U.S. patent application number 16/207285 was filed with the patent office on 2019-04-04 for anthracycline derivatives for treating tumor diseases.
The applicant listed for this patent is Produkem Molekulares Design GmbH. Invention is credited to Christian R. Noe, Sebastien Queva, Michael Sonntagbauer, Ernst Urban.
Application Number | 20190100548 16/207285 |
Document ID | / |
Family ID | 50487596 |
Filed Date | 2019-04-04 |
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United States Patent
Application |
20190100548 |
Kind Code |
A1 |
Noe; Christian R. ; et
al. |
April 4, 2019 |
Anthracycline Derivatives For Treating Tumor Diseases
Abstract
The invention relates to anthracycline derivative compounds for
treating tumor diseases, and related methods, compositions, and
kits.
Inventors: |
Noe; Christian R.; (Wien,
AT) ; Sonntagbauer; Michael; (Wien, AT) ;
Queva; Sebastien; (Saint Ouen L Aumone, FR) ; Urban;
Ernst; (Perchtoldsdorf, AT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Produkem Molekulares Design GmbH |
Wien |
|
AT |
|
|
Family ID: |
50487596 |
Appl. No.: |
16/207285 |
Filed: |
December 3, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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14435907 |
Apr 15, 2015 |
10144753 |
|
|
PCT/EP2013/071520 |
Oct 15, 2013 |
|
|
|
16207285 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 307/20 20130101;
C07D 317/32 20130101; C07H 15/252 20130101; C07C 15/28 20130101;
C07D 317/26 20130101; A61P 35/00 20180101; C07D 317/34 20130101;
C07C 2603/44 20170501; C07C 45/59 20130101; C07H 15/08 20130101;
C07C 2603/24 20170501; C07F 7/1804 20130101; C07H 15/244
20130101 |
International
Class: |
C07H 15/244 20060101
C07H015/244; C07F 7/18 20060101 C07F007/18; C07C 15/28 20060101
C07C015/28; C07D 317/32 20060101 C07D317/32; C07C 45/59 20060101
C07C045/59; C07D 307/20 20060101 C07D307/20; C07H 15/252 20060101
C07H015/252; C07H 15/08 20060101 C07H015/08; C07D 317/34 20060101
C07D317/34; C07D 317/26 20060101 C07D317/26 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 15, 2012 |
AT |
A 1114/2012 |
Claims
1. A compound of the formula (IX) ##STR00034##
2. A compound of the general formula (X) ##STR00035## in which
R.sub.1 is a hydrogen atom, a hydroxyl or methoxy group, a halogen
atom, especially a fluorine, chlorine or bromine atom, or an
NO.sub.2 group.
3. A compound of the general formula (XI) ##STR00036## in which
R.sub.1 is a hydrogen atom, a hydroxyl or methoxy group, a halogen
atom, especially a fluorine, chlorine or bromine atom, or an
NO.sub.2 group.
4. A compound of the general formula (XII) ##STR00037## in which
R.sub.1 is a hydrogen atom, a hydroxyl or methoxy group, a halogen
atom, especially a fluorine, chlorine or bromine atom, or an
NO.sub.2 group.
5. A compound of the general formula (XIII) ##STR00038## in which
R.sub.1 is a hydrogen atom, a hydroxyl or methoxy group, a halogen
atom, especially a fluorine, chlorine or bromine atom, or an
NO.sub.2 group.
6. A compound of the general formula (XIV) ##STR00039## in which
R.sub.1 is a hydrogen atom, a hydroxyl or methoxy group, a halogen
atom, especially a fluorine, chlorine or bromine atom, or an
NO.sub.2 group.
7. A compound of the general formula (XV) ##STR00040## in which
R.sub.1 is a hydrogen atom, a hydroxyl or methoxy group, a halogen
atom, especially a fluorine, chlorine or bromine atom, or an
NO.sub.2 group.
8. A process for preparing compounds of the general formula (I),
characterized in that an open-chain sugar compound of the general
formula (II) ##STR00041## in which R.sub.7 and R.sub.5 are the same
and are each alkyl or alkylene having 2 to 3 carbon atoms; R.sub.9
and R.sub.10 are each an alkyl group having 1 to 3 carbon atoms;
Y.dbd.[C(.dbd.O)], [C(.dbd.N)--OH] or [CH--OH],
[CH--NR.sub.5R.sub.6] in both possible stereoisomeric arrangements,
where R.sub.5 and R.sub.6 are either each a hydrogen atom or are
one hydrogen atom and one trifluoroacetyl group (TFA); in which
X.dbd.O, S or NR with R=hydrogen or a C.sub.1 to C.sub.4 alkyl
group; R.sub.4 is an unbranched or branched alkyl or heteroalkyl
chain having a chain length of 1 to 19 elements, where a maximum of
6 heteroatoms (O, N, S) in any combination are separated from one
another by at least two carbon atoms, is converted by cleaving the
diol and aldehyde protecting group to give a pyranose of the
general formula (III) ##STR00042## in which Y.dbd.[C(.dbd.O)],
[C(.dbd.N)--OH] or [CH--OH], [CH--NR.sub.5R.sub.6] in both possible
stereoisomeric arrangements, where R.sub.5 and R.sub.6 are either
each a hydrogen atom or are one hydrogen atom and one
trifluoroacetyl group (TFA); in which X.dbd.O, S or NR with
R=hydrogen or a C.sub.1 to C.sub.4 alkyl group; R.sub.4 is an
unbranched or branched alkyl or heteroalkyl chain having a chain
length of 1 to 19 elements, where a maximum of 6 heteroatoms (O, N,
S) in any combination are separated from one another by at least
two carbon atoms, which is subsequently protected, preferably as
O-trifluoroacetyl or O-para-nitrobenzoyl, forming compounds of the
general formula (IIIa) or (IIIb) ##STR00043## in which
Y.dbd.[C(.dbd.O)], [C(.dbd.N)--OH] or [CH--OH], [CH--NR5R6] in both
possible stereoisomeric arrangements, where R5 and R6 are either
each a hydrogen atom or are one hydrogen atom and one
trifluoroacetyl group (TFA); in which X.dbd.O, S or NR with
R=hydrogen or a C1 to C4 alkyl group; R4 is an unbranched or
branched alkyl or heteroalkyl chain having a chain length of 1 to
19 elements, where a maximum of 6 heteroatoms (O, N, S) in any
combination are separated from one another by at least two carbon
atoms, and these are subsequently glycosylated with a tetracyclic
aglycone of the anthracycline (AA) structure type to give a
compound of the general formula IIIc ##STR00044## in which AA is a
tetracyclic aglycone of the anthracycline structure type and X, Y,
R.sub.3 and R.sub.4 are each as defined in formula I, but in the
preferred embodiment the activated pyranoses of the general formula
(IIIa) or (IIIb) are reacted in a glycosidation reaction with an
anthraquinone-derived aglycone of the general formula (IV)
##STR00045## in which R.sub.1 and R.sub.2 are each as defined in
formula (I), wherein a reaction activation is effected, giving
compounds of the general formula (Ia) ##STR00046## in which R.sub.1
is a hydrogen atom, a hydroxyl or methoxy group, a halogen atom or
an NO.sub.2 group, R.sub.2 is a hydrogen atom, a hydroxyl or
methoxy group, or an acyl or aroyl radical, R.sub.4 is defined as
--(CH.sub.2--CH.sub.2--O).sub.n-- with n=1 to 6, and in which there
is a hydrogen atom or a C.sub.1 to C.sub.4 alkyl group on the
terminal oxygen atom of the chain.
9. The process as claimed in claim 8, characterized in that
compounds of the general formula (II) are prepared by coupling a C2
unit of the general formula (V) ##STR00047## in which R.sub.7 and
R.sub.8 are each as defined in formula (II) to a protected
derivative of L-threose (enantiomerically pure C4 unit) of the
general formula (VI) ##STR00048## in which X, R.sub.9, R.sub.10 are
each as defined in formula (II) and Z=hydrogen, or at least or more
than one, preferably one or two, methyl, fluorine, chlorine,
bromine or nitro groups, and the resulting addition product of the
general formula (VII) ##STR00049## in which R.sub.7, R.sub.8,
R.sub.9, R.sub.10 are each as defined in formula (II), and
Z=hydrogen, or at least or more than one, preferably one or two,
methyl, fluorine, chlorine, bromine or nitro groups, and
Y.dbd.CH--OH, is oxidized by oxidation to the ketone
[Y.dbd.C(.dbd.O)] of the general formula (VII) and then the
nitrogen is introduced, preferably via an oxime
[Y.dbd.C(.dbd.N)--OH] of the general formula (VII), in which the
protecting group on X is subsequently detached and R.sub.4 as
defined in formula (I) is introduced, wherein the introduction of
an unbranched or branched alkyl or heteroalkyl chain on X is
effected by substitution, preferably with the aid of a
non-nucleophilic base, wherein the alkyl or heteroalkyl chain to be
introduced is activated with a leaving group beforehand and the
resultant oxime [Y.dbd.C(.dbd.N)--OH] of the general formula (II)
is subsequently reduced with a metal hydride, forming amines
[Y.dbd.CH--NH.sub.2] of the general formula (II), which are
subsequently protected, forming a sugar compound of the general
formula (II) [Y.dbd.CH--NR.sub.5R.sub.6] in which R.sub.5/R.sub.6
are different and are each as defined in formula (I).
10. A process for preparing compounds of the general formula (IV)
##STR00050## in which R.sub.1 is a hydrogen atom, a hydroxyl or
methoxy group, a halogen atom, especially a fluorine, chlorine or
bromine atom, or an NO.sub.2 group, and R.sub.2 is hydrogen,
characterized in that a tricyclic bromide of the general formula
(VIII) ##STR00051## in which R.sub.1 is a hydrogen atom, a hydroxyl
or methoxy group, a halogen atom, especially a fluorine, chlorine
or bromine atom, or an NO.sub.2 group, is reacted with a synthon of
the formula (IX) ##STR00052## wherein the compound of the formula
(IX) is deprotonated, and the subsequent alkylation leads to
formation of an enantiomerically pure compound of the general
formula (X) ##STR00053## in which R.sub.1 is a hydrogen atom, a
hydroxyl or methoxy group, a halogen atom, especially a fluorine,
chlorine or bromine atom, or an NO.sub.2 group, which is reacted
with an organometallic reagent to give a compound of the general
formula (XI) ##STR00054## in which R.sub.1 is a hydrogen atom, a
hydroxyl or methoxy group, a halogen atom, especially a fluorine,
chlorine or bromine atom, or an NO.sub.2 group, and the keto group
in the compound of the general formula (XI) is reduced in a hydride
reduction to a hydroxyl group and then is ketalized to give a
compound of the general formula (XII) ##STR00055## in which R.sub.1
is a hydrogen atom, a hydroxyl or methoxy group, a halogen atom,
especially a fluorine, chlorine or bromine atom, or an NO.sub.2
group, and subsequently the protecting group in the general formula
(XII) is eliminated and the hydroxyl group released is oxidized by
oxidation to give an aldehyde of the general formula (XIII)
##STR00056## in which R.sub.1 is a hydrogen atom, a hydroxyl or
methoxy group, a halogen atom, especially a fluorine, chlorine or
bromine atom, or an NO.sub.2 group, and the compound of the general
formula (XIII) thus obtained is converted by oxidative dealkylation
to the anthraquinone derivative of the general formula XIV
##STR00057## in which R.sub.1 is a hydrogen atom, a hydroxyl or
methoxy group, a halogen atom, especially a fluorine, chlorine or
bromine atom, or an NO.sub.2 group, and subsequent detachment of
the remaining protecting groups gives the hemiacetal of the general
formula (XV) ##STR00058## in which R.sub.1 is a hydrogen atom, a
hydroxyl or methoxy group, a halogen atom, especially a fluorine,
chlorine or bromine atom, or an NO.sub.2 group, the latter is
cyclized to give the compound of the general formula (XVI)
##STR00059## in which R.sub.1 is a hydrogen atom, a hydroxyl or
methoxy group, a halogen atom, especially a fluorine, chlorine or
bromine atom, or an NO.sub.2 group, R.sub.12 and R.sub.13 are each
a hydrogen atom, or are one hydrogen atom and one hydroxyl group in
any combination, and the side chain hydroxyl group is oxidized to
give a compound of the general formula (XVII) ##STR00060## in which
R.sub.1 is a hydrogen atom, a hydroxyl or methoxy group, a halogen
atom, especially a fluorine, chlorine or bromine atom, or an
NO.sub.2 group, R.sub.12 and R.sub.13 are each a hydrogen atom, or
are one hydrogen atom and one hydroxyl group in any combination,
and, provided that R.sub.12 and R.sub.13 are each a hydrogen atom,
is then hydroxylated to give a compound of the general formula (IV)
in which R.sub.1 is a hydrogen atom, a hydroxyl or methoxy group, a
halogen atom, especially a fluorine, chlorine or bromine atom, or
an NO.sub.2 group, and R.sub.2 is hydrogen ##STR00061##
Description
REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. application Ser.
No. 14/435,907, filed Apr. 15, 2015, which is the National Stage of
International Patent Application No. PCT/EP2013/071520, filed on
Oct. 15, 2013, which claims priority from Austria Patent
Application No. A 1114/2012, filed on Oct. 15, 2012. Each patent
application identified above is incorporated here by reference in
its entirety.
DESCRIPTION
[0002] Anthracyclines are used on a large scale in a broad spectrum
of neoplastic disorders. However, the clinical use thereof is
greatly limited by dose-dependent side effects and occurrence of
tumor resistances. In order to get round these problems, two basic
strategies have been pursued to date.
[0003] Firstly, attempts are made by "drug targeting" techniques to
increase the enrichment or release of the active ingredients in the
neoplastic tissue. This involves using prodrugs, wherein the
anthracyclines are joined to peptides, carbohydrates, antibodies or
synthetic polymers, and specific, particularly liposomal,
formulations of the drugs. Examples of this are described in detail
in the literature (Krohn K. "Anthracycline Chemistry and Biology
II" Topics in current chemistry, 283 (2008), 73-140).
[0004] The second strategy is the design of novel anthracycline
active ingredients. Since conventional anthracyclines are generally
obtained by purely fermentative methods, the options for chemical
modifications remain limited and are restricted to a few functional
groups. Modifications are also only viable at particular positions,
since the planar structure of the molecule has to be preserved in
order to achieve the DNA-intercalating action. The functional
groups most commonly utilized for modifications in the aglycone are
the hydroxyl group at position 14, the keto group at position 13
and, in the sugar moiety, the 3'-amino group and the 4'-hydroxyl
group.
##STR00001##
Anthracycline Base Structure
[0005] Examples of such modifications are anthracycline
disaccharides, including sabarubicin, which has already been tested
clinically (M. Bigioni et al., Antitumour effect of combination
treatment with Sabarubicin (MEN 10755) and cis-platin (DDP) in
human lung tumour xenograft, Cancer chemotherapy and pharmacology,
62 (2008) 621-629.). Further known examples of sugar-modified
anthracyclines are derivatives containing a morpholino structure.
The best known representative is nemorubicin, which has likewise
been tested clinically (C. Sessa et al., Ongoing phase I and II
studies of novel anthracyclines, Cardiovascular toxicology, 7
(2007) 75-79.).
[0006] The present invention provides novel anthracyclines having
physicochemical properties, particularly basicity and
hydrophilic/lipophilic balance, altered by specific structural
modifications so as to control their pharmacodynamic and
pharmacokinetic properties. Since structural changes in an active
ingredient can severely disrupt the active ingredient-receptor
interaction, the selection of the point at which the structural
change is effected is of particular significance. In the compounds
of the present invention, some of the structural changes are
undertaken at position 6 in the sugar moiety. This position is
occupied by a methyl group in the anthracyclines employed
therapeutically. X-ray crystallography images showed that, in the
case of the anthracyclines which act as intercalators, this sugar
moiety is positioned in the "minor groove" of the DNA (C. A.
Frederick et al., Structural comparison of anticancer drug-DNA
complexes: adriamycin and daunomycin, Biochemistry, 29 (1990)
2538-2549). Through the positioning of the structure-modifying
moiety at position 6 of the sugar ring, it is possible to avoid
disruption of the structure-activity interaction. Even sterically
demanding radicals can extend into the space around the molecule
without hindering intercalation. As a result of the spatial
proximity to the acidic phosphate groups of the DNA in the minor
groove, it is additionally possible for basic radicals to interact
easily therewith.
[0007] It is a characteristic feature of the structure
modifications according to the present invention that the radicals
which modulate the properties of the active ingredient are bound
via an oxygen, nitrogen or sulfur atom to position 6 in the sugar.
The literature to date has described only halogenated derivatives
at this position, and compounds having a free hydroxyl or amino
group.
[0008] F. Arcamone, et al., Stereocontrolled glycosidation of
daunomycinone. Synthesis and biological evaluation of
6-hydroxy-L-arabino analogues of antitumor anthracyclines, Journal
of Medicinal Chemistry, 19 (1976) 733-734.
[0009] K. Nakai, et al., Synthesis and antitumor activity of
5'-demethyl-5'-trifluoromethyl-daunorubicin and -doxorubicin,
Carbohydr. Res., 320 (1999) 8-18.
[0010] E. F. Fuchs, et al., New daunorubicin analogs.
3-Amino-2,3,6-trideoxy-.alpha.- and .beta.-D-arabino- and
3,6-diamino-2,3,6-trideoxy-.alpha.-D-ribo-hexopyranosides of
daunomycinone, Journal of Antibiotics, 32 (1979) 223-238.
[0011] Patent U.S. Pat. No. 6,355,784 "Methods and compositions for
the manufacture of halogenated anthracyclines with increased
antitumor activity, other anthracyclines, halogenated sugars, and
glycosyl donors", filed June 1999, issued March 2002.
[0012] Since a methyl group, as in the sugar moieties of the
anthracyclines used therapeutically, namely acosamine and
daunosamine, cannot be functionalized by known synthetic methods,
the novel sugars unknown to date and derivatives thereof, and also
the preparation thereof which makes it possible to obtain 6'
modification of this kind, and the use thereof, also form part of
the subject matter of the invention.
[0013] The present invention provides novel anthracycline
derivatives of the general formula (I)
##STR00002##
[0014] in which R.sub.1 is a hydrogen atom, a hydroxyl or methoxy
group, a halogen atom, especially a fluorine, chlorine or bromine
atom, or an NO.sub.2 group; R.sub.2 is a hydrogen atom, a hydroxyl
or methoxy group, an acyl or aroyl radical, preferably acetyl or
benzoyl; R.sub.3 is hydrogen, trifluoroacetyl (C(.dbd.O)CF.sub.3)
or p-nitrobenzoyl (C(.dbd.O)PhNO.sub.2) and the wavy line in each
case means both possible configurations of --OR.sub.3 in relation
to the base structure; Y.dbd.[C(.dbd.O)], [C(.dbd.N)--OH] or
[CH--OH], [CH--NR.sub.5R.sub.6] in both possible stereoisomeric
arrangements, but is preferably [CH--NR.sub.5R.sub.6], where
R.sub.5 and R.sub.6 are preferably the same and are each a hydrogen
atom, but may also be different and may be a hydrogen atom or an
amino protecting group, preferably a trifluoroacetyl group (TFA);
in which X.dbd.O, S or NR with R=hydrogen or C.sub.1 to C.sub.4
alkyl, preferably methyl, ethyl, propyl and tert-butyl or n-butyl,
most preferably methyl or ethyl; in which R.sub.4 is an unbranched
or branched alkyl or heteroalkyl chain having a chain length of 1
to 19 elements, where a maximum of 6 heteroatoms (O, N, S) in any
combination are separated from one another by at least two carbon
atoms. Preferably, R.sub.4 is a (CH.sub.2--CH.sub.2--O).sub.n--
group with n=1 to 6, with a hydrogen atom or a C.sub.1 to C.sub.4
alkyl group, preferably methyl, ethyl, propyl and tert-butyl or
n-butyl, most preferably a methyl or ethyl group, bonded to the
terminal oxygen atom of the (CH.sub.2--CH.sub.2--O).sub.n--
group.
[0015] Suitable protecting groups, especially for the amino group,
are known to those skilled in the art from the prior art, for
example from "Protective Groups in Organic Synthesis" (Greene,
Wuts) 4th edition, John Wiley & Sons, Inc., pages 781 to
783.
[0016] In a preferred embodiment, according to formula (Ia),
##STR00003##
in which R.sub.1 is a hydrogen atom, a hydroxyl or methoxy group, a
halogen atom, especially a fluorine, chlorine or bromine atom, or
an NO.sub.2 group; R.sub.2 is a hydrogen atom, a hydroxyl or
methoxy group, an acyl or aroyl radical, preferably acetyl or
benzoyl; the amino group and also the hydroxyl group may be present
in either possible stereochemical arrangement; R.sub.4 is defined
as the (CH.sub.2--CH.sub.2--O).sub.n-- group with n=1 to 6,
preferably n=3, 4 or 5, and in which there is a hydrogen atom or a
C.sub.1 to C.sub.4 alkyl group, preferably methyl, ethyl, propyl
and tert-butyl or n-butyl, on the terminal oxygen atom of the
chain, most preferably a methyl group or ethyl group bonded to the
terminal oxygen atom of the chain.
[0017] The present invention further provides a process for
preparing the anthracycline derivatives of the general formula (I),
wherein an open-chain sugar compound of the general formula
(II)
##STR00004##
in which R.sub.7 and R.sub.8 are the same and are each alkyl or
alkylene having 2 to 3 carbon atoms; R.sub.9 and R.sub.10 are each
an alkyl group having 1 to 3 carbon atoms; X, Y and R.sub.4 are
each as defined in formula (I) is cyclized. For a compounds of the
general formula (II) to be intramolecularly cyclized, the diol and
aldehyde protecting group has to be cleaved; this is accomplished
under acidic conditions, preferably in a mixture of trifluoroacetic
acid in tetrahydrofuran/water as solvent at a temperature of about
20.degree. C. to 100.degree. C., preferably at 55 to 65.degree. C.
The resulting pyranose of the general formula (III)
##STR00005##
in which X, Y and R.sub.4 are each as defined in formula (I) forms
as a mixture of the two anomers at position 1 in the general
formula (III), which need not be separated since both anomers are
suitable for the glycosylation.
[0018] Subsequently, compounds of the general formula (III) are
glycosylated with a tetracyclic aglycone of the anthracycline (AA)
structure type. Preferably, AA is an intercalatable tetracyclic
aglycone of the anthracycline structure type.
[0019] A number of reactions may be used as the glycosylation
reaction. The compound III can be used directly in the reaction or
can preferably be activated beforehand for the glycosylation. This
activation is preferably conducted with p-nitrobenzoyl chloride in
pyridine at a temperature of -10.degree. C. to 50.degree. C.,
preferably at about 0.degree. C. This reaction leads to compounds
of the general formula (IIIa). Likewise of good suitability for
activation is trifluoroacetic anhydride in diethyl ether, in which
case the reaction is conducted at from -10.degree. C. to 50.degree.
C., preferably at about 0.degree. C., and gives compounds of the
general formula (IIIb)
##STR00006##
In IIIa and IIIb, X, Y and R.sub.4 are each as defined in formula
(I).
[0020] The glycosylation with a tetracyclic aglycone of the
anthracycline (AA) structure type leads to a compound of the
general formula IIIc
##STR00007##
in which AA is a tetracyclic aglycone of the anthracycline
structure type, preferably an intercalatable tetracyclic aglycone,
and X, Y, R.sub.3 and R.sub.4 are each as defined in formula I.
[0021] The subsequent detachment of the protecting groups can be
conducted by methods described in detail in the literature (T.
Matsumoto, M. Osaki, K. Yamada, F. Matsuda, S. Terashima,
14-Fluoroanthracyclines. Novel syntheses and antitumor activity,
Chemical & Pharmaceutical Bulletin, 36 (1988) 3793-3804); (Y.
Kimura, M. Suzuki, T. Matsumoto, R. Abe, S. Terashima, Novel
glycosidation of 4-demethoxyanthracyclinones by the use of
trimethylsilyl triflate. Syntheses of optically active
4-demethoxydaunorubicin and 4-demethoxyadriamycin, Bulletin of the
Chemical Society of Japan, 59 (1986) 423-431).
[0022] In the preferred embodiment, the activated pyranoses of the
general formula (IIIa) or (IIIb) are reacted in a glycosidation
reaction with an anthraquinone-derived aglycone of the general
formula (IV)
##STR00008##
in which R.sub.1 is a hydrogen atom, a hydroxyl or methoxy group, a
halogen atom, especially a fluorine, chlorine or bromine atom, or
an NO.sub.2 group; R.sub.2 is a hydrogen atom, a hydroxyl or
methoxy group, an acyl or aroyl radical, preferably acetyl or
benzoyl, wherein a reaction activation is effected. For example,
reaction activation is effected by using trimethylsilyl
trifluoromethanesulfonate (TMSOTf) in a mixture of
dichloromethane/diethyl ether at temperatures of about 0 to
-70.degree. C., preferably between 0 and -20.degree. C. The
protecting groups still present on the sugar [TFA,
C(.dbd.O)PhNO.sub.2] can be detached under basic conditions,
preferably with sodium hydroxide solution, giving compounds of the
general formula (Ia)
##STR00009##
in which R.sub.1 is a hydrogen atom, a hydroxyl or methoxy group, a
halogen atom, especially a fluorine, chlorine or bromine atom, or
an NO.sub.2 group; R.sub.2 is a hydrogen atom, a hydroxyl or
methoxy group, an acyl or aroyl radical, preferably acetyl or
benzoyl, R.sub.4 is defined as --(CH.sub.2--CH.sub.2--O).sub.n--
with n=1 to 6, preferably n=3, 4 and 5, and in which there is a
hydrogen atom or a C.sub.1 to C.sub.4 alkyl group, preferably
methyl, ethyl, propyl and tert-butyl or n-butyl, most preferably a
methyl group or ethyl group, on the terminal oxygen atom of the
chain.
[0023] The open-chain sugar compounds of the general formula (II),
together with the processes for preparation thereof, form a further
part of the subject matter of the present invention.
[0024] Open-chain sugar compounds of the general formula (II)
##STR00010##
can be prepared by total synthesis, preferably employing the
addition of a C2 unit of the general formula (V)
##STR00011##
in which R.sub.7 and R.sub.8 are each as defined in formula (II)
with a protected derivative of L-threose (enantiomerically pure C4
unit) of the general formula (VI)
##STR00012##
in which X, R.sub.9, R.sub.10 are each as defined in formula (II)
and Z=hydrogen, or at least or two or more, preferably one or two,
methyl, fluorine, chlorine, bromine or nitro groups.
[0025] Compounds of the general formula (VI) in which X.dbd.O and
R.sub.9 and/or R.sub.10 is a methyl group have been described in
detail in the literature (S. Morgenlie, Identification of the
products of periodate oxidation of some mono-O-isopropylidene
derivatives of aldoses and alditols by g.l.c.-m.s, Carbohydr. Res.,
138 (1985) 329-334); (N. Cohen, B. L. Banner, R. J. Lopresti,
Synthesis of optically active leukotriene (SRS-A) intermediates,
Tetrahedron Letters, 21 (1980) 4163-4166).
[0026] The C--C bond between compounds of the general formula (V)
and compounds of the general formula (VI) is preferably formed by a
Grignard reaction, preferably in an aprotic solvent such as
tetrahydrofuran, methyl tert-butyl ether or diethyl ether at a
temperature of about 0.degree. C. to 100.degree. C., preferably at
room temperature, forming compounds of the general formula
(VII)
##STR00013##
in which R.sub.7, R.sub.8, R.sub.9, R.sub.10 are each as defined in
formula (II); X, R.sub.9, R.sub.10 are each as defined in formula
(II) and Z=hydrogen, or at least or more than one, preferably one
or two, methyl, fluorine, chlorine, bromine or nitro groups, and
Y.dbd.CH--OH in both possible stereoisomeric arrangements.
[0027] This addition product is subsequently oxidized to the ketone
[Y.dbd.C(.dbd.O)] of the general formula (VII), preferably by a
Swern oxidation in dichloromethane at low temperatures, preferably
at -50.degree. C. to -90.degree. C., most preferably at -60.degree.
C.
[0028] Various methods are available for introduction of the
nitrogen into the molecule. The best way is to effect this reaction
by converting the ketone [Y.dbd.C(.dbd.O)] of the general formula
(VII) to an oxime [Y.dbd.C(.dbd.N)--OH] of the general formula
(VII), preference being given to conducting this reaction with
hydroxylamine hydrochloride, preferably in pyridine at 20.degree.
C. to 80.degree. C., most preferably at about 55.degree. C.
[0029] Subsequently, the aroyl protecting group on X is detached,
preferably in a basic medium, preferably by means of NaOH in
THF/H.sub.2O. After the elimination, an R4 radical as defined in
formula I is introduced, the introduction of an unbranched or
branched alkyl or heteroalkyl chain on X preferably being effected
by nucleophilic substitution, more preferably with the aid of a
non-nucleophilic base, such as sodium hydride, in THF or DMF, and
the R4 radical to be introduced being activated beforehand. For
activation, preference is given to using a tosylate radical as
leaving group, for example para-toluenesulfonyl chloride, NaOH and
tetrahydrofuran/water at temperatures of 0.degree. C. to 60.degree.
C.
[0030] The resultant oxime [Y.dbd.C(.dbd.N)--OH] of the general
formula (II) is reduced to the amine [Y.dbd.CH--NH.sub.2] of the
general formula (II). A multitude of reagents are available for
this reaction, and those of particularly good suitability include
chiral and non-chiral metal hydrides such as sodium
bis(2-methoxyethoxy)aluminum dihydride or LiAlH.sub.4. Preferably,
this reaction is conducted with sodium bis(2-methoxyethoxy)aluminum
dihydride or LiAlH.sub.4 in toluene or THF at 0.degree. C. to
100.degree. C., preferably at room temperature.
[0031] The resulting amino group is in turn provided with a
protecting group suitable for selective detachment after ring
closure and glycosylation, the trifluoroacetyl group being
particularly suitable for this purpose, and it being possible to
conduct the reaction with trifluoroacetic anhydride in pyridine as
solvent, preferably at 0.degree. C. to 60.degree. C., preferably at
room temperature, thus forming a sugar compound of the general
formula (II) [Y.dbd.CH--NR.sub.5R.sub.6] in which R.sub.5/R.sub.6
are different and are each as defined in formula (I).
[0032] The present invention further provides a process for
preparing anthraquinone-derived aglycones of the general formula
(IV)
##STR00014##
which are prepared by total synthesis, in its preferred embodiment
by conducting the stereoselective alkylation based on the Seebach
reaction (Seebach, D.; Sting, A. R.; Hoffmann, M. Angewandte
Chemie, International Edition in English 1997, 35, 2708), while the
Marschalk reaction is employed in the cyclization (Marschalk, C.;
Koenig, F.; Ouroussoff, N. Bulletin de la Societe Chimique de
France, Memoires 1936, 3, 1545).
[0033] The ring system is prepared by the reaction of a tricyclic
bromide of the general formula (VIII)
##STR00015##
in which R.sub.1 is as defined in formula (I) with a synthon of the
general formula (IX)
##STR00016##
wherein the compound of the general formula (IX) is first
deprotonated with a non-nucleophilic base, for example LDA (lithium
diisopropylamide), LiHMDS (lithium bis(trimethylsilyl)amide), but
preferably with KHMDS (potassium bis(trimethylsilyl)amide), in a
polar aprotic solvent (e.g. dimethylformamide or tetrahydrofuran).
The reaction is effected preferably at -40.degree. C. to
-90.degree. C., most preferably at -60.degree. C. to -80.degree.
C., the very most preferably at -76.degree. C.
[0034] The subsequent alkylation leads to the formation of an
enantiomerically pure compound of the general formula (X)
##STR00017##
in which R.sub.1 is a hydrogen atom, a hydroxyl or methoxy group, a
halogen atom, especially a fluorine, chlorine or bromine atom, or
an NO.sub.2 group.
[0035] The reaction of a compound of the general formula (X) with
an organometallic reagent such as organomagnesium, -lithium or
-sodium, preferably with methyllithium, in an aprotic solvent, for
example tetrahydrofuran, at -40.degree. C. to -90.degree. C.,
preferably at -50.degree. C. to -80.degree. C., most preferably at
-78.degree. C., gives a compound of the formula (XI)
##STR00018##
in which R.sub.1 is a hydrogen atom, a hydroxyl or methoxy group, a
halogen atom, especially a fluorine, chlorine or bromine atom, or
an NO.sub.2 group.
[0036] The keto group in the compound of the general formula (XI)
is reduced in a reduction reaction, preferably a hydride reduction,
for example with sodium borohydride in ethanol as solvent,
preferably at 10.degree. C. to 70.degree. C., preferably at room
temperature, to a hydroxyl group and then is ketalized to give a
compound of the general formula (XII)
##STR00019##
in which R.sub.1 is a hydrogen atom, a hydroxyl or methoxy group, a
halogen atom, especially a fluorine, chlorine or bromine atom, or
an NO.sub.2 group.
[0037] The ketalization can preferably be conducted with
dimethoxypropane and p-toluenesulfonic acid in acetone. After the
cleavage of the silyl protecting group, which is best effected with
a fluoride reagent, for example tetrabutylammonium fluoride (TBAF)
in THF, preferably at room temperature, the hydroxyl group released
is oxidized to the aldehyde of the general formula (XIII)
##STR00020##
in which R.sub.1 is a hydrogen atom, a hydroxyl or methoxy group, a
halogen atom, especially a fluorine, chlorine or bromine atom, or
an NO.sub.2 group; preferably by a Swern oxidation.
[0038] The compound of the general formula (XIII) thus obtained is
converted by oxidative dealkylation preferably employing a cerium
salt (cerium(IV) ammonium nitrate, preferably in acetonitrile at
0.degree. C. to 10.degree. C., most preferably at about 2.degree.
C.) to the anthraquinone derivative of the general formula
(XIV)
##STR00021##
in which R.sub.1 is a hydrogen atom, a hydroxyl or methoxy group, a
halogen atom, especially a fluorine, chlorine or bromine atom, or
an NO.sub.2 group.
[0039] The remaining protecting groups (e.g. methoxy and acetonide)
are detached under acidic conditions, for which purpose preference
is given to using Lewis acids such as BBr.sub.3 (boron tribromide),
BI.sub.3 (boron triiodide), BF.sub.3 (boron trifluoride) or
AlCl.sub.3 (aluminum chloride), preferably BCl.sub.3 (boron
trichloride) in DCM, preferably at 0.degree. C.-10.degree. C., most
preferably at about 2.degree. C., giving the hemiacetal of the
general formula (XV)
##STR00022##
in which R.sub.1 is a hydrogen atom, a hydroxyl or methoxy group, a
halogen atom, especially a fluorine, chlorine or bromine atom, or
an NO.sub.2 group.
[0040] Formula (XV) is subsequently cyclized, preferably with the
aid of a Marschalk reaction in tetrahydrofuran/methanol as
solvents, preferably in a temperature range from -10.degree. C. to
room temperature, to give the compound of the general formula
(XVI)
##STR00023##
in which R.sub.1 is a hydrogen atom, a hydroxyl or methoxy group, a
halogen atom, especially a fluorine, chlorine or bromine atom, or
an NO.sub.2 group, R.sub.12 and R.sub.13 are each a hydrogen atom,
or are one hydrogen atom and one hydroxyl group in any
combination.
[0041] The side chain hydroxyl group is subsequently oxidized, for
which purpose Dess-Martin periodinane is particularly suitable,
preferably at room temperature, in order thus to obtain a compound
of the general formula (XVII)
##STR00024##
in which R.sub.1 is a hydrogen atom, a hydroxyl or methoxy group, a
halogen atom, especially a fluorine, chlorine or bromine atom, or
an NO.sub.2 group, R.sub.12 and R.sub.13 are each a hydrogen atom,
or are one hydrogen atom and one hydroxyl group in any
combination.
[0042] The compound of the formula (XVII), provided that R.sub.12
and R.sub.13 are each a hydrogen atom, is then hydroxylated, for
which purpose N-bromosuccinimide and azobis(isobutyronitrile) in
CCL.sub.4 are particularly suitable, preference being given to
effecting the hydroxylation under reflux, to form a compound of the
general formula (IV) in which R.sub.1 is a hydrogen atom, a
hydroxyl or methoxy group, a halogen atom, especially a fluorine,
chlorine or bromine atom, or an NO.sub.2 group, and R.sub.2 is
hydrogen
##STR00025##
[0043] Compounds of the general formula (I), (Ia) and (IIIc) of the
present invention, in non-radioactive cell proliferation and
cytotoxicity tests on tumor cell lines, for example the two tumor
cell lines MCF-7 and KB-3-1, show statistically significant effects
in terms of their cytotoxic effect and their propensity to inhibit
cell proliferation.
[0044] Accordingly, the present invention further relates to
pharmaceutical composition comprising one or more compounds of the
formula (I), (Ia) and (IIIc) and optionally one or more
pharmaceutically acceptable substances selected from auxiliaries,
carriers, diluents and solvents.
[0045] Suitable auxiliaries, carriers, diluents and solvents are
known to those skilled in the art.
[0046] The present invention further relates to a pharmaceutical
kit comprising (i) one or more compounds of the formula (I), (Ia)
and (IIIc), or a pharmaceutical composition comprising one or more
compounds of the formula (I), (Ia) and (IIIc) and optionally one or
more pharmaceutically acceptable substances selected from
auxiliaries, carriers, diluents and solvents, and (ii) at least one
antiproliferative or cytotoxic active ingredient.
[0047] The compounds of the formula (I), (Ia) and (IIIc), a
pharmaceutical composition or a pharmaceutical kit according to the
present invention can be used as a medicament or as a tool in
biomedical research.
[0048] Compounds of the formula (I), (Ia) and (IIIc), a
pharmaceutical composition or a pharmaceutical kit according to the
present invention can additionally be used for treatment of
diseases or disease states which can be at least partly alleviated
by therapy. The diseases or disease states are selected from
proliferative diseases, preferably cancer.
[0049] The compounds of the formula (I), (Ia) and (IIIc), a
pharmaceutical composition or a pharmaceutical kit according to the
present invention can be used as single-drug preparations or in
combination with other active ingredients, preferably active
ingredients which likewise inhibit cell proliferation or can
display a cytotoxic effect. Examples include the known active
ingredients bleomycin, vinblastin, dacarbazine, cyclophosphamide,
etoposide (phosphate), procarbazine, vincristin, prednisone,
cisplatin, carboplatin, 5-fluorouracil, docetaxel, which even now
are being used in combination with anthracyclines (e.g. ABVD,
BEACOPP, ECF, TAC, TEC).
[0050] It is likewise possible to use the compounds of the formula
(I), (Ia) and (IIIc) of the present invention together with
recombinant active ingredients (biologics) which can enhance the
effect of the inventive compounds in a specific manner, for example
as antibodies.
[0051] The present invention is now illustrated in detail by the
examples which follow.
EXAMPLE 1
[0052]
N-[(2S,3S,4S)-3,6-dihydroxy-2-[2-[2-[2-[2-(2-methoxy-ethoxy)ethoxy]-
ethoxy]ethoxy]ethoxymethyl]tetrahydro-pyran-4-yl]-2,2,2-trifluoroacetamide-
; formula (III);
R.sub.4.dbd.[(--CH.sub.2--CH.sub.2--O).sub.5--CH.sub.3]; X.dbd.O;
Y.dbd.[CH--NR.sub.5R.sub.6], R.sub.5.dbd.H,
R.sub.6.dbd.[C(.dbd.O)CF.sub.3]
[0053] To a solution of 8.9 g (17.2 mmol) of
N-[2-(1,3-dioxolan-2-yl)-1-[(4S,5S)-5-[2-[2-2-[2-(2-methoxy-ethoxy)ethoxy-
]ethoxy]ethoxy]ethoxymethyl]-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]-2,2,2-t-
rifluoroacetamide (II) in THF/H.sub.2O (4:1) are added dropwise 43
mL (0.56 mol) of trifluoroacetic acid. Subsequently, the mixture is
stirred at 60.degree. C. for 30 min. Then the reaction mixture is
emptied onto 100 mL of ice-water and 87 g (1.03 mol) of solid
NaHCO.sub.3 are added until pH 6-7 is attained. The reaction
mixture is subsequently filtered and extracted with 3.times. with
200 mL of dichloromethane each time. The combined organic phases
are dried over sodium sulfate, filtered and concentrated by
evaporation. The resultant oil is purified by chromatography
(eluent: DCM/MeOH 100:3->100:5->10:1, v/v). 2.1 g (27%) of
colorless oil are isolated. The anomeric ratio is
.alpha.:.beta.=76:24.
[0054] .sup.1H NMR (a), (500 MHz; CDCl.sub.3): .delta. (ppm)=7.09
(m, 1H, NH); 5.41 (m, 1H, H-1); 4.47 (m, 1H, H-3); 4.18 (m, 1H,
H-5); 3.92 (m, 1H, H-4); 3.79-3.69 (m, 2H, H-6/1, H-6/2); 3.62 (m,
18H, CH.sub.2O); 3.55 (m, 2H, MeOCH.sub.2); 3.35 (s, 3H, OMe);
2.00-1.91 (m, 1H, H-2/1); 1.87-1.84 (m, 1H, H-2/2)
[0055] .sup.1H NMR (13), (500 MHz; CDCl.sub.3): .delta. (ppm)=7.29
(m, 1H, NH); 5.18 (m, 1H, H-1); 4.16-4.06 (m, 1H, H-3); 3.82 (m,
1H, H-4); 3.79-3.69 (m, 2H, H-6/1, H-6/2); 3.62 (m, 19H, CH.sub.2O,
H-5); 3.55 (m, 2H, CH.sub.2O); 3.35 (s, 3H, OMe); 2.04-2.00 (m, 1H,
H-2/1); 1.80-1.74 (m, 1H, H-2/2).
EXAMPLE 2
[0056]
[(4S,5S,6S)-6-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]-ethoxy]ethoxy]et-
hoxymethyl]-5-(4-nitrobenzoyl)oxy-4-[(2,2,2-trifluoroacetyl)amino]tetrahyd-
ropyran-2-yl] 4-nitrobenzoate; formula (IIIa);
R.sub.3.dbd.R.sub.11.dbd.[C(.dbd.O)PhNO.sub.2];
R.sub.4.dbd.[(--CH.sub.2--CH.sub.2--O).sub.5--CH.sub.3]; X.dbd.O;
Y.dbd.[CH--NR.sub.5R.sub.6], R.sub.5.dbd.H,
R.sub.6.dbd.[C(.dbd.O)CF.sub.3]
[0057] To a solution of 1.67 g (3.38 mmol) of
N-[(3S,4S,6S)-3,6-dihydroxy-2-[2-[2-[2-[2-(2-methoxy-ethoxy)ethoxy]ethoxy-
]ethoxy]ethoxymethyl]tetrahydro-pyran-4-yl]-2,2,2-trifluoroacetamide
(II) in pyridine is cooled to 0.degree. C. under inert gas.
Subsequently, 1.75 g (9.43 mmol) of p-nitrobenzoyl chloride are
added and the reaction mixture is warmed to room temperature within
12 h. The reaction is quenched with H.sub.2O and then all solvents
are evaporated off. The residue is taken up in dichloromethane and
washed once H.sub.2O, three times with semisaturated NaHCO.sub.3
solution and once with saturated NaCl solution, dried over sodium
sulfate, filtered and concentrated by evaporation. The resulting
oil is purified by chromatography (eluent: ethyl acetate/petroleum
ether 1:1->3:2->2:1, v/v). 1.94 g (72%) are obtained as a
white foam. The anomeric ratio is .alpha.:.beta.=76:24.
[0058] .sup.1H NMR (.alpha.), (200 MHz; CDCl.sub.3): .delta.
(ppm)=8.30 (m, 8H, Ar); 6.88 (d, 1H, J=6.56 Hz, NH); 6.67 (m, 1H,
H-1); 5.76 (m, 1H, H-4); 4.80 (m, 1H, H-5); 4.46 (m, 1H, H-3);
3.63-3.46 (m, 22H, H-6/1, H-6/2, CH.sub.2O); 3.34 (s, 3H, OMe);
2.39-2.33 (m, 2H, H-2/1, H-2/2)
[0059] .sup.1H NMR (.beta.), (200 MHz; CDCl.sub.3): .delta.
(ppm)=8.28 (m, 8H, Ar); 6.90 (m, 1H, NH); 6.15 (m, 1H, H-1); 5.64
(m, 1H, H-4); 4.51 (m, 1H, H-5); 4.18 (m, 1H, H-3); 3.69-3.52 (m,
22H, H-6/1, H-6/2, CH.sub.2O); 3.34 (s, 3H, OMe); 2.44-2.17 (m, 2H,
H-2/1, H-2/2).
EXAMPLE 3
[0060]
[(2S,3S,4S,6R)-6-[[(1S,3S)-3-acetyl-3,5,12-trihydroxy-10-methoxy-6,-
11-dioxo-2,4-dihydro-1H-tetracen-1-yl]-oxy]-2-[2-[2-[2-[2-(2-methoxyethoxy-
)ethoxy]ethoxy]-ethoxy]ethoxymethyl]-4-[(2,2,2-trifluoroacetyl)amino]-tetr-
ahydropyran-3-yl] 4-nitrobenzoate; formula (I); R.sub.1.dbd.OMe;
R.sub.2.dbd.H; R.sub.3.dbd.[C(.dbd.O)PhNO.sub.2];
R.sub.4.dbd.[(--CH.sub.2--CH.sub.2--O).sub.5--CH.sub.3]; X.dbd.O;
Y.dbd.[CH--NR.sub.5R.sub.6], R.sub.5.dbd.H,
R.sub.6.dbd.[C(.dbd.O)CF.sub.3]
[0061] To a solution of 225 mg (0.28 mmol)
[(4S,5S,6S)-6-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]-ethoxyme-
thyl]-5-(4-nitrobenzoyl)oxy-4-[(2,2,2-trifluoroacetyl)amino]tetrahydropyra-
n-2-yl] 4-nitro-benzoate, (III), in 15 mL of dichloromethane and 12
mL of Et.sub.2O are added 1.1 g of 4 A molecular sieve. Under inert
gas, 129 mg (0.58 mmol) of trimethylsilyl trifluoromethanesulfonate
are added dropwise at -40.degree. C. and the mixture is stirred at
0.degree. C. for 1 h, the mixture is cooled to -20.degree. C. and
56 mg (0.14 mmol) of
(7S,9S)-9-acetyl-6,7,9,11-tetrahydroxy-4-methoxy-8,10-dihydro-7H-tetracen-
e-5,12-dione, (IV), dissolved in 9 mL of tetrahydrofuran, are added
dropwise. Subsequently, the mixture is stirred at -10.degree. C. to
-15.degree. C. for 6 h. Added to the reaction mixture are saturated
NaHCO.sub.3 solution and dichloromethane, and the phases are
separated. The aqueous phase we extracted repeatedly with
dichloromethane. The combined organic phases are washed with
H.sub.2O and saturated NaCl solution, dried over sodium sulfate,
filtered and concentrated by evaporation. The resulting residue is
purified by chromatography (eluent: DCM/MeOH
100:1->100:2->100:4, v/v). 118 mg (82%) of orange-red solid
are obtained.
[0062] .sup.1H NMR (500 MHz, CDCl.sub.3): .delta. (ppm)=13.93 (s,
1H, OH-6); 13.15 (s, 1H, OH-11); 8.30-8.23 (m, 4H, Ar); 7.90 (d,
1H, J=7.55 Hz, H-1); 7.76-7.72 (m, 1H, H-2); 7.35 (d, 1H, J=8.5 Hz,
H-3); 6.72 (m, 1H, NH); 5.69 (m, 1H, H-1'); 5.62 (m, 1H, H-4');
5.20 (m, 1H, H-7); 4.56-4.53 (m, 1H, H-5'); 4.48-4.40 (m, 1H,
H-3'); 4.04 (s, 3H, ArOMe); 3.68-3.45 (m, 22H, CH.sub.2O, H-6);
3.33 (s, 3H, OMe); 3.12 (m, 1H, H-10/1); 2.88 (m, 1H, H-10/2); 2.57
(m, 1H, H-8/1); 2.43 (s, 3H, H-14); 2.18-2.02 (m, 3H, H-8/2,
H-2')
EXAMPLE 4
[0063]
N-[(2S,3S,4S,6R)-6-[[(1S,3S)-3-acetyl-3,5,12-trihydroxy-10-methoxy--
6,11-dioxo-2,4-dihydro-1H-tetracen-1-yl]oxy]-3-hydroxy-2-[2-[2-[2-[2-(2-me-
thoxy-ethoxy)ethoxy]ethoxy]ethoxy]ethoxymethyl]
tetrahydro-pyran-4-yl]-2,2,2-trifluoroacetamide; formula (I);
R.sub.1.dbd.OMe; R.sub.2.dbd.R.sub.3.dbd.H;
R.sub.4.dbd.[(--CH.sub.2--CH.sub.2--O).sub.5--CH.sub.3]; X.dbd.O;
Y.dbd.[CH--NR.sub.5R.sub.6], R.sub.5.dbd.H,
R.sub.6.dbd.[C(.dbd.O)CF.sub.3]
[0064] A solution of 99 mg (0.1 mmol) of
[(2S,3S,4S,6R)-6-[[(1S,3S)-3-acetyl-3,5,12-trihydroxy-10-methoxy-6,11-dio-
xo-2,4-dihydro-1H-tetracen-1-yl]oxy]-2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy-
]ethoxy]ethoxy]ethoxymethyl]-4-[(2,2,2-trifluoroacetyl)amino]tetrahydropyr-
an-3-yl] 4-nitrobenzoate, (I), in 52.1 mL of methanol and 0.1 mL of
dichloromethane is cooled to 0.degree. C. Subsequently, 1.3 mL of
0.1 N NaOH are added dropwise and the mixture is stirred at
0.degree. C. for 30 min. The reaction mixture we then neutralized
with glacial acetic acid, and ethyl acetate and saturated NaCl
solution are added. The phases are separated and the aqueous phase
is extracted once with ethyl acetate. The combined organic phases
are washed with saturated NaCl solution, dried over sodium sulfate,
filtered and concentrated by evaporation. The resultant residue is
purified by chromatography (eluent: DCM/MeOH 100:4, v/v). 75.9 mg
(89%) of orange-red solid are obtained.
[0065] .sup.1H NMR (500 MHz, CDCl.sub.3): .delta. (ppm)=13.94 (s,
1H, OH-6); 13.23 (s, 1H, OH-11); 7.99 (d, 1H, J=7.55 Hz, H-1); 7.75
(t, 1H, J=8.02 Hz, H-2); 7.36 (d, 1H, J=8.5 Hz, H-3); 7.10 (m, 1H,
NH); 5.56 (m, 1H, H-1'); 5.25 (m, 1H, H-7); 4.22-4.14 (m, 1H,
H-3'); 4.14-4.11 (m, 1H, H-5'); 4.05 (s, 3H, ArOMe); 3.98 (m, 1H,
H-4'); 3.87-3.71 (m, 2H, H-6/1, H-6/2); 3.69-3.53 (m, 20H,
CH.sub.2O); 3.35 (s, 3H, OMe); 3.27-3.17 (m, 1H, H-10/1); 2.87-2.84
(m, 1H, H-10/2); 2.39 (s, 3H, H-14); 2.37-2.34 (m, 1H, H-8/1);
2.12-2.01 (m, 2H, H-8/2, H-2'/1); 1.86-1.83 (m, 1H, H-2'/2)
EXAMPLE 5
[0066]
(7S,9S)-9-acetyl-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-[2-[2-[2-[2-(-
2-methoxyethoxy)ethoxy]ethoxy]ethoxy]-ethoxymethyl]tetrahydropyran-2-yl]ox-
y-6,9,11-trihydroxy-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione;
formula (I); R.sub.1.dbd.OMe; R.sub.2.dbd.R.sub.3.dbd.H;
R.sub.4.dbd.[(--CH.sub.2--CH.sub.2--O).sub.5--CH.sub.3]; X.dbd.O;
Y.dbd.[CH--NH.sub.2]
[0067] A solution of 60 mg (0.07 mmol) of
N-[(2S,3S,4S,6R)-6-[[(1S,3S)-3-acetyl-3,5,12-trihydroxy-10-methoxy-6,11-d-
ioxo-2,4-dihydro-1H-tetracen-1-yl]-oxy]-3-hydroxy-2-[2-[2-[2-[2-(2-methoxy-
ethoxy)ethoxy]-ethoxy]ethoxy]ethoxymethyl]tetrahydropyran-4-yl]-2,2,2-trif-
luoroacetamide, (I), in 12.5 mL of 1 N NaOH is stirred at room
temperature for 20 min. The reaction mixture is subsequently
neutralized with 12.5 mL of 1N HCl and extracted with
dichloromethane until the extracts no longer have any orange color.
The combined organic phases are washed with saturated NaCl
solution, dried over sodium sulfate, filtered and concentrated by
evaporation. The resulting residue is purified by chromatography
(eluent: DCM/MeOH 10:1->10:2, v/v). 13 mg (24%) of orange-red
solid are obtained.
[0068] .sup.1H NMR (500 MHz, CDCl.sub.3): .delta. (ppm)=13.81 (s,
1H, OH-6); 13.12 (s, 1H, OH-11); 7.85 (d, 1H, J=6.9 Hz, H-1); 7.67
(t, 1H, J=7.57 Hz, H-2); 7.36 (m, 1H, H-3); 5.52 (m, 1H, H-1');
5.00 (m, 1H, H-7); 4.27 (m, 1H, H-4'); 4.19 (m, 1H, H-5'); 3.95 (s,
3H, ArOMe); 3.91-3.50 (m, 23H, H-3', H-6', CH.sub.2O); 3.33 (s, 3H,
OMe); 3.13-3.10 (m, 1H, H-10/1); 2.81-2.77 (m, 1H, H-10/2); 2.38
(s, 3H, H-14); 2.35 (m, 1H, H-8/1); 2.18-2.00 (m, 3H, H-2',
H-8/2)
EXAMPLE 6
[0069]
[(4S,5S)-5-[2-(1,3-dioxolan-2-yl)-1-hydroxyethyl]-2,2-dimethyl-1,3--
dioxolan-4-yl]methyl benzoate; formula (VII);
R.sub.7.dbd.R.sub.5.dbd.CH.sub.2;
R.sub.9.dbd.R.sub.10.dbd.CH.sub.3; X.dbd.O; Y.dbd.[CH--OH]
[0070] A solution of 4.20 g (0.17 mol) of magnesium turnings and 2
mg (0.015 mmol) of elemental iodine in 200 mL of THF is heated to
boiling under argon for 10 min. Subsequently, 26 g (0.15 mol) of
2-bromomethyl-1,3-dioxolane (V) are added dropwise until the onset
of the reaction becomes apparent. The rest of the
2-bromomethyl-1,3-dioxolane (V) is metered in subsequently such
that the reaction mixture boils gently. After the addition has
ended, the reaction mixture is stirred at 80.degree. C. for 2 h.
Thereafter, 20 g (0.08 mol) of
[(4S,5R)-5-formyl-2,2-dimethyl-1,3-dioxolan-4-yl]methyl benzoate
(VI), dissolved in 30 mL of THF, are added dropwise to the reaction
mixture and the mixture is stirred at room temperature for 6 h. 200
mL of saturated NH.sub.4Cl solution and 200 mL of ice are added to
the reaction mixture, which is stirred for 5 min. Subsequently, 300
mL of ethyl acetate are added, phases are separated and the aqueous
phase is extracted with 100 mL of ethyl acetate. The combined
organic phases are washed with 100 mL of saturated NH.sub.4Cl
solution, dried over Na.sub.2SO.sub.4, filtered and concentrated by
evaporation. 25 g (92%) of yellow oil (51:49 mixture of the
diastereomers of 3') are obtained.
[0071] .sup.1H NMR (diastereomer 1), (500 MHz, CDCl.sub.3): .delta.
(ppm)=8.06 (m, 2H, Ar); 7.56 (m, 1H, Ar); 7.44 (m, 2H, Ar); 5.09
(m, 1H, H-1); 4.66 (dd, J1=11.6 Hz, J2=2.5 Hz, 1H, H-6/1); 4.39
(dd, J1=11.6 Hz, J2=5.6 Hz, 1H, H-6/2); 4.31 (m, 1H, H-5);
4.08-3.80 (m, 6H, H-4, H-3, 2.times.OCH.sub.2); 2.18-2.14 (m, 1H,
H-2/1); 1.90-1.81 (m, 1H, H-2/2); 1.42 (s, 3H, MeC); 1.41 (s, 3H,
MeC)
[0072] .sup.1H NMR (diastereomer 2), (500 MHz, CDCl.sub.3): .delta.
(ppm)=8.06 (m, 2H, Ar); 7.56 (m, 1H, Ar); 7.44 (m, 2H, Ar); 5.09
(m, 1H, H-1); 4.55 (m, 1H, H-6/1); 4.48-4.31 (m, 2H, H-6/2, H-5);
4.08-3.80 (m, 6H, H-4, H-3, 2.times.OCH.sub.2); 2.03-1.92 (m, 2H,
H-2/1, H-2/2); 1.45 (s, 3H, MeC); 1.44 (s, 3H, MeC)
EXAMPLE 7
[0073]
[(4S,5R)-5-[2-(1,3-dioxolan-2-yl)acetyl]-2,2-dimethyl-1,3-dioxolan--
4-yl]methyl benzoate; formula (VII);
R.sub.7.dbd.R.sub.5.dbd.CH.sub.2;
R.sub.9.dbd.R.sub.10.dbd.CH.sub.3; X.dbd.O; Y.dbd.[C(.dbd.O)]
[0074] A solution of 22.7 mL (0.31 mol) of DMSO and 10 mL of
dichloromethane is cooled to -70.degree. C., and 18.53 g (0.14 mol)
of oxalyl chloride are slowly added dropwise under inert gas, in
such a way that the temperature does not exceed -60.degree. C. The
reaction mixture is stirred at -70.degree. C. for 50 minutes.
Subsequently, 34.22 g (0.1 mol) of
[(4S,5S)-5-[2-(1,3-dioxolan-2-yl)-1-hydroxyethyl]-2,2-dimethyl-1,-
3-dioxolan-4-yl]methyl benzoate (II) dissolved in 20 mL of
dichloromethane are added dropwise, making sure that the
temperature does not exceed -60.degree. C. Subsequently, the
reaction mixture is stirred at -70.degree. C. for 50 min.
Thereafter, 79.84 g (0.73 mol) of triethylamine are added dropwise
and the mixture is stirred at -70.degree. C. for a further 30 min.
The reaction mixture is then warmed gradually to room temperature
and 250 mL of H.sub.2O and 200 mL of dichloromethane are added. The
phases are separated and the aqueous phase is extracted once with
100 mL of dichloromethane. The combined organic phases are washed
once with 100 mL of sulfuric acid (0.1% in H.sub.2O), once with 100
mL of saturated NaHCO.sub.3 solution (and once with 100 mL of
saturated NaCl solution), dried over Na.sub.2SO.sub.4, filtered and
concentrated by evaporation. 33.73 g (99%) of colorless oil are
obtained.
[0075] .sup.1H NMR (500 MHz; CDCl.sub.3): .delta. (ppm)=8.02 (d,
J=7.2 Hz, 2H, Ar); 7.53 (t, J=7.2 Hz, 1H, Ar); 7.41 (t, J=7.6 Hz,
2H, Ar); 5.30 (t, J=5.2 Hz, 1H, H-1); 4.62 (dd, J1=11.6 Hz, J2=3.1
Hz, 1H, H-6/1); 4.37 (m, 3H, H-4, H-5, H-6/2); 3.94 (m, 2H,
OCH.sub.2); 3.83 (m, 2H, OCH.sub.2); 3.04 (d, J=5.3, 2H, H-2/1,
H-2/2); 1.44 (s, 3H, MeC); 1.41 (s, 3H, MeC)
EXAMPLE 8
[0076]
[(4S,5S)-5-[(E)-C-(1,3-dioxolan-2-ylmethyl)-N-hydroxy-carbonimidoyl-
]-2,2-dimethyl-1,3-dioxolan-4-yl]methyl benzoate; formula (VII);
R.sub.7.dbd.R.sub.8.dbd.CH.sub.2;
R.sub.9.dbd.R.sub.10.dbd.CH.sub.3; X.dbd.O;
Y.dbd.[C(.dbd.N)--OH]
[0077] To a solution of 24.52 g (0.07 mol) of
[(4S,5R)-5-[2-(1,3-dioxolan-2-yl)acetyl]-2,2-dimethyl-1,3-dioxolan-4-yl]m-
ethyl benzoate (II) in 80 mL of pyridine are added 31.58 g (0.45
mol) of hydroxylamine hydrochloride (NH.sub.2OH. HCl). This is
followed by stirring under inert gas at 55.degree. C. for 13 h. The
pyridine is removed by means of a rotary evaporator and the residue
is then dried under high vacuum. Thereafter, 250 mL of H.sub.2O and
250 mL of ethyl acetate are added and the phases are separated. The
aqueous phase is extracted four times with ethyl acetate
(4.times.50 mL). The combined organic phases are washed with
saturated NaCl solution and dried over sodium sulfate, filtered and
concentrated by evaporation. 24.24 g (94%) of yellow oil are
obtained.
[0078] .sup.1H NMR (500 MHz; CDCl.sub.3): .delta. (ppm)=8.05 (d,
J=7.2 Hz, 2H, Ar); 7.56 (t, J=7.2 Hz, 1H, Ar); 7.43 (t, J=7.7 Hz,
2H, Ar); 5.31 (t, J=4.7 Hz, 1H, H-1); 4.58 (m, 3H, H-4, H-5,
H-6/1); 4.40 (m, 1H, H-6/2); 3.98 (m, 2H, OCH.sub.2); 3.84 (m, 2H,
OCH.sub.2); 2.78 (m, 2H, H-2/1, H-2/2); 1.46 (s, 6H, Me.sub.2C)
EXAMPLE 9
[0079]
2-(1,3-dioxolan-2-yl)-1-[(4S,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-
-dioxolan-4-yl]ethanone oxime; formula (II);
R.sub.7.dbd.R.sub.8.dbd.CH.sub.2;
R.sub.9.dbd.R.sub.10.dbd.CH.sub.3; R.sub.4.dbd.H; X.dbd.O;
Y.dbd.[C(.dbd.N)--OH]
[0080] To a solution of 16.0 g (43.79 mmol) of
[(4S,5S)-5-[(E)-C-(1,3-dioxolan-2-ylmethyl)-N-hydroxycarbon-imidoyl]-2,2--
dimethyl-1,3-dioxolan-4-yl]methyl benzoate (II) in 340 mL of
THF/H.sub.2O (1:1) are added dropwise 32 mL of 2N NaOH (63.96
mmol), and the mixture is stirred at 60.degree. C. for 18 h. After
cooling to room temperature, 200 mL of MTBE are added, the phases
are separated and the aqueous phase is extracted four times with
MTBE. The combined organic phases are washed with saturated NaCl
solution and dried over sodium sulfate, filtered and concentrated.
9.31 g (81%) of yellow oil are obtained.
[0081] .sup.1H NMR (500 MHz; CDCl.sub.3): .delta. (ppm)=9.07 (s,
1H, OH); 5.35 (t, J=5.3 Hz, 1H, H-1); 4.45 (d, J=8.5 Hz, 1H, H-4);
4.27 (m, 1H, H-5); 3.97 (m, 2H, OCH.sub.2); 3.78 (m, 3H, OCH.sub.2,
H-6); 3.09 (s, 1H, OH); 2.74 (m, 2H, H-2/1, H-2/2); 1.43 (s, 6H,
Me.sub.2C)
EXAMPLE 10
[0082]
2-(1,3-dioxolan-2-yl)-1-[(4S,5S)-5-[2-[2-[2-[2-(2-methoxyethoxy)eth-
oxy]ethoxy]ethoxy]ethoxymethyl]-2,2-dimethyl-1,3-dioxolan-4-yl]ethanone
oxime; formula (II); R.sub.7.dbd.R.sub.8.dbd.CH.sub.2;
R.sub.9.dbd.R.sub.10.dbd.CH.sub.3;
R.sub.4.dbd.[(--CH.sub.2--CH.sub.2--O).sub.5--CH.sub.3]; X.dbd.O;
Y.dbd.[C(.dbd.N)--OH]
[0083] To a solution of 7.8 g (29.9 mmol) of
2-(1,3-dioxolan-2-yl)-1-[(4S,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxo-
lan-4-yl]ethanone oxime (II) in 150 mL of THF are added 2.26 g of
sodium hydride (95%) (89.8 mmol) in portions and the mixture is
stirred at room temperature under inert gas for 1.5 h.
Subsequently, 24.3 g (60 mmol) of
2-[2-[2-[2-(2-methoxyethoxy)ethoxy]-ethoxy]ethoxy]ethyl
4-methylbenzenesulfonate dissolved in 50 mL of THF are added
dropwise and the mixture is stirred at 60.degree. C. for a further
5 h. The reaction is then quenched with saturated NH.sub.4Cl
solution. Thereafter, 300 mL of DCM are added, the phases are
separated and the aqueous phase is extracted four times with DCM.
The combined organic phases are dried over Na.sub.2SO.sub.4,
filtered and concentrated by evaporation. The resulting oil is
purified by chromatography (eluent: toluene/acetone 2:1->1:1,
v/v). 12.4 g (84%) of yellow oil are obtained.
[0084] .sup.1H NMR (500 MHz; CDCl.sub.3): .delta. (ppm)=5.32 (t,
J=5.3 Hz, 1H, H-1); 4.38 (m, 1H, H-5); 4.28 (d, J=8.2 Hz, 1H, H-4);
3.95 (m, 2H, OCH.sub.2); 3.82 (m, 2H, OCH.sub.2); 3.64 (m, 18H,
CH.sub.2O); 3.52 (m, 4H, H-6, MeOCH.sub.2); 3.35 (s, 3H, OMe); 2.73
(d, J=5.7 Hz, 2H, H-2/1, H-2/2); 1.42 (s, 3H, MeC); 1.40 (s, 3H,
MeC)
EXAMPLE 11
[0085]
(1S)-2-(1,3-dioxolan-2-yl)-1-[(4S,5S)-5-[2-[2-[2-[2-(2-methoxyethox-
y)ethoxy]ethoxy]ethoxy]ethoxymethyl]-2,2-dimethyl-1,3-dioxolan-4-yl]ethana-
mine; formula (II); R.sub.7.dbd.R.sub.8.dbd.CH.sub.2;
R.sub.9.dbd.R.sub.10.dbd.CH.sub.3;
R.sub.4.dbd.[(--CH.sub.2--CH.sub.2--O).sub.5--CH.sub.3]; X.dbd.O;
Y.dbd.[CH--NH.sub.2]; Y.dbd.[CH--NR.sub.5R.sub.6],
R.sub.5.dbd.R.sub.6.dbd.H
[0086] A solution of 12.4 g (25 mmol) of
2-(1,3-dioxolan-2-yl)-1-[(4S,5S)-5-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]-e-
thoxy]ethoxy]ethoxymethyl]-2,2-dimethyl-1,3-dioxolan-4-yl]ethanone
oxime (II) in 125 mL of THF under inert gas is cooled to 0.degree.
C. Connecting, 3.1 g (82.2 mmol) of lithium aluminum hydride
(LiAlH.sub.4) are added gradually while stirring. This is followed
by stirring at RT for 4 h. The reaction is quenched with NaOH
solution (5M), 100 mL of EtOAc are added and the mixture is stirred
for 10 min. The reaction mixture is then filtered and the phases
are separated. The combined organic phases are washed with
saturated NaCl solution and dried over sodium sulfate, filtered and
concentrated by evaporation. 9.8 g (81%) of yellow oil (mixture of
the diastereomers 57:43 of 3') are obtained.
[0087] .sup.1H NMR (200 MHz; CDCl.sub.3): .delta. (ppm)=5.01 (t,
J=4.73 Hz, 1H, H-1); 4.20-3.77 (m, 7H, H-4, H-5, H-6,
2.times.OCH.sub.2); 3.64 (m, 18H, CH.sub.2O); 3.53 (m, 2H,
MeOCH.sub.2); 3.35 (s, 3H, OMe); 3.19-3.00 (m, 1H, H-3); 2.24-1.56
(m, 2H, H-2); 1.38 (s, 3H, MeC); 1.37 (s, 3H, MeC)
EXAMPLE 12
[0088]
N-[2-(1,3-dioxolan-2-yl)-1-[(4S,5S)-5-[2-[2-[2-[2-(2-methoxyethoxy)-
ethoxy]ethoxy]ethoxy]ethoxymethyl]-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]-2-
,2,2-trifluoro-acetamide; formula (II);
R.sub.7.dbd.R.sub.8.dbd.CH.sub.2;
R.sub.9.dbd.R.sub.10.dbd.CH.sub.3;
R.sub.4.dbd.[(--CH.sub.2--CH.sub.2--O).sub.5--CH.sub.3]; X.dbd.O;
Y.dbd.[CH--NR.sub.5R.sub.6], R.sub.5.dbd.H,
R.sub.6.dbd.[C(.dbd.O)CF.sub.3]
[0089] To a solution of 9.8 g (20.3 mmol) of
(1S)-2-(1,3-dioxolan-2-yl)-1-[(4S,5S)-5-[2-[2-[2-[2-(2-methoxy-ethoxy)eth-
oxy]ethoxy]ethoxy]ethoxymethyl]-2,2-dimethyl-1,3-dioxolan-4-yl]ethanamine
(II) in 196 mL of DCM and 9.6 mL of pyridine is added 0.05 g (0.4
mmol) of 4-(dimethylamino)pyridine. The reaction mixture is cooled
to -17.degree. C. and 6.41 g (30.5 mmol) of trifluoroacetic
anhydride are added dropwise. Thereafter, the mixture is warmed to
room temperature within 4 h while stirring, all the solvents are
concentrated by evaporation and the residue is taken up in
dichloromethane. The organic phase is washed with semi-saturated
NaHCO.sub.3 solution and saturated NaCl solution, dried over sodium
sulfate, filtered and concentrated by evaporation. The resulting
oil is purified by chromatography (eluent: petroleum ether/acetone
2:1, v/v). 9.5 g (80%) of yellow oil (mixture of the diastereomers
57:43 of 3') are obtained.
[0090] .sup.1H NMR (diastereomer 1), (500 MHz; CDCl.sub.3): .delta.
(ppm)=7.65 (d, J=8.85 Hz, 1H, NH); 4.99 (t, J=4.6 Hz, 1H, H-1);
4.30 (m, 1H, H-3); 3.92 (m, 7H, H-4, H-5, H-6, 2.times.OCH.sub.2);
3.62 (m, 18H, CH.sub.2O); 3.52 (m, 2H, MeOCH.sub.2); 3.35 (s, 3H,
OMe); 2.04 (m, 2H, H-2); 1.38 (s, 3H, MeC); 1.37 (s, 3H, MeC)
[0091] .sup.1H NMR (diastereomer 2), (500 MHz; CDCl.sub.3): .delta.
(ppm)=6.95 (d, J=9.15 Hz, 1H, NH); 4.96 (t, J=4.4 Hz, 1H, H-1);
4.40 (m, 1H, H-3); 3.92 (m, 7H, H-4, H-5, H-6, 2.times.OCH.sub.2);
3.62 (m, 18H, CH.sub.2O); 3.52 (m, 2H, MeOCH.sub.2); 3.35 (s, 3H,
OMe); 2.04 (m, 2H, H-2); 1.38 (s, 3H, MeC); 1.1.37 (s, 3H, MeC)
EXAMPLE 13
[0092]
(2S,5S)-2-tert-butyl-5-[2-(tert-butyl(dimethyl)silyl)-oxyethyl]-1,3-
-dioxolan-4-one; formula (IX)
[0093] 40 g of 2-[(2S,4S)-2-tert-butyl-5-oxo-1,3-dioxolan-4-yl]
acetic acid are dissolved in 300 mL of THF under an argon
atmosphere and cooled to 0.degree. C. 238 mL of BH.sub.3.THF
complex (1M in THF) are added gradually within one hour, in such a
way that the temperature does not rise above 5.degree. C. On
completion of addition of the reagent, the reaction mixture is
stirred at 0.degree. C. for 20 min, warmed to room temperature and
stirred for 3.5 hours. The reaction mixture is partitioned between
saturated NH.sub.4Cl solution and EtOAc. The phases are separated
and the aqueous phase is extracted with EtOAc. The combined organic
phases are washed with 5% aqueous NaHCO.sub.3 solution and
saturated sodium chloride solution, dried over Na.sub.2SO.sub.4,
filtered and concentrated by evaporation under reduced pressure. 32
g of intermediate are obtained, which can be used directly in the
next stage without further purification.
[0094] 43 g of TBDMSCl in 500 mL of DCM are admixed with 45.1 g of
pyridine. The solution is stirred for 10 min, then the
intermediate, dissolved in 100 mL of DCM, is added. The reaction
mixture is stirred at room temperature for 16 hours and then poured
onto water. The phases are separated, the organic phase is washed
with 5% aqueous NaHCO.sub.3 solution, dried over Na.sub.2SO.sub.4,
filtered and concentrated by evaporation under reduced pressure.
The crude product is purified by means of flash chromatography over
silica gel with toluene as eluent. 52.3 g of
(2S,5S)-2-tert-butyl-5-[2-(tert-butyl(dimethyl)silyl)oxyethyl]--
1,3-dioxolan-4-one are obtained as a colorless oil.
[0095] .sup.1H NMR (500 MHz; CDCl.sub.3): .delta. (ppm)=5.15 (s,
1H, H-5); 4.43 (dd, 1H, 3.8 Hz, 8.5 Hz, H-3); 3.80 (m, 2H, H-1);
2.12 (m, 1H, H-2/1); 1.86 (m, 1H, H-2/2); 0.97 (s, 9H,
H-tBuCH.sub.3); 0.89 (s, 9H, H-SitBuCH.sub.3); 0.06 (s, 6H,
H--SiCH.sub.3).
EXAMPLE 14 (ALKYLATION REACTION)
[0096]
(2S,5S)-2-tert-butyl-5-[2-(tert-butyl(dimethyl)silyl)-oxyethyl]-5-[-
(1,4,9,10-tetramethoxy-2-anthryl)methyl]-1,3-dioxolan-4-one;
formula (X); R.sub.1.dbd.H
[0097] To a solution of 18 g of KHMDS in 680 mL of anhydrous THF is
added dropwise, under an argon atmosphere at -76.degree. C., a
solution of 25.6 g of
(2S,5S)-2-tert-butyl-5-[2-(tert-butyl(dimethyl)silyl)oxyethyl]-1,3-d-
ioxolan-4-one in 30 mL of THF, in such a way that the temperature
does not rise above -72.degree. C. The reaction mixture is stirred
at -76.degree. C. for 50 minutes. A solution of 22 g of
2-(bromomethyl)-1,4,9,10-tetramethoxyanthracene in 40 mL of THF is
added dropwise at -75.degree. C. The mixture is then stirred at
this temperature for 20 min. The reaction mixture is partitioned
between 1N HCl and EtOAc. The aqueous phase is extracted with EtOAc
and the combined organic phases are dried over Na.sub.2SO.sub.4,
filtered and concentrated by evaporation under reduced pressure.
The crude product is digested in a mixture of 50 mL of MTBE and 200
mL of PE, filtered and washed with PE. 23.4 g of
(2S,5S)-2-tert-butyl-5-[2-(tert-butyl(dimethyl)silyl)oxyethyl]--
5-[(1,4,9,10-tetra-methoxy-2-anthryl)methyl-1,3-dioxolan-4-one are
obtained as a yellow solid. The filtrate is concentrated by
evaporation under reduced pressure and separated by means of column
chromatography (silica gel, toluene/EtOAc 30/1). In this way, a
further 7.4 g of
(2S,5S)-2-tert-butyl-5-[2-(tert-butyl(dimethyl)-silyl)oxyethyl]-5-[(1,4,9-
,10-tetramethoxy-2-anthryl)-methyl-1,3-dioxolan-4-one are
obtained.
[0098] .sup.1H NMR (500 MHz; CDCl.sub.3): .delta. (ppm)=8.35 (m,
2H, H-5 and H-8); 7.52 (m, 2H, H-6 and H-7); 6.64 (s, 1H, H-3);
4.84 (s, 1H, H-acetal); 4.02 (s, 3H, OCH.sub.3-4); 4.00 (s, 3H,
OCH.sub.3-10); 3.95 (s, 3H, OCH.sub.3-9); 3.83 (m, 2H, H-4'); 3.75
(s, 3H, OCH.sub.3-1); 3.44 (d, 1H, J=13.9 Hz, H-1'/1); 3.18 (d, 1H,
J=13.9 Hz, H-1'/2); 2.17 (m, 2H, H-3'); 0.89 (s, 9H,
H-tBuCH.sub.3); 0.88 (s, 9H, H-SitBuCH.sub.3); 0.05 (s, 3H,
H--SiCH.sub.3); 0.04 (s, 3H, H--SiCH.sub.3).
EXAMPLE 15
[0099]
(3S)-5-(tert-Butyl(dimethyl)silyl)oxy-3-hydroxy-3-[(1,4,9,10-tetram-
ethoxy-2-anthryl)methyl]pentan-2-one; formula (XI);
R.sub.1.dbd.H
[0100] To a solution of 62 g of
(2S,5S)-2-tert-butyl-5-[2-(tert-butyl(dimethyl)silyl)oxyethyl]-5-[(1,4,9,-
10-tetramethoxy-2-anthryl)methyl]-1,3-dioxolan-4-one in 700 mL of
anhydrous THF are added dropwise, under an argon atmosphere at
-78.degree. C., 164 mL of MeLi (1.6 M in Et.sub.2O), in such a way
that the temperature does not rise above -71.degree. C. The
reaction mixture is stirred at -75.degree. C. for 1.5 hours and
then partitioned between saturated NH.sub.4Cl solution and EtOAc.
The aqueous phase is extracted with EtOAc. The combined organic
phases are dried over Na.sub.2SO.sub.4, filtered and concentrated
by evaporation under reduced pressure. The crude product is
purified by means of column chromatography (silica gel,
toluene/EtOAc, 10/1). 54.2 g of
(3S)-5-(tert-butyl-(dimethyl)silyl)oxy-3-hydroxy-3-[(1,4,9,10-tetra-metho-
xy-2-anthryl)methyl]pentan-2-one are obtained as a yellow foam.
[0101] .sup.1H NMR (500 MHz; CDCl.sub.3): .delta. (ppm)=16.67 (m,
2H, H-5 and H-8); 7.51 (m, 2H, H-6 and H-7); 6.70 (s, 1H, H-3);
4.01 (s, 3H, OCH.sub.3-4); 3.98 (s, 3H, OCH.sub.3-10); 3.92 (s, 3H,
OCH.sub.3-9); 3.82 (td, 1H, J=4.1 Hz, 9.2 Hz, H-4'/1); 3.77 (s, 3H,
OCH.sub.3-1); 3.70 (dt, 1H, J =5.1 Hz, 10.4 Hz, H-4'/2); 3.27 (d,
1H, J=12.9 Hz, H-1'/1); 3.12 (d, 1H, J=12.9 Hz, H-1'/2); 2.39 (m,
1H, H-3'/1); 2.33 (s, 3H, CH.sub.3); 1.96 (dt, 1H, J=4.4 Hz, 14.2
Hz, H-3'/2); 0.86 (s, 9H, H-SitBuCH.sub.3); 0.02 (s, 3H,
H--SiCH.sub.3); 0.01 (s, 3H, H--SiCH.sub.3).
EXAMPLE 16
[0102] a. Reduction of the Keto Group
(2S,3S)-5-(tert-Butyl(dimethyl)silyl)oxy-3-[(1,4,9,10-tetramethoxy-2-anthr-
yl)methyl]pentane-2,3-diol
[0103] To a solution of 33.8 g of
(3S)-5-(tert-butyl-(dimethyl)silyl)oxy-3-hydroxy-3-[(1,4,9,10-tetra-metho-
xy-2-anthryl)methyl]pentan-2-one in 340 mL of EtOH are added, under
an argon atmosphere, 2.36 g of NaBH.sub.4. The reaction mixture is
stirred at RT for one hour and then quenched with saturated sodium
chloride solution and EtOAc. The aqueous phase is extracted with
EtOAc. The combined organic phases are dried over Na.sub.2SO.sub.4,
filtered and concentrated by evaporation under reduced pressure.
The crude product is purified by means of flash chromatography
(silica gel, toluene/EtOAc=5:1). 30.70 g
(2S,3S)-5-(tert-butyl(dimethyl)silyl)oxy-3-[(1,4,9,10-tetramethoxy-2-anth-
ryl)methyl]pentane-2,3-diol are obtained as a yellow foam.
b. Ketalization:
[0104]
tert-Butyldimethyl-[2-[(4S,5S)-2,2,5-trimethyl-4-[(1,4,9,10-tetrame-
thoxy-2-anthryl)methyl]-1,3-dioxolan-4-yl]ethoxy]silane; formula
(XII), R.sub.1.dbd.H
[0105] To a solution of 5.26 g of the alcoholic intermediate in 100
mL of dry acetone are added, under an argon atmosphere, 2.6 mL of
dimethoxypropane followed by 0.09 g of pTsOH. The reaction mixture
is stirred at RT for 1.5 hours and then partitioned between
saturated NaHCO.sub.3 solution and EtOAc. The phases are separated:
the aqueous phase is extracted with EtOAc. The combined organic
phases are dried over Na.sub.2SO.sub.4, filtered and concentrated
by evaporation under reduced pressure. The crude product is
purified by means of flash chromatography (silica gel,
toluene/EtOAc, 40/1). 4.66 g of
tert-butyldimethyl-[2-[(4S,5S)-2,2,5-trimethyl-4-[(1,4,9,10-tetramethoxy--
2-anthryl)methyl]-1,3-dioxolan-4-yl]ethoxy]silane are obtained as a
yellow foam.
[0106] .sup.1H NMR (500 MHz; CDCl.sub.3): .delta. (ppm)=8.35 (m,
2H, H-5 and H-8); 7.50 (m, 2H, H-6 and H-7); 6.97 (s, 1H, H-3);
4.54 (q, 1H, J=6.3 Hz, H-5'); 4.02 (s, 3H, OCH.sub.3-4); 3.98 (s,
3H, OCH.sub.3-10); 3.92 (s, 3H, OCH.sub.3-9); 3.73 (s, 3H,
OCH.sub.3-1); 3.69 (m, 2H, H-4'); 3.19 (d, 1H, J=13.6 Hz, H-1'/1);
2.75 (d, 1H, J=13.6 Hz, H-1'/2); 1.91 (m, 1H, H-3'/1); 1.77 (m, 1H,
H-3'/2); 1.74 (s, 3H, H-acetonide); 1.45 (d, 3H, J=6.3 Hz,
CH.sub.3); 1.44 (s, 3H, H-acetonide); 0.86 (s, 9H,
H-SitBuCH.sub.3); 0.01 (s, 6H, H--SiCH.sub.3).
EXAMPLE 17
[0107] a. Detachment of the TBDMS Group
2-[(4S,5S)-2,2,5-Trimethyl-4-[(1,4,9,10-tetramethoxy-2-anthryl)methyl]-1,3-
-dioxolan-4-yl]ethanol
[0108] To a solution of 4.57 g of
tert-butyldimethyl-[2-[(4S,5S)-2,2,5-trimethyl-4-[(1,4,9,10-tetramethoxy--
2-anthryl)methyl]-1,3-dioxolan-4-yl]ethoxy]silane in 90 mL of
anhydrous THF are added at RT, under an argon atmosphere, 19.5 mL
of TBAF (1M in THF). The reaction mixture is stirred at RT for 1
hour. The reaction mixture is partitioned between saturated
NaHCO.sub.3 solution and EtOAc. The aqueous phase is extracted with
EtOAc. The combined organic phases are dried over Na.sub.2SO.sub.4,
filtered and concentrated by evaporation under reduced pressure.
603 g of
2-[(4S,5S)-2,2,5-trimethyl-4-[(1,4,9,10-tetramethoxy-2-anthryl)methyl]-1,-
3-dioxolan-4-yl]ethanol are obtained as a yellow foam.
[0109] .sup.1H NMR (500 MHz; CDCl.sub.3): .delta. (ppm)=8.35 (m,
2H, H-5 and H-8); 7.51 (m, 2H, H-6 and H-7); 6.93 (s, 1H, H-3);
4.37 (q, 1H, J=6.3 Hz, H-5'); 4.02 (s, 3H, OCH.sub.3-4); 4.00 (s,
3H, OCH.sub.3-10); 3.93 (s, 3H, OCH.sub.3-9); 3.81 (m, 1H, H-4'/1);
3.78 (s, 3H, OCH.sub.3-1); 3.66 (m, 1H, H-4'/2); 3.22 (d, 1H,
J=13.6 Hz, H-1'/1; 2.81 (brs, 1H, OH-4'); 2.75 (d, 1H, J=13.6 Hz,
H-1'/2); 1.88 (m, 2H, H-3'); 1.75 (s, 3H, H-acetonide); 1.48 (d,
3H, J=6.3 Hz, CH.sub.3); 1.47 (s, 3H, H-acetonide).
b. Oxidation of the Primary Alcohol to the Aldehyde:
[0110]
2-[(4S,5S)-2,2,5-Trimethyl-4-[(1,4,9,10-tetramethoxy-2-anthryl)meth-
yl]-1,3-dioxolan-4-yl]acetaldehyde; formula (XIII);
R.sub.1.dbd.H
[0111] Added dropwise to a solution of 0.99 mL of DMSO in 55 mL of
DCM at -70.degree. C. is 0.61 mL of oxalyl chloride under an argon
atmosphere. The mixture is stirred at -70.degree. C. for 1 hour.
Subsequently, 2.19 g of
2-[(4S,5S)-2,2,5-trimethyl-4-[(1,4,9,10-tetramethoxy-2-anthryl)-methyl-
]-1,3-dioxolan-4-yl]ethanol in 4 mL of DCM are added gradually at
-70.degree. C. The reaction mixture is stirred for 1 hour. 4.27 mL
of Et.sub.3N are added at the same temperature. Stirring is
continued while gradually warming to 0.degree. C. for another 1
hour. The reaction mixture is partitioned between saturated sodium
chloride solution and EtOAc. The organic phase is washed
successively with saturated NH.sub.4Cl solution, saturated
NaHCO.sub.3 solution and saturated sodium chloride solution, dried
over Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure. 2.1 g of
2-[(4S,5S)-2,2,5-trimethyl-4-[(1,4,9,10-tetramethoxy-2-anthryl)methyl]-1,-
3-dioxolan-4-yl]acetaldehyde are obtained as a yellow foam.
[0112] .sup.1H NMR (500 MHz; CDCl.sub.3): .delta. (ppm)=9.65 (dd,
1H, J=1.3 Hz, 2.2 Hz, H-4'); 8.34 (m, 2H, H-5 and H-8); 7.51 (m,
2H, H-6 and H-7); 6.81 (s, 1H, H-3); 4.28 (q, 1H, J=6.3 Hz, H-5');
4.03 (s, 3H, OCH.sub.3-4); 3.99 (s, 3H, OCH.sub.3-10); 3.91 (s, 3H,
OCH.sub.3-9); 3.70 (s, 3H, OCH.sub.3-1); 3.23 (d, 1H, J=13.6 Hz,
H-1'/1); 2.77 (dd, 1H, J=2.2 Hz, 16.4 Hz, H-3'/1); 2.73 (d, 1H,
J=13.6 Hz, H-1'/2); 2.62 (dd, 1H, J=1.3 Hz, 16.34 Hz, H-3'/2); 1.74
(s, 3H, H-acetonide); 1.55 (d, 3H, J=6.3 Hz, CH.sub.3); 1.40 (s,
3H, H-acetonide).
c. Oxidative Demethylation:
[0113]
2-[(4S,5S)-4-[(1,4-dimethoxy-9,10-dioxo-2-anthryl)-methyl]-2,2,5-tr-
imethyl-1,3-dioxolan-4-yl]acetaldehyde; formula (XIV),
R.sub.1.dbd.H
[0114] To a solution of 2.08 g of
2-[(4S,5S)-2,2,5-trimethyl-4-[(1,4,9,10-tetramethoxy-2-anthryl)methyl]-1,-
3-dioxolan-4-yl]acetaldehyde in 60 mL of CH.sub.3CN is added, at
2.degree. C., a solution of 7.3 g of CAN in 130 mL of water. After
stirring for 30 min, the reaction mixture is diluted with 80 mL of
water. The aqueous phase is extracted with EtOAc. The combined
organic phases are dried and concentrated by evaporation. The
resulting mixture is separated by chromatography (eluent:
toluene/EtOAc 6:1). 1.91 g of
2-[(4S,5S)-4-[(1,4-dimethoxy-9,10-dioxo-2-anthryl)methyl]-2,2,5-trimethyl-
-1,3-dioxolan-4-yl]acetaldehyde are obtained as a yellow solid.
[0115] .sup.1H NMR (500 MHz; CDCl.sub.3): .delta. (ppm)=9.62 (dd,
1H, J=1.6 Hz, 2.5 Hz, H-4'); 8.16 (m, 2H, H-5 and H-8); 7.71 (m,
2H, H-6 and H-7); 7.45 (s, 1H, H-3); 4.25 (q, 1H, J=6.3 Hz, H-5');
4.00 (s, 3H, OCH.sub.3-4); 3.81 (s, 3H, OCH.sub.3-1); 3.18 (d, 1H,
J=12.9 Hz, H-1'/1); 2.66 (d, 1H, J=12.9 Hz, H-1'/2); 2.65 (dd, 1H,
J=2.5 Hz and 16.4 Hz, H-3'/1); 2.48 (dd, 1H, J=1.6 Hz, 16.4 Hz,
H-3'/2); 1.64 (s, 3H, H-acetonide); 1.50 (d, 3H, J=6.3 Hz,
CH.sub.3); 1.34 (s, 3H, H-acetonide).
EXAMPLE 18
[0116]
2-[[(2S,3S)-3,5-dihydroxy-2-methyltetrahydrofuran-3-yl]methyl]-1,4--
dihydroxyanthracene-9,10-dione; formula (XV); R.sub.1.dbd.H
[0117] To a solution of 1 g of
2-[(4S,5S)-4-[(1,4-dimethoxy-9,10-dioxo-2-anthryl)methyl]-2,2,5-trimethyl-
-1,3-dioxolan-4-yl]acetaldehyde in 55 mL of DCM are added dropwise
at 2.degree. C., under an argon atmosphere, 13.7 mL of BCl.sub.3
(1M in DCM). The reaction mixture is stirred for 40 min, and 0.5 N
NaOH and DCM are added. The phases are separated; the organic phase
is washed with 0.5 N NaOH. The combined aqueous phases are
acidified to pH=6 at 0.degree. C. with 1 N HCl and extracted with
DCM. The combined organic phases are dried and concentrated by
evaporation. 0.79 g of
2-[[(2S,3S)-3,5-dihydroxy-2-methyltetrahydrofuran-3-yl]methyl]-1,4-dihydr-
oxy-anthracene-9,10-dione is obtained as a red solid.
[0118] .sup.1H NMR (500 MHz; CDCl.sub.3): .delta. (ppm)=13.66 (s,
1H, OH-1); 12.87 (s, 1H, OH-4); 8.36 (m, 2H, H-5 and H-8); 7.85 (m,
2H, H-6 and H-7); 7.29 (s, 1H, H-3); 5.38 (m, 1H, H-4'); 4.01 (q,
1H, J=6.3 Hz, H-6'); 3.52 (d, 1H, J=7.3 Hz, OH-4'); 3.39 (s, 1H,
OH-2'); 3.07 (d, 1H, J=13.6 Hz, H-1'/1); 2.90 (d, 1H, J=13.6 Hz,
H-1'/2); 2.21 (dd, 1H, J=5.1, 13.3 Hz, H-3'/1; 1.99 (d, 1H, J=13.3
Hz, H-3'/2); 1.34 (d, 3H, J=6.3 Hz, CH.sub.3).
EXAMPLE 19
[0119] a. Intramolecular Ring Closure as Per Marschalk
[0120]
(7R,9S)-6,7,9,11-tetrahydroxy-9-[(1S)-1-hydroxyethyl]-8,10-dihydro--
7H-tetracene-5,12-dione; formula (XVI); R.sub.1, R.sub.13.dbd.H;
R.sub.12.dbd.OH and
(7S,9S)-6,7,9,11-tetrahydroxy-9-[(1S)-1-hydroxyethyl]-8,10-dihydro-7H-tet-
racene-5,12-dione; formula (XVI); R.sub.1, R.sub.12.dbd.H;
R.sub.13.dbd.OH
[0121] To a solution of 70 mg of
2-[[(2S,3S)-3,5-dihydroxy-2-methyltetrahydrofuran-3-yl]methyl]-1,4-dihydr-
oxy-anthracene-9,10-dione in 5 mL of THF and 5 mL of MeOH is added
dropwise, under an argon atmosphere at -10.degree. C., a solution
of 38 mg of NaOH and 49 mg of Na.sub.2S.sub.2O.sub.4 in 1.2 mL of
water. After stirring for two hours, the reaction mixture is
quenched by blowing air in for 30 min. The reaction mixture is
admixed with 0.05 N HCl and EtOAc. The phases are separated; the
aqueous phase is extracted with EtOAc. The combined organic phases
are dried and concentrated by evaporation. The resulting mixture is
separated by chromatography (eluent: toluene/isopropanol 30:1). 37
mg of a mixture of (7R,9S)-6,7,9,11-tetrahydroxy-9-[(1
S)-1-hydroxy-ethyl]-8,10-dihydro-7H-tetracene-5,12-dione and
(7S,9S)-6,7,9,11-tetrahydroxy-9-[(1S)-1-hydroxyethyl]-8,10-dihydro-7H-tet-
racene-5,12-dione are obtained as a red solid.
(7R,9S)-6,7,9,11-tetrahydroxy-9-[(1S)-1-hydroxyethyl]-8,10-dihydro-7H-tetr-
acene-5,12-dione
[0122] .sup.1H NMR (500 MHz; CDCl.sub.3): .delta.=13.60 (s, 1H,
OH-6); 13.33 (s, 1H, OH-11); 8.23 (m, 2H, H-1 and H-4); 7.95 (m,
2H, H-2 and H-3); 5.17 (d, 1H, J=5.7 Hz, OH-7); 5.05 (m, 1H, H-7);
4.85 (d, 1H, J=5.7 Hz, OH-13); 4.45 (s, 1H, OH-9); 3.54 (q, 1H,
J=6.3 Hz, H-13); 2.85 (d, 1H, J=18.3 Hz, H-10/1); 2.68 (d, 1H,
J=18.3 Hz, H-10/2); 2.14 (m, 1H, H-8/1); 1.75 (m, 1H, H-8/2); 1.14
(d, 3H, J=6.3 Hz, CH.sub.3).
(7S,9S)-6,7,9,11-tetrahydroxy-9-[(1S)-1-hydroxyethyl]-8,10-dihydro-7H-tetr-
acene-5,12-dione
[0123] .sup.1H NMR (500 MHz; CDCl.sub.3): .delta.=13.42 (s, 1H,
OH-6); 13.30 (s, 1H, OH-11); 8.23 (m, 2H, H-1 and H-4); 7.95 (m,
2H, H-2 and H-3); 5.30 (d, 1H, J=7.9 Hz, OH-7); 5.14 (s, 1H, OH-9);
5.00 (m, 1H, H-7); 4.81 (d, 1H, J=5.7 Hz, OH-13); 3.54 (q, 1H, 6.3
Hz, H-13); 2.88 (d, 1H, J=18.3 Hz, H-10/1); 2.75 (d, 1H, J=18.3 Hz,
H-10/2); 2.14 (m, 1H, H-8/1); 1.75 (m, 1H, H-8/2); 1.16 (d, 3H,
J=6.3 Hz, CH.sub.3).
b. Intramolecular Ring Closure as Per Marschalk
[0124]
(9R)-6,9,11-trihydroxy-9-[(1S)-1-hydroxyethyl]-8,10-dihydro-7H-tetr-
acene-5,12-dione; formula (XVI); R.sub.1, R.sub.12,
R.sub.13.dbd.H
[0125] To a solution of 0.79 g of
2-[[(2S,3S)-3,5-Dihydroxy-2-methyltetrahydrofuran-3-yl]methyl]-1,4-dihydr-
oxy-anthracene-9,10-dione in 31 mL of THF and 31 mL of MeOH is
added dropwise, under an argon atmosphere at RT, a solution of 0.43
g of NaOH and 0.56 g of Na.sub.2S.sub.2O.sub.4 in 5.3 mL of water.
After stirring for 1.5 hours, the reaction mixture is quenched by
blowing in air for 30 min. The reaction mixture is admixed with
0.05 N HCl and EtOAc. The phases are separated; the aqueous phase
is extracted with EtOAc. The combined organic phases are dried and
concentrated by evaporation. The resulting mixture is purified by
digesting with toluene/EtOAc (1:1). 0.51 g of
(9R)-6,9,11-trihydroxy-9-[(1S)-1-hydroxyethyl]-8,10-dihydro-7H-tetra-
cene-5,12-dione is obtained as a red solid.
[0126] .sup.1H NMR (500 MHz; CDCl.sub.3): .delta. (ppm)=13.36 (s,
1H, OH-11); 13.35 (s, 1H, OH-6); 8.21 (m, 2H, H-1 and H-4); 7.94
(m, 2H, H-2 and H-3); 4.69 (d, 1H, J=6.3 Hz, OH-13); 4.28 (s, 1H,
OH-9); 3.56 (m, 1H, H-13); 2.82 (d, 1H, J=18.3 Hz, H-7/1); 2.66 (m,
3H, H-7/2 and H-10); 1.88 (m, 1H, H-8/1); 1.51 (m, 1H, H-8/2); 1.14
(d, 3H, J=6.3 Hz, CH.sub.3).
EXAMPLE 20
a: Oxidation of the Side Chain Hydroxyl Group
[0127]
(9R)-9-Acetyl-6,9,11-trihydroxy-8,10-dihydro-7H-tetracene-5,12-dion-
e; formula (XVII); R.sub.1.dbd.H
[0128] To a solution of 0.8 g of
(9R)-6,9,11-trihydroxy-9-[(1S)-1-hydroxyethyl]-8,10-dihydro-7H-tetracene--
5,12-dione (0.80 g, 2.258 mmol) in 45 mL of DCM are added, at RT
under an argon atmosphere, 1.58 g of Dess-Martin periodinane (97%).
After stirring for 5 hours, the reaction mixture is admixed with
saturated NaHCO.sub.3 solution and EtOAc. The phases are separated;
the aqueous phase is extracted with EtOAc. The combined organic
phases are dried and concentrated by evaporation. The resulting
mixture is separated by chromatography (eluent: DCM/EtOAc 7:1).
0.60 g of
(9R)-9-acetyl-6,9,11-trihydroxy-8,10-dihydro-7H-tetracene-5,12-dione
(1.694 mmol, 75%) is obtained as a red solid.
[0129] .sup.1H NMR (500 MHz; CDCl.sub.3): .delta. (ppm)=13.48 (s,
1H, OH-11); 13.47 (s, 1H, OH-6); 8.35 (m, 2H, H-1 and H-4); 7.83
(m, 2H, H-2 and H-3); 3.16 (m, 1H, H-7/1); 3.07 (d, 1H, J=18 Hz,
H-10/1); 2.95 (m, 2H, H-10/2 and H-7/2); 2.39 (s, 3H, CH3); 2.00
(m, 2H, H-8).
b: Hydroxylation at C-7
[0130]
(7S,9S)-9-acetyl-6,7,9,11-tetrahydroxy-8,10-dihydro-7H-tetracene-5,-
12-dione; formula (IV); R.sub.1.dbd.R.sub.2.dbd.H
[0131] To a suspension of 130 mg of
(9R)-9-acetyl-6,9,11-trihydroxy-8,10-dihydro-7H-tetracene-5,12-dione
in 35 mL of CCl.sub.4 are added successively 1 mL of water, 74 mg
of NBS and 18 mg of AIBN. The reaction mixture is subsequently
heated under reflux for 90 minutes. A further 33 mg of NBS are
added and the reaction mixture is heated under reflux for a further
2 hours. The reaction mixture is cooled to 20.degree. C. and
diluted with 15 mL of 10% K.sub.2CO.sub.3 solution and 20 mL of
THF. After stirring for 10 minutes, the aqueous phase is brought to
pH=1 with 1 N HCl and extracted with DCM. The combined organic
phases are dried, filtered and concentrated under reduced pressure.
The crude product is purified by chromatography on silica gel with
toluene/EtOAc (10/1), giving 35 mg of
(9R)-9-acetyl-6,9,11-trihydroxy-8,10-dihydro-7H-tetracene-5,12-dione,
16 mg of
(7R,9S)-9-acetyl-6,7,9,11-tetrahydroxy-8,10-dihydro-7H-tetracene-5,-
12-dione and 48 mg of
(7S,9S)-9-acetyl-6,7,9,11-tetrahydroxy-8,10-dihydro-7H-tetracene-5,12-dio-
ne as a red solid. [00133]
(7S,9S)-9-acetyl-6,7,9,11-tetrahydroxy-8,10-dihydro-7H-tetracene-5,12-dio-
ne
[0132] .sup.1H NMR (500 MHz; CDCl.sub.3): .delta. (ppm)=13.53 (s,
1H, OH-6); 13.25 (s, 1H, OH-11); 8.31 (m, 2H, H-1 and H-4); 7.84
(m, 2H, H-2 and H-3); 5.29 (brs, 1H, H-7); 4.58 (s, 1H, OH-9); 3.86
(d, 1H, J=5.0 Hz, OH-7); 3.17 (dd, 1H, J=2.2 Hz, 18.6 Hz, H-10/1);
2.94 (d, 1H, J=18.6 Hz, H-10/2); 2.44 (s, 3H, CH.sub.3); 2.35 (m,
1H, H-8/1); 2.17 (dd, 1H, J=5.1 Hz, 14.5 Hz, H-8/2).
(7R,9S)-9-acetyl-6,7,9,11-tetrahydroxy-8,10-dihydro-7H-tetracene-5,12-dion-
e
[0133] .sup.1H NMR (500 MHz; CDCl.sub.3): .delta. (ppm)=13.93 (s,
1H, OH-6); 13.30 (s, 1H, OH-11); 8.35 (m, 2H, H-1 and H-4); 7.85
(m, 1H, H-2 and H-3); 5.40 (dd, 1H, J=7.9 Hz, 8.6 Hz, H-7); 4.28
(d, 1H, J=1.6 Hz, OH-7); 3.90 (s, 1H, OH-9); 3.10 (d, 1H, J=18.0
Hz, H-10/1); 2.94 (d, 1H, J=18.0 Hz, H-10/2); 2.41 (s, 3H,
CH.sub.3); 2.35 (m, 1H, H-8/1); 2.18 (dd, 1H, J=9.8 Hz, 13.0 Hz,
H-8/2).
EXAMPLE 21
Epimerization of
(7R,9S)-9-acetyl-6,7,9,11-tetra-hydroxy-8,10-dihydro-7H-tetracene-5,12-di-
one
[0134] 26 mg of
(7R,9S)-9-acetyl-6,7,9,11-tetrahydroxy-8,10-dihydro-7H-tetracene-5,12-dio-
ne, which may be contaminated with
(7S,9S)-9-acetyl-6,7,9,11-tetra-hydroxy-8,10-dihydro-7H-tetracene-5,12-di-
one, are dissolved in 1.3 mL of TFA. After stirring at RT for two
hours, the reaction mixture is admixed with water and extracted
with DCM. The combined organic phases are dried and concentrated by
evaporation. The crude product is dissolved in 1 mL of acetone.
Thereafter, saturated NaHCO.sub.3 solution is added. After stirring
for 10 min, the mixture is extracted with DCM. The combined organic
phases are dried and concentrated by evaporation. The resulting
product is purified by chromatography (eluent: toluene/EtOAc 10:1).
15 mg of
(7S,9S)-9-acetyl-6,7,9,11-tetrahydroxy-8,10-dihydro-7H-tetracene-5,12-dio-
ne are obtained as a red solid.
[0135] .sup.1H NMR (500 MHz; CDCl.sub.3): .delta. (ppm)=13.53 (s,
1H, OH-6); 13.25 (s, 1H, OH-11); 8.31 (m, 2H, H-1 and H-4); 7.84
(m, 2H, H-2 and H-3); 5.29 (brs, 1H, H-7); 4.58 (s, 1H, OH-9); 3.86
(d, 1H, J=5.0 Hz, OH-7); 3.17 (dd, 1H, J=2.2 Hz, 18.6 Hz, H-10/1);
2.94 (d, 1H, J=18.6 Hz, H-10/2); 2.44 (s, 3H, CH.sub.3); 2.35 (m,
1H, H-8/1); 2.17 (dd, 1H, J=5.1 Hz, 14.5 Hz, H-8/2).
[0136] The invention further relates to the following items of
subject matter/compounds and uses:
[0137] 1'. A compound of the general formula (I)
##STR00026##
in which R.sub.1 is a hydrogen atom or a hydroxyl or methoxy group;
R.sub.2 is a hydrogen atom or a hydroxyl group; R.sub.3 is hydrogen
or a suitable hydroxyl protecting group and the wavy line in each
case means both possible configurations of --OR.sub.3 in relation
to the base structure; Y.dbd.[C(.dbd.O)], [C(.dbd.N)--OH] or
[CH--OH], [CH--NR.sub.5R.sub.6] in both possible stereoisomeric
arrangements, where R.sub.5 and R.sub.6 are the same or different
and are each a hydrogen atom, or a suitable amino protecting group
as known in the prior art, for instance from "Protective Groups in
Organic Synthesis" (Greene, Wuts) 4th edition, John Wiley &
Sons, Inc., pages 696 to 927, especially a trifluoroacetyl,
unbranched or branched lower alkyl, where "lower alkyl" means a
carbon number from 1 to 4, or an alkylene chain
(--CH.sub.2--CZ.sub.2--CZ.sub.2--CH.sub.2--,
--CH.sub.2--CZ.sub.2--CZ.sub.2--CZ.sub.2--CH.sub.2--,
--CH.sub.2--O--CZ.sub.2--CH.sub.2--,
--CH.sub.2--O--CZ.sub.2--CZ.sub.2--CH.sub.2--,
--CH.sub.2--CZ.sub.2--O--CZ.sub.2--CH.sub.2--) where Z is defined
as hydrogen, lower alkyl or lower alkoxy in any combination; in
which X .dbd.O, S or NR; where R=hydrogen or lower alkyl; R.sub.4
is an unbranched or branched alkyl or heteroalkyl chain having a
chain length of 1 to 19 elements, where a maximum of 6 heteroatoms
(O, N, S) in any combination are separated from one another by at
least two carbon atoms.
[0138] 2'. A compound of the general formula (I) in which X.dbd.O
and R1, R2, R3, R4 and Y are each as defined in item 1.
[0139] 3'. A compound of the general formula (I) in which X.dbd.NR
and R.sub.1, R.sub.2, R.sub.3, R.sub.4 and Y are each as defined in
item 1.
[0140] 4'. A compound of the general formula (I) in which X.dbd.S
and R.sub.1, R.sub.2, R.sub.3, R.sub.4 and Y are each as defined in
item f.
[0141] 5'. A compound as claimed in items 1' to 4' in which R.sub.4
contains at least one ethylene glycol unit
(--O--CH.sub.2--CH.sub.2--O--).
[0142] 6'. A process for preparing compounds of the general formula
(I) according to items 1' to 5, characterized in that an open-chain
sugar compound of the general formula (II)
##STR00027##
in which R.sub.7 and R.sub.5 are the same and are each alkyl or
alkylene having 2 to 3 carbon atoms; R.sub.9 and R.sub.10 are each
an alkyl group having 1 to 3 carbon atoms; X and Y are each as
defined in formula (I) of item 1; R.sub.4 is hydrogen or a suitable
hydroxyl protecting group as known in the prior art, for instance
from "Protective Groups in Organic Synthesis" (Greene, Wuts) 4th
edition, John Wiley & Sons, Inc., pages 16 to 288, especially a
benzoyl group, or is as defined for R.sub.4 in formula (I), is
cyclized to give a sugar compound of the general formula (III)
##STR00028##
in which X, Y and R.sub.4 are each as defined in formula (II),
R.sub.3 and R.sub.11 are each an activating group known for
glycosylation [C(.dbd.O)PhNO.sub.2, OTFA] and the wavy lines in
each case mean both possible configurations of --OR.sub.3 and
--OR.sub.11 in relation to the base structure, and is reacted with
an anthraquinone-derived aglycone of the general formula (IV)
##STR00029##
in which R.sub.1 and R.sub.2 are each as defined in item 1', and
then the protecting groups still present on the sugar are detached
under basic conditions, preferably with sodium hydroxide solution,
in order to obtain compounds of the general formula (I) as per item
1'.
[0143] 7'. The process as claimed in item 6, characterized in that
the compound of the general formula (II) to be cyclized is prepared
by joining a C2 unit of the general formula (V)
##STR00030##
in which R.sub.7 and R.sub.8 are each as defined in formula (II) to
a protected derivative of L-threose (enantiomerically pure C4 unit)
of the general formula (VI)
##STR00031##
in which X, R.sub.4, R.sub.9, R.sub.10 are each as defined in
formula (II), by known methods, wherein preference is given to C--C
bond formation by means of a Grignard reaction in an aprotic
solvent such as tetrahydrofuran, and the resulting addition product
of the general formula (II) in which [Y.dbd.CH--OH] can
subsequently be oxidized by known methods such as oxidation with
chromium compounds, but preferably by means of Swern oxidation to
give the ketone [Y.dbd.C(.dbd.O)] of the general formula (II), in
order then to introduce the nitrogen at position 3 by known
methods, for example by reductive amination, but preferably by
preparation of an oxime [Y.dbd.C(.dbd.N)--OH] of the general
formula (II), which is subsequently reduced, but, if R.sub.4 is
hydrogen or a hydroxyl protecting group, may be deprotected
beforehand if necessary and derivatized according to the
description for R.sub.4 in formula (I), in which case the
introduction of an unbranched or branched alkyl or heteroalkyl
chain on X is effected by known methods, for example Finkelstein
reaction, but preferably via a nucleophilic substitution, where the
chain to be introduced is activated beforehand with a good leaving
groups such as tosylate or mesylate, and then oximes of the general
formula (II) [Y.dbd.C(.dbd.N)--OH] are reduced, for which it is
possible to use known methods, preferably a complex hydride in an
aprotic solvent such as toluene or THF, forming amines of the
general formula (II) [Y.dbd.CH--NH.sub.2] which are optionally
derivatized further or protected at this site
[Y.dbd.CH--NR.sub.5R.sub.6] where R.sub.5 and R.sub.6 are each as
defined in the general formula (I).
[0144] 8'. A compound of the general formula (III)
##STR00032##
in which X, Y and R.sub.4 are each as defined in formula (II) and
R.sub.6 and R.sub.11 are each hydrogen or an activating group known
for glycosylation [OC(.dbd.O)PhNO.sub.2, OTFA] and the wavy lines
in each case mean both possible configurations of --OR.sub.3 and
--OR.sub.11 in relation to the base structure.
[0145] 9'. A compound as claimed in item 8', characterized in that
R.sub.3 and R.sub.11 are each hydrogen, Y.dbd.[CH--NR.sub.5R.sub.6]
where R.sub.5 is hydrogen and R.sub.6 is TFA, X.dbd.O and R.sub.4
comprises at least one ethylene glycol unit
(--O--CH.sub.2--CH.sub.2--O--).
[0146] 10'. A compound as claimed in item 9', characterized in that
R.sub.3 and R.sub.11 are each p-nitrobenzoyl.
[0147] 11'. A compound of the general formula (II)
##STR00033##
in which R.sub.7 and R.sub.8 are the same and are each alkyl or
alkylene having 2 to 3 carbon atoms; R.sub.9 and R.sub.10 are each
an alkyl group having 1 to 3 carbon atoms; X and Y are each as
defined in formula (I); R.sub.4 is hydrogen or a suitable hydroxyl
protecting group as known in the prior art, for instance from
"Protective Groups in Organic Synthesis" (Greene, Wuts) 4th
edition, John Wiley & Sons, Inc., pages 16 to 288, especially a
benzoyl group, or is as defined in formula (I).
[0148] 12'. The use of compounds of the general formula I alone or
in combination with other active ingredients in medicaments.
[0149] 13'. The use of compounds of the general formula III as a
structural element in drugs.
* * * * *