Fredericamycin derivatives

Abstract

The invention relates to novel fredericamycin derivatives, to drugs containing said derivatives or the salts thereof, and to the use of the fredericamycin derivatives for treating diseases, especially cancer diseases.

1 . A compound according to the general formula Ia or Ib: 
       
         
           
           
               
               
           
         
         wherein in each 
         R1 means H, C 1 -C 6  alkyl, cycloalkyl, or C 1 -C 4  alkylcycloalkyl, 
         R2 means H, C 1 -C 14  alkyl, C 2 -C 14  alkenyl, aryl, C 1 -C 4  alkylaryl, heteroaryl, C 1 -C 4  alkylheteroaryl, C 2 -C 4  alkenylheteroaryl, cycloalkyl, C 1 -C 4  alkylcycloalkyl, heterocycloalkyl, C 1 -C 4  alkylheterocycloalkyl, C m H 2m+o−p Y p (with m=1 to 6, for o=1, p=1, to 2m+o; for m=2 to 6, o=−1, p=1 to 2m+o; for m=4 to 6, o=−2, p=1 to 2m+o; Y=independently selected from the group consisting of halogen, OH, OR21, NH 2 , NHR21, NR21R22, and SH, SR21), (CH 2 ) r CH 2 NHCOR21, (CH 2 ) r CH 2 OCOR21, (CH 2 ) r CH 2 NHCSR21, (CH 2 ) r CH 2 S(O) n R21, with n=0, 1, 2, (CH 2 ) r CH 2 SCOR21, (CH 2 ) r CH 2 OSO 2 —R21, (CH 2 ) r CHO, (CH 2 ) r CH═NOH, (CH 2 ) r CH(OH)R21, —(CH 2 ) r CH═NOR21, (CH 2 ) r CH═NOCOR21, (CH 2 ) r CH═NOCH 2 CONR21R22, (CH 2 ) r CH═NOCH(CH 3 )CONR21R22, (CH 2 ) r CH═NOC(CH 3 ) 2 CONR21R22, (CH 2 ) r CH═N—NHCO—R23, (CH 2 ) r CH═N—NHC(O)NH—R23, (CH 2 ) r CH═N—NHC(S)NH—R23, (CH 2 ) r CH═N—NHC(NH)NH—R23, (CH 2 ) r CH═N—NHC(NH)—R23, (CH 2 ) r CH═N—NHCO—CH 2 NHCOR21, (CH 2 ) r CH═N—O—CH 2 NHCOR21, (CH 2 ) r CH═N—NHCS—R23, (CH 2 ) r CH═CR24R25 (trans or cis), (CH 2 ) r COOH, (CH 2 ) r COOR21, (CH 2 ) r CONR21R22, —(CH 2 ) r CH═NR21, (CH 2 ) r CH═N—NR21R22, 
       
       
         
           
           
               
               
           
         
       
       and the (CH 2 ) r -chain elongated residue (CH 2 ) r CH═N—N—(C 3 NX′R211R212R213R214) (with X′═NR215, O, S, and R211, R212, R213, R214, R215 being independently H or C 1 -C 6  alkyl), —(CH 2 ) r CH═N—NHSO 2  aryl, or —(CH 2 ) r CH═N—NHSO 2  heteroaryl, with r=0, 1, 2, 3, 4, 5,
 R21, R22 are independently H, C 1 -C 14  alkyl, C 1 -C 14  alkanoyl, C 1 -C 6  alkylhydroxy, C 1 -C 6  alkoxy, C 1 -C 6  alkylamino, C 1 -C 6  alkylamino-C 1 -C 6  alkyl, C 1 -C 6  alkylamino-di-C 1 -C 6 -alkyl, cycloalkyl, C 1 -C 4  alkylcycloalkyl, heterocycloalkyl, C 1 -C 4  alkylheterocycloalkyl, aryl, aryloyl, C 1 -C 4  alkylaryl, heteroaryl, heteroaryloyl, C 1 -C 4  alkylheteroaryl, cycloalkanoyl, C 1 -C 4  alkanoylcycloalkyl, heterocycloalkanoyl, C 1 -C 4  alkanoylheterocycloalkyl, C 1 -C 4  alkanoylaryl, C 1 -C 4  alkanoylheteroaryl, mono- and di-sugar residues linked through a C atom which would carry an OH residue in the sugar, wherein the sugars are independently selected from the group consisting of glucuronic acid and its stereoisomers at all optical atoms, aldopentoses, aldohexoses, including their desoxy compounds (as e.g. glucose, desoxyglucose, ribose, desoxyribose), or R21 and R22, together with the N, form a ring with 4, 5, 6, 7, or 8 members, which may optionally contain still another heteroatom selected from the group N, O, and S, 
 R23 independently of R21, has the same meanings as R21, or CH 2 -pyridinium salts, CH 2 -tri-C 1 -C 6  alkylammonium salts, CONH 2 , CSNH 2 , CN, or CH 2 CN, 
 R24 independently of R21, has the same meanings as R21, or H, CN, COCH 3 , COOH, COOR21, CONR21R22, NH 2 , or NHCOR21, 
 R25 independently of R21, has the same meanings as R21, or H, CN, COCH 3 , COOH, COOR21, CONR21R22, NH 2 , or NHCOR21, 
 R24, R25 together with the N, form a ring with 4, 5, 6, 7, or 8 members, which may optionally contain still another heteroatom selected from the group N, O, and S, 
 R3 means H, F, Cl, Br, I, OH, OR31, NO 2 , NH 2 , NHR31, NR31R32, NHCHO, NHCOR31, NHCOCF 3 , CH 3−m hal m  (with hal=Cl, F, and m=1, 2, 3), or OCOR31, 
 R31, R32 are independently C 1 -C 6  alkyl, or R31 and R32, together with the N, form a ring with 4, 5, 6, 7, or 8 members, which may optionally contain still another heteroatom selected from the group N, O, and S, 
 R5 means H, C 1 -C 20  alkyl, cycloalkyl, C 2 -C 20  alkenyl, C 2 -C 10  alkinyl, C 1 -C 4  alkylcycloalkyl, heterocycloalkyl, C 1 -C 4  alkylheterocycloalkyl, aryl, C 1 -C 4  alkylaryl, heteroaryl, C 1 -C 4  alkylheteroaryl, C m H 2m+o−p Y p  (with m=1 to 6, for o=1, p=1 to 2m+o; for m=2 to 6, o=−1, p=1 to 2m+o; for m=4 to 6, o=−2, p=1 to 2m+o; Y=independently selected from the group consisting of halogen, OH, OR51, NH 2 , NHR51, NR51R52, SH, SR21), (CH 2 ) s CH 2 NHCOR51, (CH 2 ) s CH 2 NHCSR51, (CH 2 ) s CH 2 S(O)nR51, with n=0, 1, 2, (CH 2 ) s CH 2 SCOR51, (CH 2 ) s CH 2 OCOR51, (CH 2 ) s CH 2 OSO 2 —R51, (CH 2 ) s CH(OH)R51, (CH 2 ) s COOH, (CH 2 ) s COOR51, (CH 2 ) s CONR51R52, with s=0, 1, 2, 3, 4, 5, mono- and di-sugar residues linked through a C atom which would carry an OH residue in the sugar, wherein the sugars are independently selected from the group consisting of glucuronic acid and its stereo isomers at all optical atoms, aldopentoses, aldohexoses, including their desoxy compounds (as e.g. glucose, desoxyglucose, ribose, desoxyribose), with the mono-sugar residues such as aldopentoses, aldohexoses, including their desoxy compounds, with R51, R52 which are capable of independently adopting the meaning of R21, R22, 
 R4, R6, R7 independently mean H, C 1 -C 6  alkyl, CO—R41, 
 R41 independently from R21, has the same meanings as R21, 
 X means O, S, NH, N—R8, wherein R8 independently from R5 may adopt the same meaning as R5, or R5 and R8, together with the N, form a ring with 4, 5, 6, 7, or 8 members, which may optionally contain still another heteroatom selected from the group N, O, and S, 
 or X—R5 may together be H, 
 Y means O, S, NR9, wherein R9 may be H or C 1 -C 6  alkyl, 
 as well their stereoisomers, tautomers, and their physiologically tolerable salts or inclusion compounds, wherein the residues for Formula Ia may not concomitantly adopt the following meaning, except in case of cyclodextrin inclusion compounds: R1: H, C 1 -C 6  alkyl, R2: C 1 -C 6  alkyl, C 2 -C 6  alkenyl, R3: H, R4 and R6 identical, and independently H, C 1 -C 6  alkyl, CO—R41, with R41 being C 1 -C 6  alkyl, aryl, and R7 being H, C 1 -C 6  alkyl, Y: O, and for Formula Ib: R1: H, R2: pentyl, 1-pentenyl, 3-pentenyl, 1,3-pentdienyl, R3: H, R4 and R6 being H, and X—R5 being methoxy, Y: O. 
 
     
     
         2 . The compound according to  claim 1 , wherein Formula Ia or Ib adopts the stereochemistry of Formula IIa or IIb 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of Formula Ia, Ib, IIa, IIb according to  claim 2 , wherein R2 has a water solubility that is at least two times higher compared to R2 being CH═CH—CH═CH—CH 3 , with all other residues being maintained. 
     
     
         4 . The compound according to  claim 1 , wherein R3 means F, Cl, Br, I, OH, OR31, NO 2 , NH 2 , NHR31, NR31R32, NHCHO, NHCOR31, NHCOCF 3 , CH 3−m hal m  (with hal=Cl, F, and m=1, 2, 3), or OCOR31. 
     
     
         5 . The compound according to  claim 1 , wherein R3 means (CH 2 ) r CHO, (CH 2 ) r CH═NOH, —(CH 2 ) r CH═NOR21, (CH 2 ) r CH═NOCOR21, (CH 2 ) r CH═NOCH 2 CONR21R22, (CH 2 ) r CH═NOCH(CH 3 )CONR21R22, (CH 2 ) r CH═NOC(CH 3 ) 2 CONR21R22, (CH 2 ) r CH═N—NHCO—R23, (CH 2 ) r CH═N—NHC(O)NH—R23, (CH 2 ) r CH═N—NHC(S)NH—R23, (CH 2 ) r CH═N—NHC(NH)NH—R23, (CH 2 ) r CH═N—NHC(NH)—R23, (CH 2 ) r CH═N—NHCO—CH 2 NHCOR21, (CH 2 ) r CH═N—O—CH 2 NHCOR21, (CH 2 ) r CH═N—NHCS—R23, (CH 2 ) r CH═CR24R25 (trans or cis), (CH 2 ) r CH═NR21, (CH 2 ) r CH═N—NR21R22, 
       
         
           
           
               
               
           
         
       
       and the (CH 2 ) r -chain elongated residue (CH 2 ) r CH═N—N—(C 3 NX′R211R212R213R214) (with X′═NR215, O, S, and R211, R212, R213, R214, R215 being independently H or C 1 -C 6  alkyl), (CH 2 ) r CH═N—NHSO 2  aryl, (CH 2 ) r CH═N—NHSO 2  heteroaryl, with r=0, 1, 2, 3, 4, 5. 
     
     
         6 . The compound according to  claim 1 , wherein X means N or S, or X—R5 is OH. 
     
     
         7 . The compound according to  claim 1 , wherein
 R1 means H, C 1 -C 5  alkyl, cycloalkyl,   R2 means C 1 -C 5  alkyl, C 1 -C 4  alkylaryl, C 2 -C 5  alkenyl, heteroaryl, C 1 -C 4  alkylheteroaryl, CHF 2 , CF 3 , polyol side chain, CH 2 Y (Y═F, Cl, Br, I), CH 2 NH 2 , CH 2 NR21R22, CH 2 NHCOR23, CH 2 NHCSR23, CH 2 SH, CH 2 S(O) n R21, with n=0, 1, 2, CH 2 SCOR21, CH 2 OH, CH 2 OR21, CH 2 OSO 2 —R21, CHO, CH(OR21) 2 , CH(SR21) 2 , CN, CH═NOH, CH═NOR21, CH═NOCOR21, CH═N—NHCO—R32, CH═CR24, R25 (trans or cis), COOH, COOR21, CONR21R22,   —CH═NR21, —CH═N—NR21R22,   
       
         
           
           
               
               
           
         
       
       (with X′═NR215, O, S, and R211, R212, R213, R214, R215 being independently H or C 1 -C 6  alkyl), —CH═N—NHSO 2  aryl, —CH═N—NHSO 2  heteroaryl, or CH═N—NHCO—R23,
 R21, R22 independently mean C 1 -C 6  alkyl, cycloalkyl, aryl, C 1 -C 4  alkylaryl, heteroaryl, or C 1 -C 4  alkylheteroaryl, 
 R23 independently of R21, has the same meanings as R21, or CH 2 -pyridinium salts, or CH 2 -tri-C 1 -C 6  alkylammonium salts, 
 R24 independently of R21, has the same meanings as R21, or H, CN, COCH 3 , COOH, COOR21, CONR21R22, NH 2 , or NHCOR21, 
 R25 independently of R21, has the same meanings as R21, or H, CN, COCH 3 , COOH, COOR21, CONR21R22, NH 2 , or NHCOR21, 
 R24, R25 together mean C 4 -C 8  cycloalkyl, 
 R3 means F, Cl, Br, I, NO 2 , NH 2 , or NHCOR31, 
 R31 independently means C 1 -C 6  alkyl, 
 R5 means H, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, C 1 -C 6  alkenyl, C 1 -C 6  alkinyl, C 1 -C 4  alkylcycloalkyl, heterocycloalkyl, C 1 -C 4  alkylheterocycloalkyl, aryl, C 1 -C 4  alkylaryl, heteroaryl, C 1 -C 4  alkylheteroaryl, C m H 2m+o−p Y p  (with m=1 to 6, for o=1, p=1 to 2m+o; for m=2 to 6, o=−1, p=1 to 2m+o; for m=4 to 6, o=−2, p=1 to 2m+o; Y=independently selected from the group consisting of halogen, OH, OR21, NH 2 , NHR21, NR21R22, SH, SR21), hydroxyalkyl with one or more OH groups, 
 R4, R6, R7 independently mean H, C 1 -C 5  alkyl, or CO—R41, 
 R41 independently from R21, has the same meanings as R21, 
 X means O, S, NH, or N—R8, 
 Y means O, or S. 
 
     
     
         8 . The compound according to  claim 1  in the form of an inclusion compound with cyclodextrin. 
     
     
         9 . Drugs containing compounds according to  claim 1 , a carrier and adjuvants. 
     
     
         10 . Drugs according to  claim 9  in combination with further agents for tumor treatment. 
     
     
         11 . A method of treating a tumor in a patient comprising administering to said patient an effective amount of a compound according to  claim 1 , particularly of those that can be treated by inhibition of the topoisomerases I and/or II, and by which apoptosis is induced. 
     
     
         12 . A method of treating parasites in a patient comprising administering to said patient an effective amount of a compound according to  claim 1 , or a compound in which the following meanings can be concomitantly adopted in case of Formula Ia: R1: H, C 1 -C 6  alkyl, R2: C 1 -C 6  alkyl, C 2 -C 6  alkenyl, R3: H, R4 and R6 identical, and independently H, C 1 -C 6  alkyl, CO—R41, with R41 being C 1 -C 6  alkyl, aryl, and R7 being H, C 1 -C 6  alkyl, and in case of Formula Ib: R1: H, R2: pentyl, 1-pentenyl, 3-pentenyl, 1,3-pentdienyl, R3: H, R4 and R6 being H, and X—R5 being methoxy. 
     
     
         13 . A method of treating immunosuppression in a patient comprising administering to said patient an effective amount of a compound according to  claim 1 , or a compound in which the following meanings can be concomitantly adopted in case of Formula Ia: R1: H, C 1 -C 6  alkyl, R2: C 1 -C 6  alkyl, C 2 -C 6  alkenyl, R3: H, R4 and R6 identical, and independently H, C 1 -C 6  alkyl, CO—R41, with R41 being C 1 -C 6  alkyl, aryl, and R7 being H, C 1 -C 6  alkyl, and in case of Formula Ib: R1: H, R2: pentyl, 1-pentenyl, 3-pentenyl, 1,3-pentdienyl, R3: H, R4 and R6 being H, and X—R5 being methoxy. 
     
     
         14 . A method for treating neurodermitis in a patient comprising administering to said patient an effective amount of a compound according to  claim 1  or a compound in which the following meanings can be concomitantly adopted in case of Formula Ia: R1: H, C 1 -C 6  alkyl, R2: C 1 -C 6  alkyl, C 2 -C 6  alkenyl, R3: H, R4 and R6 identical, and independently H, C 1 -C 6  alkyl, CO—R41, with R41 being C 1 -C 6  alkyl, aryl, and R7 being H, C 1 -C 6  alkyl, and in case of Formula Ib: R1: H, R2: pentyl, 1-pentenyl, 3-pentenyl, 1,3-pentdienyl, R3: H, R4 and R6 being H, and X—R5 being methoxy.