colorectal cancer cells, gastric cancer cells, squamous cancer cells, small-cell lung cancer cells, and testicular cancer cells. 
     
     
         40 . The conjugate of  claim 36 , wherein the cell-binding agent is an antibody, a single chain antibody, an antibody fragment that specifically binds to the target cell, a monoclonal antibody, a single chain monoclonal antibody, or a monoclonal antibody fragment that specifically binds the a target cell, a chimeric antibody, a chimeric antibody fragment that specifically binds to the target cell, a domain antibody, a domain antibody fragment that specifically binds to the target cell, a lymphokine, a hormone, a vitamin, a growth factor, a colony stimulating factor, or a nutrient-transport molecule. 
     
     
         41 . The conjugate of  claim 40 , wherein the antibody is a resurfaced antibody, a resurfaced single chain antibody, or a resurfaced antibody fragment; a monoclonal antibody, a single chain monoclonal antibody, or a monoclonal antibody fragment thereof; a chimeric antibody fragment, a domain antibody, or a domain antibody fragment; a humanized antibody, a humanized single chain antibody, or a humanized antibody fragment. 
     
     
         42 . A pharmaceutical composition comprising the compound of  claim 32 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         43 . The pharmaceutical composition of  claim 42 , further comprising a second compound, which is a chemotherapeutic agent. 
     
     
         44 . A method of treating a cancer in a mammal, comprising administering to said mammal a therapeutically effective amount of the compound of  claim 32 , or a pharmaceutically acceptable salt thereof. 
     
     
         45 . The method of  claim 44 , further comprising administering to said mammal a second compound, which is a chemotherapeutic agent. 
     
     
         46 . The method of  claim 45 , wherein said chemotherapeutic agent is administered to said mammal sequentially.