HRP950250A2 - Novel dihydrodibenzoquinolinediones - Google Patents

Description

Description

This invention relates to new bis-1,2-dihydro-3H-dibenzisoquinoline-1,3-diones and their salts, processes for their preparation, pharmaceutical compositions containing them and methods of their use for the treatment of malignant, mainly human solid tumor cancers .

The use of bis-naphthalimide for the treatment of tumor cancer is already known (see, for example, US 4,847,883, US 5,986,059 and DE 4,232,739). Furthermore, dibenzisoquinolines with anticancer activity were described in EP 536,208.

This invention relates to bis-1,2-dihydro-3H-dibenzisoquinoline-1,3-diones of formula 1

[image]

where X, X, Y and Y are the same or different, or each of njl is H, NO2, NH2, C1-C6-alkylamino, di-C1-C6-alkylamino, NH-C1-C6-acyl, OH, C1- H6-Alkoxy, Halogen, Trihalomethyl, C1-C6-Alkyl, Formyl, C1-C6-Alkylcarbonyl, Ureyl, C1-C6-Alkylureyl, and A is a C4-C12 bridge terminated at one, two or three positions with a secondary or a tertiary amino group, where two nitrogen atoms can additionally be connected to each other with a C1-C4-alkylene group and their salts with physiologically acceptable acids.

One class of compounds of this invention are the bis-1,2-dihydro-3H-dibenzisoquinoline-1,3-diones of formula 1 wherein at least one of X, X', Y and Y' is not H, i.e. where X, X ', Y and Y' are identical and are selected from the group consisting of NO2, NH2, NH-lower acyl, C1-C6-alkylamino, di-C1-C6-alkylamino, OH, C1-C6-alkoxy, halogen, trihaloraethyl, C1 -C6-alkyl, formyl, C1-C6-alkylcarbonyl, ureyl and C1-C6-alkylureyl.

Generally in various embodiments of this class preferably none of X, X', Y and Y' is NO2.

One subclass of the preceding compounds are the bis-1,2-dihydro-3H-dibenzisoquinoline-1,3-diones of formula 1 wherein at least one of X, X', Y and Y' is NH2, NH-lower acyl, C1-C6- alkylamino or di-C1-C6-alkylamino. This class includes, inter alia, compounds of formula 1 wherein X and Y are H; X' and y' are NHCOCH2; and -A- is -CH(CH3)-CH2-NH-CH2-CH2-NH-CH2-CH(CH3) - or - (CH2)2-NH-(CH2)3-NH-(CH2)2-

The second class of compounds of this invention are bis-1,2-dihydro-3H-benzisoquinoline-1,3-diones of formula 1 in which A is Cn-NR-Cn, or Cn-NR-Cn,-NR'-Cn, where Cn, Cn. and Cn, the same or different, and each of the C1-4-alkylene radicals, R and R' are H, C1-4-alkyl, benzyl, phenyl or phenyl substituted with a halogen atom or a C1-4-alkyl group or an amino group.

One subclass of these compounds are the bis-1,2-dihydro-3H-dibenzisoquinoline-1,3-diones of formula 1 where the bridging moiety A, which connects the two ring systems, is:

-CH2-CH2-NR-CH2-CH2-NR'-CH2-CH2

or

-CH2-CH2-NR-CH2-CH2-CH2-NR'-CH2-CH2

where R and R' are as previously defined. These compounds include those in which all of X and X' and R and R are H.

Compounds I of this invention can be synthesized according to the following methods;

1. By the reaction of anthracene-1,9-dicarboxylic anhydride of formula II with polyamine of formula III:

[image]

A suitable dicarboxylic acid or dicarboxylic acid halide can be used instead of the acid anhydride;

2. by the reaction of anthracene-1,9-dicarboxylic amide VI with the compound of formula VII:

[image]

where Hal means a halogen atom, preferably bromine;

3. - if A is interrupted between two nitrogen atoms - by the reaction of a compound of formula IV with a diamine of formula V:

[image]

where B and D are alkylene residues such that 2B plus D contains 4 to 12 carbon atoms.

Reaction 1 is carried out by reacting compound II with half an equivalent of polyamine of formula III in an organic solvent such as alcohols (especially ethanol), acetone, DMSO, THF, DMF, according to the invention they can be formulated into pharmaceutical compositions and administered to patients using conventional materials and methods such as which are those described in Brafia et. al., U.S. 4,874,833 and US 5,206,249 (the contents of both documents are incorporated herein by reference). See especially US 5,206,249 column 22, line 10 through the end of column 23.

The compounds according to the present invention have cytotoxic activity useful in the treatment of various cancers. The relative efficacy of these compounds can be evaluated by in vitro assays and in vivo assays generally accepted in the art, including those described in US 5,206,249 (see particularly column 10 through column 22, line 9). Efficacy in such trials demonstrates their utility for the treatment of human solid tumors and proves an important therapeutic benefit: in the treatment of cancers, particularly solid tumor cancers, such as colon cancer, breast tumors, prostate cancer, and non-small cell lung cancer. With regard to activity, toxicity and/or solubility, the new compounds show better properties than compounds of the earlier type.

A. Methodology in vitro

Cytotoxicity can be measured by standard methodology for confluent cell lines such as the microculture tetrazole assay (MTT). Details of this trial were published in Cancer Research 48;589-601, 1988). Exponentially growing cultures of tumor samples, such as HT-29 colon carcinoma or LX-1 lung tumor, were used to prepare cultures on microtitre plates. 5,000-20,000 each of dioxane, aromatic hydrocarbons (especially toluene), or any inert solvent are planted. The reaction temperature must be between -20°C and the boiling point of the solvent. Sometimes high temperatures are an advantage.

Reactions 2 and 3 are carried out under the same conditions, but in the presence of a base.

The final product is filtered off or the reaction mixture is evaporated to dryness under reduced pressure, and the residue is purified in the usual way by crystallization or chromatography.

The starting compounds II-VI can be prepared by methods known from the literature, or are available as commercial products. The thus obtained bis-1,2-dihydro-3H-dibenzolzoquinoline-1,3-diones are used as such or can be acidified with a suitable mineral or organic acid to obtain a pharmaceutically acceptable salt, i.e. the methanesulfonate or acetate salt, which can isolate by filtering. Free base salts may also be prepared by acidifying a suspension of the free base in ethyl alcohol, dichloromethane, ether, etc., with a suitable mineral or organic acid and the resulting solid separated by filtration.

Other salt-forming acids are known in the art, see, e.g., Brafia et. al., U.S. patent 4,874,833.

This invention further encompasses pharmaceutical compositions which, together with a pharmaceutically acceptable carrier, contain a compound according to the invention, which compound inhibits a tumor. It also relates to methods of treating a tumor in a mammal, which treatment comprises administering a compound of the invention to a mammal having such a tumor in a tumor-inhibiting amount. Cell junctions per well on 96-well plates (in 150 µl medium), and grown overnight at 37°C. Test compounds were added diluted tenfold in variations from 10-4 M to 19-10 M. Then the cells were incubated for 48-72 hours. To determine the number of viable cells, MTT dye (50 μl of a solution of 3 mg/ml 3-(4,5-dimethylthiazol-2-μl)-2,5-diphenyltetrazole bromide in salt solution) was added to each well. This mixture was incubated at 37°C for 5 hours, and then 50 μl of 25% SDS (pH 2) was added to each well. After overnight incubation, the absorbance of each well was read at 550 nm using an ELISA reader. The values for the average +/- SD were calculated from the data for four dishes each using the formula for % T/C

(% cells treated/control) .

[image]

The concentration of the test compound that gave a T/C of 50% growth inhibition was denoted as IC50.

B Methodology in vivo

The compounds according to the invention can be further tested by any of the various methods of preclinical testing of the activity in vivo, which methods show clinical utility. Such tests can be performed with hairless mice into which tumor tissue, preferably of human origin, is transplanted ("xenografted"), as is well known in the art. The antitumor efficacy of the test compounds was evaluated by subsequent administration to xenograft-bearing mice.

Specifically, human tumors grown in athymic hairless mice were transplanted into new recipient animals, using approximately 50 mg tumor fragments. The day of transplantation is marked as day 0. Six days later, mice were injected intravenously or intraperitoneally with the test compounds, in groups of 5-10 mice per dose. The compounds were administered daily for 5 days, 10 days or 15 days, in amounts of 10-100 mg/kg body weight. Tumor volumes were calculated using diameters measured twice a week. Tumor volumes, whose diameters were measured with Vernier calipers, were calculated using the formula:

(length x width2) /2 = mm3 (tumor volume)

Average tumor volumes were calculated for each treated group, and T/C values were determined for each group relative to untreated control tumors. A T/C value of 1.0 or greater indicates that the compound does not affect tumor growth/ while values <1.0 indicate some reduction in tumor mass. Values of 0.15-0.49 can be considered to reflect moderate activity and <0.01 - 0.14 as good to excellent activity. An extraordinary effect is shown by a compound that ensures complete regression of the tumor material (after therapy there is no visible tumor mass). Compounds contributing to T/C values >0.5 are considered ineffective.

The invention may be further understood by the following examples, in which parts and percentages are by weight unless otherwise stated.

Example 1

N,N'-bis-[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]-isoquinolin-2-yl)ethyl]-1,3-propanediamine

A mixture of 1.6 g (6 mmol) of anthracene-1,9-dicarboxylic anhydride in 40 ml of toluene was mixed with 0.5 g (3 mmol) of N,N -bis(2-aminoethyl)-1,3-propanediamine dissolved in in 10 ml of toluene. The mixture is refluxed for 4 hours and then filtered. The solution is allowed to cool and the resulting solid is filtered off, washed, dried and recrystallized from toluene. 0.93 g (50%) of N,N'-bis-[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquinolin-2-yl)ethyl]- 1,3-propanediamine. Melting point 191°C (toluene).

1H-NMR (CDCl3) δ = 1.84 (q, 2H, J = 6 Hz, -CH2-); 2.74 (broad, s, 2H, NH) ; 2.89 (t, 4H, J = 6Hz, CH2); 3.02 (t, 4H, J = 6Hz, CH2); 4.31 (t, 4H, J = 6Hz/ CH 2 ); 7.54 (m, 4H, H-5 and H-9); 7.73 (m, 2H, H-10); 7.89 (d, 2H, J = 8 Hz, H-8); 8.22 (d, 1H, J = 8 Hz, H-4); 8.51 (s, 2H, H-7); 8.57 (d, 2H, J = 8 Hz, H-6); 9.78 (d, 2H, J = 8 Hz, H-11) p.p.m.

Anal. calculated for C39H32NO4O4;- C75.46, H 5.19; N 9.02. Found: C 75.14; H 5.37; N 8.78%. Acetate melting point 155°C. Melting point of methanesulfonate 243°C.

Example 2

N,N'-bis[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]-isoquinolin-2-yl)ethyl]-1,2-ethylenediamine

As an example 1. Utilization 66%. Melting point 203°C (DMF-H2O) .

Example 3

N,N'-bis[3-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]-isoquinolin-2-yl)propyl]-1,4-butanediamine

As an example 1. Utilization 46%. Melting point 1830C (toluene).

Example 4

[3-(1,2-dihydro-1,3-dioxo-3, 4-dibenz[de,h] isoquinolin-2-yl)propyl][4-(1,2-dihydro-1,3-dioxo- 3,4-dibenz[de,h]-isoquinolin-2-yl)butyl]amine

As an example 1. Utilization 41%. Melting point 244°C (DMF).

Example 5

N,N'-bis[2-1,2-dihydro-1,3-dloxo-3H-dibenz[de,h]-isoquinolin-2-yl)ethyl]-1,4-butanediamine

As an example 1. Utilization 40%. Melting point 179°C (toluene).

Example 6

Bis[3-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquinolin-2-yl)propyl]methylamine

As an example 1. Utilization 35%. Melting point 194°C (toluene).

Example 7

Bis[3-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquinolin-2-yl)propyl]amine

As an example 1. Utilization 83%. Melting point 184°C (toluene).

Example 8

[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h] isoquinolin-2-yl)ethyl][3-(1,2-dihydro-1,3-dioxo-3H- dibenz[de,h]-isoquinolin-2-yl)propyl]amn

As an example 1. Utilization 78%. Melting point 260°C (DMF).

Example 9

Bis[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquinolin-2-yl)ethyl]amine

As an example 1. Utilization 53%. Melting point 271°C (DMF-H2O) .

Example 10

N,N'-bis[3-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]-isoquinolin-2-yl)propyl]-1,2-ethylenediamine

As an example 1. Utilization 61%. Melting point 180°C (toluene).

Example 11

N,N'-bis[3-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]-isoquinolin-2-yl)propyl]-1,3-propanediamine

As an example 1. Utilization 41%. Melting point 140°C (toluene).

Example 12

N, N-bis[(1,2-dihydro-8-nitro-3H-dibenz[de,h]isoquinolin-2-yl)ethyl]1 3-propanediamine

As an example 1. Utilization 52%. Melting point >340°C (toluene).

Example 13

N,N'-bis[2-(1,2-dihydro-8-nitro-3H-dibenz[de,h]isoquinolin-2-yl)ethyl]1,3-ethylenediamine

As an example 1. Utilization 57%. Melting point >340°C (toluene).

Example 14

N,N'-bis[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]-isoquinolin-2-yl)ethyl]-N,N'-dimethyl-1,2 -ethylenediamine

As an example 1. Utilization 77%. Above 255°C (toluene).

Example 15

N,N'-bis[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]-isoquinolin-2-yl)ethyl]-1,5-pentanediamine

As an example 1. Utilization 25%. Melting point 122°C (toluene).

Example 16

N,N'-bis[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]-isoquinolin-2-yl)ethyl] hexahydropyrinylidine

A mixture of 0.5 g (0.8 mmol) of N,N'-bis[2-(1,2-dihydro-1,3-dioxo-3H-dlbenz[de,h]isoquinolin-2-yl)ethyl] -1,3-propanediamine and 1 ml of 36% formaldehyde in 100 ml of ethanol is refluxed for 7 hours. The solid is filtered off, washed, dried and recrystallized from toluene. 0.3 g (58%) of N,N'-bis[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]-isoquinolin-2-yl)ethyl]hexahydropyrimidine are obtained . Melting point 222°C (toluene).

Example 17

N,N'-bis[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]-isoquinolin-2-yl)ethyl]-1,3-propanediamine

A mixture of 1.47 g (5 mmol) of anthracene-1,9-dicarboxylic acid dimethyl ester in 50 ml of toluene was mixed with 0.4 g (2.5 mmol) of N,N-bis(2-aminoethyl)-1, of 3-propanediamine in 20 ml of toluene. The suspension is refluxed for 24 hours and then cooled to room temperature. The solid is filtered off, dried, and recrystallized from toluene. 0.65 g (42%) of N,N'-bis[2-(1,2-dihydro-1,3-dioxo-3H-dibenz [de,h]-isoquinolin-2-yl)ethyl]- 1,3-propanediamine. Melting point 191°C.

Example 18

N,N'-bis[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]-isoquinolin-2-yl) ethyl]-1, 3-propanediamine

0.4 g (2.5 mmol) of N,N'-bis (2-aminoethyl)-1,3-propane-diamine in 20 ml of toluene is added to a mixture of 1.51 g (5 mmol) of anthracene-1 dichloride, of 9-dicarboxylic acid in 50 ml of toluene. The suspension is refluxed for 20 hours and then cooled to room temperature. The solid is filtered off, dried and recrystallized from toluene. 0.54 g (35%) of N,N'-bis[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]-isoquinolin-2-yl)ethyl]- 1,3-propanediamine. Melting point 191°C.

Example 19

N,N'-bis[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]-isoquinolin-2-yl)ethyl]-1,3-propanediamine

A. 2-(2-hydroxyethyl)-1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-dione

A mixture of 1.51 g (6 mmol) of anhydride of anthracene-1,9-dicarboxylic acid and 0.4 g (6.5 mmol) of ethanolamine in 50 ml of toluene was refluxed for 5 hours and then cooled to room temperature. The solid is filtered off, dried and recrystallized from toluene. 1.5 g (85%) of 2-(2-hydroxyethyl)-1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-dione are obtained. Melting point 211°C.

B. 2-[2-(p-toluenesulfonyloxy)ethyl]-1,2-dihydro-3H-dibenz-[de,h] isoquinoline-1,3-dione

A mixture of 1.01 g (3.5 mmol) of 2-(2-hydroxyethyl)-1,2-dihydro-3H-dibenz [de, h] isoquinoline-1,3-dione in 10 ml of pyridine was mixed with 0, 69 g (3.6 mmol) of p-toluenesulfonyl chloride. The mixture is stirred at room temperature for 24 hours and poured into 50 ml of cold water. The solid was collected, washed with water, dried in vacuo and recrystallized from dimethylformamide water. 1.2 g (77%) of 2-[2-(p-toluenesulfonyloxy)ethyl]-1,2-dihydro-3H-dibenz[de,h]-isoquinoline-1,3-dione is obtained. Melting point 240°C.

C. N,N'-bis[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquinolin-2-yl)ethyl]-1,3-propanediamine

A mixture of 2.2 g (5 mmol) of 2-[2-(p-toluenesulfonyl-oxy)ethyl]-1,2-dihydro-3H-dibenz[de,h] isoquinoline-1,3-

dione, 0.4 g (2.5 mmol) of 1,3-propanediamine in 200 ml of acetonitrile is refluxed in the presence of 0.6 g (5.6 mmol) of sodium carbonate for 24 hours. The reaction mixture is concentrated in vacuo. The residue was mixed with water (100 ml) and extracted with dichloroethane. The organic layers are collected, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue is chromatographed eluting with dichloromethane, methanol and acetic acid (80:15:5). The fractions obtained are collected, concentrated in vacuo and recrystallized from toluene. 0.3 g (20%) of N,N'-bis[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]-isoquinolin-2-yl)ethyl]- 1,3-propanediamine. Melting point 191°C.

Example 20

N,N'-bis[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquinolin-2-yl)ethyl]-1,3-propanediamine

A. 1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-dione

1.51 g (6 mmol) of anthracene-1,9-dicarboxylic acid anhydride was mixed with 10 ml of ammonium chloride (28%). After refluxing for 16 hours, the solid was collected, washed with water, dried in vacuo and recrystallized from dimethylformamide. 1.3 g (86%) of 1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-dione is obtained. Melting point 310°C.

B. N,N'-bis[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquinolin-2-yl)ethyl]-1,3-propanediamine

A mixture of 1.23 g (5 mmol) of 1,2-dihydro-3H-dibenz-[de,h] isoquinoline-1,3-dione in 100 ml of ethanol was mixed with 280 mg (5 mmol) of potassium hydroxide in 50 ml of ethanol. After refluxing for 3 hours, 0.65 g (2.5 mmol) of N,N-bis(2-bromomethyl)-1,3-propanediamine in 50 ml of ethanol was added and everything was refluxed for 24 hours. The reaction mixture is concentrated in vacuo. The residue was mixed with water (100 ml) and extracted with dichloromethane. The organic layers are collected, dried with magnesium sulfate, filtered and concentrated in vacuo.

The residue is chromatographed, washing with dichloromethane, ethanol and acetic acid (0:15:5). The fractions obtained are collected, concentrated in vacuo and recrystallized from toluene. 0.31 g (20%) of N,N'-bis[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h] isoquinolin-2-yl)ethyl]-1 is obtained ,3-propanediamine. Melting point 191°C.

Example 21

N,N'-bis[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquinolin-2-yl)ethyl]-1/3-propanediamine

A. N-bis[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquinolin-2-yl)ethyl]-N-(2-aminoethyl)-1,3- propanediamine

A solution of 5.0 g (31 mmol) of N,N'-bis(2-aminoethyl)-1,3-propanediamine in 200 ml of ethanol 99% was mixed with 1.5 g (6 mmol) of anhydride anthracene-1,9 -dicarboxylic acid in 100 ml of ethanol and stirred for 24 hours at room temperature. The solid is collected on a filter, washed with ethanol and recrystallized from ethanol. 0.5 g (20%) of N-bis[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquinolin-2-yl)ethyl]-N-(2 -aminoethyl)-1,3-propanediamine. Melting point 150°C.

B. N,N'-bis[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquinolin-2-yl)ethyl]-1,3-propanediamine

A mixture of 1.0 g (2.5 mmol) N-[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquinolin-2-yl)ethyl]-N'- (2-amino-ethyl)-1,3-propanediamine in 50 ml of toluene is mixed with 0.62 g (2.5 mmol) of anhydride of anthracene-1,9-dicarboxylic acid in 10 ml of toluene, refluxed for 6 hours and cooled to room temperature. The solid was collected, dried in vacuo and recrystallized from toluene. 0.8 g (48%) of N,N'-bis[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquinolin-2-yl)ethyl]-1 is obtained ,3-propanediamine. Melting point 191°C.

Claims (6)

1. Compound of formula I [image] characterized in that X, X', Y and Y' are the same or different and each is H, NO2, NH2, C1-C6-alkylamino, di-C1-C6-alkylamino, NH-C1-C6-acyl, OH, C1-C6-Alkoxy, Halogen, Trihalomethyl, C1-C6-Alkyl, Formyl, C1-C6-Alkylcarbonyl, Ureyl, C1-C6-Alkylureyl, and A is a C4-C12 bridge that is interrupted at one, two or three positions with a secondary or tertiary amino group, where two nitrogen atoms can additionally be linked to each other with a C1-4-alkylene group, or its salt with physiologically acceptable acids. 2. Bis-1,2-dihydro-3H-dibenzisoquinoline-1,3-dione according to claim 1, characterized in that X, X', Y and Y' represent hydrogen. 3. Bis-1,2-dihydro-3H-dibenzisoquinoline-1,3-dione according to claim 1, characterized in that it has the form of a salt of acetic or methanesulfonic acid. 4. Pharmaceutical composition, characterized in that it includes a pharmaceutically acceptable carrier substance and a therapeutically effective amount of the compound according to claim 1. 5. A method of treating a tumor in humans, comprising administering a compound according to claim 1 to a patient with such a tumor in a tumor-inhibiting amount. 6. The method of preparing the compound of formula I according to claim I, characterized in that 1. anhydride of anthracene-1,9-dicarboxylic acid of formula I [image] or the corresponding free acid, or acid halide reacts with the compound of formula II H2N-A-NH2 II or 2. anthracene-1,9-dicarboxylic amide VI [image] reacts with a compound of formula VII Hal-A-Hal VII, where Hal is a halogen atom, or 3. - if A is interrupted between two nitrogen stomata - compound of formula IV [image] reacts with a diamine of formula V H2N-D-NH2V, where B plus D are alkylene radicals, such that 2B plus D contains 4 to 12 carbon atoms.