Note: Descriptions are shown in the official language in which they were submitted.
CA 02761440 2011-12-16
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Fredericamycin derivatives /
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 tumor diseases.
Fredericamycin has been isolated 1981 from Streptomyces griseus, and
demonstrates anti-
tumor activity.
Fredericamycin and some derivatives of fredericamycin 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 US 4673768, alkali salts of the fredericamycin A are described. In US
4584377,
fredericamycin derivatives are described, particularly derivatives acylated in
ring E and F. In
US 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 la or Ib:
CA 02761440 2011-12-16
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0
R6--O X\
R7
Y O O
R1,N OI~R4
\ I / O
R2
R3 la
HO
X
R6-'O \R5
R7
Y O OH
R4
R1N O
\ I / O
R2
R3 Ib
wherein in each,
RI means H, C1-C6 alkyl, cycloalkyl, C1-C4 alkylcycloalkyl,
R2 means H, CI-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, OR2 1, NH2, NHR2 1, NR2 1 R22, SH,
SR2 1),
(CH2)rCH2NHCOR21, (CH2)rCH2OCOR21, (CH2)rCH2NHCSR21, (CH2),CH2S(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=NOCH2CONR21 R22, (CH2)rCH=NOCH(CH3)CONR21 R22, -
(CH2)rCH=NOC(CH3)2CONR21R22, (CH2)1CH=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)1CH=N-NHCS-R23, (CH2)1CH=CR24R25 (trans or cis), (CH2)r000H,
(CH2)r000R21, (CH2)rCONR21 R22, -(CH2)rCH=NR21, (CH2)rCH=N-NR21 R22,
CA 02761440 2011-12-16
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X`
R212 N
1.9
R
( ), and the (CH2)r chain elongated residue (CH2)rCH=N-N-
(C3NX'R211R212R213R214) (with X' = NR215, 0, S, and 8211, R212, R213, R214,
R215
being independently H or C1-C6 alkyl), -(CH2)rCH=N-NHSO2 aryl, -(CH2)TCH=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, 0, 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, COON,
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, 0, S,
CA 02761440 2011-12-16
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R3 means H, F, Cl, Br, I, OH, OR31, NO2, NH2, NHR31, NR31R32, NHCHO,
NHCOR3 1, NHCOCF3, CH3_thalt (with hal = Cl, F, particularly F, and t = 1, 2,
3), OCOR3 1,
R31, R32 are independently C1-C6 alkyl, or R3 I 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, 0, S,
R5 means H, C1-C20 alkyl, cycloalkyl, C2-C20 alkenyl, C2-Clo alkinyl, C1-C4
alkyl
cycloalkyl, heterocycloalkyl, C1-C4 alkyl heterocycloalkyl, aryl, C1-C4
alkylaryl, heteroaryl,
C1-C4 alkylheteroaryl, C,,,H2m+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, NR51 R52, SH, SR21),
(CH2)SCH2NHCOR51, (CH2)SCH2NHCSR51, (CH2),CH2 S(O)nR5 1, with n = 0, 1, 2,
(CH2)SCH2SCOR51, (CH2)sCH2OCOR51, (CH2)SCH2OSO2-R51, (CH2)sCH(OH)R51,
(CH2)S000H, (CH2),000R51, (CH2),CONR51R52, 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 R2 1, has the same meanings as R21,
X means 0, 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,
0, S,
or X-R5 may together be H,
CA 02761440 2011-12-16
Y means 0, 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 la 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 lb: R1:
H, R2: pentyl, 1-pentenyl, 3-pentenyl, 1,3-pentdienyl, R3: H, R4 and R6 being
H, and X-R5
being methoxy, Y: 0. Preferably, the substituents do not concomitantly adopt
the following
meaning: R1, R3: H, R2: H, alkyl, hydroxyalkyl, particularly monohydroxyalkyl,
alkoxyalkyl,
CF3, (CH2),COOH, CHO, CONH2, (CH2)rCH2NHCO alkyl, (CH2)rCH20CO 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
X, R6
R6-'
0 014
1120-
II a
R3
O
XI R6
I7 OH
V of 0--R4
R2 llb
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la may not concomitantly adopt the following meaning, except in the case of
cyclodextrin
inclusion compounds: Rl: 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 lb: R1: H, R2: pentyl, 1-
pentenyl, 3-pentenyl,
1,3-pentdienyl, R3: H, R4 and R6 being H, and X-R5 being methoxy, Y: 0.
The invention further relates to compounds of Formula Ia, lb, 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 Crõ H2,,,+o-pY'p (with in =
I to 6, for o = 1, p =
Y =
in _
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)r000H, (CH2)r000R21, (CH2)rCONR21R22. Still particularly
preferred is the group of the aldehyde-derived residues (CH2),CHO,
(CH2)rCH=NOH, -
(CH2)rCH=NOR21, (CH2)rCH=NOCOR21, (CH2)rCH=NOCH2CONR21R22, (CH2)1CH=N-
NHCO-R23, (CH2),CH=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-0-CH2NHCOR21, (CH2)rCH=N NHCS-R23, (CH2)rCH=CR24R25 (trans or
8211 X' H
NN
8212
8213 N
cis), (CH2)rCH=NR21, (CH2)rCH=N-NR21R22, 8214 and the
(CH2)r chain elongated residue (CH2)rCH=N-N-(C3NX'R211R212R213R214) (with X' _
NR215, 0, S, and R211, R212, R213, R214, R215 being independently H or C1-C6
alkyl), -
(CH2)rCH=N-NHS02 aryl, (CH2)rCH=N-NHS02 heteroaryl, (CH2)1CH=CH heteroaryl,
with r
= 0, 1, 2, 3, 4, 5, preferably 0.
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From the aldehydes and thereof derived compounds, such are preferred in which
at least RI or
r3 are not H, if R4 to R7 are H or alkyl.
Preferred residues in R2 are further heteroaryl, cycloaryl, C1-C4
alkylcycloalkyl,
heterocycloalkyl, C1-C4 alkyl heterocycloalkyl, C,,,H2,,,+o-pY'p (with m = 1
to 6, for o = 1, p = 1
to 2m+o; for m = 2 to 6, o = -1, p = l to 2m+o; for m = 4 to 6, o = -2, p = l
to 2m+o; Y' _
independently selected from the group of halogen, OH, 0R21, NH2, NHR2 1,
NR21R22, SH,
SR21), CH2NHCOR21, CH2NHCSR21, CH2S(O)nR21, with n = 0, 1, 2, CH2SCOR21,
CH2OSO2-R21, CH(OH)R21, CH=NOCOR21, -CH=NOCH2CONR21R22, -
CH=N0CH(CH3)-CONR21 R22, CH=NOC(CH3)2CONR11 R22, 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-NP21R22,
8211 X' NNC
R2I2 I
8213 N
8214 , (with X' = NR215, 0, S, and R21 1, R212, R213, R214, R215
being independently H or C1-C6 alkyl), CH=N-NHSO2 aryl, H=N-NHS02 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-thal, (with
hal = Cl, F, particularly F, and t = 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 la or Ila, 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:
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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, CONR21 R22, -CH=NR21, -CH=N-NR21
R22,
R ,,c
8212
8213 N
8214 , (with X' = NR215, O, S, and 8211, 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, NHCOR3 1,
R31 independently means C1-C6 alkyl,
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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, NR21 R22, 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 R2 1, has the same meanings as R2 1,
X means 0, S, NH, N-R8,
Y means 0, S, NH,
as well their stereoisomers, tautomers, and their physiologically tolerable
salts or inclusion
compounds, wherein the residues for Formula la may not concomitantly adopt the
following
meaning, except in case of cyclodextrin inclusion compounds: RI: 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:
RI: H, R2: pentyl, 1-pentenyl, 3-pentenyl, 1,3-pentdienyl, R3: H, R4 and R6
being H, and X-
R5 being methoxy.
0, S, particularly 0, are preferred for Y.
0, 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.
CA 02761440 2011-12-16
For R2 also preferred is the residue -CHOHCHOHCHOHCHOHCH3.
Furthermore, the following residues are preferred for R2: -CHCH-2-methyl-4-
thiazyl,
S~
N
particularly R , 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, I, particularly F, Cl, Br, I.
Particularly preferred for R2 is C--C8 alkyl, C2-C8 alkenyl, CH=NOR1, with R21
being C1-C8
alkyl, CI-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
CA 02761440 2011-12-16
11
II. Tumors 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 la: R1: H, C,-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 lb: 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, C 1.4 alkyl may be methyl, ethyl, 1-
propyl, 2-propyl,
2-methyl-2-propyl, 2-methyl-l-propyl, 1-butyl, 2-butyl, C1_6 alkyl, e.g. C1
alkyl, pentyl, 1-
pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 4-methyl-l-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-
CA 02761440 2011-12-16
12
propenyl, 2-propenyl, 2-methyl-2-propenyl, 2-methyl-l-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-l-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-l-pentinyl, or 3,3-dimethylbutinyl.
The term "halogen" stands for fluorine, chlorine, bromine, iodine, preferably
bromine and
chlorine.
The term "NM R22" 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 carbohydrate 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, SRI 1, C1-C6 alkylhydroxy, C1-C6 alkyl-OR1 1, COOH, COOR11, NH2,
NHRI 1,
NR11RI2, halogen, aryl, C1-C4 alkylaryl, heteroaryl, C1-C4 heteroalkylaryl,
wherein the
residues R11 and R12 independently can mean C1-C1o 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
CA 02761440 2011-12-16
13
function(s), carbothionyl function(s), or a carbonyl function and a
carbothionyl function, for
example pyrrolidine, piperidine, morpholine or
N -N
Ozzzz 14- J
S
Y = CH2, S, 0 NH, NC1-C6
alkyl
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, SRI 1, C1-C6 alkylhydroxy, C1-C6
alkyl-OR11,
COOH, COORI 1, NH2, NHR11, NR11R12, halogen, wherein the residues R11 and R12
independently can mean C1-Clo 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, 0, S.
Apart from phenyl and 1-naphthyl and 2-naphthyl, preferred aryls are:
OMS
H3C CH3 CH3 Cf,
C#
CA 02761440 2011-12-16
14
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, 0, in
which at least I ring system is aromatic, and those with up to 3 substituents,
preferably up to 1
substituent, wherein the substituents independently can have the meaning CI-C6
alkyl, OH,
NO2, CN, CF3, OR11, SH, SR11, C1-C6 alkylhydroxy, C1-C6 alkyl-ORI1, COOH,
COOR11,
NH2, NHCORI 1, NHR11, NR11R12, halogen, or phenyl, wherein the residues R11
and R12
independently can have the above indicated meanings.
Preferred heteroaryls are:
ell,
.104
CA
N-N
N
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 annelated
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,
CA 02761440 2011-12-16
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 g/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 lb and IIb can be obtained
from the
appropriate compounds of Formulas la and IIa 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).
CA 02761440 2011-12-16
16
Diagram 1
Ito
lte
0 KO O,
H H_'
OH OH
Fredericam in (2)
b
K -0-0
b
CH Asa Hw
OM
a) 0504, N-methylmorpholine-N-oxide, CH2, C12, CH;OH, H2O
b) KOH pyridine
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).
Diagram 2
0 eHIQI
0
0
OHD C*t OH ~M H N 0
[1 DH (2) (4)
a) NaIO4-H2O-DMF or carrier bound -104-H20-DMF
CA 02761440 2011-12-16
17
The fredericamycin aldehyde (4) can be reacted with acylhydrazones,
hydroxylamine, and 0-
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
Diagram 3
tom.
HO GH
era 0
0
H
(4) (table 1/3)
Table 1
Example/compound R m/eõaX(nm)
5/118 601.3 504.0
Ha
6/119 635.2 486.0
Ha
LOP
4
CA 02761440 2011-12-16
18
R Compound Example
111 18
N
105 19
H
113 20
C
H
AN'N%."
S
S
Synthesis of oximether
Diagram 4
NO O-k
0
Q HO, OH
OM
HF'$
Ct DMF
(4) (table 2/3)
Table 2
Example/compound R m/e ?õax(nm)
7/122 -H 516.1 500.0
8/120 -CH3 531.2 500.0
9/121 607.2 504.0
Fl;.
CA 02761440 2011-12-16
19
10/123 678.1 504.0
OH,
21/116 /116 630.1 504.0
112
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.
Diagram 5
Ho R2 a
OH 0 044
a
(R1= halogen, I, Br, Cl) (table 3)
Table 3
Formula for table 3:
Example/Compound R1 R2 Calculated Actual UVmax Yield
mass mass
100 C5H5N2 H 592.1230 593.10 500 95
CA 02761440 2011-12-16
''0
101
F
F F
N +H
H
HN
C5H3F3N3 H 661,1056 662,11 500 95
102
O
NH
C6H5N20 H 620,1179 621,11 492 95
103
N
TL
HN
C6H5N20 H 620,1179 621,11 500 95
CA 02761440 2011-12-16
21
104
N
C2H2N3 H 567,1026 568,11 500 80
105
(19) N
NH +H
H
C3H6N3 H 583,1339 584,10 492 95
106
O
O NH +H C5H4NO2 H 609,1019 610,09 492 95
207
0
1
NH
HzN
C7H7N20 H 634,1335 635,13 492 95
108
H2N
+H
NHCSNH2 H 574,0794 558,05 492 95
1G9
O
NH H
C5H4NOS H 625, 0791 626,08 492 95
110
NH
HN-S`
C10H9N20 a ET2 34 92 67 o
CA 02761440 2011-12-16
111
N`
C5H11N2 H 598,1699 599,14 492 95
112
0
-~-H
NH
0
C2H3N202 H 586,0971 587,10 492 95
113
(20) S
~~0 -~-H
S N
C3H2NOS2 H 631,0355 632,05 500 95
114
0
FN -~- H
N
C3H3N20 H 582,1022. 583,13 492 95
115
NH,
0
HN
C7H7N20 H 634,1335 635,16 492 70
216
N
NJ
+H
C6H12N02 H 629,1645 630,14 492 85
ii
CH4\~ H _ ,1182 ..50,11 or
L' 05
CA 02761440 2011-12-16
118
H
+H
O
C4H9N20 H 600,1492 601,16 492 85
119
N 1
+H
~NH
O
C7H8N20 H 635,1414 635,13 492 85
120(8)
0 +H
OMe H 530,0961 531,12 492 90
121 (9)
O --
qH
OCH2Ph H 606,1274 607,16 492 95
122 (7)
HO +H
OH H 516,0804 517,11 482 95
12
(10) HO
HO
H
+H
He .~
C6H1106 H 67E,1332 679,14 500 95
124
O
W, +H
O-H C7H7N20 H <.34,X335 635,15 492 u
J
CA 02761440 2011-12-16
24
125
0
NH +H
NHCONH2 H 556,1022 559,12 492 95
126
co --H
HN
127 C7H13N20 H 640,1805 641,13 492 95
G
+H
0
128 C7H6CIO H 640,0884 641,10 492 95
II
N
+H
0 NH
C5H5N205 H 640,0900 641,10 492 95
129
e, -/l
N /
04~NH +H
C5H6N30 H 623,1288 624,13 500 90
130
o
NH
H
+H
0 NH
4-
C4H7N202 H 614,1284 615,13 492 95
131
0 H
^M
07H14N3C H E 9 4 656 19 4 50
CA 02761440 2011-12-16
132
0
NJ
H
+H
0~-NH
C6H11N202 H 642,1597 643,17 492 60
133
H
N--
+H
O
C3H7N20 H 586,1335 587,15 492 70
134 (
-- H
o NH
C6H13N20 H 628,1805 629,17 492 70
135
+H
C4H1ONO H 587,1539 588,14 492 90
236
p
H
+H
0
C13H18C1N20 H 752,1885 753,19 492 85
137
H
c
~t-
C5H12N0 H 601-1,1696 602,19 492 70
138
N
a
C5H5N2 C1 52~,084C% 627,07 50 G 95
CA 02761440 2011-12-16
26
139
F
F F
aX
N
N
HV
C5H3F3N3 Cl 695,0666 696,06 500 95
140
O
~-NH
4- aX
C
)I-
N
C6H5N20 Cl 654,0789 655,07 500 95
141
N
`' aX
0
HN
C6H5N20 Cl 654,0789 655,07 500 95
142
~N\
aX
N
C2H2N3 Cl 601,0636 602,06 500 90
143
(NH aX
H
C3H6N3 Cl 617,0949 618,08 500 95
144
0
0 NH aX
C5H4N02 Cl 643,0629 644,05 500 95
1LL
LL --
0
NH
e~z ^L' a~f
H,N
C7H7N20
C1 66E,0946 669,07 50G 9_`
CA 02761440 2011-12-16
146
H2N
s cl
NHCSNH2 Cl 608,0404 609,07 500 95
147
O
s aX
C5H4NOS Cl 659,0401 660,07 500 95
148
NH
HN
C10H9N20 Cl 706,1102 707,16 500 95
149
N`
~/11 aX
N
C5H11N2 Cl 632,1309 633,16 500 95
150
O
CX
NN
C2H3N202 Cl 620,0582 621,09 500 95
151
O -X
S~N a
C3H2NOS2 Cl 664,9965 645,31 500 95
152
0
a
FN
N
C 3H3N2C' Cl 616, 0632 617,10 500 95
CA 02761440 2011-12-16
28
153
NNz
a
0
HN
C7H7N20 Cl 668,0946 669,13 500 95
154
r-o
NJ k
Ic a
0
C6H12N02 Cl 663,1255 664,16 500 95
155
~11
NH a3t
m
CH4N3 Cl 591,0792 592,11 500 95
156
/ a
0
C4H9N20 Cl 634,1102 635,14 500 95
157
OL
a
o
C7H8N20 Cl 669,1024 669,12 500 95
158
0 a
OMe Cl 564,0571 565,09 500 95
155
a3`
qc
CCH2Ph Cl 640, 0624 Ã41,12 500 9=,
CA 02761440 2011-12-16
160 29
aX
OH Cl 550,0415 551,06 500 95
161
Ho
Ho
aX
0
H3
C6H1106 Cl 712,0943 713,10 500 95
162
O
aX
/ 1 ~
H
H
C7H7N20 Cl 668,0946 669,09 500 95
163
0
nti aX
NHCONH2 Cl 592,0633 593,07 500 90
164
CN
-~,- aX
0
C7H13N20 Cl 674,1415 675,11 500 95
165
Cl a`
0
k
C7H6CiC Cl 674,0494. 675,03 500 90
16Ã
II v
N / x
a`
0-' NH
C5H5N20S Cl 674,051C' 675,02 500 95
CA 02761440 2011-12-16
167
N
N
a
o
C5H6N30 Cl 657,0898 658,06 500 90
168
o`
NH
O fLNH
C4H7N202 Cl 648,0895 649,07 500 95
169
NJ X
0
C7H14N30 Cl 689,1524 690,15 500 60
170
/moo
NJ
a
o
C6H11N202 Cl 676,1208 677,13 500 60
171
H
N--
f () )-"
NH
C3H7N20 Cl= 620,0946 621,11 500 70
172
,N--
ON
C6H13N20 ca 662,1415 663,12 500 70
173
aC
0
C4ri20N0 C1 621, 1150 62_, 1 0 500 6
CA 02761440 2011-12-16
.~1
179
al-~
0
}
C13118C1N20 Cl 786,1495 787,16 500 90
175
ax ,
0
C5H12N0 Cl 635,1306 636,10 500 75
176
Bra
HN
,.Jr
C5H5N2 Br 670, 0334 670,99 500 95
177
F
F F
N Sr-11
HJ
C5H3F3N3 Br 739,0161 739,99 500 95
178
O
NH
C5, N
C6H5N20 Er 698,0284 E99,00 500 90
179
N
Br
O
HN
C6H5N2C Er 698,0284 699,00 500 90,
160
N\>
N Er
4-
-C-9 H2Iv rr 695rC_3';' ~,-5r ac 402
iU
CA 02761440 2011-12-16
181
N
C NH Bra
tC
C3H6N3 Br 661,0443 662,01 492- 95
182
0
0 ~-NH Bra
C514N02 Br 687,0124 688,99 492 95
183
0
Bra
H,N
C7H7N20 Br 712,0440 713,03 500 95
184
S Bra
NHCSNH2 Br 651,9899 653,04 500 95
185
0
S NFi Bra
C5H4NOS Br 702,9895 704,02 492 95
186
Br ~
HN
C1OH9N20 ?r 750,0597 751,10 500 5
187
N
0 Brs`
N
C5H11N2 676,080 E.77,10 492 0`
CA 02761440 2011-12-16
188
O
Bra
NH
0
C2H3N202 Er 664,0076 665,05 500 95
189
S--~0
S N er
C3H2NOS2 Br 708,9460 709,99 492 95
190
0
1-N Bra
C3H3N20 Br 660,0127 661,05 492 95
191
1 ` NHZ
Bfn
O
HN
C7H7N20 Br 712,0440 713,08 492 70
192
/`moo
1 fir
o/
C6H12N02 Er 707, 0750 708,06 500 95
193
CH4N3 Er 635,0287 636,02 5.00 95
194
O
L 4 _. aV 2 0 6 8.0597 6 ~%, 0Ã 500 G.-`_
CA 02761440 2011-12-16
y
195
N~ L
Br
~-NH
196 C7H8N20 Br 713,0518 713,03 500 95
0 Bra
197 OMe Br 608,0066 609,03 492 95
Brx
o
198 OCH2Ph Br 684,0379 685,05 492 95
HO er
19 9 OH Br 593,9909 595,01 492 95
HO
HO
O Br
0
H5 -
C6H1106 Er 756,0437 757,00 500 90
200
O
Brk
C7H7N20 Er 712,0440 713,00 500 90
201
NFC0 NH2 Br 636,0127 c--7,00 492 90
CA 02761440 2011-12-16
202
ON Jo 8rx
HN
C7H13N20 Br 718,0910 719,00 500 90
203
ci / 1
Br
0
C71i6C10 Br 717,9989 718,00 492 95
204
1-s
Sr
N YNH
0
C5H5N20S Br 718,0004 718,97 492 95
205
Oll N
Bx
O~NH
C5H6N30 Br 701,0392 702,01 500 95
206
o"
NH Br X,
C% NH
C4H7N202 Br 692,0389 693,03 492
~ J
207
Br y!
C7H14N30 Er 733,1018 734,10 500 90
208
NJ
(N &
,~)NH
C6ii12N.202 E= 720,0702 -/2-1,10 5000 9~
CA 02761440 2011-12-16
209 .36
H
N--
Br
O fZ-,NH
C31-i7N20 Br 664,0440 665,08 500 95
210
N.~
Bra
O;-NH
C6H13N20 Br 706,0910 707,09 500 90
211
N-.
Bra
O
C41-110N0 Br 665,0644 666,08 500 95
212
0
C13H18C1N20 Br 830,0989 831,11 500 95
213
B r~
C5H121q0 Br 679,0801 680,09 492 95
214
C
Gi-Pr H 558,1274 559,21 500 99
215
C
0-nn-Hex 000 1j43 6 3 r 00 cc
CA 02761440 2011-12-16
37
216
F
0 / +H
0
X
C7H6FO H 624,118.0 625,28 500 99
217
+H
C7H6C1O H 640,0884 641,27 5100 99
218
F
0-0
C7H6FO H 624,1180 625,31 500 99
219
air
0
X
01-Pr Cl 592,0884 593,28 500 810
220
adz'
C
x
O-n-Hex Cl 634,1354 635,36 5010 90
221
F
O
C7H6FO Cl 658,0790 659,32 500 85
222
a
aX
0
C7H6C10 Cl 674,0494 .75,31 5000 60
CA 02761440 2011-12-16
38
223
F
0-. air
o
X
C7H6FO Cl 658,0790 659,34 500 80
224
Bra
O
01-Pr Br 636,0379 639,30 492 90
225
Br4
0
O-n-Hex Br 678,0848 679,37 492 95
226
F
Br+
0
C7H6FO Br 702,0284 703,34 492 95
227
a
~ / Bra
x
C7H6C1O Br 717,9989 719,34 492 95
228
F
0
C7H6FO Er 702,0284 705,35 492 95
229
0
0i-Pr 1 684,0200 1E5,30 500 99.
CA 02761440 2011-12-16
39
230
0
O-n-Hex I 726,0669 727,41 5.00 99
231
F
0
C7H6FO I 750,0105 751,38 500 99
232
C7H6C1O I 765,9810 767,36 500 99
233
F
I-r-
0
X
C7H6FO 1 750,0105 751,38 500 99
234
O
OCH2Ph I 732,0200 733,38 500 99
235
~o\
. NJ
( I~
C
C6H12N02 7 755, 0571 756,33 50'0 99
236
0 I
OMe 6-55,9887 657, 32 492 95
CA 02761440 2011-12-16
237
0
C7H6C1O I 765,9810 767,38 492 99
238
0
C13H18C1N20 I 878,0810 879,45 500 99
239
HO OH 1 641,9730 643,31 492 99
240 ~
~N
N- 14-
s -NH
o X
C7H14N30 I 781,0840 782,39 500 99
241
co>
NJ Iy
o k
C6H11N202 I 768,0523 769,38 500 99
242
0
0
C2H3N202 2 711,9897 713,37 500 99
CA 02761440 2011-12-16
41
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)).
Diagram 5
4*0
= o 0
CH a
Q TZ
(4) j12).
C b
p i5
HO Ho
MN
C)M
F!~ 4
'OK
(13)
a) NaC102, NaH2PO4, 2,3-dimethylbutene-2
b) KOH, -H20, DMF
c) NaBH4
Fredericamycin aldehyde (4) can be oxidized with the oxidizing agent sodium
chlorite
(NaC102), 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
CA 02761440 2011-12-16
42
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.
Diagram 6
~-a
8
a, b HO D C61,
Hilt Q
Hal
Fredericamycin
a) N-bromosuccinimide, DMF, 0 C;
b) N-iodosuccinimide, DMF, 0 C;
CA 02761440 2011-12-16
43
o
~o ~ ~' ~ ros ari
Wit" ~ Gl
Frn
0
Selectovor
F
"3 0
a
Her
b ? 0 0 cI
CI
31
NaIO4
~t d
ego +~, ,~
w-q
o o der -I 1 ! IH
H Br 7)
(4)
I: l
Fr ca na dshyd CI: (39)
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-Homer (see diagram 7).
CA 02761440 2011-12-16
44
Diagram 7
' No
H HN
0 9
H
J41 (23)
a) 1T '11> uar idit
o~p~oy
The compound (24) is the precursor of an N-methylated fredericamycin
derivative (diagram
8).
Diagram 8
400 HMO
13
1'} (24)
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):
CA 02761440 2011-12-16
Diagram 9
Flo
a OH P&H2 W)
Fredericamyt nt 26
Br2
0
IiCS 0
CH
26
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).
Diagram 10
0
SOH
R2 K,
HO R3
0
O OH
CA 02761440 2011-12-16
46
Table 4
Example R1 R2 R3 UVmax m/e Yield
(nm) (%)
243 H 504 (M+H) 554 97
K2
244H 500 (M+) 582 96
H,
245 H 500 (M+H) 568 70
246 H 504 .(M+H) 597 36
H
HIC,
s H
247 Br 504 (M+) 71
c 632/634
N
248 H 500 (M+H) 566 91
H
249 H 499 (M+) 569 52
H3
250 H 504 (M+H) 616 99
251 ~ H 500 (M+) 580 99
CA 02761440 2011-12-16
47
252 H 499 (M+H) 622 20
OR iy~i
253 H 500 (M+H) 669 99
k
254 H 504 (M+H) 653 48
in F4
255#1= H 504 (M+H) 594 50
cr- 256 H 499 (M+H) 99
H2 632/634
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.
Diagram 11
Fla
HC D UN1 ~f~, Eil H'k;
C G
"a OM "a I OH
s
HN HN
U LJ
F.1 ftY
A2
C
to
O , U CH
CA 02761440 2011-12-16
48
Table 5
RI R2,, Ny R,3 Example
257
HfNy
258
Br 259
H 260
H 261
H 262
H 263
264
cI%
H 265
CA 02761440 2011-12-16
49
266
H 267
H 268
w
H 269
ILI,
Br 270
Preparation of heterocyclic fredericamycin derivatives
The fredericamycin aldehyde (4) can be reacted to pyridal acetone (271)
according to Wittig
or Wittig-Homer. 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.
Diagram 12
1 ~ a
rrO ~e II
O 0
0 Hy teal __
TUG
{4}
DMF
o a
a a
Nio QN ~(~ ~
MM
1~}y pr
(272)
CA 02761440 2011-12-16
TMG: Tetramethylguanidine
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).
Diagram 13
HO
o PAS
OF4 OM
Pyn, R,
H, (277)
Fredericamycin (1) forms inclusion compounds such as (25) with polysugars such
as a-
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).
CA 02761440 2011-12-16
51
0' 0
C G G
CyclodeArin
V *?
22)
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 pg/mL at 5 test concentrations
Table 7
Example / reference IC70 g/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
CA 02761440 2011-12-16
52
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-1(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 (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-: We = 606.2 (M+-H), Amax: 504Ø
CA 02761440 2011-12-16
53
Example 2
Tri-potassium-l-desoxy-5-C- [(8R)-4',9,9'-trihydroxy-6'-m ethoxy-1,1',3',5',8'-
pentaoxo-
1,1',2,3',5',6,7,8'-octabydrospiro[cyclopenta [g]isoquinoline-8,2'-
cyclopenta[b]-
naphthalene]-3-y1]pentitol (3)
Twelve (12.0) mg (19.8 mol) 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 gmol) tetrahydroxy fredericamycin (tetrol (2)) are
dissolved in 4 mL
DMF. Under vigorous stirring, an aqueous sodium iodate solution (300 mg Na104
in 1 mL
water) is added dropwise within one hour. After I 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 pmol) fredericamycin tetrol (2) are
dissolved in 8
mL pyridine. 180 L 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, UVm:
504.0 rim.
CA 02761440 2011-12-16
54
Example 4
1-[2-Oxo-2-((2E)-2-{ [(8 S)-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 pmol) fredericamycin aldehyde (4) are dissolved under
argon in 1.5
mL absolute DMF. Addition of 9.1 mg (47.9 pmol, 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 pmol, 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 3x 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 gmol) fredericamycin aldehyde (4) are dissolved in 3 mL
DMF. At
room temperature 7.5 mg (40.0 mol) acethydrazinopyridinium chloride (Girard
reagent P)
dissolved in 75 L 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; k,,,ax: 486Ø
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-
carbaldebyde oxime (122)
CA 02761440 2011-12-16
Ten (10) mg (19.4 mol) fredericamycin aldehyde (4) are dissolved in 2 mL DMF.
After
addition of 3.1 mg (44.6 pmol) hydroxylammonium chloride, 3.2 l 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-: We = 516.1; Xõa: 500.0 nm.
Example 7
(8S)-4',9,9'-trihyd roxy-6'-m eth oxy-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 mol) fredericamycin aldehyde (4) are dissolved in 2 mL DMF.
After
addition of 3.4 mg (40.7 mol) O-mehylhydroxylammonium chloride and 3.2 pl
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+: We = 531.2; kmmx: 500Ø
Example 8
(8S)-4',9,9'-trihydroxy-6'-m 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-
carbaldehyde-O-benzyloxime (9)
Ten (10) mg (19.4 mol) fredericamycin aldehyde (4) are dissolved in 2 mL DMF.
After
addition of 6.4 mg (43.2 pmol) O-benzylhydroxylammonium chloride and 3.2 gl
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+: We = 607.2; X,.: 504.0 nm.
CA 02761440 2011-12-16
56
Example 9
1-0-({(1E)-[(8S)-4',9,9'-trihydroxy-6'-m etboxy-1,1',3',5',8'-pentaoxo-
1,1',2,3',5',6,7,8'-
octabydrospiro[cyclopenta[g]isoquinoline-8,2'-cyclopenta[b]-naphthalene]-3-
yl]metbylene}amino)-p-D-glucopyranose (10)
Two (2.0) mg (4.0 mol) fredericamycin aldehyde (4) are dissolved in 150 L
DMF, and 0.86
mg (4.4 pmol) (3-aminoxy-D-glucopyranose is added. The mixture is stirred for
24 h at room
temperature, and 5 mg (15.0 pmol) 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;
4.: 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'-
octabydrospiro [cyclopenta [g]isoquinoline-8,2'-cyclopenta [b] -naphthalene]-
1,1',3',5',8'(2H)-pentone (11)
Thirty (30) mg (49.4 pmol) tetrahydroxy fredericamycin (2) were dissolved in 2
mL pyridine.
Twenty (20) mg (93.0 mol) sodium metaperiodate dissolved in 0.3 ml water are
added. After
stirring for 4 h, 10 mg (260 gmol) 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;
Xax: 504.0 nm.
Example 11
(8S)-4',9,9'-trihydroxy-6'-m eth oxy-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 mol) fredericamycin aldehyde (4) are dissolved in I mL
dichloromethane and 0.5 ml t-butanol. Addition of 250 pl 2,4-dimethylbutene.
Under stirring
at room temperature, a solution of 6.0 mg (53.1 mol) sodium chlorite (80%)
and 5.1 mg
sodium hydrogenphosphate in 250 l water are added dropwise.
CA 02761440 2011-12-16
57
After 2.5 h, again a solution of 10.0 mg (88.5 mol) sodium chlorite and 5 mg
sodium
dihydrogenphosphate in 200 l 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 (RP 18, acetonitrile-water-
acetic acid).
Red amorphous powder.
Yield: 68.3 mg (53.5% of the theoretical value). E': We = 516.1; X ax: 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] isoquin oline-8,2'-cyclopenta [b]-naphthalene]-
3-
carboxylate (13)
6.9 mg (13.3 mol) 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 pmol) 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; ?max: 504.0
nm.
Example 13
(8S)-5-bromo-4',9,9'-trihydroxy-6'-m ethoxy-1,1',3',5',8'-pentaoxo-
1,1',2,3',5',6,7,8'-
octabydrospiro[cyclopenta [g] isoquinoline-8,2'-cyclopenta [b]-naphthalene]-
1,1',3',5',8'(21H)-pentone (14)
Twenty (20) mg (37.1 mol) fredericamycin (1) were dissolved in 250 l DMF,
and then 6. 3
mg (35.3 gmol) N-bromosuccinimide in 250 l 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. We = 616.1/618.1;
? a,,: 486.0
nm.
CA 02761440 2011-12-16
58
Example 14
(8 S)-5-i odo-4',9,9'-trihyd roxy-6'-m ethoxy-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 pmol) fredericamycin (1) were dissolved in 1.0 l
DMF, and then
33.0 mg (150.0 mol) N-iodosuccinimide in 500 l 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;
~,,,,ax: 484.0 nm.
Example 15
Methyl-2-{ [(benzyloxy)carbonyl] am ino}-3- [(8S)-4',9,9'-trihydroxy-6'-m
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]acrylate (23)
Sixty six (66) mg (200 pmol) Z-a-phosphonoglycine trimethylester are dissolved
under argon
in 1 mL absolute pyridine, and 25 L 1, 1,3,3 -tetramethylguanidine are added
at 0 C. After 40
min. 20 mg (40 mol) 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 x with acetic acid. The
raw product is
purified by preparative HPLC (RP 18, acetonitrile-water).
Yield: 10.0 mg (36% of the theoretical value). M/e = 706.4; a,,,,ax: 492.0 nm.
Example 16
(8S)-9-hydroxy-4',6',9'-trim eth oxy-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 mol) fredericamycin (1) were dissolved under protective gas
in 4 ml
absolute DMF. At RT, 400 pl (4311 mol) methyliodide and 81 mg powdered
potassium
carbonate are added. The reactions mixture is then stirred at RT for 20 h, and
is then
CA 02761440 2011-12-16
59
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; Xmax:
368.0 nm.
Example 17
Fredericamycin A 1:2 complex with a-cyclodextrin (22)
Ten (10) mg fredericamycin (0.025 mMol) are added to a solution of 50 mg a-
cyclodextrin
(0.050 mMol) in 500 pl dimethylsulfoxide. The solution is then diluted with 5
ml water. A
stock solution prepared in such way can be diluted as desired with water.
XI., = 504.0 nm.
Example 18
4',9,9'-Trihydroxy-6'-meth oxy-1,1',3',5',8'-pentaoxo-1,1',2,3',5',6,7,8'-
octahyd rospiro [cyclopenta [g] isoquinoline-8,2'-cyclopenta [b]-naphthalene]-
3-
carbaidehyde(4-m ethylpiperazine-1-yl)hydrazone (111)
Five (5) mg (9.42 mol) fredericamycin aldehyde (4) are dissolved in 500 tl
DMF and 25 1
trifluoracetic acid. At room temperature, 1.30 mg (11.3 mol) 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)+; X
,ax: 504.0
rim.
Example 19
4',9,9'-Trihydroxy-6'-m etb oxy-1,1',3',5',8'-pentaoxo-1,1',2,3',5',6,7,8'-
octahyd rospiro [cyclopenta [g] isoquinolin a-8,2'-cyclopenta [b]-naphthalene]-
3-
carbaldehyde-4,5-dihydro-1H-imidazole-2-yl-hydrazone (123)
Five (5.00) mg (9.42 pmol) fredericamycin aldehyde (4) are dissolved in 500 l
DMF and 25
l trifluoracetic acid. At room temperature, 2.05 mg (11.3 pmol) 2-hydrazino-2-
imidazolin
CA 02761440 2011-12-16
460
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)+;
Xmax: 504.0
nm.
Example 20
4',9,9'-Trihydroxy-6'-m eth oxy-3- {(E)- [(4-oxo-2-thioxo-1,3-th iazolidin-3-
yl)imino] m ethyl) -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 mol) fredericamycin aldehyde (4) are dissolved in 500 1
DMF and 25
l trifluoracetic acid. At room temperature, 1.67 mg (11.3 pmol) 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)+; 2
ax: 504.0
nm.
Example 21
4',9,9'-Trihyd roxy-6'-m 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-
carbaldehyde-O-(2-morpholine-4-ylethyl)oxime (27)
Five (5.00) mg (9.42 gmol) fredericamycin aldehyde (4) are dissolved in 500 l
DMF and 25
l trifluoracetic acid. At room temperature, 2.47 mg (11.3 mol) 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 pmol, coating:
3.0 mmol/g) as
well as I 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.
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Red powder. Yield: 6.1 mg (98% of the theoretical value). M/e = 630 (M+H)+;
Amax: 504.0
nm.
Example 22
(8S)-5-chloro-4',6',9'-trim ethoxy-2-m 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 (34)
Three hundred (300) mg (556.6 mol) fredericamycin (1) are dissolved under
argon in 10 pl
DMF, and then 75.0 mg (556.6 mol) 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;
4ax: 504.0
M.
Example 23
(8 S)-5-flu o ro-4',9,9' -trihydroxy-6' -m eth oxy-3- [ (1 E,3E)-p en to-1,3-
dienyl] -6,7-
dihyd rospiro [cyclopenta [g] isoq uin olive-8,2'-cyclopenta [b]-naphthalene]-
1,1',3',5',8'(2H)-pentone (35)
Fifty (50) mg (92.8 pmol) fredericamycin (1) are dissolved in 5 ml DMF under
argon, and
then 33.0 mg (93.5 mol) 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 (RP 18,
acetonitrile-
water-acetic acid).
Yield: 7.1 mg (14% of the theoretical value) red crystal mass. M/e = 557; 4ax:
504.0 nm.
Example 24
1-Desoxy-5-C-[(8R)-5-chloro-4',9,9'-trihydroxy-6'-m 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 (36)
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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;õ.: 504Ø
Example 25
(8S)-4',9,9'-trihyd roxy-5-brom o-6'-m ethoxy-1,1',3',5',8'-pentaoxo-
1,1',2,3',5',6,7,8'-
octahyd rospiro [cyclopenta [g] isoquin oline-8,2'-cyclopenta [b] -
naphthalene]-3-
carbaldehyde (37)
Hundred (100) mg (200 pmol) fredericamycin aldehyde (4) are dissolved under
argon in 5 ml
DMF. Then, 200 l of a IM bromine solution in DMF is added. After stirring for
1.5 h at RT,
another 20 pl 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;
T,,r,ax: 504Ø
Example 26
1,2,3,4-Tetrahydro-5-brom o-4',9,9'-trihydroxy-6'-m 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 (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.
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Red crystal powder 8.1 mg (88% of the theoretical value) m/e = 621/623;
?,,,,ax: 499 Mn.
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'(211)-pentone-
Twenty (20) mg (37.1 pmol) fredericamycin are dissolved in 1 ml DMF under
argon, then
4.76 mg (44.50 pmol) benzylamine are added at room temperature. According to
HPLC
(RP 18, 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); 2õa,;:
492 rim.
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 .imol) 5-chiorofredericamycin are dissolved in 1 ml DMF
under argon,
then 1.12 mg (10.45 pmol) 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); ? ax: 492
M.
Example 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)-penton e
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Ten (10) mg (18.6 pmol) fredericamycin are dissolved in 1 ml DMF under argon,
then 1.36
mg (22.3 pmol) 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); .: 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 pmol) fredericamycin are dissolved in 1 ml DMF under argon,
then 2.7 l
(22.3 pmol) 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); Xõax: 492
run.
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] isoquin olive-8,2'-cyclopenta [b]-naphthalene]-
3-
carbaldehydepyridine-2-yl-hydrazone (100)
Yield: (95% of the theoretical value) MS: M/e = 593.1; Am : 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)
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Yield: (95% of the theoretical value) MS: M/e = 562.1; 2ax: 500.0 nm.
Example 102
N'-[(1 E)-(4',9,9'-trihyd roxy-6'-m 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)methylene]pyridyl-3-carbohydrazine (102)
Yield: (95% of the theoretical value) MS: M/e = 621.1; 2 ma,,: 492.0 run.
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; 500.0 run.
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; kmR, : 500.0 nm.
Example 105
4',9,9'-Trihyd roxy-6'-m eth oxy-1,1',3',5',8'-pentaoxo-1,1',2,3',5',6,7,8'-
octahydrospiro [cyclopenta [g]isoquinoline-8,2'-cyclopenta[b]-naphthalene]-3-
carbaldebyde-4,5-dihydro-1H-imidazole-2ylhydrazone (105)
Yield: (95% of the theoretical value) MS: M/e = 584.1; 4a,t: 492.0 nm.
Example 106
N'-[(1 E)-(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)m ethylene] -2-furohydrazine (106)
Yield: (95% of the theoretical value) MS: M/e = 610.0; 4.:492.0 nm.
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Example 107
4-Amino-N'-[(IE)-(4',9,9'-trihydroxy-6'-methoxy-1,1',3',5',8'-pentaoxo-
1,1',2,3',5',6,7,8'-
octahydrospiro [cyclopenta [glisoquinoline-8,2'-cyclopenta [b] -naphthalene]-3-
yl)methylene]benzohydrazine (107)
Yield: (95% of the theoretical value) MS: We = 635.1;492.0 run.
Example 108
4',9,9'-Trihydroxy-6'-methoxy-1,1',3',5',8'-pentaoxo-1,1',2,3',5',6,7,8'-
octahydrospiro [cyclopenta [glisoquinoline-8,2'-cyclopenta [b]-naphthalene]-3-
carbaldehydethiosemicarbazone (108)
Yield: (95% of the theoretical value) MS: We = 558.0;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]isoquin oline-8,2'-cyclopenta[b]-naphthalene]-3-
yl)methylene]thiophene-2-carbohydrazine (109)
Yield: (95% of the theoretical value) MS: We = 626.0; : 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 [glisoquinoline-8,2'-cyclopenta
[b]-
naphthalene]-3-yl)methylenelacetohydrazine (110)
Yield: (95% of the theoretical value) MS: We = 673.1; 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[glisoquinoline-8,2'-cyclopenta [bl-naphthalene]-3-
carbaldehyde(4-methylpiperazine-1-yl)hydrazone (111)
Yield: (95% of the theoretical value) MS: We = 599.1; ~,,.: 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[glisoquinoline-8,2'-cyclopenta[b]-naphthalene]-3-
yl)methylenel-hydrazine; acetamide (112)
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Yield: (95% of the theoretical value) MS: M/e = 587.1; 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; Amax: 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-
yI)methylene]-hydrazino)acetonitrile (114)
Yield: (95% of the theoretical value) MS: M/e = 583.1; X,.: 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; ? ax: 492.0 nm.
Example 116
4',9,9'-trihyd roxy-6'-methoxy-1,1',3',5',8'-pentaoxo-1,1',2,3',5',6,7,8'-
octahyd rospiro [cyclopenta [g] isoquin olive-8,2'-cyclopenta [b] -
naphthalene]-3-
carbaldehyde O-[2-morpholine-4-yl-ethyl]oxime (116)
Yield: (85% of the theoretical value) MS: We = 630.1; 2 : 492.0 nm.
Example 117
(2E)-2-[(4',9,9' -trihydroxy-6'-m eth oxy-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; X,,,ax: 500.0 nm.
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Example 118
2-(Dimetbylam ino)-N'-[(1E)-(4',9,9'-trihydroxy-6'-m ethoxy-1,1',3',5',8'-
pentaoxo-
1,1',2,3',5',6,7,8'-octahydrospiro[cyclopenta [g]isoquinoline-8,2'-
cyclopenta[b]-
naphthalenej-3-yl)m ethylene] acetohydrazine (118)
Yield: (85% of the theoretical value) MS: M/e = 601.1; ?ax: 492.0 mn.
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)ethyljpyridinium chloride (119)
Yield: (85% of the theoretical value) MS: M/e = 635.1; X,.: 492.0 run.
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 [gjisoquinoline-8,2'-cyclopenta [b] -naphthalene] -
3-
carbaldehyde O-methyloxime (120)
Yield: (90% of the theoretical value) MS: M/e = 531.1; ax: 492.0 mn.
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-
carbaldebyde O-benzyloxime (121)
Yield: (95% of the theoretical value) MS: M/e = 607.1; a,,,ax: 492.0 mn.
Example 122
4',9,9'-Trihydroxy-6'-methoxy-1,1',3',5',8'-pentaoxo-1,1',2,3',5',6,7,8'-
octahydrospiro[cyclopenta 1g1 isoquinoline-8,2'-cyclopenta[b]-naphthalene]-3-
carbaldehyde oxime (122)
Yield: (95% of the theoretical value) MS: M/e = 517.1; ,aX: 482.0 nm.
Example 123
1-0-({(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)-[i-D-glucopyranose (123)
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Yield: (95% of the theoretical value) MS: M/e = 679.1; 4,,,: 500.0 nm.
Example 124
4',9,9'-Tribyd roxy-6'-m etb oxy-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;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; 2,a,: 492.0 nm.
Example 126
2-Piperidino-4-yl-N'-[(1 E)-(4',9,9'-trihyd roxy-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; ~,,n.: 492.0 nm.
Example 127
4',9,9'-Trihydroxy-6' -m 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-
carbaldehyde O-(3-chlorobenzyl)oxime (127)
Yield: (95% of the theoretical value) MS: We = 641.1; ?ax: 492.0 nm.
Example 128
N'-[(1E)-(4',9,9'-trihydroxy-6'-m 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)methylene]-(2-methyl-1,3-thiazole-4y1)carbohydrazide (128)
Yield: (95% of the theoretical value) MS: We = 641.1; X ax: 492.0 nm.
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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[bJ-
naphthalene]-3-yl)methylene]acetohydrazide (129)
Yield: (90% of the theoretical value) MS: M/e = 624.1; Aax: 500.0 nm.
Example 130
2-(Acetylamino)-N'-[(1 E)-(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
[bJ-
naphthalene] -3-yl)methylene]acetohydrazide (130)
Yield: (95% of the theoretical value) MS: M/e = 615.1; Xa,,: 492.0 nm.
Example 131
2-(4-Methylpiperazine-1-yl)-N'-[(1 E)-(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]-
naphthaleneJ-3-yl)methylene]acetohydrazide (131)
Yield: (50% of the theoretical value) MS: M/e = 656.1; a,,,,a,,: 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[gJ isoquinoline-8,2'-
cyclopenta[bJ-
naphthaleneJ-3-yl)methylene] acetohydrazide (132)
Yield: (60% of the theoretical value) MS: M/e = 643.1; a,,,,a,t: 492.0 nm.
Example 133
2-(Methylamino) }V'-[(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: We = 587.1; a,IõaX: 492.0 nm.
Example 134
2-[Isopropyl(methyl) amino] -N'-[(IE)-(4',9,9'-trihydroxy-6'-methoxy-
1,1',3',5',8'-
pentaoxo-1,1',2,3',5',6,7,8'-octahydrospiro Icyclopenta[gJisoquinoline-8,2'-
cyclopenta[bJ-
naphthalene]-3-yl)methylene]acetohydrazide (134)
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Yield: (70% of the theoretical value) MS: M/e = 629.1; 2,.: 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-
carbaidehyde 0-[2-(dimethylamino)ethyl]oxime (127)
Yield: (90% of the theoretical value) MS: M/e = 588.1; 4ax: 492.0 nm.
Example 136
4',9,9'-Trihydroxy-6'-m ethoxy-1,1',3',5',8'-pentaoxo-1,1',2,3',5',6,7,8'-
octahydrospiro [cyclopenta [g] isoquinolin a-8,2'-cyclopenta [b]-naphthalene]-
3-
carbaldehyde 0-[3-(4-(3-chlorophenyl)-piperazine-1-yl)propyl]oxime (136)
Yield: (85% of the theoretical value) MS: M/e = 753.1; Xmax: 492.0 nm.
Example 137
4',9,9'-Trihydroxy-6'-m ethoxy-1,1',3',5',8'-pentaoxo-1,1',2,3',5',6,7,8'-
octahydrospiro[cyclopenta[gJisoquinoline-8,2'-cyclopenta [b]-naphthalene]-3-
carbaldehyde 0-[3-(dimethylamino)propyl]oxime (137)
Yield: (70% of the theoretical value) MS: M/e = 602.1; ~,,.: 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; 4ax: 500.0 nm.
Example 139
(8S)-5-chloro-4',9,9'-trihydroxy-6'-m ethoxy-1,1',3',5',8'-pentaoxo-
1,1',2,3',5',6,7,8'-
octahydrospiro [cyclopenta [g] isoquin olive-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; 1a,,: 500.0 nm.
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Example 140
(8S)-5-chloro-N'-[(1E)-(4',9,9'-trihydroxy-6'-m 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)m ethylene] pyridyl-3-carbohydrazine (140)
Yield: (95% of the theoretical value) MS: M/e = 655.0; 4: 500.0 nm.
Example 141
(8S)-5-chloro-N'-[(1E)-(4',9,9'-trihydroxy-6'-m 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)m ethylene] isonicotinohydrazide (141)
Yield: (95% of the theoretical value) MS: M/e = 655.0; 4 : 500.0 nm.
Example 142
(8S)-5-chloro-4',9,9'-trihydroxy-6'-metboxy-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: We = 602.0; õ: 500.0 nm.
Example 143
(8 S)-5-chloro-4',9,9'-trihyd roxy-6'-m 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-
carbaldehyde-4,5-dihydro-1H-imidazole-2-ylhydrazone (143)
Yield: (95% of the theoretical value) MS: M/e = 618.0; ? : 500.0 nm.
Example 144
(8S)-5-chloro-N'-[(1 E)-(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)m ethylene]-2-furohydrazide (144)
Yield: (95% of the theoretical value) MS: We = 644.0; a,,r,: 500.0 nm.
Example 145
(8S)-5-chloro-4-amino-N'-[(1 E)-(4',9,9'-trihyd roxy-6'-methoxy-1,1',3',5',8'-
pentaoxo-
1,1',2,3',5',6,7,8'-octahydrospiro [cyclopenta [g]isoquinoline-8,2'-cyclopenta
[b]-
napbthalene]-3-yl)methylene]-benzohydrazide (145)
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Yield: (95% of the theoretical value) MS: M/e = 669.0; kax: 500.0 run.
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; Amax: 500.0 nm.
Example 147
(8S)-5-chloro-N'-[(1E)-(4',9,9'-trihydroxy-6'-m 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)methylene]thiophene-2-carbohydrazide (147)
Yield: (95% of the theoretical value) MS: M/e = 660.0; ,ax: 500.0 nm.
Example 148
(8S)-5-chloro-2-(1H-indole-3-yl)-N'-[(lE)-(4',9,9'-trihydroxy-6'-m 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)m ethylene] acetohydrazide (148)
Yield: (95% of the theoretical value) MS: We = 707.1; ax: 500.0 ran.
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; ?: 500.0 nm.
Example 150
(8S)-5-chloro-2-ox o-2-{(2E)-2-[4',9,9'-trihyd roxy-6'-meth oxy-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; õa,,: 500.0 nm.
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Example 151
(8S)-5-chloro-4',9,9'-trihydroxy-6'-m ethoxy-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; a.,,,.: 500.0 nm.
Example 152
(8S)-5-chloro-{(2E)-2-[4',9,9'-trihydroxy-6'-m 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)methylene]hydrazino)acetonitrile (152)
Yield: (95% of the theoretical value) MS: M/e = 617.1; Ama,,: 500.0 nm.
Example 153
(8S)-5-chloro-2-amino-N'-[(IE)-(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: We = 669.1; ~,.: 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 0-[2-morpholine-4-yl-ethyl)oxime (154)
Yield: (95% of the theoretical value) MS: M/e = 664.1; an,aX: 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; ~,,,,.: 500.0 nm.
Example 156
(8S)-5-chloro-2-(dim ethylamino) 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)m ethylene] acetohydrazide (156)
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Yield: (95% of the theoretical value) MS: M/e = 635.1; Xax: 500.0 nm.
Example 157
(8S)-5-chloro-l-[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 [gi isoquinoline-8,2'-
cyclopenta [b]-
naphthalene]-3-yl)methylene] hydrazino)ethyl]pyridinium chloride (157)
Yield: (95% of the theoretical value) MS: We = 669.1; a,,,: 500.0 nm.
Example 158
(8S)-5-chloro-4',9,9'-trihyd roxy-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;ax: 500.0 nm.
Example 159
(8S)-5-chloro-4',9,9'-trihy droxy-6'-m 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-
carbaldehyde-O-benzyloxime (159)
Yield: (95% of the theoretical value) MS: M/e = 641.1; ? ,1: 500.0 nm.
Example 160
(8S)-5-chloro-4',9,9'-trihyd roxy-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: We = 551.1; Xax: 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-y1)methylene]amino)-p-D-glucopyranose (161)
Yield: (95% of the theoretical value) MS: We = 713.1; ~,nax: 500.0 nm.
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Example 162
(8S)-5-chlo ro-4',9,9'-trihydroxy-6'-m etb oxy-1,1',3',5',8'-pentaoxo-
1,1',2,3',5',6,7,8'-
octahydrospiro Icyclopenta [g] isoquinoline-8,2'-cyclopenta[b]-naphthalene]-3-
carbaldehyde-phenylsemicarbazone (162)
Yield: (95% of the theoretical value) MS: M/e = 669.1; 500.0 nm.
Example 163
(8S)-5-chloro-4',9,9'-trihydroxy-6'-m 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-
carbaldehydesemicarbazone (163)
Yield: (90% of the theoretical value) MS: We = 593.0; a,,,,a,,: 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'-octabydrospiro [cyclopenta
[g]isoquinoline-8,2'-
cyclopenta [b] -naphthalene] -3-yl)methylene] acetohydrazide (164)
Yield: (95% of the theoretical value) MS: M/e = 675.1; a,,,,: 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; Xn a,,: 500.0 nm.
Example 166
(8S)-5-chloro-N'- [(1E)-(4',9,9'-trihydroxy-6'-m eth oxy-1,1',3',5',8'-penta
oxo-
1,1',2,3',5',6,7,8'-octahyd rospiro [cyclopenta [g] is oquin oline-8,2'-
cyclopenta [b]-
naphthalene]-3-yl)methylene]a-2-methyl-1,3-thiazole-4yl-carbohydrazide (166)
Yield: (95% of the theoretical value) MS: We = 675.0; Am.: 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)
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Yield: (90% of the theoretical value) MS: M/e = 658.1; 500.0 nm.
Example 168
(8S)-5-chloro-2-(acetylamino) ]V'-[(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[bJ-
naphthalene]-3-yl)m ethylene]acetohydrazide (164)
Yield: (95% of the theoretical value) MS: M/e = 649.0; 2: 500.0 nm.
Example 169
(8S)-5-chloro-2-(4-m ethylpiperazine-1-yl)-N-[(1 E)-(4',9,9'-trihydroxy-6'-m
ethoxy-
1,1',3',5',8'-penta oxo-1,1',2,3',5',6,7,8'-octahydrospiro [cyclopenta [g]
isoq uinoline-8,2'-
cyclopenta[bJ-naphthalene]-3-yl)methylene]acetohydrazide (169)
Yield: (60% of the theoretical value) MS: M/e = 690.1; 1m..: 500.0 run.
Example 170
(8S)-5-chloro-2-m o rph olio e-4-yl-N - [(1 E)-(4',9,9'-trihyd roxy-6'-m eth
oxy-1,1',3',5',8'-
pentaoxo-1,1',2,3',5',6,7,8'-octahydrospiro[cyclopenta [g]isoquinoline-8,2'-
cyclopenta [bJ-
naphthalene]-3-yl)methylene]acetohydrazide (170)
Yield: (60% of the theoretical value) MS: M/e = 677.1; 2 m.: 500.0 nm.
Example 171
(8S)-5-chloro-2-(methylamin o)-N-[(lE)-(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 [bJ-
naphthalene]-3-yl)methylene]acetohydrazide (171)
Yield: (70% of the theoretical value) MS: M/e = 621.1; a, n.: 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; Xm.: 500.0 nm.
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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 0-[2-(dimethylamino)ethyl]-oxime (173)
Yield: (60% of the theoretical value) MS: We = 622.0; kax: 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 0-[3-(4-(3-chlorophenyl)-piperazine-1-yl)propyl]-oxime (174)
Yield: (90% of the theoretical value) MS:.M/e = 787.1; tax: 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] isoquin olive-8,2'-cyclopenta [b]-naphthalene]-
3-
carbaldehyde 0-[3-(dimethylamino)propyl]oxime (175)
Yield: (75% of the theoretical value) MS: We = 636.1; 4ax: 500.0 nm.
Example 176
(8S)-5-brow o-4',9,9'-trihyd roxy-6'-m 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-
carbaldehydepyridine-2-yl-hydrazone (176)
Yield: (95% of the theoretical value) MS: We = 670.9; X : 500.0 nm.
Example 177
(8S)-5-brow o-4',9,9'-trihyd roxy-6'-m 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-
carbaldehyde [4-(trifluorom ethyl)pyrimidine-2-yl]hydrazone (177)
Yield: (95% of the theoretical value) MS: M/e = 739.9; 4ax: 500.0 nm.
Example 178
(8S)-5-bromo 1V'-[(lE)-(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)
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Yield: (90% of the theoretical value) MS: We = 699.0; X,,,ax: 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; X: 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; 4,,.: 492.0 nm.
Example 181
(8S)-5-brom o-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: Mle = 662.0; ? : 492.0 nm.
Example 182
(8S)-5-bromo-N-[(1E)-(4',9,9'-trihydroxy-6'-m eth oxy-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; X : 492.0 nm.
Example 183
(8S)-5-bromo-4-amino-N-[(1E)-(4',9,9'-tribydroxy-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)m ethylene] benzohydrazide (183)
Yield: (95% of the theoretical value) MS: M/e = 713.0; ~,,,: 500.0 nm.
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Example 184
(8S)-5-brow o-4',9,9'-trihydroxy-6'-m etboxy-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: We = 653.0; Aax: 500.0 nm.
Example 185
(8S)-5-brow o-N-[(1.)-(4',9,9'-trihydroxy-6'-m eth oxy-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: We = 704.0; : 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'-octahyd rospiro [cyclopenta [glisoquinoline-8,2'-
cyclopenta [b]-
napbthalenel-3-yl)methylene]acetohydrazide (186)
Yield: (95% of the theoretical value) MS: We = 751.1; a,,,,.: 500.0 nm.
Example 187
(8S)-5-brow o-4',9,9'-trihy droxy-6'-metboxy-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: We = 677.1; ax: 500.0 nm.
Example 188
(8S)-5-brom o-2-oxo-2-{(2E)-2- [(4',9,9'-trihyd roxy-6'-metboxy-1,1',3',5',8'-
pentaox o-
1,1',2,3',5',6,7,8'-octahydrospiro [cyclopenta [glisoqu in oline-8,2'-
cyclopenta [bl-
naphthalenel-3-yl)methylene]hydrazino}acetamide (188)
Yield: (95% of the theoretical value) MS: We = 665.0; ?,ma,t: 500.0 nm.
Example 189
(8S)-5-bromo-4',9,9'-trihyd roxy-6'-methoxy-1,1',3',5',8'-pentaoxo-
1,1',2,3',5',6,7,8'-
octahydrospiro [cyclopenta [glisoquinoline-8,2'-cyclopenta[b]-naphthalene]-
1,1',3',5',8'(211)-peptone (189)
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Yield: (95% of the theoretical value) MS: M/e = 709.9; a,,,, : 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]-
napbthalene]-3-yl)methylene]hydrazino}acetonitrile (190)
Yield: (95% of the theoretical value) MS: M/e = 661.0; 500.0 nm.
Example 191
(8S)-5-brow o-2-amino-N-[(1E)-(4',9,9'-trihydroxy-6'-m 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)methylene]benzohydrazide (191)
Yield: (70% of the theoretical value) MS: We = 713.0; Xma,,: 492.0 rim.
Example 192
(8S)-5-brom o-4',9,9'-trihyd roxy-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 0-[2-morpholine-4-yl-ethyl)oxime (192)
Yield: (95% of the theoretical value) MS: M/e = 708.0; 4,: 500.0 run.
Example 193
(8S)-5-bromo-(2E)-2-[(4',9,9'-trihydroxy-6'-m 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)methylene]hydrazinecarboximidamide (193)
Yield: (95% of the theoretical value) MS: We = 636.0; kma,,: 500.0 rim.
Example 194
(8S)-5-bromo-2-(dimethylam ino)-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]-
napbthalene]-3-yl)methylene]acetohydrazide (194)
Yield: (95% of the theoretical value) MS: M/e = 679.0; 4.: 500.0 rim.
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Example 195
(8S)-5-bromo-l-[2-oxo-2-((2E)-2-{ [(8S)-4',9,9'-trihydroxy-6'-m 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)methylene}hydrazino)ethyl]pyridinium chloride (195)
Yield: (95% of the theoretical value) MS: M/e = 713.0; 7 : 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; õax: 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; X: 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: We = 595.0; 2õ: 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)-p-D-glucopyranose (199)
Yield: (90% of the theoretical value) MS: M/e = 757.0; X : 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)
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Yield: (90% of the theoretical value) MS: M/e = 713.0; 500.0 nm.
Example 201
(8S)-5-brow o-4',9,9'-trihydroxy-6'-m 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-
carbaldehydesemicarbazone (201)
Yield: (90% of the theoretical value) MS: We = 637.0;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: We = 719.0; Xmx: 500.0 nm.
Example 203
(8S)-5-bromo-4',9,9'-trihydroxy-6'-m 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-
carbaldehyde O-(3-chlorobenzyl)oxime (203)
Yield: (95% of the theoretical value) MS: We = 718.0; 492.0 nm.
Example 204
(8S)-5-brow o-N-[(LE)-(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-l,3-thiazole-4y)-carbohydrazide (204)
Yield: (95% of the theoretical value) MS: We = 718.9; "fllax: 492.0 run.
Example 205
(8S)-5-bromo-2-(1H-imidazole-1-yl)-N-[(lE). (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: We = 702.0; a,fl ,(: 500.0 nm.
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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; Xnax: 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-y1)methylene]acetohydrazide (207)
Yield: (90% of the theoretical value) MS: We = 734.1; ~,max: 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'-octabydrospiro[cyclopenta [g]isoquinoline-8,2'-
cyclopenta [b]-
naphthalen a]-3-yl)methylene] acetohydrazide (208)
Yield: (95% of the theoretical value) MS: M/e = 721.1; ?,,õax: 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'-octabydrospiro[cyclopenta [g]isoquinoline-8,2'-
cyclopenta[b]-
naphthalene]-3-yl)m ethylene] acetohydrazide (209)
Yield: (95% of the theoretical value) MS: M/e = 665.0; kaa: 500.0 nm.
Example 210
(8S)-5-bromo-2-[isopropy](methyi)amino] 1V'-[(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'-
cyc] openta[b]-naphthalene]-3-yl)methylene]acetohydrazide (210)
Yield: (95% of the theoretical value) MS: M/e = 707.0; a, ,a,,: 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)
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Yield: (95% of the theoretical value) MS: We = 666.0; ax: 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 0-[3-(4-(3-chlorophenyl)-piperazine-1-yl)propyl]oxime (212)
Yield: (95% of the theoretical value) MS: M/e = 831.0; ~,,.: 500.0 nm.
Example 213
(8 S)-5-brow o-4',9,9'-trihyd roxy-6'-m eth oxy-1,1',3',5',8'-pen to oxo-
1,1',2,3',5',6,7,8'-
octahydrospiro[cyclopenta[g] isoquinoline-8,2'-cyclopenta[b]-naphthalene]-3-
carbaldehyde 0-[3-(dimethylamino)propyl]oxime (213)
Yield: (95% of the theoretical value) MS: M/e = 680.0; ax: 492.0 ran.
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 0-isopropyloxime (214)
Yield: (95% of the theoretical value) MS: M/e = 559.2;ax: 500.0 rim.
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-
carbaldebyde O-n-hexyloxime (215)
Yield: (99% of the theoretical value) MS: We = 601.3; A,a,: 500.0 nm.
Example 216
(8S)-4',9,9'-trihydroxy-6'-m 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-
carbaldehyde 0-(4-fluorobenzyl)oxime (216)
Yield: (99% of the theoretical value) MS: M/e = 625.2; ax: 500.0 rim.
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Example 217
(8S)-4',9,9'-trihydroxy-6'-methoxy-1,1',3',5',8'-pentaoxo-1,1',2,3',5',6,7,8'-
octahydrospiro Icyclopenta [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; A,ma,,: 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'-
octahyd rospiro [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; Xmax: 500.0 nm.
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; Amax: 500.0 nm.
Example 220
(8 S)-5-ch l o ro-4',9,9'-trihyd roxy-6'-m eth oxy-1,1',3',5',8'-p en to oxo-
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; ,max: 500.0 nm.
Example 221
(8S)-5-chloro-4',9,9'-trihydroxy-6'-m 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-
carbaldehyde O-(4-fluorobenzyl)oxime (221)
Yield: (85% of the theoretical value) MS: M/e = 659.3; X ax: 500.0 nm.
Example 222
(8S)-5-chloro-4',9,9'-trihydroxy-6'-m 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-
carbaldehyde O-(4-chlorobenzyl)oxime (222)
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Yield: (80% of the theoretical value) MS: We = 675.3; ? ax: 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[gjisoquinoline-8,2'-cyclopenta[b]-naphthalene]-3-
carbaldehyde O-(3-fluorobenzyl)oxime (223)
Yield: (80% of the theoretical value) MS: M/e = 659.3; k.,,x: 500.0 run.
Example 224
(8S)-5-brow o-4',9,9'-trihyd roxy-6'-m eth oxy-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; Xm : 492.0 nm.
Example 225
(8S)-5-bromo-4',9,9'-trihydroxy-6'-m ethoxy-1,1',3',5',8'-pentaoxo-
1,1',2,3',5',6,7,8'-
octabydrospiro[cyclopenta[gjisoquinoline-8,2'-cyclopenta [bj-naphthalene]-3-
carbaldehyde O-n-hexyloxime (225)
Yield: (95% of the theoretical value) MS: We = 679.3; Ama,t: 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; 4ax: 492.0 nrn.
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[gjisoquinoline-8,2'-cyclopenta [b]-naphthalene]-3-
carbaldehyde O-(4-chlorobenz),l)oxime (227)
Yield: (95% of the theoretical value) MS: M/e = 719.3; ?aa: 492.0 nm.
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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: We = 705.3; ?.max: 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: We = 685.3; Xmax: 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: We = 727.4; ?max: 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: We = 751.3; Amax: 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] isoquin oline-8,2'-cyclopenta [b]-naphthalene]-
3-
carbaidehyde O-(4-chlorobenzyl)oxime (232)
Yield: (99% of the theoretical value) MS: We = 767.3; Xax: 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-
carbaldebyde O-(3-fluorobenzyl)oxime (233)
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Yield: (99% of the theoretical value) MS: M/e = 751.3; 4ax: 500.0 run.
Example 234
(8S)-5-iod o-4',9,9'-trihyd roxy-6'-m 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-
carbaldehyde O-benzyloxime (234)
Yield: (99% of the theoretical value) MS: M/e = 733.3; 4ax: 500.0 nm.
Example 235
(8S)-5-iodo-4',9,9'-trihydroxy-6'-m 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-
carbaldehyde 0-[2-morpholine-4-yl-ethyl)oxime (235)
Yield: (99% of the theoretical value) MS: M/e = 756.3; 4at: 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; 4ax: 492.0 nm.
Example 237
(8S)-5-iod o-4',9,9'-trihy droxy-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: We = 767.3; ?õax: 492.0 nm.
Example 238
(8S)-5-iodo-4',9,9'-trihydroxy-6'-m 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-
carbaldehyde O-[3-(4-(3-chlorophenyl)-piperazine-1-yl)propyl]oxime (238)
Yield: (99% of the theoretical value) MS: We = 879.4; a,õ.: 500.0 nm.
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Example 239
(8S)-5-iod o-4',9,9'-trihydroxy-6'-methoxy-1,1',3',5',8'-pentaoxo-
1,1',2,3',5',6,7,8'-
octahydrospiro[cyclopenta[gJisoquinoline-8,2'-cyclopenta [b]-naphthalene]-3-
carbaldehyde oxime (239)
Yield: (99% of the theoretical value) MS: We = 643.3; X,,.: 492.0 nm.
Example 240
(8S)-5-iodo-2-(4-m ethylpiperazin e-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]-naphthaleneJ-3-yl)methylene]acetohydrazide (240)
Yield: (99% of the theoretical value) MS: M/e = 782.3; Xma,,: 500.0 nm.
Example 241
(8S)-5-iodo-2-m orph oline-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[bJ-
naphtha] ene]-3-yl)methylene]acetohydrazide (241)
Yield: (99% of the theoretical value) MS: M/e = 782.3;aX: 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; Xa,,: 500.0 nm.
Example 243
(8S)-4',9,9'-trihydroxy-6' -ethoxy-3- [(1 E,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% CF3000H). After drying and concentration,
a
chromatographically homogenous, red powder is left.
Yield: 5.0 mg (97% of the theoretical value) MS = 554 (M+H)+; X,,,a,,: 504.0
nm.
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Example 244
(8S)-4',9,9'-trihydroxy-6'-n-butoxy-3- [(1 E,3E)-penta-1,3-dienyl] -6,7-
dihydrospiro[cyclopenta[g]isoquinoline-8,2'-cyclopenta[b]-naphthalene]-1,1'-
3',5',8'(2H)-pen tone (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 I h
at this temperature,
and is then cooled. It is transferred onto water and shaken out with ethyl
acetate (0.1%
CF3000H). After drying and concentration, a chromatographically homogenous red
powder
is left.
Yield: 6.2 mg (96% of the theoretical value) MS = 582 (M)+; õ: 500.0 nm.
Example 245
(8S)-4',9,9'-trihy droxy-6'-n-isopropyloxy-3- [(1 E,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)+; ~,,,,,.: 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
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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)+; Xõaa: 504.0
rim.
Example 247
(8S)-5-bromo-4',9,9'-trihydroxy-6'-(2-dim ethylaminoethoxy)-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)+; %ax: 504.0
nm.
Example 248
(8 S)-4',9,9'-trihyd roxy-6'-allyloxy-3- [(1 E,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)+; 500.0 nm.
The compounds 249, 250, 251, 252, 253, 254, 255 were generated analogously to
the
instructions 244-248:
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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)+; Xmax: 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)+; ?,a,,: 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)+; 500.0 nm.
Example 252
1-Desoxy-5-C- [ (8R)-4',9,9'-trihydroxy-6' -ethoxy-1,1',3',5',8' -p en to ox o-
1,1',2,3',5',6',7',8' -
octahydrospiro [cyclopenta [g]isoquinoline-8,2'-cyclopenta[b]-naphthalene]-3-
y1]pentitol
(252)
Yield: 2.0 mg (20 % of the theoretical value); MS = 622 (M+H)+; ?nax: 499.0
nm.
Example 253
(8S)-4',9,9'-trihyd roxy-6'-(2-t-butoxyca rbonylamin oethoxy)-3-[(1 E,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)+; 2,õ na,(: 500.0
nm.
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)
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Yield: 5.8 mg (48 % of the theoretical value); MS = 653 (M+H)+; 500.0 nm.
Example 255
1-D esoxy-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)+; kax: 500.0 nm.
Example 256
(8S)-4',9,9'-trihydroxy-6'-(2-bromoethoxy)-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 (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)+; ?,,,ax:
499.0 nm.
Example 257
(8S)-5-iod o-4',9,9'-trihydroxy-6'-cyclopropylam ino-3-[(1 E,3E)-penta-1,3-
dienyl]-6,7-
dihydrospiro [eyc] openta [g]isoquinoline-8,2'-cyclopenta[b]-naphthalene]-1,1'-
3',5',8'(2H)-pentone (257)
Five (5.0) mg (7.5 mol) 5-iodofredericamycin (15) are dissolved under argon
in 1.0 ml
anhydrous DMF. After addition of 0.64 mg (11.2 gmmol) 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)+; õ.: 504.0 nm.
Example 258
(8S)-5-iodo-4',9,9'-trihydroxy-6'-n-butylamino-3-[(lE,3E)-penta-1,3-dienyl]-
6,7-
dihydrospiro [cyclopenta [g] isoquinolin a-8,2'-cyclopenta [b]-naphthalene]-
1,1'-
3',5',8'(2H)-pentone (258)
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Five (5.0) mg (7.5 pmol) 5-iodofredericamycin (15) are dissolved under argon
in 1.0 ml
anhydrous DMF. After addition of 0.82 mg (11.2 mmol) 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)+; a,,n : 504.0 nm.
Example 259
(8S)-5-bromo-4',9,9'-trihydroxy-6'-n-butylamino-3-[(1E,3E)-penta-l,3-dienyl]-
6,7-
dihydrospiro[cyclopenta [g]isoquinoline-8,2'-cyclopenta[b]-naphthalene]-1,1'-
3',5',8'(2H)-pentone (259)
Five (5.0) mg (8.1 pmol) 5-bromofredericamycin (15) are dissolved under argon
in 1.0 ml
anhydrous DMF. After addition of 0.89 mg (12.2 pmmol) 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)+; A: 504.0 nm.
Example 260
(8S)-4',9,9'-trihydroxy-6'-cyclopropylamino-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 (260)
Five (5.0) mg (9.3 pmol) fredericamycin (1) are dissolved under argon in 1.0
ml anhydrous
DMF. After addition of 2.12 mg (37.2 pmmol) 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)+; 510.0 nm.
Example 261
(8S)-4',9,9'-trihydroxy-6'-anilino-3-[(1 E,3E)-penta-1,3-dienyl]-6,7-
dihydrospiro [cyclopenta [g] isoquin oline-8,2'-cyclopenta [b]-naphthalene]-
1,1'-
3',5',8'(2H)-pentone (261)
Five (5.0) mg (9.3 pmol) fredericamycin (1) are dissolved under argon in 1.0
ml anhydrous
DMF. After addition of 3.46 mg (37.2 pn mol) aniline and 37.2 pg
stannous(IV)chloride (1.0
M in CH2C12), 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
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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)+; : 504.0 nm.
Example 262
(8S)-4',9,9'-trihydroxy-6'-piperidino-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 (262)
Five (5.0) mg (9.3 pmol) fredericamycin (1) are dissolved under argon in 1.0
ml anhydrous
DMF. After addition of 3.16 ing (37.2 gmmol) 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)+; )4,,a,,: 504.0 nm.
Example 263
(8S)-4',9,9'-trihydroxy-6'-dim ethylam in o-3- [(1 E,3E)-penta-1,3-dienyl]-6,7-
dihydrospiro[cyclopenta[g]isoquinoline-8,2'-cyclopenta[b]-naphthalene]-1,1'-
3',5',8'(2H)-pentone (263)
Five (5.0) mg (9.3 .tmol) fredericamycin (1) are dissolved under argon in 1.0
ml anhydrous
DMF. After addition of 1.67 mg (37.2 mmol) 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)+; 526.0 nm.
Example 264
(8S)-4',9,9'-trihydroxy-6'-isopropylamino-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 (264)
Five (5.0) mg (9.3 pmol) fredericamycin (1) are dissolved under argon in 1.0
ml anhydrous
DMF. After addition of 2.19 mg (37.2 pmmol) 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)+; ?,,,ax: 504.0 run.
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Example 265
(8S)-4',9,9'-trihydroxy-6'-methylamino-3-[(1 E,3E)-penta-1,3-dienyl]-6,7-
dihydrospiro [cyclopenta [g] isoquinoline-8,2'-cyclopenta [b]-naphthalene]-
1,1'-
3',5',8'(2H)-pentone (265)
Five (5.0) mg (9.3 pmol) fredericamycin (1) are dissolved under argon in 1.0
ml anhydrous
DMF. After addition of 0.34 mg (11.1 gmmol) 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)+; 504.0 nm.
Example 266
(8S)-5-iodo-4',9,9'-trihydroxy-6'-methylamino-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 (266)
Five (5.0) mg (7.5 mol) 5-iodofredericamycin (1) are dissolved under argon in
1.0 ml
anhydrous DMF. After addition of 0.28 mg (9.0 mmol) 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)+; 2,,,,: 492.0 nm.
Example 267
(8S)-4',9,9'-trihydroxy-6'-morpholino-3- [(1 E,3E)-penta-1,3-dienyl]-6,7-
dihydrospiro[cyclopenta[g]isoquinoline-8,2'-cyclopenta[b]-naphthalene]-1,1'-
3',5',8'(2H)-pentone (267)
Five (5.0) mg (9.3 mol) fredericamycin (1) are dissolved under argon in 1.0
ml anhydrous
DMF. After addition of 3.24 mg (37.2 mmol) 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)+; Xmax: 518.0 nm.
Example 268
(8S)-4',9,9'-trihydroxy-6'-amino-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 (268)
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Five (5.0) mg (9.3 pmol) fredericamycin (1) are dissolved under argon in 1.0
ml anhydrous
DMF. After addition of 0.67 mg (37.2 mmol) 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)+; X : 504.0 nm.
Example 269
(8S)-4',9,9'-trihydroxy-6'-pyrrolidino-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 (269)
Five (5.0) mg (9.3 mol) fredericamycin (1) are dissolved under argon in 1.0
ml anhydrous
DMF. After addition of 0.99 mg (13.9 mmol) 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)+; Xmax: 554.0 nrn.
Example 270
(8S)-5-bromo-4',9,9'-trihydroxy-6'-m ethylamino-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 (270)
Five (5.0) mg (8.1 pmol) 5-bromofredericamycin (1) are dissolved under argon
in 1.0 ml
anhydrous DMF. After addition of 0.70 mg (12.2 mmol) 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)+; 4a,;: 492.0 rim.
Example 271
2-[Acetyl]-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
(271)
79.5 mg (479 mol) (2-oxo-propyl)-phosphonic acid dimethylester are dissolved
under argon
in 8 ml absolute pyridine, and 60.2 l (479 pmol) 1,1,3,3-tetramethylguanidine
are added at
0 C. After 5 minutes, 80.0 mg (159.7 pmol) fredericamycin aldehyde (4) is
added at 00 C.
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99
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; X: 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 [cyclopenta [g] isoquinoline-8,2'-cyclopenta [b] -
naphthalene]-3-yl] ethene
(272)
Fifty (50.0) mg (92.4 gmol) acetyl fredericamycin are dissolved under argon in
5 ml absolute
DMF, and then 36.9 mg (231.1 mol) bromine as a I 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+; X.: 504.0 nm.
Example 273
2-[2-Amino-thiazole-4-yl]-3-[(8S)-4',9,9'-trihydroxy-6'-methylamino-3-[(lE,3E)-
penta-
1,3-dienyl]-6,7-dihydrospiro [cyclopenta [g] isoquinoline-8,2'-cyclopenta [b]-
naphthalene]-
3-yl]ethene (273)
Twenty (20.0) mg (28.7 gmol) bromoacetyl fredericamycin (273) are dissolved
under argon
in 4ml absolute DMF. At room temperature, first 3.3 mg (43.0 tmol) thiourea,
and then 20
mg IR120 H+ 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); ?
a,: 492.0 nm.
Example 274
2-[2-Phenyl-thiazole-4-yl] -3-[(8S)-4',9,9'-trihydroxy-6'-methylamino-3-[(l
E,3E)-yenta-
1,3-dienyl]-6,7-dihydrospiro [cyclopenta [g] isoq uin olive-8,2'-cyclopenta
[b]-naphthalene]-
3-yl]ethene (274)
Five (5.0) mg (7.2 gmol) bromoacetyl fredericamycin (273) are dissolved under
argon in I ml
absolute DMF. At room temperature, first 1.5 mg (10.8 gmol) thiobenzamide, and
then 5 mg
IR120 H+ 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.
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100
Yield: 3.0 mg (57 % of the theoretical value); M/e = 737.2/739.2; (M+H); Amax:
492.0 nm.
Example 275
2-[2-Acetylamino-thiazole-4-ylj-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 (275)
Five (5.0) mg (7.2 pmol) bromoacetyl fredericamycin (273) are dissolved under
argon in 1 ml
absolute DMF. At room temperature, first 1.3 mg (10.8 mol) acetylthiourea,
and then 5 mg
IR120 H+ 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); 492.0
nm.
Example 276
2-[2-Methyl-thiazole-4-yl]-3-[(8S)-4',9,9'-trihydroxy-6'-methylamino-3-
j(1E,3E)-penta-
1,3-dienylj-6,7-dihyd rospiro [cyclopenta [g] isoquin olio a-8,2'-cyclopenta
[b]-naphth alenej-
3-yl]ethene (276)
Five (5.0) mg (7.2 mol) bromoacetyl fredericamycin (273) are dissolved under
argon in I ml
absolute DMF. At room temperature, first 0.81 mg (10.8 mol) thioacetamide,
and then 5 mg
IR120 H+ 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); ? ax:
492.0 nm.
Example 277
(8S)-4',9,9'-trihydroxy-6'-methylamino-3-[(1E,3E)-yenta-l,3-dienylj-6,7-
dihydrospiro [cyclopenta [g] isoquinoline-8,2'-cyclopenta [b]-naphthalene]-1-
thio-,1'-
3',5',8'(2H)-tetrone-thiofredericamycin (277)
Ten (10.0) mg (18.5 mol) 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-sulf de.
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); We = 55.7; (M+1-1); 504.0 nm.
CA 02761440 2011-12-16
101
Example A
Water solubility of the fredericamycin derivatives
The water solubility of the various fredericamycin derivatives can be
determined in a 0.9%
NaCI 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)).
