Note: Descriptions are shown in the official language in which they were submitted.
- 1 _ 140690
BEHRINGWERKE Aktiengesellschaft
Semi-synthetic rhodomycins, a process for their prepara-
tion and their use as cytostatics
The invention relates to compounds of the formula I and
their salts with an inorganic or organic acid
I
S
in Which:
R1 is hydrogen or a hydroxyl group
R2 is hydrogen or a structure of the formula II or IV
or, together vith R3, of the formula III
~C.5 ~ 3
1O ~~'~
x
I) III IV
R3 is hydrogen or a structure of the formula II or IV
or, together with R2, of the formula III,
R4 is hydrogen, trimethylsilyl, a protective group
which is customary in carbohydrate chemistry, prefer-
15 ably acetyl, trifluoroacetyl, benzoyl or substituted
benzoyl, such as para-nitrobenzoyl, a structure of
the formula II or a structure of the formula IV,
RS is hydrogen, methyl, hydroxymethyl, acyloxymethyl,
(C1-C8> or alkoxymethyl (C1-C8),
R6, R7 and R8 independently of one another are hydrogen,
~3~0~90
_ - 2 -
hydroxyl, aliphatic acyloxy (C1-C8), benzoyloxy or
substituted benzoyloxy, such as para-nitrobenzoyl-
oxy, alkoxy (C1-C8), allyloxy, benzyloxy or substi-
tuted benzyloxy or halogen, and R7 can furthermore
be NH2, NHacyl (C1-C8>, N(alkyl)2 (C1-C8),
N(CH2CN)2, NH(CH2CN) or azido, and
X is a bidentate protective group which is customary
in carbohydrate chemistry, preferably alkylboronyl,
phenylboronyl, an alkyl ortho-carboxylate, preferably
methyl orthoformate or ethyl orthoacetate, or a
ketal or acetal, preferably isopropylidene or ben-
zylidene,
the compounds where R1=R2=R3=R4=H, R1=OH and
R2=R3=R4=H, R1=R3=R4=H and R2=a-L-daunosaminyl
or a-L-rhodosaminyl or 4'-acyl-a-L-rhodosaminyl,
R1=OH or H, R3=H and R2=R4=a-L-rhodosaminyl or
4'-acyl-a-L-rhodosaminyl and R1=R2=R3=H and R4=
a-L-rhodosaminyl being excluded.
Numerous anthracyclines exhibit cytostatic activity, and
some are used for the therapy of tumors.
Known compounds are S-rhodomycins (structures of the
formula I where R1=H) in which position 7 and position
10 are linked a-glycosidically with L-rhodosamine or in
which only position 7 is linked a-glycosidically with L-
rhodosamine or L-daunosamine, and s-iso-rhodomycins
(structures of the formula I where R1=OH) in which posi-
tion 7 and 10 are each linked with a-L-rhodosamine, and
the photolytic mono-demethylation products of these L-
rhodosamine glycosides and s-rhodomycinone with oligo-
saccharide side chains on positions 7 or 10 or on 7 and
10, which are called cytorhodins. The microbial glyco-
sidation of a trisaccharide consisting of L-rhodosamine,
L-deoxyfucose and cinerulose A on the 7-position of the
S-rhodomycinone is kno~n from Journal of Antibiotics 33,
1331 ( 1980 > .
~.~4a~9~
- 3 -
No chemical glycosidation process for S-rhodomycinone or
s-iso-rhodomycinone has as yet been described. Because
of the many glycosidation possibilities of the three hy-
droxyl groups in the A ring of the S-rhodomycinone (struc-
ture of the for~ula I where R~=R2=R3=R4=H), selective
glycosidations are incomparably more difficult.
Surprisingly, it has been found that S-rhodomycinone and
S-iso-rhodomycinone can be glycosidated selectively using
certain protective groups on positions 7, 9 and 10 and
the glycosides thus obtained, in particular 7-0-a-L-
acosaeinyl-B-rhodomycinone or 7-0-(3'-N,N-dimethyl-a-L-
acosa~ninyl)-B-rhodomycinone have a cytostatic activity
comparable to that of adriamycin.
The present invention is therefore based on the object
of preparing, starting from the B-(iso-)rhodomycinones
obtainable biologically, novel mono-, bis- and tris-
glycosyl-B-(iso-)rhodoaycinones which are distinguished
by cytostatic activity and are therefore suitable for the
treateent of tumors.
This object has been achieved by preparation of compounds
of the above~entioned formula I with the definitions
given there for R~ to Rs and X and the exceptions
given.
The invention thus relates to compounds of this formula
I with the definitions and exceptions given.
In the following list of compounds of the formula I with
the radicals R~ to R8 given therein, the group of
compounds following a group of compounds is in each case
preferable to that group.
1) R~ to R8 have the meanings given.
2) R~ and R4 have the meanings given, R2 and R3
independently of one another are hydrogen or a
1340690
- 4 -
structure of the formula II or IV with the meanings
given for RS to R8.
3) R1 is hydrogen and the other definitions are as
under 2).
4> R3 is hydrogen and the other definitions are as
under 2).
5) R1 and R4 have the meanings given and R2 and R3
independently of one another are hydrogen or a struc-
ture of the formula II or IV, in Which RS is methyl,
R6 and R7 have the meanings given and R8 is hydrogen
or halogen.
b) R1 is hydrogen and the other definitions are as
under 5).
7) R3 is hydrogen and the other definitions are as
under 5).
8) R1 and R4 have the meanings given and R2 and R3
independently of one another are hydrogen or a
structure of the formula II or IV, in which RS is
methyl, Rb has the meaning given, R7 is NH2,
NHacyl (C1-C8), N(alkyl)2 (C1-C8), N(CH2CN)2,
NH(CH2CN) or azido and R8 is hydrogen or halogen.
9) R1 is hydrogen and the other definitions are as
under 8).
10) R3 is hydrogen and the other definitions are as
under 8>.
11) R1 and R4 have the meanings given and R2 and R3
independently of one another are hydrogen or a
structure of the formula II or IV, in which RS is
methyl, R6 and R7 have the meanings given and R8 is
hydrogen or halogen, and the structures of the for-
mula II or IV belong to the L-series of carbohydrates.
12> R1 is hydrogen and the other definitions are as
under 11).
13) R3 is hydrogen and the other definitions are as
under 11).
14) R1 and R4 have the meanings given and R2 and R3
independently of one another are hydrogen or a
structure of the formula II or IV, in which RS is
- - 1340690
- 5 -
met hyl,R6 given, is NH2,
has R7
the
meaning
NHa cyl (C1-C8), N(alkyl)2 (C1-CS), CH2CN)2,
N(
NH( CH2CN) azido R8 is or halogen,
or and hydrogen and
the str uctures II or V belong to
of I the
the
formula
L-s eries of
carbohydrates.
15) R1 is ydrogen and other ons are as
h the definiti
und er 4).
1
16) R3 is ydrogen and other ons are as
h the definiti
und er 4).
1
17) R1 and R3 hydrogen and the other definitions
are
are as under 2>.
18) R1 and R3 hydrogen and the other definitions
are
are as under 5).
19> R1 and R3 hydrogen and the other definitions
are
are as under 8).
20> R1 and R3 hydrogen and the other definitions
are
are as under 11).
21) R1 and R3 hydrogen and the other definitions
are
are as under 14).
22) R2 and R3 hydrogen and the other definitions
are
are as under 2).
23) R3 and R4 hydrogen and the other definitions
are
are as under 2).
24) R2 and R3 hydrogen and the other definitions
are
are as under 5).
25) R3 and R4 hydrogen and the other definitions
are
are as under 5).
26) R2 and R3 hydrogen and the other definitions
are
are as under 8).
27) R3 and R4 hydrogen and the other definitions
are
are as under 8).
28) R2 and R3 hydrogen and the other definitions
are
are as under 11).
29) R3 and R4 hydrogen and the other definitions
are
are as under 11).
30) R2 and R3 hydrogen and the other definitions
are
are as under 14).
31) R3 and R4 hydrogen and the other definitions
are
~34os9o
- 6 -
are as under 14).
32) R1, R2 and R3 are hydrogen and R4 is as under 2).
33) R1, R3 and R4 are hydrogen and R2 is as under 2).
34) R1, R2 and R3 are hydrogen and R4 is as under 5).
S 35> R1, R3 and R4 are hydrogen and R2 is as under 5).
36) R1, R2 and R3 are hydrogen and R4 is as under 8).
37) R1, R3 and R4 are hydrogen and R2 is as under 8).
38) R1, R2 and R3 are hydrogen and R4 is as under 11>.
39) R1, R3 and R4 are hydrogen and R2 is as under 11).
40) R1, R2 and R3 are hydrogen and R4 is as under 14).
41) R1, R3 and R4 are hydrogen and R2 is as under 14).
The invention also relates to a process for the prepara-
tion of a compound of the formula I with the definitions
given, which comprises first selectively blocking a com-
pound of the formula I in which R1 has the meaning ini-
tially given and R2 to R4 are hydrogen by a structure of
the formula III on positions 7 and 9 as described below,
a co~apound of the formula I in which R2 and R3 together
are a structure of the formula III being obtained, and
subsequently replacing R4=H by an acyl protective group,
a trimethylsilyl group or a carbohydrate derivative of
the structure II or IV and if appropriate deblocking the
compound and/or modifying it on the amino function, after
~rhich, following selective splitting off of the protec-
tive groups on position 7 and 9, either only position 7
or positions 7 and 9 can be glycosidated and the glycosyl
radicals can be deblocked and modified, or, after intro-
duction of an acyl group or trimethylsilyt group at posi-
tion 10 and subsequent selective deblocking at positions 7
and 9, first glycosidating the compound at position 7 or
simultaneously at positions 7 and 9, subsequently de-
blocking the compound completely or partly and if appro-
priate modifying it on the amino functions, and only then
glycosidating position 10 and modifying this glycoside,
these steps in detail being carried out by
a) reacting a compound of the forsuta I in Which R1 has
~.3~0690
- 7 -
the meaning initially given and R2 to R4 are hydrogen
with a boric acid, such as phenylboric acid, or with
a ketone, such as acetone, or a ketal, such as 2,2-
dimethoxypropane, or an acetal, such as benzaldehyde
dimethyl acetal, in a suitable organic solvent, such
as toluene or dimethylformamide or mixtures thereof,
with a catalyst, such as a mineral, carboxylic or
sulfonic acid, at a temperature between 0°C and the
boiling point of the solvent, if appropriate with the
addition of a dehydrating agent, such as a 4R mol-
ecular sieve, to give a compound of the formula I
in which R1 has the meaning initially given and R2
together with R3 form a compound of the formula III,
which is isolated by filtration and by removal of the
solvent and crystallized out of an organic solvent,
such as petroleum ether, after which the hydroxyl
group on position 10 is derivatized in a suitable
manner,
b) if appropriate acylating with a carboxylic acid
anhydride, such as acetic anhydride or trifluoroacetic
anhydride, or a phenylcarboxylic acid anhydride or a
carboxylic acid halide or by reacting with trimethyl-
silyl trifluoromethanesulfonate in a suitable organic
solvent, such as chloroform, methylene chloride,
toluene or mixtures thereof, at a temperature between
-40oC and the boiling point of the solvent and in the
presence of a base, such as triethylamine or pyridine,
to give a compound of the formula I in which
R1 has the meaning initially given,
R2 together with R3 is a structure of the formula III
and
R4 is acyl or trimethylsilyl,
c) or, for example, reacting the compound obtained under
a) with 3,4-dihydro-2H-pyran in a suitable organic
solvent, such as chloroform, methylene chloride,
di~nethylformamide or toluene, in the presence of a
l~~os9o
_8_
catalyst, such as para-toluenesulfonic acid and a
desiccant, such as a 4~ molecular sieve, at a tem-
perature between -30°C and the boiling point of the
solvent, to give a compound of the formula I in which
R~ has the meaning initially given,
R2 together with R3 is a structure of the formula III
and
R4 is a structure of the formula II, where RS to Rb
are hydrogen,
d) or, for example, reacting the compound obtained under
a) with a carbohydrate derivative of the formula V
v
in which
RS to R8, as suitable protective groups, have the
meanings initially given and
R9 is halogen, such as Cl or Br, 0-acyl or another
leaving group which is customary for glycosida-
tion reactions,
under the conditions customary in carbohydrate chemis-
try, to give a compound of the formula I in vhich
R~ has the meaning initially given,
R2 together with R3 is a structure of the formula
III and
R4 is a structure of the formula II,
e) or, for example, reacting the compound obtained under
a) with a functionalized carbohydrate of the general
formula V or VI
1340690
~5
daJ~c~ \" ,.~9
v~
in which
R5 to R8 have the meanings initially given, with the
exception of hydroxymethyl, hydroxyl, NH2,
N(CH2CN)2 and NH(CH2CN) and
R9 is acyl which is bonded via oxygen, such as ali-
phatic acyloxy (C1-C8), such as acetyl, benzoyl-
oxy or substituted benzoyloxy, such as para-
nitrobenzoyloxy,
in the presence of an organic solvent, such as chloro-
form, methylene chloride, toluene, ether, dimethyl-
formamide, acetone, acetonitrile or nitromethane or
mixtures thereof, a catalyst, such as para-toluene-
sulfonic acid or a trialkylsilyl trifluoromethane-
sulfonate, and if appropriate an acid-trapping agent
and a desiccant, such as a molecular sieve, at a reac-
tion temperature of -70°C to +30°C under a protective
gas atmosphere, such as nitrogen or argon, to give a
compound of the formula I
in which
R1 has the meaning given,
R2 together with R3 is a structure of the formula
III and
R4 is a structure of the formula II or IV, in which
R5 to R8 have the meanings initially given, with the
exception of hydroxymethyl, hydroxyl, NH2,
N(CH2CN)2 and NH(CH2CN),
f) and, if appropriate, possibly deblocking the compound
1340690
- 10 -
of stages b) to e) on positions 7 and 9 by reacting
this compound in a suitable organic solvent, such as
chloroform, methylene chloride, dimethylformamide,
toluene or methanol, with a catalyst, such as dilute
aqueous solutions of carboxylic acids or para-
toluenesulfonic acid, and if appropriate with a diol,
such as 2-methyl-2,4-pentanediol, at a temperature
between 0oC and the boiling point of the solvent, to
give a compound of the general formula I in which
R1 has the meaning given,
R2 and R3 are hydrogen and
R4 has the meaning given, with the exception of
hydrogen,
g) and subsequently, if appropriate, possibly selectively
partly or completely deblocking the compound of stage
f) in which R4 is a structure of the formula II or IV
with, as radicals RS to R8, one of the protective
groups customary in carbohydrate chemistry, in a manner
which is known per se on the protected hydroxyl func-
tions and/or on the protected amino functions under the
conditions customary in carbohydrate chemistry by means
of an inorganic or organic base, such as alkali metal
or alkaline earth metal hydroxides, sodium carbonate
and triethylamine, in a solvent, such as water,
methanol, ethanol or tetrahydrofuran or mixtures
thereof, to give a compound of the formula I in which
R1 is hydrogen or hydroxyl,
R2 and R3 are hydrogen and
R4 is a structure of the formula II or IV, in which
RS is hydrogen, methyl, hydroxymethyl or alkoxymethyl,
R6 is hydrogen, hydroxyl, alkoxy or halogen,
R7 is NH2 N(alkyl)2, azido, hydroxyl or alkoxy and
R8 has the same meaning as R6 but is independent
thereof,
h) and, if appropriate, reacting the compound of stage
g) of the formula I, in which
~~~:0690
- 11 -
_ R1 to R3 have the meanings given under g) and
R4 is a structure of the formula II, in which
R5, R6 and R8 have the meanings given under g) and
R7 is NH2,
under the conditions which are known per se for
reductive amination, to give the corresponding com-
pound of the formula I in which
R1 to R3 have the meanings given under g) and
R4 is a structure of the formula II,
in which
R5, R6 and R8 have the meanings given under g) and
R6 is N(alkyl)2, or
i) furthermore converting a compound of stage g> of the
general formula I in which
R1 to R3 have the meanings given under g) and
R4 is a structure of the formula II in which
R5, R6 and R7 have the meanings given under g) and
R7 is NH2,
by reaction with iodoacetonitrile or bromoacetonitrile
in a suitable solvent, for example dimethylformamide,
in the presence of a suitable base, such as triethyl-
amine, into a compound of the formula I in which R1
to R3 have the meanings given under g) and R4 is a
structure of the formula II, in which
R5, R6 a~~d R8 have the meanings given under g) and
R7 is N(CH2CN)2 or NH(CH2CN) and
k) if appropriate glycosidating the compound formed in
stage f>, h) or i) under the conditions already men-
tioned in stage e), either only position 7 or simul-
taneously positions 7 and 9 being glycosidated, depend
ing on the amount of glycosyl donor used, to give
134~6~~
- 12 -
products which correspond to the general formula I in
which
R1 has the meaning given,
R2 is a structure of the formula II or IV, in which
R5 to R8 have the meanings initially given, pith the
exception of hydroxymethyl, hydroxyl, NH2,
N(CH2CN)2 and NH(CH2CN),
R3 is hydrogen or corresponds to R2 and
R4 is acyl, trimethylsilyl or a structure of the
general formula II or IV in which
RS to R8 have the meanings initially mentioned, with
the exception of hydroxymethyl, hydroxyl and NH2,
and, if appropriate,
l) converting one of the compounds formed in stage f), h)
or i) with a glycal of the formula VI, in which RS to
R7 have the meanings given in stage e), in the presence
of an organic solvent, such as chloroform, methylene
chloride, toluene, ether, acetone or acetonitrile or
mixtures thereof, with N-iodosuccinimide and if appro-
priate with a desiccant, such as a molecular sieve, at
a tesperature from -40°C to +40°C under a protective
gas atmosphere, such as nitrogen or argon, into a com-
pound of the formula I in which
R1 has the meaning given and
R2 is a structure of the formula II, in which
RS is hydrogen, methyl, acyloxymethyl (C1-C8) or
alkoxymethyl (C1-C8),
R6 is acyloxy, alkyloxy, allyloxy or benzyloxy,
R7 is acyloxy, alkyloxy, allyloxy, benzyloxy, NHacyl,
N(alkyl)2 or azido and
R8 is iodine, and
R3 and R4 have the meanings given in stage k), and
m) if appropriate deblocking the compound forged in stage
k) or L) in accordance with the conditions of stage
g), to give a compound of the formula I in which
R1 has the meaning given and
1340fi90
13
R2 is a structure of the formula II or IV, in which
RS is hydrogen, methyl, hydroxymethyl or alkyloxy-
methyl,
R6 is hydrogen, hydroxyl, alkyloxy or halogen,
R7 is NH2 or N(alkyl)2, azido, hydroxyl or
alkoxy and
R8 has the same meaning as R6, but is independent
thereof,
R3 is hydrogen or corresponds to R2 and
R4 is hydrogen, trimethylsilyl or a structure of the
general formula II or IV, in which
RS is hydrogen, methyl, hydroxymethyl or alkoxymethyl,
R6 is hydrogen, hydroxyl, alkoxy or halogen,
R7 is NH2, N(alkyl)2, N(CH2CN)2 or NH(CH2CN),
azido, hydroxyl or alkoxy and
R8 has the same meaning as R6, but is independent
thereof, or
n) also deblocking the compound formed in stage k) or t)
under the conditions of stage g> so that only position
10 is selectively deblocked, to give a compound of the
formula I in which
R1 has the meaning given,
R2 is a structure of the formula II or IV, in which
RS to R8 have the meanings initially given, with
the exception of hydroxymethyl, hydroxyl and NH2,
R3 is hydrogen or corresponds to R2 and
R4 is hydrogen,
o) and subsequently, if appropriate, converting the com-
pound of stage m), in which R2 is a structure of the
formula II where R7 is NH2 and R3 is hydrogen or
R2, into the corresponding compounds in which R6 is
N(alkyl)2, again in the manner of reductive amina-
tion described for stage h), or, if appropriate,
p) converting a co~apound of stage gin) in which R2 is a
structure of the formula II, where R7 is NH2 and R3
1340690
- 14 -
is hydrogen or R2, into the corresponding cyano-
methyl derivatives in which
R7 is N(CH2CN)2 or NH(CH2CN) in accordance with
the conditions of stage i), and, if appropriate,
q) glycosidating a compound of stage n) under the condi-
tions already given in stage e), either only position
or simultaneously positions 9 and 10 being glyco-
sidated, depending on the amount of glycosyl donor
used, to give a compound of the formula I in which
10 R1 is hydrogen or hydroxyl and
R2 is a structure of the general formula II or IV,
in which
RS to R8 have the meanings initially given, with the
exception of hydroxymethyl, hydroxyl and NH2,
R3 is hydrogen or R2 or R4 and
R4 is a structure of the general formula II or IV,
in which
RS to R8 have the meanings initially given, with the
exception of hydroxymethyl, hydroxyl, NH2,
N(CH2CN)2 or NH(CH2CN), and, if appropriate,
r) also carrying out the reaction of stages c), d) and l)
on a compound of stage n) so as to give a compound of
the formula I in which
R1 has the meaning initially given and
R2 is a structure of the formula II or IV, in which
RS to R8 have the meanings initially given, with the
exception of hydroxymethyl, hydroxyl and NH2,
R3 is hydrogen or R2 or R4 and
R4 is a structure of the general formula II or IV in
which
RS to R8 have the meanings initially given, with the
exception of hydroxymethyl, hydroxyl, NH2,
N(CH2CN)2 and NH(CH2CN), and, if appropriate,
s) deblocking this compound of stage q) or r) again as
1340690
- 15 -
described in stage g), to give a compound of the
formula I in which
R1 has the meaning initially given and
R2, R3 and R4 independently of one another are
hydrogen or a structure of the formula II or IV,
in Which
R5 to R8 have the meanings initially given, with the
exception of acyloxymethyl, acyloxy, benzoyloxy
or substituted benzoyloxy or NHacyl, and, if
appropriate,
t) converting the compound of stage s) into the corres-
ponding derivative in which the radical R7, which in
stage s) was an NH2 group, is converted into
N(alkyl)2, by means of reduction amination in
accordance pith stage h), or
u) moreover converting a compound of stage s> into the
corresponding cyanomethyl derivative in which the
radical R7, which in stage s) Was an NH2 group,
into NH(CH2CN) in accordance with the conditions of
stage i),
v) and, if appropriate, reacting a compound of the
formula I in which
R1, R2 and R3 have the meanings given and
R4 is trimethylsilyl,
with tetrabutylammonium fluoride in an organic solvent,
such as tetrahydrofuran, diethyl ether, dioxane or
mixtures thereof, at temperatures between -40oC and
the boiling point of the solvent, to give a compound
of the formula I in which
R1, R2 and R3 have the meanings given above and
R4 is hydroxyl,
w) and, if appropriate, converting compounds of the for-
mula I in which R1, R2, R3 and R4 have the meanings
given and R7 is NH2, N(alkyl)2 (C1-C8), N(CH2CN)2
X340690
- 16 -
or NH(CH2CN> into the salt of an inorganic or organic
acid.
The invention also relates to medicaments which contain
one or more compounds of the formula I or salts thereof
with an inorganic acid, such as HCI, or an organic acid,
such as glutamic acid or glucoronic acid, as the active
substance.
Such a compound can be processed together with the cus-
tomary pharmaceutical formulating agents and/or diluents
to give a medicament which is used in particular in cancer
therapy.
The method of dosage and use essentially correspond here
to those for the known anthracyclines, such as adriamycin,
daunomycin or aclacinomycin.
The medicaments prepared in this way can also addition-
ally contain other active substances as long as these do
not exhibit undesirable side effects together with the
compounds according to the invention.
The invention also relates to a composition containing a
compound of the formula I, with the definitions and excep-
tions given, and a carrier substance.
The invention furthermore relates to the use of a com-
pound of the formula I, with the definitions and excep-
tions given, as a medicament.
The cytostatic activity of the compounds according to the
invention has been tested with the aid of L1210 leukemia
cells from mice. Colony formation of L1210 leukemia
cells on agar plates was used for this. This method is
used to demonstrate the influence of the test substances
on the growth behavior of the cells folloring incubation
for 1 hour or over several generations. At a cell cycle
134~D6~0
- 17 -
time of 10-12 hours, about 14 successive generations are
thereby observed over the test period of 7 days. In this
test, the cytostatic substances according to the inven-
tion effect a reduction of the number of colonies to be
observed in comparison with an untreated control sample.
Details of the test method are to be found from the fol-
lowing procedure for the determination of colony formation.
Procedure for determination of colony formation of L1210
leukemia cells in soft agar
500 leukemia cells per plate were incubated with differ-
ent concentrations of the test substance at 37°C for 1
hour. The cells were then washed twice with McCoySA
medium and finally poured into Petri dishes, after addi-
tion of 0.3X agar. Controls were incubated only with
fresh medium. Instead of incubation for one hour, in
some cases different concentrations and test substances
were admixed to the upper agar layer in order thus to
achieve continuous exposure of the cells over the entire
incubation period. After the agar had solidified, the
plates were incubated in an incubating cabinet at 37°C
for 7 days (SX by volume of C02, 95X relative atmospheric
humidity). The number of colonies formed with a diameter
of more than 60 um was then counted. The results were
stated as the number of colonies in the treated agar
plates as a percentage of the untreated control. The
IC50 was determined from the resulting dose-effect
curve as a measure of the activity of the substance. The
results for the compounds described here are summarized
in comparison with adriamycin in the following Table 1.
1340690
_ .
Table 1, Part 1:
Substance No. Long-term 1 hour incubation
(Example) incubation ICSp (ug/a~l)
ICSp (u9/ml)
Adriamycin 0.02 0.04
8 ~1 ~1
g 0.6 X10
0.9 6.5
11 ~1 ~l
12 0.5 >1
13 0.03 >1
14 0.024 >1
0.004 0.02
16 0.006 0.02
17 0.004 0.09
18 0.13 >1
lg 0.11 71
21 0 . 5 71
24 ~ 1 i 1
71 71
27 71 71
28 > 1 71
29 ~ 10 >1
0.5 n
X340690
- 19 -
Table 1, Part 2:
Substance No. Long-term 1 hour incubation
(Example) incubation ICSp (lt9~ml>
ICSQ (ug~ml)
33 71 J 1
34 0.026 0.09
35 >1 ~ 1
37 )1 71
38 )1 ]1
4C 0.85 71
42 0.16 >1
44 >1
45 0.29
46 0.11
48 0.095
49 ~1
50 0.1
51 0.4 0.68
52 0.66
53 0.04 0.05
i3~os9o
- 20 -
Exa~eples
The structures of the compounds prepared were determined
by means of 1H- and 13C-NMR spectroscopy, incorporating
two-dimensional NMR methods and other mufti-pulsed tech-
piques, as well as MS and IR spectroscopy. The course of
the reaction and the resulting compounds were investiga-
ted by thin layer chromatography or by the high perform-
ance liquid chromatography technique.
The following examples illustrate the invention in more
detail without limiting it:
Example 1:
7,9-0-Phenyl-boronyl-B-rhodomycinone (1)
(Compound of the formula I where R1=R4=H and R2 and
R3=X, where X=phenylboronyl)
A solution of S-rhodomycinone (740 mg = 1.92 mmol) and
phenylboric acid (360 mg = 2.95 mmol) in toluene (150 ml)
was heated under reflux together with activated 4~ mole-
cular sieve (3 g) for 9 hours, the reaction being moni-
tored by thin layer chromatography (mobile phase:
toluene/methanol - 10:1).
After the solution had been cooled, it was filtered and
the solvent was stripped off under a high vacuum. The
precipitate was dissolved in chloroform and crystallized
out with petroleum ether.
Yield: 800 mg (1.7 mmol - 88%)
- 21- ~34osso
Example 2:
7,9-0-Isopropylidene-S-rhodomycinone (2)
(Compound of the formula I where R1=R4=H and R2 and
R3=X, vhere X - isopropylidene)
para-Toluenesulfonic acid (150 mg> vas added to a sol-
ution of S-rhodomycinone (300 mg - 0.78 ~nmol) in 30 ml of
dry N,N-dimethylformamide (130 ml) and 2,2-dimethoxy-
propane (36 ml) and the mixture was stirred on a rotary
evaporator at 50°C under 320 mbar for 60 hours, further
2,2-dimethoxypropane (35 ml) being added. After the
solution had been concentrated, the residue vas taken up
in methylene chloride, the mixture was extracted by
shaking with aqueous sodium bicarbonate solution and the
extract vas dried and concentrated. Separation by column
chromatography (mobile phase: chloroform/acetone/acetic
acid/water/triethylamine = 95:5:1:0.25:0.1) gave the
product in crystalline form.
Yield: 150 mg (0.35 mmol - 45%)
Example 3:
7-9-0-Benzylidene-S-rhodomycinone (3)
(Compound of the formula I where R1=R4=H and R2 and
R3=X, vhere X - benzylidene)
para-Toluenesulfonic acid (10 mg) was added to a solution
of s-rhodomycinone (30 mg = 0.08 mmol) in dry N,N-di-
methylformamide (5 ml) and benzaldehyde dimethyl acetal
(2 ml) and the mixture vas stirred on a rotary evaporator
at 50°C under 50 mbar for one hour. After the solution
had been concentrated, the residue was taken up in
methylene chloride, the mixture was extracted by shaking
with aqueous sodium bicarbonate solution and the extract
vas dried and concentrated.
- 22 - ~3~0690
Yield: 35 mg (0.07 mmol - 90%>
The two exo/endo-isomers can be separated by chromato-
graphy (mobile phase: toluene/methanol - 10:1).
Example 4:
10-0-Trifluoroacetyl-B-rhodomycinone (4)
(Compound of the formula I where R1=R2=R3=H and R4=
trifluoroacetyl)
Trifluoroacetic anhydride (4 ml - 283 mmol) and triethyl-
amine (0.2 ml) were added to a solution of 7,9-0-phenyl-
boronyl-s-rhodomycinone (compound 1) (230 mg = 0.49 mmol)
in dry methylene chloride (50 ml) at 0oC and the mixture
was stirred at 0°C for 30 minutes.
After the solvent had been stripped off and the residue
had been concentrated several times with toluene, the
residue was dissolved in methanol and the solution was
brought to pH 2.5 with hydrochloric acid, the product
precipitating out after stirring for 4 hours. The pre-
cipitate was dissolved in methylene chloride, the solu-
tion was washed with eater and, after drying, the organic
phase was concentrated.
Yield: 150 mg (0.31 ~nmol - 63%)
Example 5:
10-Tetrahydropyranyl-S-rhodomycinone (5>
(Compound of the formula I where R1=R2=R3=H and R4=
structure II where R5=R6=R7=R8=H)
A catalytic amount of para-toluenesulfonic acid (20 mg>
was added to a solution of 7,9-0-phenylboronyl-B-rhodo-
mycinone (500 mg = 1.06 mmol> and 3,4-dihydro-2H-pyran
(2.5 ml) in dry methylene chloride (125 ml) with 4~
~~~os9o
- 23 -
molecular sieve and the mixture was stirred at room tem-
perature for half an hour. After the molecular sieve had
been filtered off, the filtrate was washed with aqueous
sodium bicarbonate solution and dried with sodium sulfate
and the solvent was distilled off.
This crude product was dried under a high vacuum and then
added to a solution of 2-methyl-2,4-pentanediol (5 ml)
in dry methylene chloride (40 ml), and the mixture Was
stirred with a catalytic amount of glacial acetic acid
(0.2 ml) at room temperature for 48 hours.
The mixture was then extracted by shaking with aqueous
sodium bicarbonate solution and with water and the
extract was dried over sodium sulfate. Separation by
column chromatography (mobile phase: toluene/methanol -
10:1) gave the pure product.
Yield: 210 mg (0.45 mmol - 42%)
Example 6:
10-0-Trimethylsilyl-S-rhodomycinone <6)
(Compound of the formula I where R1=R2=R3=H and R4=
trimethylsilyl)
Trimethylsilyl trifluoromethanesulfonate (110 ul) was
added to a solution of 7,9-0-phenylboronyl-S-rhodomycin-
one (100 mg = 0.21 mmol) and pyridine (85 ul) in dry
methylene chloride and 4~ molecular sieve at -40°C and
the mixture was stirred for 1.5 hours.
The reaction mixture was filtered, the filtrate was
extracted by shaking with aqueous sodium bicarbonate
solution and the extract was dried over sodium sulfate
and concentrated.
To split off the boronyl ester, the crude product was
1340690
- 24 -
dissolved in dry methylene chloride (10 ml), 2-methyl-
2,4-pentanediol (0.55 ml) and glacial acetic acid
(0.1 ml) were added and the mixture was stirred at room
temperature for 48 hours. The reaction mixture was
extracted by shaking with water, the extract was dried
over sodium sulfate and concentrated and the residue was
separated by column chromatography (mobile phase:
methylene chloride/acetic acid/formic acid = 20:1:0,1)
Yield: 57 mg (0.11 mmol - 52X)
Example 7:
10-0-(4-0-Paranitrobenzoyl-3-N-trifluoroacetyl-a-L-
acosaminyl)-7,9-0-phenylboronyl-S-rhodomycinone (7)
(Compound of the formula I where R1=H, R2 and R3=
phenylboronyl and R4=structure II - a-L-acosaminyl
where R5=CH3, R6=OpN8z, R7=NHTFA and R8=H)
A solution of 1,5-anhydro-4-0-paranitrobenzoyl-2,3,6-tri-
deoxy-3-N-trifluoroacetyl-L-arabino-hex-1-enitol (87 mg =
0.23 mmol) in dry ethylene chloride (4 ml) was added to
a solution of 7,9-0-phenylboronyl-B-rhodomycinone (com-
pound 1) (100 mg = 0.21 mmol) in dry methylene chloride
(8 ml) and 4~ molecular sieve, and trimethylsilyl tri-
fluoromethanesulfonate (40 ul - 0.22 mmol) was added
under a protective gas atmosphere (argon) at -40°C.
After the mixture had been warmed to -20°C, it was
stirred at this temperature for a further 4 hours and the
reaction was then ended by adding triethylamine (80 ul)
to the solution. After filtration, the solution was
washed with aqueous sodium bicarbonate solution, dried
over sodium sulfonate and concentrated and stripping with
toluene was performed several times.
Crude yield: 180 mg (quantitative)
130690
- 25 -
Example 8:
10-0-(4-0-Paranitrobenzoyl-3-N-trifluoro-acetyl-a-L-
acosaminyl>-S-rhodomycinone (8)
(Compound of the formula I where R1=R2=R3=H and R4=
structure II= a-L-acosaminyl where R5=CH3, R6=OpNBz,
R7=NHTFA and R8=H)
A solution of the crude mixture of compound 7 (180 mg =
0.21 mmol) in dry methylene chloride (20 ml) was stirred
with 2-methyl-2,4-pentanediol (3.2 ml) and glacial acetic
acid (0.2 ml) at room temperature for 24 hours. For
working up, stripping with toluene was performed several
times and 150 mg of crude product were crystallized out
of diethyl ether/petroleum ether and purified by column
chromatography (mobile phase: methylene chloride/acetone/
formic acid = 20:1:0.2).
Yield: 120 mg (0.16 mmol - 75%)
Example 9:
10-0-(4-0-Paranitrobenzoyl-3-N-trifluoroacetyl-a-L-
daunosaminyl)-s-rhodomycinone (9)
(Compound of the formula I where R1=R2=R3=H and R4=
structure II = a-L-daunosaminyl where R5=CH3, R6=OpNBz,
R7=NHTFA and R8=H)
7,9-0-Phenyl-boronyl-S-rhodomycinone (compound 1)
(150 mg = 0.318 mmol) and 1,4-di-0-paranitrobenzoyl-3-N-
trifluoroacetyl-L-daunosamine (190 mg = 0.35 mmol) were
reacted with trimethylsilyl trifluoromethanesulfonate
(0.11 ml - 0.61 mmol) in accordance with the instructions
of Example 7.
The crude product thereby formed was deblocked in accord-
ance with the instructions of Example 8 for the purpose
of splitting off the boric acid ester.
- 26 - 1340690
w Yield: 180 mg (0.24 mmol - 75%)
Example 10:
10-0-a-L-Acosaminyl-S-rhodomycinone (10)
(Compound of the formula I where R1=R2=R3=H and R4=
structure II= a-L-acosaminyl where RS=CH3, R6=OH,
R7=NH2 and R8=H)
A solution of compound 8 (36 mg = 47 umol) in methanol
(2 ml) and O.SN sodium hydroxide solution (2 ml) was
stirred at room temperature for 30 minutes and the pH was
then brought to 2.5 with hydrochloric acid. The mixture
was then extracted by shaking with chloroform several
times. The aqueous phase was neutralized with sodium bi-
carbonate solution and extracted by shaking with chloro-
form several times. This chloroform phase was dried with
sodium sulfate and concentrated.
Yield: 17.5 mg (34 umol - 72X)
Example 11:
10-0-a-L-Daunosaminyl-B-rhodomycinone (11)
(Compound of the formula I where R1=R2=R3=H and R4=
structure II=a-L-daunosaminyl where RS=CH3, R6=OH,
R7=NHz and R8=H
Compound 9 (53 mg = 70 umol) was deblocked and the pro-
duct was worked up in accordance with the conditions des-
cribed for Example 10.
Yield: 23 mg (45 umol - 64X)
_ 27 _ 1340690
Example 12: ,
10-0-(3-N,N-Dimethyl-a-L-acosaminyl)-S-rhodomycinone (12)
(Compound of the formula I where R1=R2=R3=H and R4=
structure II=a-L-acosaminyl where RS=CH3, R6=OH, R7=
N(CH3)2 and R8=H>
A solution of compound 10 (23 mg = 42 umol) in methanol
(2 ml> is stirred with sodium cyanoborohydride (16 mg =
250 umol) and formaldehyde (63 ul, 37% strength - 860
umol) at room temperature for two hours. The mixture is
then neutralized with hydrochloric acid and purified by
chromatography (mobile phase: chloroform/methanol/acetic
acid/water/triethylamine = 80:20:10:4:0.2).
Yield: 15 mg (28 umol - 67X)
Example 13:
7-0-(4-0-Paranitrobenzoyl-3-N-trifluoroacetyl-a-L-acos-
aminyl)-10-0-trifluoroacetyl-S-rhodomycinone (13)
(Compound of the formula I where R1=R3=H, R4=trifluoro-
acetyl and R2=structure II=a-L-acosaminyl where R5=CH3,
R6=OpNBz, R7=NHTFA and R8=H)
Compound 4 (90 mg = 0.19 mmol) was reacted under the
conditions described in Example 7.
Crude yield: 150 mg (0.18 nmol - 95%)
Example 14:
7-0-(4-0-Paranitrobenzoyl-3-N-trifluoroacetyl-a-L-acos-
aminyl)-s-rhodomycinone (14)
(Compound of the formula I where R1=R3=R4=H and R2=
structure II=a-L-acosaminyl where RS=CH3, R6=OpNBz,
R7=NHTFA and R8=H)
- 28 -
w A solution of compound 13 (100 mg = 0.12 mmol) in
methanol (5 ml) was brought to pH 10 with 0.1 N sodium
hydroxide solution and stirred for 10 minutes.
The reaction mixture was neutralized with diluted hydro-
chloric acid and the solvent was distilled off. The
residue was taken up in methylene chloride and the mix-
ture was washed with water, dried over sodium sulfate and
concentrated.
Crude yield: 85 mg (0.11 mmol - 92%)
Example 15:
7-0-a-L-Acosaminyl-R-rhodomycinone (15)
(Compound of the formula I where R1=R3=R4=H and R2=
structure II=a-L-acosaminyl where R5=CH3, R6=OH, R7=
NH2 and R8=H)
Compound 14 (27 mg = 35 umol) was deblocked and the pro-
duct worked up in accordance with the conditions des-
cribed for Example 10.
Yield: 15 mg (29 umol - 83X)
Example 16:
7-0-(3-N,N-Dimethyl-a-L-acosaminyl)-S-rhodomycinone (16)
(Compound of the formula I where R1=R3=R4=H, R2=
structure II=a-L-acosaminyl where R5=CH3, R6=OH, R7=
N(CH3)2 and R8=H)
Compound 15 (15 mg = 29 umol) was reacted under the con-
ditions of Example 12.
Yield: 13 mg (24 umol - 83X)
~~4fl690
- 29 -
Example 17:
7-0-(3-N-Cyanomethyl-a-L-daunosaminyl)-s-rhodomycinone
(17)
(Compound of the formula I where R1=R3=R4=H and R2=
structure II=a-L-daunosaminyl where R5=CH3, R6=OH,
R7=NH(CH2CN) and R8=H)
7-0-a-L-Daunosaminyl-S-rhodomycinone (200 mg = 0.39 mmol)
was dissolved in dry N,N-dimethylformamide (30 ml) and,
after addition of triethylamine (0.16 ml) and iodoaceto-
nitrite (0.283 ml>, the mixture was stirred at room tem-
perature for 15 hours. The reaction mixture was then
evaporated under a high vacuum and the residue was puri-
fied by column chromatography over 50 g of silica gel
(eluting agent: methylene chloride/acetone/acetic acid =
5:2: 1 )
Yield: 157 mg (0.28 mmol - 73X>
MS: M+H+ - 555
Example 18:
7-0-(4-0-Paranitrobenzoyl-3-N-trifluoroacetyl-a-L-daunos-
aminyl)-10-0-trifluoroacetyl-S-rhodomycinone (18)
(Compound of the formula I where R1=R3=H, R4=trifluoro-
acetyl and R2=structure II=a-L-daunosaminyl where
R5=CH3, R6=OpNBz, R7=NHTFA and R8=H)
10-0-Trifluoroacetyl-B-rhodomycinone (500 mg = 1.03 mmol>
was dissolved in a mixture of methylene chloride and
acetone (1:1; 40 ml). Molecular sieve (4~, dried powder,
500 mg) and 1,4-di-0-paranitrobenzoyl-3-N-trifluoro-
acetyl-L-daunosamine (1.1 g = 2.06 mmol) were added to
the solution and the mixture was cooled to -30°C, with
exclusion of atmospheric humidity. Trimethylsilyl tri-
fluoromethanesulfonate (0.9 ml - 5.15 mmol) was added
dropwise to the stirred suspension. After 2 hours, tri-
~,3~0690
- 30 -
ethylamine (0.8 ml) was added. The mixture was filtered
at room temperature and the filtrate was washed out three
times with ice-water. The organic phase was dried over
sodium sulfate and evaporated under a waterpump vacuum.
The resulting crude product was purified by column
chromatography (silica gel 60/35-70, supplied by Amicon,
eluting agent: methylene chloride/petroleum ether/acetone
- 5:5:1).
Yield: 750 mg (0.88 mmol = 85~)
Example 19:
7-0-(4-0-P~ranitrobenzoyl-3-N-trifluoroacetyl-o~-L-dauno s-
aminyl)-(3-rhodomycinone (19)
(Compound of the formula I where R1=R3=R4=H and R2=
structure II=OC-L-daunosaminyl where R5=CH3, R6=OpNBz,
R~=NHTFA and R8=H)
Compound 18 (660 mg = 0.77 mmol) was dissolved in 30 ml
of a mixture of chloroform and methanol 1:1. 0.01 N
aqueous sodium hydroxide solution (30 ml) was then added
dropwise (ph 7.5). After 3 hours, the solution was
neutralized with 0.1 N aqueous hydrochloric acid and
evaporated in vacuo. The product, which is uniform
according to thin layer chromatography, was purified by
column chromatography over 200 g of silica gel 60/35-70
supplied by Amicon (mobile phase: methylene chloride/
acetone = 15:1 to 5:1).
Yield: 570 mg (0.75 mmol = 97~)
Example 20:
7-0-(4-0-Paranitrobenzoyl-3-N-trifluoroacetyl-oc-L-dauno s-
aminyl)-10-0-tetrahydropyranyl-(3-rhodomycinone (20)
(Compound of the formula I where R1=R3=H, R2=structure
II=OC-L-daunosaminyl where R5=CH3 , R6=OpNBz , R~=NHTFA
.340
- 31 -
and R8=H; and R4=structure II where R5=R6=R7=R8=H)
Compound 19 (150 mg = 0.2 mmol) was dissolved in methyl-
ene chloride (20 ml). Paratoluenesulfonic acid (10 mg)
and 3,4-dihydro-2H-pyran (2 ml) were added at room tem-
perature, with stirring. After 24 hours, the reaction
mixture was washed out three times with a total of 100 ml
of ice-water. The organic phase was dried over sodium
sulfate and evaporated. The crude product was purified
over silica gel (eluting agent: methylene chloride/
petroleum ether/acetone = 5:5:1)
Yield: 150 mg (0.178 mmol - 89X)
Example 21:
7-0-a-L-Daunosaminyl-10-0-tetrahydropyranyl-S-rhodomycin-
one (21 )
(Compound of the formula I where R1=R3=H, R2=structure
II=a-L-daunosaminyl where RS=CH3, R6=OH, R7=NH2, and
R8=H; and R4=structure II where RS=R6=R7=R8=H)
Compound 20 (150 mg = 0.17 mmol) was dissolved in chloro-
form/methanol 1:1 (20 ml) at room temperature and 1 N
aqueous NaOH solution (1 ml) was added. After stirring
for 1 hour, the solution was neutralized with 1 N hydro-
chloric acid and evaporated. The residue was further
purified by column chromatography (silica gel, eluting
agent: methylene chloride/methanol 5:1).
Yield: 87 mg (0.145 mmol - 82X)
Example 22:
7-0-(3-Azido-4-0-paranitrobenzoyl-2,3,6-trideoxy-ae-L-
arabinohexopyranosyl)-10-0-trifluoroacetyl-s-rhodomycin-
one (22)
134069p
- 32 -
(Compound of the formula I where R1=R3=H and R2=
structure II=a-L-2,3,6-trideoxyarabinohexopyranosyl
where RS=CH3, R6=OpNBz, R7=N3, R8=H and R4=trifluoro-
acetyl)
Compound 4 (100 mg = 0.21 mmol) vas dissolved in a mix-
ture of methylene chloride and acetone 5:1 (10 ~nl), and
molecular sieve 4~ (100 mg) was added as a dried powder.
After addition of 3-azido-2,3,6-trideoxy-4-0-paranitro-
benzoyl-L-arabino-1-hex-1-enitol (127 mg = 0.42 mmol>,
dissolved in methylene chloride (S ml>, the mixture was
cooled to -30°C and trimethylsilyl trifluoromethane-
sulfonate (46 mg = 0.21 mmol) was added. The reaction
temperature vas raised to -lOoC after 4 hours. Further
3-azido-2,3,6-trideoxy-4-0-paranitrobenzoyl-L-arabino-1-
hex-1-enitol (36 mg = 0.21 mmol), dissolved in ~nethylene
chloride (25 ~nl) was then added. After a further 16
hours, the reaction mixture vas neutralized with triethyl-
amine, filtered and evaporated. The resulting crude pro-
duct was purified by column chromatography (silica gel;
eluting agent: methylene chloride)
Yield: 127 mg (0.16 mmol - 77X)
Example 23:
7-0-(3-Azido-2,3,6-trideoxy-a-L-arabinohexopyranosyl)-S-
rhodomycinone (23)
(Compound of the formula I where R1=R3=R4=H and R2=
structure II=a-L-2,3,6-trideoxy-arabinohexopyranosyl
where RS=CH3, R6=OH, R7=N3 and R8=H)
Compound 22 (100 mg = 0.13 mmol)was dissolved in chloro-
form/methanol 1:1 (10 ml>, and 1 N NaOH solution (0.5 ml)
is added at room temperature, with stirring. After 1
hour, the reaction batchwas neutralized with 1 N HCI.
After the solventhad been evaporated off, toluene was
added to the product and the ~nixturewas evaporated to
1340690
- 33 -
dryness again. The resulting productwas dissolved in
chloroform/methanol 3:1 and the insoluble constituents
were filtered off. After the filtratehad been concentra-
ted, the crude productwas purified by column chromato-
graphy over 50 g of silica gel (methylene chloride/
acetone 10:1)
Yield: 53 mg (0.098 mmol - 75X)
Example 24:
7-0-(3,4-Di-0-acetyl-2,6-dideoxy-2-iodo-a-L-talopyrano-
syl)-10-0-tetrahydropyranyl-S-rhodomycinone (24)
(Compound of the formula I where R1=R3=H, R2=structure
II=2,6-dideoxy-a-L-talopyranosyl where RS=CH3, R6=R7=OAc
and R8=I; and R4=structure II where RS=R6=R7=R8=H)
N-Iodosuccininide (36 mg = 0.16 mmol) was added to a
solution of compound 5 (30 mg = 0.06 mmol) and 3,4-di-0-
acetyl-1,5-anhydro-2,6-dideoxy-L-lyxo-hex-1-enitol
(26 mg - 0.12 mmol) in 3 ml of dry acetonitrile with
activated 3 ~ molecular sieve at -lOoC under a protec-
tive gas at~osphere (argon) and the mixture was brought
to room temperature during the reaction time of 4 days.
After filtration, the filtrate was diluted with methylene
chloride and the organic phase was extracted by shaking
first with aqueous sodium thiosulfate solution, then with
sodium bicarbonate solution and subsequently with water,
dried and purified by chromatography (mobile phase:
toluene/methanol - 10:1).
Non-optimized yield: 10 mg (0.013 mmol - 20X)
1340690
- 34 -
Examt~ 1 a 2 5
7-0- ( 3 , 4-Di-0-acetyl-2 , 6-dideoxy-2 -iodo-oc-L-mannopyrano-
syL)-10-0-tetrahydropyranyl-~3-rhodomycinone (25)
(Compound of the formula I where R1=R3, RZ=structure
II=2,6-dideoxy-oc-L-mannopyranosyl where R5=CH3, R6=R~=
OAc and R8=I; and R4=structure II where R5=R6=R~=R8=H)
Compound 5 (70 mg = 0.15 mmol) was reacted with 3,4-di-
0-acetyl-1, 5-anhydro-2 , 6-dideoxy-L-arabinohex-1-enitol
and the product worked up analogously to Example 24.
Non-optimized yield: 45 mg (0.056 mmol = 37~)
Example 26:
7-0 - ( 3 , 4-Di-0 -acetyl-2 , 6 -d ideoxy-2 -i odo-a-L -manno-
pyranosyl)-(3-rhodomycinone (26)
(Compound of the formula I where R1=R3=R4=H, R2=
structure II=2,6-dideoxy-oc-L-mannopyranosyl where R5=
CH3, R6=R~=OAc and R8=I)
Acid ion exchanger (Dowex*50 WXS) was added to a solution
of compound 25 (34 mg = 0.04 mmol) in 2 ml of methanol
and the mixture was stirred for 24 hours. After the ion
exchanger had been filtered, the filtrate was purified by
chromatography (mobile phase: methylene chloride/
acetone/ formic acid = 20:1:0.1).
Non-optimized yield: 13 mg (0.018 mmol = 45~)
Example 27:
7,10-Di-0-(4-0-paranitrobenzoyl-3-N-trifluoroacetyl-a-L-
daunosaminyl)-(3-rhodomycinone (27)
(Compound of the formula I where R1=R3=H and R2=R4=
structure II=OC-L-daunosaminyl where R5=CH3, R6=OpNBz,
R~=NHTFA and R8=H)
*Denotes Trade-mark
g
134os9o
- 35 -
Compound 9 vas reacted vith 1,4-di-0-paranitrobenzoyl-3-
N-trifluoroacetyl-L-daunosamine and trimethylsilyl tri-
fluoromethanesulfonate and the product vorked up analo-
gously to Example 7.
Example 28:
7,10-Di-0-(4-0-acetyl-3-N-trifluoroacetyl-a-L-daunosamin-
yl)-S-rhodomycinone (28)
(Compound of the formula I vhere R1=R3=H and R2=R4=
structure II=a-L-daunosaminyl vhere RS=CH3, R6=OAc,
R7=NHTFA and R8=H)
Conpound 1 vas reacted with 1,4-di-0-acetyl-3-N-tri-
fluoroacetyl-L-daunosamine and trimethylsilyl trifluoro-
oethanesulfonate analogously to Example 7 and the product
vas then deblocked at positions 7 and 9 analogously to
Example 8 and reacted vith 1,4-di-0-acetyl-3-N-trifluoro-
acetyl-L-daunosamine and tri~nethylsilyl trifluoromethane-
sulfonate again analogously to Example 7.
Example 29:
7,10-Di-0-a-L-daunosaminyl-S-rhodomycinone (29)
(Compound of the formula I vhere R1=R3=H and R2=R4=
structure II=a-L-daunosaminyl vhere RS=CH3, R6=OH, R7=
NH2 and R8=H)
Compound 27 vas deblocked and the product vorked up in
accordance vith the conditions described for compound 10.
Compound 30:
7,10-0-Di-(3-N-cyanomethyl-a-L-daunosaminyl)-s-rhodomy-
cinone (30)
(Compound of the formula I vhere R1=R3=H and R2=R4=
structure II=a-L-daunosaminyl vhere RS=CH3, R6=OH,
R7=NH(CH2CN) and R8=H)
1340690
- 36 -
The compound described in the title was prepared analo-
gously starting from compound 29 (132 mg - 0.2 mmol> and
iodoacetonitrile (0.15 ml), as already described in
Example 17.
Yield: 76.6 mg (0.11 mmol - 53%)
MS: M+H+ - 723
Example 31:
7,10-Di-0-(4-0-paranitrobenzoyl-3-N-trifluoroacetyl-a-L-
acosaminyl)-s-rhodomycinone (31)
(Compound of the formula I where R1=R3=H and R2=R4=
structure II=a-L-acosaminyl where RS=CH3, Rb=OpN8z,
R7=NHTFA and R8=H)
Compound 8 was reacted and the product worked up analo-
gously to Example 7.
Example 32:
7,10-Di-0-(4-0-acetyl-3-N-trifluoroacetyl-a-L-acosaminyl)-
B-rhodomycinone <32)
(Compound of the formula I where R1=R3=H and R2=R4=
structure II=a-L-acosaminyl where RS=CH3, Rb=OAc,
R7=NHTFA and R8=H)
Compound 1 was reacted with 1,4-di-0-acetyl-3-N-trifluoro-
acetyl-L-acosamine analogously to Example 28.
Example 33:
7,10-Di-0-a-L-acosaminyl-S-rhodomycinone (33)
(Compound of the formula I where R1=R3=H and R2=R4=
structure II= a-L-acosaminyl where RS=CH3, Rb=OH, R7=
NH2 and R8=H)
- 37 - .340690
Compound 31 was deblocked and the product worked up
analogously to the conditions described for compound 10.
Example 34:
7,10-Di-0-(3-N,N-dimethyl-a-L-acosaminyl)-~-rhodomycinone
(34>
(Compound of the formula I where R1=RS=H and R2=R4=
structure II where R5=CH3, R6=OH, R7=N(CH3)2 and
R8=H)
Compound 33 was reacted analogously to the conditions of
Example 12.
Example 35:
7-0-(4-0-Paranitrobenzoyl-3-N-trifluoroacetyl-a-L-aco-
saminyl)-10-0-<4-0-paranitrobenzoyl-3-N-trifluoroacetyl-
a-L-daunosaminyl)-S-rhodomycinone (35)
(Compound of the formula I where R1=R3=H and R2=
structure II=a-L-acosaminyl where R5=CH3, R6=OpNBz,
R7=NHTFA and R8=H; and R3=structure II=a-L-dauno-
saminyl where R5=CH3, R6=OpNBz, R7=NHTFA and R8=H)
Compound 9 was reacted and the product worked up analo-
gously to Example 7.
Example 36:
7-0-(4-0-Acetyl-3-N-trifluoroacetyl-a-L-acosaminyl)-10-0-
(4-0-paranitrobenzoyl-3-N-trifluoroacetyl-a-L-daunosamin-
yl)-~-rhodomycinone (36)
(Compound of the formula I where R1=R3=H, R2=structure
II=a-L-acosaminyl where R5=CH3, R6=OAc, R7=NHTFA and
R8=H; and R4=structure II=a-L-daunosaminyl where R5=CH3,
R6=OpNBz, R7=NHTFA and R8=H)
Compound 9 was reacted with 1,4-di-0-acetyl-3-N-trifluoro-
acetyl-L-acosamine and the product worked up analogously
- 38 - 1340690
to Exaople 7.
Example 37:
7-0-a-L-Acosaminyl-10-0-a-L-daunosaminyl-B-rhodomycinone
(37)
(Compound of the formula I where R~=R3=H, R2=structure
II=a-L-acosaminyl where RS=CH3, R6=OH, R7=NH2 and
R8=H; and R4=structure II=a-L-daunosaminyl where RS=
CH3, R6=OH, R7=NH2 and R8=H)
Compound 35 was deblocked and the product worked up in
accordance with the conditions described for compound 10.
Example 38:
7-0-(4-0-Henzoyl-a-L-rhodosaminyl)-10-0-(4-0-paranitro-
benzoyl-3-N-trifluoroacetyl-a-L-acosaminyC>-S-rhodomycin-
one (38)
(Compound of the formula I where R~=R3=H, R2=structure
II=a-L-rhodossminyl where RS=CH3, R6=OHz, R7=N(CH3)2
and R8=H and R4=structure II=a-L-acosaminyl where RS=
CH3, R6=OpNBz, R7=NHTFA and R8=H)
7-0-(4-0-benzoyl-a-L-rhodosaminyl>-S-rhodomycinone was
reacted and the product corked up analogously to Example
7.
Example 39:
10-0-(4-0-Paranitrobenzoyl-3-N-trifluoroacetyl-a-L-acos-
aminyl)-7-0-a-L-rhodosaminyl-S-rhodomycinone (39)
(Compound of the formula I where R~=R3=H and R2=struc-
ture II=a-L-rhodosaminyl where RS=CH3, R6=OH, RT=
N(CH3)2 and R8=H; and R4=structure II=a-L-acosaminyl
where RS=CH3, R6=OpNHz, RT=NHTFA and R8=H)
7-0-a-L-Rhodosaminyl-B-rhodomycinone was reacted and the
product corked up analogously to Example T.
134990
- 39 -
Example 40:
10-0-a-L-Acosaminyl-7-0-a-L-rhodosaminyl-B-rhodomycinone
(40)
(Compound of the formula I where R1=R3=H, R2=structure
II=a-L-rhodosaminyl where R5=CH3, R6=OH, R7=N(CH3)2
and R8=H and R4=structure II=a-L-acosaminyl where R5=
CH3, R6=OH, R7=NH2 and R8=H)
Compound 38 was deblocked and the product worked up
analogously to the conditions described for compound 10.
Example 41:
10-0-(4-0-Acetyl-2,3,6-trideoxy-a-L-erythro-hex-2-eno-
pyranosyl)-7-0-(4-0-paranitrobenzoyl-3-N-trifluoroacetyl-
a-L-daunosaminyl)-S-rhodomycinone (41)
(Compound of the formula I where R1=R3=H, R2=structure
II=a-L-daunosaminyl where R5=CH3, R6=OpNBz, R7=NHTFA
and R8=H; and R4=structure IV=a-L-erythro-hex-2-eno-
pyranosyl where R6=OAc)
Compound 19 (400 mg = 0.52 mmol) was dissolved in methyl-
ene chloride/acetone (50 ml). After addition of 3,4-di-
0-acetyl-L-rhamnal (225 mg = 1.0 mmol> and molecular
sieve 4~ (dried powder) (400 mg), the suspension was
cooled to -40oC. Trimethylsilyl trifluoromethanesul-
fonate was then added dropwise (60 mg = 2.6 mmol). After
2 hours, further 3,4-di-0-acetyl-L-rhamnal (225 mg) was
added to the suspension. After 24 hours, the reaction
mixture was neutralized with triethylamine and worked up
in the customary manner.
Yield: 180 mg (0.2 mmol - 37X)
134069Q
- 40 -
Example 42:
10-0-(2,3,6-Trideoxy-a-L-erythro-hex-2-enopyranosyl)-7-0-
a-L-daunosaminyl-S-rhodomycinone (42)
(Compound of the formula I where R1=R3=H, R2=structure
II=a-L-daunosaminyl where RS=CH3, R60H, R7=NH2 and R8=H;
and R4=structure IV=a-L-erythro-hex-2-eno-pyranosyl
where R6=OH)
Compound 41 (100 mg = 0.13 mmol) was dissolved in methanol
(10 ml), and 1 N aqueous NaOH solution (10 ml) was added.
The reaction mixture was stirred at room temperature for
24 hours and then neutralized with 1 N hydrochloric acid.
After the solvent had been evaporated off, the residue
was purified by column chromatography over silica gel
(eluting agent: chloroform/methanol 5:1).
Yield: 60 mg (0.096 mmol - 74X)
FAB-MS: m/z 628 = M+H+
Example 43:
7,9,10-Tri-0-(4-0-Paranitrobenzoyl-3-N-trifluoroacetyl-
a-L-acosaminyl)-S-rhodomycinone (43)
(Compound of the formula I where R1=H and R2=R3=R4=
structure II=a-L-acosaminyl where RS=CH3, R6=OpNBz, R7=
NHTFA and R8=H)
Compound 8 was reacted analogously to Example 7 but with
twice the equimolar amount of 1,5-anhydro-4-0-paranitro-
benzoyl-2,3,6-trideoxy-3-N-trifluoroacetyl-L-arabino-
hex-1-enitol at OoC.
Example 44:
7,9,10-Tri-0-a-L-acosaminyl-S-rhodomycinone (44)
(Compound of the formula I where R1=H and R2=R3=R4=
structure II=a-L-acosaminyl where RS=CH3, R6=OH, R7=
~34os9p
- 41 -
NH2 and Rg=H)
Compound 43 was deblocked and the product worked up
analogously to the conditions described for compound 10.
Melting point: 225°C
Example 45:
7-0- (3-N-Trifluoroacetyl-a-L-acosaminyl) -(3-rhodomycinone
(45)
(Compound of the formula I where R1=R3=R4=H and R2=
structure II=oC-L-acosaminyl where R5=CH3, R6=OH, R~=
NHTFA and R8=H)
A solution of compound 13 (27 mg - 32 ~mol) in dry
methanol (2 ml) and 2 drops of methanolic sodium methano-
late solution (33~ strength) was stirred at room tempera-
ture for one hour, neutralized with acid ion exchanger
(Dowex*WX8), filtered and concentrated and the residue
was purified by chromatography (mobile phase: methylene
chloride/methanol/formic acid = 10 . 1 . 0.2).
Yield: 15 mg (25 ~.mol = 78~)
Example 46:
7-0-a-L-Ristosaminyl-(3-rhodomycinone (46)
(Compound of the formula I where R1=R3=R4=H and R2=
structure II = oC-L-ristosaminyl where R5=CH3, R6=OH,
R~=NH2 and R9=H )
Compound 4 was reacted with 1,5-anhydro-4-0-paranitro-
benzoyl-2, 3, 6-trideoxy-3-N-trifluoroacetyl-L-ribo-hex-1-
enitol under the conditions described in Example 7 and
the product was deblocked under the conditions described
in Example 10.
Melting point: 217°C
MS: M+H+ = 516
*Denotes Trade-mark
- 42 - 1340690
MS: M+H+ - 516
Example 47:
7-0-(3-N-Trifluoroacetyl-a-L-ristosaminyl)-B-rhodomycin-
one (47)
(Compound of the formula I where R1=R3=R4=H and R2=
structure II - a-L-ristosaminyl where RS=CH3, R6=OH,
RT=NHTFA and R8=H)
Compound 4 was reacted with 1,5-anhydro-4-0-paranitro-
benzoyl-2,3,6-trideoxy-3-N-trifluoroacetyl-L-ribo-hex-1-
enitol under the conditions described in Example 7 and
the product was deblocked under the conditions described
in Example 45.
Melting point: 178oC
MS : M+H+ - 612
Example 48:
7-0-(4-0-eenzyl-a-L-acosaminyl)-s-rhodomycinone l48)
(Compound of the formula I where R1=R3=R4=H and R2=
structure II - a-L-acosaminyl where RS=CH3, R6=OBn, R7=
NH2 and R8=H)
Compound 4 was reacted with 1,5-anhydro-4-0-benzyl-2,3,6-
trideoxy-3-N-trifluoroacetyl-L-arabino-hex-1-enitol under
the conditions described in Example 7 and the product was
deblocked under the conditions described in Example 10.
MS: M+H+ - 606
i34os9o
- 43 -
Example 49:
7-0-(4-0-Benzyl-3-N-trifluoroacetyl-a,-L-acosaminyl) -(3-
rhodomycinone (49)
(Compound of the formula I where R1=R3=R4=H and R2=
structure II - oc-L-acosaminyl where R5=CH3, R6=OBn, R~=
NHTFA and Rg=H)
Compound 4 was reacted with 1,5-anhydro-4-0-benzyl-2,3,6-
trideoxy-3-N-trifluoroacetyl-L-arabino-hex-1-enitol under
the conditions described in Example 7 and the product was
deblocked under the conditions dexcribed in Example 45.
Example 50:
7-0-(2,6-Dideoxy-2-iodo-a-L-mannopyranosyl)-~3-rhodomycin-
one (50)
(Compound of the formula I where R1=R3=R4=H and R2=
structure II - 2,6-dideoxy-oc-L-mannopyranosyl where R5=
CH3, R6=OH, R~=OH and R8=I)
Compound 26 was dissolved in dry methanol and two drops
of methanolic sodium methanolate solution (33~ strength)
and the solution was stirred at room temperature for 2
hours, neutralized with acidic ion exchanger (Dowex*WX8),
filtered and concentrated.
Melting point: 158°C
Examt~le 51:
7, 10 -Di-0 - ( 4-0 -benzyl-oc-L-a cosaminyl ) -~3-rhodomycinone
(51) (Compound of the formula I where R1=R3=H and R2=R4=
structure II = oC-L-acosaminyl where R5=CH3, R6=OBn,
R~=NH2 and R8=H)
Compound 1 was reacted with 1,5-anhydro-4-0-benzyl-2,3,6-
trideoxy-3-N-trifluoroacetyl-L-hex-1-enitol analogously
*Denotes Trade-mark
44 -
to Example 7, the product was then deblocked on the
aglycone analogously to Example 8 and glycosidated again
with 1,5-anhydro-4-0-benzyl-2,3,6-trideoxy-3-N-trifluoro-
acetyl-L-hex-1-enitol analogously to Example 7, and the
product was deblocked analogously to Example 10.
MS: M+H+ - 826
Example 52:
7-0-(4-Oeoxy-3-N-trifluoroacetyl-a-L-daunosaminyl)-~-
rhodomycinone (52)
(Compound of the formula I where R1=R3=H and R2=R4=
structure II = a-L-daunosaminyl where RS=CH3, R6=H, R7=
NHTFA and R8=H)
Compound 4 was reacted with 1-0-paranitrobenzoyl-4-deoxy-
3-N-trifluoroacetyl-L-daunosamine under the conditions
described in Example 7 and the product was deblocked
under the conditions described in Example 45.
Example 53:
7-0-(4-Deoxy-a-L-daunosaminyl)-S-rhodomycinone (52)
(Compound of the formula I where R1=R3=H and R2=R4=
structure II = oc-L-daunosaminyl where RS=CH3, R6=H, R7=
NH2 and R8=H)
Compound 4 was reacted with 1-0-paranitrobenzoyl-4-deoxy-
3-N-trifluoroacetyl-L-daunosamine under the conditions
described in Example 7 and the product was deblocked
under the conditions described in Example 10.
The 1N-NMR data of some of the novel compounds 'H53
described above are compiled in the following Tables 2
and 3.
l~4osso
- 45 -
Table 2
1H-NMR data of various compounds of the fors~ula I
The substance numbers in the first lines correspond to
the particular example numbers. The chemical shift is
stated in ppm, tetramethylsilane being used as the
internal standard. Unless indicated otherwise, the
spectra are measured in CDCl3 as the solvent.
Abbreviations: s: singlet
d: doublet
t: triplet
q: quartet
m: multiplet
dd: doublet of a doublet
ddd: doublet of a doublet of a doublet
dq: doublet of a quartet
a) measured at 300 MHz
b) 8-phenyl 7.4-7.27 m
c) measured at 270 MHz
d) compound 3a and 3b are exo-endo-isomers
e> benzylidene-CH 5.41s, aromatic benzylidene 7.36-7.20m
f) benzylidene-CH 6.13s, aromatic benzylidene 7.36-7.17m
g) tetrahydropyranyl ring H-1 4.91m and 4.99m,
ring protons 4.0-3.1m,
since the substance is present as a diastereomer mix
ture (R/S on the THP ring C-1), some signals are pre
sent in duplicate
h) measured at 400 MHz
i) 0-trimethylsilyl 0.13s
k) B-phenyl 7.35-7.17m
l) solvent CDCl3 + CD30D
m) solvent CDCl3 + d6-DMSO
n) N(CH3)2 2.086 s
o) tetrahydropyranyl H-1 5.09dd
OAc 2.03s, 2.09s
- 46 - 1340690
p) tetrahydropyranyl H-1 5.04dd;
ring protons 4.2-3.Om
OAc 2.03s, 2.01s
q) OAc 2.04s, 2.01s
r) solvent CDCl3 + dioxane
s) measured at 200 MHz
t) benzyl CH2 4.77d, 4.66d, aromatic benzyl 7.37m
u) benzyl CH2 4.46d, 4.33d, aromatic benzyl 7.29-7.12m
v) measured at 90 MHz
1340690
- 47 -
Table 2, Part 1:
la,b) 2c) 3aa,de) 3ba,d,f)
H-1 7.907dd 7.821d 7.85dd 7.82dd
H-2 7.698t 7.645t 7.67t 7.64t
H-3 7.774dd 7.262d 7.29dd 7.25dd
H-7 5.672t 5.279t 5.67dd 5.54t
H-8a 2.293dd 2.39dd 2.31dd 2.67dd
H-8b 2.19dd 2.13dd 1.79dd 2.16dd
H-10 4.973d 4.782d 4.94d 4.84d
H-13a 2.22-1.79m 1.95m 1.98-1.71m 1.99-1.89m
H-13b 2.22-1.79m 1.76m 1.98-1.71m 1.99-1.89m
H3-14 1.236t 1.048t 1.07t 1.11t
H-1' - - - _
H-2a' - - - _
H-2e' - - - _
H-3 - - - _
'
H-4' - - - _
H-5' - - - _
H3-6' - - - _
OH-4 12.145s 12.151s 12.09s 11.96s
OH-6 12.78s 12.683s 12.67s 12.66s
OH-11 13.575s 13.498s 13.70s 13.51s
OH-7 - - - _
OH-9 - - - _
H-10 2.68d 3.18d 2.80d
NHTFA - - - _
pNBz - - - _
~~~06~0
- 48 -
Table 2, Part 2:
4a) 5C, g) 6h, i) 7a,
k)
H-1 7.902dd 7.78d 7.891dd 7.77d
H-2 7.745t 7.64t 7.715t 7.599t
H-3 7.347dd 7.24d 7.312dd 7.70dd
H-7 5.345dt 5.19dd/5.14dd 5.231t 5.680
H-8a 2.408dt 2.30dd 2.228dd 2.45dd
H-8b 2.054ddd 2.05d 2.146dt 2.18d
H-10 6.344d 4.94s/4.81s 4.822d 4.956s
H-13a 1.73m 1.75m 1.718m 1.83m
H-13b 1.56m 1.75m 1.718m 1.83m
H3-14 1.103t 1.03t 1.075t 1.18t
H-1' - - - 5.64d
H-2a' - - - 1.83m
H-2e' - - - 2.12m
H-3' - - - 4.44m
H-4 - - - 4.786t
H-5' - - - 4.18dq
H3-6~ - - - 1.27d
OH-4 12.010s 11.97s 12.106s 12.032s
OH-6 12.806s 12.81s 12.897s 12.714s
OH-11 13.345d 13.66s/13.6s 13.626s 13.694s
OH-7 3.452d 3.478d -
OH-9 3.756s 3.148s
OH-10 - - -
NHTFA - 6.45d 6.44d
pNBz - 8.28-8.08m 8.34-8.15m
X340690
- 49 -
Table 2) Part 3:
8c) 9h) 10x1) llh,m)
H-1 7.91dd 7.905dd 7.774d 7.812d
H-2 7.73t 7.726t 7.621t 7.653t
H-3 7.34dd 7.344dd 7.209d 7.243d
H-7 5.31d 5.279t 5.087d 5.089d
H-8a 2.36dd 2.308dd 2.154d 2.125dd
H-8b 2.22d 2.195d 2.06d 2.04d
H-10 4.98s 5.020s 4.87s 4.886s
H-13a 1.95-1.72m 1.88-1.38m 1.82m 1.75m
H-13b 1.95-1.72m 1.88-1.38m 1.82m 1.70m
H3-14 1.16t 1.135t 1.02t 1.018t
H-1' 5.57d 5.659d 5.31d 5.302d
H-2a' 1.8m 2.16-1.89m 1.49m 1.60m
H-2e' 2.09dd 2.16-1.89m 2.09m 2.01m
H-3' 4.48d 4.493m 2.87m 2.9m
H-4' 4.82t 5.409s 2.87m 3.317s
H-5' 4.21dq 4.314q 3.66dq 3.881q
H3-6' 1.29d 1.228d 1.236d 1.202d
OH-4 12.06s 12.041s
OH-6 12.89s 12.894s
OH-11 13.72s 13.735s
OH-7 3.54d 3.491d
OH-9 3.34s 3.248s
OH-10 - -
NHTFA - -
pNBz - -
X340690
- 50 -
Table 2, Part 4:
l2h,n) 13h) 14h) l5hm)
H-1 7.821d 7.908d 7.800d 7.78d
H-2 7.644t 7.738t 7.622t 7.64t
H-3 7.245d 7.334d 7.229d 7.21d
H-7 5.167d 5.246t 5.063t 4.995t
H-8a 2.2-2.09m 2.40dd 2.24-1.99m 2.105m
H-8b 2.2-2.09m 2.45d 2.24-1.99m 2.105m
H-10 4.908s 6.414d 4.854d 4.70s
H-13a 1.85-1.66m 1.75m 1.86-1.69m 1.75-1.60m
H-13b 1.85-1.66m 1.75m 1.86-1.69m 1.75-1.60m
H3-14 1.039t 1.125t 1.073t 0.99t
H-1' 5.417d 5.520d 5.419 5.29d
H-2a' 1.489ddd 1.86ddd 2.24-1.99m 1.49m
H-2e' 2.194ddd 2.01ddd 2.24-1.99m 1.94m
H-3' 2.602ddd 4.3m 4.38m 2.8m
H-4' 3.012t 4.84t 4.891t 2.8m
H-5' 3.699dq 4.3m 4.278dq 3.77dq
H3-6' 1.268d 1.330d 1.238d 1.23d
OH-4 12.002s 12.023s
OH-6 12.813s 12.796s
OH-11 13.380s 13.551s
OH-7 - _
OH-9 3.819s 3.575s
OH-10 - 3.615d
NHTFA - 6.47d -
pNBz - 8.25-8.9m 8.22-8.09m -
134os9o
- 51 -
Table 2. Part 5:
16a) 18h) 19h,1) 23h,r)
H-1 7.79dd 7.74d 7.70d 7.78dd
H-2 7.634t 7.65t 7.62t 7.59t
H-3 7.229dd 7.22d 7.17d 7.21dd
H-7 5.059dd 5.25d 5.06s 4.96dd
H-8a 2.22-2.02m 2.47d 2.13m 2.10m
H-8b 2.22-2.02m 2.08dd 2.13m 2.10m
H-10 4.857d 6.33s 4.78s 4.74s
H-13a 1.90-1.52m 1.77m 1.88m 1.75m
H-13b 1.90-1.52m 1.53m 1.68m 1.65m
H3-14 1.054t 1.10t 1.05t 1.02t
H-1' 5.472d 5.65s 5.53s 5.23dd
H-2a' 1.90-1.52m 1.90ddd 1.92m
H-2e' 2.22-2.02m 2.13m 2.10m
H-3' 2.578ddd 4.48m 4.34m 4.04m
H-4' 3.101t 5.49s 5.42s 3.45m
H-5' 3.857dq 4.48m 4.44q 3.55dq
H3-6' 1.320d 1.27d 1.16d 1.25d
OH-4 11.84s
OH-6 12.68s
OH-11 13.22s
OH-7 - - -
OH-9 3.881s 3.85s
OH-10 -
NHTFA - 6.61d
pNBz - 8.25m 8.23m
.~3~~69~1
- 52 -
Table 2, Part 6:
24h,o) 25h,p) 26a,q)
H-1 7.88d 7.90d 7.83d
H-2 7.69t 7.69t 7.69t
H-3 7.30d 7.31d 7.28d
H-7 5.12t 5.07t 5.02dd
H-8a 2.22d
H-8b 2.11dd
H-10 4.98s 5.04s 4.88s
H-13a 1.91-1.70m
H-13b 1.91-1.70m
H3-14 1.13t 1.17t 1.10t
H-1' 5.79s 5.37s 5.71d
H-2a' - - -
H-2e' 4.56dd 4.61dd 4.66dd
H-3' 4.27d 4.29dd 4.32dd
H-4' 4.86s 5.16t 5.18t
H-5' 4.08q 4.04dq 4.17dq
H3-6' 1.21d 1.24d 1.29d
OH-4 12.12s 12.12s 12.04s
OH-6 12.89s 12.90s 12.79s
OH-11 13.78s 13.81s 13.51s
OH-7 - - -
OH-9 3.37s
OH-10 - - 2.80s
NHTFA - - -
pNBz _ _ -
- 53 - 1340690
Table 2, Part 7:
44a~ 45s~ 46a~ 47a~
H-1 7.83dd 7.80d 7.75dd 7.88d
H-2 7.65t 7.69t 7.64t 7.?3t
H-3 7.26dd 7.24d 7.15dd 7.32d
H-7 5.22m 5.02t 4.87m 4.96d
H-8a 2.20m 2.08m
H-8b 2.20m 2.08m
H-10 5.lls 4.82m 4.60s 4.81s
H-13a 1.72m 1.78m -
H-13b 1.72m 1.78m -
H3-14 0.90t 1.06t 1.04t 1.09t
H-1' S.35d 5.42d 5.35s
H-2a' 2.20m 2.08m
H-2e' 2.20m 2.08m
H-3' 3.80m 3.66m 4.39ddd
H-4' 3.16t 3.52dd 3.50dd
H-5' 3.96dq 4.14dq 4.15dq
H3-6' 1.32d 1.37d 1.34d
OH-4 12.08s
OH-fi 12.79s
OH-11 13.59s
OH-7 _ _
OH-9
OH-10
NHTFA 7.75d - B.Old
pNHz
:1340690
- 54 -
Table 2, Part 8:
48a't~ 49h'u~ 50a~ 52~)
H-1 7.88d 7.86d 7.91dd 7.92dd
H-2 7.72t 7.70t 7.76t 7.71t
H-3 7.32d 7.31d 7.35dd 7.28dd
H-7 5.13m 5.24s 5.07d 5.12t
H-8a 2.22d 2.37d
H-8b 2.16dd 2.lOm
N-10 4.91s 5.09s 4.Sld 4.95d
H-13a 1.9-1.5m 1.98m 1.7m
H-13b 1.9-1.5m 1.98m 1.7m
H3-14 l.llt 1.03t 1.08t 1.13t
H-1' 5.43d 5.27d 5.71s 5.52d
H-2a' 2.2-1.5m 2.lOm -
H-2e' 2.2-1.5m 2.19ddd 4.45dd
H-3' 3.09ddd 3.93m 3.97dd 4.2m
H-4' 2.91t 3.09t
H-5' 3.98dq 3.39dq 4.2m
H3-6' 1.41d 0.98d 1.38d 1.28d
OH-4 l2.lls 12.18s 12.14s
OH-6 12.88s 12.93s 12.77s
OH-11 13.65s 13.72s 13.52s
OH-7 - - - -
0~1-9
OH-10 2.68d
NHTFA 6.09d 5.92d
pNBz - -
1340690
Table 3
1H-NMR data of various compounds of the formula I
The substance numbers of the first line correspond to the
particular example numbers. The chemical shift is stated
in ppm, tetramethylsilane being used as the internal
standard. Unless stated otherwise, the spectra are
measured in CDCl3 as the solvent.
Abbreviations: s: singlet
d: doublet
t: triplet
q: quartet
m: multiplet
dd: doublet of a doublet
ddd: doublet of a doublet of a doublet
dq: doublet of a quartet
The carbohydrate protons with a single dash (H-1' etc.)
relate to the carbohydrates as R2, and the carbohydrate
protons with a double dash (H-1" etc.) relate to the
carbohydrates as R4 in the general formula I
a) measured at 270 MHz
b) the values sre exchangeable in pairs
c> measured at 300 MHz
d) OAc 2.21s
e> measured at 400 MHz
f) solvent CDCl3 + d6-DMSO
g) OAc 2.01s, 1.99s
h) solvent D20
i) N(CH3)2 2.10s, 2.07s
k) OBz 7.72-7.Sbm;
N(CH3)2 2.28s
l> in the case of the protons of the three carbohydrate
radicals, the allocation of the carbohydrate ring
protons to the individual carbohydrate radicals is
1340fi9p
- 56 -
uncertain.
H-1 5.66d, 5.59d, 5.43d
H-3 4.74-4.65m, 2 x 4.52-4.35m
H-4 3 x 4.99-4.76m
H-5 2 x 4.20-4.08m, 3.47dq
H3-6 1.37d, 1.27d, 0.84d
NHTFA 2 x 6.67d, 6.45d
134a690
- 57 -
Table 3, Part 1:
27a) 28~,d) 29e,f)
H-1 7.795d 7.905d 7.74d
H-2 7.651t 7.718t 7.59t
H-3 7.241d 7.314d 7.18d
H-7 5.157t 5.138t 4.96t
H-8a 2.24-1.94m 1.69-1.48m
H-8b 2.24-1.94m 1.69-1.48mm
H-10 5.071s 4.873s 4.78s
H-13a 1.85-1.66m 1.69-1.48m
H-13b 1.85-1.66m 1.69-1.48m
H3-14 1.107t 1.065t 0.92t
H-1' 5.431db) 5.507db) 5.25db)
H-2a' 1.85-1.66m 1.69-1.48m
H-2e' 2.24-1.94m 1.69-1.48m
H-3' 4.47-4.42m 4.53mb)
H-4' 5.595sb) 5.14sb) 3.29sb)
H-5' 4.47-4.42mb)4.34qb)
H3-6' 1.232db) 1.26db) 1.16db)
H-1' 5.347db) 5.34db) 5.19db)
'
H-2a 1.85-1.66m 1.69-1.48m
"
H-2e 2.24-1.94m 1.69-1.48m
"
H-3 4 . 47-4 4 . 53mb)
" . 42m
H-4' 5.589sb) 5.14sb) 3.26sb)
'
H-5' 4.309qb) 4.20qb) 3.79qb)
'
H3-6 1.147db) 1. 2ldb) 1. l2db)
' '
OH-4 11.902s 12.158s
OH-6 12.804s 12.901s
OH-11 13.683s 13.674s
OH-9 3.287s
NHTFA 6.29d/6.24d 6.54d/6.30d -
pNBz 8.30-8.18m - -
X340690
- 58 -
Table 3, Part 2:
31~) 32e,g) 33e,h) 34a, t, i)
H-1 7.85d 7.81dd 7.50d 7.81dd
H-2 7.66t 7.63t 7.35t 7.64t
H-3 7.27d 7.24dd 7.09d 7.24dd
H-7 5.15m 5.07d 5.07t
H-8a 2.29m 2.33-1.92m 1.83-1.39m
H-8b 2.29m 2.33-1.92m 1.83-1.39m
H-10 4.98s 4.93s 4.92s
H-13a 1.93-1.68m 1.82-1.6m 1.83-1.39m
H-13b 1.93-1.68m 1.82-1.6m 1.83-1.39m
H3-14 1.13t 1.07s 1.03t 1.04t
H-1' 5.45d 5.39db) 5.47db) 5.46db)
H-2a' 1.85ddd 1.82-1.6m 1.83-1.39m
H-2e' 2.35ddd 2.33-1.92m 1.83-1.39m
H-3' 4.28m 4.15mb) 2.8-2.5m
H-4' 4.83t 4.55tb) 3.09tb)
H-5 4 . 3 Odq 4 . lldqb) 3 . 83dqb)
'
H3-6' 1.27d 1.21db) 1.33db) 1.31db)
H-1' 5.50d 5.38db) 5.35db) 5.42db)
'
H-2a 1.76ddd 1.82-1.6m 1.83-1.39m
"
H-2e 2.02ddd 2.33-1.92m 1.83-1.39m
"
H-3 4.34m 4.15m 2.8-2.5m
"
H-4' 4.74t 4.47tb) 3.01tb)
'
H-5' 4.12dq 3.96dqb) 3 .70dqb)
'
H3-6' 1.23d 1.17db) 1.33db) 1.27db)
'
OH-4 12.01s 11.98s 12.07s
OH-6 12.84s 12.78s 12.84s
OH-11 13.71s 13.65s 13.60s
OH-9 3.30s 3.26s 3.53s
NHTFA 6.39d/6.33d 6.62d/6.55d - -
pNBz 8.02-8.36m - - -
- 59 - X340690
Table 3) Part 3:
35e> 36e~ 37e>
H-1 7.94dd 7.82dd 7.90dd
H-2 7.76t 7.64t 7.71t
H-3 7.36dd 7.25dd 7.32dd
H-7 5.22t 5.08t 5.10m
H-8a 2.36-1.60m
H-8b 2.36-1.60m
H-10 5.12s 4.99s 4.96s
H-13a 2.08-1.79m 2.36-1.60m
H-13b 2.08-1.79m 2.36-1.60m
H3-14 1.21t 1.09t 1.09t
H-1' 5.55db> 5.59db> 5.38sb~
H-2a' 2.08-1.79m 2.36-1.60m
H-2e' 2.08-1.79m 2.36-1.60m
H-3' 4.55-4.32m 4.12ddd 2.78m
H-4' 4.93t 4.54t 2.92t
H-5' 4.55-4.32m 4.12dq 3.83dq
H3-6' 1.37db> 1.22db~ 1.34db>
H-1' 5.45db~ 5.39db> 5.37sb>
'
H-2a 2.08-1.79m 2.36-1.60m
"
H-2e 2.08-1.79m 2.36-1.60m
"
H-3 4.55-4.32m 4.412ddd 3.04m
"
H-4 5.71s 5.34s 3.37s
"
H-5 4.55-4.32m 4.24q 3.96q
"
H3-6' 1.28db~ 1.16db~ 1.28db>
'
OH-4 12.09s 11.97s
OH-6 12.93s 12.79s
OH-11 13.83s 13.70s
OH-9 3.41s 3.29s
NHTFA 6.54d/6.25d 6.25d/6.13d
pNBz 8.36-8.2m 8.26-8.09m
F
x.340690
- 60 -
Table 3, Part 4:
38e,k> 39e) 40e) 43a,1)
H-1 7.87d 7.83d 7.89d 7.92d
H-2 7.46t 7.65t 7.71t 7.74t
H-3 7.31d 7.26d 7.32d 7.36d
H-7 5.23s 5.14m 5.13t 5.29t
H-8a 2.05-2.02m 1.9-1.65m
H-8b 2.05-2.02m 1.9-1.65m
H-10 4.99s 4.91s 4.95s 5.35s
H-13a 1.93-1.74m 1.9-1.65m
H-13b 1.93-1.74m 1.9-1.65m
H3-14 1.15t 1.14t 1.09t 1.29t
H-1' 5.54s 5.49sb) 5.46db)
H-2a' 1.93-1.74m
H-2e' 2.21m
H-3' 2.69ddd 2.23m
H-4' 5.54s 3.62s 3.67s
H-5' 4.27q 3.97q 4.02q
H3-6' 1.26d 1.34d 1.37db)
H-1' 5.68d 5.44sb) 5.37db)
'
H-2a 1.93-1.74m
"
H-2e 2.21m
"
H-3 4.44ddd 4.37m 2.76m
"
H-4 4.79t 4.73t 2.85t
"
H-5 4.16dq 4.13dq
"
H3-6 1. 21d 1. 19d 1. 30db)
"
OH-4 12.07s 12.08s 12.14s
OH-6 12.88s 12.80s 13.13s
OH-11 13.78s 13.74s 13.92s
OH-9 3.42s
NHTFA 6.58d 6.28d
pNBz 8.27-8.08m 8.24-8.08m 8.34-7.96m
