AU614954B2 - Semi-synthetic rhodomycins, a process for their preparation and their use as cytostatics - Google Patents

Abstract

Novel cytostatically active anthracyclines of the formula I, which are optionally present as a salt of an inorganic or organic acid <IMAGE> in which the radical R<1> is hydrogen or hydroxyl, R<2> is hydrogen, a structure of the formula II or IV or together with R<3> is a structure of the formula III, R<3> is hydrogen, a structure of the formula II or IV or together with R<2> is a structure of the formula III, R<4> is hydrogen, an acyl group, trimethylsilyl, a structure of the formula II or a structure of the formula IV <IMAGE> R<5> in this case is hydrogen, methyl, hydroxymethylene, acyloxymethylene or alkyloxymethylene, R<6> is hydrogen, hydroxyl, acyloxy, alkyloxy, allyloxy, benzyloxy or halogen, R<7> has the same meaning as R<6> and can additionally be NH2, NHacyl, N(alkyl)3, N(CH2CN)2, NH(CH2CN) or azido, and R<8> has the same meaning as R<6>, where the following compounds of the formula I are excepted: 1. R<1>=R<3>=R<4>=H, R<2>= alpha -L-daunosaminyl 2. R<1>=R<3>=R<4>=H, R<2>= alpha -L-rhodosaminyl or its 4'-acyl derivatives 3. R<1>=R<3>=H, R<2>=R<4>= alpha -L-rhodosaminyl or its 4'-acyl derivatives 4. R<1>=OH, R<3>=H, R<2>=R<4>= alpha -L-rhodosaminyl or its 4'-acyl derivatives 5. R<1>=R<2>=R<3>=H, R<4>= alpha -L-rhodosaminyl or its 4'-acyl derivatives.

Description

COMMONWEALTH OF AUSTRALIA614 54 PATENTS ACT 1962-69 COMPLETE SPECIFICATION

(ORIGINAL)

Class I nt. Class Application Number: Lodged: Cor~ielte Specification Lodged: Accepted: Published: lriorlty *Reltited Art 4aeo4 plcn:BHIGWREATEGSLSHF Amdes of Applicant: DE-3N5 ER0 Aarbur ENGedelSCubicoAFTran Actual Inventor: Address for Service: MANFRED GERKEN, CENEK KOLAR, HANS PETER KRAEMER, DIETER HOFFMANN and PETER HERMENTIN EDWD. WATERS SONS, 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.

Complete Specification for the invention entitled: SEMI-SYNTHETIC RHODOMYCINS, A PROCESS FOR THEIR PREPARATION AND THEIR USE AS GYTOSTATICS The following statement is a full description of this invention, including the best methiod of performning it known to ',us ~i-Lli I- 1 BEHRINGWERKE Aktiengesellschaft 87/B 012 Ma 627 Dr.Ha/Bn rt f V I 4 ef 64 4.

Semi-synthetic rhodomycins, a process for their preparation and their use as cytostatirs The invention relates to compounds of the formula I and their salts with an inorganic or organic acid 0 Ho CR4 I 1I I V OH 0 HO R 2 in which: R1 is hydrogen or a hydroxyl group

R

2 is hydrogen or a structure of the formula II or IV or, together with R of the formula III 10 x\ X R3 is hydrogen or a structure of the formula II or IV or, together with R 2 of the formula III,

R

4 is hydrogen, trimethylsilyl, a protective group which is customary in carbohydrate chemistry, preferably acetyl, trifluoroacetyl, benzoyl or substituted benzoyl, such as para-nitrobenzoyl, a structure of the formula II or a structure of the formula IV,

R

5 is hydrogen, methyl, hydroxymethyl, acyloxymethyl, (Cl-C8) or alkoxymethyl (C1-C8),

R

6

R

7 and R 8 independently of one another are hydrogen, la hydroxyL, aLiphatic acyLoxy benzoyLoxy or substituted benzoyLoxy, such as para-nitrobenzoyLaLkoxy (C1-c8), atLyLoxy, benzyLoxy or substItuted benzyLoxy or halogen, and R 7 can furthermore be NH 2 NHacyL (C-C8) N(aLkyL) 2 N(CH2CN)2, NH(CH 2 CN) 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 benzyl idene, the compounds where R 1 =R 2

=R

3

=R

4

R

1 0OH and 15R3R4H R=R 3

=R

4 =H adR=c-L-daunosaminyt is or (%-L-rhodosaminyL or 4'-acyt-ci-L-rhodosaminyl, 4~ 1 0H or H, R =H and R =R =ca-L-rhodosamnyL or 4'-acyL-ci-L-rhodosaminyL and RX=R 2

=R

3 =H and R 4 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 R 1 in which position 7 and position are Linked a-gLycosidicaLLy with L-rhodosamine or in which only position 7 is Linked ct-gLycosidicaLLy with Lrhodosamine or L-daunosamine, and 0-iso-rhodomycins (structures of the formula I where R 1 0OH) in which position 7 and 10 are each Linked with a-L-rhodosamine, and the photoLytic mono-demethyLation products of these Lrhodosamine gLycosides and 0-rhodomycinone with oLigosaccharide side chains on positions 7 or 10 or on 7 and which are called cytorhodins. The microbial gLycnsidation of a trisaccharide consisting of L-rhodosarnine, L-deoxyfucose and cineruLose A on the 7-position of the 0-rhodomycinone is known from Journal, of Antibiotics 33, 1331 (1980).

r -3 No chemical glycosidation process for 0-rhodomycinone or B-iso-rhodomycinone has as yet been described. Because of the many glycosidation possibilities of the three hydroxyl groups in the A ring of the B-rhodomycinone (structure of the formula I where R1=R 2

=R

3 selective glycosidations are incomparably more difficult.

Surprisingly, it has been found that B-rhodomycinone and B-iso-rhodomycinone can be glycosidated selectively using certain protective groups on positions 7, 9 and 10 and the glycosides thus obtained, in particular r3 acosaminyl-B-rhodomycinone or 7-O-(3'-N,N-dimethyL-~-LacosaminyL)-B-rhodomycinone have a cytostatic activity comparable to that of adriamycin.

The present invention is therefore based on the object 15 of preparing, starting from the 8-(iso-)rhodomycinones obtainable biologically, novel mono-, bis- and trisglycosyl-B-(iso-)rhodomycinords which are distinguished 4 6a by cytostatic activity and are therefore suitable for the 4*4* treatment of tumors.

20 This object has been achieved by preparation of compounds of the abovementioned formula I with the definitions given there for R to R 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 R given therein, the group of compounds following a group of compounds is in each case preferable to that group.

1) R to R have the meanings given.

2) R and R 4 have the meanings given, R 2 and R independently of one another are hydrogen or a -4 structure of the formula II or IV with the meanings given for R 5 to R 8 3) R 1 is hydrogen and the other definitions are as under 2).

4) R 3 is hydrogen and the other definitions are as under 2).

R and R4 have the meanings given and R 2 and R independently of one another are hydrogen or a structure of the formula II or IV, in which R is methyl,

R

6 and R 7 have the meanings given and R 8 is hydrogen or halogen.

0 ,04 6) R is hydrogen and the other definitions are as O .0 under 04-0 S7) R is hydrogen and the other definitions are as o0 15 under 5).

8) R and R 4 have the meanings given and R 2 and R 0 independently of one another are hydrogen or a structure of the formula II or IV, in which R 5 is methyl, R 6 has the meaning given, R is NH 2 S 20 NHacyl (C1-C8), NCalkyl) 2 (C1-C8), N(CH 2

CN)

2

NH(CH

2 CN) or azido and R 8 is hydrogen or halogen.

4440 9) R is hydrogen and the other definitions are as under 8).

R

3 is hydrogen and the other definitions are as under 8).

11) R and R 4 have the meanings given and R 2 and R independently of one another are hydrogen or a structure of the formula II or IV, in which R 5 is R6 78 methyl, Rand R have the meanings given and R 8 is hydrogen or halogen, and the structures of the formula II or IV belong to the L-series of carbohydrates.

12) R I is hydrogen and the other definitions are as under 11).

13) R is hydrogen and the other definitions are as under 11).

14) R and R 4 have the meanings given and R 2 and R independently of one another are hydrogen or a structure of the formula II or IV, in which R 5 is -C

J

5 methyl, R 6 has the meaning given, R 7 is NH 2 NHacyl (C1-C8), N(alkyl)2 (C1-C8), N(CH 2 CN)2,

NH(CH

2 CN) or azido and R 8 is hydrogen or halogen, and the structures of the formula II or IV belong to the L-series of carbohydrates.

R

1 is hydrogen and the other definitions are as under 14).

16) R 3 is hydrogen and the other definitions are as under 14).

17) R 1 and R 3 are hydrogen and the other definitions S 44 4' 4 4 44 Itr 4* 46 @4 18) 19) 15 20) 21) 22) 23) 24) 25 26) 30 27) are as under 2).

R

1 and R 3 are hydrogen and are as under R1 and R 3 are hydrogen and are as under 8).

R1 and R 3 are hydrogen and are as under 11).

R

1 and R 3 are hydrogen and are as under 14).

R

2 and R 3 are hydrogen and are as under 2).

R

3 and R are hydrogen and are as under 2).

R

2 and R 3 are hydrogen and are as under

R

3 and R 4 are hydrogen and are as under

R

2 and R 3 are hydrogen and are as under 8).

R

3 and R 4 are hydrogen and the other definitions the other definitions the other definitions the other definitions the other definitions the other definitions the other definitions the other definitions the other definitions the other definitions

I

i are as under 8).

28) 29) 31)

R

2 and R 3 are hydrogen and the other definitions are as under 11).

R

3 and R are hydrogen and the other definitions are as under 11).

R

2 and R 3 are hydrogen and the other definitions are as under 14).

R

3 and R are hydrogen and the other definitions -6 are as under 14).

32) Rif R 2 and R 3 are hydrogen and R4is as under 2).

33) Rif R 3 and R4are hydrogen and R2is as under 2).

34) Rif R 2 and R3are hydrogen and R4is as under 35) Rif R 3 and R4are hydrogen and R 2 is as under 36) Rif R 2 and R3are hydrogen and R4is as under 8).

37) Rif R 3 and R4are hydrogen and R2is as under 8).

38 1

R

2 an 3 aehdonadR 4 i sudr1) 39) R f R 3 and Rare hydrogen and R 2 is as under 11).

94) Rif R3 and R4are hydrogen and R2is as under 14).

41) R f R 3 and Rare hydrogen and R 2 is as under 14).

The invention also relates to a process for the preparation of a compound of the formula I with the definitions given, which comprises first selectively blocking a comnpound of the formula I in which Rhas the meaning initiaLLy given and Rto Rare hydrogen by a structure of the formula III on positions 7 and 9 as described below, a compound of the formula I in which R 2 anR3tghe area trctreofthe formula III bigobtained, and subsequently replacing R 4 =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 which, following selective splitting off of the protective 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 introduction of an acyL group or trimethyLsiLyt group at position 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 deblocking the compound completely or partly and if appropriate modifying it on the amino functions, and only then gLycosidating position 10 and modifying this gtycoside, these steps in detail being carried out by a) reacting a compound of the formula I in which R 1 has 7 the meaning initially given and R 2 to R 4 are hydrogen with a boric acid, such as phenylboric acid, or with a ketone, such as acetone, or a ketal, such as 2,2dimethoxypropane, 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 0 C and the boiling point of the solvent, if appropriate with the addition of a dehydrating agent, such as a 48 molecular sieve, to give a compound of the formula I in which R 1 has the meaning initially given and R 2 together with R 3 form a compound of the formula III, too which is isolated by filtration and by removal of the 15 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 trimethylsilyl trifluoromethanesulfonate in a suitable organic solvent, such as chloroform, methylene chloride, toluene or mixtures thereof, at a temperature between 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

R

1 has the meaning initially given,

R

2 together with R 3 is a structure of the formula III and

R

4 is acyl or trimethylsilyl, c) or, for example, reacting the compound obtained under a) with 3,4-dihdro-2-pyran in a suitable organic solvent, such as chloroform, methylene chloride, dimethylformamide or toluene, in the presence of a 18 catalyst, such as para-toluenesulfonic acid and a desiccant, such as a 48 molecular sieve, at a temperature between -30 0 C and the boiling point of the solvent, to give a compound of the formula I in which R1 has the meaning initially given,

R

2 together with R 3 is a structure of the formula III and

R

4 is a structure of the formula II, where R 5 to R are hydrogen, d) or, for example, reacting the compound obtained under a) with a carbohydrate derivative of the formula V tFt' S V i in which R to to R as suitable protective groups, have the meanings initially given and R9 is halogen, such as Cl or Br, 0-acyl or another i leaving group which is customary for glycosidation reactions, under the conditions customary in carbohydrate chemistry, to give a compound of the formula I in which R has the meaning initially given,

R

2 together with R 3 is a structure of the formula III and R 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 -1 9 F e V

VI

in which to R 8 have the meanings initially given, with the exception of hydroxymethyl, hydroxyl, NH 2

N(CH

2 CN)2 and NH(CH 2 CN) and R9 is acyl which is bonded via oxygen, such as ali- 00o phatic acyloxy (C1-C8), such as acetyl, benzoyloxy or substituted benzoyloxy, such as para- 0600 nitrobenzoyLoxy, 0000 O. 10 in the presence of an organic solvent, such as chloro- 0 0 form, methylene chloride, toluene, ether, dimethylformamide, acetone, acetonitrile or nitromethane or o mixtures thereof, a catalyst, such as para-toluenesulfonic acid or a trialkylsilyl trifluoromethane-

OO

sulfonate, and if appropriate an acid-trapping agent and a desiccant, such as a molecular sieve, at a reaction temperature of -70 0 C to +30 0 C under a protective gas atmosphere, such as nitrogen or argon, to give a compound of the formula I 0 a in which

R

1 has the meaning given,

R

2 together with R is a structure of the formula III and R is a structure of the formula II or IV, in which

R

5 to R 8 have the meanings initially given, with the exception of hydroxymethyl, hydroxyl, NH 2

N(CH

2

CN)

2 and NH(CH 2

CN),

f) and, if appropriate, possibly deblocking the compound 10 of stages b) to e) on positions 7 and 9 by reacting this compound in a suitable organic solvent, such as chloroform, methylene chloride, dimethylformamide, toluene or methanol, with a catalyst, such as dilute aqueous solutions of carboxylic acids or paratoluenesulfonic acid, and if appropriate with a diol, such as 2 methyl-2,4-pentanediol, at a temperature between OOC and the boiling point of the solvent, to give a compound of the general formula I in which

R

1 has the meaning given,

R

2 and R 3 are hydrogen and

R

4 has the meaning given, with the exception of o hydrogen, g) and subsequently, if appropriate, possibly selectively 15 partly or completely deblocking the compound of stage f) in which R is a structure of the formula II or IV with, as radicals R 5 to R 8 one of the protective groups customary in carbohydrate chemistry, in a manner which is known per se on the protected hydroxyl func- 00 S 20 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, S 25 methanol, ethanol or tetrahydrofuran or mixtures thereof, to give a compound of the formula I in which R is hydrogen or hydroxyl,

R

2 and R 3 are hydrogen and R is a structure of the formula II or IV, in which

R

5 is hydrogen, methyl, hydroxymethyl or alkoxymethyl,

R

6 is hydrogen, hydroxyl, alkoxy or halogen,

R

7 is NH 2 N(alkyl) 2 azido, hydroxyl or alkoxy and

R

8 has the same meaning as R 6 but is independent thereof, h) and, if appropriate, reacting the compound of stage g) of the formula I, in which 11

R

1 to R 3 have the meanings given under g) and

R

4 is a structure of the formula II, in which

R

5

R

6 and R 8 have the meanings given under g) and

R

7 is NH2, under the conditions which are known per se for reductive amination, to give the corresponding compound of the formula I in which R to R 3 have the meanings given under g) and R4 is a structure of the formula II, in which

R

5

R

6 and R 8 have the meanings given under g) and

R

7 is N(alkyl)2, or 44* i) furthermore converting a compound of stage g) of the general formula I in which 15 R 1 to R 3 have the meanings given under g) and SR" is a structure of the formula II in which

R

5

R

6 and R have the meanings given under g) and ,i R 7 is NH 2 by reaction with iodoacetonitrile or bromoacetonitrile in a suitable solvent, for example dimethylformamide, in the presence of a suitable base, such ar, triethylamine, into a compound of the formula I in which R to R 3 have the meanings given under g) and R is a structure of the formula II, in which R, R 6 and R 8 have the meanings given under g) and

R

7 is N(CH 2

CN)

2 or NH(CH 2 CN) and k) if appropriate glycosidating the compound formed in stage h) or i) under the conditions already mentioned in stage either only position 7 or simultaneously positions 7 and 9 being glycosidated, depending on the amount of glycosyl donor used, to give i if 12 products which correspond to the general formula I in which R1 has the meaning given, R is a structure of the formula II or IV, in which 5 0 R to R have the meanings initially given, with the exception of hydroxymethyl, hydroxyl, NH 2 N(CH2CN) 2 and NH(CH2CN),

R

3 is hydrogen or corresponds to R 2 and R is acyL, trimethylsilyl or a structure of the general formula II or IV in which R to R have the meanings initially mentioned, with the exception of hydroxymethyL, hydroxyl and NH 2 and, if appropriate, t t a I) converting one of the compounds formed in stage h) or i) with a glycal of the formula VI, in which R to 7 I" R have the meanings given in stage in the ,'resence of an organic solvent, such as chloroform, methylene chloride, toluene, ether, acetone or acetonitrile or mixtures thereof, with N-iodosuccinimide and if appro- S 20 priate with a desiccant, such as a molecular sieve, at t* a temperature from -40°C to +40°C under a protective gas atmosphere, such as nitrogen or argon, into a compound of the formula I in which R has the meaning given and

R

2 is a structure of the formula II, in which R is hydrogen, methyl, acyloxymethyl (C1-C8) or alkoxymethyl (Cl-C8), 6 R is acyloxy, alkyloxy, allyloxy or benzyloxy, R is acyloxy, alkyloxy, allyloxy, benzyLoxy, NHacyL, N(alkyL)7 or azido and R is iodine, and 3 4 R and R 4 have the meanings given in stage and m) if appropriate deblocking the compound formed in stage k) or L) in accordance with the conditions of stage to give a compound of the formula 1 in which RR has the meaning given and i

C

4,44 4 4C 4 44 1 44 @4 13

R

2 is a structure of the formula II or IV, in which

R

5 is hydrogen, methyl, hydroxymethyl or alkyloxymethyl,

R

6 is hydrogen, hydroxyl, alkyloxy or halogen,

R

7 is NH 2 or N(alkyl) 2 azido, hydroxyl or alkoxy and

R

8 has the same meaning as R 6 but is independent thereof,

R

3 is hydrogen or corresponds to R 2 and

R

4 is hydrogen, trimethylsilyl or a structure of the general formula II or IV, in which

R

5 is hydrogen, methyl, hydroxymethyl or alkoxymethyl,

R

6 is hydrogen, hydroxyl, alkoxy or halogen,

R

7 is NH2, N(alkyl) 2

N(CH

2

CN)

2 or NH(CH 2

CN),

15 azido, hydroxyl or alkoxy and R has the same meaning as R 6 but is independent thereof, or n) also deblocking the compound formed in stage k) or I) under the conditions of stage g) so that only position 10 is selectively deblocked, to give a compound of the formula I in which R has the meaning given,

R

2 is a structure of the formula II or IV, in which

R

S to R 8 have the meanings initially given, with the exception of hydroxymethyl, hydroxyl and NH 2

R

3 is hydrogen or corresponds to R 2 and

R

4 is hydrogen, o) and subsequently, if appropriate, converting the compound of stage in which R 2 is a structure of the formula II where R 7 is NH 2 and R 3 is hydrogen or

R

2 into the corresponding compounds in which R 6 is N(alkyL)2, again in the manner of reductive amination described for stage or, if appropriate, p) converting a compound of stage m) in which R 2 is a structure of the formula II, where R is NH2 and R 4 4 4P 4 44 4 4444 4444 44,4.

4444 9 4*44 4 4I 4 4 4 4 4 44 4 44 44 4 4 4 14 is hydrogen or R 2 into the corresponding cyanomethyl derivatives in which

R

7 is N(CH 2

CN)

2 or NH(CH 2 CN) in accordance with the conditions of stage and, if appropriate, q) glycosidating a compound of stage n) under the conditions already given in stage either only position 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 R is hydrogen or

R

2 is a structure in which

R

5 to R 8 have the exception of

R

3 is hydrogen or R is a structure in which

R

5 to R 8 have the exception of 20 N(CH 2 CN)2 or hydroxyl and of the general formula II or IV, meanings initially given, with the hydroxymethyl, hydroxyl and NH2,

R

2 or R and of the general formula II or IV, meanings initially given, ith the hydroxymethyl, hydroxyl, NH 2

NH(CH

2 CN), and, if appropriate, r) also carrying out the reaction of stages d) and I) on a compound of stage n) so as to give a compound of the formula I in which

R

1 has the meaning initially given and R is a structure of the formula II or IV, in which

R

5 to R 8 have the meanings initially given, with the exception of hydroxymethyl, hydroxyl and NH 2

R

3 is hydrogen or R or R 4 and R is a structure of the general formula II or IV in which R to R 8 have the mcanings initially given, with the exception of hydroxymethyl, hydroxyl, NH 2

N(CH

2

CN)

2 and NH(CH 2 CN), and, if appropriate, s) deblocking this compound of stage q) or r) again as 15 described in stage to give a compound of the formula I in which R' has the meaning initially given and R R and R independently of one another are hydrogen or a structure of the formula II or IV, in which 5 8 R to R have the meanings initially given, with the exception of acyloxymethyl, acyloxy, benzoyloxy or substituted benzoyloxy or NHacyl, and, if appropriate, lt rae ti

II

at a ta tt at I 1 4r t) converting the compound of stage s) into the corresponding derivative in which the radical R 7 which in stage s) was an NH2 group, is converted into N(aLkyl) 2 by means of reduction amination in 15 accordance with stage or u) moreover converting a compound of stage s) into the corresponding cyanomethyl derivative in which the radical R 7 which in stage s) was an NH 2 group, into NH(CH 2 CN) in accordance with the conditions of 20 stage i), v) and, if appropriate, reacting a compound of the formula I in which R R2 and R3 have the meanings given and R is trimethylsilyl, with tetrabutylammonium fluoride in an organic solvent, such as tetrahydrofuran, diethyl ether, dioxane or mixtures thereof, at temperatures between -40 0 C and the boiling point of the solvent, to give a compound of the formula I in which R, R and R have the meanings given above and R is hydroxyl, w) and, if appropriate, converting compounds of the formula I in which R R R and R have the meanings given and R 7 is NH 2 N(alkyl) 2 (C1-C8), N(CH 2

CN)

2 S16 or NH(CH 2 CN) in.o 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 HCL, or an organic acid, such as ilutamic acid or glucoronic acid, as the active substance.

Such a compound can be processed together with the customary 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.

f* The medicaments prepared in this way can also additionally contain other active substances as Long as these do S' not exhibit undesirable side effects together with the compounds according to the invention.

ii The invention also relates to a composition containing a compound of the formula I, with the definitions and exceptions given, and a carrier substance.

The invention furthermore relates to the use of a compound of the formula I, with the definitions and exceptions 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 following incubation for 1 hour or over several generations. At a cell cycle

A~

;r r 17 time of 10-12 hours, about 14 successive generations are thereby observed over the test period of 7 days. In this test, the cytostatic substances according to the invention effect 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 different concentratiors of the test substance at 37 0 C for 1 hour. The cells were then washed twice with medium and finally poured into Petri dishes, after addition of 0.3% 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 it .achieve continuous exposure of the cells over the entire I incubation period. After the agar had solidified, the plates were incubated in an incubating cabinet at 37 0

C

for 7 days by volume of CO2, 95% relative atmospheric humidity). The number o. colonies formed with a diameter of more than 60 pm was then counted. The results were stated as the number of colonies in the treated agar S 25 plates as a percentage of the untreated control. The

IC

50 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.

18 Table 1, Part 1: Substance No. Long-term 1 hour incubation (Example) incubation ICS 0 (pig/mL)

IC

50 (jig/mL) Adriamycin 0.02 0.04 8 >1 9 0.6 0.9 ,,12 0.5 >1 13 0.03 >1 14 0.024 .04 .0 0.004 0.02 17 0.004 0.09 is 0.13 7 19 0.11 21 0.5 >1 >1 >1 27 >1 711 28 )1 71 29 >10 >1 0.5 1

V.

I

19 Table 1, Part 2: Substance No.

(Example) Long-term incubation

IC

5 0 (pg/mi 1 hour incubation

IC

50 (jig/mL) 0.026 >1 1 >1 0.85 0.16

II

-3' 1 0.09 >1 >1 >1 ,,1 >1 >1 0.29 0.11 0.095 71 tie.

tie, eel.

C

C t it I I I It

I-

'4 1 itt,

'I

0.1 0.4 0.68 0.66 0.0o5 0.04

I:

20 Examples The structures of the compounds prepared were determined by means of 1 H- and 13 C-NMR spectroscopy, incorporating two-dimensional NMR methods and other multi-pulsed techniques, as well as MS and IR spectroscopy. 'The course of the reaction and the resulting compounds were investigated by thin layer chromatography or by the high performance liquid chromatography technique.

The following examples illustrate the invention in more detail without Limiting it: e Example 1: te 7,9-O-Phenyl-boronyl-B-rhodomycinone (1) (Compound of the formula I where R=R4=H and R 2 and R where X=phenylboronyl) A solution of B-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 49 molecular sieve (3 g) for 9 hours, the reaction being monifF 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%) -I 21 Example 2: 7,9-0-Isopropylidene-B-rhodomycinone (2) (Compound of the formula I where R =R =H and R 2 and R3=X, where X isopropylidene) para-Toluenesulfonic acid (150 mg) was added to a solution of B-rhodomycinone (300 mg 0.78 mmoL) in 30 ml of dry N,N-dimethylformamide (130 ml) and 2,2-dimethoxypropane (36 ml) and the mixture was stirred on a rotary evaporator at 50 0 C under 320 mbar for 60 hours, further 2,2-dimethoxypropane (35 ml) being added. After the solution had been concentrated, the residue was taken up S' in methylene chloride, the mixture was extracted by shaking with aqueous sodium bicarbonate solution and the extract was dried and concentrated. Separation by column 15 chromatography (mobile phase: chloroform/acetone/acetic Sacid/water/triethylamine 95:5:1:0.25:0.1) gave the Sproduct in crystalline form.

Yield: 150 mg (0.35 mmol Example 3: 'ttt 7-9-0-Benzylidene-B-rhodomycinone (3) 1 4= 2 (Compound of the formula I where R =R H and R and R where X benzylidene) para-Toluenesulfonic acid (10 mg) was added to a solution of B-rhodomycinone (30 mg 0.08 mmol) in dry N,N-dimethylformamide (5 ml) and benzaldehyde dimethyl acetal (2 ml) and the mixture was stirred on a rotary evaporator at 50°C under 50 mbar for one hour. After the solution had ueen concentrated, the residue was taken up in methylene chloride, the mixture was extracted by shaking with aqueous sodium bicarbonate solution and the extract was dried and concentrated.

*4 22 Yield: 35 mg (0.07 mmol The two exo/endo-isomers can be separated by chromatography (mobile phase: totuene/methanol 10:1).

Example 4: 10-0-TrifluoroacetyL-0-rhodomycinone (4) (Compound of the formuLa I where R 1

=R

2

=R

3 =H and R 4 trifluoroacetyl) Trifluoroacetic anhydride (4 mL 283 mmol) and triethylamine (0.2 mL) were added to a solution of 7,9-0-phenylboronyL-$-rhodomycinone (compound 1) (230 mg 0.49 mmol) Cfec in dry methylene chloride (50 ml) at 0OC and the mixture was stirred at DOC for 30 minutes.

too* After the solvent had been stripped off and the residue had been concentrated several times with toluene, the residue was dissolved in methano and the solution was brought to pH 2.5 with hydrochloric acid, the product precipitating out after stirring for 4 hours. The precipitate was dissolved in methylene chloride, the solu- £199 tion was washed with water and, after drying, the organic phase was concentrated.

Yield: 150 mg (0.31 mmol 63%) Example 10-TetrahydropyranyL-8-rhodomycinone (Compound of the formula 1 where R 1

=R

2 =R3=H and R4= structure II where R5=R 6 =R7=R 8

H)

A catalytic amount of para-toluenesulfonic acid (20 mg) was added to a solution of 7,9-0-phenyboronyt-8-rhodomycinone (500 mg 1.06 mmol) and 3,4-dihydro-2H-pyran (2.5 mL) in dry methylene chloride (125 ml) with 49 I i -23 molecular sieve and the mixture was stirred at room temperature 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 S sodium bicarbonate solution and with water and the extract was dried over sodium sulfate. Separation by r" column chromatography (mobile phase: toluene/methanol 10:1) gave the pure product.

i Yield: 210 mg (0.45 mmol 42%) Example 6: 0 -O-Trimethylsilyl-8-rhodomycinone (6) (Compound of the formula I where R =R =R H and R trimethylsilyl) Trimethylsilyl trifluoromethanesulfonate (110 ul) was added to a solution of 7,9-0-phenylboronyl--rhodomycinone (100 mg 0.21 mmol) and pyridine (85 jl) in dry methylene chloride and 49 molecular sieve at -40 0 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 ~c I

I

QDKEY~Bls~C-~'r~;CXPiscF--t-~_ tir~3~:' iii-- 24 dissolved in dry methylene chloride (10 ml), 2-methyl- 2,4-pentanedio (0.55 ml and glacial acetic acid (0.1 ml) were added and the mixture was stirred at room V 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 52%) Example 7: 10--(4-0-Paranitrobenzoyl-3-N-trifluoroacetyL-a-L- Sacosaminyl)-7,9-0-phenyborony-8-rhodomycinone (7) 1 2 3 (Compound of the formula I where R R and R I!c 4*4 phenylboronyl and R 4 =structure II I-L-acosaminyl 15 where R 5

CH

3

R

6 =0pNBz, R 7 =NHTFA and R =H) A solution of 1,5-anhydro-4-0-paranitrobenzoy-2,3,6-trideoxy-3-N-trifluoroacetyL-L-arabino-hex-1-enitoL (87 mg 0.23 mmoL) in dry methytene chtoride (4 mL) was added to a solution of 7,9-0-phenyborony-8-rhodomycinone (compound 1) (100 mg 0.21 mmol) in dry methylene chloride 'i (8 m) and 49 molecular sieve, and trimethylsilyl trifluoromethanesulfonate (40 pL 0.22 mmol) was added under a protective gas atmosphere (argon) at -40 0

C.

n, After the mixture had been warmed to -20 0 C, it was stirred at this temperature for a further 4 hours and the reaction was then ended by adding triethylamine (80 uil) 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) 4 25 Example 8: 10-0-(4-0-ParanitrobenzoyL-3-N-trif~uoro-acetYL-a-LacosaminyL)-B-rhodomycinone (8) (Compound of the formula I where R=R 2

=R

3 =H and R4 structure II= a-L-acosaminyL where R 5 CH3, R 6 OpNBz,

R

7 =NHTFA and R 8

=H)

A solution of the crude mi-xture of compound 7 (180 mg 0.21 mmoL) in dry methyLene chloride (20 ml) was stirred with 2-methyL-2,4-pentanedioL (3.2 mW 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 o Example 9: 00 10-0-(4-O-ParanitrobenzoyL-3-N-trifLuoroacetyL-a-L- 0:06 daunosaminyL)-B-rhodomycinone (9) (Compound of the formula I where R 1

=R

2

=R

3 =H andR4 structure II c-L-daunosaminyL where R 5 =CHS, R 6 =OpNBz,

R

7 =NHTFA and RS=H) 7,9-0-PhenyL-boronyL-8-rhodomycinone (compound 1) (150 mg 0.318 mmoL) and 1,4-di-O-paranitrobenzoyL-3-NtrifLuoroacetyL-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 dlebLocked in accordance with the instructions of Example 8 for the purpose of splitting off the boric acie ester.

26 Yield: 180 mg (0.24 mmL Example 10-0-a-L-Acosaminyt-6-rhodomycinone (Compound of the formula I where R 1 R2=RR3=H and R= structure II= a-L-acosaminy where R 5

=CH

3

R

6 =0H,

R

7

=NH

2 and R8H) A solution of compound 8 (36 mg 47 pmol) in methano (2 ml) and 0.5N 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 too' times. The aqueous phase was neutralized with sodium bicarbonate solution and extracted by shaking with chloroform several times. This chloroform phase was dried with sodium sulfate and concentrated.

Yield: 17.5 mg (34 Vmol 72%) Example 11: *l1 10-0-a-L-Daunosaminy-B-rhodomycinone (11) (Compound of the formula I where R 1

=F

2

=R

3 =H and R 4 structure IIra-L-daunosaminyL where R 5

=CH

3

R

6

=OH,

R =NHz and R 8

H

Compound 9 (53 mg 70 imol) was deblocked and the product was worked up in accordance with the conditions described for Example Yield: 23 mg (45 Umol 64%) -27- Example 12: 10-O-(3-N,N-DimethyL-a-L-acosaminyL)-$-rhodomycinone (12) (Compound of the formuta I where R=R 2 =R 3 =H andR4 structure II=m-L-acosaminyL where R 5

=CH

3

R

6 0OH, R 7 N(CH3)2 and R 8

=H)

A solution of compound 10 (23 mg 42 jimoL) in methanol (2 Wl is stirred with sodium cyar.oborohydridle (16 mg 250 jimoL) and formalehydle (63 iiL, 37% strength 860 jjmoL) 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).

Yiel: 15 mg (28 limoL 67%) Example 13: 7-0-(4-O-ParanitrobenzoyL-3-N-tr ifLuoroacetyL-ct-L-acosaminyL)-10-O-trifLuoroacetyL-B-rhodomycinone (13) (Compound of the formula I where R 1

=R

3

R

4 =tr ifLuoroacetyL and R 2 =structure II=ct-L-acosaminyL where R5=CH 3

R

6 =OpNBz, R 7 =NHTFA and R 8

=H)

Compound 4 (90 mg 0.19 mmoL) was reacted under the Sete'conditions described in Example 7.

Crude yield: 150 mg (0.18 mmol Example 14: (4-0-Par an itrobenzoyL-3-N-trif LuoroacetyL-a-L-a cosaminyL)-S-rhodomycinone (14) (Compound of the formula I where RlR=4Hand R 2 structure II=a-L-accsaminyL where R 5

=CH

3

R

6 =OpNBz,

R

7 =NHTFA and R 8

=H)

F 28 A solution of compound 13 (100 mg 0.12 mmol) in methano (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 hydrochloric acid and the solvent was distilled off. The residue was taken up in methylene chloride and the mixture was washed with water, dried over sodium sulfate and concentrated.

Crude yield: 85 mg (0.11 mmol 92%) Example I 7-0-a-L-Acosaminyl-B-rhodomycinone 1 3=R4= and R2 I (Compound of the formula I where R 1

=R

3 4 H and R structure II=a-L-acosaminy where R 5

=CH

3

R

6 =OH, R=

SNH

2 and R =H) Compound 14 (27 mg 35 jmo) was deblocked and the product worked up in accordance with the conditions desa cribed for Example I Yield: 15 mg (29 Umol 83X) Example 16: 7-0-(3-N,N-Dimethyl-a-L-acosaminyl)-$-rhodomycinone (16) 1 3= 4= 2= (Compound of the formula I where R =R R H, R 6 7, structure II=t-L-acosaminy whe-e R CH 3 R =0H, R N(CH3) 2 and R 8

=H)

Compound 15 (15 mg 29 umol) was reacted under the conditions of Example 12.

Yield: 13 mg (24 Vmol 83%) -29- ExampLe 17:1 7-O-(3-N-CyanomethyL-cz-L-daunosaminyL)-$-rhodomyc inane (17) (Compound of the formuLa I where R 1

=R

3

=R

4 H and R 2 structure Il=ct-L-daunosaminyL where R 5 =CH3, R 6

=H,

R =NH(CH 2 CN) and R =H) (200 mg 0.39 mmol) was dlissolved in dry N,N-dimethylformamide (30 ml) and, after addition of triethyLamine (0.16 ml) and iodloacetonitrite (0.283 ml), the mixture was stirred at room tern perature for 15 hours. The reaction mixture was then evaporated under a high vacuum and the residue was puniit'. fied by column chromatography over 50 g of silica gel (eLuting agent: nethyLene chloridle/acetone/acetic acid= 5 :2 :1) Yiel: 157 mg (0.28 nimoL 73%) MS: M+H 555 rxampLe 18: %Ott7-0-(4-O-Parani trobenzoyt-3-N-tr ifLuoroacetyL-a-L-daunosaminyL)-10-O-trifLuoroacetyL-0-rhodomycinone (18) (Compound of the formula I where iluro acetyL and R=structure II=a-L-daunosaminyL where

R

5

=CH

3

R

6 =OpNBz, R 7 =NHTFA and R 8

H)

(500 mg =1.03 mmoL) was dlissoLved in a mixture of methyLene chloridle and acetone 40 ml). Molecular sieve (49, dried powder, 500 mig) and 1,4-di-O-parani trobenzoyL-3-N-tr if Luoroacetyt-L-daunosamine (1.1 g 2.06 nimot) were added to the solution and the mixture was cooled to -30 0 C, with excLusion of atmospheric humidity. TrimethytsityL triftuoromethanesutfonate (0.9 ml 5.15 nimot) was added dropwise to the stirred suspension. After 2 hours, trieothyLamin. (0.8 Wl 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 umoL Example 19: 7--4-0-Pa ran it robenzoyL-3-N-tr if Luoroacety L-cs-L-daunosaminyL)-B-rhodomycinone (19) a(Compound of the formula I where R 1 =R 3

=R

4 =H and R 2 structure HIm-L-daunosaminyL where R =CH 3

R

6 =OpNBz, R =NHTFA and R =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) wa's then added L dropwise (pH After 3 hours, the solution was neutralized with 0.1 N aqueous hydrochloric acid and evaporated in vacua. The product, which is uniform according to thin Layer chromatography, was purified by column chromatography over 200 g of silica gel 60/35-70 {1 supplied by Amicon (mobile phase: methyLene chLoride/ acetone =15:1 to 5:1).

Yield: 570 mg (0.75 mmoL= 97%) Example 7--4-0-Pa ran it robenzoyL-3-N-tr ifLuo roacetyL-ci-L-daunosaminyL )-10-0-tetrahydropyranyL-B-rhodomyc inane (Compound of the formula I where R 1

"R

3

R

2 =st ructure UIa-L-daunosaminyL where R 5

CH

3

R

6 =OpNBz, R 7

NHTFA

311 31 and R and R =3tructure II wnere R 5 =R R 7 R8=H) Compound 19 (150 mg 0.2 mmol) was dissolved in methyLene chloride (20 Paratoluenesulfonic acid (10 mg) and 3,4-dihydro-2H-pyran (2 ml) were added at room temperature, 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 mmo 89%) Examrple 21: eta.

7-0-a-L-Daunosaminy-10-0-tetrahydropyrany--rhodomycinone (21) 15 (Compound of the formula I where R =R 3 H, R 2 structure 6 7 II=a-L-daunosaminy where R 5

=CH

3

R

6

R

7

=NH

2 and 4,4 5 6R=8H R and R 4 =structure II where R =R 6

=R

7

R

8

=H)

Compound 20 (150 mg 0.17 mmol) was dissolved in chioroform/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 hydrochloric 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 82%) Example 22: 7-0-(3-Azido-4-0-paranitrobenzoy-2,3,6-trideoxy-i-Larabinohexopyranosyl)-10-0-trifluoroacetyL-0-rhodomycinone (22) 32 (Compound of the formula I where R =R 3 =H and R2= structure II=c-L-2,3,6-trideoxyarabinohexopyranosyL where R 5

=CH

3

R

6 =OpNBz, R =N 3 R =H and R =trifluoroacetyl) Compound 4 (100 mg 0.21 mmol) was dissolved in a mixture of methylene chloride and acetone 5:1 (10 and molecular sieve 49 (100 mg) was added as a dried powder.

After addition of 3-azido-2,3,6-trideoxy-4-0-paranitrobenzoy-L-arabino-1-hex-1-enitol (127 mg 0.42 mmol), dissolved in methylene chloride (5 ml), the mixture was cooled to -30 0 C and trimethylsilyl trifluoromethanesulfonate (46 mg 0.21 mmol) was added. The reaction temperature was raised to -10 0 C after 4 hours. Further 3-azido-2,3,6-trideoxy-4-0-paranitrobenzoyl-L-arabino-1- 15 hex-1-enito (36 mg 0.21 mmol), dissolved in methylene chloride (25 ml) was then added. After a further 16 hours, the reaction mixture was neutralized with triethylqo amine, filtered and evaporated. The resulting crude product was purified by column chromatography (silica gel; eluting agent: methyLene chloride) 0 Yield: 127 mg (0.16 mmo 77%) Example 23: 7-0-(3-Azido-2,3,6-trideoxy-a-L-arabinohexopyranosyL)rhodomycinone (23) 3 4, 2= (Compound of the formula I where R 1 =R R =H and R structure II=a-L-2,3,6-trideoxy-arabinohexopyranosyL 5 6 7, 8 where R =CH 3 R =OH, R =N 3 and R =H) Compound 22 (100 mg 0.13 mmol)was dissolved in chloroform/methanol 1:1 (10 mi), 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 mixturewas evaporated to 33 dryness again. The resulting productwas dissolved in chloroform/methanol 3:1 and the insoluble constituents were filtered off. After the filtratehad been concentrated, the crude productwas purified by column chromatography over 50 g of silica gel (methylene chloride/ acetone 10:1) Yield: 53 mg (0.098 mmol Example 24: 7-0-(3,4-Di--acety-2,6-dideoxy-2-iodo-a-L-taLopyranosyl)-10-0-tetrahydropyranyl-8-rhodomycinone (24) (Compound of the formula I where R 1

=R

3

R

2 =structure XI=2,6-dideoxy--L-taopyranosy where R 5

CH

3

R

6

=R

7 =OAc 8t 4; 5= 6=R78=H and R and R =structure II where R R =RH) N-Iodosuccinimide (36 mg 0.16 mmol) was added to a 15 solution of compound 5 (30 mg 0.06 mmol) and 3,4-di-Oacety-1,5-anhydro-2,6-dideoxy-L-Lyxo-hex-1-enitoL (26 mg 0.12 mmol) in 3 ml of dry acetonitrile with r activated 3 A molecular sieve at -10 0 C under a protec- Stive gas atmosphere (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, S 25 dried and purified by chromatography (mobile phase: totuene/methanol 10:1).

Non-optimized yield: 10 mg (0.013 mmol

V

4 p 1 -34- Example 7-,-(,4-D1-0-accety-2,6-dideox y-2-iodo--L-mannopyran syL)-10-0-tetrahydropyranyL-B-rhodomycinone (Compound of the formula I where R 1

=R

3

R

2 =structure II=2,6-dideoxy-Q-L-mannopyranosyL where R 5

=CH

3

R

6

=R

7 OAc and R and R 4 structure II where R 5

=R

6

=R

7

=R

8

=H)

Compound 5 (70 mg 0.15 mmoL) was reacted with 3,4-di- O-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 umol 37%) Example 26: too: 7-0-(3,4-D i-0-acetyL-2,6-dideoxy-2-iodo-a-L-manno-

S;C,

0#00 pyranosyl)-B-rhodomycinone (26) (Compound of the formula I where R 1

=R

3

=R

4

R

2 structure II= 2,6-dideoxy-e-L-mannopyranosyL where R

CH

3

R

6

=R

7 =OAc and R 8 =1) Acid ion exchanger (Dowex 50 WXS) was added to a solution ALI? 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 Example 27: 7,10-Di-o-(4-0-paranitrobenzoy-3-N-trifLuoroacetyL-a-Ldaunosaminyl)-S-rhodomycinane (27) (Compound of the formula I where R 1

=R

3 =H and R 2 structure IIcL-L-daunosaminyl where R 5

=CH

3

R

6 =OpNBz,

R

7 =NHTFA and R 8

=H)

Compound 9 was reacted with 1,4-di-0-paranitrobenzoyL-3- N-triftuoroacetyL-L-daunosamine and trimethyLsi LyL trifLuoromethanesutfonate and the product worked up analogousLy to Exampte 7.

ExampLe 28: 7,1O-Di-0-(4-0-acetyL-3-N-trifLuoroacetyL-E-L-daunosaminyt)-S-rhodomycinone (28) (Compound of the formula I where R 1

=R

3 =H and R 2

=R

4 structure ll=ct-L-daunosaminyL where R 5

=CH

3

R

6 =OAc,

R

7 =NHTFA and R 8

=H)

Compound 1 was reacted w'ith 1,4-di-0-acetyL-3-N-triftuoroacetyL-L-daunosamine and trimethyLsiLyL trifluoromethanesutfonate analogously to Example 7 and the product was then dlebLocked at positions 7 and 9 analogously to Example 8 and reacted with 1,d-di-O-acetyL-3-N-trifLuoroacetyL-L-daunosamine and trimethylsiLyL trifLuoromethanesuLfonate again analogously to Example 7.

t Example 29: 4 St 7,10-Di-0-a-L-daunosaminyL-B-rhodomyc inone (29) t I 3 H an 2= tit. 20 (Compound of the formuta I where R 1

=R

3 HadR= 4 structure II=(%-L-daunosaminyL where R 5

=CH

3

R

6 QOH, R 7

NH

2 and R 8

=H)

Compound 27 was dleblocked and the product worked up in accordance with the conditions described for compound Compound 7,10-O-Di-(3-N-cyanomethyL-a-L-daunosaminyLU-O-rhodomycinone (Compound of the formula I where R 1

=R

3 =H and R 2

R

4 structure IIot-L-daunosaminyL where R 5

=CH

3

R

6

=OH,

R 7

=NH(CH

2 CN) and R 8

=H)

-36 The compound described in the titte was prepareiJ analogously starting from compound 29 (132 mg 0.2 mmol) and iodoacetonitriLe (0.15 mW, as already described in Example 17.

Yiel: 76.6 mg (0.11 mmol 53%) MS: M+H +=723 ExampLe 31: 7,10-Di-o-(4-O-paranitrobenzoyL-3-N-trifLuoroacetyL-c-L- 1 cosaminyl)-B-rhodomycinone (31) 1 (Compound of the formula I where R 1 RHan structure II~a-L-acosaminyL where R CH 3 R OpNBz,

R

7 =NHTFA and R 8

=H)

Compound 8 was reacted and the product worked up anaLogously to ExampLe 7.

Example 32: 7,10-Di-0-(4-O-acetyL-3-N-trifLuoroacetyL-a-L-acosaminyL S-rhodlomycinone (32) (Compound of the formula I where R=3Hand R=4 structure 11oa-L-acosaminyL where R 5

=CH

3

R

6 =OAc,

R

7 =NHTFA and R 8

=H)

Compound 1 was reacted with 1,4-di-O-acetyL-3-N-trifLuoro- L acetyL-L-acosamine analogously to Example 28.

Example 33: 7,010-D i-O-(x-L-acosaminyL-B-rhodomyc inone (33) (Compound of the formula I where R'=R 3 =H and R=4 structure II= a-L-acosaminyL where R 5

=CH

3

R

6 =OH, R 7

NH

2 and R 8

=H)

-37- Compound 31 was dlebtocked and the product worked up analogously to the conditions described for compound Example 34: 7,10-Di-o-(3-N,N-dimethyL-a-L-acosaminyL)-8-rhodomycinone (34) (Compound of the formula I where R 1

=R

3 =H and R 2

=R

4 structure II where R 5

=CH

3

R

6 0OH, R 7

CH

3 2 and

R

8

:H)

Compound 33 was reacted analogously to the conditions of Example 12.

Example rft 7-O-(4-O-Paranitrobenzoyt-3-N-trifLuoroacetyL-t-L-aco- .j saminyL )-10-O-(4-O-paran itrobenzoyL-3-N-trifLuoroacetyLa-L-daunosaminyL)-8-rhodomycinone (Compound of the formula I where R n structure II=a-L-acosaminyL where R 5

=CH

3 R OpNBz, RzNHTFA and R=;and R structure II~a-L-daunot saiy hr H, 6=OpNBz, R 7 =NHTFA and R 8

=H

4. K Compound 9 was reacted and the product worked up anaLo- V g 20 gousLy to Example 7.

Example 36: 7-O-(4-O-AcetyL-3-N-tr ifLuoroacetyL-i-L-acosaminyL itrobenzoyL-3-N-trifLuoroacetyL--L-daunosaminyL)-p-rhodomycinone (36) 1=R3=H, 2=s r c p ~25 (Compound of the formula I where R=RH ~trct II~a-L-acosaminyL where R 5

=CH

3

R

6 =OAc, R 7 =NHTFA and

R

8 and R 4 =structure II=(x-L-daunosaminyL where R 5

=CH

3

R

6 =0pM~z, R 7 =NHTFA and R 8

=H)

Compound 9 was reacted with 1,4-di-O-acetyL-3-N-trifLuoroacetyL-L-acosamine and the product worked up anaLogously -38 to Example 7.

ExampLe 37: 7-0-a-L-AcosaminyL-10-0-ot-L-daunosaminyL-B-rhodomycinone (37) (Compound of the formula I where R 1 =R 3

R

2 =st ructure II=Qt-L-acosaminyL where R 5

=CH

3

R

6 0OH, R 7

=NH

2 and R=;and R 4 structure IlIa-L-daunosaminyL where R 5

CH

3

R

6 =OH, R 7

=NH

2 and 8H Compound 35 was deblocked and the product worked up in accordance with the conditions described for compound ExampLe 38: 7-0-C4-O-BenzoyL-ci-L-rhodosaminyL )-10-O-C4-O-paranitrotic.

#04: benzoyL-3-N-trifLuoroacetyL-a-L-acosaminyL)-B-rhodomyc inone (38) (Compound of the formula I where R 1

=R

3

R

2 =st ructure II=a-L-rhodosaminyL where R 5

=CH

3

R

6 =08z, R 7

=N(CH)

and R 8 =H and R 4 =structure II~c-L-acosaminyL where

CR

6 =OpNBz, R 7 =NHTFA and R 8

=H)

1l 7-0-(4-O-benzoyL-ot-L-rhodosaminyL)-0-rhodomycinone was reacted and the product worked up analogously to ExampLe 7.

444344 Example 39: 10-0-(4-O-ParanitrobenzoyL-3-N-trifLuorodcetyL-L-L-acosaminyL )-7-O-a-L-rhodosaminyL-B-rhodomyc inone (39) (Compound of the formula I where R 1

=R

3 H and R2=structure Il=a-L-rhodosaminyL where R 5

=CH

3

R

6 =OH, R 7

NCCH

3 2 and RH;and R 4 =structure II~c-L-acosaminyL where R 5

=CH

3

R

6 =OpNBz, R 7 =NHTFA and R 8

=H)

7-O-og-L-RhodosaminyL-B-rhodomycinone was reacted and the product worked up anaLogousLy to Example 7.

39 Example 10-0-c-L-AcosaminyL-7-O-ct-L-rhodosaminyL-0-rhodomyc inone (Compound of the formula I where R 1

=R

3 R 2 st ructure II=cx-L-rhodosaminyL where R 5

=CH

3 R 6 OH, R 7 =N(CH3) 2 an 8 =H and R 4 =structure II=cz-L-acosaminyL

C

3

R

6 =OH, R =NH 2 and R 8

=H)

Compound 38 was debLocked and the product worked up analogously to the conditions described for compound Example 41: 10-O-(4-0-AcetyL-2,3,6-tr ideoxy-ca-L-erythro-hex-2-enopyranosyL )-7-O-(4-O-parani trobenzoyL-3-N-trifLuoroaciutyLx-L-daunosaminyL)-$-rhodomycinone (41) s~~j (Compound of the formula I where RR=H Rstuue II=a-L-daunosaminyL where R =HRp~,R HF and R=H; and R 4 =structure IV=a-L-erythro-hex-2-eno- 4 4 4 pyranosyL where R 6 =OAc) Compound 19 (400 mg =0.52 mmoL) was dlissolved in methylene chloridle/acetone (50 ml). After addition of 3,4-di- O-acetyL-L-rhamnaL (225 mg 1.0 mmoL) and molecular sieve 49 (dried powder) (400 mg), the suspension was 4 46 cooled to -40 0 C. TrimethyLsiLyL trifLuoromethanesuLfonate was then added dropwise (60 mg 2.6 mmoL). After 42 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.

Yiel: 180 mg (0.2 mmol= 37%) Example 42: 10-0-(2,3,6-Trideoxy-a-L-erythro-hex-2-enopyranosyL a-L-daunosaminyL-0-rhodomycinone (42) (Compound of the formula I where R 1

=R

3 R 2structure R5-CH3 R6OH, R7=NH 2 andRS II~a-L-daunosaminyL where R-3, and R 4 =s tructure IV~a-L-erythro-hex-2-eno-pyranosyL where R =OH) Compound 41 (100 mg =0.13 nimoL) was dissolved in methanol 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 !;oLv'mnt had been evaporated off, the residue was purified by column chromatography over silica gel (eLuting agent: chloroform/methanol 5:1).

15 Yiel: 60 mg (0.096 mmoL 74%) FAB-MS: m/z 6?8 =M+H ExampLe 43: 7, 9,10-Tr i-0- (4-0-Pa ranit robenzoy L-3-N-tr if Luoroac ety I- V ot-L-acosaminyL)-B-rhodomycinone (43) (Compound of the formula I where R an structure II=a-L-acosaminyL where R=C 3 7 NHTFA and R 8

=H)

Compound 8 was reacted analogousLy to Example 7 but with twice the equimoLar amount of 1,5-anhydro-4-O-paranitrobenzoyL-2,3,6-tr ideoxy-3-N-tr ifLuoroacetyL-L-arabinohex-1-enitoL at 0 0

C.

Example 44: 7,9,10-Tri-O-a-L-acosaminyL-0-rhodomyc inone (44) (Compound of the formula I where RlHand R 2

=R

3

=R

4 structure II~a-L-acosaminyL where R =CH 3

R

6 =H 7 41 8,

NH

2 and R =H) Compound 43 was deblocked and the product worked up analogously to the conditions described for compound MeLting point: 225 0

C

Example 7-O-(3-N-Trifluoroacetyl-a-L-acosaminy)-B-rhodomycinone (Compound of the formula I where R 1

=R

3

=R

4 =H and R2= structure II=ac-L-acosaminyL where R5=CH 3

R

6 =OH, R 7 8 NHTFA and R8=H) A solution of compound 13 (27 mg 32 jimol) in dry s, methanol (2 mL) and 2 drops of methanolic sodium methanolate solution (33% strength) was stirred at room temperature for one hour, neutralized with acid ion exchanger 1 15 (Dowex WX8), filtered and concentrated and the residue Ii was purified by chromatography (mobile phase: methylene t chloride/methanol/formic acid 10 1 0.2).

SYield: 15 ag (25 jmol 78%) Example 46: 7-O-a-L-RistosaminyL-B-rhodomycinone (46) (Compound of the formuLa I where R 1

R

3 =R =H and R2 5 structure II a-L-ristosaminyl where R=CH 3

R

6

=OH,

R

7

=NH

2 and R 9

=H)

Compound 4 was reacted with 1,5-anhydro-4-0-paranitrobenzoyl-2,3,6-trideoxy-3-N-trifluoroacetyL-L-ribo-hex-1enitoL under the conditions described in Example 7 and the product was deblocked P-nder the conditions described in Example Melting point: 217 0

C

MS: M+H+ 516 42 MS: M+H 516 Example 47: 7-0-(3-N-TrifLuoroacetyL-ct-L-ristosaminyL)-8-rhodomycinone (47) (compound of the formula I where R 1 =R 3

=R

4 =H andR2 structure II a-L-ristosaminyL where R5 =CH3, R 6

=OH,

R7=NHTFA and 'R 8

=H)

Compound 4 was reacted with 1,5-anhydro-4-0-paranitrobenzoyL-2,3,6-trideoxy-3-N-trifLuoroacetyL-L-ribo-hex-l- EflitoL u~nder the conditions described in Example 7 and the product was deblocked under the conditions described in Example Melting point: 178 0

C

MS: M+H =612 Example 48: 999 7-0-(4-O-BenzyL-at-L-acosaminyL )-B-rhodomycinone (48) 9.(Compound of the formula I where R 1

=R

3

=R

4 =H and R 2 9 99structure II ci-L-acosaminyL where R 5

=CH

3

R

6 =08n, R 7 N 2 and RB=H) Compound 4 was reacted with 1,5-anhydro-4-0-benzyL-2,3,6tr ideoxy-3-N-trifLuoroacetyL-L-arabino-hex-1-enitoL under the conditions described in Example 7 and the product was 4 9 debtocked under the conditions described in Example MS M+H +=606 -43- ExampLe 49: 7-O-(4-0-8enzyl-3-N-trifLuoroacetyL-a-L-acosaminyL)-Brhodomycinone (49) (Compound of the formula I where R 1

=R

3

=R

4 =H and R 2 structure II e-L-acosaminyl where R 5

=CH

3

R

6 OBn, R 7 NHTFA and R 8

=H)

Compound 4 was reacted with 1,5-anhydro-4--benzyl-2,3,6trideoxy-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 Example 7-0-(2,6-Dideoxy-2-iodo-a-L-mannopyranosyL)-B-rhodomycin- Str one (Compound of the formula I where R 1

=R

3

=R

4 =H and R 2 structure II 2,6-dideoxy-a-L-mannopyranosyL where

CH

3 R 6 H, R 7 =OH and R 8

=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 CDowex WX8), filtered and concentrated.

Melting point: 158 0

C

ExampLe 51: 7,10-Di-o-C4-0-benzyL-a-L-acosaminyL)-Q-rhodomycinone (51) (Compound of the formula I where R 1

=R

3 -H and R 2

=R

4 structure II (x-L-acosaminyl where R 5

=CH

3

R

6 OBn, R 7

=NH

2 and R 8

SH)

Compound 1 was reacted with 1,5-anhydro-4-O-benzyL-2,3,6trideoxy-3-N-trifluoroacetyl-L-hex-1-enitoL analogously t 44 to ExampLe 7, the product was then deblocked on the aglycone analogously to Example 8 and glycosidated again with 1,5-anhydro-4-O-benzyl-2,3,6-trideoxy-3-N-trifLuoroacetyl-L-hex-1-enitoL analogously to Example 7, and the product was debLocked analogously to Example MS: M+H+ 826 Example 52: 7-0-(4-Deoxy-3-N-trifLuoroacetyl--L-daunosaminyL)-8rhodomycinone (52) (Compound of the formula I where RtR 3 =H and R 2

R

4 structure II a-L-daunosaminyl where R 5

=CH

3

R

6

R

7 NHTFA and R 8

=H)

fct Compound 4 was reacted with 1-O-paranitrobenzoyl-4-deoxy- 3-N-trifLuoroacety-L-daunosamine under the conditions described in Example 7 and the product was deblocked under the conditions described in Example Example 53: 7-0-(4-Deoxy--L-daunosaminyl)-Srhodomycinone (52) 1=R3 2=R4= i rrr (Compound of the formula I where R =RH and R R structure II c-L-daunosaminyl where R =CH 3

R

6

R

7

NH

2 and R 8

=H)

Compound 4 was reacted with 1-0-paranitrobenzoy-4-deoxy- 3-N-trifluoroacety-L-daunosamine under the conditions described in Example 7 and the product was deblocked under the conditions described in Example The 1 N-NMR data of some of the novel compounds 1-53 described above are compiled in the following Tables 2 and 3.

'V r- c U i Table 2 1 H-NMR data of various compounds of the formula I The substance numbers in the first lines correspond to the particular example numbers. The chemical shift is stated in ppm, tetramethylsiane 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 4: quartet m: multipet '4 dd: doublet of a doublet ddd: doublet of a doublet of a doubLet dq: doublet of a quartet a) measured at 300 MHz b) B-phenyl 7.4-7.27 m St 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 benzyidene 7.36-7.17m g) tetrahydropyranyl ring H-1 4.91m and 4.99m, ring protons 4.0-3.lm, SAsince the substance is present as a diastereomer mix- 25 ture (R/S on the THP ring some signals are prei sent in duplicate h) measured at 400 MHz i) 0-trimethylsilyl 0.13s k) B-phenyl 7.35-7.17m 1) solvent CDCL3 CD 3 0D m) solvent CDCL 3 d 6

-DMSO

n) N(CH 3 2 2.086 s o) tetrahydropyranyl H-1 5.09dd OAc 2.03s, 2.09s 46 p) tetrahydropyranyL H-i 5.O4dd; ring protons 4.2-3.Om OAc 2.03s, 2.01s q) OAc 2.04s, 2.01s r) solvent CDCL 3 dioxane s) measured at 200 MHz t) benzyt CH 2 4.77d, 4.66d, aromatic benzyL 7.37m u) benzyl CH 2 4.46d, 4.33d, aromatic benzyL 7.29-7.12m v) measured at 90 MHz it qr *644 0**e 6O* 44*4 0~r+ *000t 4bC -7 47 TabLe 2, Part 1: 1 a,b) 2 c 3 aa,de) 3 bald,f) iii.

ti'S **54

C

41*4 I I 4 4' 4,4 4 '4 it S 4 44 H -I H- Z H H-7 H-Sa H-Sb H 1 H-13a H-13b H- -14 3 H-i1 H-2a' H-2e' H-3' H-4't H-6 OH -4 OH -6 OH-il1 OH-7 OH -9 NH TEA pNB: 7.907dd 7.698t .174dd 2 295dd 2. 19dd 4 973 d 2.22-1 .79m 1 .236t 12. 145S 12 .78S 13. 5 5s 7 .82 1d 7 6 45 t 7.262d 5. 279t 2.39dd 2. 13dd 4 .782d 1 95rn I .76m 1 .048t 12.151is 12 .683,- 13 .498s 2 .68d 7 .85dd 7 67 t 7. 29dd S 7dd 2 .3ldd 1 .79d 4 .94d 1 .98-1 .71M 1 98 -1 1 r 1 .07t 12.09s 12.67s 13. 70s 3 .18d 7.82dd 7. 6 4t 7 5 5 4t 2.67dd 216dd 4 84d 1 .99-1 1 .99-1 11 t 11 96s 12 .66s 13 .51S 2.80d 89M 89m 48 TabLe 2, Part 2: c,g) 6 h,i) 7 a,k)

(I

S

t St I #44* 4 4145

I

555554 t S H-1 H- 3 H 7; H-Sa H-Sb H-1 0 H-13a H-13b H--14 H-1' H-2al H-?e' H-3' H-41 H-S H-6 OH -4 OH -6 OH-il1 OH -7 OH -9 OH-i 0

NHTFA

pNB: 7.902dd .7 74 5t .347dd 5.345dt 2 .408dt 2 05;4ddd 6.344d 1 .73m 1 .56m 1 .1 03t 12 .010s 12.806s 13. 345d 3 45 2d 3.756s 7 .78d 7 64t 7.24d 5.19dd/5.14dd 2.30dd 2. 056d 4. 94s/4.81 s 1 .75Sm 1 .75m 1 .03t 11 .97S 12. 81 s 13.66 13 .65 7 .89166d 7 '715St 7.312d6 5 .2 31 t 2 .22866 2 1 46dt 4 .8 226d 1 .718m 1 7,1 Sm 1 .075t 7.776d 5 .680 2.4566 2. 186 4 .956s 1 .83m 1 .83m 1 1St 5 .64d 1 83M 2 12 Tr.

4 .44m 4 '786t 4 1 8dq 1 .27d 12. 032s 12. 114 s 13 .69'ls 12.1 06s 12 .897Is 13 .626s 3 .478d 3. 148S 6 .446 8.34-8. 6.456d 8 .28-8 .08M *I tsr Pa t t a. a.

S 1 4r i It 49 TabLe 2, Part 3: 8 c) 9 h) 10 a,l) 11 h,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-Sa 2.36dd 2.308dd 2.154d 2.125dd H-Sb 2.22U 2.195d 2.06d 2.04d 4.98s 5.020s 4.87s 4.886s H-13a 1.95-1.72 1.85-1.38m 1.82m 1.75m H-13b 1 .95-1.7'm 1 .88-1 .38m 1 .82m 1 .7Gm H--14 1 .16r 1.135t 1.02t 1.01St 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.O9dd 2.16-1.89m 2.09m 2.Olm H-3' 4.48d 4.493m 2.87m 2.9m H-4' 4.82t 5.409 2.87m 3.317s H-5' 4.21dq 4.314q 3.66dq 3.881q H--6 1 I.29d 1.228d 1.236d 1.202d OH-4 12.06s 12.041s OH-6 12.89s 12.894s OH-1i 13.72s 13.735s OH-7 3.54d 3.491d OH-9 3.34s 3.248s

NHTFA

pNBz 1 lable 2, Part 4: 1 2h,n) 13 h) 1 4 h) 15 h,rm)

'I

CI 4 4444 4.4

SI

4 4L 4 4 44 H-1 H-2 H-3 H- 7 H-8a H-Sb H-8b H-13a H- 13b H--14

H-I'

H-2a' H-2e' H-3' H-4'

H-S'

OH -4 OH -6 OH -1 OH -7 OH-9 OH-i 0

NHTFA

pNBz 7. 821d .6.14t 7.24 d 5 .167d 2 .2-2 .09m 2 09m 4.908s 1 .83-1 .66m 1 .85-1 .66m 1 .039t 5 .417d 1.489ddd 2.1 94ddd 2.6Q2ddd 3.01 2t 3 .699dq 1 .268d 7.908d 7.738t 7 .334d 5 .246t 2 .4Odd 2.45d 6.414d 1 .75m 1 .75m 1 .125t 5 .520d 1 .86ddd 2.0iddd 4 .3m 4 .84t 4 .3m 1 .330d 12.002s 12.813s 13 .380s 3.819s 6 .47d 8.25-8. 9m 7.800d 7. 6 22t 7.229d 5 .063c 2.24-1 .99m 2.24-1 .99m 4 .854d 1 .86-1 .69m 1 .86-1 .69n 1 .073c 5.419 2.24-1 .99m 2.24-1 .99m 4 .38m 4 .891t 4 .278dq 1 .238d 12.023s 12 .796s 13.551s 3.575s 3 .615d 8.22-8 .09m 7 .78d 7 .64t 7.21d 4 .995t 2 .1 Z.1 4.70s 1.75-1 1 .75-1 0.99t 5. 29d I .49m 1 .94m 2.8m 2 .8m 3.77dq 1 23d a 51 TabLe 2, Part 16 a) 18 h) 19 h,1) 23 hr) H-1 7.79dd 7.74d 7.70d 7.78dd H-2 7.634r 7.65t 7.62t 7.59t H-3 .2-9dd 7.22d 7.17d 7.2dd 5.059dd 5.25d 5.06s 4.96dd H-8a 2.22-2.02m 2.47d 2.13m 2.10m H-Sb 2.22-2.02m 2.Odd 2.13m 2.10m 4.S57d 6.33s 4.78s 4.745 H-13a 1.90-1.52m 1.77m 1.88m 1.75m H-13b 1.90-1.52, 1.53m 1.68mn 1.65m H-14 1 .054t 1 .lot 1 .05t 1 .02t 5. 42d 5.65s 5.53s 5.23dd H-2a' 1 .90-1 .52m 1 .90ddd 1 .92m H-2e' 2.22-2.02m 2.13m 2.1om 1 H-3 2.578ddd 4.48m 4.34m 4.04m H-4' 3.101t 5.49s 5.42s 3.45m 3.657dq 4.48m 4.44q 3.55dq H3-61 1.320d 1.27d 1.16d 1.25d OH-4 11 .84s OH-6 12.68s OH-i 13.22s OH-7 OH-9 3.881s 3.85s NHTFA 6.61d pNBz 8.25m 8.23-n -52- Table 2, Part 6: 2 4 h,O) 2 5 h ,p 2 6 a, q) f;H-1 7.88d 7.90d 7.83d H-2 7. 6 9t '69t 7 .69t H-3 7.30d 7.31d 7.28d H75.12t 5.07t 5.O2dd IH-8a 2 .22d H-Sb 2.1 ldd 4 8s 5.04s 4.88s H -13 a 1. 91 -1 H-13b1.11.0 5.79s 5.37s 5 .71 d H- Za' 44aH-2e' 4.56dd 4 .61 dd 4.66dd j H-3' 4 -7 '1 4.29dd 4.32dd VH-4' 4 .86s 5 .1 6t 5 .1S8t 4.08q 4.04dq 4.17dq IH--6' 1i.21d 1 .24d 1 .29d I OH-4 12.12s 12 1 s 12 .04s OH-6 12.89s 12.90s 12.79s OH-l1 13.78s 13.81s 13.5Ss OH OH-9 3.37s 2.80s

NHTFA---

pNBz -53- TabLe 2, Part 7: 44 a) 45 s) 4 47 a) H-i 7.83dd 7.80d 7.75dd 7.88d H-2 7.65t 7.69t 7.64t 7.73t Hi-3 7.26dd 7.24d 7.l5dd 7.32d H-7 5.22m 5.02t 4.87m 4.96di H-8a 2.20m 2.08m H-8b 2.20m 2.08mn 5.11s 4.82m 4.60s 4.81s H-13a 1.72m 1.78mn H-13b 1.72m 1.78m H -14 0.90t 1.06t 1.04t 1.09t H-i' 5.35d 5.42d 5.35s -2al 2.20m 2.08m H-2el 2.20mn 2.08m H-3' 3.80mn 3.66m 4.39ddd 4 F f t t H-41 3.16t 3.52dd 3.50dd IH-51 3.96dq 4.i4dq H6 1.32d 1.37d 1.34d OH-4 12.08s OH-6 12.79s OH-il 13.59s OH-7 OH-9 OH-iO NHTFA 7.75d -8.01d pNBz I I 54 TabLe 2, Part 8: 48 a, t 49 h,u) 5 0 a) 52 v t I 1.4 4, 0 t09~ 0 qz~, 1640 0 046140 I I 1. 64 It 1.

I It H-1 H-2 H-3 H-7 H-Ba H-8b H- 13 a H-13b H 3 -14 H-1I H-2a' H-2e' H-3' H-4' H-51 H 3 6 OH-4 OH -6 OH-il OH -7 OH-9 OH-iD

NHTFA

pNB z 7.88d 7. 72t 7. 32d 5. 13m 2. 22d 2. 16dd 4.91s 1. 9-1. 5m 1. .9-1 5m 1. lit 5.43d 2. 2-1. 5m 2. 2 5m 3.O9ddd 2.91t 3. 98dq 1. 41d 7. 86d 7. 70t 7.31 d 5.24s 2. 37d 2. 1Dm 5.09s 1. 98m 1. 98M 1. 03t 5.27d 2. 1Dm 2. 19ddd 3. 93m 3.09t 3. 39dq 0. 98d 12.11s 12. B8s 13. 65s 7. 91dd 7. 76t 7. 3Sdd 5.D07d 4. 81d 1. 7m 1 .7m 1.08~t 5.71s 4.45dd 3. 97'd 1. 38d 12.1l8s 12. 93s 13. 72s 7. 92dd 7.71t 7.28dd 5. 12t 4. 1 13t 5. 52d 4. 2m 4. 2m 1. 28d1 12. 14s 12.77s 13. 52s 2.68d 5. 92d 6.09d 55 Table 3 1 H-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 CDCL 3 as the solvent.

Abbreviations: s: singlet d: doublet t: triplet q: quartet m: multiplet dd: doublet of a doublet 44t ti ddd: doublet of a doublet of a doublet S 15 dq: doublet of a quartet e 0 The carbohydrate protons with a single dash etc.) relate to the carbohydrates as R 2 and the carbohydrate o. protons with a double dash etc.) relate to the 4 I4 carbohydrates as R in the general formula I 20 a) measured at 270 MHz b) the values are exchangeable in pairs c) measured at 300 MHz I ri) OAc 2.21s Se) measured at 400 MHz f) solvent CDCL 3 d 6

-DMSO

I g) OAc 2.01s, 1.99s h) solvent D 2 0 0 i) N(CH 3 2 2.10s, 2.07s k) OBz 7.72-7.56m;

N(CH

3 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 56 uncertain.

H 1 H-3 H-4 H-5

H

3 -6

NHTFA

5.66d, 5.59d, 5.43d 4.74-4.65m, 2 x 4.52-4.35mi 3 x 4.99-4.76m 2 x 4..20-4.08m, 3.47dq 1.37d, 1.27d, 0.84d 2 x 6.67d, 6.45d 4,.

Oeog 4 4@ 4 4 a 4 44 U 4 I It Table 3, Part 1: 57 28c,d) 29 e,f) 9

SI

(I S *t 'i

I!

i- t jI i' i :i r 1-~41~ H-i H-2 H-3 H-7 H-8a H-Lb H-Eb H-i3a H-13b H-2a' H-2e' H-3' H-4 H.-61 H-i'' H-2a' H-2e H-3I H-4', H-5" H--611 OH-4 OH-6 OH-li OH-9

NHTFA

pNBz 7.79Sd *,651t 7.241d 5. 1 57t 2.24-1 .94m 2.24-1 .94J 5 .071s 1 .85-i .66m 1.55-i .66m 1 .i07t 5 .431db 1.85-i .66m 2.2 4 -i.94m 4.47-4 .42m 5 .595S b 4.47-4.42 1 232 db) s.347db) 1.85-i1.66m 2.24-i.94m 4.47-4 .42m 5 .589s b) 4.39qqb) 1.1 47 db) 11.902s 12.804s 13.683s 3.287s 6.29d/6.24d 8.30-818m 7.905d 7.71St 7 .314d 5. 138t 4.873s 1 .065t 5 507db) 4 .53 b) 5 .14sb) 4*3 4 qb) 1 26 db) 5 .34d b 4.5 3 mb) 5.145 b) 4.20qb) 1 2 1db) 12.158s 12.901s 13.674s 6.54d/6.30d 7 74d 7 .59t 7.18 d 4 96t 1.69-1-V48m 1.69;1 .48mm 4 .78s 1.69-1.48m 1.69-1.

4 8m 0.92t 5.25d b) 1 .69-i 4 8, 1 .69-1 .48m 3.29S b) 1.1 6 db) S.1 9 db) 1.69-i.48m 1.69-1.48m 3.26s b) 3.79 qb) 1.12db) 58 Table 3, Part 2: 3 1 c) 32 e,g) 33 e,h) 34 a,fi)

I

0 09 46 #4 I lilt H-i H-2 H-3 H- 7 H-8a H-Sb H-8b H-i3a H-13b H-i' H-2a' H-2e' H-3'

H-'

H- H-i1 H-2a' H-2eI H-3' H-4' 3 OH-4 OH-6 OH-il OH-9

NHTFA

pNBz 7 83d 7.66t 7.2d 5 .1 m 2 .29m 2 .29m 4.98s 1 .93-i .68m 1.93-1 8m 1 .13t 5 .J5d 1 .S5ddd 2.35ddd 4 .28m 4 .83t 4.30dq 1 .27d 5 50d 1 .76ddd 2. O2ddd 4.34m 4 .74t 4 .1 Zdq 1 .23d 12.01 12 .84s 13.71s 3.30s 6.39d/6.33d 8.02-8.36m 7 .81dd 7. 63t .24dd 5 07d 2.33-1.92n 2.33-i .92m 4.93s 1.82-i .6m 1 .82-1 .6m 1 .07s 5 .39db) 1 .82-1 .6m 2.33-1 .92m 4.1 5 mb) 4 4.11 dqb) 1 .21db 5. 3 8db) 1 .82-1 .6m 2.33-i .92m 4.15m 4 1 S m b 3.96dqb) 1 .17db) 11.98s 12.78s 15.65s 3.26s 6.62d/6.55d 7 50d I .35t 7. 09d 1 .03t s.

4 7 dbb 7.81dd 7.64t 7 .24dd S .07t 1.83-1 .39n 1.83-i .39n 4.92s 1.83-i .39m 1.83-1 .39m 1 .04t S.46db) 1.83-1 .39m 1.83-1 .39m 2.8-2 .Sm 3.83dqb) 1 3 1db) 5 .42db 1.83-1 .39m 1.83-1 .39n 2.8-2 .Sn 3.01 tb) 3.70dqb) 1 .27db) 12.07s 12.84s 13.60s 3.53s I .3db) 5.35d b 1 .33db) 59 Table 3, Part 3: 3 6 e) 3 7 e) i #4 nr 4 I Ti C #4 IttS *444 I t H-1 H-2 H-3 H-7 H-8a H-Sb H-13a H-13b H--14 H-1' H-?a' H-2e' H-3' H-1 H-5' H-6' H-?a H-2al H-2eI H-3I H-4'

'I

H--6I OH-4 OH-6 OH-il OH-9

NHTFA

pNBz 7 94dd 7 .36dd 5. 22t 5.1 2s 2.08-1.79m 2.08-1 .79m 1 .21t 5.5d5db) 2.08-1 .79m 2.08-1 .79m 4.55-4.3"m 4.93t 4.55-4 .32m 1 3 7 db) .45db) 2.08-1 .79m 2.08-1 .79m 4.55-4.32m 5.71 s 4.55-4 .32m 1 2 sdb) 12.09s 12.93s 13.83s 3.41s 6.54d/6.25d 8.36-8.2m 7 .82dd 7 .64t 7 .25dd 5. 08t 2.36-1 2.36-1 4.99s 2.36-1 2.36-1 1 .09t 5.S9db) 2.36-1 2.36-1 4 .1 2ddd 4. 54t 4.12dq 1 2 4db) 5 .39d b 2.36-1 2.36-1 4 .4!2ddd 5.34s 4.24q 1 .1 6 db) 11.97s 12.795 13.70s 3.29s 6.25d/6.13d 8.26-8 .09m 7 .9Odd 71t 7 32dd 5. 1Gm 4 .96s 1 .09t 5 .38sQb) 2.78m 2 .92 t 3 .83dq 1 34 db) 5 .37sb) 3 04m 3.31s 3.96q 1 2 8 ab) 60 TabLe 3, Part 4: 38 e,k) 39 e 40 e 4 ,a 1 (4 414# 444, 44$ 144 I I I

I

LI

I

H-1 H-2 H-3 H- 7 H-8a H-8b H 10 H-i3a H-il3b H--14 H-i' H-2a' H-3' H-4'9 H-i' H-2a a' H-2e''I H-3' H-4' OH -4 OH -6 OH I1 OH -9

NHTFA

pNB z 7 87 7 4 6 t 7.31d 5 .23s 2 .05-2.0-1m 2 .05-2.0O-1m 4 .995 1 .93-1 .74mn 1 .93-i .74mn 1 .i5t 5 .54s 1 .93-i .74mn 2 .21m 2 .69ddd 5 .54S 4 27q 1 .26d 68 d 1 .93-1 .74m 2 .21m 4 .44ddd 4 79t 4 6dq i .21id 12 07 s 12 .88s 13 3.78s 6 5 8d 8.2"1-8 .08m 7. 83d 7 6 5t 7 2 6d 1 4m 4.91s 1 .14t 5 4sb 2 .23m 3 .62s 3 97 q 1 .34d 4 .37m 4 .73t 4 .1 3dq 1 19d 12 .08s 12 .80~s 13 74 s 3-42s 6 .2 8d 8.24-8.08m 7 8 9d 7 .71 t 7 32 d 5 .1 3t 1 .9-1 1 .9-i 4 .95s 1 .9-i 1 .9-1 1 .09-t 5 .46d b 7 .9 2d 7. 174t 7 3 6d 5. 2 9t 5.35S 1 .29t 3 .67s 4 02q 1 .37dob 5 37 d b 2 .76m 2 8 1 .30d b 12 14s 13 .1 3s 13.92s 8.34-7.96m

Claims (7)

1. A compound of the formula I or a saLt thereof with an inorganic or organic acid 1 P11 q CR CR3 OH O HO in which: R is hydrogen or a hydroxyl group R 2 is hydrogen or a structure of the formula II or IV 23 R3 is hydrogen or a structure of the formuLa II or IV or, together with R 3 of the formula III rZ CH VI trcH t t V R3 is hydrogen or a structure of the formula II or IV or, together with R of the formula III, R is hydrogen, trimethylsilyl, a protective group which is customary in carbohydrate chemistry, prefer- ably acetyl, trifluoroacetyl, benzoyl or substituted benzoyL, such as para-nitrobenzoyL, a structure of the formula II or a structure of the formuLa IV, is hydrogen, methyl, hydroxymethyl, acytoxymethyl, (C1-CB) or alkoxymethyl (C1-C8), R 6 8 R6, R and R independently of one another are hydrogen, hydroxyl, aliphatic acyloxy (Cl-C8), benzoyloxy or substituted benzoyloxy, such as para-nitrobenzoyl- oxy, alkoxy (Cl-C8), alLyLoxy, benzyloxy or substi- tuted benzyloxy or halogen, and R 7 can furthermore be NH 2 NHacyL (Cl-C8), N(alkyl) 2 (C1-C8), 62 N(CH 2 CN) 2 NH(CH 2 CN) 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 R =R2=R 3 =R4=H, R 1 =OH and R2=R3=R 4 R 1 =R3=R =H and R2=a-L-daunosaminyl or a-L-rhodosaminyl or 4'-acyl-c-L-rhodosaminyl, R 1 =OH or H, R3=H and R R4=a-L-rhodosaminyl or 4'-acyl-a-L-rhodosaminyL and R =R 2 =R3=H and R a-L-rhodosaminyl being excluded. S, 2. A compound as claimed in claim 1, wherein R 2 and R 3 independently of one another are hydrogen 4° or a structure of the formula II or IV with the mean- ings of R to R given in claim 1.

3. A compound as claimed in claim 1, 4 t 4 S" wherein ft R 2 and R independently of one another are hydrogen or a structure of the formula II or IV in which R 5 is Smethy, R 6 and R 7 have the meanings given in claim 1 and R 8 is hydrogen or halogen.

4. A compound as claimed in claim 1, S wherein R 2 and R 3 independently of one another are hydrogen or a structure of the formula II or IV in which R is methyl, R 6 has the meaning given in claim 1, R 7 is NH 2 NHacyL (C1-C8), N(alkyl) 2 (C1-C8), N(CH 2 CN) 2 NH(CH 2 CN) or azido and R is hydrogen or halogen. A compound as claimed in claim 1, wherein R 2 and R 3 independently of one another are hydrogen 7 7 I~ 63 or a structure of the formula II or IV, in which R is methyl, R and R 7 have the meanings given in claim 1 and R is hydrogen or halogen and the structures of the formula II or IV belong to the L-series of carbo- hydrates. t, .4 f tt

6. A compound as claimed in claim 1, wherein R and R independently of one another are hydrogen or a structure of the formula II or IV, in which R is methyl, R 6 has the meaning given in claim 1, R 7 is NH 2 NHacyl (C1-C8), N(alkyl) 2 (C1-C8), N(CH 2 CN) 2 NH(CH 2 CN) or azido and R 8 is hydrogen or halogen, and the structures of the formula II or IV belong to the L-series of carbohydrates.

7. 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 has the meaning initially given and R 2 to R 4 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 4A mole- cular sieve, to give a compound of the formula I in which R1 has the meaning initially given and R 2 together with R 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, :i 13 :i 64 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 thereor, at a temperature between 0 C and the boiling point of the solvent and in the pesence of a base, such as triethylamine or pyridine, to give a compound of the formula I in which R1 has the meaning initially given, R together with R 3 is a structure of the formula IIT and R 4 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, dimethylformamide or toluene, in the pre- sence of a catalyst, such as para-toluenesulfonic acid and a desiccant, such as 4A molecular sieve, at a temperature between -30 0 C and the boiling point of the solvent, to give a compound of the formula I in which R1 has the meaning initially given, R 2 together with R 3 is a structure of the formula III and R is a structure 3f the formula II, where R to R is hydrogen, d) or, for example, reacting the compound rbtained under a) with a carbohydrate derivative of the formula V 65 789 V in which 5 8 R to R, as suitable protective groups, have the meanings initially given and R 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 which R has the meaning initially given, R together with R is a structure of the formula III and R 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 s 0\a% V V1 in which 5 8 R to R 8 have the meanings initially given, with the exception of hydroxymethyl, hydroxyl, NH 2 N(CH 2 CN) 2 and NH(CH 2 CN) and R is acyl vhich is bonded via oxygen, such as ali- 66 phatic acyloxy (C1-C8), such as acetyl, benzoyl- oxy or substituted benzoyloxy, such as para- nitrobenzoyloxy, in the presence of an organic solve t, 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 molecular sieve, at a reac- tion temperature of -70 0 C to +30 0 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 R 3 is a structure of the formula III and R is a structure of the formula II or IV, in which R 5 to R 8 have the meanings initially given, with the exception of hydroxymethyl, hydroxyl, NH 2 N(CH 2 CN) 2 and NH(CH 2 CN), 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 paratolu- enesulfonic acid, and if appropriate with a diol, such as 2-methyl-2,4-pentanediol, at a temperature between 0 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, R 2 and R are hydrogen and R has the meaning given, with the exception of hydrogen, 67 g) and subsequently, if appropriate, possibly selectively partly or completely deblocking the compound of stage f) in which R 4 is a structure of the formula II or IV with, as radicals R 5 to R one of the protective groups customary in ca- ohydrate chemistry, in a manner which is known per se on the protected hydroxyl functions 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 hydrox- ides, sodium carbonate and triethylamine, in a sol- vent, such as water, methanol, ethanol or tetrahydro- furan or mixtures thereof, to give a compound of the formula I in which R is hydrogen or hydroxyl, R 2 and R 3 are hydrogen and R is a structure of the formula II or IV, in which R is hydrogen, methyl, hydroxymethyl or alkoxymethyl, R is hydrogen, hydroxyl, alkoxy or halogen, R 7 is NH 2 N(Jlkyl) 2 azido, hydroxyl or alkoxy and R 8 has the same meaning as R 6 but is independent thereof, h) and, if appropriate, reacting the compound of stage g) of the formula I, in which I R 3 R to R have the meanings given under g) and R is a structure of the formula II, in which R R and R have the meanings given under g) and .R 7 is NH 2 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 R have the meanings given under g) and R is a structure of the formula II, in which u ao os- .n o o 68 R R6 and have the meanings given under g) and R 7 is N(alkyl) 2 or i) furthermore converting a compound of stage g) of the general formula I in which R 1 to R 3 have the meanings given under g) and R is a structure of the formula II in which R R 6 and R have the meanings given under g) and R 7 is NH 2 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 R to R have the meanings given under g) and R is a structure of the formula II, in which R 5 R 6 and R have the meanings given under g) and R 7 is N(CH 2 CN) 2 or NH(CH 2 CN) and k) if appropriate glycosidating the compound formed in stage h) or i) under the conditions already men- tioned in stage either only position 7 or simul- taneously positions 7 and 9 being glycosidated, depend- ing on the amount of glycosyl donor used, to give products which correspond to the general formula I in which R has the meaning given, R 2 is a structure of the formula II or IV, in which R 5 to R 8 have the meanings initially given, with the exception of hydroxymethyl, hydroxyl, NH 2 N(CH 2 CN) 2 and NH(CH 2 CN), R 3 is hydrogen or corresponds to R 2 and R 4 is acyl, trimethylsilyl or a structure of the general formula II or IV in which R 5 to R 8 have the meanings initially mentioned, with the exception of hydroxymethyl, hydroxyl and NH 2 and, if appropriate, 0 0 69 L) converting one of the compounds formed in stage h) or i) with a glycal of the formula VI, in which R to R 7 have the meanings given in stage in the pres- ence of an organic solvent, such as chloroform, methylene chloride, toluene, ether, acetone or aceto- nitrile or mixtures thereof, with N-iodosuccinimide and if appropriate with a desiccant, such as molecu- lar sieve, at a temperature from -40 0 C to +40 0 C under a protective gas atmosphere, such as nitrogen or argon, into a compound of the formula I in which R1 has the meaning given and R 2 is a structure of the formula II, in which R 5 is hydrogen, methyl, acyloxymethyl (C1-C8) or alkoxymethyl (C1-C8), R 6 is acyloxy, alkyloxy, allyloxy or benzyloxy, R 7 is acyloxy, alkyloxy, allyloxy, benzyloxy, NHacyl, N(alkyl) 2 or azido and R is iodine, and R and R have the meanings given in stage and m) if appropriate deblocking the compound formed in stage k) or L) in accordance with the conditions of stage to give a compound of the formula I in which R 1 has the meaning given and R2 is a structure of the formula II or IV, in which R 5 is hydrogen, methyl, hydroxymethyl or alkyloxy- methyl, R 6 is hydrogen, hydroxyL, alkyloxy or halogen, R7 is NH 2 or N(alkyi)?, azido, hydroxyl or alkoxy and R 8 has the same meaning as R but is independent thereof, R 3 is hydrogen or corresponds to R 2 and R is hydrogen, trimethylsiLyl or a structure of the general formula II or IV, in which R 5 is hydrogen, methyl, hydroxymethyl or alkoxymethyL, R is hydrogen, hydroxyl, alkoxy or halogen, 70 R 7 is NH 2 N(alkyl) 2 N(CH 2 CN) 2 or NH(CH 2 CN), azido, hydroxyl or alkoxy and R has the same meaning as R 6 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 is selectively deblocked, to give a compound of the formula I in which R1 has the meaning given, R 2 is a structure of the formula II or IV, in which R to R8 have the meanings initially given, with the exception of hydroxymethyl, hydroxyl and NH 2 R 3 is hydrogen or corresponds to R 2 and R is hydrogen, o) and subsequently, if appropriate, converting the com- pound of stage in which R 2 is a structure of the formula II where R is NH 2 and R 3 is hydrogen or R 2 into the corresponding compounds in which R 6 is N(alkyl) 2 again in the manner of reductive amina- tion described for stage or, if appropriate, p) converting a compound of stage m) in which R is a structure of the formula II, where R 7 is NH 2 and R is hydrogen or R 2 into the corresponding cyano- methyl derivatives in which R 7 is N(CH 2 CN) 2 or NH(CH 2 CN) in accordance with the conditions of stage and, if appropriate, q) glycosidating a compound of stage n) under the condi- tions already given in stage 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 R1 is hydrogen or hydroxyl and R 2 is a structure of the general formula II or IV, 71 in which R 5 to R have the meanings initially given, with the exception of hydroxymethyl, hydroxyl and NH 2 R is hydrogen or R or R and R 4 is a structure of the general formula II or IV, in which 5 8 R to R have the meanings initially given, with the exception of hydroxymethyl, hydroxyl, NH 2 N(CH 2 CN) 2 or NH(CH 2 CN), and, if appropriate, r) also carrying out the reaction of stages d) and I) on a compound of stage n) so as to give a compound of the formula I in which R has the meaning initially given and R 2 is a structure of the formula II or IV, in which R to R8 have the meanings initially given, with the exception of hydroxymethyl, hydroxyl and NH 2 R 3 is hydrogen or R or R and R is a structure of the general formula II or IV in which R 5 to R 8 have the meanings initially given, with the exception of hydroxymethyl, hydroxyL, NH 2 N(CH 2 CN) 2 and NH(CH 2 CN), and, if appropriate, s) deblocking this compound of stage q) or r) again as described in stage to give a compound of the formula I in which R has the meaning initially given and 2 3 4 R R and R independently of one another are hydrogen or a structure of the formula II or IV, Sin which R 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 R 7 which in 7 72 stage s) was an NH 2 group, is converted into N(alkyl) 2 by means of reduction amination in accordance with stage or u) moreover converting a compound of stage s) into the corresponding cyanomethyl derivative in which the radical R which in stage s) was an NH 2 group, into NH(CH 2 CN) in accordance with the conditions of stage i), v) and, if appropriate, reacting a compound of the formula I in which R R and R have the meanings given and R 4 is trimethyLsilyl, with tetrabutyLammonium fluoride in an organic solvent, such as tetrahydrofuran, diethyl ether, dioxane or mixtures thereof, at temperatures between -40 0 C and the boiling point of the solvent, to give a compound of the formula I in which R R and Rhave the meanings given above and R is hydroxyl, u) and, if appropriate, converting compounds of the formula I in which R R 2 R 3 and R have the meanings given and R 7 is NH 2 N(alkyl) 2 (C1-C8), N(CH 2 CN) 2 or NH(CH 2 CN) into the salt of an inorganic or organic Sacid.

8. The process as claimed in claim 7, wherein a compound of the formula I in which R has the meaning initially given, R 2 together with R 3 forms a structure of the formula III and R 4 is hydrogen, is converted by acylation with a carboxylic acid anhyd- ride, such as acetic anhydride or trifluoroacetic anhydride, or a phenylcarboxylic acid anhydride or a carboxylic acid halide or by reaction with trimethyl- silyl trifluoromethanesulfonate in an organic solvent,

66. 73 such as chloroform, methylene chloride or toluene or mixtures thereof, at a temperature between -40°C and the boiling point of the solvent and in the presence of a base, such as triethylamine or pyridine, into a compound of the formula I in which R 1 has the meaning initially given, R 2 together with R 3 is a structure of the formula III and R is acyl or trimethylsilyl, or wherein a compound of the formula I in which R 1 has the meaning initially given, R 2 together with R 3 forms a structure of the formula III and R is hydro- gen, is converted by reaction with 3,4-dihydro-2H- pyran in a suitable organic solvent, such as chloro- form, methylene chloride, dimethylformamide or toluene, in the presence of a catalyst, such as para-toluene- sulfonic acid, and a desiccant, such as 4A molecular sieve, at a temperature between -30 0 C and the boiling point of the solvent, into a compound of the formula I in which R I has the meaning initially given, R 2 together with R 3 is a structure of the formula III and R is a structure of the formula II where R 5 to R are hydrogen. 9. The process as claimed in claim 7, Sj! wherein a compound of the formula I in which R has the meaning initially given, R 2 together with R 3 forms a structure of the formula III and R 4 has the meaning given, excluding hydrogen, can be deblocked at posi- tions 7 and 9 by reacting this compound in a suitable organic solvent, such as chloroform, methylene chlor- ide, dimethylformamide, toluene or methanol, with a 74 catalyst, such as dilute aqueous solutions of carboxy- lic acids or para-toluenesulfonic acid, and if approp- riate with a diol, such as 2-methyl-2,4-pentanediol, at a temperature between 0 0 C and the boiling point of the solvent, to give a compound of the general formula I in which R 1 has the meaning given, R 2 and R are hydrogen and R has the meaning given, with the exception of hydrogen. The process as claimed in claim 7, wherein a compound of the formula I in which R to R have the meanings given, but R 2 or R must be hydrogen and 5 8 R to R cannot be hydroxyl, hydroxymethyl or NH 2 is reacted with a functionalized carbohydrate of the general formula V or VI in which V VI 5 8 R 5 to R have the meanings initially given, with the exception of hydroxymethyl, hydroxyl, NH 2 N(CH 2 CN) 2 and NH(CH 2 CN) and R is an acyl protective group bonded via oxygen, such as aliphatic acyloxy (C1-C8), such as acetyl, benzoyloxy or substituted benzoyloxy, such as para- nitrobenzoyloxy, in the presence of an organic solvent, such as chloroform, methylene chloride, toluene, ether, dimethylformamide, acetone, acetonitrile or nitro- methane or mixtures thereof, a catalyst, such as para-toluenesulfonic acid or a trialkylsilyl tri- 75 fluoromethanesuLfonate, and if appropriate an acid- trapping agent and a desiccant, such as molecular sieve, at a reaction temperature of -700C to +30 0 C under a protective gas atmosphere, such as nitrogen or argon, to gie a compound of the formula I in which R1 has the meaning given, R2 together with R 3 is a structure of the formula III or R 2 R 3 or R is a structure of the formula II or IV, in which R 5 to R 8 have the meanings initially given, with S, the exception of hydroxymethyl, hydroxyl and NH 2 or wherein a compound of the formula I in which R1 to R 4 have the meanings given, but R 2 or R 4 must be hydrogen and R 5 to R 8 cannot be hydroxyL, hydroxy- methyl or NH 2 is converted in the presence of an organic solvent, such as chloroform, methylene chloride, toluene, ether, acetone or acetonitrile or mixtures thereof, with a glycal of the formula VI, in which R to R have the meanings initially given, with the exception of hydroxymethyl, hydroxyl, NH 2 N(CH 2 CN) 2 and NH(CH 2 CN), with N-iodosuccinimide and if appropriate with a desiccant, such as mole- cular sieve, at a temperature of -40 0 C to +40 0 C under a protective gas atmosphere, such as nitrogen or argon, into a compound of the formula I in which R has the meaning given, 2 3 2 together with R is a structure of the formula III or R 2 R or R is a structure of the formula II or IV, in which R to R 8 have the meanings initially given, with the exception of hydroxymethyl, hydroxyl, NH 2 N(CH 2 CN) 2 and NH(CH 2 CN). 1 76 11. Method of treatment of tumours comprising administering the compound of claim 1 to a patient. DATED this 25th day of June, 1991. BEHRINGWERKE AKTIENGESELLSCHAFT r si nan ooao *cno ol es ro WATERMARK PATENT TRADEMARK ATTORNEYS, 290 Burwood Road, HAWTHORN. VIC. 3122 AUSTRALIA DBM:JMW:JZ 00 0 0J '00~~