DE2801748A1 - DIMERE INDOLDIHYDROINDOLES, METHOD FOR THEIR MANUFACTURE AND USE - Google Patents

Description

PFENNING MAAS

MEIM IO - LEMKE - Mockery

SCKLE'SSHElMSfiSTR.

βΟΟΟ MUNICH 43

X-473OA

Eli Lilly and Company, Indianapolis, Indiana, V.St.A. Dimer indole dihydroindoles, process for their preparation and

their use

8098 2 9/0986

ΊΟ

The invention relates to derivatives of 4'-deoxy VLB "A" and 4'-Deoxy VLB "B".

The invention relates to dimeric indole dihydroindoles of the formula

5 '

7 'e' / \ f

it 'TV ^4> f

W Y

R ⁴

I H

9 / s \

frr ^CH2

CO-CH ₃

in which mean

the group OH or O-C-CH- ,,

Il -5

the group CHO or, if R denotes the group OH, the group CH. ,,

809529/0960

- / ■

ΑΛ

one of the radicals ₄ R and R

Hydrogen and

the other of these radicals is the group C ₃ H ₅ ,

R hydrogen,

and pharmaceutically acceptable salts of these compounds.

The invention also relates to the use of the compounds of the formula I or their pharmaceutically acceptable salts as active ingredients in pharmaceutical preparations which contain an inert carrier and have anti-tumor activity.

The invention is a process for the production of dimeric 1-formylindoldxhydroindoles of the formula

5 '

H- - - R ⁴

-O-CH3

CH30—

! CHO

Formula II,

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C-O-CHs

- y -

2301748

in which mean

the group OH or O-C-CH .. and

Ii -3

one of

₃ leftovers
R and R

Hydrogen and

the other

this rests the group

and their pharmaceutically acceptable salts, characterized in that that a dimeric 1-methylindole dihydroindole of the formula

⁷ '

s'

12'1
13 '«

CHaO-

Formula III,

CHa

δ09 »29 / 096δ

.Jf.

13 in which R, R and R have the meanings given above, reacted with a chromic acid oxidizing agent in a reaction mixture at low temperature and the free base or a a pharmaceutically acceptable salt is obtained therefrom.

The invention also relates to a process for the preparation of dimeric 4-deacetylindole dihydroindoles of the formula

- Formula IV ₇

in which mean

R is the group CH ₃ or CHO and

one of the ^ remnants . R and R are hydrogen and

the other of these remnants is the group

809 * 29/0966

and their pharmaceutically acceptable salts, characterized in that that a dimeric 4-acetoxyindoldxhydroxndole of the formula

7 '

Formula V,

2 3 4 in which R, R and R have the meanings given above,

hydrolyzed in a reaction mixture and the free base or a pharmaceutically acceptable salt of the 4-deacety! compound is won.

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

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

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These include Leurosin (US Pat. No. 3,337,057) and Vincaleukoblastin (Vinblastine), hereinafter referred to as VLB (US Pat. No. 3,097,137), Leurosidine (Vinrosidine) and Leurocristin (VCR or vincristine) (both in U.S. Patent No. 3,205,220), 4'-deoxy VLB "A" and "B", Tetrahedron Letters, 783 (1968) (desacetylleurosine hydrazide is also described there), 4-deacetoxyvinblastine (U.S. Patent 3,954,773), 4-deacetoxy-3'-hydroxyvinblastine (U.S. Patent 3,944,554), Leurocolombin (U.S. Patent 3,890,325), Leuroformin (N-Formy11eurosin, Belgian Patent 811,110) and vincadiolin (U.S. Patent 3,887,565). Two of these alkaloids, VLB and Leurocristin, are already in use as drugs to treat malignancies, particularly leukemia and related diseases in humans.

The dimeric indole dihydroindole alkaloids available from Vinca rosea can be represented by the formula I. if

1 2 3 4

xn dxeser formula R is acetoxy, R is methyl, R is hydroxyl, R is ethyl and R is hydrogen, then it is

1 2 3 4

VLB; when R acetoxy, R formyl, R hydroxyl, R ethyl and

5

R is hydrogen, it is vincristine; if R

2 3 4 5

Acetoxy, R methyl, R ethyl, R hydroxyl and R hydrogen

1 2

means if it is Leurosidin; when R is acetoxy, R

3 5 4

Methyl, R and R are hydrogen and R is ethyl

12 5 is 4'-deoxy VLB "A"; when R, R and R are the same Have the same meanings as for 4'-Deoxy VLB "A", but R is ethyl and R is hydrogen, it is 4'-deoxy VLB "B" and when R is acetoxy, R is methyl, R is ethyl and R and R together are an alpha-epoxy ring, it is Leurosin.

Of the alkaloids mentioned above, vincristine is the most beneficial, but also the one that can be obtained from Vinca in the smallest quantities. Recently, an oxidative process for the conversion of the relatively more abundant in VLB occurring vincristine was developed by Chromsäureoxxdation at low (-60 ⁰ C) temperatures (US Patent 3,899,493). In the fraction from Vinca containing dimeric indodihydroindoles there are more

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-y-

28017AÖ

Relatively abundant alkaloids such as Leurosirf * are preserved and it would be desirable to convert this directly or indirectly into vincristine or another active ingredient with comparable oncolytic Transfer effect. It is known that leurosin can be removed by treatment with Raney nickel in absolute ethanol upon boiling under reflux in 4'-deoxy VLB "B" (in addition to fluctuating amounts of 4'-Deoxy-VLB "A") can be transferred - compare Neuss, Gorman, Cone and Huckstep, Tetrahedron Letters 783-7 (1968). Leurosin does have oncolytic activity in experimental cases Tumors have been shown in mice, but the clinical effect is limited. 4'-Deoxy VLB "A" and 4'-Deoxy VLB "B" are reported been given that they have a reproducible effect in experimental Tumors in mice are absent.

The object of the invention is the transfer of leurosine. via 4'-deoxy VLB "A" and "B" into oncolytically effective derivatives of 4 ¹ -deoxy VLB "A" and "B" and thus the indirect conversion of the relatively abundant alkaloid leuurosine into an active ingredient of greater clinical benefit .

4 1 2

A compound of the formula I wherein R is ethyl, R is acetoxy, R

3 5
CHO and R and R represent hydrogen atoms, is referred to as 4'-deoxyvincristine. A compound in the formula of which R is hydroxy but the other groups are the same is called 4'-deoxy-4-deacetylvincristine. Since the accompanying alkaloid of vincristine, which at 4 'has the opposite configuration of hydrogen and ethyl to that found in vincristine, is not known, the compounds

3 4

fertilize, in the formula of which R is ethyl and R is hydrogen, based on Leurosidin, which at 4 ^{1 has} the same configuration as 4'-Deoxy-VLB "B", and 'as derivatives of 1-Formylleurosidin, ie as 4'- Deoxy-1-formylleurosidine (or 4'-deoxyepivincristine), and as 4'-deoxy-4-deacetyl-1-formylleurosidine when R stands for acetoxy or for hydroxy. It can be seen from each of the foregoing designations that the 1-methyl group of leuosidine has been replaced with a formyl group and that the term "1-desmethyl" has been omitted for simplicity.

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To non-toxic acids that can be used in the manufacture of pharmaceuticals acceptable acid addition salts of the invention Suitable compounds include inorganic acids, such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, Hydroiodic acid, nitrous acid and phosphorous acid Acid, and organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids and alkanedioic acids, aromatic acids, aliphatic and aromatic Sulfonic acids and the like. The pharmaceutically acceptable salts thus include the sulfates, pyrosulfates and bisulf ate, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, Chlorides, bromides, iodides, acetates, propionates, decanoates, Caprylates, acrylates, formates, isobutyrates, caprates, heptanoates, Propiolate, Oxalate, Malonate, Succinate, Suberate, Sebacate, Fumarates, maleates, benzoates, chlorobenzoates, methylbenzoates, Dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, Terephthalates, benzenesulfonates, toluenesulfonates, chlorobenzenesulfonates, xylenesulfonates, phenylacetates, phenylpropionates, Phenylbutyrate, citrate, lactate, 2-hydroxybutyrate, glycolate, Malates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates and naphthalene-2-sulfonates.

The compounds according to the invention, in whose formula I R denotes formyl, are obtained by low-temperature oxidation of 4'-deoxy VLB "A" or 4'-Deoxy-VLB "B" with chromic acid under acidic conditions, e.g. with chromium trioxide and acetic acid.

4'-Deoxy VLB "A" and ¹¹ 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 at a low temperature (-60 ⁰ C) with chromium trioxide without conversion of the 4-hydroxy group into a ketone to 4'-deoxy-4-desacetylvincristin and '4'-deoxy-4-desacetyl-1-formylleurosidin be oxidized.

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The preferred way of carrying out the above hydrolysis is sodium carbonate in methanol at reflux temperature. Hydrazine hydrate can be used. Other bases that can be used are, for example, potassium t-butoxide, sodium or potassium methoxide or ethoxide, pyridine triethylamine or other tertiary amines and urea in polar organic solvents, for example 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-1-formylleurosidine are affected will. Bases which only act in non-polar solvents can also be used, ie 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 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 was added dropwise within 5 minutes under stirring 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 of about -50 ⁰ C. The reaction mixture is at this temperature about

809829 / 09B6

Stirred for 30 minutes and then cooled to -65 ⁰ C and mixed at this temperature with 12 ml 14 n aqueous ammonium hydroxide. 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 each time. The organic layers are combined and washed with dilute aqueous sodium bisulfite, separated and dried. Evaporation of the organic solvents gives 4'-deoxyvincristine as a residue. The chromatography of this residue on 50 g of silicon dioxide (activity I) serves to further purify 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 forerun of 100 ml, 20 ml fractions are collected. Fractions 8 to 20 are combined. By evaporating the solvents from the combined fractions, 279 mg of a light brown solid are obtained which gives only one spot on thin layer chromatography, that is to say is pure.

The 4'-deoxyvincristine free base thus obtained has the following physical key figure:

Mass spectrum: m / e 808 (M ⁺ ), 806, 707 Infrared spectrum: 3465, 1745, 1687, 1220 cm " ¹ Ultravxolet spectrum: 210, 222, 255, 290, 298 with 100 MHz NMR spectrum: methyl singlets at 3.88, 3.67

and 2.07 delta,

4'-Deoxyvincristine is dissolved as a brownish solid in acetone, and the acetone solution is mixed with 0.96 ml of 0.36 M (2%, v / v) sulfuric acid added in absolute ethanol. A green one forms

809529/0966

Solution which is left to ^{stand at about 0} ° C. overnight. Crystallization is initiated by scraping 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 from ethanol is filtered off and the filter residue is washed with ethanol. The total yield of 4'-deoxyvincristine sulfate is 266 mg.

In the same way, 794 mg of 4'-deoxy-VLB ¹¹ B "can be oxidized with 900 mg of chromium trioxide in 10 ml of glacial acetic acid and 1 ml of water to give 4'-deoxy-1-formylleurosidine cleaning shows the presence of a major and minor stain and traces of other components Recrystallizing the residue from anhydrous ethanol, after filtering off and washing the residue with cold ethanol, gives pure crystalline material which gives only one spot.

In the chromatography of the crystalline free base thus obtained on 50 g of silica using a solvent system from equal parts of methylene dichloride and ethyl acetate, which contains 20, 30, 45 or 60 percent by volume of methanol, as eluent as follows:

solvent

1: 1 20% 1: 1 30% 1: 1 45% 1: 1 60%

200 100 100 400

809529/0966

1 60 50 ml 100 50 ml 50 ml 20th ml 20th ml 1 ml 1 ml

the following fractions are obtained:

Fraction volume of the eluate

1 2 3 4 5 6 7

Fractions 4 to 7 are combined and give 597 mg of a brownish residue, from which in turn 435 mg of white crystalline 4 ^l -deoxy-1-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: (CHCl ₃ ) 3470, 1743, 1690, 1222 cm " ¹ .

Ultraviolet spectrum: (C ₀ H ₁ -OH) 210, 222, 254, 290, 298 nm.

100 MHz Nuclear Magnetic Resonance Spectrum: methyl singlets 3.87, 3.65 and 2.07 delta.

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

The sulfate is made by dissolving 435 mg of the free base in 10 ml of warm ethanol and adding 1.5 ml of 2 percent sulfuric acid made in ethanol. Crystalline 4'-deoxy-1-formylleurosidine sulfate separates out on cooling.

Example 2 Preparation of 4'-deoxy-4-deacetyl-i-formylleurosidine

744 mg of 4'-deoxy-1-formylleurosidine are mixed with 10 ml of anhydrous Methanol is mixed and the mixture is heated to reflux, the solid dissolving and becoming a clear

809S29 / 0966

Solution is obtained. After adding 200 mg of solid sodium carbonate the reaction mixture is stirred for 7.2 hours, after which time the thin layer chromatogram of the crude reaction product shows that practically all of the 4'-deoxy-1-formylleurosidine used as the starting material disappeared. The solvent is evaporated and the residue, which is the same as in the one described above Reaction formed 4'-deoxy-4-deacetyl-i-formylleurosidine contains, is distributed between water and methylene dichloride. The organic layer is separated and dried and delivers after evaporation of the solvent 506 mg of a white, solid substance, the practically pure 4'-deoxy-4-deacetyl-iformylleurosidine represents.

The physical characteristics of the compound are as follows: Mass spectrum: m / e 766 (M ⁺ ), 764, 735, 254, 252, 205, 138

Infrared spectrum: (CHCl ₃ ) 3450, 1734, 1680, 1596, 1495, 1456, 1434 cm " ¹ .

100 MHz NMR Spectrum: (CDCl ₃ ) shows N-formyl at delta 8.80, methyl singlets _{at 3.89 (C 16 -OCH 3} ) and 3.66 (C ₁₈ -CO ₂ CH ₃ ), broadened multiplet at 3 , 82 (C ₃ -CO ₂ CH ₃ ), and no N-CH ₃ at about 2.75 (or OCOCH ₃ at about 2.06).

The corresponding sulfate is described as in the following examples, using acetone as the solvent and made from 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 easily soluble but the sulfate is not soluble.

4 ^l -deoxy-4-deacetylvincristine and its sulfate are prepared in the same way from 4'-deoxyvincristine.

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Example 3

Another possible procedure for the preparation of 4'-deoxy-4- deacetyl-1-formylleurosidine

A reaction mixture of 1.48 g of 4'-deoxy VLB "B", 1 g of sodium carbonate and 100 ml of methanol is added under a nitrogen atmosphere heated to reflux. Thin layer chromatography of a sample taken after 2 hours shows that the hydrolysis to remove the 4-acetyl group is only about has expired halfway. After standing overnight at room temperature, the reaction mixture is again for 8 1/2 hours heated to reflux. Thin-layer chromatography a sample using ether / diethylamine / toluene / methanol (20: 1: 1: 1) shows that the reaction is now too The end has passed. The residue obtained after evaporation of the solvent is dissolved in a mixture of methylene dichloride and dissolved in water. The methylene chloride layer is separated and dried. The by evaporation of the solvent The residue obtained contains, according to its thin-layer chromatogram, a very polar substance and the expected 4'-deoxy-4-deacetylleurosidine. The residue making up 1.33 g is dissolved in benzene, in which the strongly polar material is practically is insoluble and is separated by filtration. The filtrate is evaporated to dryness and the resulting 500 mg Residue is put on Woelm silica gel using ether / Diethylamine / toluene (20: 1: 1) as the solvent system (with increasing amounts of methanol) to elute. The course of the chromatography is followed by thin layer chromatography and fractions in which 4'-deoxy-4-deacetylleurosidine is proven are united. After evaporation of the solvent of the combined fractions, 348 mg of base are obtained obtained, which is mixed with 1.28 ml of 2 percent sulfuric acid in methanol (0.36m). Filtering gives 315 mg 4'-Deoxy-4-deacetylleurosidine sulfate was obtained.

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4'-Deoxy-4-deacetylleurosidine has the following physical properties Characteristics:

Mass spectrum: m / e 752 (M ⁺ ), 750, 693, 691, 555, 338, 240.138

Infrared spectrum: (CHCl ₃ ) 3455, 1724, 1610, 1497, 1457, 1431 cm " ¹

100 MHz pmr spectrum: S JJJg ¹ S 9.43 (br s, 1, C ₃ -OH), 7.92 (br s, 1, indole-NH), 7.47-7.63 (m, 1 , C ₁₁ -H), 7.06 to 7.31 (m, 3, C _12, _ _14, -H) _f 6.58 (s, 1, C ₁₄ -H), 6.10 (s, 1, C ₁₇ -H), 5.78-5.87 (m, 2, C _g? -H), 4.10 (m, 1, C ₄ -H), 3.83 (s, 3,
C ₁₆ -OCH ₃ ), 3.78 (s, 3, C ₃ -CO ₂ CH ₃ ), 3.70 (s, 1, C ₃ -H), 3.58 (s, 3, C ₁₈ -CO ₂ CH ₃ ), 2.75 (s, 3, N-CH ₃ ), 0.76-1.06 (m, 6,

^C 21.21 '~ ^H) '

834 mg of 4'-deoxy-4-deacetylleurosidine, obtained from filtrates and containing about 30 to 40% of the above-mentioned polar material, are dissolved in a mixture of 100 ml of acetone and 7 ml of acetic acid. The solution is stirred for 15 minutes at room temperature and then in a dry ice-acetone bath under an atmosphere of nitrogen, to -65 ⁰ C.
cooled down. 1110 mg of chromium trioxide are dissolved in 13 ml of glacial acetic acid and 2 ml of water. This solution is added dropwise to the solution of 4 · -deoxy-4-deacetylleurosidine. The reaction mixture is 1 hour in the temperature range of
-60 to -65 ⁰ C and then mixed with 35 ml of 14m aqueous ammonium hydroxide. It is then poured onto ice and the aqueous suspension formed is extracted several times with chloroform. The chloroform extracts are combined, washed with water and dried. Removal of the chloroform in vacuo gives 794 mg of a residue, the thin layer chromatography of which shows that it consists of material which

809829/0966

gives only one spot besides the original very low R _{f contamination.} This residue is chromatographed on Woelm silica gel using an initial eluent of ethyl ether / diethylamine / toluene (20: 1: 1) with a methanol content of 0.9%. The eluent is used in 150 ml portions. The percentage of methanol is increased to 15% with each subsequent 150 ml portion. The fractions whose Dünnschichtchtomatogramm shows that they contain 4 ^I -deoxy-4-desacetyl-1-formylleurosidin are combined and, after evaporation of the solvent 293 mg of pure 4'-deoxy-4-desacetyl-1-formylleurosidin. The sulfate is prepared as described above.

4'-Deoxy-4-deacetylvincristine can, as described above, by hydrolysis of 4'-deoxy-VLB "A" to 4'-deoxy-4-deacetyl-VLB and oxidation of the latter compound with CrO ₃ in acetic acid at -6O ⁰ C.

The compounds of the formula I according to the invention, in particular those in whose formula R is acetoxy, are powerful anti-tumor agents. The compound 4 ^f -deoxy-4-deacetylleurosidine is also an oncolytic agent. To demonstrate the effectiveness of these active ingredients against transplanted tumors in mice, the active ingredient is administered intraperitoneally in a specific dose 7 to 10 days after tumor implantation or instead on the first, fifth and ninth day after implantation.

In Table I the results of several tests are compiled, in which transplanted tumors in mice were successfully treated with a compound of the invention. (ROS is an abbreviation for Ridgeway osteogenic sarcoma, GLS for Gardner Lymphsarcoma; P1534 (J) and L1210 are leukemia; 755 is adenocarcinoma and B16 is melanoma).

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Tabel

link tumor mg / kg χ days Meet percent inhibition ro 4'-deoxy-1-desmethyl- B16 0.9 χ 3 type of operation or renewal CO 1-formylleurosidine, 0.25-0.6 χ 3 IP of survival free base 755 0.6 χ 3 IP toxic 0.4 χ 3 IP 98-146 0.25 χ 3 IP 54 0.2-0.3 χ 10 IP 73 0.06-0.135 X 10 IP 47 0.03-0.09 χ 9 IP toxic O P1534 (J) 0.18 χ 10 IP 33-93 co P1534 (J) 0.08-0.18 10 IP 8-72 cm GLS 0.25-0.6 χ 3 IP toxic ro 4'-deoxy-1-desmethyl- GLS 0.18 χ 3 IP 9-46 co 1-formylleurosidine 0.4 χ 3 IP 73-100 j ^ 9 O sulfate 0.6 χ 3 IP 100 σ> 0.25 χ 3 IP 100 σ> 1.1210 0.4-0.6 χ 3 IP toxic 0.25 χ 3 IP toxic ROS 0.4 χ 3 IP toxic 0.18 χ 3 IP 65 * 0.25 χ 3 IP 100 IP 93 toxic

* 1 or more undefined survivors

Table I (continued)

οσ σ co

tumor mg / kg χ days Meet percent inhibition B16 0.30-0.9 χ 3 type of operation or renewal link 755 0.25-1.8 χ 9-10 IP the survival time 4 -deoxyvincristine- 0.06-0.13 χ 9-10 IP 36-143 * sulfate 0.9 χ 3 IP toxic 0.1-0.3 χ 3 IP 15-100 GLS 0.4-0.6 χ 3 IP toxic 0.18-0.25 χ 3 IP 36-100 B16 0.15-0.6 χ 3 IP toxic GLS 0.6 χ 3 IP 62-94 4'-deoxy-4-deacetyl 0.25-0.40 χ 3 31-62 ** 1-desmethyl-1-formyl- 0.18 χ 3 toxic ^r leurosidine sulfate 755 0.6 χ 3 94-100 Jio 0.4 χ 3 IP 95 -fi 4'-deoxy-4-deacetyl 0.25 χ 3 IP toxic leurosidine sulfate B16 0.6 χ 3 IP 37 0.3 χ 3 IP 32 0.15 χ 3 - IP toxic** GLS 0.9 χ 3 IP 103 ** 0.6 χ 3 IP 77 ** 0.4 χ 3 IP toxic IP 63 toxic tsJ OO O

* 1 or more undefined survivors

postponed treatment on the 5th, 9th and 13th day

OO

When the new compounds are used as anti-tumor agents, administration can be by the parenteral or oral route. For oral administration, a pharmaceutically acceptable salt of a base of Formula II with a non-toxic acid, for example the sulfate, is mixed with starch or other carrier and the mixture is placed in gelatin capsules containing 7.5 to 50 mg of active ingredient. The antineoplastically active salt can also be mixed with starch, a binder or lubricant, and the mixture compressed into tablets which contain 7.5 to 50 mg of the salt. The tablets may be scored to allow lower or divided doses to be used. However, parenteral administration is preferred. For this purpose, isotonic solutions are used which contain 1 to 10 mg / ml of a salt of an indole dihydroindole of the formula II, for example the sulfate. The compounds are administered in proportions of 0.01 to 1 mg / kg, preferably 0.1 to 1 mg / kg of body weight, once or twice a week or every two weeks, depending on the potency and toxicity of the active ingredient. Another way of determining a therapeutic dose is based on the body surface area, with a dose in the range from 0.1 to 10 mg / m ² body surface area being administered every 7 or 14 days.

In the clinical application of the compounds according to the invention, the same type of administration and the the same carriers were chosen and the same type of tumors treated as indicated for vincristine or VLB. Included can use the compounds according to the invention in lower doses administered as vincristine and VLB. In clinical trials, as with other antitux norin drugs, special attention should be paid to to observe the effect of the oncolytic compounds of the invention against the ten "Signal" tumors described on page 266 of "The Design of Clinical Trials in Canser Therapy "edited by Staquet (Futura Publishing Company, 1973).

«09029/0966

Claims (21)

PrENNlNQ-MAAS MEINiG-LEMKE-Mockery 8CHLEiSSHEiMERSTR. 299 βΟΟΟ MUNICH 40 Claims Dimer indole dihydroxndoles of the general formula 11 ' ₄ > JR * -R ⁵ Forjuel I, K. • GH » C-O-CHs it in which mean the group OH or O-C-C 1 is the group CHO or, when R is the group OH means the group CH ₃ , 809829 / 096B ORIGINAL INSPECTED - Α4Ϊ - 2001748 one of the leftovers 3 4 R and R are hydrogen and the other of these remnants is the group R hydrogen, and their pharmaceutically acceptable salts, 2. Compounds according to claim 1 , in the formula R is the group O-C-CH 3 Ö means. 3. Compounds according to claim 1 , in whose formula R denotes the group OH. 4. As a compound according to claim 1 4'-deoxyvincristine. 5. As a compound according to claim 1 4'-deoxy-1-formylleurosidxn. 6. As a compound according to claim 1 4'-deoxy-4-deacetyl-iformylleurosidine. 809829/0966 -ta - Z8017A8 7. As a compound according to claim 1 4'-deoxy-4-deacetylleurosidine. 8. As compounds according to claim 1, the sulfates of the compounds according to claims 1 to 7. 9. Medicament containing an inert carrier and a compound according to any one of claims 1 to 8 as an active ingredient. 10. Process for the preparation of dimeric 1-formyl-indole dihydroindoles the formula s' • R 11 ' ν _e y \ ^K Formula II, 14 ' I.
H ■ f — CC-CHa II
O CHs Il 0 in which mean the group OH or 0-C-CH-., Il -5 803829/0966 one of the leftovers R ³ and R ⁴ -fr- 801748 Hydrogen and the other of these leftovers the group and their pharmaceutically acceptable salts, thereby characterized in that a dimeric 1-methylindole dihydroindole the formula 7 ' ^12th Formula III, i2 '"f-0-0-CHa ¹⁴ IJ It H 9 / s \ τι CH3O- i I. » CHs C-O-CH3 Il O 13 4
wherein R , R and R are as defined above, reacted with a chromic acid oxidizing agent in a reaction mixture at low temperature and the free base or a pharmaceutically acceptable salt thereof is recovered. 809829/0966 11. The method according to claim 10, characterized that chromium trioxide and acetic acid are used as chromic acid oxidizing agents. 12. The method according to claim 10 or 11, characterized in that the reaction at -50 to -65 ⁰ C is carried out. 13. The method according to any one of claims 10 to 12, characterized in that the used Reaction mixture contains acetone and acetic acid. 14. The method according to any one of claims 10 to 13, characterized characterized in that 4'-deoxy VLB "A" is used as the starting material. 15. The method according to any one of claims 10 to 13, characterized in that as the starting material 4'-Deoxy VLB "B" is used. 16. The method according to any one of claims 10 to 13, characterized in that as the starting material 4 * -deoxy-4-deacetylleurosidine is used. 17. Process for the preparation of dimeric 4-deacetylindole dihydroindoles the formula 809829/0966 28Ü1748 ¹ M. 1S '< 14 ' S ' Jf ■ f-C-O-CHs CHsO- Formula IV, Λ · <Ι1 A?. · vry -OH CO-CH ₃ Il Hs one of the radicals R ³ and R ⁴ the group CH ₃ or CHO and Hydrogen and the other of these radicals are the group C ₃ Hc, and their pharmaceutically acceptable salts, thereby characterized in that a dimeric 4-acetoxyindole dihydroindole the formula 809829/0963 yi - ^14th I \ f 4 ^ · ι I ir Formula V, CHaO- Vv « B ^ 1 5 »CHs 1 L ^ i-O-C-CHs C-O-CHs Il 2 3 4 worm R, R and R have the meanings given above, hydrolyzed in a reaction mixture and the 4-deacetyl compound is obtained as the free base or as a pharmaceutically acceptable salt thereof. 18. The method according to claim 17, characterized that sodium carbonate is used for the hydrolysis. 19. The method according to claim 17 or 18, characterized characterized in that the hydrolysis is carried out in anhydrous methanol. 809t29 / 096e -ψ- 20. The method according to any one of claims 17 to 19, characterized in that as the starting material 4'-Deoxy-1-formylleurosidine is used. 21. The method according to any one of claims 17 to 19, characterized in that as the starting material 4'-Deoxy VLB "B" is used. 809 * 29/098 $