DD297638A5 - ACRYLOYL-SUBSTITUTED PYRROL DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATES CONTAINING THEREOF - Google Patents

Abstract

The invention relates to acryloyl-substituted pyrrole derivatives, processes for their preparation and pharmaceutical preparations containing these compounds. Described are novel acryloyl-substituted pyrrole derivatives, the general formula * show the cytostatic properties against tumor cells. Formula (I) {pyrrole derivatives; Method; manufacture; Antitumor agent}

Description

Z-NH

H' (IV)

Il j 2

° Jn

where Z Η, ν / Λ-CO-

or H _{2 is} N-Het-CO-, and n, R 4, B and Het wio are defined above, or a salt thereof, with a compound of formula (V)

»/ I ^(V)

^{2 R} 3

wherein R ₁ , R ₂ , R ₃ and X are as defined above to obtain a compound of the formula (I)

where A is a group -NH-v / -C- or -NH-Het-C-

or a salt thereof.

5. The method according to claim 4, characterized by further converting the compound of formula (I) into a pharmaceutically acceptable salt thereof.

6. The method according to claim 4, characterized in that the pharmaceutical salt is the hydrochloride.

Pharmaceutical preparation, characterized in that it contains an acryloyl-substituted pyrrole derivative according to claims 1 to 3, together with a pharmaceutically acceptable carrier and / or diluent.

8. A pharmaceutical preparation according to claim 7, for use as an antitumor agent.

Field of application of the invention

The invention relates to acryloyl-substituted pyrrole derivatives, a process for their preparation and pharmaceutical compositions containing these compounds.

Explanation of the essence of the invention

The invention relates to novel pyrrole derivatives which can be regarded as derivatives of distamycin A. Distamycin A is a known compound having the following formula:

HOC - KH

CH.

O.

Distamycin A is described, for example, in Nature 203,1064 (1964).

The invention relates to acryloyl-substituted pyrrole derivatives of the general formula (I)

C C

CNH

Il

CH

(I)

wherein η is an integer of 1 to 5; R ₁ and R ₂ , which may be the same or different, each represents hydrogen, halogen, -CN, -NO ₂ , C 1 -C ₄ alkyl, or a group

R _{3 is} hydrogen, halogen, -CN, or -NO ₂ ; each R _{4 is} independently hydrogen or C 1 -C ₄ alkyl! A is a bond, a group

NH

-C-

or a group NH-Het-CO- wherein Het is a saturated or unsaturated pentatomic or hexatomatic heteromonocyclic ring; and

B a group "

NH

/ ₅

or - (CH.) -Nf 2 m \

^R 5

wherein m is 1,2 or 3 and each R _{6 is} independently a C 1 -C ₄ alkyl group.

The invention also relates to the pharmaceutically acceptable salts of the compounds of formula (I) and to the possible isomers covered by formula (I) both separately and in admixture. In the above formula (I), η is preferably 3.4 or 5; A is preferably a bond or a group

-NH ^ Y-CO-

or a group NH-Het-CO-; B is preferably a group

-C or

NH.

wherein m is preferably 1 and each Re is methyl.

When A is a group -NH-Het-CO-, wherein Het is a heteromonocyclic ring as defined above, then this is preferably an unsaturated pentatomic or hexatic heteromonocyclic ring containing at least one, preferably one or two, heteroatom (s) from O, S and N, contains. Examples of said heteromonocyclic rings are thiophane, thiazole, pyridine, isoxazole, furan, triazole and imidazole.

If R | and R _{2 are the} same, then these substituents are preferably hydrogen. When R _t and R _{2 are} different, then Ri is preferably hydrogen and R ₂ is preferably halo, with chlorine or bromine being the preferred halogen.

When R3 is halogen, then this substituent is preferably chlorine or bromine.

Preferably, each group R _{4 is} independently Ci-Ct-alkyl, especially methyl. It is most preferred that all R ₄ groups are methyl.

As already stated, the present invention also encompasses the pharmaceutically acceptable salts of the compounds of the formula (I),

These salts are the salts with pharmaceutically acceptable acids, either inorganic acids, such as. B.

Hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid, or organic acids, such as. Citric acid, tartaric acid, maleic acid, fumaric acid, methanesulfonic acid and ethanesulfonic acid.

A preferred class of compounds of the invention is given by compounds of formula (I) wherein η is 3,4 or 5;

A is a bond or the group -NH-

CO-

, NH

B is a group -C

or

NH.

CH

R ₁ and R _{2 are} hydrogen;

R _{3 is} chloro or bromo and R _{4 is} methyl, especially in the form of the salts with hydrochloric acid.

Specific examples of preferred compounds according to the invention, especially in the form of salts with hydrochloric acid, are the following compounds:

N-deformyl-NMA-chloracryloyD-dictamycinA; ß-lN-methyl-methyM ^ -IN-fN-methyl ^ -F-N-methyl ^ -ta-chloracrylamidol-pyrrole-2-carboxamido) pyrrole-2-carboxamido) pyrrole-2-carboxamido) pyrrole-2- carboxamido) propionamidine; N-deformyl-N- (abromacryloyl) -distamycinA; SS (N-methyl-4- (N-methyl-4- (N-methyl-4- (N-methyl-4- (a-bromoacrylamido) pyrrole 2-carboxamido) - pyrrole ^ -carboxamidol-pyrrole ^ -carboxamidol-pyrrole ^ -carboxamidol-propionamidine; β- (N-methyl-4- (N-methyl-4- (N-methyl-4- (N-methyl) 4- (N-methyl-4- (α-bromoacrylamido) pyrrole-2-carboxamido) pyrrole-2-carboxamido) -pyrrole-2-carboxamido) -pyrrole-2-carboxamido) -pyrrole-2-carboxamido) - propionamidine; N-Deformyl-N- (4- (a-bromoacrylamido) -benzoyl) -distamycin A; 3- (N -methyl-4- (N-methyl-4- (N-methyl-4- (N-methyl -4- (a-chloroacrylamido) -pyrrole-2-carboxamido) -pyrrole-2-carboxamido) -pyrrole-2-carboxamido-pyrrole-carboxamidol-propyl-dimethylamine.

The compounds of the formula (I) are prepared by a process which is characterized in that

A) a compound of the formula (II)

Γ 1

(II)

wherein η, R ₄ and B are as defined above, or a salt thereof, with a compound of the formula (III)

(III)

wherein R ₁ , R ₂ , R ₃ and A are as defined above and X is hydroxy or a leaving group, to give a compound of the formula (I) or a salt thereof; or B) a compound of the formula (IV)

Z-NH

• CNH

Il 0

.CH

(IV)

wherein Z

or H _{2 is} N-Het-CO-, and η, R <, Bund Het are as defined above, or a salt thereof, with a compound of formula (V)

OR _s

= C-C-X

^R 3 wherein R ₁ , R ₂ , R ₃ and X are as defined above to give a compound of formula (I),

C-

or a salt thereof.

The leaving group X in the compounds (III) and (V) may be, for example, halogen, especially chlorine, or another displaceable group, such as 2,4,5-trichlorophenoxy, 2,4-dinitrophenoxy, succinimido-N-oxy, Imidazolyl, pivaloyloxy, KOCC (CH ₃ I ₃ I

O or ethyloxyformate (-O-C-O-Et)

where A is a group -NH- (/ -C- or -NH-Het-C-

or isopropyloxyformate [-O-CO-CH (CH ₃ I ₂ ]

A resulting compound of formula (I) may, if desired, be converted to a pharmaceutically acceptable salt.

The reaction between a compound of formula (II) and a compound of formula (III) wherein X is -OH is preferably carried out at a molar ratio of (II) :( III) of 1: 1 to 1: 2 in an organic Solvents, such as. B.

Dimethylsulfoxide, Hexamethylphosphotriamid, dimethylacetamide or, preferably, dimethylformamide, or their aqueous mixtures, in the presence of an organic base such. For example, triethylamine or diisopropyl-ethylamine or an inorganic base such as sodium bicarbonate and a condensing agent such as N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide or, preferably, Ν, Ν'-Dicyclohexylcarbodiimid performed. The reaction temperature may vary from about -1O ⁰ C to about 50'C and the reaction time from about 1 to about 12 hours.

The reaction between a compound of formula (II) and a compound of formula (III) wherein X is a leaving group, e.g. B.

2,4,5-trichlorophenoxy or succinimido-N-oxy or imidazolyl is usually at a molar ratio of (II): (III) from 1: 1 to 1: 2 in an organic solvent such. As dimethylformamide or pyridine, and in the presence of an organic base, for. Diisopropylethylamine, at a temperature of about 0 ° C to about 25 ° C and over a period of about 2 hours to about 10 hours. Similar reaction conditions can be used when X in the compound (III) is a halogen atom. The reaction between a compound of formula (IV) and a compound of formula (V) may be carried out under analogous conditions as above for the reaction between compounds of formula (II) and compounds of formula (III) with the corresponding meanings of X. become.

The compounds of formula (I) prepared by the procedures described above can be purified by conventional methods such as silica gel or alumina column chromatography and / or by recrystallization from organic solvents such as lower aliphatic alcohols or dimethylformamide.

The compounds of the formula (II) are known compounds or they can be prepared by known methods from known compounds: cf. z. Arcamone et al. Gazzetta Chim. Ital. 97, 1097 (1967).

The compounds of formula (IV) can be prepared by methods known in organic chemistry.

In particular, for example, compounds of the formula (IV) in which Z is a group

CO

is, be prepared by reacting a compound of formula (II) with p-nitrobenzoyl chloride and reducing the resulting nitro compound by known methods.

The compounds of the formula (III) are known compounds or they can be prepared by standard methods, as described, for example, in J.C.S. 1947-1032 and JACS 62,3495 (1940).

Thus, e.g. Compounds of the formula (III) in which A is

CO-

is prepared by reacting p-aminobenzoic acid with the activated acrylic acid derivative in a conventional manner.

The compounds of the present invention exhibit cytostatic properties against tumor cells, such that they may be useful as antineoplastic agents to control, for example, the growth of various tumors, e.g. As carcinomas, such as breast cancer, lung cancer, bladder cancer, colon carcinoma, as well as tumors of the ovaries and the endometrium to inhibit. Other neoplasias for which the compounds of the invention could find application are

z. B. sarcomere, z. B. soft tissue and bone, and hematological malignancies, such as . B. leukemia.

The cytotoxicity of the compounds according to the invention was tested, for example, in mouse L1210 leukemia cells according to the following procedure. Cells were separated from in vivo tumors and stored in cell culture. The cells were used until the 10th passage. Cytotoxicity was determined by counting the surviving cells after 4 hours of treatment and 48 hours of growth in the drug-free medium. The percentage of cell growth in the treated cultures was compared to that of the controls. The ID _W values (doses inhibiting 50% of cell growth, based on the controls) were calculated from the dose response curves.

For example, in the above test for the compound according to the invention, β- (N-methyl-4- (N-methyl-4- (N-methyl-4- (N-methyl-4- (α-bromoacrylamido) -pyrrole -2-carboxamido) -pyrrol-2-carboxamido) -pyrrole-2-carboxamido) -pyrrole-2-carboxamido) -propionamidine, hydrochloride, an ID _M value of 0.003 γ / ml was found.

The compounds of the invention may be prepared in usual ways, for example parenterally, e.g. B. by intravenous injection or infusion, intramuscularly, subcutaneously, topically or perorally.

The dose depends on the age, weight and condition of the patient as well as the route of administration.

For example, a suitable dosage for administration to the adult may be in the range of about 0.05 to about 100 mg p ^r o dose 1-4 times per day.

The pharmaceutical compositions of the invention contain a compound of formula (I) as an active ingredient together with one or more pharmaceutically acceptable excipients.

The pharmaceutical preparations according to the invention are usually prepared by conventional methods and administered in pharmaceutically suitable form.

For example, solutions for intravenous injection or infusion may contain as carrier, for example, sterile water, or they may preferably be in the form of sterile aqueous isotonic saline solutions.

Suspensions or solutions for intramuscular injection may contain, together with the active ingredient, a pharmaceutically acceptable carrier, e.g. As sterile water, olive oil, ethyl oleate, glycols, z. For example, propylene glycol and, if desired, a suitable amount of lidocaine hydrochloride.

In forms for topical application, eg. For example, creams, lotions or pastes for use in dermatological treatments, the active ingredient may be mixed with conventional oily or emulsifying excipients.

The solid peroral forms, e.g. As tablets and capsules, together with the active ingredient diluents, for. B. Lautose, dextrose, sucrose, cellulose, corn starch and potato starch; Lubricant, e.g. Silicic acid, talc, stearic acid, magnesium or calcium stearate, and / or polyethylene glycols; Binder, e.g.. Starches, gum arabic, gelatin, methylcellulose, carboxymethylcellulose, polyvinylpyrrolidone; Disintegrating agents, e.g. B starch, alginic acid, alginates, sodium starch glycolate; foaming mixtures, dyes, sweeteners, humectants, e.g. Lecithin, polysorbates, lauryl sulfates, and generally non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. The said pharmaceutical preparations can be prepared in a known manner, for example by mixing, granulation, tableting, sugar coating or film coating processes.

The invention is illustrated in the examples.

The abbreviations DMF and THF mean dimethylformamide or tetrahydrofuran.

example 1

To a solution of α-bromoacrylic acid (226 mg) in dry DMF (5 ml) was added Ν, Ν'-dicyclohexylcarbodiimide (228 mg) and the resulting suspension was stirred at room temperature for 20 minutes. The mixture was added to a solution of N-deformyl distamycin A dihydrochloride (526 mg) in DMF (10 ml) and sodium bicarbonate (84 mg).

The suspension was stirred at room temperature for 4 hours. After filtration, the solvent was evaporated to dryness in vacuo. The residue was chromatographed on silica gel with methylene chloride: methanol 80:20 as eluent to give N-deformyl-N- (α-bromoacryloyl) -distamycin A, hydrochloride (310 mg). UV Xmax (EtOH 95 °) (ε): 242 (23772), 312 (33961) nm; FD-MS: m / z 586, M ⁺ +1; 568, M ⁺ NH ₃ ; 505, M ⁺ -HBr; NMR (DMSO-d ₆ ): δ 2.62 (2H, t); 3.45 (2H, m); 3.81 (3H, s); 3.85 (6H, s); 6.20 (1H, d); 6.70 (1H, d); 6.9-7.3 (6H, m); 8.18 (1H, t); 8.6 (2H, bs); 8.96 (2H, bs); 9.88 (1H, s); 9.93 (1H, s); 10.29 (1H, s).

By analogous procedure, the following compounds were obtained:

N-Deformyl-N-chloroacryloyD-distamycin A, hydrochloride, U.V. Xmax (EtOH 95 °) (ε): 242 (23080), 310 (32972) nm; FD-MS:

m / z: 542, M ⁺ + 1; 505, M ⁺ HCI; 524, M ⁺ NH ₃ ;

N.M.R. (DMSO-de): δ 2.65 (2H, t); 3.50 (2H, m); 3.80 (3H, s); 3.83 (3H, s); 3.84 (3H, s); 5.98 (1H, d); 6.40 (1H, d); 6.90-7.30 (6H, m); 8.20 (1H, t); 8.75 (2H, bs); 9.04 (2H, bs); 9.89 (1H, s); 9.95 (1 H, s); 10.32 (1H, s).

SS (N-methyl-4- (N-methyl-4- (N-methyl-4- (N-methyl-4- (a-chloroacrylamido) pyrrole-2-carboxamido) pyrrole-2-carboxamido) - pyrrole-2-carboxamido) -pyrrole-2-carboxamido) -propionamidine, hydrochloride.

UV Amax (EtOH 95 °) (ε): 244 (30055), 314 (46098) nm; FAB-MS: m / z: 664, M ⁺ + 1; 602, M ⁺ -CH ₂ = CCI-; NMR (DMSO-d _e ): δ 2.62 (2H, t); 3.2-4.00 (14H, m); 5.99 (1H, d); 6.39 (1H, d); 6.90-7.30 (8H, m); 8.20 (1H, t); 8.80 (2H, bs); 9.00 (2 H, bs); 9.90 (2H, s); 9.93 (1H, s); 10,30 (1H, s).

SS (N-methyl-4- (N-methyl-4- (N-methyl-4- (N-methyl-4- (a-bromoacrylamido) pyrrole-2-carboxamido) pyrrole-2-carboxamido) - pyrrole-2-carboxamido) -pyrrole-2-carboxamido) -propionamidine, hydrochloride; UV Amax (EtOH 95 °) (ε): 242 (29,876), 314 (45,224) nm; FAB-MS: m / z: 708, M ⁺ I; 628, M ⁺ -Br; NMR (DMSO-d _e ): δ 2.63 (2H, t); 3.50 (2H, t), 3.80 (3H, s), 3.84 (3H, s), 3.85 (6H, s); 6.19 (1 Hd); 6.69 (1H, d); 6.90-7.25 (8H, m); 8,12 (1H, t); 8.63 (2H, bs); 8.89 (2H, bs); 9.80 (1H, s); 9.83 (1H, s); 9.86 (1H, s); 10,30 (1H, s).

3- (N-methyl-4- (N-methyl-4- (N-methyl-4- (N-methyl-4- (a-chloroacrylamido) pyrrole-2-carboxamido) pyrrole-2-carboxamido) - pyrrole-2-carboxamido) pyrrole-2-carboxamido) propyl-dimethylamine,

UV λmax (EtOH 95 °) (ε): 239 (29707), 313 (43738); FAB MS: M / z; 679, M + 1; 589, M ⁺ -CH ₂ = CCI-CO-:

N.M.R. (DMSO-ds): δ 1.66 (2H, m); 2:17 (6H, s); 2.25 (2H, t); 3.20 (2H, m); 3.80 (3H, s); 3.83 (9H, s); 5.99 (1H, d); 6.37 (1H, d); 6.75-7.30 (8H, m); 8.03 (1H, t); 9.83 (1H, s); 9.90 (1H, s); 9.92 (1H, s); 10.23 (1H, s).

P-IN-methyl-IN-methyl-IN-methyl-IN-methyl-IN-methyl-1-bromo-acrylarnidol-pyrrole-carboxaminol-pyrrole-C-carboxamido-pyrrole-2-carboxamido-pyrrole-2-carboxamido -pyrrol-2-carboxamido) -propionamidine, hydrochloride, UV Xmax (EtOH 95 °) (ε): 240 (34947312 (53018);

NMR (DMSO-d ₆ ): δ 2.61 (2H, t); 3.48 (2H, m); 3.82 (15H, bs); 6.21 (1H, d); 6.80 (1H, d); 6.9-7.3 (10H, m); 8.19 (1 H, t); 8.73 (2H ₁ bs); 8.93 (2H, bs); 9.90 (4H, bs); 10.28 (1H, bs).

Example 2

To a solution of (El-β-fp-methoxybenzyl-β-bromo-acrylic acid (428 mg), prepared according to JOC 26 755 (1961) in dry DMF (10 ml) cooled to ⁰ ° C., was N.N. '-Dicyclohexylcarbodiimide (288 mg) was added and the resulting solution was stirred at ⁰ ° C. for 20 minutes.

N-deformyl-distamycin A dihydrochloride (526mg) was added, and the mixture was stirred for 30 minutes at 0 ⁰ C and then for 4 hours at Hardly temperature. After filtration, the solvent was evaporated to dryness in vacuo and the residue was chromatographed on silica gel with methylene chloride: methanol 80:20 as eluent to give N-deformyl-N-IEI-β-lp-methoxybenzoyl-β-bromoacryloyD-distamycin A , Hydrochloride (265mg) were obtained.

UV Xmax (EtOH 95 °) (ε): 225 (33007), 304 (32704) nm; FAB-MS: m / z: 720, M ⁺ + 1; 511,389,267; NMR (DMSO-d _e ): δ 2.62 (2H, t); 3.48 (2H, m); 3.71 (3H, s); 3.74 (3H, s); 3.79 (3H, s); 3.81 (3H, s); 6.68 (1H, s); 6.75-7.20 (6H, m); 6.88 (2H, m); 7.25 (2H, m); 8.19 (1H, t); 8.54 (2H, bs); 8.93 (2H, bs); 9.88 (1H, s); 9.90 (1H, s); 10,30 (1H, s).

By analogous procedure, the following compound was obtained:

N-Deformyl-N- (4- (a-bromoacrylamido) -benzoyl) -distamycin A, hydrochloride,

U.V. Xmax (EtOH 95 °) (ε): 241 (31387), 311 (48156) nrn;

N.M.R. (DMSO-de): δ 2.62 (2H, t); 3.45 (2H, m); 3.81 (3H, s); 3.85 (3H, s); 3.86 (3H, s); 6.34 (1H, d); 6.84 (1H, d); 6.9-7.4 (6H, m); 7.7-8.1 (4H, m); 8.20 (1H, t); 8.72 (2H, bs); 9.00 (2H, bs); 9.90 (1H, s); 9.96 (1 H, s); 10.30 (1H, s); 10.56 (1H, s).

Example 3

To a solution of acrylic acid (245 mg) in dry THF (10 ml) cooled to -10 ° C was added triethylamine (0.47 ml) and pivaloyl chloride (0.41 ml).

The resulting suspension was stirred at -10 ^c C for 20 minutes. The whole was added to a cooled solution of N-deformyl distamycin A dihydrochloride (526 mg) in DMF (10 ml) and NaHCO ₃ (84 mg).

The mixture was stirred at 0 ° C for 30 minutes and then at room temperature for 4 hours.

The solvent was evaporated to dryness in vacuo and the residue was chromatographed on silica gel with methylene chloride: methanol 80:20 as eluent to give N-deformyl-N-acryloyl-distamycin A, hydrochloride (290r, 19).

UV λmax (EtOH 95 °) (ε): 242 (23229), 308 (34164); FD-MS: m / z: 508, M ⁺ + 1; 490, M ⁺ NH ₃ ; 437th

NMR (DMSO-d _e ): δ 2.63 (2H, t); 3.50 (2H, m); 3.81 (3H, s); 3.85 (3H, s); 3.89 (3H, s); 5.66 (1H, dd); 6.19 (1H, dd); 6.46 (1H, dd); 6.90-7.30 (6H, m); 8.20 (1H, t); 8, 60-9, 20 (4H, b); 9.88 (1H, s); 9.90 (1H, s); 10.18 (1 H, s).

By analogous procedure, the following compounds were orhaltan:

N-Deformyl-N-dZJ-β-chloroacryloyl-distamycin A, hydrochloride.

UV Xmax (EtOH 95 °) (ε): 243 (23254), 311 (35288) nm; FD-MS: m / z: 541, M ⁺ ; 505, M ⁺ HCI; 478; NMR (DMSO-d _e ): δ 2.64 (2H, t); 3.50 (2H, m); 3.80 (3H, s); 3.86 (6H, s); 6.52 (1H, d); 6.89 (1H, d); 6.9-7.3 (6H, m); 8.22 (1H, t); 8.85 (4H, bt); 9.89 (1H, s); 9.93 (1H, s); 10.28 (1H, s).

N-Deformyl-N - ((E) -β-chloroacryloyl) -distamycin A, hydrochloride.

UVXmax (EtOH 95 °) (ε): 241 (24584), 312 (35517) nm; FD-MS: m / z: 505, M ⁺ -HCI, 478.

N.M.R. (DMSO-de): δ 2.64 (2H, t); 3.50 (2H, m); 3.80 (3H, s); 3.86 (6H, s); 6.70 (1H, d); 7.30 (1H, d); 6.9-7.3 (6H, m); 8.22 (1H, t); 8.85 (4H, bt); 9.89 (1H, s); 9.93 (1H, s); 10.5 (1 H, s).

Example 4

To a stirred solution of N-deformyl distamycin A dihydrochloride (2.5g) in water (30ml) and dioxane (40ml) was added gently sodium bicarbonate (2g). The mixture was cooled to 5 ° C and then treated with vigorous stirring with a solution of p-nitrobenzoyl chloride (2.5g) in dioxane (25ml) over 1h.

The reaction mixture was stirred for 1 hour, acidified to pH 4 with 2N HCl and then evaporated to dryness in vacuo. The residue was treated with acetone (200 ml), stirred for 1 hour and filtered to give N-deformyl-N- (p-nitrobenzoyl) -distamycin-A, hydrochloride (2.6 g).

Example 5

The compound N-Deformyl-N- (p-nitrobenzoyl) -distamycin-A, hydrochloride (2.6g) was dissolved in a mixture of CH ₃ OH (150ml) and 2N HCl (10ml) and on a Pd catalyst (10% on charcoal) under a H _r pressure (50 psi) for 4 hours.

The catalyst was filtered off and the resulting solution was evaporated to dryness in vacuo.

The residue was treated with ethanol (10 ml), stirred for 1 hour and filtered to give N-deformyl-N- (p-aminobenzoyl) -distamycin A, dihydrochloride (2 g).

N.M.R. (DMSO-de): δ 2.62 (2H, t); 3.45 (2H, m); 3.81 (3H, s); 3.85 (3H, s); 3.86 (3H, s); 6.90-7.40 (6H, m); 7.10-7.70 (4H, m); 8.20 (1H, t); 8.52 (3H, bs); 8.72 (2H, bs); 9.00 (2H, bs); 9.90 (1H, s); 9.96 (1H, s); 10,30 (1H, s).

Examples

Preparation for intramuscular injection 20 mg / ml

An injectable pharmaceutical preparation can be prepared by reacting 20 g of β- (N-methyl-4- (N-methyl-4- (N-methyl-4- (N-methyl-4- (α-bromoacrylamido) -pyrrole). 2-carboxamido) -pyrrol-2-carboxamido) -pyrrole-2-carboxamir, o) -pyrrole-2-carboxamidol-propionamidine, hydrochloride in water for injection (1000 ml) and sealed in ampoules with 1-bml.

Claims (2)

claims: wherein η is an integer of 1 to 5; R ₁ and R ₂ , which may be the same or different, each represents hydrogen, halogen, -CN, -NO ₂ , C ₁ -C ₄ -alkyl, or a group R _{3 is} hydrogen, halogen, -CN, or -NO ₂ ; each R _{4 is} independently hydrogen or C ₁ -C ₄ alkyl; A is a bond, a group -C- NH or a group -NH-Het-CO-, wherein Het is a saturated or unsaturated pentatomic or hexatomatic heteromonocyclic ring; and B is a group _c NH NH, JW- '\ NJ or - wherein m is 1,2 or 3 and each R _{6 is} independently a C 1 -C ₄ alkyl group, as well as the pharmaceutically acceptable salts thereof. 2. acryloyl-substituted pyrrole derivatives according to claim 1, characterized in that in the formula (I) η is 3.4 or 5; A is a bond or the group -NH - \\ \ -QQ- is; B is a group -c NH NH or -CH ₂ -N "' is; R ₁ and R _{2 are} hydrogen; R _{3 is} chloro or bromo and R _{4 is} methyl. 3. Acryloyl-substituted pyrrole derivatives according to claim 1 or 2, characterized in that the compound of formula (I) of N-deformyl-N-fa-chloracryloyD-distamycin A; β- (N-methyl-4- (N -methyl-4- (N-methyl-4- (N-methyl-4- (α-chloroacrylamido) -pyrrole-2-carboxamido) -pyrrole-2-carboxamido-pyrrole ^ -carboxamido-pyrrole ^ -carboxamidoj-propionamidine; N-deformyl-N- (abromacryloy O-distamycin A; ß- (N-methyl-4- (N-methyl-4- (N-methyl-4- (N-methyl) 4- (abromacrylamido) -pyrrole-2-carboxamido) -pyrrole-2-carboxamido) -pyrrole-2-carboxamido) -pyrrole-2-carboxamido) -propionamidine; β- (N-methyl-4- (N-methyl- 4- (N-methyl-4- (N-methyl-4- (N-rr! ethyl-4- (a-bromacrylamidoj-pyrrole ^ -carboxamidoj-pyrrole ^ -carboxamidoj-pyrrole ^ -carboxamidoj-pyrrole 2-carboxamido) pyrrole-2-carboxamido) propionamidine; N-Deformyl-N- (4- (α-bromoacrylamido) -benzoy O-distamycin A; S-i-N-methyl-N-methyl-N-methyl-Ni-methyl-α-chloroacrylamido) -pyrrole-2 -carboxamido) -pyrrol-2-carboxamido) -pyrrole-2-carboxamido) -pyrrole-2-carboxamido) -propyl-dimethylamine and the pharmaceutically acceptable salts thereof. 4. Process for the preparation of an acryloyl-substituted pyrrole derivative of the general formula (I) wherein η is an integer of 1 to 5; R ₁ and R ₂ , which may be the same or different, each represents hydrogen, halogen, -CN, -NO ₂ , C ₁ -C ₄ alkyl, or a group R _{3 is} hydrogen, halogen, -CN, or -NO ₂ ; each R _{4 is} independently hydrogen or C ₁ -C ₄ alkyl; A is a bond, a group -NH --C - or a group -NH-Het-CO-, wherein Het is a saturated or unsaturated pentatomic or hexatomatic heteromonocyclic ring; and NH-, -C ^ N- B is a group -C -C -C. 2 m \ wherein m is 1,2 or 3 and each R _{5 is} independently a C 1 -C ₄ alkyl group; ode. a pharmaceutically acceptable salt thereof, characterized in that A) a compound of the formula (II) CONH .CH wherein n, R ₄ and B are as defined above, or a salt thereof, with a compound of the formula (III) R O _c "cCAX (HO ² R ₃ wherein R ₁ , R ₂ , R ₃ and A are as defined above and X is hydroxy or a leaving group to give a compound of formula (I) or a salt thereof; or B) a compound of the formula (IV)