CH648320A5 - CYTOSTATIC COMPOUNDS, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS. - Google Patents

Description

The invention relates to new cytostatic compounds of the general formula I.

(I)

ch30

wherein

R4 represents β-hydroxyl and R3 represents α-ethyl or R4 represents hydrogen and R3 represents β-ethyl.

R "is a straight-chain alkyl group with 1 or 3-10 carbon atoms, a branched alkyl group with 3-10 carbon atoms, the carbon atom bonded to the> N-CH: -0- group being a primary or secondary carbon atom, or one in the alkyl part 1- Arylalkyl group containing 3 carbon atoms,

R1 stands for the methoxy group and 6s R2 for the acetyl group.

The compounds of general formula I according to the invention have a cytostatic effect.

The compounds of general formula I are invented

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manufactured according to the invention by using compounds of the general formula II

HO

CH

wherein the meaning of R1, R2, R3 and R4 is the same as above, or their acid addition salts with an excess of an alcohol of the general formula III

R "- OH (III)

wherein the meaning of R "is the same as above, in the presence of chromium trioxide, an organic solvent, in an acidic medium at temperatures between -60 and -30 ° C, adjust the pH of the reaction mixture to 8-10 and the resulting Compound of the general formula I isolated.

In this reaction, the group / N-CH3 is modified in compounds of the formula II, and this modification can be carried out practically on all bis-indole alkaloids containing the structural unit N-CH3.

The starting materials of the general formula II are known. Vinblastine (R1 = methoxy, R2 = acetyl, R3 = α-ethyl and R4 = β-hydroxyl) is described in US Pat. No. 3,097,137. The isolation of 20'-deoxy-leurosidine was done by N. Neuss et al. [Tetrahedron Letters 1968,783] and the synthesis of the same compound by Potier et al. [I. At the. Chem. Soc. 98, 7017 (1976)]. The raw materials themselves have a cytostatic effect. The new derivatives made from them are also cytostatic, but are less toxic than the starting materials.

The acute toxicity of the compounds according to the invention was investigated in self-bred male "Swiss mice" weighing 27-31 g. Each group consisted of 6 mice. 80 injection solutions were prepared from the substances to be examined by adding physiological saline and, if necessary, a few drops of Viveen. The solutions were injected intraperitoneally in ascending order from the non-mortality dose to the 100% mortality dose and the results were calculated using the Lichfield and Wil-coxon method. The results and also the comparative values for the known compounds vinblastine, vindezin and vinkristin are summarized in the following table.

Connection LD so paralyzing

(mg / kg) side effect

N-desmethyl-N- (methoxymethyl) -

vinblastin

-100

-

N-desmethyl-N- (propoxymethyl) -

vinblastin

- 80

-

N-desmethyl-N- (isobutoxymethyl) -

vinblastin

60

-

N-desmethyl-N- (heptoxymethyl) -

vinblastin

- 60

-

N-desmethyl-N- (benzyloxymethyl) -

vinblastin

- 70

-

Vinkristin

4.2

+

Vinblastine

7.6

-

Vindezin

4.0

+

The toxicity of the new compounds is therefore 15-25 times lower than that of Vinkristin and Vindezins and 8-13 times lower than that of Vinblastine. In contrast to Vinkristin and Vindezin, there are no symptoms of paralysis as a side effect with the new compounds until the LD 50 value is reached.

The cytostatic effects of the new compounds were examined on tissue cultures and on different transplanted tumor strains.

The compounds of the present invention to be examined were dissolved in various amounts (from the threshold dose 1 x 10 -3 ug / ml to the upper limit of 100 µg / ml) in the tissue culture (HeLa culture), and after 24 hours, the cultures were microscopically examined in vivo. Taking into account the cells locked in the metaphase, the following results were obtained.

Compound strong blocking dose ([ig / ml)

N-desmethyl-N- (methoxymethyl) -vin-

blastin

0.001

N-desmethyl-N- (propoxymethyl) -vin-

blastin

0.001

N-desmethyl-N- (isobutoxymethyl) -vin-

blastin

0.001

N-desmethyl-N- (heptoxymethyl) -vin-

blastin

0.001

N-desmethyl-N- (benzyloxymethyl) -vin-

blastin

0.01

Experiments with colored tissue cultures were also carried out under similar conditions, which gave the possibility of observing finer differences. The observed effects can be classified into five levels:

The first stage is characteristic of the dose causing the minimal effect: the proportion of blocked mitoses increases. Some of these are degenerate, for example triple mitosis, or there are some separated chromosomes at the poles. Most of the time, the anaphases have already disappeared. In the second stage, in which strong metaphase blockage occurs, normal mitosis can practically no longer be observed. The chromosomes are arranged in a loose ball. The proportion of cells in the interphase is low. In the third stage are

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the chromosomes crowded (coalesced) as a dense mass in the middle of the cell. This is pyknomitosis or “ball metaphase”. In the fourth stage, the effect on the interphase cells shows that there are relatively few blocked cells because the cells are no longer able to enter mitosis. The cytoplasm of the cells in the interphase is spread out, its edge uneven, "fringed", the cell often assumes an elongated, fibroblast-like shape. Finally, in the fifth phase, the cytoplasm is filled with a fine reticular structure, and it is evident that the interphase cell was destroyed by the treatment. These five levels of effectiveness can be distinguished from one another.

The following could be determined from the tests:

the most effective compound is the heptoxy derivative. Already in a dose of 0.001 µg / ml it causes a strong blockage of the metaphase. Pycnomitosis occurs at a dose of 0.1 [ig / ml, the interphase cell effect at a dose of 1-10 [ig / ml. The isobutoxy derivative has an order of magnitude weaker: at the lowest dose of 0.001 [ig / ml, normal mitoses still occurred. The weakest effect was shown by the benzyloxy derivative, which in the lowest dose had a minimal blocking effect with a few degenerate mitoses, but already without anaphases. At 0.01 | ig / ml, the blocking is moderate; severe blockage and pyknomitosis only occur at a dose of 1 ng / ml.

The effect on i.p. Transplantable tumors (mouse-10 leukemia P 388 and ascites lymphoma NK / Ly) were examined in the following way.

P 388 leukemia is maintained in BDF hybrid mice, and groups of 6 animals are given 10® tumor cells / animal i.p. transplanted. 24 hours after the transplantation, the daily i.p. treatment with the new compounds is started; The body weight and condition of the animals are checked every day. The effect achieved is expressed as a percentage of the lifespan of the control group. As shown in 20 of the following table, the lifespan of animals infected and treated with P388 leukemia is significantly longer than that of the control.

connection

Dose mg / kg average lifespan (days)

Effect in%

i.p.

treated

Control control

N-desmethyl-N- (heptoxymethyl) vinblastine

8x0.4

14.3

10.3

139

8x4.0

18.7

10.3

181

8x8.0

. 21.3

9.9

217

N-desmethyl-N- (benzyloxymethyl) vinblastine

8x0.4

13.0

10.3

126

8x4.0

18.3

10.3

178

5x8.0

19.2

9.9

195

N-desmethyl-N- (isobutoxymethyl) vinblastine

8x0.4

13.7

10.3

133

8x4.0

20.0

10.3

194

8 x 8.0

20.5

9.9

208

N-Desmethyl-N- (methoxymethyl) vinblastine

8x1.0

12.7

10.3

122

8x2.0

18.7

10.5

178

16.8

155

8x4.0

19.0

11.1

171

17.7

163

8x6.0

19.2

10.5

182

8x8.0

18.7

10.8

172

20.2

205

N-desmethyl-N- (propoxymethyl) vinblastine *

8x1.0

15.0

10.3

145

8x2.0

20.8

10.5

198

8x4.0

19.0

11.1

171

8x8.0

20.2

9.9

205

8x 10

14.7

10.3

142

* The compound N-desmethyl-N- (propoxymethyl) vinblastine was found to be toxic at a dosage of 8x10 mg / kg, since tumor-free animals also died.

"Swiss-H / Riop out-bred" mice from our own breeding were i.p. 5 x 106 ascites tumor cells transplanted. Each group consisted of 10 animals. Treatment was started 24 hours after the transplant. The compounds were administered daily for five days. The average lifespan of the control compound group was 15.7 days.

Similar experiments were also carried out with N-desmethyl-N- (methoxymethyl) -20'-deoxy-leurosidine. In addition to the dose, the number of treatments was also varied.

Dose mg / kg average lifespan (days) effect in%

i.p. deals with control of control

N-Desmethyl-N- (methoxymethyl) -20'-deoxyleurosidine

4x8 21.8 12.1 180

8x4 20.8 11.6 180

4x7 17.1 12.1 142

8x1 21.7 12.2 178

8x0.5 15.3 12.2 126

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The effect of the compounds is expressed in a significant extension of the service life, as the following table shows.

Compound and dose on the 25th day on the 30th day live tumor free

N-Desmethyl-N- (heptoxymethyl) vinblastine 3/10

5x6.0 mg / kg i.p. 10/10 7/10

N-Desmethyl-N- (isobutoxymethyl) vinblastine 7/10

5 x 4.0 mg / kg op. 10/10 10/10

The tumor inhibitory effect of the new compounds in dissolved form, preferably in acetic anhydride, to which P388 and NK / Ly is given in doses of 4-8 mg / kg.day reaction mixture.

characterizes and the action of the known diindole alkaloids The reaction is carried out at temperatures between -60 and equivalent, but the new compounds are substantially -30 ° C, preferably -50 and -60 ° C suitably less toxic than the compounds of similar structure. a protective gas atmosphere. The course of the

For the purposes of human medicine, the compound reaction can be followed using a suitable analytical method, fertilizing primarily intravenously or used as an infusion, for example by thin layer chromatography. will. The response time depends on the

As already mentioned above, the alcohols given relate to the general formula III and, in the present invention, also refer to a process for the preparation of the general 20 minutes to one hour.

new connections. The reaction is carried out at temperatures of 2 s. After the reaction has ended, the pH of the reac is adjusted from -60 to -30 ° C. and the working mixture is preferably adjusted to 8-10, and the mixture is thereby adjusted in a range from -50 to - 60 ° C. After isolation, any acetic anhydride is completely decomposed. The compound according to the invention can also be cleaned. Adjustment of the pH will expediently be at -50.degree. started and generally ended at 0- + 30 ° C. It is

According to the invention, one starts from a compound which is preferred, the reaction mixture for a further 5-10 minutes with the common formula II or its acid addition salt. Stir the room temperature.

Starting compound is usually in a suitable. The crude product obtained can be extracted and

Solvents, conveniently isolated in acetone or a chlorine evaporation. There may also be some N-Des-

hydrocarbon, preferably in anhydrous methyl or N-desmethyl-N-formyl derivative

Dichloromethane, chloroform or dichloroethane. The 35 included. Of these, the target product is conveniently present in the presence of an acid, which facilitates both the dissolution and the separation by chromatography. The reaction is also preferred as the adsorbent. It is advisable to work in a partially deactivated aluminum oxide or fine-grained

weakly acidic medium, preferably niges silica gel being used as the acid. The isolated product is an organic acid, such as glacial acetic acid, adipic acid, pelargonium, if necessary purified by recrystallization.

acid and optionally also a small amount of an inorganic acid. The invention is based on the following examples. As organic acids are explained in more detail, but these examples are not particularly suitable for acids which are restricted to the starting compound.

form the general formula II acid addition salts.

The acid can be present in traces or in an equimolar amount. Example 1

lie. 45 N-desmethyl-N- (methoxymethyl) vinblastine

The alcohol of the general formula 1.0 g (1.1 mmol) of vinblastine sulfate used as reactant is preferably used in a mixture III in a large excess. from 240 ml of alcohol-free absolute dichloromethane, 8 ml As alcohol, for example, straight-chain alkanols are dissolved with methanol and 25 ml of glacial acetic acid and the solution is dissolved

1 or 3-10 carbon atoms into consideration (the reaction is cooled to -55 ° C. The ethanol is the subject of the own earlier application RI-so of 5 minutes in a dry nitrogen stream under inten-708 to the vinblastine solution). Methanol, propanol, butanol, vigorous stirring and the solution of 0.5 g amyl alcohol and heptanol, cooled to - 55 ° C, are primarily used. Alka (5.0 mmol) chromium trioxide in 40 ml acetic anhydride noie with a branched chain and 3-10 carbon atoms are also added. The temperature of the reaction mixture is allowed to change, the carbon adjacent to the OH grappa not rising above -50 ° C. The course of the oxidation will not be a tertiary carbon atom, since in the case of 55 it is monitored by thin-layer chromatography (adsorbent: DC-tertiary alcohols the reaction does not proceed. Appropriate aluminum foil-silica gel 60 F254, Art. 5554; flow agent: diethyl-isobutanol, isopropanol, etc .. From the ether: ethanol: benzene: diethylamine = 10: 0.5: 0.5: 0.5). The usable oxidation in the alkyl part containing 1 -3 carbon atoms is generally complete after 20-30 minutes, tend arylalkyl alcohols, for example benzyl. Then 190 ml of concentrated alcohol and phenethyl alcohol are used in the reaction mixture. 60 aqueous ammonia solution and 200 g ice added, the cooling

As mentioned, the alcohol of the general formula III lung is maintained. The temperature of the mixture used in excess. The respective molar ratio increases to a value between 0 and + 10 ° C. It won't reactant depends on the alcohol used. Generally cooled and the mixture, the pH of which is 8.5-9, the alcohol in 50-150-fold molar excess, is stirred vigorously for 10 minutes. The live shot used. 65 are separated from each other and the aqueous phase

The reaction of the compounds of the general formula extracted three times with 30 ml of dichloromethane. The extracts mein II and III are first in the presence of chromium trioxide four times with 25 ml 1: 1 diluted ammonia. The chromium trioxide (Cr03) is expediently washed in niak and then twice with 30 ml water and

0

7

648 320

then dried over magnesium sulfate, filtered, and the filtrate is evaporated in vacuo. 0.85 g of crude product are obtained, of which 0.3 g is chromatographed on a column filled with activity II-III alumina with dichloromethane. Fractions of 6 ml each are collected and these are examined by thin layer chromatography (adsorbent: DC aluminum foil silica gel 60 F254, item 5554; flow agent: dichloromethane and methanol in a ratio of 5: 0.4; detection with iodine vapor or UV light of the wavelength 254 nm).

The fractions containing the same alkaloid are combined and the resulting groups are evaporated separately. The target compound is contained in fractions 6-25. 64% chromatographically uniform N-desmethyl-N- (methoxymethyl) vinblastine are obtained, which melts at 205-210 ° C (ethanol). [a0 = + 23 ° (c = 1, chloroform).

'H NMR (CDCb, 100 MHz): 8 9.05 (s, 1H, Cie-OH), 8.05 (s, 1H, NaH), 7.35 (s, 1H, Ci2, H) 7, 13-7.26 (m, 3H, Co, -Cii, -H), 6.68 (s, 1H, Co-H), 6.33 (s, IH, C12-H), 5.84 (i.e. , 1H, Cm-H), 5.37 (s, 1 H, C17-H), 5.28 (d, 1H, Cis-H), 4.42 (2H,> Na-CH2-O-), 4.18 (s, IH, C2-H), 3.97 (s, 3H, C16-CO2CH3), 3.77 (s, 3H, C11-OCH3), 3.62 (s, 3H, Cio.- CChCm), 3.26 (s, 3H, -OCH3), 2.73 (s, IH, C21-H), 2.09 (s, 3H, OCOCHs), 0.8-0.96 (2t, 6H , C18-H3, C18-H3).

MS m / e: 840 (M + 100%), 810, 809.781, 751,681,651,650, 601,499,355,282,243,241,154, 149.

Example 2

N-desmethyl-N- (isobutoxymethyl) vinblastine

0.5 g (0.55 mmol) of vinblastine sulfate is dissolved in a mixture of 120 ml of absolute dichloromethane, 3.7 ml of isobutanol and 12.5 ml of glacial acetic acid, and the solution is cooled to -55 ° C. To the solution is added the cooled to -55 ° C solution of 0.25 g (2.5 mmol) of chromium trioxide in 40 ml of acetic anhydride. The course of the reaction is monitored by thin-layer chromatography in the manner described in Example 1 (adsorbent: DC plastic film silica gel 60 F254, item 5735; solvent: ether, ethanol, benzene and diethylamine in a ratio of 10: 0.5: 0.5: 0.5). The reaction takes place in 140 minutes. The reaction mixture is worked up in the manner described in Example 1. 0.65 g of crude product are obtained, which is purified by column chromatography on silica gel 60 (Art. 9385) with dichloroethane as the solvent. Developed and eluted with dichloromethane, fractions of 10 ml each were collected.

There is no alkaloid in the first 330 ml of eluate. Elution is continued with dichloromethane containing 3% methanol. The first 90 ml of the eluate now obtained contains the target compound. It is isolated by evaporating the eluate. Yield: 169 mg (35%).

Mp: 215-218 ° C.

IR (KBr): 3400 (NH, OH), 1730 (CO2CH3), 1605.1220 cm "1 (OAc).

1 H NMR (CDCh, 100 MHz): 5 8.1 (s, 1H, NaH), 7.5 (m, 1H, Ci2, -H), 7.05-7.2 (m, 3H, C <>, - Cn, -H), 6.70 (s, 1H, Cs-H), 6.36 (s, IH, C12-H), 5.87 (d, IH, Ci4-H), 5 , 37 (s, 1H, Cn-H), 5.20 (d, 1H, Cis-H), 4.75,4.15 (2H, JabIOHz,> Na-CH: -0), 4.0 ( s, IH, C2-H), 3.78.3.75 (2s, 6H, CO2CH3), 3.63 (s, 3H, C11-OCH3), 2.75 (s, IH, C2iH), 2, l (s, 3H, OCOCHs), 0.95-0.70 (12H, CHs groups).

MS m / e: 882 (M +, 100%), 864,851,823,810,779,751,723, 651,650, 514, 355,346,329,154.

Example 3

N-Desmethyl-N- (heptoxymethyl) vinblastine The procedure described in Example 2 is followed, but 3.7 ml of 1-heptanol are used as the reagent. The response time is approximately 90 minutes. Working up the reaction mixture gives about 4 g of crude product, which is dissolved in 30 ml of dichloromethane and applied to a silica gel 60 column. It is eluted with dichloromethane. Fractions of 10 ml each are collected. The first 300 ml contain no alkaloid. Elution is continued with dichloromethane containing 3% methanol. The first 120 ml of the eluate now obtained contains the target product. Yield: 21%, melting point: 200-205 ° C (acetone ether).

IR (KBr): 3450 (OH, NH), 1740 (CO2CH3), 1610.1220 cm ~ '(OAc).

'H NMR (CDCb, 100 MHz): 5 8.07 (s, 1H, NaH), 7.52 (m, 1H, Ci2, -H), 7.2-7.02 (m, 3H, Cs .-Cn.-H), 6.70 (s, 1H, Cs-H), 6.35 (s, IH, C12-H), 5.85 (dd, 1H, Cw-H), 5.39 (s, 1H, Cn-H), 5.30 (d, 1H, Cis-H), 4.75,4.15 (2H, JabIOHz,> Na-CH2-O-), 4.0 (s, IH, C2-H), 3.803.75 (2s, 6H, CO2CH3), 3.65 (s, 3H, C11-OCH3), 2.75 (s, IH, C21-H), 2.10 (s, 1H, OCOCHs), 0.7-1.0 (3t, 9H, CHs groups).

MS m / e: 924 (M +, 100%), 906, 893, 865, 822, 810,765,751, 737,651,650,649,469,455,355,282,154, 135, 122.

Example 4

N-Desmethyl-N- (benzyloxymethyl) vinblastine The procedure described in Example 2 is followed, with the difference that 4.3 ml of benzyl alcohol are used instead of the isobutanol. After a reaction time of 45 minutes, 4 ml of a crude oily consistency product are obtained, which is isolated by means of preparative paper chromatography (adsorbent: silica gel PF254 + 366 ', solvent mixture: mixture of 100 ml dichloromethane and 8 ml methanol). Yield: 75 mg (15%), mp: 215-218 ° C (methylene chloride ether).

IR (KBr): 3400 (OH, NH), 1740 (CO2CH3), 1610, 1230 cm "1 (OAc).

'H NMR (CDCb, 100 MHz): 5 3.07 (s, 1H, NaH), 7.52 (m, 1H, Ci2, -H), 7.2-7.8 (m, 3H, Cv -Cii, -H), 3H aromatic), 6.75 (s, 1H, Co-H), 6.20 (s, IH, C12-H), 5.85 (dd, 1H, Cm-H), 5.41 (s, 1H, Cn-H), 5.30 (d, 1H, Cis-H), 4.80.4.20 (2H, Jab 10 Hz,> Na-CH2-0-), 4 , 40 (s, 2H, benzyl-CH2), 4.00 (s, 1H, C2-H), 3.70, 3.68 (2s, 6H, CO2CH3), 3.63 (s, 3H, C11- OCH3), 2.75 (s, IH, C21-H), 1.0-0.70 (2t, 6H, CHs groups).

MS m / e: 916 (M +, 100%), 885, 857, 822, 810,796,779,757, 751,737,651,650,649,514,355,346,329,282,154, 135.

Example 5

N-Desmethyl-N- (methoxymethyl) vinblastine 5 g (5.5 mmol) of vinblastine sulfate are dissolved in 150 ml of water. The vinblastine base is released by adding concentrated ammonia (pH 8) and extracted with four 50 ml portions of dichloromethane. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness in vacuo. 4 g of vinblastine base are obtained. The substance is dissolved in a mixture of 1000 ml of alcohol-free dichloromethane, 120 ml of acetic acid and 6 ml of methanol and the solution is cooled to -55 ° C. The solution, cooled to -55 ° C., of 2.5 g (25 mmol) of chromium trioxide in 470 ml of acetic anhydride is added to the solution within about 5 minutes. The reaction mixture is stirred at -55 ° C for 45 minutes and then poured into a mixture of 940 ml of concentrated ammonia and 940 ml of ice water. Care is taken to ensure that the temperature s

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does not rise above 30 ° C. The phases are then separated and the organic phase is shaken out with 1 liter of 1% ammonia. The organic phase is then separated off, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The 3.8 g of crude product obtained are purified by column chromatography. The column consists of 230 g of activity II-III aluminum oxide (Brockmann) and is conditioned with benzene. The crude product is dissolved in 20 ml of a mixture of benzene and chloroform prepared in a ratio of 8: 2 and applied to the column. Elute with the same solvent mixture (about 8 liters), and 100 ml fractions are collected. The fractions containing an identical substance are combined and evaporated (adsorbent: silica gel; flow agent: benzene, ethanol, diethylamine, diethyl ether in a ratio of 5: 5: 5: 100). 2.1 g of product are obtained. After recrystallization from 6 ml of ethanol, the yield is 1.5 g. The physical constants correspond to those of the product according to Example 1.

Example 6

N-Desmethyl-N- (propoxymethyl) vinblastine The procedure described in Example 5 is followed, but 4.5 ml of propanol are used instead of methanol. 0.6 g of the above product are obtained, which melts at 200-210 ° C. [a] o = + 31.2 ° (c = 1, chloroform).

'H NMR (CDCb, 100 MHz): 5 9.05 (s, 1H, Cie-OH), 8.06 (s, 1H, NaH), 7.34 (m, 1H, Ci2, -H), 7.34-7.12 (m, 3H, Cs, -Cn, -H), 6.68 (s, 1H, Cs-H), 6.35 (s, 1H, Ci2-H), 5.84 (dd, IH, Ci4-H), 5.36 (s, IH, Cit-H), 5.28 (d, IH, C15-H), 4.75, 4.15 (2H, Jab 10 Hz, Na-Cto-O -), 4.18 (s, IH, C2-H), 3.78 (s, 3H, CO2CH3), 3.75 (s, 3H, C11-OCH3), 3.62 (s , 3H, CO2CH3), 2.73 (s, IH, C21-H), 2.09 (s, 3H, OCOCHs), 0.65-0.94 (m, 9H, CH3 groups)

Example 7

N-Desmethyl-N- (methoxymethyl) vinblastine The procedure described in Example 1 is followed, but vinblastine dihydrochloride is used instead of the vinblastine sulfate. The physical constants of the product obtained in 28% yield correspond to those given in Example 1.

Example 8

N-Desmethyl-N- (methoxymethyl) vinblastine The procedure described in Example 1 is followed, but alcohol-free chloroform, dichloroethane or acetone is used instead of dichloromethane. Yield: 40-50% (depending on the solvent used). The physical data correspond to those given in Example 1.

10 Example 9

N-Desmethyl-N- (methoxymethyl) -20'-deoxy-leurosidine 60 mg (0.067 mmol) 20'-deoxy-leurosidine sulfate (which is obtained by catalytic hydrogenation of 3 ', 4'-anhydro-vinblastine in methanol with palladium-carbon and is then produced sulfate) are dissolved in a mixture of 20 ml of absolute dichloromethane, 1.5 ml of glacial acetic acid and 0.5 ml of methanol. The solution is cooled to -55 ° C and a solution of 30 mg (0.3 mmol) of chromium trioxide in 3.5 ml of acetic anhydride, cooled to -55 ° C, is added. The reaction takes place within 60 minutes. The reaction mixture is concentrated in a mixture of 12 ml. Poured in ammonia and 12 g of ice. When the phases have separated from one another, the aqueous phase is shaken out three times with 10 ml of dichloromethane. The combined organic phases are washed twice with 10 ml of 1: 1 diluted ammonia and then with 2x5 ml of water. After drying, the organic phase is evaporated. 48 mg of crude product are obtained, which is purified by column chromatography (adsorbent: silica gel 30 0.040-0.063 mm, Merck, Art. 9385; solvent: dichloromethane, then dichloromethane containing 3% methanol). 18 mg (32%) of product are obtained, which melts at 185-190 ° C. with decomposition. [a] d = +50 (c = 1, chloroform). IR (KBr): 3400 (NH), 1720 (C02CH3), 1610.1230 cm "'(OAc) 35 46 mg (22%) N-desmethyl-N-formyl-20'-deoxy- leurosidine, mp: 205-210 ° (decomposition), [a] D = + 54 ° (c = l, chloroform)

40 'H NMR of the main product (CDCb): 8 7.95 (s, 1H, Na-H), 7.54 (m, IH, C12-H), 7.2-7.1 (m, 3H, C9, -Cii, -H), 6.56 (s, 1H, C9-H), 6.11 (s, 1H, Ci2-H), 5.87 (dd, 1H, Cm-H), 5, 46 (s, IH, C17-H), 5.37 (d, 1H, Cis-H), 4.72.4.15 (2H,> Na-CH2-0-), 3.80.3.75 , 3.61 (9H, CO2CH3, C11-OCH3), 2.11 (s, 1H, 45 OCOCH3), 1.0-0.6 (6H, CHs groups).

B

Claims (17)

648320 2. N-desmethyl-N- (methoxymethyl) vinblastine according to claim 1. 2nd PATENT CLAIMS 1. Compounds of general formula I HO wherein R4 stands for ß-hydroxyl and R3 for a-ethyl or R4 for hydrogen and R3 for ß-ethyl, R "is a straight-chain alkyl group with 1 or 3-10 carbon atoms, a branched alkyl group with 3-10 carbon atoms, the carbon atom bonded to the> N-CH2-0 group being a primary or secondary carbon atom, or one in the alkyl part 1-3 Arylalkyl group containing carbon atoms. R1 stands for methoxy group and R2 for the acetyl group. 3rd 648 320 3. N-desmethyl-N- (isobutoxymethyl) vinblastine according to claim 1. 4. N-desmethyl-N- (heptoxymethyl) vinblastine according to claim 1. 5 5. N-desmethyl-N- (benzyloxymethyl) vinblastine according to claim 1. 6. N-desmethyl-N- (propoxymethyl) vinblastine according to claim 1. 7. N-desmethyl-N- (methoxymethyl) -20'-deoxy-leuro-sidin according to claim 1. 8. Process for the preparation of compounds of general formula I. HO CUi 0 <£ " wherein R4 for ß-hydroxyl and R3 for α-ethyl or R4 for hydrogen and R3 for ß-ethyl are R "a straight-chain alkyl group with 1 or 3-10 carbon atoms, a branched alkyl group with 3-10 carbon atoms, which is the> N -CH2-0- group carbon atom is a primary or secondary carbon atom, or an arylalkyl group containing 1-3 carbon atoms in the alkyl part, R1 for the methoxy group, and R2 represents the acetyl group, characterized in that compounds of the general formula II or their acid addition salts with an excess of an alcohol of the general formula III R "-OH (III) wherein the meaning of R "is the same as above, in the presence of chromium trioxide in a suitable organic solvent in an acidic medium at temperatures between -60 and -30 ° C, adjust the pH of the reaction mixture to 8-10 and the resulting Compound of the general formula I isolated. 9. The method according to claim 8, characterized in that the alcohol of general formula III, based on the compound of general formula II, is used in 50-150 times the equimolar amount. 10th is 20th 25th 30th 35 40 45 50 55 60 65 10. The method according to claim 8, characterized in that chlorinated hydrocarbons are used as the organic solvent. 11. The method according to claim 8 for the preparation of N-desmethyl-N- (methoxymethyl) vinblastine, characterized in that vinblastine or its acid addition salt is reacted with methanol in the presence of chromium trioxide. 12. The method according to claim 8 for the preparation of N-desmethyl-N- (propoxymethyl) vinblastine, characterized in that vinblastine or its acid addition salt is reacted with propanol in the presence of chromium trioxide. 13. The method according to claim 8 for the preparation of N-desmethyl-N- (isobutoxymethyl) vinblastine, characterized in that vinblastine or its acid addition salt is reacted with isobutanol in the presence of chromium trioxide. 14. The method according to claim 8 for the preparation of N-desmethyl-N- (heptoxymethyl) vinblastine, characterized in that vinblastine or its acid addition salt is reacted with 1-heptanol in the presence of chromium trioxide. 15. The method according to claim 8 for the preparation of N-desmethyl-N- (benzyloxymethyl) vinblastine, characterized in that vinblastine or its acid addition salt is reacted with benzyl alcohol in the presence of chromium trioxide. 16. The method according to claim 8 for the preparation of N-DesmethyI-N- (methoxymethyI) -20'-deoxy-Ieurosidin, characterized in that 20 '-deoxy-leurosidin s or its acid addition salt is reacted with methanol in the presence of chromium trioxide. 17. Medicament, characterized in that it contains at least one compound of the general formula I as active ingredient (I) OR " bliss R4 stands for ß-hydroxyl and R3 for a-ethyl or R4 for hydrogen and R3 for ß-ethyl, R "is a straight-chain alkyl group with 1 or 3-10 carbon atoms, a branched alkyl group with 3-10 carbon atoms, the carbon atom bonded to the> N-CH2-0 group being a primary or secondary carbon atom, or one in the alkyl part 1-3 Arylalkyl group containing carbon atoms means R1 contains the methoxy group and R2 represents the acetyl group.