CH635106A5 - Dimeric indolodihydroindoles, processes for their preparation, and their use - Google Patents

Description

The invention further relates to antitumor drugs which contain a compound of the formula I or a pharmaceutically acceptable salt therein as the active ingredient component. R: the group CHO or, if R 'is the group OH, the subject of the invention is also a process for the manufacture of the group CH ,, one of the residues of compounds of the formula in which

R1 is the group OH or O-C-CHj,

O

1 2

7 '6' y * \ ^

11 'T — f

R

.. ii i17. r

N f ^ -C-O-CHs

I II

H 0

f

I o

II

Formula (II)

V8 \

-N 7

CHsO-Ov 6

1

»

3 | S |

CHz

/

, CH:

CHO

C-O-CHa

II

0

in what mean

R1 the group OH or O-C-CH3,

O

40

one of the leftovers

R3 and R4 are hydrogen and the other of these radicals is the group C2H5, or its salts, which is characterized in that a dimeric 1-methyl indole dihydroindole of the formula

• r

\ 1 O 'e a'

y-y

5 '

«R3 3 '•

Formula (III)

e M "C-O-CH3

'! "h; 0

9 / aN -N

CHsO—

ü 9 IN 7 *

'v \ t ° A} • / •

1 ° r l

V »V ^ OH '

CH3

C-0-CH3

II

0

635 106

6

where R1. R '' and R4 have the meanings given above. The invention further relates to a process for the preparation of dimeric 4-deacetylindole dihydroindoles with a chromic acid oxidizing agent at a low temperature and the free base or a salt thereof is obtained. formula

9 m 4 <

11 I il9 '

/ * 1 o '* s' »s

, / \ \ 8 'X /

IS '? * • Ç "2

M 4'nA R-

17th

1 3 'A 1 6' A '1 8' «1 '

V'V Vc

I.

H

Formula (IV)

r-o-11

0

CHsO— <

»

y> \

f bl 71

1 '° I I

I A 1 A e1

ff V

• • e O •

4th

CHz

/

£ ms

® ^ 0H

R

C-O-CHs

II

0

in what mean

R ~ the group CH3 or CHO and one of the residues

R3 and R4 are hydrogen and the other of these radicals is the group CiHs, or their salts, which is characterized in that a dimeric 4-acetoxyindole dihydroindoI of the formula

40 5 '

11, o

- î — L-4 '

y V ° 'V <= 7

, 8T W.Y.

V5 V Vc-o-CH3

f R "

Formula (V)

I.

H

0

e

9 / 8N

Fl 7J

iA

fi 5

I 13

CHsO-i16 ®.

\ A / ^

CHa

é ~ 0-C-CH3 II

e ^ OH

/

.CHs

0

R "

C-0-CH3

II

0

where R :. R3 and R4 have the meanings given above. hydrolyzed in a reaction mixture and the free base or a salt of the 4-deacetyl compound is obtained.

The dimeric indole dihydroindoles of formula I inhibit tumors in acid hosts.

Several naturally occurring alkaloids that can be obtained from Vinca rosea have been shown to be effective in treating experimental malignant ulcers in animals.

These include leurosine (US Pat. No. 3370057), vincaleukoblastin (vinblastine), hereinafter referred to as VLB (US Pat. No. 3097137), leurosidine (vinrosidine) and leurocristine (VCR or vincristine) (both in US Pat. No. 3205220), 4 '-Deoxy-VLB "A" and "B", Tetrahedron Letters, 783 (1968) (desacetylleurosine hydrazide is also described there), 4-desacetoxyvinblastine (US Pat. No. 3,945,554), leurocolombin (US Pat. No. 3,890,325), leuroformin (N-formylleurosin , BE-PS 811110) and Vincadiolin (US-PS 3 887 565). Two of these alkaloids, VLB and leurocristine, are already commercially available as medicines for the treatment of malignancies, particularly leukemias and related diseases in humans.

The dimeric indoldihydroindolal kaloids obtainable from Vinca rosea can be represented by the formula I.

In this formula, if R1 is acetoxy, R2 is methyl, R3 is hydroxyl, R4 is ethyl and R 'is hydrogen, then it is VLB; when R1 is acetoxy, R2 is formyl, R3 is hydroxyl, R4 is ethyl and R1 is hydrogen, it is vincristine; when R1 is acetoxy, R2 is methyl, R3 is ethyl, R4 is hydroxyl and R5 is hydrogen, it is leurosidine; if R1 is acetoxy, R2 is methyl, R3 and R? Is hydrogen and R4 is ethyl, it is 4'-deoxy-VLB "A"; if R1, R2 and R5 have the same meanings as for 4'-deoxy VLB "A", but R3 is ethyl and R4 is hydrogen, it is 4'-deoxy-VLB "B" and if R1 is acetoxy, R2 methyl, R3 ethyl and R4 and R5 together represent an alpha epoxy ring, it is leurosine.

Of the above-mentioned alkaloids, vincristine is the most advantageous but also the least available from vinca. Recently, an oxidative process for converting the relatively abundant VLB to vincristine by chromic acid oxidation at low (-60 ° C) temperatures has been developed (US Pat. No. 3,899,493). The fraction of vinca containing dimeric indodihydroindoles contains other relatively abundant alkaloids such as leurosine and it would be desirable to convert them directly or indirectly into vincristine or another active ingredient with a comparable oncolytic effect. It is known that leurosine can be converted into 4'-deoxy-VLB "B" (in addition to fluctuating amounts of 4'-deoxy-VLB "A") by treatment with Raney nickel in absolute ethanol when boiling under reflux - compare Neuss , Gorman, Cone and Huckstep, Tetrahedron Letters 783-7 (1968). Although leurosine has shown oncolytic efficacy in experimental tumors in mice, the clinical effect is limited. 4'-Deoxy-VLB "A" and 4'-deoxy-VLB "B" have been reported to lack reproducible effects in experimental tumors in mice.

The object of the invention is the conversion of leurosine via 4'-deoxy-VLB "A" and "B" into oncolytically active derivatives of 4'-deoxy-VLB "A" and "B" and thus the indirect transfer of the relatively abundant alkaloid Leurosin into an active ingredient of greater clinical utility.

A compound of the formula I in which R4 is ethyl, R 'is acetoxy, R: CHO and R3 and R ^ are hydrogen atoms is referred to as 4'-deoxyvincristine. A compound in which formula R1 is hydroxv but the other groups are the same is called 4'-deoxy-4-deacetylvincristine. Since the accompanying caloid of vincristine, which is at 4 'the opposite

635 106

If the configuration of hydrogen and ethyl is not known as that found in vincristine, the compounds in the formula in which R3 is ethyl and R4 is hydrogen are referred back to leurosidine which has the same configuration at 4 'as 4'-deoxy-VLB "B "and referred to as derivatives of 1-formylleuro-sidin, i.e. H. as 4'-deoxy-l-formylleurosidine (or 4'-deoxyepivincristine), and as 4'-deoxy-4-deacetyl-l-formylleu-rosidine when R1 is acetoxy or hydroxy. It can be seen from each of the above designations that the 1-methyl group of leurosidine has been replaced by a formyl group and that the term "1-desmethyl" has been omitted for simplicity.

Non-toxic acids which are suitable for the preparation of pharmaceutically acceptable acid addition salts of the compounds according to the invention include, in particular, inorganic acids, such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid and phosphorous acid, and organic acids, such as aliphatic mono - And dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic and -alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like. The pharmaceutically acceptable salts thus preferably include the sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates , Isobutyrates, caprates, heptanoates, propalates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, benzoates, chlorobenzoates, methylbenzoates, dinotrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, benzene sulfonate sulfonates, toluenesulfonyl sulfonates, toluenesulfonyl sulfonates, toluenesulfonyl sulfonates, toluenesulfonyl sulfonates, toluenesulfonyl sulfonates, toluenesulfonyl sulfonates, toluenesulfonyl sulfonates , Phenylacetate, Phenylpropionate, Phenylbutyrate, Citrate, Lactate, 2-Hydroxybutyrate, Glycol-late. Malates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates and naphthalene-2-sulfonates.

The compounds according to the invention, in the formula IR2 of which means formyl, are by low-temperature oxidation of 4'-deoxy-VLB "A" or 4'-deoxy-VLB "B" with chromic acid, preferably under acidic conditions, for. B. with chromium trioxide and acetic acid.

4'-Deoxy-VLB "A" and "B" or their 1-formyl derivatives can be hydrolyzed to the corresponding 4-deacetyl derivatives under acidic or alkaline conditions. These 4-deacetyl derivatives of 4'-deoxy-VLB "A" and "B" can then be converted into 4'-deoxy-4-deacetylvincristine and with chromium trioxide at low temperature (-60 ° C) without converting the 4-hydroxy group into a ketone 4'-Deoxy-4-deacetyl-l-formylleurosidine can be oxidized.

In the preferred mode of performing the above hydrolysis, sodium carbonate in methanol is used at the reflux temperature. Hydrazine hydrate can be used. Other bases that can be used are e.g. potassium t-butoxide, sodium or potassium methoxide or ethoxide, pyridine triethylamine or other tertiary amines and urea in polar organic solvents, e.g. B. the lower alkanols. Dilute sodium and potassium hydroxide can also be used, for example in methanol, but care must be taken to avoid base concentrations and reaction temperatures at which other hydrolyzable groups in 4'-deoxyvincristine or 4'-deoxy-l-formylleurosidine are affected will. Bases acting only in non-polar solvents can also be used, i.e. Sodium or lithium hydride in benzene, ether or tetrahydrofuran or the sodium salt of dimethyl sulfoxide in DMSO. Temperatures between room temperature (25 ° C) and the boiling point of the respective solvent can be used. The hydrolysis can also be carried out under acidic conditions, for example

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

635 106

8th

io

15

play in absolute methanol saturated with anhydrous hydrogen chloride at 0 ° C.

The invention is further illustrated by the following examples.

Example 1 Preparation of 4'-deoxyvincristine 582 mg of chromium trioxide are dissolved in 5.8 ml of acetic acid and 0.6 ml of water. This oxidizing solution is added dropwise to a solution of 4.62 mg of 4'-deoxy-VLB "A" in 58 ml of acetone and 2.9 ml of glacial acetic acid at about -50 ° C. over 5 minutes with stirring. The reaction mixture is stirred at this temperature for about 30 minutes and then cooled to -65 ° C. and 12 ml of 14N aqueous ammonium hydroxide are added at this temperature. The alkalized reaction mixture is then poured onto 400 ml of a mixture of ice and water, and the aqueous layer is extracted with 150 ml of ether and then three times with 150 ml of chloroform. The organic layers are combined and washed with dilute aqueous sodium bisulfite, separated and dried. Evaporation of the organic solvents gives 4'-deoxyvin-cristine as a residue. The chromatography of this residue on 50 g of silicon dioxide (activity I) is used for further purification of the desired compound. The chromatogram is developed as follows: 300 ml of ethyl acetate-methanol (3: 1) and then 300 ml of ethyl acetate-methanol (1: 1). After a preliminary run of 100 ml, 20 ml fractions are collected. Fractions 8 to 20 are pooled. Evaporation of the solvents from the combined fractions gives 279 mg of a light brown solid which gives only one spot in thin layer chromatography, ie is pure.

solvent

amount

1: 1

20%

200

1: 1

30%

100

1: 1

45%

100

1: 1

60%

400

the following fractions will be obtained:

fraction

Volume of the eluate

1

160 ml

2nd

100 ml

3rd

50 ml

4th

50 ml

5

50 ml

6

120 ml

7

120 ml

25th

30th

The free base of 4'-deoxyvincristine thus obtained has the following physical characteristic number:

Mass spectrum: m / e 808 (M +), 806, 707 Infrared spectrum: 3465.1745, 1687, 1220 cm-1 Ultraviolet spectrum: 210, 222, 255, 290, 298 nm 100 MHz NMR spectrum: methyl singlet at 3.88.3, 67 and 2.07 delta.

4'-Deoxyvincristin is dissolved as a brownish solid in acetone, and 0.96 ml of 0.36 m (2%, v / v) sulfuric acid in absolute ethanol is added to the acetone solution. A green solution is formed which is left to stand at about 0 ° C overnight. Crystallization is initiated by scratching or seeding and the solid crystalline 4'-deoxyvincristine sulfate is filtered off. The filter residue is washed with cold acetone. The sulfate is somewhat soluble in acetone, which is why the filtrate is evaporated to dryness and the residue obtained is recrystallized from ethanol. The crystalline 4'-deoxyvincristine sulfate thus obtained is filtered off and the filter residue is washed with ethanol. The overall yield of 4'-deoxyvincristine sulfate is 266 mg.

In the same way, 794 mg of 4'-deoxy-VLB «B» with 900 mg of chromium trioxide in 10 ml of glacial acetic acid and 1 ml of water can be oxidized to 4'-deoxy-1-formylleurosidine. Thin layer chromatography of the residue, which is obtained directly from the oxidation mixture before cleaning, shows the presence of a larger and a smaller spot as well as traces of other constituents. By recrystallizing the residue from anhydrous ethanol, after filtering off and washing the residue with cold ethanol, pure crystalline material is obtained which gives only one stain.

When the crystalline free base thus obtained was chromatographed on 50 g of silicon dioxide using a solvent system composed of equal parts of methylene dichloride and ethyl acetate, which contained 20.30, 45 and 60% by volume of methanol, respectively, as follows:

35

40

45

50

55

60

Fractions 4 to 7 are combined and give 597 mg of a brownish residue, from which in turn 435 mg of white crystalline 4'-deoxy-l-formylleurosidine are obtained (from ethanol). The connection has the following physical characteristics:

Mass spectrum: m / e 808 (M +), 806, 777, 775, 336, 138, 136. Infrared spectrum: (CHC13) 3470, 1743, 1690, 1222 cm-1. Ultraviolet spectrum: (C2H5OH) 210, 222, 254, 290, 298 nm. 100 MHz NMR spectrum: methyl singlet 3.87.3.65 and 2.07 delta.

pKa '= 9.0 and 4.9 (in 66% DMF).

The sulfate is prepared by dissolving 435 mg of the free base in 10 ml of warm ethanol and adding 1.5 ml of 2 percent sulfuric acid in ethanol. Crystalline 4'-deoxy-l-formylleurosidine sulfate separates out on cooling.

Example 2

Preparation of 4'-deoxy-4-deacetyl-l-formylleurosidine 744 mg of 4'-deoxy-l-formylleurosidine are mixed with 10 ml of anhydrous methanol, and the mixture is heated to boiling under reflux, the solid dissolving and a clear Solution is obtained. After adding 200 mg of solid sodium carbonate, the reaction mixture is stirred for 7.2 hours, after which the thin-layer chromatogram of the crude reaction product shows that practically all of the 4'-deoxy-l-formylleurosidine used as starting material has disappeared. The solvent is evaporated and the residue containing the 4'-deoxy-4-deacetyl-l-formylleurosidine formed in the above-described reaction is partitioned between water and methylene dichloride. The organic layer is separated and dried and, after evaporation of the solvent, provides 506 mg of a white solid substance which is practically pure 4'-deoxy-4-deacetyl-l-formylleu-rosidine.

The connection has the following physical characteristics: Mass spectrum: m / e 766 (M +), 764, 735, 254, 252, 205, 138 Infrared spectrum: (CHC13) 3450.1734.1680.1595.1495.1456, 1434 cm- '.

100 MHz NMR spectrum: (CDC13) shows N-formyl at delta 8.80, methyl singlet at 3.89 (C, 6-OCH3) and 3.66 (CiS-C02CH3), broadened multiplet at 3.82 (C3- C02CH3), and no N-CH3 at about 2.75 (or OCOCH3 at about 2.06).

The corresponding sulfate is prepared as described in the following examples using acetone as solvent and 0.26 ml of 2 percent sulfuric acid in ethanol. Other solvents can be used, and it is preferred to use a solvent in which the base is light but the sulfate is not soluble.

9 635 106

4'-Deoxy-4-deacetyl vincristine and its sulfate are prepared in the 834 mg 4'-deoxy-4-deacetylleurosidine, which from filtrates in the same way from 4'-deoxyvincristine. obtained, and containing about 30 to 40% of the polar material mentioned above, are dissolved in a mixture of 100 ml of Example 3 acetone and 7 ml of acetic acid. The solution is stirred for 15 minutes. Further possible procedure for the preparation of 4'-deoxy-5 at room temperature and then cooled to -65 ° C. in a dry ice-4-deacetyl-l-formyl-leurosidine acetone bath under a nitrogen atmosphere. 1110 mg of chromium trioxide are dissolved in 13 ml of glacial acetic acid and 2 ml of a reaction mixture of 1,48g4'-deoxy-VLB «B», 1 g of water. This solution is added dropwise to the sodium carbonate solution and 100 ml of methanol is added under a stick of 4'-deoxy-4-deacetylleurosidine. The reaction atmosphere is heated to boiling under reflux. The ionic mixture is stirred for 1 hour in the temperature range from -60 to thin-layer chromatography of a -65 ° C. taken after 2 hours and then with 35 ml of 14 M aqueous ammonium hyen sample shows that hydrolysis to remove the 4-hydroxide is added. Then it is poured onto ice and the acetyl group formed has expired only about halfway. After standing aqueous suspension is left several times with chloroform, the reaction is carried out overnight at room temperature. The chloroform extracts are combined, mixed with water again for 8: hours at the boil under reflux and dried. Heated by removing the chloroform. Thin layer chromatography of a sample under vacuum gives 794 mg of a residue, the use of ether / diethylamine / toluene / methanol thin layer chromatography shows that it consists of material (20: 1: 1: 1) shows that the reaction is now complete has gone. The residue obtained after evaporation of the solvent, apart from the original contamination with a very low residue, tends to give only one stain. This residue is dissolved in a mixture of methylene dichloride and water. 20 Woelm silica gel using an initial elution with the methylene dichloride layer is separated and dried. Using ethyl ether / diethylamine / toluene (20: 1: 1) with a residue of 0.9% methanol obtained by evaporation of the solvent. According to its thin layer chromatogram, the elution agent contains a very small amount of 150 ml. The percentage polar substance and the expected 4'-deoxy-4-deacetylleurosi content of methanol is din with each subsequent 150 ml portion. The 1.33 g residue is dissolved in benzene, increased 25 to 15%. The fractions whose thin-layer tomato-in which the highly polar material is practically insoluble and shows by grammes that they are 4'-deoxy-4-deacetyl-1-formylleurosidine filtered off. The filtrate is contained to dryness, is combined and, after evaporation of the vapor, gives and the residue, which makes up 500 mg, is made up of 293 mg of pure 4'-deoxy-4-deacetyl-1-formylleu silica gel using Woelm solvent using ether / Diethylamine / toluene rosidine. The sulfate is made as described above. (20: 1: 1) as a solvent system (with increasing amounts of 30 4'-deoxy-4-deacetylvincristin can, as described above, methanol) chromatographed for elution. The course of the by methyl hydrolysis of 4'-deoxy-VLB "A" to 4'-deoxy-4-desace chromatography is followed by thin-layer chromatography veryl-VLB and oxidation of the latter compound with Cr03 and fractions in which 4'-deoxy -4-deacetylleurosidine in acetic acid at -60 ° C.

is proven, are united. After evaporation of the compounds of the formula I according to the invention, in particular

Solvent of the combined fractions, 348 mg of base 35, in particular those in whose formula R1 means acetoxy, are obtained with 1.28 ml of 2 percent sulfuric acid in metha-strong antitumor agent. The compound 4'-deoxy-4-deacetyl-

nol (0.36m) is added. By filtering 315 mg of 4'-leurosidine is also an oncolytic agent. To prove the

Obtain deoxy-4-deacetylleurosidine sulfate. Effectiveness of these drugs against transplanted tumors in

4'-Deoxy-4-desacetylleurosidin has the following physical mice, the active ingredient is intraperitoneally in a certain

Characteristics: 40 dose 7-10 days after tumor implantation or instead on

Mass spectrum: m / e 752 (M +), 750,693,691,555,338,240,138 administered on the first, fifth and ninth day after implantation.

Infrared spectrum: (CHC13) 3455.1724.1610.1497.1457, is sufficient.

1431 cm ~~ ^ _ Table I summarizes the results of several experiments.

100 MHz pmr spectrum: ô tms'5 9.43 (br s, 1, C3-OH), 7.92 (br s, set in which transplanted tumors in mice with

I, indole-NH), 7.47-7.63 (m, 1, C | ,, -H), 7.06-7.31 (m, 3, C, 2'.i4- 45 of a compound according to the invention successfully treated

H), 6.58 (s, 1, C | 4-H), 6.10 (s, 1, C17-H), 5.78-5.87 (m, 2, C6 7-H). (ROS is an abbreviation for Ridgeway osteogenes

4.10 (m, l, C4-H), 3.83 (s, 3, C16-OCH3), 3.78 (s, 3, C3-C02CH3), Sarcom, GLS for Gardner Lymphsarcom; P1534 (J) and L1210

3.70 (s, 1, C -> - H), 3.58 (s, 3, C18-CO2CH3), 2.75 (s, 3, N-CH3) are leukaemias; CA755 is an adenocarcinoma and B16istein

0.76-1.06 (in, 6, Co, ->, - H). "'' Melanoma).

so

Table I

connection

Tumor mg / kg x days

Type of administration percentage inhibition or prolongation of survival

4'-deoxy-l-desmethyl

B 16

0.9 X 3

IP

toxic

1-formylleurosidine,

0.25 - 0.6 x 3

IP

98-146

free base

755

0.6 x 3

IP

54

0.4 x 3

IP

73

0.25 X 3

IP

47

0.2 - 0.3 x 10

IP

toxic

0.06 - 0.135 x 10

IP

33-93

0.03 - 0.09 x 9

IP

8-72

P1534 (J)

0.18 x 10

IP

toxic

P1534 (J)

0.08 - 0.18 x 10

IP

9-46

GLS

0.25 - 0.6 X 3

IP

73-100

635 106

10th

Table I (continued)

percentage inhibition administration or prolongation

Tumor compound mg / kg x days

4'-deoxy-1-desmethyl-

GLS

0.18 x 3

IP

100

1 -formylleurosidine-

0.4 X 3

IP

100

sulfate

0.6 x 3

IP

toxic

0.25 x 3

IP

toxic

L1210

0.4-0.6 x 3

IP

toxic

0.25 x 3

IP

65 4

ROS

0.4 x 3

IP

100

0.18 x 3

IP

93

0.25 x 3

IP

toxic

4'-deoxyvincristine

B16

0.30 - 0.9 X 3

IP

36-143

sulfate

755

0.25-1.8 x 9-10

IP

toxic

0.06-0.13 x 9-10

IP

15-100

0.9 x 3

IP

toxic

0.1 -0.3 x 3

IP

36-100

GLS

0.4 - 0.6 x 3

IP

toxic

0.18-0.25 x 3

IP

62-94

4'-deoxy-4-deacetyl

B16

0.15-0.6 x 3

IP

31 - 62 5

1-desmethyl-1-formyl-

GLS

0.6 x 3

toxic ieurosidine sulfate

0.25 - 0.40 x 3

94-100

0.18 x 3

95

4'-deoxy-4-deacetyl

755

0.6 x 3

IP

toxic leurosidine sulfate

0.4 x 3

IP

37

0.25 x 3

IP

32

B16

0.6 x 3

IP

toxic

0.3 x 3

IP

103

0.15 x 3

IP

77 **

GLS

0.9 x 3

IP

toxic

0.6 x 3

IP

63

0.4 x 3

IP

toxic

:: 1 or more undefined survivors • postponed treatment on days 5, 9 and 13

When using the new compounds as an anti-tumor depends on the potency and the toxicity of the active ingredient,

Medium can be administered parenterally or orally. Another way of determining a therapeutic dose

Ways. For oral administration, a pharmaceutical is based on the body surface, with a dose in the range of a tolerably acceptable salt of a base of formula II with a 50 of 0.1 to 10 mg / m 2 body surface every 7 or 14 days of non-toxic acid, for example that Sulfate, with starch or administered.

mixed with another carrier and the mixture is mixed in

Gelatin capsules are introduced, which contain 7.5 to 50 mg of active ingredient. The antineoplastic salt can also be fertilized with starch, first the same route of administration and that of a binder or lubricant are mixed, and the mixture is chosen 55 identical carriers and the same type of tumors gently pressed to tablets, the 7.5 to 50 mg of the salt is as specified for vincristine or VLB. Included. The tablets can be indented so that the compounds according to the invention can be used in lower, divided or divided doses. The doses are administered as vincristine and VLB. In the case of clini-parenteral administration, however, is preferred. For this, see tests, as with other antitumor agents, uses special isotonic solutions which contain 1 to 10 mg / ml of a salt on the action of the oncolytic compounds of the inven- an indole dihydroindole of the formula II, for. B. the sulfate, against the ten “signal” tumors on the side. The compounds are used in ratios of 0.01 to 1 266 by “The Design of Clinical Trials in Canser Therapy” mg / kg , preferably from 0.1 to 1 mg / kg body weight entered or issued by Staquet (Futura Publishing Company, 1973), administered twice a week or every two weeks, as indicated by.

M

Claims (9)

635 106 PATENT CLAIMS 1. Dimer indole dihydroindoles of the general formula A 4 '> R4 11 '1 4' ' , A, o '\ 12 î n — ü î , 31 ü, a. SK's-v Formd (1) •, 1 5 N f-C-O-CHs 1 4 | - ~ C- 1] II 9/8 \ H i 0 | Tö 7j] 1 »è î -î e R® .CHS \ '^ \ / ru / M 5 S 9 59 "'- * ° CHS CHsO— »x 6- A Ì.2 4,« --- R1 ». . «9.2 I v "Xe \ / \: / ( 30th OH O I. D2 C-O-CHo II 0 in which 2. As compounds according to claim 1: R1 the group OH or O-C-CH3, 4'-deoxyvincristine, II 4'-deoxy-l-formylleurosidine, O 4'-deoxy-4-deacetyl-l-formylleurosidine, and 4'-deoxy-4-deacetylleurosidine and its salts. R2 represents the group CHO or, if R1 represents the group OH, 3. As compounds according to claim 1 or 2: the sulfates, the group CH3, one of the residues 4. Antitumor drugs containing an inert carrier ,, and a pharmaceutically active compound of the formula R and R are hydrogen and the other of these radicals is the group or pharmaceutically acceptable salt as an active ingredient. : r "40 5. Process for the preparation of dimeric 1-formyl-indoldi- R5 hydrogen, and their salts. hydroindoles of the formula 5 ' A R3 R4 ,, r-Y ^ -r , 2.f irx- T, M ç -— C 'f-C-O-CHc 14, l ©. H ! O II e i 7iî > X'A / I yTS-I CH3O— «v e es o -— R V / e \ / • N e — OH ! CHO C-O-CH3 II 0 635 106 in what mean R1 the group OH or O-C-CH ,, O one of the leftovers R1 and R4 are hydrogen and the other of these radicals is the group C2H5 or its salts, characterized in that a dimeric 1-methyl indole dihydroindole of the formula , K ET ,, f r.:4 - ./W'x? \? S> V Formula (III) I. H CH.? f — C-O-CHs ! S 9 / 8S i 1 ® 6.® i / iK \ 1 ^ \ / .CHs • CH2 wherein R ', R-' and R4 have the meanings given above, characterized in that the reaction is carried out at -50 to -65 ° C with a chromic acid oxidizing agent at low temperature. structure and the free base or a salt thereof is obtained. 35 3. The method according to claims 5 or 7 for the production of 6. The method according to claim 5 for the preparation of dimeric 1-dimeric 1-formyl-indoldihydroindole of the formula II, characterized in that formyl-indoldihydroindole of the formula II, characterized in that the reaction mixture contains acetone and Essignet that contains chromium trioxide and acid as chromic acid oxidizing agent. Acetic acid is used. 7. The method according to claim 5 or 6 for the preparation of 40 9. Process for the preparation of dimeric 4-deacetyindinedi-dimeric 1-formylindole dihydroindole of the formula II, thereby hydroindoles of the formula 11 r ~ Ln Formula (IV) / V ° Xs - \ ^ , a Î ou. r Y A, 5 / \, s / 1 ' 0 Fl 7 | T, / X CH Ii: if ~ i: Î ";; i H R ' C-O-CHs tl 0 635 106 4th wherein R "1 and R are hydrogen and the other of these radicals is the group R: the group CH, or CHO and one of the radicals C: H5, or their salts, characterized in that that a dimeric 4-acetoxvindole dihydroindole of the formula 5 ' - R3 P / - - - ; H 1 9 IO «5 3; . / \ \ 9 '\ /. :: i o-J :. it. / ~ v ° formula (V) > 1 f ^ -C-O-CHs 1- I 'U H O s / a V 'Fi 1 '<! 1 / \ jCHS r / 1 \ \ * y \ / m / 915 $ f '' "CHz 13 CH3O-O-C-CH3 s RS K C-O-CHs i! 0 wherein R2, R1 and R4 have the meanings given above, hydrolyzed in a reaction mixture and the 4-deacetylver bond is obtained as a free base or as a salt thereof. 35 The invention relates to derivatives of 4'-deoxy-VLB 10. The method according to claim 9 for the preparation of a dimeric "A" and 4'-deoxy-VLB "B". 4-deacetyl-indole-dihydroindole, characterized in that a dimeric 4-acetoxy-indole-dihydroindole with sodium car- The invention relates to dimeric indole dihydroindole bonate in anhydrous methanol. of the formula 635 106 R3 and R4 are hydrogen and the other of these radicals is the group C2H5, R5 is hydrogen, and salts of these compounds.