# Patent

## Title
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.

## Background
RELATED APPLICATIONS
This application is a national stage application (under 35 U.S.C. 371) of PCT/EP03/02922 filed Mar. 20, 2003 which claims benefit to German Application Serial No. 102 48 451.1 filed Oct. 17, 2002 and German Application Serial No. 102 13 580.0 filed Mar. 26, 2002.
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, particularly cancer diseases.
Fredericamycin has been isolated 1981 from Streptomyces griseus, and demonstrates anti-cancer activity.
Fredericamycin and several fredericamycin derivatives are known.
In Heterocycles 37 (1994) 1893-1912, J. Am. Chem. Soc. 116 (1994) 9921-9926, J. Am. Chem. Soc. 116 (1994) 11275-11286, J. Am. Chem. Soc. 117 (1995) 11839-11849, JP 2000-072752, and in J. Am. Chem. Soc. 123 (2001), various total syntheses of fredericamycin A have been described, some being enantio-selective.
In U.S. Pat. No. 4,673,768, alkali salts of the fredericamycin A are described. In U.S. Pat. No. 4,584,377, fredericamycin derivatives are described, particularly derivatives acylated in ring E and F. In U.S. Pat. No. 5,166,208, fredericamycin derivatives are described as well, particularly derivatives carrying thio and amino substituents in ring F. The derivatives are generated semi-synthetically or fully synthetically.
Surprisingly it was found that fredericamycin derivatives, especially those derivatized in ring A, represent potent drugs. Also, a possibility was found to introduce such residues in ring A semi-synthetically, with which the water solubility and/or the biological effect, the spectrum of action in comparison with fredericamycin, can be significantly increased. Furthermore, an alternative method was found to make fredericamycin and its derivatives water-soluble by generating cyclodextrin inclusion compounds.
The invention relates to novel fredericamycin derivatives with the general Formula Ia or Ib:




wherein in each,

    R1 means H, C1-C6 alkyl, cycloalkyl, C1-C4 alkylcycloalkyl,
    R2 means H, C1-C14 alkyl, C2-C14 alkenyl, aryl, C1-C4 alkylaryl, heteroaryl, C1-C4 alkyl heteroaryl, C2-C4 alkenylheteroaryl, cycloalkyl, C1-C4 alkylcycloalkyl, heterocycloalkyl, C1-C4 alkylheterocycloalkyl, CmH2m+o−pY′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, NH2, NHR21, NR21R22, SH, SR21), (CH2)rCH2NHCOR21, (CH2)rCH2OCOR21, (CH2)rCH2NHCSR21, (CH2)rCH2S(O)nR21, with n=0, 1, 2, (CH2)rCH2SCOR21, (CH2)rCH2OSO2—R21, (CH2)rCHO, (CH2)rCH═NOH, (CH2)rCH(OH)R21, —(CH2)rCH═NOR21, (CH2)rCH═NOCOR21, (CH2)rCH═NOCH2CONR21R22, (CH2)rCH═NOCH(CH3)CONR21R22, —(CH2)rCH═NOC(CH3)2CONR21R22, (CH2)rCH═N—NHCO—R23, (CH2)rCH═N—NHC(O)NH—R23, (CH2)rCH═N—NHC(S)NH—R23, (CH2)rCH═N—NHC(NH)NH—R23, (CH2)rCH═N—NHC(NH)—R23, (CH2)1CH═N—NHCO—CH2NHCOR21, (CH2)rCH═N—O—CH2NHCOR21, (CH2)rCH═N—NHCS—R23, (CH2)rCH═CR24R25 (trans or cis), (CH2)rCOOH, (CH2)rCOOR21, (CH2)rCONR21R22, —(CH2)rCH═NR21, (CH2)rCH═N—NR21R22,






and the (CH2)r-chain elongated residue (CH2)rCH═N—N—(C3NX′R211R212R213R214) (with X′═NR215, O, S, and R211, R212, R213, R214, R215 being independently H or C1-C6 alkyl), —(CH2)rCH═N—NHSO2 aryl, —(CH2)rCH═N—NHSO2 heteroaryl, with r=0, 1, 2, 3, 4, 5, preferably 0,

    R21, R22 are independently H, C1-C14 alkyl, C1-C14 alkanoyl, C1-C6 alkylhydroxy, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylamino-C1-C6 alkyl, C1-C6 alkylamino-di-C1-C6 alkyl, cycloalkyl, C1-C4 alkylcycloalkyl, heterocycloalkyl, C1-C4 alkylheterocycloalkyl, aryl, aryloyl, C1-C4 alkylaryl, heteroaryl, heteroaryloyl, C1-C4 alkylheteroaryl, cycloalkanoyl, C1-C4 alkanoylcycloalkyl, heterocycloalkanoyl, C1-C4 alkanoylheterocycloalkyl, C1-C4 alkanoylaryl, C1-C4 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 stereo isomers 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, S,
    R23 independently of R21, has the same meanings as R21, or CH2-pyridinium salts, CH2-tri-C1-C6 alkylammonium salts, CONH2, CSNH2, CN, CH2CN,
    R24 independently of R21, has the same meanings as R21, or H, CN, COCH3, COOH, COOR21, CONR21R22, NH2, NHCOR21,
    R25 independently of R21, has the same meanings as R21, or H, CN, COCH3, COOH, COOR21, CONR21R22, NH2, 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, S,
    R3 means H, F, Cl, Br, I, OH, OR31, NO2, NH2, NHR31, NR31R32, NHCHO, NHCOR31, NHCOCF3, CH3-mhalm (with hal=Cl, F, particularly F, and m=1, 2, 3), OCOR31,
    R31, R32 are independently C1-C6 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, S,
    R5 means H, C1-C20 alkyl, cycloalkyl, C2-C20 alkenyl, C2-C10 alkinyl, C1-C4 alkyl cycloalkyl, heterocycloalkyl, C1-C4 alkyl heterocycloalkyl, aryl, C1-C4 alkylaryl, heteroaryl, C1-C4 alkylheteroaryl, CmH2m+o−pY′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, NH2, NHR51, NR51R52, SH, SR21), (CH2)rCH2NHCOR51, (CH2)rCH2NHCSR51, (CH2)rCH2S(O)nR51, with n=0, 1, 2, (CH2)rCH2SCOR51, (CH2)rCH2OCOR51, (CH2)rCH2OSO2—R51, (CH2)rCH(OH)R51, (CH2)rCOOH, (CH2)rCOOR51, (CH2)rCONR51R52, with s=0, 1, 2, 3, 4, 5, preferably 0, 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 (as e.g. glucose, desoxyglucose, ribose, desoxyribose) being preferred, with R51, R52 which are capable of independently adopting the meaning of R21, R22,
    R4, R6, R7 independently mean H, C1-C6 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, S,
    or X—R5 may together be H,
    Y means O, S, NR9, wherein R9 may be H or C1-C6 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, C1-C6 alkyl, R2: C1-C6 alkyl, C2-C6 alkenyl, R3: H, R4 and R6 identical, and independently H, C1-C6 alkyl, CO—R41, with R41 being C1-C6 alkyl, aryl, and R7 being H, C1-C6 alkyl, Y: 0, 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. Preferably, the substituents do not concomitantly adopt the following meaning: R1, R3: H, R2: H, alkyl, hydroxyalkyl, particularly monohydroxyalkyl, alkoxyalkyl, CF3, (CH2)rCOOH, CHO, CONH2, (CH2)rCH2NHCO alkyl, (CH2)rCH2OCO alkyl, (CH2)rCH2NHCS alkyl, CH═NOH, CH═NO alkyl, aryl, alkylaryl, alkylheteroaryl, alkenyl, hydroxyalkenyl, particularly monohydroxyalkenyl, R4, R6, R7: H, alkyl, X—R5: H, R5: H, alkyl, aryl.



Preferred are compounds of Formula IIa or IIb




wherein the meaning of the residues R1-R41, X is as described above, their tautomers and their physiologically tolerable salts or inclusion compounds, wherein the residues for Formula Ia may not concomitantly adopt the following meaning, except in the case of cyclodextrin inclusion compounds: R1: H, C1-C6 alkyl, R2: C1-C6 alkyl, C2-C6 alkenyl, R3: H, R4 and R6 identical, and independently H, C1-C6 alkyl, CO—R41, with R41 being C1-C6 alkyl, aryl, and R7 being H, C1-C6 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.

The invention further relates to compounds of Formula Ia, Ib, IIa or IIb, in which the residues R, except for R2, have the above described meanings, and the water solubility of R2 is at least two times higher, preferably at least five timer higher, more preferred at least ten times higher, especially preferred at least fifty time higher, particularly one hundred times higher, or even five hundred times higher than of R2 being CH═CH—CH═CH—CH3, when all other residues are maintained. The increase in the water solubility is achieved e.g. by introduction of groups which can form additional hydrogen bonds, and/or are polar, and/or are ionic. A key intermediate are compounds with an aldehyde function in R2.
For R2 preferred is also the group of the residues CmH2m+o−pY′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 of halogen, OH, OR21, NH2, NHR21, NR21R22, SH, SR21), (CH2)rCH2NHCOR21, (CH2)rCH2OCOR21, (CH2)rCH2NHCSR21, (CH2)rCH2S(O)nR21, with n=0, 1, 2, (CH2)rCH2SCOR21, (CH2)rCH2OSO2—R21, (CH2)rCH(OH)R21, (CH2)rCOOH, (CH2)rCOOR21, (CH2)rCONR21R22. Still particularly preferred is the group of the aldehyde-derived residues (CH2)rCHO, (CH2)rCH═NOH, —(CH2)rCH═NOR21, (CH2)rCH═NOCOR21, (CH2)rCH═NOCH2CONR21R22, (CH2)rCH═N—NHCO—R23, (CH2)rCH═N—NHC(O)NH—R23, (CH2)1CH═N—NHC(S)NH—R23, (CH2)rCH═N—NHC(NH)NH—R23, (CH2)rCH═N—NHC(NH)—R23, (CH2)rCH═N—NHCO—CH2NHCOR21, (CH2)rCH═N—O—CH2NHCOR21, (CH2)rCH═N—NHCS—R23, (CH2)rCH═CR24R25 (trans or cis), (CH2)rCH═NR21, (CH2)rCH═N—NR21R22,




and the (CH2)r-chain elongated residue (CH2)rCH═N—N—(C3NX′R211R212R213R214) (with X′═NR215, O, S, and R211, R212, R213, R214, R215 being independently H or C1-C6 alkyl), —(CH2)rCH═N—NHSO2 aryl, (CH2)rCH═N—NHSO2 heteroaryl, (CH2)rCH═CH heteroaryl, with r=0, 1, 2, 3, 4, 5, preferably 0.

From the aldehydes and thereof derived compounds, such are preferred in which at least R1 or R3 are not H, if R4 to R7 are H or alkyl.
Preferred residues in R2 are further heteroaryl, cycloaryl, alkylcycloalkyl, heterocycloalkyl, C1-C4 alkyl heterocycloalkyl, CmH2m+o−pY′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 of halogen, OH, OR21, NH2, NHR21, NR21R22, SH, SR21), CH2NHCOR21, CH2NHCSR21, CH2S(O)nR21, with n=0, 1, 2, CH2SCOR21, CH2OSO2—R21, CH(OH)R21, CH═NOCOR21, —CH═NOCH2CONR21R22, —CH═NOCH(CH3)—CONR21R22, CH═NOC(CH3)2CONR11R22, CH═N—NHCO—R23, —CH═N—NHCO—CH2NHCOR21, CH═N—O—CH2NHCOR21, —CH═N—NHCS—R23, CH═CR24R25 (trans or cis), CONR21R22, —CH═NR21, —CH═N—NR21R22,




(with X′═NR215, O, S, and R211, R212, R213, R214, R215 being independently H or C1-C6 alkyl), CH═N—NHSO2 aryl, H═N—NHSO2 heteroaryl.

Furthermore, compounds as described above are preferred, in which R3 means F, Cl, Br, I, OH, OR31, NO2, NH2, NHR31, NR31R32, NHCHO, NHCOR31, NHCOCF3, CH3-mhalm (with hal=Cl, F, particularly F, and m=1, 2, 3), OCOR31, with the above described meanings for R31, R32.
Also preferred are compounds as described above, in which X means N or S, especially when R3 is H or halogen, and/or R2 is alkenyl, particularly butadienyl or 1,3-pentdienyl.
Also preferred are compounds as described above, in which X—R5 is OH, and particularly their salts, and preferred in compounds of Formula Ia or Ia, since this acidic OH group may easily be deprotonized, which increases the water solubility and/or the biological efficacy.
Furthermore preferred are still compounds as described above, wherein the residues R preferably independently adopt one or more of the following meanings:

    R1 means H, C1-C5 alkyl, cycloalkyl, especially H,
    R2 means C1-C5 alkyl, C1-C4 alkylaryl, C2-C5 alkenyl, heteroaryl, C1-C4 alkylheteroaryl, C2-C4 alkenylheteraryl, CHF2, CF3, polyol side chain, particularly CHOH—CHOH—CHOH—CHOH—CH3, CHOH—CHOH—CH═CH—CH3, CH═CH—CHOH—CHOH—CH3, CH2Y′ (Y′═F, Cl, Br, I), CH2NH2, CH2NR21R22, CH2NHCOR23, CH2NHCSR23, CH2SH, CH2S(O)nR21, with n=0, 1, 2, CH2SCOR21, particularly CH2OH, CH2OR21, CH2OSO2—R21, particularly CHO, CH(OR21)2, CH(SR21)2, CN, CH═NOH, CH═NOR21, CH═NOCOR21, CH═N—NHCO—R32, CH═CR24, R25 (trans or cis), particularly COOH (particularly their physiologically tolerable salts), COOR21, CONR21R22, —CH═NR21, —CH═N—NR21R22,






(with X′═NR215, O, S, and R211, R212, R213, R214, R215 being independently H or C1-C6 alkyl), —CH═N—NHSO2 aryl, —CH═N—NHSO2 heteroaryl, CH═N—NHCO—R23,

    R21, R22 independently mean C1-C6 alkyl, cycloalkyl, aryl, C1-C4 alkylaryl, heteroaryl, C1-C4 alkylheteroaryl,
    R23 independently of R21, has the same meanings as R21, or CH2-pyridinium salts, CH2-tri-C1-C6 alkylammonium salts,
    R24 independently of R21, has the same meanings as R21, or H, CN, COCH3, COOH, COOR21, CONR21R22, NH2, NHCOR21,
    R25 independently of R21, has the same meanings as R21, or H, CN, COCH3, COOH, COOR21, CONR21R22, NH2, NHCOR21,
    R24, R25 together mean C4-C8 cycloalkyl,
    R3 means F, Cl, Br, I, NO2, NH2, NHCOR31,
    R31 independently means C1-C6 alkyl,
    R5 means H, C1-C6 alkyl, particularly C1-C3 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C1-C6 alkenyl, C1-C6 alkinyls, C1-C4 alkylcycloalkyl, heterocycloalkyl, C1-C4 alkylheterocycloalkyl, aryl, C1-C4 alkylaryl, heteroaryl, C1-C4 alkylheteroaryl, CmH2m+o−pY′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, NH2, NHR21, NR21R22, SH, SR21), particularly preferred is hydroxyalkyl with one or more OH groups,
    R4, R6, R7 independently means H, C1-C5 alkyl, CO—R41,
    R41 independently from R21, has the same meanings as R21,
    X means O, S, NH, N—R8,
    Y means O, S, NH,

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, C1-C6 alkyl, R2: C1-C6 alkyl, C2-C6 alkenyl, R3: H, R4 and R6 are identical, and independently are H, C1-C6 alkyl, CO—R41, with R41 being C1-C6 alkyl, aryl, and R7 being H, C1-C6 alkyl, 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.

    O, S, particularly O, are preferred for Y.
    O, NH, N—R8 are preferred for X.
    H, methyl, ethyl, propyl, particularly methyl, are preferred for R5.
    H, methyl, ethyl, propyl, particularly methyl, are preferred for R8.
    OCH3, NH2, N(CH3)2 are preferred for XR5.


For R2 also preferred is the residue —CHOHCHOHCHOHCHOHCH3.
Furthermore, the following residues are preferred for R2: —CHCH-2-methyl-4-thiazyl, particularly




wherein R′′ particularly is alkyl or NHCO alkyl, CH═NOR21, with R21 being methyl, ethyl, n-propyl, isopropyl, n-butyl, n-hexyl, benzyl, halogen benzyl, particularly fluorobenzyl and chlorobenzyl, —CH2CH2 morpholinyl.

Especially preferred are the compounds, the stereo isomers, tautomers, and physiologically tolerable salts or inclusion compounds of which, selected from the group consisting of the compounds of the examples and the compounds, demonstrate combinations of the various substituents of the examples.
Particularly preferred for R3 is H, F, Cl, Br, J, particularly F, Cl, Br, J.
Particularly preferred for R2 is C1-C8 alkyl, C2-C8 alkenyl, CH═NOR1, with R21 being C1-C8 alkyl, C1-C8 alkenyl, aryl or heteroaryl, C1-C2 alkylaryl, particularly benzyl, C1-C2 alkylheteroaryl, wherein aryl or heteroaryl in particular have only one ring system which may be substituted once or twice with a substituent such as halogen, methyl, CF3, OH, OMe.
Particularly preferred are derivatives of fredericamycin A in which only the above indicated, particularly preferred meanings of R2 and/or R3 are realized.
The invention furthermore relates to drugs containing the above compounds of Formula I or II together with the usual carriers and adjuvants.
Also preferred are the above mentioned drugs in combination with other agents for cancer treatment.
These compounds according to the invention are used for preparation of drugs for treatment of cancers, particularly such that may be treated by inhibition of the topoisomerases I and/or II. Cancers that can be treated with the substances according to the invention are e.g. leukemia, lung cancer, melanomas, uterus tumors, prostate tumors and colon tumors.
Also, fredericamycin A and its derivatives act against an unknown target in the cell cycle leading to apoptosis in tumor cells. Furthermore, the compounds according to the invention, and compounds which have concomitantly adopted the following meanings in Formula Ia: R1: H, C1-C6 alkyl, R2: C1-C6 alkyl, C2-C6 alkenyl, R3: H, R4 and R6 identically and independently H, C1-C6 alkyl, CO—R41, with R41 being C1-C6 alkyl, aryl, and R7 being H, C1-C6 alkyl, and in 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, are used for preparation of drugs for treatment of neurodermitis, parasites and for immunosuppression.
The invention also relates to a method for preparation of fredericamycin derivatives in which R2 as intermediate is —CHOHCHOHCHOHCHOHCH3. These compounds are preferably transformed into aldehydes for further derivatization.
In the description and the claims, the substituents are described by the following definitions:
The term “alkyl” by itself or as part of another substituent means a linear or branched alkyl chain radical of the respectively indicated length, in which optionally a CH2 group may be substituted by a carbonyl function. Thus, C1-4 alkyl may be methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl, 2-butyl, C1-6 alkyl, e.g. C1-4 alkyl, pentyl, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 4-methyl-1-pentyl, or 3,3-dimethylbutyl.
The term “C1-C6 alkylhydroxy” by itself or as part of another substituent means a linear or branched alkyl chain radical of the respectively indicated length which may be saturated or unsaturated, and which carries an OH group, e.g. hydroxymethyl, hydroxymethyl, 1-hydroxypropyl, 2-hydroxypropyl.
The term “alkenyl” by itself or as part of another substituent means a linear or branched alkyl chain radical with one or more C═C double bonds of the respectively indicated length, several double bonds being preferably conjugated. Thus, C2-6 alkenyl may for example be ethenyl, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 1,3-butdienyl, 2,4-butdienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1,3-pentdienyl, 2,4-pentdienyl, 1,4-pentdienyl, 1-hexenyl, 2-hexenyl, 1,3-hediexyl, 4-methyl-1-pentenyl, or 3,3-dimethylbutenyl.
The term “alkinyl” by itself or as part of another substituent means a linear or branched alkyl chain radical with one or more C—C triple bonds of the respectively indicated length. Thus, C2-6 alkinyl may for example be ethinyl, 1-propinyl, 2-propinyl, 2-methyl-2-propinyl, 2-methyl-1-propinyl, 1-butinyl, 2-butinyl, 1,3-butdiinyl, 2,4-butdiinyl, 1-pentinyl, 2-pentinyl, 3-pentinyl, 1-hexinyl, 2-hexinyl, 4-methyl-1-pentinyl, or 3,3-dimethylbutinyl.
The term “halogen” stands for fluorine, chlorine, bromine, iodine, preferably bromine and chlorine.
The term “NR21R22” preferably stands for a dialkylamino group, wherein the two alkyl groups together with the N can form a ring with 5 or 6 members with optionally one more heteroatom N or O.
The term “cycloalkyl” by itself or as part of another Substituent comprises unsaturated (mono or poly, preferably mono) or saturated, cyclic hydrocarbon groups with 3 to 10 C atoms, preferably 3 to 8 C atoms, such as e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohex-2-enyl, cyclohex-3-enyl, cyclohex-2,4-dienyl, 4-methylcyclohexyl, 3-methylcyclohexyl, cycloheptyl or cyclooctyl. Saturated cycloalkyls are preferred. The cycloalkyls may be substituted with up to 3 substituents, preferably with up to 1 substituent, wherein the substituents independently can have the meaning C1-C6 alkyl, OH, NO2, CN, CF3, OR11, SH, SR11, C1-C6 alkylhydroxy, C1-C6 alkyl-OR11, COOH, COOR11, NH2, NHR11, NR11R12, halogen, aryl, C1-C4 alkylaryl, heteroaryl, C1-C4 heteroalkylaryl, wherein the residues R11 and R12 independently can mean C1-C10 alkyl, cycloalkyl, C1-C4 alkylcycloalkyl.
The term “heterocycloalkyl” by itself or as part of another substituent includes cycloalkyl groups, wherein up to two CH2 groups may be substituted by oxygen, sulfur or nitrogen atoms, and one or two other CH2 groups may be substituted by one or two carbonyl function(s), carbothionyl function(s), or a carbonyl function and a carbothionyl function, for example pyrrolidine, piperidine, morpholine or




The heterocycloalkyls may be substituted as with the cycloalkyls.
The term “aryl” by itself or as part of another substituent includes aromatic ring systems with up to 3 rings, in which at least 1 ring system is aromatic, and those with up to 3 substituents, preferably up to 1 substituent, wherein the substituents independently can have the meaning C1-C6 alkyl, OH, NO2, CN, CF3, OR11, SH, SR11, C1-C6 alkylhydroxy, C1-C6 alkyl-OR11, COOH, COOR11, NH2, NHR11, NR11R12, halogen, wherein the residues R11 and R12 independently can mean C1-C10 alkyl, cycloalkyl, C1-C4 alkylcycloalkyl, or R11 and R12, together with the N, form a ring with 4, 5, 6, 7 or 8 members optionally containing still another heteroatom selected from the group N, O, S.
Apart from phenyl and 1-naphthyl and 2-naphthyl, preferred aryls are:




The term “heteroaryl” by itself or as part of another substituent includes aromatic ring systems with up to 3 rings and with up to 3 identical or different heteroatoms N, S, O, in which at least 1 ring system is aromatic, and those with up to 3 substituents, preferably up to 1 substituent, wherein the substituents independently can have the meaning C1-C6 alkyl, OH, NO2, CN, CF3, OR11, SH, SR11, C1-C6 alkylhydroxy, C1-C6 alkyl-OR11, COOH, COOR11, NH2, NHCOR11, NHR11, NR11R12, halogen, or phenyl, wherein the residues R11 and R12 independently can have the above indicated meanings.
Preferred heteroaryls are:




The term “ring system” generally refers to rings with 3, 4, 5, 6, 7, 8, 9, or 10 members. Preferred are rings with 5 and 6 members. Furthermore, ring systems with one or 2 annealed rings are preferred.
The compounds of Formula I may be present as such, or, if they contain acidic or basic groups, in the form of their salts with physiologically tolerable bases or acids. Examples for such acids are: hydrochloric acid, citric acid, trifluoracetic acid, tartaric acid, lactic acid, phosphoric acid, methane sulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid, succinic acid, hydroxysuccinic acid, sulfuric acid, glutaric acid, aspartic acid, pyruvic acid, benzoic acid, glucuronic acid, oxalic acid, ascorbic acid, and acetylglycine. Examples for bases are alkali ions, preferably Na, K, particularly preferred the tri-potassium and tri-sodium salts, alkaline earth ions, preferably C, Mg, ammonium ions.
The compounds according to the invention may be administered orally in the usual way. The application may also be i.v., i.m., with vapors, or sprays through the nasopharynx.
The dosage depends on age, condition and weight of the patient as well as on the type of application. Usually, the daily dose of the active ingredient per person is between 0.1 μg/kg and 1 g/kg orally. This dosage may be given as 2 to 4 split dosages, or once per day as a slow release form.
The novel compounds may be used in the usual solid or liquid pharmaceutical application forms, e.g. as tablets, film tablets, capsules, powder, granules, coated tablets, solutions, or sprays. These are produced in the usual way. The agents can be processed with the usual pharmaceutical adjuvants such as tablet binders, fillers, preservatives, disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardation agents, antioxidants, and/or propellants (see H. Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). Usually, the so obtained application forms contain the active ingredient in amounts of 0.1 to 99 percent per weight.
Experimental Part
Fredericamycin A can be prepared by fermentation or fully synthetically according to the known methods. The reduced forms of the Formulas Ib and IIb can be obtained from the appropriate compounds of Formulas Ia and Ia using mild reducing agents.
Preparation of the Substances
For synthesis of water soluble fredericamycin derivatives, fredericamycin (1) was first hydroxylized with osmium(IV)oxide at the diene side chain. The resulting compound (2) shows significantly higher water solubility compared to the original compound fredericamycin (1). In order to further increase the water solubility, (2) was transformed into the tri-potassium salt (3) (see diagram 1).




The fredericamycin tetrol (2) serves, among others, as an important intermediate for the synthesis of other fredericamycin derivatives with increased solubility and/or better action profile. By iodate cleavage with sodium periodate or carrier-bound periodate, the tetrol side chain may be degraded with very high yields to fredericamycin aldehyde (4) (see diagram 2).




The fredericamycin aldehyde (4) can be reacted with acylhydrazones, hydroxylamine, and O-alkylhydroxylamine to the appropriate hydrazone (see diagram 3), or oxime and oximether (see diagram 4). The reaction can be performed at room temperature in solvents such as DMF or pyridine, and is finished after a few minutes to hours.
Synthesis of Hydrazones














TABLE 1





Example/





compound
R
m/e
λmax(nm)







5/118




601.3
504.0


 


6/119




635.2
486.0

























R
Compound
Example











111
18


 






105
19


 






113
20









Synthesis of Oximether















TABLE 2





Example/





compound
R′
m/e
λmax(nm)







7/122
—H
516.1
500.0


8/120
—CH3
531.2
500.0


 


9/121




607.2
504.0


 


10/123




678.1
504.0


 


21/116




630.1
504.0









Analogously, the compounds 100-242 can be generated according to the instructions below (table 3). The hereby used hydrazines, hydrazones and hydroxylamines are available commercially, or have been produced according to instructions known from the literature.











TABLE 3







Formula for table 3:


 








 
















Calculated
Actual




Example/Compound
R2′
R3
mass
mass
UVmax
Yield





100








592.1230
593.10
500
95



C5H5N2
H






 


101








661,1056
662,11
500
95



C5H3F3N3
H






 


102








620,1179
621,11
492
95



C6H5N2O
H






 


103








620,1179
621,11
500
95



C6H5N2O
H






 


104








567,1026
568,11
500
80



C2H2N3
H






 


105 (19)








583,1339
584,10
492
95



C3H6N3
H






 


106








609,1019
610,09
492
95



C5H4NO2
H






 


107








634,1335
635,13
492
95



C7H7N2O
H






 


108








574,0794
558,05
492
95



NHCSNH2
H






 


109








625,0791
626,08
492
95



C5H4NOS
H






 


110








672,1492
673,15
492
95



C10H9N2O
H






 


111








598,1699
599,14
492
95



C5H11N2
H






 


112








586,0971
587,10
492
95



C2H3N2O2
H






 


113 (20)








631,0,55
632,05
500
95



C3H2NOS2
H






 


114








582,1022
583,13
492
95



C3H3N2O
H






 


115








634,1335
635,16
492
70



C7H7N2O
H






 


116








629,1645
630,14
492
85



C6H12NO2
H






 


117








557,1182
558,11
500
95



CH4N3
H






 


118








600,1492
601,16
492
85



C4H9N2O
H






 


119








635,1414
635,13
495
85



C7H8N2O
H






120 (8)








530,0961
531,12
492
90



OMe
H






 


121 (9)








606,1274
607,16
492
95



OCH2Ph
H






 


122








516,0804
517,11
482
95



OH
H






 


123 (10)








678,1332
679,14
500
95



C6H11O6
H






 


124








634,1335
635,15
492
95



C7H7N2O







 


125








558,1022
559,12
492
95



NHCONH2
H






 


126








640,1805
614,13
492
95



C7H13N2O
H






 


127








640,0884
641,10
492
95



C7H6ClO
H






 


128








640,0900
641,10
492
95



C5H5N2OS
H






 


129








623,1288
624,13
500
90



C5H6N3O
H






 


130








614,1284
615,13
492
95



C4H7N2O2
H






 


131








655,1914
656,19
492
50



C7H14N3O
H






 


132








642,1597
643,17
492
60



C6H11N2O2
H






 


133








586,1335
587,15
492
70



C3H7N2O
H






 


134








628,1805
629,17
492
70



C6H13N2O
H






 


135








587,1539
588,14
492
90



C4H10NO
H






 


136








752,1885
753,19
492
85



C13H18ClN2O
H






 


137








601,1696
602,19
492
70



C5H12NO
H






 


138








626,0840
627,07
500
95



C5H5N2
Cl






 


139








695,0666
696,06
500
95



C5H3F3N3
Cl






 


140








654,0789
655,07
500
95



C6H5N2O
Cl






 


141








654,0789
655,07
500
95



C6H5N2O
Cl






 


142








601,0636
602,06
500
90



C2H2N3
Cl






 


143








617,0949
618,08
500
95



C3H6N3
Cl






 


144








643,0629
644,05
500
95



C5H4NO2
Cl






 


145








668,0946
669,07
500
95



C7H7N2O
Cl






 


146








608,0404
609,07
500
95



NHCSNH2
Cl






 


147








659,0401
660,07
500
95



C5H4NOS
Cl






 


148








706,1102
707,16
500
95



C10H9N2O
Cl






 


149








632,1309
633,16
500
95



C5H11N2
Cl






 


150








620,0582
621,09
500
95



C2H3N2O2
Cl






 


151








664,9965
645,31
500
95



C3H2NOS2
Cl






 


152








616,0633
617,10
500
95



C3H3N2O
Cl






 


153








668,0946
669,13
500
95



C7H7N2O
Cl






 


154








663,1255
664,16
500
95



C6H12NO2
Cl






 


155








591,0792
592,11
500
95


 


156








634,1102
635,14
500
95



C4H9N2O
Cl






 


157








669,1024
669,12
500
95



C7H8N2O
Cl






 


158








564,0571
565,09
500
95



OMe
Cl






 


159








640,0884
641,12
500
95



OCH2Ph
Cl






 


160








550,0415
551,06
500
95



OH
Cl






 


161








712,0943
713,10
500
95



C6H11O6
Cl






 


162








668,0946
669,09
500
95



C7H7N2O
Cl






 


163








592,0633
593,07
500
90



NHCONH2
Cl






 


164








674,1415
675,11
500
95



C7H13N2O
Cl






 


165








674,0494
675,03
500
90



C7H6ClO
Cl






 


166








674,0510
675,02
500
95



C5H5N2OS
Cl






 


167








657,0898
658,06
500
95



C5H6N3O
Cl






 


168








648,0895
649,07
500
95



C4H7N2O2
Cl






 


169








689,1524
690,15
500
60



C7H14N3O
Cl






 


170








676,1208
677,13
500
60



C6H11N2O2
Cl






 


171








620,0946
621,11
500
70



C3H7N2O
Cl






 


172








662,1415
663,12
500
70



C6H13N2O
Cl






 


173








621,1150
622,10
500
60



C4H10NO
Cl






 


174








786,1495
787,16
500
90



C13H18ClN2O
Cl






 


175








635,1306
636,10
500
75



C5H12NO
Cl






 


176








670,0334
670,99
500
95



C5H5N2
Br






 


177








739,0161
739,99
500
95


 


178








698,0284
699,00
500
90



C6H5N2O
Br






 


179








698,0284
699,00
500
90



C6H5N2O
Br






 


180








645,0130
645,99
492
70



C2H2N3
Br






 


181








661,0443
662,01
492
95



C3H6N3
Br






 


182








687,0124
688,99
492
95



C5H4NO2
Br






 


183








712,0440
713,03
500
95



C7H7N2O
Br






 


184








651,9899
653,04
500
95



NHCSNH2
Br






 


185








702,9895
704,02
492
95



C5H4NOS
Br






 


186








750,0597
751,10
500
95



C10H9N2O
Br






 


187








676,0804
677,10
492
95



C5H11N2
Br






 


188








664,0076
665,05
500
95



C2H3N2O2
Br






 


189








708,9460
709,99
492
95



C3H2NOS2
Br






 


190








660,0127
661,05
492
95



C3H3N2O
Br






 


191








712,0440
713,08
492
70



C7H7N2O
Br






 


192








707,0750
708,06
500
95



C6H12NO2
Br






 


193








635,0287
636,02
500
95



CH4N3
Br






 


194








678,0597
679,06
500
95



C4H9N2O
Br






 


195








713,0518
713,03
500
95



C7H8N2O
Br






 


196








608,0066
609,03
492
95



OMe
Br






 


197








684,0379
685,05
492
95



OCH2Ph
Br






 


198








593,9909
595,01
492
95



OH
Br






 


199








756,0437
757,00
500
90



C6H11O6
Br






 


200








712,0440
713,00
500
90



C7H7N2O
Br






 


201








636,0127
637,00
492
90



NHCONH2
Br






 


202








718,0910
719,00
500
90



C7H13N2O
Br






 


203








717,9989
718,00
492
95



C7H6ClO
Br






 


204








718,0004
718,97
492
95



C5H5N2OS
Br






 


205








701,0392
702,01
500
95



C5H6N3O
Br






 


206








692,0389
693,03
492
95



C4H7N2O2
Br






 


207








733,1018
734,10
500
90



C7H14N3O
Br






 


208








720,0702
721,10
500
95



C6H11N2O2
Br






 


209








664,0440
665,08
500
95



C3H7N2O
Br






 


210








706,0910
707,09
500
90



C6H13N2O
Br






 


211








665,0644
666,08
500
95



C4H10NO
Br






 


212








830,0989
831,11
500
95



C13H18ClN2O
Br






 


213








679,0801
680,09
492
95



C5H12NO
Br






 


214








558,1274
559,21
500
99



Oi—Pr
H






 


215








600,1743
601,30
500
99



O-n-hex
H






 


216








624,1180
625,28
500
99



C7H6FO
H






 


217








640,0884
641,27
500
99



C7H6ClO
H






 


218








624,1180
625,31
500
99



C7H6FO
H






 


219








592,0884
593,28
500
80



Oi—Pr
Cl






 


220








634,1354
635,36
500
90



O-n-hex
Cl






 


221








658,0790
659,32
500
85



C7H6FO
Cl






 


222








674,0494
675,31
500
80



C7H6ClO
Cl






 


223








658,0790
659,34
500
80



C7H6FO
Cl






 


224








636,0379
639,30
492
90



Oi—Pr
Br






 


225








678,0848
679,37
492
95



O-n-hex
Br






 


226








702,0284
703,34
492
95



C7H6FO
Br






 


227








717,9989
719,34
492
95



C7H6ClO
Br






 


228








702,0284
705,35
492
95



C7H6FO
Br






 


229








684,0200
685,30
500
99



Oi—Pr
I






 


230








726,0669
727,41
500
99



O-n-hex
I






 


231








750,0105
751,38
500
99



C7H6FO
I






 


232








765,9810
767,36
500
99



C7H6ClO
I






 


233








750,0105
751,38
500
99



C7H6FO
I






 


234








732,0200
733,38
500
99



OCH2Ph
I






 


235








755,0571
756,33
500
99



C6H12NO2
I






 


236








655,9887
657,32
492
95



OMe
I






 


237








765,9810
767,38
492
99



C7H6ClO
I






 


238








878,0810
879,45
500
99



C13H18ClN2O
I






 


239








641,9730
643,31
492
99



OH
I






 


240








781,0840
782,39
500
99



C7H14N3O
I






 


241








768,0523
769,38
500
99



C6H11N2O2
I






 


242








711.9897
713.37
500
99



C2H3N2O2
I









Reduction and Oxidation of Fredericamycin Aldehyde (4)

Fredericamycin aldehyde (4) can be reacted with a common reducing agent such as sodium borohydrid in a solvent such as DMF or pyridine to hydroxymethyl fredericamycin (11). The reaction can be summarized as a single pot reaction (iodate cleavage of fredericamycin tetrol (2) to fredericamycin aldehyde (4) (see diagram 2) and reduction without isolation of the intermediates to fredericamycin alcohol (11)).




Fredericamycin aldehyde (4) can be oxidized with the oxidizing agent sodium chlorite (NaClO2), a buffer such as sodium dihydrogenphosphate in presence of an alkene such as 2,3-dimethylbutene with very good yields to fredericamycin carboxylic acid (12). The usually employed oxidation methods such as those being used in preparative chemistry for the oxidation of aldehydes to carboxylic acids (oxidation with chromium(VI) compounds, manganese(VII) compounds as well as peroxo acid) did not lead to success. Only the use of the above described oxidation method provided the desired product. The literature describes oxidations of 2-pyridone-6-aldehydes with silver ions and potassium permanganate in an alkaline medium. This method, however, is not suited for fredericamycin and its derivatives since fredericamycin (1) contains base-labile (-reactive) groups (OH groups) causing undesired side reactions.
The potassium salt of the fredericamycin acid (13) was obtained according to a common method by stoichiometric neutralization.
Substitution in the B Ring
Fredericamycin (1) can be reacted with halogenation agents such as N-bromosuccinimide (NBS) and N-iodosuccinimide (NIS) with good yields to the substituted 5-bromo or 5-iodo fredericamycin derivatives (14) and (15) (diagram 6). The fredericamycin aldehyde (4) and (36) can be transformed with elemental bromine, NBS, BrI, NIS, and NCS to the appropriate halogen-substituted fredericamycin aldehyde (37), (38) and (39).
The appropriate fluorine compound is accessible, too.







Both of the two following fredericamycin compounds (23) and (24) are also precursors. (23) is the precursor for an amino acid-linked fredericamycin derivative.
The preparation of (23) may be recognized as proof that the aldehyde (4) may be reacted with phosphorylides according to Wittig or Wittig-Horner (see diagram 7).




The compound (24) is the precursor of an N-methylated fredericamycin derivative (diagram 8).




Fredericamycin may be transformed by palladium/hydrogen almost quantatively to tetrahydro fredericamycin (25), and may be halogenated in the nucleus according to the above described methods, e.g. to the bromine compound (26) (diagram 9):




Surprisingly it has also been found that the methoxy groups in fredericamycin and the derivatives according to the invention can be exchanged under alkali or earth alkali acetate catalysis by oxygen nucleophiles such as alcohols or polyols. Thereby, the alcohols can carry a multitude of different substituents (table 4).

















TABLE 4









UVmax

Yield


Example
R2
R3
R5
(nm)
m/e
(%)







243




H




504
(M + H) 554
97


 


244




H




500
(M+) 582
96


 


245




H




500
(M + H) 568
70


 


246




H




504
(M + H) 597
36


 


247




Br




504
(M+) 632/634
71


 


248




H




500
(M + H) 566
91


 


249




H




499
(M+) 569
52


 


250




H




504
(M + H) 616
99


 


251




H




500
(M+) 580
99


 


252




H




499
(M + H) 622
20


 


253




H




500
(M + H) 669
99


 


254




H




504
(M + H) 653
48


 


255




H




504
(M + H) 594
50


 


256




H




499
(M + H) 632/634
99









Exchange of the Methoxy Group at the F Ring

The exchange of the methoxy groups at the F ring of the fredericamycin and at the derivatives is possible by primary, secondary or aromatic amines. Thereby, the components are stirred with the appropriate primary or secondary amines at room temperature in DMF or in another inert solvent. With aromatic amines, a catalysis with Lewis acids such as stannous(IV)chloride, etc. is required.













TABLE 5





R3




Example







I




257


 


I




258


 


Br




259


 


H




260


 


H




261


 


H




262


 


H




263


 


H




264


 


H




265


 


I




266


 


H




267


 


H




268


 


H




269


 


Br




270









Preparation of Heterocyclic Fredericamycin Derivatives

The fredericamycin aldehyde (4) can be reacted to pyridal acetone (271) according to Wittig or Wittig-Horner. Bromation with bromine in DMF yields the dibromo-derivative (272) substituted in the side chain and at the B ring. With the appropriately substituted thioamides or thioureas, the respective thiazole derivatives (273-276) are accessible.













TABLE 6






R′′
Example








NH2
273



Ph
274



CH3CONH
275



CH3
276









Preparation of Thioanalogoues of Fredericamycin Derivatives

By sulfurization of fredericamycin or its derivatives with Lawesson reagent or P4S10 in pyridine, the derivatives analogous to thiopyridone are accessible (see diagram 13).
Preparation of Thioanalogoues of Fredericamycin Derivatives
By sulfurization of fredericamycin or its derivatives with Lawesson reagent or P4S10 in pyridine, The derivatives analogous to thiopyridone are accessible (see diagram 13).




Fredericamycin (1) forms inclusion compounds such as (25) with polysugars such as α-cyclodextrin, that have good water solubility compared to the original substance.
The dextrin inclusion compounds form easily if the components are mixed in the appropriate stoichiometric ratio in a suitable solvent such as DMSO (see diagram 11).




Biological Activity Against 12 Cancer Cell Lines:

LCL (H460, lung), MACL (MCF7, breast), LXFL (52L, lung), LXFA (629L, lung), MEXF (462NL, melanoma), MEXF (514L, melanoma), MAXF (401NL, breast), RXF (944L, renal), RXF (486L, renal), UXF (1138L, uterus), PRXF (PC3M, prostate), PRXF (22RV1).
Efficacy (IC70) Averaged Over all Cell Lines in μg/mL at 5 Test Concentrations









TABLE 7






Example/reference
IC70 μg/mL


















adriamycin
0.0210



cisplatin
37.1020



fredericamycin
0.2790



1
0.1130



13
0.0050



14
0.0070



22
0.0080



23
0.0110



121
0.2020



127
0.1550



192
0.0750



196
0.0950



197
0.0340



198
0.2560



203
0.1590



212
0.2100



214
0.0220



215
0.0720



217
0.1290



218
0.0760



224
0.0470



225
0.1110



230
0.0910



232
0.3170



233
0.1000



234
0.0520



235
0.0810



236
0.1210



265
0.1330



275
0.3680



276
0.0840











EXAMPLES
Example 1
1-Desoxy-5-C-[(8R)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphalene]-3-yl]pentitol (2)
Two hundred (200) mg (0.38 mmol) fredericamycin A (1) are dissolved in 30 mL dichloromethane. After addition of 20 mL methanol and 4.4 ml water, 350 mg (2.6 mmol) N-methylmorpholine-N-oxide are added. Under vigorous stirring, 0.2 ml of a 2.5% osmium(IV)oxide solution in t-butanol is added dropwise. The reaction mixture is acidified with 2-3 drops of trifluoracetic acid. After stirring for 48 hours, the reaction is complete according to HPLC control (RP18, acetonitrile water (0.2% acetic acid)). The reaction mixture is added to 400 ml water under vigorous stirring, and the dark red crystalline solid is sucked off through a filter. Drying in HV. Yield: 195 mg (87% of the theoretical value) dark red powder. ES−: M/e=606.2 (M+−H), λmax: 504.0.
Example 2
Tri-potassium-1-desoxy-5-C-[(8R)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl]pentitol (3)
Twelve (12.0) mg (19.8 μmol) fredericamycin tetrol (2) are dissolved in 1.5 mL absolute pyridine under nitrogen atmosphere. The solution is gassed for 30 min with argon at 0° C. Under the argon atmosphere, 5.94 mL of a 0.01 N KOH solution are added at once at 0° C. The reaction solution immediately turns turquoise. The reaction mixture is stirred for another 1 hour, and subsequently is frozen and lyophilized. Yield: 13.2 mg (100% of the theoretical value); deep blue crystal mass.
Example 3
(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde (4)
1.) Fifty (50) mg (82.3 μmol) tetrahydroxy fredericamycin (tetrol (2)) are dissolved in 4 mL DMF. Under vigorous stirring, an aqueous sodium iodate solution (300 mg NaIO4 in 1 mL water) is added dropwise within one hour. After 1 h stirring at room temperature, 2 drops of trifluoracetic acid are added. After stirring for another 30 min, the reaction solution is diluted with 3 ml DMF, and 150 mg NaIO4 dissolved in 0.5 ml water are added.
After another hour, 100 mL water are added. The supernatant over the precipitate is sucked off, and dryed in HV. Dark red crystal powder. Yield: 41 mg (100% of the theoretical value). M/e=501.3, UVmax: 504.0 nm.
2.) One hundred and nine (109) mg (179 μmol) fredericamycin tetrol (2) are dissolved in 8 mL pyridine. 180 μL water are added. To the reaction mixture, 450 mg (1.08 mmol, 6 eq.) (polystryrylmethyl)trimethylammonium periodate resin are added. Then the mixture is stirred for 12 h at RT. The resin is filtered off; washing and concentrating until dry. Dark red residue.
Yield: 89.9 mg (100% of the theoretical value). M/e=501.3, UVmax: 504.0 nm.
Example 4
1-[2-Oxo-2-((2E)-2-{[(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl]methylene)ethyl]-dimethylamino trifluoroacetate (118)
Twenty (20) mg (39.9 μmol) fredericamycin aldehyde (4) are dissolved under argon in 1.5 mL absolute DMF. Addition of 9.1 mg (47.9 μmol, 1.2 eq.) acetylhydrazide dimethylammoniumchloride (Girard reagent D) and 20 mg polyvinylpyridine (2% DVB). The mixture is stirred for 2.5 h. Then, 27 mg (80 μmol, 2.0 eq.) aldehyde Wang resin (coating: 3.0 mmol/g) are added and stirred for another 1 h. Then, the resin is filtered, and washed 3× with DMF. Concentration in high vacuum. The residue is dissolved in 1 ml trifluoracetic acid, and concentrated after 10 min until dry.
Red solid; Yield: 28.5 mg (100%); ES+: M/e=601.3, UVmax: 504.0 nm.
Example 5
1-[2-Oxo-2-((2E)-2-{[(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl]methylene}hydrazino)-ethyl]pyridinium chloride (119)
Fifteen (15) mg (29.9 μmol) fredericamycin aldehyde (4) are dissolved in 3 mL DMF. At room temperature 7.5 mg (40.0 μmol) acethydrazinopyridinium chloride (Girard reagent P) dissolved in 75 μL water are added. The reaction mixture is stirred for 1.5 h at room temperature, and the course of the reaction is monitored by HPLC. When finished, acetic acid ethyl ester is added to the reaction mixture, until a precipitation occurs. After the crystallization is finished, the red solid is sucked off.
Yield: 9.1 mg (44% of the theoretical value). M/e=635.2; λmax: 486.0.
Example 6
(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde oxime (122)
Ten (10) mg (19.4 μmol) fredericamycin aldehyde (4) are dissolved in 2 mL DMF. After addition of 3.1 mg (44.6 μmol) hydroxylammonium chloride, 3.2 μl pyridine are added. Stirring for 2 h at room temperature. The reaction mixture is added to 50 ml water and extracted 3 times with ethyl acetate. After drying and concentration, a deep red amorphous crystal powder was left (HPLC clean).
Yield: 7.4 mg (72% of the theoretical value). ES−: M/e=516.1; λmax: 500.0 nm.
Example 7
(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde-O-methyloxime (8)
Ten (10) mg (19.4 μmol) fredericamycin aldehyde (4) are dissolved in 2 mL DMF. After addition of 3.4 mg (40.7 μmol) O-methylhydroxylammonium chloride and 3.2 μl pyridine, the reaction mixture is stirred for 2 h at room temperature. Then, it is added to 100 ml water, and the supernatant is sucked off from the red precipitate (HPLC clean).
Yield: 7.6 mg (71% of the theoretical value). ES+: M/e=531.2; λmax: 500.0.
Example 8
(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde-O-benzyloxime (9)
Ten (10) mg (19.4 μmol) fredericamycin aldehyde (4) are dissolved in 2 mL DMF. After addition of 6.4 mg (43.2 μmol) O-benzylhydroxylammonium chloride and 3.2 μl pyridine, the reaction mixture is stirred for 2 h at room temperature. Then, it is added to 50 ml water, and the supernatant is sucked off from the red precipitate (HPLC clean).
Yield: 6.8 mg (57% of the theoretical value). ES+: M/e=607.2; λmax: 504.0 nm.
Example 9
1-O-({(1E)-[(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl]methylene}amino)-β-D-glucopyranose (10)
Two (2.0) mg (4.0 μmol) fredericamycin aldehyde (4) are dissolved in 150 μL DMF, and 0.86 mg (4.4 μmol) β-aminoxy-D-glucopyranose is added. The mixture is stirred for 24 h at room temperature, and 5 mg (15.0 μmol) aldehyde Wang resin (coating: 3.0 mmol/g) is added. After stirring for another 3 h, the resin is filtered off, washed with DMF, and the filtrate is concentrated in high vacuum until dry.
Yield: 2.7 mg (99% of the theoretical value), red powder; ES−: M/e=678.1; λmax: 504.0 nm.
Example 10
(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′,3′,5′,8′(2H)-pentone (11)
Thirty (30) mg (49.4 μmol) tetrahydroxy fredericamycin (2) were dissolved in 2 mL pyridine. Twenty (20) mg (93.0 μmol) sodium metaperiodate dissolved in 0.3 ml water are added. After stirring for 4 h, 10 mg (260 μmol) sodium borohydride are added. After 12 h, concentration until dry, and the residue is separated by preparative HPLC.
Yield: 2.6 mg (13% of the theoretical value) red powder. ES−: M/e=503.2; λmax: 504.0 nm.
Example 11
(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carboxylic acid (12)
Fifteen (15) mg (29.9 μmol) fredericamycin aldehyde (4) are dissolved in 1 mL dichloromethane and 0.5 ml t-butanol. Addition of 250 μl 2,4-dimethylbutene. Under stirring at room temperature, a solution of 6.0 mg (53.1 μmol) sodium chlorite (80%) and 5.1 mg sodium hydrogenphosphate in 250 μl water are added dropwise.
After 2.5 h, again a solution of 10.0 mg (88.5 μmol) sodium chlorite and 5 mg sodium dihydrogenphosphate in 200 μl water are added. After altogether 4 h, it is put on water, and extracted with ethyl acetate.
The raw mixture was purified by preparative HPLC (RP18, acetonitrile-water-acetic acid). Red amorphous powder.
Yield: 68.3 mg (53.5% of the theoretical value). E−: M/e=516.1; λmax: 504.0 nm.
Example 12
Potassium(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carboxylate (13)
6.9 mg (13.3 μmol) Fredericamycin carboxylic acid (12) are dissolved in 5 mL DMF under nitrogen. At room temperature and under oxygen exclusion and vigorous stirring, 1.27 mL (12.7 μmol) of an aqueous 0.01 N KOH solution is added dropwise. It is stirred for 15 minutes at room temperature, and concentrated in high vacuum until dry.
Yield: 7.40 mg (100% of the theoretical value). E−: M/e=516.1; λmax: 504.0 nm.
Example 13
(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′,3′,5′,8′(2H)-pentone (14)
Twenty (20) mg (37.1 μmol) fredericamycin (1) were dissolved in 250 μl DMF, and then 6. 3 mg (35.3 μmol) N-bromosuccinimide in 250 μl DMF were added within one hour at 0° C. The reaction was stirred in a slowly thawing ice bath over night. Then, the DMF is removed in high vacuum, and the residue is purified by preparative HPLC.
Yield: 7 mg (32% of the theoretical value) red crystal mass. M/e=616.1/618.1; λmax: 486.0 nm.
Example 14
(8S)-5-iodo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′,3′,5′,8′(2H)-pentone (15)
Eighty four (84) mg (158 μmol) fredericamycin (1) were dissolved in 1.0 μl DMF, and then 33.0 mg (150.0 μmol) N-iodosuccinimide in 500 μl DMF were added within one hour at 0° C. The reaction was stirred in a slowly thawing ice bath over night. Then, the DMF is removed in high vacuum, and the residue (120 mg (14) with a content of 80%) is purified by preparative HPLC (gradient CH3CN 50-90% over 16 min.)
Yield: 18 mg (17% of the theoretical value) red crystal mass. M/e=665.0; λmax: 484.0 nm.
Example 15
Methyl-2-{[(benzyloxy)carbonyl]amino}-3-[(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl]acrylate (23)
Sixty six (66) mg (200 μmol) Z-α-phosphonoglycine trimethylester are dissolved under argon in 1 mL absolute pyridine, and 25 μL 1,1,3,3-tetramethylguanidine are added at 0° C. After 40 min. 20 mg (40 μmol) fredericamycin aldehyde (4) is added at 0° C. After 15 min. 20 ml 1 M acetic acid is added, and the mixture is extracted 3× with acetic acid. The raw product is purified by preparative HPLC (RP18, acetonitrile-water).
Yield: 10.0 mg (36% of the theoretical value). M/e=706.4; λmax: 492.0 nm.
Example 16
(8S)-9-hydroxy-4′,6′,9′-trimethoxy-2-methyl-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′,3′,5′,8′(2H)-pentone (24)
Ten (10) mg (15 μmol) fredericamycin (1) were dissolved under protective gas in 4 ml absolute DMF. At RT, 400 μl (4311 μmol) methyliodide and 81 mg powdered potassium carbonate are added. The reactions mixture is then stirred at RT for 20 h, and is then transferred onto water. Extraction with ethyl acetate, and purification of the residue by separating chromatography on chloroform/methanol 30/1.
Yield: 4 mg (37% of the theoretical value). Yellow residue. M/e=582.3; λmax: 368.0 nm.
Example 17
Fredericamycin A 1:2 complex with α-cyclodextrin (22)
Ten (10) mg fredericamycin (0.025 mMol) are added to a solution of 50 mg α-cyclodextrin (0.050 mMol) in 500 μl dimethylsulfoxide. The solution is then diluted with 5 ml water. A stock solution prepared in such way can be diluted as desired with water.
λmax=504.0 nm.
Example 18
4′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde(4-methylpiperazine-1-yl)hydrazone (111)
Five (5) mg (9.42 μmol) fredericamycin aldehyde (4) are dissolved in 500 μl DMF and 25 μl trifluoracetic acid. At room temperature, 1.30 mg (11.3 μmol) 1-amino-4-methyl-piperazine is added. After stirring for 4.5 h at room temperature, 1 equivalent each of Wang aldehyde resin and sulfonohydrazide resin is added and stirred for 2 h.
Filtration and concentration of the reaction solution at high vacuum.
Red powder. Yield: 5.4 mg (91% of the theoretical value). M/e=599 (M+H)+; λmax: 504.0 nm.
Example 19
4′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde-4,5-dihydro-1H-imidazole-2-yl-hydrazone (123)
Five (5.00) mg (9.42 μmol) fredericamycin aldehyde (4) are dissolved in 500 μl DMF and 25 μl trifluoracetic acid. At room temperature, 2.05 mg (11.3 μmol) 2-hydrazino-2-imidazolin hydrobromide is added. After stirring for 4.5 h at room temperature, 1 equivalent each of Wang aldehyde resin and sulfonohydrazide resin are added and stirred for 2 h. Separation of the resin by filtration and concentration of the reaction solution at high vacuum.
Red powder. Yield: 3.9 mg (67% of the theoretical value). M/e=584 (M+H)+; λmax: 504.0 nm.
Example 20
4′,9,9′-Trihydroxy-6′-methoxy-3-{(E)-[(4-oxo-2-thioxo-1,3-thiazolidin-3-yl)imino]methyl)-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′,3′,5′,8′(2H)-pentone (123)
Five (5.00) mg (9.42 μmol) fredericamycin aldehyde (4) are dissolved in 500 μl DMF and 25 μl trifluoracetic acid. At room temperature, 1.67 mg (11.3 μmol) 2N-aminorhodanide are added. After stirring for 4.5 h at room temperature, 1 equivalent each of Wang aldehyde resin and sulfonohydrazide resin are added and stirred for 2 h.
Filtration and concentration of the reaction solution.
Red powder. Yield: 4.1 mg (65% of the theoretical value). M/e=599 (M+H)+; λmax: 504.0 nm.
Example 21
4′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopentag]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde-O-(2-morpholine-4-ylethyl)oxime (27)
Five (5.00) mg (9.42 μmol) fredericamycin aldehyde (4) are dissolved in 500 μl DMF and 25 μl trifluoracetic acid. At room temperature, 2.47 mg (11.3 μmol) N-(aminoxyethyl)morpholine dihydrochloride is added. After stirring for 4.5 h at room temperature, 1 equivalent of Wang aldehyde resin (3.1 mg, 9.4 μmol, coating: 3.0 mmol/g) as well as 1 equivalent sulfonohydrazide resin (6.1 mg, 9.4 mmol, 1.5 mmol) are added and stirred for 2 h.
Filtration and concentration of the reaction solution.
Red powder. Yield: 6.1 mg (98% of the theoretical value). M/e=630 (M+H)+; λmax: 504.0 nm.
Example 22
(8S)-5-chloro-4′,6′,9′-trimethoxy-2-methoxy-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′,3′,5′,8′(2H)-pentone (34)
Three hundred (300) mg (556.6 μmol) fredericamycin (1) are dissolved under argon in 10 μl DMF, and then 75.0 mg (556.6 μmol) N-chlorosuccinimide are added. The reaction is stirred for 5 h at 40° C. The reaction mixture is then added to 400 ml methanol/water 1:1, and the red precipitate is sucked off and dried at high vacuum.
Yield: 305 mg (96% of the theoretical value) red crystal mass. M/e=573/575; λmax: 504.0 nm.
Example 23
(8S)-5-fluoro-4′,9,9′-trihydroxy-6′-methoxy-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′,3′,5′,8′(2H)-pentone (35)
Fifty (50) mg (92.8 μmol) fredericamycin (1) are dissolved in 5 ml DMF under argon, and then 33.0 mg (93.5 μmol) 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) Selectfluor (is added. The reaction is stirred for 24 h at room temperature. The reaction mixture is then added to 200 ml water, and is extracted with ethyl acetate. The concentrated raw product is purified by preparative HPLC (RP18, acetonitrile-water-acetic acid).
Yield: 7.1 mg (14% of the theoretical value) red crystal mass. M/e=557; λmax: 504.0 nm.
Example 24
1-Desoxy-5-C-[(8R)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl]-pentitol (36)
Hundred twenty (120) mg (209 mmol) chlorofredericamycin (34) are dissolved in 25.0 ml dichloromethane. After addition of 3.6 ml methanol and 0.8 ml water, 197 mg (1.46 mmol) N-methylmorpholine-N-oxide is added. Under vigorous stirring, 0.12 ml of a 2.5% solution of osmium(IV)oxide in t-butanol is added dropwise. After stirring for 27 hours, the reaction is complete, according to HPLC monitoring (RP18, acetonitrile-water (0.2% acetic acid)). The reaction mixture is added to 200 ml water under vigorous stirring, and the dark red solid is sucked off. Drying in HV.
Yield: 101 mg (75% of the theoretical value) dark red powder. M/e=641/643; λmax: 504.0.
Example 25
(8S)-4′,9,9′-trihydroxy-5-bromo-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde (37)
Hundred (100) mg (200 μmol) fredericamycin aldehyde (4) are dissolved under argon in 5 ml DMF. Then, 200 μl of a 1M bromine solution in DMF is added. After stirring for 1.5 h at RT, another 20 μl bromine solution are added. According to HPLC monitoring, the reaction mixture is complete after 3.5 h.
Add to 150 ml water, and shake out with dichloromethane.
Yield: 96 mg (83% of the theoretical value) dark red powder. M/e=579/581; λmax: 504.0.
Example 26
1,2,3,4-Tetrahydro-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′,3′,5′,8′(2H)-pentone (26)
Eight (8.0) mg (0.0128 mmol) 1,2,3,4-tetrahydrofredericamycin (25) are dissolved in 1 ml absolute DMF under nitrogen. Then a solution of 2.3 mg (0.0128 mmol) bromine in 0.25 ml DMF is added dropwise to the solution. Stirring at room temperature over 24 h. The reaction mixture is concentrated to half volume in high vacuum, and is then transferred onto 100 ml water. The supernatant is sucked off from the precipitate and dried in a vacuum.
Red crystal powder 8.1 mg (88% of the theoretical value) m/e=621/623; λmax: 499 nm.
Example 27
(8S)-4′,9,9′-trihydroxy-6′-benzylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′,3′,5′,8′(2H)-pentone
Twenty (20) mg (37.1 μmol) fredericamycin are dissolved in 1 ml DMF under argon, then 4.76 mg (44.50 μmol) benzylamine are added at room temperature. According to HPLC (RP18, acetonitrile/water), a homogenous new product has formed after 3 h. The reaction mixture is concentrated at high vacuum until dry.
Red crystal mass; Yield: 23 mg (100% of the theoretical value) M/e=615.3 (M+H); λmax: 492 nm.
Example 28
(8S)-5-chloro-4′,9,9′-trihydroxy-6′-benzylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′,3′,5′,8′(2H)-pentone
Five (5.0) mg (8.71 μmol) 5-chlorofredericamycin are dissolved in 1 ml DMF under argon, then 1.12 mg (10.45 μmol) benzylamine are added at room temperature. After 29 h, the reaction mixture is concentrated at high vacuum until dry.
Red crystal mass; Yield: 5 mg (89% of the theoretical value) M/e=649.1 (M+H); λmax: 492 nm.
Example 28
Translator: 28a
(8S)-4′,9,9′-trihydroxy-6′-ethanolamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′,3′,5′,8′(2H)-pentone
Ten (10) mg (18.6 μmol) fredericamycin are dissolved in 1 ml DMF under argon, then 1.36 mg (22.3 μmol) ethanolamine are added at room temperature. According to HPLC (RP18, acetonitrile/water), a homogenous new product has formed after 3 h. The reaction mixture is concentrated at high vacuum until dry.
Red crystal mass; Yield: 9 mg (85% of the theoretical value) M/e=569.3 (M+H); λmax: 500 nm.
Example 29
(8S)-4′,9,9′-trihydroxy-6′-(4-piperidylmethylamino)-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′,3′,5′,8′(2H)-pentone
Ten (10) mg (18.6 μmol) fredericamycin are dissolved in 1 ml DMF under argon, then 2.7 PI (22.3 μmol) 4-aminomethylpiperidine are added at room temperature. The reaction mixture is concentrated at high vacuum until dry after 24 h.
Red crystal mass; Yield: 11 mg (99% of the theoretical value) M/e=622.3 (M+H); λmax: 492 nm.
Examples 100-142
The compounds 100-142 can be generated analogously to examples 7, 8, 9, 10, 18, 19 and 20:
Example 100
4′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydepyridine-2-yl-hydrazone (100)
Yield: (95% of the theoretical value) MS: M/e=593.1; λmax: 500.0 nm.
Example 101
4′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde[4-(trifluoromethyl)pyrimidine-2-yl]hydrazone (101)
Yield: (95% of the theoretical value) MS: M/e=562.1; λmax: 500.0 nm.
Example 102
N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]pyridyl-3-carbohydrazine (102)
Yield: (95% of the theoretical value) MS: M/e=621.1; λmax: 492.0 nm.
Example 103
N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]isonicotinohydrazine (103)
Yield: (95% of the theoretical value) MS: M/e=621.1; λmax: 500.0 nm.
Example 104
4′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde-1,2,4-triazole-4-ylhydrazone (104)
Yield: (80% of the theoretical value) MS: M/e=568.1; λmax: 500.0 nm.
Example 105
4′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde-4,5-dihydro-1H-imidazole-2ylhydrazone (105)
Yield: (95% of the theoretical value) MS: M/e=584.1; λmax: 492.0 nm.
Example 106
N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]-2-furohydrazine (106)
Yield: (95% of the theoretical value) MS: M/e=610.0; λmax: 492.0 nm.
Example 107
4-Amino-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]benzohydrazine (107)
Yield: (95% of the theoretical value) MS: M/e=635.1; λmax: 492.0 nm.
Example 108
4′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydethiosemicarbazone (108)
Yield: (95% of the theoretical value) MS: M/e=558.0; λmax: 492.0 nm.
Example 109
N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]thiophene-2-carbohydrazine (109)
Yield: (95% of the theoretical value) MS: M/e=626.0; λmax: 492.0 nm.
Example 110
2-(1H-indole-3-yl)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazine (110)
Yield: (95% of the theoretical value) MS: M/e=673.1; lλmax: 492.0 nm.
Example 111
4′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde(4-methylpiperazine-1-yl)hydrazone (111)
Yield: (95% of the theoretical value) MS: M/e=599.1; λmax: 492.0 nm.
Example 112
2-Oxo-2-{(2E)-2-[(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]-hydrazino)acetamide (112)
Yield: (95% of the theoretical value) MS: M/e=587.1; λmax: 492.0 nm.
Example 113
4′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′,3′,5′,8′(2H)-pentone (113)
Yield: (95% of the theoretical value) MS: M/e=632.0; λmax; λmax:500.0 nm.
Example 114
{(2E)-2-[(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]-hydrazino}acetonitrile (114)
Yield: (95% of the theoretical value) MS: M/e=583.1; λmax: 492.0 nm.
Example 115
2-Amino-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]benzohydrazine (115)
Yield: (95% of the theoretical value) MS: M/e=635.1; λmax: 492.0 nm.
Example 116
4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-[2-morpholine-4-yl-ethyl]oxime (116)
Yield: (85% of the theoretical value) MS: M/e=630.1; λmax: 492.0 nm.
Example 117
(2E)-2-[(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]hydrazinecarboximidamide (117)
Yield: (95% of the theoretical value) MS: M/e=558.1; λmax: 500.0 nm.
Example 118
2-(Dimethylamino)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazine (118)
Yield: (85% of the theoretical value) MS: M/e=601.1; λmax: 492.0 nm.
Example 119
1-[2-Oxo-2-((2E)-2-{[(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene}hydrazino)ethyl]pyridinium chloride (119)
Yield: (85% of the theoretical value) MS: M/e=635.1; λmax: 492.0 nm.
Example 120
(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-methyloxime (120)
Yield: (90% of the theoretical value) MS: M/e=531.1; λmax: 492.0 nm.
Example 121
4′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-benzyloxime (121)
Yield: (95% of the theoretical value) MS: M/e=607.1; λmax: 492.0 nm.
Example 122
4′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde oxime (122)
Yield: (95% of the theoretical value) MS: M/e=517.1; λmax: 482.0 nm.
Example 123
1-O-({(1E)-[(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene}amino)-β-D-glucopyranose (123)
Yield: (95% of the theoretical value) MS: M/e=679.1; λmax: 500.0 nm.
Example 124
4′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde-phenylsemicarbazone (124)
Yield: (95% of the theoretical value) MS: M/e=635.1; λmax: 492.0 nm.
Example 125
4′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydesemicarbazone (125)
Yield: (95% of the theoretical value) MS: M/e=559.1; λmax: 492.0 nm.
Example 126
2-Piperidino-4-yl-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide (126)
Yield: (95% of the theoretical value) MS: M/e=641.1; λmax: 492.0 nm.
Example 127
4′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-(3-chlorobenzyl)oxime (127)
Yield: (95% of the theoretical value) MS: M/e=641.1; λmax: 492.0 nm.
Example 128
N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]-(2-methyl-1,3-thiazole-4yl)carbohydrazide (128)
Yield: (95% of the theoretical value) MS: M/e=641.1; λmax: 492.0 nm.
Example 129
2-(1H-imidazole-1-yl)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide (129)
Yield: (90% of the theoretical value) MS: M/e=624.1; λmax: 500.0 nm.
Example 130
2-(Acetylamino)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide (130)
Yield: (95% of the theoretical value) MS: M/e=615.1; λmax: 492.0 nm.
Example 131
2-(4-Methylpiperazine-1-yl)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide (131)
Yield: (50% of the theoretical value) MS: M/e=656.1; λmax: 492.0 nm.
Example 132
2-Morpholine-4-yl-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide (132)
Yield: (60% of the theoretical value) MS: M/e=643.1; λmax: 492.0 nm.
Example 133
2-(Methylamino)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide (133)
Yield: (70% of the theoretical value) MS: M/e=587.1; λmax: 492.0 nm.
Example 134
2-[Isopropyl(methyl)amino]-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide (134)
Yield: (70% of the theoretical value) MS: M/e=629.1; λmax: 492.0 nm.
Example 135
4′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-[2-(dimethylamino)ethyl]oxime (127)
Yield: (90% of the theoretical value) MS: M/e=588.1; λmax: 492.0 nm.
Example 136
4′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-[3-(4-(3-chlorophenyl)-piperazine-1-yl)propyl]oxime (136)
Yield: (85% of the theoretical value) MS: M/e=753.1; λmax: 492.0 nm.
Example 137
4′,9,9′-Trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-[3-(dimethylamino)propyl]oxime (137)
Yield: (70% of the theoretical value) MS: M/e=602.1; λmax: 492.0 nm.
Example 138
(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydepyridine-2-yl-hydrazone (138)
Yield: (95% of the theoretical value) MS: M/e=627.0; λmax: 500.0 nm.
Example 139
(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde[4-(trifluoromethyl)pyrimidine-2-yl]hydrazone (139)
Yield: (95% of the theoretical value) MS: M/e=696.0; λmax: 500.0 nm.
Example 140
(8S)-5-chloro-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]pyridyl-3-carbohydrazine (140)
Yield: (95% of the theoretical value) MS: M/e=655.0; λmax: 500.0 nm.
Example 141
(8S)-5-chloro-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]isonicotinohydrazide (141)
Yield: (95% of the theoretical value) MS: M/e=655.0; λmax: 500.0 nm.
Example 142
(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde-1,2,4-triazole-4-ylhydrazone (142)
Yield: (90% of the theoretical value) MS: M/e=602.0; λmax: 500.0 nm.
Example 143
(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde-4,5-dihydro-1H-imidazole-2-ylhydrazone (143)
Yield: (95% of the theoretical value) MS: M/e=618.0; λmax: 500.0 nm.
Example 144
(8S)-5-chloro-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]-2-furohydrazide (144)
Yield: (95% of the theoretical value) MS: M/e=644.0; λmax: 500.0 nm.
Example 145
(8S)-5-chloro-4-amino-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]-benzohydrazide (145)
Yield: (95% of the theoretical value) MS: M/e=669.0; λmax: 500.0 mm.
Example 146
(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydethiosemicarbazone (146)
Yield: (95% of the theoretical value) MS: M/e=609.0; λmax:500.0 nm.
Example 147
(8S)-5-chloro-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]thiophene-2-carbohydrazide (147)
Yield: (95% of the theoretical value) MS: M/e=660.0; λmax: 500.0 nm.
Example 148
(8S)-5-chloro-2-(1H-indole-3-yl)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide (148)
Yield: (95% of the theoretical value) MS: M/e=707.1; λmax: 500.0 nm.
Example 149
(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde(4-methylpiperazine-1-yl)hydrazone (149)
Yield: (95% of the theoretical value) MS: M/e=633.1; λmax: 500.0 nm.
Example 150
(8S)-5-chloro-2-oxo-2-{(2E)-2-[4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]hydrazino}acetamide (150)
Yield: (95% of the theoretical value) MS: M/e=621.0; λmax: 500.0 nm.
Example 151
(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′,3′,5′,8′(2H)-pentone (151)
Yield: (95% of the theoretical value) MS: M/e=665.3; λmax: 500.0 nm.
Example 152
(8S)-5-chloro-{(2E)-2-[4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]hydrazino}acetonitrile (152)
Yield: (95% of the theoretical value) MS: M/e=617.1; λmax: 500.0 nm.
Example 153
(8S)-5-chloro-2-amino-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]benzohydrazide (153)
Yield: (95% of the theoretical value) MS: M/e=669.1; λmax: 500.0 nm.
Example 154
(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-[2-morpholine-4-yl-ethyl)oxime (154)
Yield: (95% of the theoretical value) MS: M/e=664.1; λmax: 500.0 nm.
Example 155
(8S)-5-chloro-(2E)-2-[(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]hydrazinecarboximidamide (155)
Yield: (95% of the theoretical value) MS: M/e=592.1; λmax: 500.0 nm.
Example 156
(8S)-5-chloro-2-(dimethylamino)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide (156)
Yield: (95% of the theoretical value) MS: M/e=635.1; λmax: 500.0 nm.
Example 157
(8S)-5-chloro-1-[2-oxo-2-((2E)-2-1[(8S)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]hydrazino)ethyl]pyridinium chloride (157)
Yield: (95% of the theoretical value) MS: M/e=669.1; λmax: 500.0 nm.
Example 158
(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde-O-methyloxime (158)
Yield: (95% of the theoretical value) MS: M/e=565.0; λmax: 500.0 nm.
Example 159
(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde-O-benzyloxime (159)
Yield: (95% of the theoretical value) MS: M/e=641.1; λmax: 500.0 nm.
Example 160
(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde oxime (160)
Yield: (95% of the theoretical value) MS: M/e=551.1; λmax: 500.0 nm.
Example 161
(8S)-5-chloro-1-O-(((1E)-[(8S)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]amino)-β-D-glucopyranose (161)
Yield: (95% of the theoretical value) MS: M/e=713.1; λmax: 500.0 nm.
Example 162
(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde-phenylsemicarbazone (162)
Yield: (95% of the theoretical value) MS: M/e=669.1; λmax: 500.0 nm.
Example 163
(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydesemicarbazone (163)
Yield: (90% of the theoretical value) MS: M/e=593.0; λmax: 500.0 nm.
Example 164
(8S)-5-chloro-2-piperidino-4-yl-N′-[(1E)-[(8S)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide (164)
Yield: (95% of the theoretical value) MS: M/e=675.1; λmax: 500.0 nm.
Example 165
(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-(3-chlorobenzyl)oxime (165)
Yield: (90% of the theoretical value) MS: M/e=675.0; λmax: 500.0 nm.
Example 166
(8S)-5-chloro-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]a-2-methyl-1,3-thiazole-4yl-carbohydrazide (166)
Yield: (95% of the theoretical value) MS: M/e=675.0; λmax: 500.0 nm.
Example 167
(8S)-5-chloro-2-(1H-imidazole-1-yl)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide (1647)
Yield: (90% of the theoretical value) MS: M/e=658.1; λmax: 500.0 nm.
Example 168
(8S)-5-chloro-2-(acetylamino)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide (164)
Yield: (95% of the theoretical value) MS: M/e=649.0; λmax: 500.0 nm.
Example 169
(8S)-5-chloro-2-(4-methylpiperazine-1-yl)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide (169)
Yield: (60% of the theoretical value) MS: M/e=690.1; λmax: 500.0 nm.
Example 170
(8S)-5-chloro-2-morpholine-4-yl-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide (170)
Yield: (60% of the theoretical value) MS: M/e=677.1; λmax: 500.0 nm.
Example 171
(8S)-5-chloro-2-(methylamino)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide (171)
Yield: (70% of the theoretical value) MS: M/e=621.1; λmax: 500.0 nm.
Example 172
(8S)-5-chloro-2-[isopropyl(methyl)amino]-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide (172)
Yield: (95% of the theoretical value) MS: M/e=675.1; λmax: 500.0 nm.
Example 173
(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-[2-(dimethylamino)ethyl]-oxime (173)
Yield: (60% of the theoretical value) MS: M/e=622.0; λmax: 500.0 nm.
Example 174
(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-[3-(4-(3-chlorophenyl)-piperazine-1-yl)propyl]-oxime (174)
Yield: (90% of the theoretical value) MS: M/e=787.1; λmax: 500.0 nm.
Example 175
(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-[3-(dimethylamino)propyl]oxime (175)
Yield: (75% of the theoretical value) MS: M/e=636.1; λmax: 500.0 nm.
Example 176
(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydepyridine-2-yl-hydrazone (176)
Yield: (95% of the theoretical value) MS: M/e=670.9; λmax: 500.0 nm.
Example 177
(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde[4-(trifluoromethyl)pyrimidine-2-yl]hydrazone (177)
Yield: (95% of the theoretical value) MS: M/e=739.9; λmax: 500.0 nm.
Example 178
(8S)-5-bromo-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]pyridyl-3-carbohydrazide (178)
Yield: (90% of the theoretical value) MS: M/e=699.0; λmax: 500.0 nm.
Example 179
(8S)-5-bromo-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]isonicotinohydrazide (179)
Yield: (90% of the theoretical value) MS: M/e=699.0; λmax: 500.0 nm.
Example 180
(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde-1,2,4-triazole-4-ylhydrazone (180)
Yield: (70% of the theoretical value) MS: M/e=645.9; λmax: 492.0 nm.
Example 181
(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde-4,5-dihydro-1H-imidazole-2-ylhydrazone (181)
Yield: (95% of the theoretical value) MS: M/e=662.0; λmax: 492.0 nm.
Example 182
(8S)-5-bromo-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]-2-furohydrazide (182)
Yield: (95% of the theoretical value) MS: M/e=688.9; λmax: 492.0 nm.
Example 183
(8S)-5-bromo-4-amino-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]benzohydrazide (183)
Yield: (95% of the theoretical value) MS: M/e=713.0; λmax: 500.0 nm.
Example 184
(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydethiosemicarbazone (184)
Yield: (95% of the theoretical value) MS: M/e=653.0; λmax: 500.0 nm.
Example 185
(8S)-5-bromo-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]thiophene-2-carbohydrazide (185)
Yield: (95% of the theoretical value) MS: M/e=704.0; λmax: 492.0 nm.
Example 186
(8S)-5-bromo-2-(1H-indole-3-yl)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide (186)
Yield: (95% of the theoretical value) MS: M/e=751.1; λmax: 500.0 nm.
Example 187
(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde(4-methylpiperazine-1-yl)hydrazone (187)
Yield: (95% of the theoretical value) MS: M/e=677.1; λmax: 500.0 nm.
Example 188
(8S)-5-bromo-2-oxo-2-[(2E)-2-[(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]hydrazino}acetamide (188)
Yield: (95% of the theoretical value) MS: M/e=665.0; λmax: 500.0 nm.
Example 189
(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′,3′,5′,8′(2H)-pentone (189)
Yield: (95% of the theoretical value) MS: M/e=709.9; λmax: 492.0 nm.
Example 190
(8S)-5-bromo-((2E)-2-[(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]hydrazino)acetonitrile (190)
Yield: (95% of the theoretical value) MS: M/e=661.0; λmax: 500.0 nm.
Example 191
(8S)-5-bromo-2-amino-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]benzohydrazide (191)
Yield: (70% of the theoretical value) MS: M/e=713.0; λmax: 492.0 nm.
Example 192
(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-[2-morpholine-4-yl-ethyl)oxime (192)
Yield: (95% of the theoretical value) MS: M/e=708.0; λmax: 500.0 nm.
Example 193
(8S)-5-bromo-(2E)-2-[(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]hydrazinecarboximidamide (193)
Yield: (95% of the theoretical value) MS: M/e=636.0; λmax: 500.0 nm.
Example 194
(8S)-5-bromo-2-(dimethylamino)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide (194)
Yield: (95% of the theoretical value) MS: M/e=679.0; λmax: 500.0 nm.
Example 195
(8S)-5-bromo-1-[2-oxo-2-((2E)-2-{[(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylenelhydrazino)ethyl]pyridinium chloride (195)
Yield: (95% of the theoretical value) MS: M/e=713.0; λmax: 500.0 nm.
Example 196
(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-methyloxime (196)
Yield: (95% of the theoretical value) MS: M/e=609.0; λmax: 492.0 nm.
Example 197
(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde-O-benzyloxime (197)
Yield: (95% of the theoretical value) MS: M/e=685.0; λmax: 492.0 nm.
Example 198
(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde oxime (198)
Yield: (95% of the theoretical value) MS: M/e=595.0; λmax: 492.0 nm.
Example 199
(8S)-5-bromo-1-O-(((1E)-[(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene}amino)-β-D-glucopyranose (199)
Yield: (90% of the theoretical value) MS: M/e=757.0; λmax: 500.0 nm.
Example 200
(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde-phenylsemicarbazone (200)
Yield: (90% of the theoretical value) MS: M/e=713.0; λmax; λmax:500.0 nm.
Example 201
(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehydesemicarbazone (201)
Yield: (90% of the theoretical value) MS: M/e=637.0; λmax: 492.0 nm.
Example 202
(8S)-5-bromo-2-piperidino-4-yl-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide (201)
Yield: (90% of the theoretical value) MS: M/e=719.0; λmax: 500.0 nm.
Example 203
(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-(3-chlorobenzyl)oxime (203)
Yield: (95% of the theoretical value) MS: M/e=718.0; λmax: 492.0 nm.
Example 204
(8S)-5-bromo-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]-2-methyl-1,3-thiazole-4yl-carbohydrazide (204)
Yield: (95% of the theoretical value) MS: M/e=718.9; λmax: 492.0 nm.
Example 205
(8S)-5-bromo-2-(1H-imidazole-1-yl)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide (205)
Yield: (95% of the theoretical value) MS: M/e=702.0; λmax: 500.0 nm.
Example 206
(8S)-5-bromo-2-(acetylamino)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide (206)
Yield: (95% of the theoretical value) MS: M/e=693.0; λmax: 492.0 nm.
Example 207
(8S)-5-bromo-2-(4-methylpiperazine-1-yl)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide (207)
Yield: (90% of the theoretical value) MS: M/e=734.1; λmax: 500.0 nm.
Example 208
(8S)-5-bromo-2-morpholine-4-yl-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide (208)
Yield: (95% of the theoretical value) MS: M/e=721.1; λmax: 500.0 nm.
Example 209
(8S)-5-bromo-2-(methylamino)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide (209)
Yield: (95% of the theoretical value) MS: M/e=665.0; λmax: 500.0 nm.
Example 210
(8S)-5-bromo-2-[isopropyl(methyl)amino]-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide (210)
Yield: (95% of the theoretical value) MS: M/e=707.0; λmax: 500.0 nm.
Example 211
(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-[2-(dimethylamino)ethyl]oxime (211)
Yield: (95% of the theoretical value) MS: M/e=666.0; λmax: 500.0 nm.
Example 212
(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-[3-(4-(3-chlorophenyl)-piperazine-1-yl)propyl]oxime (212)
Yield: (95% of the theoretical value) MS: M/e=831.0; λmax: 500.0 nm.
Example 213
(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-[3-(dimethylamino)propyl]oxime (213)
Yield: (95% of the theoretical value) MS: M/e=680.0; λmax: 492.0 nm.
Example 214
(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-isopropyloxime (214)
Yield: (95% of the theoretical value) MS: M/e=559.2; λmax: 500.0 nm.
Example 215
(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-n-hexyloxime (215)
Yield: (99% of the theoretical value) MS: M/e=601.3; λmax: 500.0 nm.
Example 216
(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-(4-fluorobenzyl)oxime (216)
Yield: (99% of the theoretical value) MS: M/e=625.2; λmax: 500.0 nm.
Example 217
(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-(4-chlorobenzyl)oxime (217)
Yield: (99% of the theoretical value) MS: M/e=641.2; λmax: 500.0 nm.
Example 218
(8S)-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-(3-fluorobenzyl)oxime (218)
Yield: (99% of the theoretical value) MS: M/e=625.3; λmax: 500.0 mm.
Example 219
(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-isopropyloxime (219)
Yield: (80% of the theoretical value) MS: M/e=593.2; λmax: 500.0 nm.
Example 220
(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-n-hexyloxime (220)
Yield: (90% of the theoretical value) MS: M/e=635.3; λmax: 500.0 nm.
Example 221
(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-(4-fluorobenzyl)oxime (221)
Yield: (85% of the theoretical value) MS: M/e=659.3; λmax: 500.0 nm.
Example 222
(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-(4-chlorobenzyl)oxime (222)
Yield: (80% of the theoretical value) MS: M/e=675.3; λmax: 500.0 nm.
Example 223
(8S)-5-chloro-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-(3-fluorobenzyl)oxime (223)
Yield: (80% of the theoretical value) MS: M/e=659.3; λmax: 500.0 nm.
Example 224
(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-isopropyloxime (224)
Yield: (90% of the theoretical value) MS: M/e=639.3; λmax: 492.0 nm.
Example 225
(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-n-hexyloxime (225)
Yield: (95% of the theoretical value) MS: M/e=679.3; λmax: 492.0 nm.
Example 226
(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-(4-fluorobenzyl)oxime (226)
Yield: (95% of the theoretical value) MS: M/e=703.3; λmax: 492.0 nm.
Example 227
(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-(4-chlorobenzyl)oxime (227)
Yield: (95% of the theoretical value) MS: M/e=719.3; λmax: 492.0 nm.
Example 228
(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-(3-fluorobenzyl)oxime (228)
Yield: (95% of the theoretical value) MS: M/e=705.3; λmax: 492.0 nm.
Example 229
(8S)-5-iodo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-isopropyloxime (229)
Yield: (99% of the theoretical value) MS: M/e=685.3; λmax:500.0 nm.
Example 230
(8S)-5-iodo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-n-hexyloxime (230)
Yield: (99% of the theoretical value) MS: M/e=727.4; λmax: 500.0 nm.
Example 231
(8S)-5-iodo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-(4-fluorobenzyl)oxime (231)
Yield: (99% of the theoretical value) MS: M/e=751.3; λmax: 500.0 nm.
Example 232
(8S)-5-iodo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-(4-chlorobenzyl)oxime (232)
Yield: (99% of the theoretical value) MS: M/e=767.3; λmax: 500.0 nm.
Example 233
(8S)-5-iodo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-(3-fluorobenzyl)oxime (233)
Yield: (99% of the theoretical value) MS: M/e=751.3; λmax: 500.0 nm.
Example 234
(8S)-5-iodo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-benzyloxime (234)
Yield: (99% of the theoretical value) MS: M/e=733.3; λmax: 500.0 nm.
Example 235
(8S)-5-iodo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-[2-morpholine-4-yl-ethyl)oxime (235)
Yield: (99% of the theoretical value) MS: M/e=756.3; λmax: 500.0 nm.
Example 236
(8S)-5-iodo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-methyloxime (236)
Yield: (95% of the theoretical value) MS: M/e=657.3; λmax: 492.0 nm.
Example 237
(8S)-5-iodo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-(3-chlorobenzyl)oxime (237)
Yield: (99% of the theoretical value) MS: M/e=767.3; λmax; λmax:492.0 nm.
Example 238
(8S)-5-iodo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde O-[3-(4-(3-chlorophenyl)-piperazine-1-yl)propyl]oxime (238)
Yield: (99% of the theoretical value) MS: M/e=879.4; λmax: 500.0 nm.
Example 239
(8S)-5-iodo-4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-carbaldehyde oxime (239)
Yield: (99% of the theoretical value) MS: M/e=643.3; λmax: 492.0 nm.
Example 240
(8S)-5-iodo-2-(4-methylpiperazine-1-yl)-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide (240)
Yield: (99% of the theoretical value) MS: M/e=782.3; λmax: 500.0 nm.
Example 241
(8S)-5-iodo-2-morpholine-4-yl-N′-[(1E)-(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopentag]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]acetohydrazide (241)
Yield: (99% of the theoretical value) MS: M/e=782.3; λmax: 500.0 nm.
Example 242
(8S)-5-iodo-2-oxo-2-{(2E)-2-[(4′,9,9′-trihydroxy-6′-methoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl)methylene]hydrazino}acetamide (242)
Yield: (99% of the theoretical value) MS: M/e=713.3; λmax: 500.0 nm.
Example 243
(8S)-4′,9,9′-trihydroxy-6′-ethoxy-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone (243)
Five (5) mg (0.0095 mmol) fredericamycin (1) are suspended in 2.0 ml ethanol. Under N2 atmosphere, 90 mg sodium acetate are added and boiled under reflux. After a few minutes, the suspension turns into a deep blue solution. After 24 h it is cooled, transferred onto water and shaken out with ethyl acetate (0.1% CF3COOH). After drying and concentration, a chromatographically homogenous, red powder is left.
Yield: 5.0 mg (97% of the theoretical value) MS=554 (M+H)+; λmax: 504.0 nm.
Example 244
(8S)-4′,9,9′-trihydroxy-6′-n-butoxy-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone (244)
Six (6) mg (0.0114 mmol) fredericamycin (1) are suspended in 3.0 ml n-butanol. Under N2 atmosphere, 50 mg potassium acetate are added and heated to 100° C. After a few minutes, the suspension turns into a deep blue solution. The solution is left for 1 h at this temperature, and is then cooled. It is transferred onto water and shaken out with ethyl acetate (0.1% CF3COOH). After drying and concentration, a chromatographically homogenous red powder is left.
Yield: 6.2 mg (96% of the theoretical value) MS=582 (M)+; λmax: 500.0 nm.
Example 245
(8S)-4′,9,9′-trihydroxy-6′-n-isopropyloxy-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone (245)
Five (5) mg (0.0095 mmol) fredericamycin (1) are suspended in 3.0 ml n-propanol. Under N2 atmosphere, 50 mg potassium acetate (anhydrous) are added and heated to 80° C. After a few minutes, the suspension turns into a deep blue solution. The solution is left for 48 h at this temperature, and is then cooled. It is transferred onto water and shaken out with ethyl acetate (0.1% CF3COOH). After drying and concentration, a chromatographically homogenous red powder is left.
Yield: 3.7 mg (70% of the theoretical value) MS=568 (M+H)+; λmax: 500.0 nm.
Example 246
(8S)-4′,9,9′-trihydroxy-6′-(2-dimethylaminoethoxy)-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone (246)
6.1 mg (0.01159 mmol) fredericamycin (1) are suspended in 3.5 ml N,N-Dimethylaminoethanol. Under N2 atmosphere, 52 mg anhydrous potassium acetate are added and heated to 80° C. After a few minutes, the suspension turns into a deep blue solution. The solution is left for 1.5 h at this temperature, and is then cooled. It is transferred onto water and shaken out with ethyl acetate (0.1% CF3COOH). After drying and concentration, a chromatographically homogenous red powder is left.
Yield: 2.4 mg (36% of the theoretical value); MS=597 (M+H)+; λmax: 504.0 nm.
Example 247
(8S)-5-bromo-4′,9,9′-trihydroxy-6′-(2-dimethylaminoethoxy)-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone (247)
Ten (10.0) mg (0.019 mmol) bromofredericamycin (14) are suspended in 3.0 ml ethanol. Under N2 atmosphere, 50 mg anhydrous potassium acetate are added and heated to 80° C. After a few minutes, the suspension turns into a deep blue solution. The solution is left for 48 h at this temperature, and is then cooled. It is transferred onto water and shaken out with ethyl acetate (0.1% CF3COOH). After drying and concentration, a chromatographically homogenous red powder is left.
Yield: 7.2 mg (71% of the theoretical value); MS=632/634 (M+H)+; λmax: 504.0 nm.
Example 248
(8S)-4′,9,9′-trihydroxy-6′-allyloxy-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone (248)
9.6 mg (0.01824 mmol) fredericamycin (1) are suspended in 3.0 ml allyl alcohol. Under N2 atmosphere, 58 mg anhydrous potassium acetate are added and heated to 70° C. After a few minutes, the suspension turns into a deep blue solution. The solution is left for 2.5 h at this temperature, and is then cooled. It is transferred onto water and shaken out with ethyl acetate (0.1% CF3COOH). After drying and concentration, a chromatographically homogenous red powder is left.
Yield: 9.2 mg (91% of the theoretical value); MS=566 (M+H)+; λmax: 500.0 nm.
The compounds 249, 250, 251, 252, 253, 254, 255 were generated analogously to the instructions 244-248:
Example 249
(8S)-4′,9,9′-trihydroxy-6′-(2-hydroxyethoxy)-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone (249)
Yield: 5.2 mg (52% of the theoretical value); MS=569 (M)+; λmax: 499.0 nm.
Example 250
(8S)-4′,9,9′-trihydroxy-6′-benzyloxy-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone (250)
Yield: 10.2 mg (99% of the theoretical value); MS=616 (M+H)+; λmax: 504.0 nm.
Example 251
(8S)-4′,9,9′-trihydroxy-6′-cyclopropylmethoxy-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone (251)
Yield: 12.9 mg (99% of the theoretical value); MS=580 (M)+; λmax:500.0 nm.
Example 252
1-Desoxy-5-C-[(8R)-4′,9,9′-trihydroxy-6′-ethoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6′,7′,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl]pentitol (252)
Yield: 2.0 mg (20% of the theoretical value); MS=622 (M+H)+; λmax: 499.0 nm.
Example 253
(8S)-4′,9,9′-trihydroxy-6′-(2-t-butoxycarbonylaminoethoxy)-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone (253)
Yield: 12.9 mg (99% of the theoretical value); MS=669 (M)+; λmax: 500.0 mm.
Example 254
(8S)-4′,9,9′-trihydroxy-6′-(2-N,N-diisopropylaminoethoxy)-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone (249)
Yield: 5.8 mg (48% of the theoretical value); MS=653 (M+H)+; λmax: 500.0 nm.
Example 255
1-Desoxy-5-C-[(8R)-4′,9,9′-trihydroxy-6′-ethoxy-1,1′,3′,5′,8′-pentaoxo-1,1′,2,3′,5′,6,7,8′-octahydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene)-3-yl]pentitol (255)
Yield: 5.5 mg (50% of the theoretical value); MS=594 (M+H)+; λmax: 500.0 nm.
Example 256
(8S)-4′,9,9′-trihydroxy-6′-(2-bromoethoxy)-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopentag]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone (256)
10.6 mg (0.02014 mmol) fredericamycin (1) are suspended in 2.0 ml bromoethanol. Under N2 atmosphere, 150 mg anhydrous potassium acetate are added and heated to 120° C. After a few minutes, the suspension turns into a deep blue solution. After 12 hours, addition of another 150 mg potassium acetate. The solution is left for another 12 h at this temperature, and is then cooled. It is transferred onto water and shaken out with ethyl acetate (0.1% CF3COOH). After drying and concentration, a chromatographically homogenous red powder is left.
Yield: 11.5 mg (99% of the theoretical value); MS=632/634 (M+H)+; λmax: 499.0 nm.
Example 257
(8S)-5-iodo-4′,9,9′-trihydroxy-6′-cyclopropylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopent[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone (257)
Five (5.0) mg (7.5 μmol) 5-iodofredericamycin (15) are dissolved under argon in 1.0 ml anhydrous DMF. After addition of 0.64 mg (11.2 μmmol) cyclopropylamine, it is stirred at room temperature for 3 h. Excess cycloprolylamine and DMF are removed at high vacuum. After drying and concentration, a chromatographically homogenous red powder is left.
Yield: 5.1 mg (99%); MS=691.3 (M+H)+; λmax: 504.0 nm.
Example 258
(8S)-5-iodo-4′,9,9′-trihydroxy-6′-n-butylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopentag]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone (258)
Five (5.0) mg (7.5 μmol) 5-iodofredericamycin (15) are dissolved under argon in 1.0 ml anhydrous DMF. After addition of 0.82 mg (11.2 μmmol) n-butylamine, it is stirred at room temperature for 20 h. Excess n-butylamine and DMF are removed at high vacuum. After drying and concentration, a chromatographically homogenous red powder is left.
Yield: 5.3 mg (99%); MS=707.3 (M+H)+; λmax: 504.0 nm.
Example 259
(8S)-5-bromo-4′,9,9′-trihydroxy-6′-n-butylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopentag]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone (259)
Five (5.0) mg (8.1 μmol) 5-bromofredericamycin (15) are dissolved under argon in 1.0 ml anhydrous DMF. After addition of 0.89 mg (12.2 μmmol) n-butylamine, it is stirred at room temperature for 20 h. Excess n-butylamine and DMF are removed at high vacuum. After drying and concentration, a chromatographically homogenous red powder is left.
Yield: 5.3 mg (99%); MS=659.4/661.4 (M+H)+; λmax: 504.0 nm.
Example 260
(8S)-4′,9,9′-trihydroxy-6′-cyclopropylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopentag]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone (260)
Five (5.0) mg (9.3 μmol) fredericamycin (1) are dissolved under argon in 1.0 ml anhydrous DMF. After addition of 2.12 mg (37.2 μmmol) cyclopropylamine, it is stirred at room temperature for 2 h. Excess cyclopropylamine and DMF are removed at high vacuum. After drying and concentration, a chromatographically homogenous red powder is left.
Yield: 5.1 mg (99%); MS=565.4 (M+H)+; λmax: 510.0 nm.
Example 261
(8S)-4′,9,9′-trihydroxy-6′-anilino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopentag]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone (261)
Five (5.0) mg (9.3 μmol) fredericamycin (1) are dissolved under argon in 1.0 ml anhydrous DMF. After addition of 3.46 mg (37.2 μmmol) aniline and 37.2 μg stannous(IV)chloride (1.0 M in CH2Cl2), it is heated to 60° C. The reaction mixture is stirred for 24 h, and then excess diethanolaminomethyl polystyrene resin is added. Stir for 1 h. Exhaust off the resin and wash with DMF. The organic phase is concentrated at high vacuum. A chromatographically homogenous red powder is left.
Yield: 5.5 mg (99%); MS=601.1 (M+H)+; λmax: 504.0 nm.
Example 262
(8S)-4′,9,9′-trihydroxy-6′-piperidino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopentag]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone (262)
Five (5.0) mg (9.3 μmol) fredericamycin (1) are dissolved under argon in 1.0 ml anhydrous DMF. After addition of 3.16 mg (37.2 μmmol) piperidine, it is stirred for 22 h at room temperature. Excess amine and DMF are removed in high vacuum. A chromatographically homogenous red powder is left.
Yield: 5.5 mg (99%); MS=593.4 (M+H)+; λmax: 504.0 nm.
Example 263
(8S)-4′,9,9′-trihydroxy-6′-dimethylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopentag]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone (263)
Five (5.0) mg (9.3 μmol) fredericamycin (1) are dissolved under argon in 1.0 ml anhydrous DMF. After addition of 1.67 mg (37.2 μmmol) dimethylamine (2M in MeOH), it is stirred for 4 h at room temperature. Excess amine and DMF are removed in high vacuum. A chromatographically homogenous red powder is left.
Yield: 5.5 mg (99%); MS=553.6 (M+H)+; λmax: 526.0 nm.
Example 264
(8S)-4′,9,9′-trihydroxy-6′-isopropylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopentag]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone (264)
Five (5.0) mg (9.3 μmol) fredericamycin (1) are dissolved under argon in 1.0 ml anhydrous DMF. After addition of 2.19 mg (37.2 μmmol) isopropylamine, it is stirred for 4 h at room temperature. Excess amine and DMF are removed in high vacuum. A chromatographically homogenous red powder is left.
Yield: 5.2 mg (99%); MS=567.3 (M+H)+; λmax: 504.0 nm.
Example 265
(8S)-4′,9,9′-trihydroxy-6′-methylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopentag]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone (265)
Five (5.0) mg (9.3 μmol) fredericamycin (1) are dissolved under argon in 1.0 ml anhydrous DMF. After addition of 0.34 mg (11.1 μmmol) methylamine (2M in CH3OH), it is stirred for 19 h at room temperature. Excess amine and DMF are removed in high vacuum. A chromatographically homogenous red powder is left.
Yield: 5.0 mg (99%); MS=539.2 (M+H)+; λmax: 504.0 nm.
Example 266
(8S)-5-iodo-4′,9,9′-trihydroxy-6′-methylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopentag]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone (266)
Five (5.0) mg (7.5 μmol) 5-iodofredericamycin (1) are dissolved under argon in 1.0 ml anhydrous DMF. After addition of 0.28 mg (9.0 μmmol) methylamine (2M in CH3OH), it is stirred for 2 h at room temperature. Excess amine and DMF are removed in high vacuum. A chromatographically homogenous red powder is left.
Yield: 5.0 mg (99%); MS=665.2 (M+H)+; λmax: 492.0 nm.
Example 267
(8S)-4′,9,9′-trihydroxy-6′-morpholino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopentag]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone (267)
Five (5.0) mg (9.3 μmol) fredericamycin (1) are dissolved under argon in 1.0 ml anhydrous DMF. After addition of 3.24 mg (37.2 μmmol) morpholine, it is stirred for 18 h at room temperature. Excess amine and DMF are removed in high vacuum. A chromatographically homogenous red powder is left.
Yield: 5.5 mg (99%); MS=595.5 (M+H)+; λmax: 518.0 nm.
Example 268
(8S)-4′,9,9′-trihydroxy-6′-amino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopentag]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone (268)
Five (5.0) mg (9.3 μmol) fredericamycin (1) are dissolved under argon in 1.0 ml anhydrous DMF. After addition of 0.67 mg (37.2 μmmol) ammonia (2M in EtOH), it is stirred for 24 h at room temperature. Excess ammonia and DMF are removed in high vacuum. A chromatographically homogenous red powder is left.
Yield: 4.8 mg (99%); MS=525.4 (M+H)+; λmax: 504.0 nm.
Example 269
(8S)-4′,9,9′-trihydroxy-6′-pyrrolidino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopentag]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone (269)
Five (5.0) mg (9.3 μmol) fredericamycin (1) are dissolved under argon in 1.0 ml anhydrous DMF. After addition of 0.99 mg (13.9 μmmol) pyrrolidine, it is stirred for 19 h at room temperature. Excess amine and DMF are removed in high vacuum. A chromatographically homogenous red powder is left.
Yield: 5.3 mg (99%); MS=579.2 (M+H)+; λmax: 554.0 nm.
Example 270
(8S)-5-bromo-4′,9,9′-trihydroxy-6′-methylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopentag]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1,1′-3′,5′,8′(2H)-pentone (270)
Five (5.0) mg (8.1 μmol) 5-bromofredericamycin (1) are dissolved under argon in 1.0 ml anhydrous DMF. After addition of 0.70 mg (12.2 μmmol) cyclopropylamine, it is stirred for 5 h at room temperature. Excess cyclopropylamine and DMF are removed in high vacuum. A chromatographically homogenous red powder is left.
Yield: 5.0 mg (99%); MS=643.4/645.4 (M+H)+; λmax: 492.0 nmn.
Example 271
2-[Acetyl]-3-[(8S)-4′,9,9′-trihydroxy-6′-methylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopent[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl]ethene (271)
79.5 mg (479 μmol) (2-oxo-propyl)-phosphonic acid dimethylester are dissolved under argon in 8 ml absolute pyridine, and 60.2 μl (479 μmol) 1,1,3,3-tetramethylguanidine are added at 0° C. After 5 minutes, 80.0 mg (159.7 μmol) fredericamycin aldehyde (4) is added at 0° C. After 2 hours, 100 ml 1 M hydrochloric acid are added, and the supernatant is sucked off from the precipitate. Dry under high vacuum.
Yield: 60.0 mg (69% of the theoretical value); M/e=542.2; λmax: 492.0 nm.
Example 272
2-[Bromoacetyl]-3-[(8S)-4′,9,9′-trihydroxy-6′-methylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopentag]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl]ethene (272)
Fifty (50.0) mg (92.4 μmol) acetyl fredericamycin are dissolved under argon in 5 ml absolute DMF, and then 36.9 mg (231.1 μmol) bromine as a 1 M bromine solution in DMF are added under exclusion of light. It is stirred for 23 h under exclusion of light, and then 100 ml water are added. The precipitate is sucked off and dried under high vacuum.
Yield: 57.0 mg (87% of the theoretical value) red powder; M/e=697.9/699.9/701.9; M+; λmax: 504.0 nm.
Example 273
2-[2-Amino-thiazole-4-yl]-3-[(8S)-4′,9,9′-trihydroxy-6′-methylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopentag]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl]ethene (273)
Twenty (20.0) mg (28.7 μmol) bromoacetyl fredericamycin (273) are dissolved under argon in 4 ml absolute DMF. At room temperature, first 3.3 mg (43.0 μmol) thiourea, and then 20 mg IR120H+ are added. After 2 hours, it is filtered off the resin, and added to 50 ml water. The precipitate is dried under high vacuum. Red powder.
Yield: 18.0 mg (93% of the theoretical value); M/e=676.1/678.1; (M+H); λmax: 492.0 nm.
Example 274
2-[2-Phenyl-thiazole-4-yl]-3-[(8S)-4′,9,9′-trihydroxy-6′-methylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopenta[g]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl]ethene (274)
Five (5.0) mg (7.2 μmol) bromoacetyl fredericamycin (273) are dissolved under argon in 1 ml absolute DMF. At room temperature, first 1.5 mg (10.8 μmol) thiobenzamide, and then 5 mg IR120H+ are added. After 3.5 h, addition of hydrazinosulfonyl resin, and stirring for 2 h. It is filtered off the resin, and added to 10 ml water. The precipitate is dried under high vacuum. Red powder.
Yield: 3.0 mg (57% of the theoretical value); M/e=737.2/739.2; (M+H); λmax: 492.0 nm.
Example 275
2-[2-Acetylamino-thiazole-4-yl]-3-[(8S)-4′,9,9′-trihydroxy-6′-methylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopentag]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl]ethene (275)
Five (5.0) mg (7.2 μmol) bromoacetyl fredericamycin (273) are dissolved under argon in 1 ml absolute DMF. At room temperature, first 1.3 mg (10.8 μmol) acetylthiourea, and then 5 mg IR120H+ are added. After 22 h, addition of hydrazinosulfonyl resin, and stirring for 2 h. It is filtered off the resin, and added to 10 ml water. The precipitate is dried under high vacuum. Red powder.
Yield: 2.0 mg (39% of the theoretical value); M/e=718.3/720.4; (M+H); λmax: 492.0 nm.
Example 276
2-[2-Methyl-thiazole-4-yl]-3-[(8S)-4′,9,9′-trihydroxy-6′-methylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopentag]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-3-yl]ethene (276)
Five (5.0) mg (7.2 μmol) bromoacetyl fredericamycin (273) are dissolved under argon in 1 ml absolute DMF. At room temperature, first 0.81 mg (10.8 μmol) thioacetamide, and then 5 mg IR120H+ are added. After 2 h, addition of hydrazinosulfonyl resin, and stirring for 2 h. It is filtered off the resin, and added to 10 ml water. The precipitate is dried at high vacuum. Red powder.
Yield: 3.0 mg (62% of the theoretical value); M/e=675.2/677.2; (M+H); λmax: 492.0 nm.
Example 277
(8S)-4′,9,9′-trihydroxy-6′-methylamino-3-[(1E,3E)-penta-1,3-dienyl]-6,7-dihydrospiro[cyclopentag]isoquinoline-8,2′-cyclopenta[b]-naphthalene]-1-thio-1,1′-3′,5′,8′(2H)-tetrone-thiofredericamycin (277)
Ten (10.0) mg (18.5 μmol) fredericamycin (1) are dissolved under argon in 2 ml absolute pyridine. After addition of 20.5 mg (92.5 mmol) phosphorous-V-sulfide, it is heated for 12 h to 60° C. Addition of another 20.5 mg (92.5 mmol) phosphorous-V-sulfide. According to HPLC (acetonitrile/water CF3COOH), the reaction was complete after 1 h. It is transferred onto water and shaken out with ethyl acetate. Dry and concentrate. Purple-red powder.
Yield: 5.0 mg (49% of the theoretical value); M/e=55.7; (M+H); λmax: 504.0 nm.
Example A
Water Solubility of the Fredericamycin Derivatives
The water solubility of the various fredericamycin derivatives can be determined in a 0.9% NaCl solution with a pH of 7.
The compounds (22) and (3) dissolve very well. Compound (6) dissolves well, and compounds (2), (10), and (13) are soluble. Compounds (5), (7), (11) and (12) are sufficiently and markedly better soluble than fredericamycin (compound (1)).

## Claims

1. A compound according to the general formula Ia or Ib:



wherein in each
R1 means H,
R3 means H, F, Cl, Br, or I and
R2 means (CH2)rCH═N—NHCO—R23, (CH2)rCH═N—NHC(O)NH—R23, (CH2)rCH═N—NHC(S)NH—R23, (CH2)rCH═N—NHC(NH)NH—R23, (CH2)rCH═N—NHC(NH)—R23, (CH2)rCH═N—NHCO—CH2NHCOR21, (CH2)rCH═N—NHCS—R23, (CH2)rCH═N—NR21R22,





(CH2)rCH═N—N—(C3NX′R211R212R213R214), —(CH2)rCH═N—NHSO2 aryl, or —(CH2)rCH═N—NHSO2 heteroaryl, with r=0, 1, 2, 3, 4, 5, wherein X′═NR215, O, or S, and R211, R212, R213, R214, and R215 are independently H or C1-C6 alkyl,
R21, R22 are independently H, C1-C14 alkyl, C1-C14 alkanoyl, C1-C6 alkylhydroxy, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6alkylamino-C1-C6 alkyl, C1-C6 alkylamino-di-C1-C6-alkyl, cycloalkyl, C1-C4 alkylcycloalkyl, heterocycloalkyl, C1-C4 alkylheterocycloalkyl, aryl, aryloyl, C1-C4 alkylaryl, heteroaryl, heteroaryloyl, C1-C4 alkylheteroaryl, cycloalkanoyl, C1-C4 alkanoylcycloalkyl, heterocycloalkanoyl, C1-C4 alkanoylheterocycloalkyl, C1-C4 alkanoylaryl, C1-C4 alkanoylheteroaryl, 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 CH2-pyridinium salts, CH2-tri-C1-C6 alkylammonium salts, CONH2, CSNH2, CN, or CH2CN,
R24 independently of R21, has the same meanings as R21, or H, CN, COCH3, COOH, COOR21, CONR21R22, NH2, or NHCOR21,
R25 independently of R21, has the same meanings as R21, or H, CN, COCH3, COOH, COOR21, CONR21R22, NH2, 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,
R31, R32 are independently C1-C6 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 C1-C20 alkyl,
R4, R6, R7 independently mean H,
R41 independently from R21, has the same meanings as R21,
X means O,
Y means O, S, NR9, wherein R9 may be H or C1-C6 alkyl,
as well their stereoisomers, tautomers, and their physiologically tolerable salts,
wherein heterocycloalkyl by itself or as part of another substituent means a group selected from the group consisting of pyrrolidine, piperidine, morpholine,





wherein Y′′ means CH2, S, O, NH, or NC1-C6 alkyl, and
wherein heteroaryl by itself or as part of another substituent means a ring system selected from the group consisting of

2. The compound according to claim 1, wherein Formula Ia or Ib adopts the stereochemistry of Formula IIa or IIb

3. The compound according to claim 1, wherein R3 means F, Cl, Br, or I.

4. The compound according to claim 1, wherein R3 means (CH2)rCH═N—NHCO—R23, (CH2)rCH═N—NHC(O)NH—R23, (CH2)rCH═N—NHC(S)NH—R23, (CH2)rCH═N—NHC(NH)NH—R23, (CH2)rCH═N—NHC(NH)—R23, (CH2)rCH═N—NHCO—CH2NHCOR21, (CH2)rCH═N—NHCS—R23, (CH2)rCH═N—NR21R22,



(CH2)rCH═N—N—(C3NX′R211R212R213R214), (CH2)rCH═N—NHSO2 aryl, or (CH2)rCH═N—NHSO2 heteroaryl, with r=0, 1, 2, 3, 4, 5, wherein X′═NR215, O, or S, and R211, R212, R213, R214, and R215 are independently H or C1-C6 alkyl.

5. The compound according to claim 1, wherein
R1 means H,
R2 means CH═N—NR21R22,





—CH═N—NHSO2 aryl, —CH═N—NHSO2 heteroaryl, or CH═N—NHCO—R23, wherein X′═NR215, O, or S, and R211, R212, R213, R214, and R215 are independently H or C1-C6 alkyl,
R21, R22 independently mean C1-C6 alkyl, cycloalkyl, aryl, C1-C4 alkylaryl, heteroaryl, or C1-C4 alkylheteroaryl,
R23 independently of R21, has the same meanings as R21, or CH2-pyridinium salts, or CH2-tri-C1-C6 alkylammonium salts,
R24 independently of R21, has the same meanings as R21, or H, CN, COCH3, COOH, COOR21, CONR21R22, NH2, or NHCOR21,
R25 independently of R21, has the same meanings as R21, or H, CN, COCH3, COOH, COOR21, CONR21R22, NH2, or NHCOR21,
R24, R25 together mean C4-C8 cycloalkyl,
R3 means F, Cl, Br, or I,
R31 independently means C1-C6 alkyl,
R5 means C1-C6 alkyl,
R4, R6, R7 independently mean H,
R41 independently from R21, has the same meanings as R21,
X means O,
Y means O, or S.

6. A composition comprising a compound according to claim 1, a carrier and adjuvants.

7. A method of treating cancer in a patient comprising administering an effective amount of a compound of claim 1 to said patient wherein said cancer is melanoma or a tumor selected from the group consisting of lung, breast, renal, uterine and prostate tumors.

8. The compound according to claim 1, wherein R3 is H, and R2 is CH═N—NHCO—R23, —CH═N—NR21R22,



or CH═N—NHCO—R23, wherein X′═NR215, O, or S, and R211, R212, R213, R214, and R215 are independently H or C1-C6 alkyl.

9. The compound of claim 1, wherein
R3 is H and
R2 is —(CH2)rCH═N—NHCO—R23, —(CH2)rCH═N—NR21R22, —(CH2)rCH═N—NHC(S)NHR23, —(CH2)rCH═N—NHC(NH)NH—R23, or —(CH2)rCH═N—NHC(O)NH—R23.

10. The compound of claim 9, wherein X is O; Y is O; R5 is C1-C20 alkyl, and R4, R6, and R7 are each independently H.

11. The compound of claim 1, wherein
R3 is Cl, Br or I; and
R2 is (CH2)rCH═CN—NR21R22, (CH2)rCH═N—NHCO—R23, (CH2)rC═N—NHC(S)NH—R23, (CH2)rCH═N—NHC(NH)NH—R23, (CH2)rCH═N—NHC(O)NH—R23, (CH2)rCH═NR21, or (CH2)rCH═N—NHCO—CH2NHCOR21.

12. The compound of claim 11, wherein X is O; Y is O; R5 is C1-C20 alkyl, and R4, R6, and R7 are each independently H.