CA1340690C - Semi-synthetic rhodomycins, a process for their preparation and their use as cytostatics - Google Patents

Abstract

The invention relates to novel cytostatic anthracyclines of the general formula I, if appropriate as the salt of an inorganic or organic acid (see formula I) in which the radicals R1 are hydrogen or hydroxyl, R2 is hydrogen, a structure of the formula II or IV or, together with R3, a structure of the formula III, R3 is hydrogen, a structure of the formula II or IV or, together with R2, a structure of the formula III, R4 is hydrogen, an acyl group, trimethylsilyl, a structure of the formula II or a structure of the formula IV

(see formula II, III, IV) and in these R5 is hydrogen, methyl, hydroxymethyl, acyloxymethyl or alkoxymethyl, R6 is hydrogen, hydroxyl, acyloxy, alkoxy, allyloxy, benzyloxy or halogen, R7 has the same meaning as R6 and can also additionally be NH2, NHacyl, N(alkyl)3, N(CH2CN)2, HN(CH2CN) or azido, and R8 has the same meaning as R6, X is alkylboronyl, phenylboronyl, an alkyl ortho-carboxylate or a ketal or acetal, the following compounds of the formula I being excluded:
1. R1=R3=R4=H, R2=.alpha.-L-daunosaminyl, 2. R1=R3=R4=H, R2=.alpha.-L-rhodosaminyl or its 4'-acyl derivatives 3. R1=R3=H, R2=R4=.alpha.-L-rhodosaminyl or its 4'-acyl derivatives 4. R1=OH, R3=H, R2=R4=.alpha.-L-rhodosaminyl or its 4'-acyl derivatives 5. R1=R2=R3=H, R4=.alpha.-L-rhodosaminyl or its 4'-acyl derivatives.
The invention also relates to a process for the preparation of the compounds and their use in medicaments.
The compounds of the invention exhibit cytostatic activity and accordingly may be used for the therapy of tumors.

Description

- 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~

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 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 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).

16) R3 is ydrogen and other ons are as h the definiti und er 4).

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 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 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

~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 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 _ 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~~

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 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 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 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 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 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.

_ .
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 28 > 1 71 29 ~ 10 >1 0.5 n Table 1, Part 2:
Substance No. Long-term 1 hour incubation (Example) incubation ICSp (lt9~ml>
ICSQ (ug~ml) 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 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 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 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) 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.

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) 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 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 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 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 (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 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) 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 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) 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 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.

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) 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 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 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 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 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 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 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 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 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 NHTFA - 6.45d 6.44d pNBz - 8.28-8.08m 8.34-8.15m 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 NHTFA - -pNBz - -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 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-9 3.881s 3.85s NHTFA - 6.61d pNBz - 8.25m 8.23m .~3~~69~1 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-9 3.37s OH-10 - - 2.80s NHTFA - - -pNBz _ _ -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 _ _ NHTFA 7.75d - B.Old pNHz :1340690 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 0~1-9 OH-10 2.68d NHTFA 6.09d 5.92d pNBz - -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 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 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 - -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 - - -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 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

Claims (49)

1. A compound of the formula I or a salt thereof with an inorganic or organic acid in which:
R1 is hydrogen or a hydroxyl group R2 is hydrogen or a structure of the formula II or IV
or, together with R3, of the formula III
R3 is hydrogen or a structure of the formula II or IV
or, together with R2, of the formula III, R4 is hydrogen, trimethylsilyl, acetyl, trifluoroacetyl, benzoyl or para-nitrobenzoyl, a structure of the formula II or a structure of the formula IV, R5 is hydrogen, methyl, hydroxymethyl, (C1-C8) acyloxymethyl or alkoxymethyl (C1-C8) R6, R7 and R8 independently of one another are hydrogen, hydroxyl, aliphatic acyloxy (C1-C8), benzoyloxy or para-nitrobenzoyloxy, (C1-C8) alkoxy, allyloxy, benzyloxy or para-nitrobenzyloxy 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 isopropylidene, benzylidene, alkylboronyl, phenylboronyl, an alkyl ortho-carboxylate or a ketal or acetal provided that the compounds where R1=R3=R4=H and R2=.alpha.-L-daunosaminyl or .alpha.-L-rhodosaminyl or 4' -acyl-.alpha.-L-rhodosaminyl, R1=OH or H, R3=H and R2=R4=.alpha.-L-rhodosaminyl or 4' -acyl-.alpha.-L-rhodosaminyl, R1=R2=R3=H and R4=.alpha.-L-rhodosaminyl, R1=OH, R2=a group of the formula II, R3=R4=H, R5=methyl, R6=OH, R7=N(alkyl)2(C1-C8) and R8=H, R1=OH, R2=a group of the formula II, R3=R4=H, R5=methyl, R6=OH, R7=NH2 and R8=H, R1=R3=R4=H, R2=a group of the formula II, R5=methyl, R6=OH, R7=NHacyl (C1-C8) and R8=H, and R1=H or OH, R2=a group of the formula II, R3=H, R4=H, or a group of the formula II, R5=methyl, R6=OH, R7=N(alkyl)2(C1-C8) and R8=H are excluded.

2. A compound as claimed in claim 1 wherein X is methyl orthoformate or ethyl orthoacetate.

3. A compound as claimed in claim 1 wherein X is isopropylidene or benzylidene.

4. A compound as claimed in claim 1, wherein R2 and R3 independently of one another are hydrogen or a structure of the formula II or IV with the meanings of R5 to R8 given in claim 1.

5. A compound as claimed in claim 1, wherein R2 and R3 independently of one another are hydrogen or a structure of the formula II or IV in which R5 is methyl, R6 and R7 have the meanings given in claim 1 and R8 is hydrogen or halogen.

6. A compound as claimed in claim 1, wherein R2 and R3 independently of one another are hydrogen or a structure of the formula II or IV in which R5 is methyl, R6 has the meaning given in claim 1, R7 is NH2, NHacyl (C1-C8), N(alkyl)2 (C1-C8), N(CH2CN)2, NH(CH2CN) or azido and R8 is hydrogen or halogen.

7. A compound as claimed in claim 1, wherein R2 and R3 independently of one another are hydrogen or a structure of the formula II or IV, in which R5 is methyl, R6 and R7 have the meanings given in claim 1 and R8 is hydrogen or halogen and the structures of the formula II or IV belong to the L-series of carbohydrates.

8. A compound as claimed in claim 1, wherein R2 and R3 independently of one another are hydrogen or a structure of the formula II or IV, in which R5 is methyl, R6 has the meaning given in claim 1, R7 is NH2, NHacyl (C1-C8), N(alkyl)2 (C1-C8), N(CH2CN)2, NH(CH2CN) or azido and R8 is hydrogen or halogen, and the structures of the formula II or IV belong to the L-series of carbohydrates.

9. A process for the preparation of a compound as claimed in claim 1, which comprises a. reacting a compound of the formula I in which R1 is hydrogen or a hydroxyl group and R2 to R4 are hydrogen with a boric acid or with a ketone or a ketal, or an acetal in a suitable organic solvent with a catalyst at a temperature between 0°C and the boiling point of the solvent, if appropriate with the addition of a dehydrating agent to give a compound of the formula I in which R1 has the meaning given in claim 1 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, b. if appropriate acylating with a carboxylic acid anhydride or a phenylcarboxylic acid anhydride or a carboxylic acid halide or by reacting with trimethylsilyl trifluoromethanesulfonate in a suitable organic solvent at a temperature between -40°C and the boiling point of the solvent and in the presence of a base to give a compound of the formula I in which R1 has the meaning given in claim 1 R2 together with R3 is a structure of the formula III and R4 is aryl or trimethylsilyl, c. or reacting the compound obtained under (a) with 3,4-dihydro-2H-pyran in a suitable organic solvent in the presence of a catalyst, and a desiccant, at a temperature between -30°C and the boiling point of the solvent, to give a compound of the formula I in which R1 has the meaning given in claim 1, R2 together with R3 is a structure of the formula III and R4 is a structure of the formula II, where R5 to R8 is hydrogen, d. or reacting the compound obtained under (a) with a carbohydrate derivative of the formula V
in which R5 to R8 are as defined in claim 1, R9 is halogen, O-acyl or another leaving group which is suitable for glycosidation reactions, to give a compound of the formula I in which R1 has the meaning given in claim 1, R2 together with R3 is a structure of the formula III and R4 is a structure of the formula II, e) or reacting the compound obtained under (a) with a functionalized carbohydrate of the general formula V or VI

in which R5 to R8 are as defined in claim 1, with the exception of hydroxymethyl, hydroxyl, NH2, N(CH2CN)2 and NH(CH2CN) and R9 is acyl which is bonded via oxygen in the presence of an organic solvent, a catalyst and if appropriate an acid-trapping agent and a desiccant at a reaction temperature of -70°C to +30°C under a protective gas atmosphere to give a compound of the formula I
in which R1 has the meaning given in claim 1, 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 given in claim 1, with the exception of hydroxymethyl, hydroxyl, NH2, N(CH2CN)2 and NH(CH2CN), f) and, if appropriate, deblocking the compound of stages (b) to (a) on positions 7 and 9 by reacting this compound in a suitable organic solvent with a catalyst, and if appropriate with a diol, at a temperature between 0°C and the boiling point of the solvent, to give a compound of the general formula I in which R1 has the meaning given in claim 1, R2 and R3 are hydrogen and R4 has the meaning given in claim 1, with the exception of hydrogen, g) and subsequently, if appropriate, 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 R5 to R8, a protective group on the protected hydroxyl functions and/or on the protected amino functions by means of an inorganic or organic base, in a solvent 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 R5 is hydrogen, methyl, hydroxymethyl or alkoxymethyl (C1-C8) R6 is hydrogen, hydroxyl, alkoxy (C1-C8) or halogen, R7 is NH2, N(alkyl)2 (C1-C8), azido, hydroxyl or alkoxy (C1-C8) 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 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, by means of reductive amination, to give the corresponding 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 and R8 have the meanings given under g) and R7 is N(alkyl)2 (C1-C8), 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 R8 have the meanings given under g) and R7 is NH2, by reaction with iodoacetonitrile or bromoacetonitrile in a suitable solvent, in the presence of a suitable base, 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 and 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 mentioned in stage e), either only position 7 or simultaneously positions 7 and 9 being glycosidated, depending on the amount of glycosyl donor used, to give products which correspond to the general formula I in which R1 has the meaning given under g), R2 is a structure of the formula II or IV in which R5 to R8 have the meanings given under g), with 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 R5 to R8 have the meanings given under g), 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 R5 to R7 have the meanings given in stage (e), in the presence of an organic solvent, with N-iodosuccinimide and if appropriate with a desiccant at a temperature from -40°C
to +40°C under a protective gas atmosphere into a compound of the formula I in which R1 has the meaning given under g) and R2 is a structure of the formula II, in which R5 is hydrogen, methyl, acyloxymethyl (C1-C8) or alkoxymethyl (C1-C8), R6 is aliphatic acyloxy (C1-C8), alkoxy (C1-C8), allyloxy or benzyloxy, R7 is aliphatic acyloxy (C1-C8), alkoxy (C1-C8), allyloxy, benzyloxy, NH acyl, N(alkyl)2 (C1-C8) or azido and R8 is iodine, and R3 and R4 have the meanings given in stage k), and m) if appropriate deblocking the compound forced in stage k) or l) in accordance with the conditions of stage g), to give s compound of the formula I in which R1 has the meaning given under g) and R2 is a structure of the formula II or IV, in which R5 is hydrogen, methyl, hydroxymethyl or alkyloxy-methyl (C1-C8), R6 is hydrogen, hydroxyl, alkoxy (C1-C8) or halogen, R7 is NH2 or N(alkyl)2 (C1-C8), azido, hydroxyl or alkoxy (C1-C8) 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 R5 is hydrogen, methyl, hydroxymethyl or alkoxymethyl (C1-C8), R6 is hydrogen, hydroxyl, alkoxy (C1-C8) or halogen R7 is NH2, N(alkyl)2 (C1-C8), N(CH2CN)2 or NH(CH2CN), azido, hydroxyl or alkoxy (C1-C8), and R8 has the same meaning as R6, but is independent thereof, or n) also deblocking the compound formed in stage k) or l) 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 under g), R2 is a structure of the formula II or IV, in which R5 to R8 have the meanings given in claim 1, 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 compound 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 R7 is N(alkyl)2 (C1-C8),in accordance with the reductive amination described for stage h), or, if appropriate, p) converting a compound 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 cyanomethyl 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 conditions already given in stage e), either only position 10 or simultaneously positions 9 and 10 being glycosidated, depending on the amount of glycosyl donor used, to give a compound of the formula I in which R1 is hydrogen or hydroxyl and R2 is a structure of the general formula II or IV, in which R5 to R8 have the meanings given in claim 1, 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 R5 to R8 have the meanings given in claim 1, with the exception of hydroxymethyl, hydroxyl, NH2, N(CH2CN)2 or NH(CH2CN), and, if appropriate, r) reacting a compound of stage n) in accordance with the reaction of stages c), d) and l) so as to give a compound of the formula I in which R1 has the meaning given in claim 1 and R2 is a structure of the formula II or IV, in which R5 to R8 have the meanings given in claim 1, 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 R5 to R8 have the meanings given in claim 1, 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 described in stage g), to give a compound of the formula I in which R1 has the meaning given in claim 1 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 given in claim 1, with the exception of (C1-C8) acyloxymethyl, aliphatic acyloxy (C1-C8), benzoyloxy or para-nitrabenzoyl or NH acyl (C1-C8), and, if appropriate, t) converting the compound of stage s) into the corresponding derivative in which the radical R7, which in stage s) was an NH2 group, is converted into N(alkyl)2 (C1-C8), by means of reduction amination in accordance with stage h), or u) 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 under s) and R4 is trimethylsilyl, with tetrabutylammonium fluoride in an organic solvent, such as tetrahydrofuran, diethyl ether, dioxane or mixtures thereof, at temperatures between -40°C 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, v) and, if appropriate, converting compounds of the formula I in which R1, R2, R3 and R4 have the meanings given in v) and R7 is NH2, N(alkyl)2 (C1-C8), N(CH2CN)2 or NH(CH2CN) into the salt of an inorganic or organic acid.
10. The process as claimed in claim 9, wherein a compound of the formula I in which R1 has the meaning given in claim 1, R2 together with R3 forms a structure of the formula III and R4 is hydrogen, is converted by acylation with a carboxylic acid anhydride, or a phenylcarboxylic acid anhydride or a carboxylic acid halide or by reaction with trimethylsilyl trifluoromethanesulfonate in an organic solvent, at a temperature between -40°C and the boiling point of the solvent and in the presence of a base, into a compound of the formula I in which R1 has the meaning given in claim 1, R2 together with R3 is a structure of the formula III
and R4 is acyl or trimethylsilyl, or wherein a compound of the formula I in which R1 has the meaning given in claim 1, R2 together with R3 forms a structure of the formula III and R4 is hydrogen, is converted by reaction with 3,4-dihydro-2H-pyran in a suitable organic solvent in the presence of a catalyst, and a desiccant at a temperature between -30°C and the boiling point of the solvent, into a compound of the formula I in which R1 has the meaning given in claim 1, R2 together with R3 is a structure of the formula III
and R4 is a structure of the formula II where R5 to R8 are hydrogen.

11. The process as claimed in claim 9.
wherein a compound of the formula I in which R1 has the meaning give in claim 1, R2 together with R3 forms a structure of the formula III and R4 has the meaning given, excluding hydrogen, can be deblocked at positions 7 and 9 by reacting this compound in a suitable organic solvent, with a catalyst and if appropriate with a diol, at a temperature between 0°C and the boiling point of the solvent, to give a compound of the general formula I
in which R1 has the meaning given in claim 1, R2 and R3 are hydrogen and R4 has the meaning given in claim 1, with the exception of hydrogen.

12. The process as claimed in claim 9, wherein a compound of the formula I in which R1 to R4 have the meanings given in claim 1, but R2 or R4 must be hydrogen and R5 to R8 cannot be hydroxyl, hydroxymethyl or NH2, is reacted with a functionalized carbohydrate of the general formula V or VI
in which R5 to R8 have the meanings given in claim 1, with the exception of hydroxymethyl, hydroxyl, NH2, N(CH2CN)2 and NH(CH2CN) and R9 is an acyl protective group bonded via oxygen, in the presence of an organic solvent, a catalyst and if appropriate an acid-trapping agent and a desiccant at a reaction temperature of -70°C to +30°C
under a protective gas atmosphere to give a compound of the formula I in which R1 has the meaning given in claim 1, R2 together with R3 is a structure of the formula III
or R2, R3 or R4 is a structure of the formula II or IV, in which R5 to R8 have the meanings given in claim 1, with the exception of hydroxymethyl, hydroxyl and NH2, or wherein a compound of the formula I in which R1 to R4 have the meanings given in claim 1, but R2 or R4 must be hydrogen and R5 to R8 cannot be hydroxyl, hydroxymethyl or NH2, is converted in the presence of an organic solvent with a glycal of the formula VI, in which R5 to R7 have the meanings given in claim 1, with the exception of hydroxymethyl, hydroxyl, NH2, N(CH2CN)2 and NH(CH2CN), with N-iodosuccinimide and if appropriate with a desiccant at a temperature of -40°C
to +40°C under a protective gas atmosphere into a compound of the formula I in which R1 has the meaning given in claim 1, R2 together with R3 is a structure of the formula III
or R2, R3 or R4 is a structure of the formula II or IV, in which R5 to R8 have the meanings given in claim 1, with the exception of hydroxymethyl, hydroxyl, NH2, N(CH2CN)2 and NH(CH2CN).

13. The process as claimed in claim 9, wherein in (a) the boric acid is phenylboric acid.

14. The process as claimed in claim 9, wherein in (a) the ketone is acetone.

15. The process as claimed in claim 9, wherein in (a) the ketal is 2,2-dimethoxypropane.

16. The process as claimed in claim 9, wherein in (a) the acetal is benzaldehyde dimethylacetal.

17. The process as claimed in claim 9, wherein in (a) the suitable organic solvent is toluene or dimethyl formamide or mixtures thereof.

18. The process as claimed in claim 9, wherein in (a) the catalyst is a mineral, carboxylic or sulfonic acid.

19. The process as claimed in claim 9, wherein in (a) the dehydrating agent is 4 .ANG. molecular sieve.

20. The process as claimed in claim 9, wherein in (a) the organic solvent is petroleum ether.

21. The process as claimed in claim 9 or 10, wherein the carboxylic acid anhydride is acetic anhydride or trifluoroacetic anyhydride.

22. The process as claimed in claim 9, wherein in (b) the suitable organic solvent is chloroform, methylene chloride toluene or mixtures thereof.

23. The process as claimed in claim 9, wherein in (b) the base is triethylamine or pyridine.

24. The process as claimed in claim 9, wherein in (c) the suitable organic solvent is chloroform, methylene chloride, dimethyl formamide or toluene.

25. The process as claimed in claim 9, wherein in (c) the catalyst is pare-toluenesulfonic acid.

26. The process as claimed in any one of claim 9 (c), (e) and (l), claim 10 and 12, wherein the desiccant is 4 molecule sieve.

27. The process as claimed in claim 9 (e) or claim 12, wherein R9 is aliphatic acyloxy (C1-C8).

28. The process as claimed in claim 9 (e) or 12, wherein R9 is acetyl, benzoyloxy or para-nitrobenzoloxy.

29. The process as claimed in claim 9 (e), wherein the organic solvent is chloroform, methylene chloride, toluene, ether, dimethyl-formamide, acetone, acetonitrile or nitromethane or mixtures thereof.

30. The process as claimed in claim 9 (e) or claim 12, wherein the catalyst is para-toluene-sulfonic acid or a trialkylsilyl trifluoromethane-sulfonate.

31. The process as claimed in claim 9 (e), (l) or claim 12, wherein the protective gas atmosphere is nitrogen or argon.

32. The process as claimed in claim 9 (f), wherein the suitable organic solvent is chloroform, methylene chloride, dimethylformamide, toluene or methanol.

33. The process as claimed in claim 9 (f) or claim 11, wherein the catalyst is a dilute aqueous solution of carboxylic acids or para-toluene sulfonic acid.

34. The process as claimed in claim 9 (f) or claim 11, wherein the diol is 2-methyl-2,4-pentanediol.

35. The process as claimed in claim 9 (g), wherein the inorganic or organic base is alkali metal or alkaline earth metal hydroxides, sodium carbonate and triethylamine.

36. The process as claimed in claim 9 (g), wherein the solvent is water, methanol, ethanol or tetrahydrofuran or mixtures thereof.

37. The process as claimed in claim 9 (i), wherein the suitable solvent is dimethylformamide.

38. The process as claimed in claim 9 (i), wherein the suitable base is triethylamine.

39. The process as claimed in claim 9 (1), wherein the organic solvent is chloroform, methylene chloride, toluene, ether, acetone or acetonitrile or mixtures thereof.

40. The process as claimed in claim 10, wherein the organic solvent is chloroform, methylene chloride or toluene, or mixtures thereof.

41. The process as claimed in claim 10, wherein the base is triethylamine or pyridine.

42. The process as claimed in claim 10, wherein the suitable organic solvent is chloroform, methylene chloride, dimethylformamide or toluene.

43. The process as claimed in claim 10, wherein the catalyst is para-toluene sulfonic acid.

44. The process as claimed in claim 12, wherein a compound of the formula I is reacted with compounds of the formula V
and VI in the presence of chloroform, methylene chloride, ether dimethylformamide, toluene, acetone, acetonitrile or nitromethane or mixtures thereof.

45. The process as claimed in claim 12, wherein the compound of the formula I is converted in the presence of chloroform, methylene chloride, ether, acetone, acetonitrile or toluene thereof, with a glycal of the formula VI.

46. The process as claimed in claim 9(d), wherein R9 is C l or B r.

47. The use of a compound as claimed in claim 1 in a medicament.

48. A use of a compound according to any one of claims 1 to 8 as a cytostatic agent.

49. A use of a compound according to any one of claims 1 to 8 in cancer therapy.