Biocompatible biodegradable fumagillin analog conjugates

Abstract

Fumagillin analog polymer conjugates, methods of making fumagillin analog polymer conjugates, compositions comprising a polymer conjugate of a fumagillin analog, and methods for treating cancer, or treating angiogenic diseases comprising administering to a subject in need thereof an effective amount of a polymer conjugate of a fumagillin analog, are described. Also described are novel fumagillin analogs, methods of making fumagillin analogs, compositions comprising at least one fumagillin analog, and methods for treating cancer, or treating angiogenic diseases comprising administering to a subject in need thereof an effective amount of a fumagillin analog.

1 .- 24 . (canceled) 
     
     
         25 . A compound of the Formula V: 
       
         
           
           
               
               
           
         
         wherein, 
         X is O, S(═O), optionally substituted CH 2 , or optionally substituted NH; 
         q is 0, 1, or 2; 
         R is (2S,3R)-2-methyl-3-(3-methylbut-2-enyl)oxirane, 2-methylhepta-2,5-diene, (2R,3S)-2-isopentyl-3-methyloxirane, 6-methylhept-2-ene, (Z)-acetaldehyde O-benzyl oxime, C 2 -heterocyclic-C 1 -C 6  alkyl, C 2 -heterocyclic-C 2 -C 6  alkenyl, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -heterocyclic-C 1 -C 6 -alkenyl-COO—C 1 -C 6  alkyl, C 2 -heterocyclic-C 1 -C 6  alkyl-COO—C 1 -C 6 -alkyl, C 1 -C 6  alkyl=N—O—C 1 -C 6  alkyl-aryl, C(O)C 1 -C 6  alkyl, CN, or halogen; 
         R 8  is selected from the group consisting of VI, VII, VIII, IX, X, XI, XII, and XIIA whose formulas are represented below: 
       
       
         
           
           
               
               
           
         
         R′—CO 2 H, optionally substituted —NH 2 —, or —N cyclic imide, NHC(O) (C 1 -C 6  alkyl)-C(O)R″, R′ is meta or para in relation to the —S— atom; and 
         R″ is —OH, —O—C 1 -C 6  alkyl, or —NH 2  optionally acylated through the carboxyl group of an amino acid; 
       
       
         
           
           
               
               
           
         
         wherein R 9  is H or C(O)R 11 ; 
         R 10  is —NH 2 , —NHCH(C 1 -C 6  alkyl)-, —NHC(O) (C 1 -C 6  alkyl), N-cyclized imide; —NH acylated through the carboxyl group of an amino acid, 
         wherein the nitrogen of the amino group of the amino acid is optionally protected, and 
         R 11  is OH, OC 1 -C 6  alkyl, or optionally substituted —NH 2 ; 
       
       
         
           
           
               
               
           
         
         wherein N 12  is H, C 1 -C 6  alkyl, —(C 1 -C 6 )—COOH, —(C 1 -C 6 )—C(O)O—(C 1 -C 6 ), —CH 2 CH 2 O—R 13 , —C(O)(C 1 -C 6  alkyl), an amino acid attached through the carboxyl group of the amino acid; 
         R 13  is —H or an amino acid attached through the carboxyl group of the amino acid, wherein the nitrogen of the amino acid is optionally protected, C(O) (C 1 -C 6  alkyl)-COR″; 
         R″ is —OH, —OC 1 -C 6  alkyl, or —NH 2  optionally acylated through the carboxyl group of an amino acid; 
         [-------] represents an optional methylene bridge (—CH 2 —) between carbons 2 and 5 of the piperazine moiety; and 
         Z′ is a bond, —C 1 -C 6  alkyl, —NHC(O)—, or —NHSO 2 —; 
       
       
         
           
           
               
               
           
         
         wherein R 14  is —H, CO 2 H, —CO 2 (C 1 -C 6  alkyl), —C(O)NH—C 1 -C 6  alkyl-OH, wherein the 0 of —C(O)NH—C 1 -C 6  alkyl-OH is optionally acylated with the carboxyl group of an amino acid; optionally substituted —NH, C 1 -C 6 -alkyl-NH 2 , wherein the NH 2  is optionally substituted; and 
         [-------] represents an optional ethylene bridge (—CH 2 CH 2 —) between carbons 1 and 4 of the cyclohexane moiety; 
       
       
         
           
           
               
               
           
         
         Z′ is a bond, —CH 2 —, —CH 2 —S—, CH 2 CH 2 —, —C(H) (Me)-, NHCH 2 ——NHCH(CH 3 )—, —NHCH 2 CH 2 —; 
         R 15  is H, optionally substituted —NH, —NHC(O) (C 1 -C 6 -alkyl), —N cyclized imide optionally containing a heteroatom within the cyclic structure, —NHC(O)CH 2 OCH 2 C(O)OH, NHC(O)CH(C 1 -C 6  alkyl)-N cyclized imide, —NHC(O)CH(R″)NHC(O)—(C 1 -C 6  alkyl)-C(O)OH, —NHC(O)—(C 1 -C 6  alkyl)-C(O)OH, —C(O)O(C 1 -C 6  alkyl), —C(O)N(H)(C 1 -C 6  alkyl)-OH, or NO 2 ; and 
         R″ or —C 1 -C 6  alkyl; 
       
       
         
           
           
               
               
           
         
         wherein Y′ is C 1 -C 3  alkyl, or NH—C 1 -C 3  alkyl and is attached to positions 1, 2, or 3 of the indole; and 
         R 16  is H, C 1 -C 6  alkyl, —CH 2 COOH, or —CH 2 CH 2 OH, wherein the O of —CH 2 CH 2 OH can be optionally acylated with an amino acid; 
       
       
         
           
           
               
               
           
         
         wherein R″ is —OH, —OC 1 -C 6  alkyl, —NH optionally acylated through the carboxyl group of an amino acid; and 
       
       
         
           
           
               
               
           
         
         wherein Y″ is C(O)N(CH 3 )(OCH 3 ), C(O)OCH 3 , CH 2 Cl, or NHC(O)CH 2 Cl. 
       
     
     
         26 .- 31 . (canceled) 
     
     
         32 . A composition comprising the compound or pharmaceutically acceptable salt of the compound of  claim 25  and a pharmaceutically acceptable carrier. 
     
     
         33 .- 35 . (canceled) 
     
     
         36 . A composition comprising a compound or pharmaceutically acceptable salt of the compound of  claim 25  and a pharmaceutically acceptable carrier. 
     
     
         37 . The composition of  claim 36 , wherein the pharmaceutically acceptable carrier is suitable for injectable administration and the composition comprises an injectable dosage form. 
     
     
         38 . A method of treating cancer, comprising administering to a subject in need thereof a compound or a pharmaceutically acceptable salt of a compound of  claim 25 , in an amount effective to treat the cancer. 
     
     
         39 . The method of  claim 38 , wherein the cancer is selected from the group consisting of anal, astrocytoma, leukemia, lymphoma, head and neck, liver, testicular, cervical, sarcoma, hemangioma, esophageal, eye, laryngeal, mouth, mesothelioma, skin, myeloma, oral, rectal, throat, bladder, breast, uterus, ovary, prostate, lung, colon, pancreas, renal, and gastric. 
     
     
         40 . A method of treating an angiogenic disease, comprising administering to a subject in need thereof a compound or a pharmaceutically acceptable salt of a compound of  claim 25 , in an amount effective to inhibit angiogenesis.