CS276981B6 - Process for preparing poly-4-aminopyrrol-2-amide derivatives - Google Patents

Description

Poly-4-aminopyrrole-2-carboxamide derivatives and process for their preparation

Technical field

The invention relates to poly-4-aminopyrrole-2-carboxamide derivatives, to a process for their preparation and to pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION

Distamycin A is a well known compound of formula

HOC

nh ₂

NH

The literature concerning distamycin A is, for example, Nature 203, 1064 (1964).

SUMMARY OF THE INVENTION

The invention provides distamycin A derivatives of the following Formula I

R

/ 1 /,

H

C-N-R.

where n is zero or an integer from 1 to 4,

R is a / -NHR ₃ where R ₃ is a '(-CON / NO) R ₄ wherein R ₄ is either unsubstituted or halogen substituted C 1 -C 4 alkyl, or b' / -CO / CH ₂ / _m -R ₅ wherein is halogen, oxiranyl, methyloxiranyl, aziridinyl am is zero, 1 or 2, b / -NRgR ₇ wherein R _g and R ₇ are the same and each represents a 2-halogen substituted alkyl with 2 to 4 carbon atoms, each of R1 is independently hydrogen or C1-C4 alkyl,

R ₂ is alkyl of 1 to 6 carbon atoms terminated with a basic group NH 2 with the proviso that when n is 1, R _{2 is} not -CH ₂ -CH ₂ -C 1 n ₂ .

The invention also encompasses the pharmaceutically acceptable salts of the compound of formula (I), subject to the above claims, as well as all possible isomers falling within formula (I) either singly or in admixture.

In the above formula I, the following meanings of the individual substituents are preferred:

When R ₄ denotes unsubstituted C 1 -C 4 alkyl, methyl and ethyl are preferred, especially methyl.

When R ₄ is C 1 -C 4 alkyl substituted by halogen, the preferred halogen is chlorine or bromine. In this case, preferred values of R _{4 are} chloroethyl and fluoroethyl. Preferred meanings for n are zero, 1 and 2.

When R 8 is halogen, it is preferably chlorine or bromine.

Preferably, Rg is oxiranyl (f) and 1-aziridinyl (zS);

A preferred value for m is zero or 2.

The C 2 -C 4 alkyl group substituted with a halogen in the 2- position is preferably 2-chloroethyl.

Each R @ 1 is preferably, independently of one another, C1 -C4 alkyl, in particular methyl, and most preferably all R @ 1 is methyl.

When R @ ₂ denotes a C1 -C6 alkyl group terminated by a basic group, such alkyl is preferably C1 -C4 alkyl, in particular ethyl or n-propyl, and the basic group is, for example, amino, mono- or di-C1-6 alkyl. Cgalkylaminoskupina, e.g. dialkylamino having 1 to 4 carbon atoms in each alkyl part, amidino group, -N = NN- / CH _3/2, or a residue of the heterocyclic nitrogen containing ring selected from the group consisting of imidazolyl, imidazolinyl, tetrahydropyrimidinyl and oxazolidinyl. These particular heterocycles should be considered to be advantageous whenever a nitrogen-containing heterocyclic ring is mentioned in this specification.

Preferred alkyl groups having 1 to 6 carbon atoms terminated with a basic group as R ₂ are, subject to the above conditions, groups of formulas

- / CH,

, - / CH ₂ / _p -

and

H

N = N-N, where p is an integer from 1 to 4.

-N = N-N

A particularly preferred meaning of R ₂ is - / CH ₂ / _D - _u. ^{T x fx} NH2 CH3 wherein p is an integer of 1 to 4, especially 2 or 3.

Pharmaceutically acceptable salts of the compounds of formula I include salts with pharmaceutically acceptable acids, either with inorganic acids such as hydrochloric, hydrobromic, nitric and sulfuric acids, or with organic acids such as acetic, trifluoroacetic, citric acid , tartaric, maleic, fumaric, methanesulfonic and ethanesulfonic.

Salts of compounds of formula I with acids can be e.g. salts of compounds of formula I wherein R ₂ is an alkyl group having 1 to 6 carbon atoms terminated by a basic group, an acid, e.g. with one of the aforementioned acids.

Specific examples of preferred compounds of formula I are:

p- (N-methyl-4-) N-methyl-4- (3-methyl-3-nitrosoureido) pyrrole-2-carboxamido / pyrrole-2-carboxamido / propionamidine, p- [N-methyl-4- / N -methyl-4- [3- (2-chloroethyl) -3-nitrosoureido] -pyrrole-2-carboxamido / -pyrrole-2-carboxamido] propionamidine, 3- (N-methyl-4-) N-methyl-4- (3-methyl-3-nitrosoureido) pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyldimethylamine,

3- (N-methyl-4- / N-methyl-4- (3- (2-chloroethyl) -3-nitrosoureido) pyrrol-2-carboxamido / pyrrole-2-carboxamido) propyldimethylamine, 3- (N-methyl) -4- (N-methyl-4-) N-methyl-4- (3-methyl-3-nitrosoureido) pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyldimethylamine,

3- (N-methyl-4- / N-methyl-4- / N-methyl-4- / 3- (2-chloroethyl) -3-nitro soureido) pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole -2-carboxamides / propyldimethylamine,

N-deformyl-N- (N-methyl-4- (3-methyl-3-nitrosoureido) pyrrole-2-carboxamido) distamycin A,

N-deformyl-N- (N-methyl-4- (3- (2-chloroethyl) -3-nitrosoureido) pyrrole-2-carboxamido) distamycin A,

3- (N-methyl-4-) N-methyl-4- (N-methyl-4-) N-methyl-4- (3-methyl-3-nitrosoureido) pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyldimethylamine,

3- (N-methyl-4- (N-methyl-4-) N-methyl-4- (N-methyl-4- (3- (2-chloroethyl) -3-nitrosoureido) pyrrole-2-carboxamido) pyrrole-2-carboxamido / CS 276981 B6 pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyldimethylamine, 3- (N-methyl-4- / N-methyl-4- (N-methyl-4-) oxirancarboxamido) pyrrole 2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyldimethylamine,

N-deformyl-N- (N-methyl-4- / oxirancarboxamido) pyrrole-2-carboxamido / distamycin A,

3- (N-methyl-4-) N-methyl-4- (N-methyl-4-) N-methyl-4- (oxirankarboxamido) pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2- carboxamido / pyrrole-2-carboxamido / propyldimethylamine,

N-deformyl-N- (N-methyl-4- (2-chloroethylcarboxamido) pyrrole-2-carboxamido) distamycin A hydrochloride,

3- (N-methyl-4- / N-methyl-4- / N-methyl-4- (3-methyloxiranecarboxamido) pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyldimethylamine,

3- (N-methyl-4- / N-methyl-4- (N-methyl-4-) - 1- (aziridine) carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyldimethylamine ,

N-deformyl-N- (N-methyl-4- (1-) aziridine / carboxamido) pyrrole-2-carboxamido / distamycin A,

3- (N-methyl-4- (N-methyl-4-) N-methyl-4- (N-methyl-4- (1-aziridine) carboxamido) pyrrole-2-carboxamido / pyrrole-2-carboxamido) pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyldimethylamine, p- / N-methyl-4- / N-methyl-4- / N, N-bis / 2-chloroethylamino // pyrrole-2 carboxamido / pyrrole-2- carboxamido / propionamidine,

3- (N-methyl-4- / N-methyl-4- (N, N-bis) 2-chloroethylamino) pyrrole-2 carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyldimethylamine,

3- (N-methyl-4- (N-methyl-4-) N-methyl-4- (N, N-bis) 2-chloroethylamino) / pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2 -carboxamido / propyldimethylamine,

N-deformyl-N- (N-methyl-4- (N, N-bis) 2-chloroethylamino) pyrrole-2 carboxamido / distamycin A,

3- (N-methyl-4- / N-methyl-4- / N-methyl-4- / N-methyl-4- (N, N-bis) 2-chloroethylamino) pyrrole-2-carboxamido / pyrrole-2- carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyldimethylamine and their pharmaceutically acceptable salts, especially hydrochlorides.

The present invention also provides a process for the preparation of a compound of formula I, which comprises reacting (A) a compound of formula V

Wherein n, R 1 and R ₂ are as defined above with a compound of formula VI

Η / V /

O il

Z '- C - N (NO) - R ₄ (VI), wherein R ₄ is as defined above and Z' is a leaving group to give a compound of formula I wherein R is - NHR ₃ and R ₃ is - CON (NO) R ₄ wherein R ₄ is as defined above, or (B) is reacted with a compound of formula V wherein R 1, R ₂ and n are as defined above with a compound of formula VII

Z-CO- (CH _{2) m} -R ₅ (VII) wherein R ₅ and m are as defined above to give a compound of formula I wherein R is -NHR ₃ and R ₃ is -CO / CH ₂ ( _m R ₅ , where m and R ₅ are as defined above), or (C), reacting a compound of formula V, wherein R _1, R ₂ and _n are as defined above, with a compound of formula VIII

(VIII), wherein X may be hydrogen or alkyl of 1 to 2 carbon atoms to give a compound of formula IX

/ IX /,

O-N-R

AND

H wherein R _HR R _{2 and} n are as defined above and each R

X has the meaning corresponding to the meaning of the symbol X in the compound of Formula VIII and Formula IX compound is halogenated to give a compound of formula I wherein R is -NR _g R _7, wherein R _G and R ₇ have the above meanings, and if desired, R ₂ modifiCS 276981 B6 plotting the compound of the above general formula I, with or without reservation as described above to give a compound of formula I with different meanings of the substituents R ₂ and / or je- if desired, converting a compound of formula I into a salt and / or, if desired, separating the mixture of isomers of formula I into individual isomers.

The leaving group Z in the compound of formula VII can be, for example, a halogen atom, such as chlorine or bromine, or an imidazolyl or phenoxy group.

The leaving group Z 'in the compound of formula VI can be, for example, an azido or trichlorophenoxy or succinimido-N-oxy group.

The reaction between the compound of formula V and the compound of formula VI is preferably carried out in the presence of a solvent and preferably using a compound of formula VI, e.g. in the range of about 1.1 to 2 moles of the compound of formula VI The solvent is preferably an inert organic solvent selected from the group consisting of, for example, dialkyl sulfoxides such as dimethyl sulfoxide, dialkylamides of aliphatic acids such as dimethylformamide or dimethylacetamide, phosphoric triamide or hexamethylphosphoramide, or, for example, dioxane, dimethoxyethane. A particularly preferred solvent is dimethylformamide (DMF). The reaction temperature may range from about -10 ° C to 25 ° C, although 0 ° C is particularly preferred.

The time required to carry out the reaction may range from about 0.5 to 6 hours.

The reaction between the compound of formula V and the compound of formula VII is preferably carried out in the presence of a solvent and preferably using an excess of the compound of formula VII, for example in the range of about 1.1 to about 2 molar parts of the compound of formula VII The solvent is preferably an inert organic solvent selected from the group consisting of dialkyl sulfoxides such as dimethyl sulfoxide, dialkylamides of aliphatic acids such as dimethylformamide, heterocyclic amines such as pyridine, aliphatic alcohols and also water. A particularly preferred solvent is DMF.

The reaction temperature may range from about -50 ° C to about 50 ° C. The reaction time may range from 0.5 to 24 hours.

The reaction between the compound of formula V and the compound of formula VIII is preferably carried out in the presence of a solvent and preferably using an excess of the compound of formula VIII, for example in the range of about 25 to 50 parts molar of compound VIII The solvent may be, for example, water, an aliphatic alcohol, such as methanol or ethanol, an aliphatic carboxylic acid, such as acetic acid, an acid, such as dimethylformamide, or a dialkylamide, an aliphatic dialkylsulfoxide, e.g.

dimethylsulfoxide, dioxane or dimethoxyethane. A particularly preferred solvent is methanol.

The reaction temperature may range from about -20 ° C to about 25 ° C.

The time required to carry out the reaction may range from about 2 to about 48 hours.

The halogenation of a compound of formula IX can be carried out by reactions generally known in organic chemistry, for example by reaction with a halogenating agent such as halogen, eg chlorine or bromine, or a thionyl halide, eg thionyl chloride, to give a compound of formula I -NR ₆ R _7, wherein each R _g and R ₇ denotes alkyl having 2-4 carbon atoms, 2-substituted by halogen, e.g. chloro or bromo.

Modifying a substituent R ₂ of compound of Formula I with or without reservation of the aforementioned conditions, to give a compound of formula I having a different meaning of R ₂ may be carried out by known methods. Examples of such modifications include:

and '/ u substituent _on R which represents alkyl having 1 to 6 carbon atoms, NH ending amidino / C · ^ / ^ conversion amidino group ^-NH 2, a heterocyclic ring, which may be e.g. 2-imidazole ring / - / or 2 -imidazoline ring (- (-)) or to a carboxy group.

Regarding the amidine conversion, for example by reaction with reindeer, while for the modifications mentioned above under a), the group on the 2-imidazole ring can be carried out with aminoacetaldehyde dimethylacetal, known to convert the amidine group into the 2-imidazoline ring using ethylenediamine. Conversion to other heterocyclic groups can be accomplished in a similar manner by known methods.

Of course, the above modification of a substituent R ₂ may be performed in the absence of interfering groups acting in the remainder of the molecule of formula I.

Otherwise, the potential presence of interfering groups operating must preliminarily protected and after completion of the modification of a substituent R ₂ reinstate normal manner.

Conversion of a compound of formula I to a salt can be accomplished by known methods.

Conventional methods such as fractional crystallization and chromatography can be used to optionally separate the mixture of isomers of Formula I into individual isomers.

Compounds of formula (V) may be obtained by reduction of the corresponding nitroderivatives which are known compounds, or may be prepared by known methods from known compounds.

The compounds of formula VI are known and can be prepared, for example, according to J. Med. Chem. (1982), 25, 178-182.

The compounds of formulas VII and VIII are known or can be prepared by known methods from known compounds. In particular, for example, the compounds of formula (VII) are either commercially available or can be prepared by activation of the starting carboxy derivatives by a conventional route.

Compounds of formula VIII are generally commercially available products.

The compounds of the formula I according to the invention can be used as antiviral and antitumor agents.

For example, they exhibit significant efficacy in preventing reproductive activity of pathogenic viruses and protect tissue cells against viral infections.

For example, they exhibit activity against DNA viruses, such as herpes-inducing viruses, such as herpes simplex and herpes zoster, Adenoviruses, retroviruses, such as Sarcoma viruses, such as the Friend strain. For example, herpes viruses, coxsackia and respiratory syncytial viruses were tested in a liquid medium as follows: a series of two-fold dilutions of compounds from 200 to 1.5 µg / ml were divided into two wells of 0.1 ml per well in 96-well tissue culture microplates.

Cell suspensions (2x10 3 cells / ml), uninfected to control cytotoxicity, or infected with approximately 5x10 ³ TCID ₅₀ viruses / cell, were immediately added at 0.1 ml / well. After 3-5 days of incubation at 37 ° C in CO ₂ (5%), the tissue cultures were evaluated by microscopic observation and the maximum tolerated dose (MxTD) and minimum inhibitory concentration (MIC) was determined. MxTD is the maximum concentration of compound that allows monolayer growth similar to that in the density and morphology control assays. MIC is the minimum concentration that determines the reduction in cytopathic effect compared to infected control assays.

Compounds were considered to be active when their effect index, calculated as MxTD / MIC ratio, was equal to or greater than 2.

The compounds of the formula I also possess cytostatic properties against tumor cells, so that they can be used, for example, to inhibit the growth of various cancers, such as carcinomas such as breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer and uterine mucosa. . Other neoplasms in which the compounds of the invention may be used are, for example, sarcomas, for example soft tissue and bone sarcomas, and hematological malignancies, such as leukemia.

The compounds of the invention may be administered by conventional routes, for example, parenterally, eg by intravenous injection or infusion, intramuscularly, subcutaneously, by topical administration or orally.

The dosage depends on the age, weight and physical condition of the patient and on the route of administration.

For example, a suitable adult dosage may range from about 0.1 to about 100 mg per dose, one to four times daily.

As mentioned above, the pharmaceutical compositions of the present invention contain a compound of formula IA as an active ingredient in combination with one or more pharmaceutically acceptable carriers.

The pharmaceutical compositions of the invention are conveniently prepared by conventional methods and are administered in a pharmaceutically acceptable form.

For example, solutions for intravenous injection or infusion may contain as carrier, for example, sterile water or more preferably sterile physiological aqueous solution.

Suspensions or solutions for intramuscular injection may contain, together with the active compound, a pharmaceutically acceptable carrier, for example sterile water, olive oil, ethyl oleate, glycols, for example propylene glycol, and optionally a suitable amount of lidocaine hydrochloride.

In formulations for topical application, for example creams, lotions or pastes for use in dermatology, the active ingredient may be admixed with conventional oily or emulsifiable carriers.

Solid oral forms such as tablets and capsules may contain, together with the active compound, diluents such as lactose, dextrose, sucrose, cellulose, corn starch and potato starch, lubricants such as silica, talc, stearic acid, magnesium stearate or calcium stearate and / or polyethylene glycols, binders, for example starches, acacia, gelatin, methylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, disaggregating agents, for example starch, alginic acid, alginates, starch sodium glycolate, effervescent mixtures, colorants, sweeteners, wetting agents, for example lecithin, laysulphate, polysorbate generally speaking, non-toxic and pharmacologically inactive substances used in pharmaceutical compositions. These pharmaceutical compositions can be manufactured in a known manner, for example by mixing, granulating, tabletting, sugar coating or film coating processes.

The table below shows the biological data of some representative compounds of the present invention, designated by international code, compared to the closest and most studied compound known in the art, distamycin A: see, for example, Merck Index, 9th Edition, p. 450 and Nature 203, 1064. 1964 /. Compounds listed in the table were tested for cytotoxicity, which is an expression of antitumor activity, in L 1210 mouse leukemia cells.

Cells were derived from tumors in vivo and introduced into cell culture. Cells were used until passage 10. Cytotoxicity was determined by counting the surviving cells after 4 hours of treatment and after 48 hours of growth in the test compound-free medium. The percentage of cells growing in the treated cultures is compared to the control. ID ₅₀ values (dose inhibiting 50% of cell growth compared to control) are calculated from dose-response curves.

Table

Compound ^ID 50 // ^{u <?} / ^M L / L 1210 leukemia cells

Distamycin A 180 FCE 25289 0,045 FCE 24813 8.8 FCE 24707 70 FCE 24663 16 FCE 24599 ' 7 FCE 25291 0.008 FCE 24662 0.06 FCE 24603 19 Dec FCE 25550 0.45 FCE 25486 0,036

FCE 25289: N-deformyl-N- (N-methyl-4-) oxirankarboxamido / pyrrole-2 carboxamido / distamycin A hydrochloride

FCE 24813: p- (N-methyl-4- / N-methyl-4- (3- (2-chloroethyl) -3-nitrosoureido) pyrrole-2-carboxamido / pyrrole-2-carboxamido) for pionamidine hydrochloride

FCE 24707: 3- (N-methyl-4- / N-methyl-4- / N-methyl-4- (3-methyl-3-nitrosoureido) pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole- 2-carboxamido / propyldimethylamine hydrochloride

FCE 24663: 3- (N-methyl-4- / N-methyl-4- / 3- (2-chloroethyl) -3-nitrosoureido) pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyldimethylamine hydrochloride

FCE 24599: 3- (N-methyl-4- / N-methyl-4- / N-methyl-4- / N-methyl-4- / 3/2-chloroethyl) -3-nitrosoureido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2 carboxamido / propyldimethylamine hydrochloride

FCE 25291: N-deformyl-N- (N-methyl-4- / N-methyl-4- / N, N-bis- / 2-chloroethylamino) // pyrrole-2-carboxamido / pyrrole-2-carboxamido / distamycin A-hydrochloride

FCE 24662: N-deformyl-N- (N-methyl-4-) - N, N-bis- (2-chloroethylamino) pyrrole-2-carboxamido / distamycin A hydrochloride

FCE 24603: p- (N-methyl-4-) N-methyl-4- (N, N-bis- (2-chloroethylamino)] - pyrrole-2-carboxamido / pyrrole-2-carboxamido / propionamidine hydrochloride

FCE 25550: 3- (N-methyl-4- / N-methyl-4- / N-methyl-4- / N-methyl-4- / N, N-bis- (2-chloroethylamino) pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamides / pyrrole-2-carboxamido / propyldimethylamine hydrochloride

FCE 25486: p- / N-methyl-4- / N-methyl-4- / N-methyl-4- / N-methyl-4- / N, N-bis- / 2-chloroethylamino // pyrrole-2- carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / ethyl- (2-imidazole) -hydrochloride

The invention also relates to a process for the preparation of a pharmaceutical composition as described above which comprises treating an effective amount of an active compound of formula I with a pharmaceutically acceptable carrier and / or diluent.

It is a further object of the present invention to provide a method of treating viral infections and tumors in a patient by administering a compound of the invention to said patients.

The abbreviations DMSO, THF, CDI, DMF, DCC, DCU and ACOH refer to dimethylsulfoxide, tetrahydrofuran, carbonyldiimidazole, dimethylformamide, dicyclohexylcarbodiimide, dicyclohexylurea and acetic acid.

The following examples illustrate but do not limit the invention. DETAILED DESCRIPTION OF THE INVENTION

Example 1

To a stirred aqueous solution of 2.03 g of N, N-dimethylaminopropylamine in 40 ml of water and 3.36 g of sodium bicarbonate was added a solution of 4 g of N-methyl-4-nitropyrrole-2-carboxylic acid chloride in 5 ml of benzene at room temperature. The resulting mixture was stirred at room temperature for 2 hours, saturated with sodium chloride and extracted twice with 50 ml of benzene each. The dried organic extracts were evaporated in vacuo and the residue was crystallized from petroleum ether. 3.5 g of pure 3- (N-methyl-4-nitropyrrole-2-carboxamido) propyldimethylamine consisting of white needles are obtained,

m.p. Mp 118-120 ° C.

NMR (DMSO-d6): δ 1.60 (2H, m), 2.12 (6H, s), (2H, m), 3.88 (3H, s), 7.37 bd), 8.35 / lH, bt

3.23 (2H, t), 3.20 (1H, d), 8.08 (1H),

Example 2

3.4 g of the compound of Example 1 are dissolved in 40 ml of ethanol and 20 ml of dilute hydrochloric acid and reduced on a palladium catalyst (5% on carbon) under a hydrogen pressure of 0.34 MPa in a Parr apparatus. 20 ml of water are added and the catalyst is filtered off. The resulting solution was evaporated and the residue was dissolved in 40 ml of water. 4 g of sodium bicarbonate are added, followed by a solution of 2.8 g of N-methyl-4-nitropyrrole-2-carboxylic acid chloride in 20 ml of benzene. The resulting mixture was stirred at room temperature for about 2 hours and then extracted with chloroform. The dried organic extracts were evaporated in vacuo and the residue was purified by column chromatography using chloroform, 95% ethanol and ammonium hydroxide (75: 25: 0.6) to give 4.7 g of 3- (N-methyl-4). N-methyl-4-nitropyrrole-2-carboxamido (pyrrole-2-carboxamido) for pyldimethylamine as a yellow solid of m.p. 178-180 ° C.

NMR (CDCl ₃ ) δ: 1.74 (2H, m), 2.30 (6H, s), 2.49 (2H, t), 3.44 (2H, m), 3.88 (3H, s) 3.99 (3H, s), 6.58 (1H, d), 7.21 (1H, d), 7.38 (1H, d), 7.6 (1H, broad r), 8, 80 (1H, broad s).

The following compounds can be obtained in an analogous manner:

3- (N-methyl-4- (N-methyl-4-) N-methyl-4-nitropyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido) propyldimethylamine, mp 175 ° C (dec.) .

NMR (DMSO-d ₆ ) δ: 1.63 (2H, m), 2.22 (6H, s), 2.38 (2H, t), 3.16 (2H, dt), 3.80 (3H) , s /, 3.85 (3H, s), 3.87 (3H, S), 3.97 (3H, s), 6.80-7.30 (6H, m), 7.59 (1H), d), 8.04 (1H, t), 8.16 (1H, d), 9.84 (1H, broad s), 9.95 (1H, broad s), 10.26 (1H, broad s) ,

3- (N-methyl-4-) N-methyl-4- (N-methyl-4-) N-methyl-4-nitropyrrole-2 carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2 carboxamido / propyldimethylamine, mp 195 ° C (decomposition)

NMR (DMSO-d6) δ: 1.64 (2H, m), 2.13 (6H, s), 2.27 (2H, t), 3.20 (2H, dt), 3.80 (3H), s /, 3.85 (3H, s), 3.88 (3H, s), 3.98 (3H, s), 6.82 (1H, d), 7.04 (2H, m),

7.18 (1H, d), 7.26 (2H, d), 7.58 (1H, d), 8.18 (1H, d), 8.02 (1H, t), 9.86 (1H) , s), 9.94 (1H, s), 10.25 (1H, s) p- [N-methyl-4- (N-methyl-4-nitropyrrole-2-carboxamido) pyrrole-2 carboxamido / propionamidine- hydrochloride

NMR (DMSO-d6) δ: 2.66 (2H, t), 3.54 (2H, m), 3.72 (3H, s), 3.97 (3H, s), 6.94 (1H), d), 7.22 (1H, d), 7.66 (1H, d), 8.17 (1H, d), 8.28 (1H, broad t), 8.30 (4H, broad signal), 10.30 (1H, broad s) β- (N-methyl-4- / N-methyl-4- (N-methyl-4-nitropyrrole-2-carboxamido) pyrrole-2-carboxamido / pyrrole-2-carboxamido) propionamidine hydrochloride

NMR (DMSO-d6) δ: 2.65 (2H, t), 3.52 (2H, m), 3.79 (3H, s), 3.85 (3H, s), 3.96 (3H), s), 6.9-7.3 (4H, m), 7.63 (1H, d), 8.15 (1H, d), 8.18 (1H). wide t /,

8.94 (4H, broad signal), 9,90 (1H, broad s),

10.27 / 1H, broad s / β- / Ν-ιηβΐ1 ^ 1-4- / Ν-ϊΐ ^ ϊ ^ 1-4- / Ν-ιηθΉ ^ 1-4- / Ν-ϊΐ ^ ϊ ^ 1-4 1-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2 carboxamido / propionamidine hydrochloride

NMR (DMSO-d6) δ: 2.64 (2H, t), 3.81 (3H, s), 3.86 (3H, s), 3.87 (3H, s), 3.95 (3H), s), 6.9-7.3 (6H, m), 7.61 (1H, d), 8.16 (1H, d), 8.19 (1H, broad t),

8.95 (4H, broad signal), 9,89 (1H, broad s),

9.95 (1H, broad s), 10.25 (1H, broad signal)

Example 3

900 mg of 3- (N-methyl-4- (N-methyl-4-nitropyrrole-2-carboxamido) pyrrole-2-carboxamido) propionamidine hydrochloride dissolved in 150 ml of ethanol, 75 ml of water and 9 ml of 2N hydrochloric acid were hydrogenated in a Parr apparatus for 54 minutes at a hydrogen pressure of 50 psi and room temperature on a palladium catalyst (10% on carbon). The catalyst was filtered off and the filtrate was evaporated in vacuo. 930 mg of crude β- / Ν-π-1,4-1-4- / Ν-ιηθϋ-4-methyl-3-carboxamido / pyrrole-2-carboxamido / propionamide dihydrochloride was obtained. The residue was dissolved in 60 mL of methanol, cooled to -20 ° C and 12 mL of ethylene oxide was added. After 15 minutes, the temperature was allowed to rise and the mixture was left at room temperature overnight. The solution was evaporated to dryness to give, after chromatography on SiO ₂ , 800 mg of pure β- (N -methyl-4-) N -methyl-4- (N, N-bis) 2-hydroxyethylamino // pyrrole-2-carboxamido (pyrrole-2-carboxamido) propionamidine hydrochloride.

Mass spectrum: m / e 419 (M ⁺ ), 420 (M ⁺ + 1), ¹ H-NMR (dimethyl-dg sulfoxide), δ: 2.63 (2H, t), 2.90-3.80] 10H, m /, 4.55 (2H, broad signal),

6.30 (1H, d), 6.52 (1H, d), 7.12 (1H, d), 8.20 (1H, t), 8.70 (2H, broad s), 9.01) 2H, broad s /, 9.63 (1H, s),

UV (EtOH 95%):? Max 245,? = 16 352 max 292,? = 15 070.

The following compounds can be obtained in an analogous manner:

N-deformyl-N- (N-methyl-4-) N, N-bis- (2-hydroxyethylamino) pyrrole-2-carboxamido distamycin A hydrochloride

NMR (DMSO-d6), δ: 2.67 (2H, t), 3.00-3.70 (10H, m), 3.79 (3H, s), 3.81 (3H, s), 3 , 85 (6H, s), 4.65 (2H, broad signal), 6.30-7.25 (8H, m), 8.26 (1H, t),

8.26 (1H, t), 8.29-9.18 (4H, broad signal),

9.72 (1H, s), 9.81 (2H, s)

Example 4

NMR (dimethyl-dg sulfoxide), δ: 2.63 m /, / 20H, 3.78 t / ,. / 3H, 3.30 with/, with/, 6.42 / 1H, d /, d /, 6.92 / 1H, d /,

A stirred solution of 717 mg of p- (N-methyl-4- / N-methyl-4- (N, N-bis- / 2-hydroxyethylamino) -pyrrole-2-carboxamido / pyrrole-2-carboxamido) propionamidine hydrochloride in 10 ml of dry pyridine was added. It was cooled in an ice bath, treated with a solution of methanesulfonyl chloride in pyridine (1.27 M, 2.7 mL) under nitrogen, and stirred at 5 ° C for 45 minutes. After addition of methanol, everything was allowed to warm to room temperature and evaporated to dryness. The crude product was chromatographed on silica, yielding 440 mg of p- (N-methyl-4-) -N-methyl-4- (N, N-bis- (2-chloroethylamino) pyrrole-4-carboxamido) pyrrole-. 2-carboxamido / propionamidine hydrochloride.

80 / 10H

3.81 / 3H, 6.55 / 1H,

7.17 (1H, d), 8.20 (1H, t), 8.70 (2H, broad s), 9.02 (2H, broad s),

9.68 (1H, s),

373 15 450

The following compounds can be obtained in an analogous manner:

N-deformyl-N- (N-methyl-4-) N, N-bis- (2-chloroethylamino) pyrrole-2 carboxamido / distamycin A hydrochloride

NMR (DMSO-d6) δ: 2.63 (2H, t), 3.20-3.9 (1H, m), 3.80-3.85 (3H, 1H, d), 6, 58 (1H, d), 6.90-7.30 (6H, (1H, t), 8.73 (2H, broad signal), broad signal), 9.70 (1H, broad s), s)

N-deformyl-N- (N-methyl-4- / N-methyl-4- (N, N-bis- (2-chloroethylamino)) - pyrrole-2-carboxamido / pyrrole-2-carboxamido / distamycin

A-hydrochloride

NMR (DMSO-d6) δ: 2.64 (2H, t), 3.35-3.75 (8H, m), 3.78-3.90 (15H, m), 6.48 (1H, d) (6.52 (1H, d), 6.90-7.25)

245 max 245, max 393

UV (EtOH 95%):

6.46 m / 8.20

9.00 (2H, 9.90 (2H), (8H, m), 8.16 (1H, t), 8.60 (2H, broad signal), 8.96 (2H, broad signal), 9.68 (1H, s), 9.98 (3H, s)

3- (N-methyl-4-) N-methyl-4- (N-methyl-4-) N, N-bis- (2-chloroethylamino) pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole- 2-carboxamido / propyldimethylamine hydrochloride

NMR (DMSO-d ₆ ) δ: 1.92 (2H, m), 2.71 (6H, s), 2.8-3.4 (4H, m),

3.2- 3.9 / 10H, m / 3.80 / 3H, 3.81 (3H, s),

3.84 (3H, S), 6.48 (1H, d), 6.51 (1H, d),

6.8-7.3 (4H, m), 8.16 (1H, broad t), 9.70 (1H, s), 9.90 (1H, s)

3- (N-methyl-4-) N-methyl-4- (N-methyl-4-) N-methyl-4- (N, N-bis- / 2-chloroethylamino) pyrrole-2-carboxamido] pyrrole- 2-carboxamido / pyrrole -2-carboxamido / pyrrole-2-carboxamido / propyldimethylamine hydrochloride

NMR (DMSO-d6) δ: 1.90 (2H, m), 2.72 (6H, s), 2.8-3.4 (4H, m),

3.2- 3.8 / 10H, m /, 3.81 / 3H, s /, 3.82 / 3H, s /,

3.85 (3H, s), 3.87 (3H, s), 6.45 (1H, d), 6.50 (1H, d), 6.8-7.3 (6H, m), 8.16 (1H, broad t),

9.75 (1H, s) 9.81 (1H, s), 9.92 (1H, s) p- N -methyl-4- / N-methyl-4- / N-methyl-4- / N methyl-4- (N, N-bis) 2-chloroethylamino // pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / ethyl- (2-imidazole) hydrochloride

NMR (DMSO-d6) δ: 2.83 (2H, broad t), 3.25-3.85 (1OH, m),

3.80-3.85 (12H, m), 6.45 (1H, d), 6.55 (1H, d),

6.9-7.3 (8H, m), 8.19 (1H), broad t, 9.72 (1H, broad s), 9.92 (2H, s) p-N-methyl-4- (N-methyl-) 4- (N-methyl-4-) N-methyl-4- (N, N-bis) 2-chloroethylamino / pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido (ethyl) - [2- (2-imidazoline) hydrochloride

NMR (DMSO-d6) δ: 2.68 (2H, broad t), 3.30-3.75 (1OH, m), 3.76 (4H, broad s), 3.80-3.85 (12H) , m /, 6.46 (1H, d), 6.51 (1H, d), 6.9-7.25 (6H, m), 8.25 (1H, broad t), 9.70 (1H) , broad s), 9.92 (2H), broad s (p-) N-methyl-4- (N-methyl-4-) N-methyl-4- (N-methyl-4-) N, N-bis / 2-chloroethylamino // pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / ethyl- 2- (3,4,5,6-tetrahydropyrimidine) hydrochloride

NMR / DMSO-d ₆ / δ: 1.74 / 2H, m /, 2.60 / 2H, t /, 3.00 to 3.75 / 12H, m /

3.79-3.85 (12H, m), 6.48 (1H, d), 6.52 (1H, d), 6.9-7.3 (6H, m), 8.24 (1H), broad t], 9.75 (1H, broad s), 9.90 (2H, s).

Example 5

To an ice-cooled solution of 0.404 g of 3- (N-methyl-4- (N-methyl-4-aminopyrrole-2-carboxamido) pyrrole-2-carboxamido) propionamidine hydrochloride in 5 ml DMF and 320 mg 2,4,5-trichlorophenyl -N-methyl-N-nitrosocarbamate (prepared according to J. Med. Chem. 25, 178 (1982)] is added dropwise a solution of 0.164 ml of diisopropylethylamine in 8 ml of DMF. The resulting solution was stirred at 0 ° C for 1 hour. The reaction mixture was evaporated in vacuo and the residue was purified by column chromatography. 251 mg of p- [N-methyl-4- (3-methyl-3-nitro-soureido) -pyrrole-2-carboxamido] -pyrrole-2-carboxamido] -propionamine-dihydrochloride are obtained.

UV (EtOH, 95%): max max

241 21 611. 294 28 207

IR (KBr): cm ^-1 3500-2800, 2500-2200, 1450, 970, 650,

NMR (DMSO-d6): 2.59 (2H, m), 3.15 (3H, s), 3.48 (2H, m), 3.79 (3H, S), 3.85 (3H), s), 7.01-7.31 (4H, m), 8.61 (2H, broad signal), 8.97 (2H, broad signal), 9.91 (2H, broad), 10.61 (1H) , wide s /.

The following compounds can be obtained in an analogous manner:

p- (N-methyl-4-) N-methyl-4- (3- (2-chloroethyl) -3-nitrosoureido) -pyrrole-2-carboxamido / pyrrole-2-carboxamido / propionamidine hydrochloride NMR / DMSO-d _g / δ: 2.61 / 2H, t /, 3.50 / 2H, m /, 3.69 / 2H, t /, 3.81 / 3H, s /, 3.87 / 3H, s /, 4 19 (2H, t), 6.90-7.25 (4H, m), 8.19 (1H, t), 8.55-10.72 (6H, m)

3- (N-methyl-4- / N-methyl-4- (3-methyl-3-nitrosoureido) pyrrole-2-carboxamido / pyrrole-2-carboxamido) propyldimethylamine hydrochloride NMR (DMSO-d6): 88 (2H, m), 2.70 (6H, s), 3.00 (2H, m), 3.16 (3H, s), 3.25 (2H, m), 3.80 (3H, s) (3.88 (3H, s), 6.90-7.20 (4H, m), 8.12 (1H, t), 9.92 (1H, s), 10.69 (1H, s))

3- (N-methyl-4- / N-methyl-4- (3- (2-chloroethyl) -3-nitrosoureido) pyrrol-2-carboxamido / pyrrole-2-carboxamido) propyldimethylamine hydrochloride

NMR (DMSO-d6) δ: 1.84 (2H, m), 2.70 (6H, s), 2.90-3.90 (6H, m),

3.81 (3H, s), 3.87 (3H, s), 4.18 (2H, t),

6.85-7.30 (4H, m), 8.15 (1H, t), 8.93-9.75 (3H, m)

3- (N-methyl-4- (N-methyl-4-) N-methyl-4- (3-methyl-3-nitrosoureido) pyrrole-2-carboxamido) pyrrole-2-carboxamido / pyrrole-2-carboxamido) propyldimethylamine hydrochloride

NMR (DMSO-d6) δ: 1.80 (2H, m), 2.53 (6H, s), 2.78 (2H, m), 3.18 (3H, s), 3.20 (2H), m / 3.80 (3H, s) 3.85 (3H)

S), 3.88 (3H, S), 6.85-7.25 (6H, m), 8.10 (1H, t), 9.85-10.70 (3H, m)

3- (N-methyl-4- / N-methyl-4- / N-methyl-4- (3- (2-chloroethyl) -3-nitro soureido) pyrrole-2-carboxamido) pyrrole-2-carboxamido / pyrrole -2-carboxamido / propyldimethylamine hydrochloride

NMR (DMSO-d6) δ: 1.98 (2H, m), 2.65 (6H, s), (3H, s), 3.87 (3H, s), 3.89 (t), 6.85 -7.30 (6H, m), 8.12 (3H, m)

N-deformyl-N- (N-methyl-4- (3-methyl-3-nitrosoureido) pyrrole-2-carboxamido) distamycin A hydrochloride

NMR (DMSO-d6) δ: 2.61 (2H, t), 3.20 (3H, s), 3.50 (2H, m), 3.82 (3H, s), 3.84 (3H), s /, 3.85 (3H, s), 3.86 (3H, s), 6.9-7.3 (8H, m), 8.15 (1H, t), 8.55 (2H), broad signal (8.94 (2H), broad signal), 8.82 (1H, s), 8.86 (1H, s), 9.90 (1H, s), 10.71 (1H),

WITH/

2.90 (2H, t), 3.81 (3H, s), 4.09 (2H, (1H, t), 9.80-10.8

N-deformyl-N- (N-methyl-4- (3- (2-chloroethyl) -3-nitrosoureido) pyrrole-2-carboxamido) distamycin A hydrochloride

NMR (DMSO-d6) δ: 2.62 (2H, t), 3.51 (2H, m), 3.69 (2H, t), 3.82 (3H, S), 3.84 (3H), s /, 3.85 (3H, s), 3.86 (3H, s), 4.20 (2H, t), 6.9-7.3 (8H, m), 8.18 (1H, t) (8.56 (2H, broad signal), 8.94 (2H, broad signal), 9.81 (1H, s), 9.87 (1H, s), 9.91 (1H, s), 10 , 70 (1H, s)

3- (N-methyl-4- / N-methyl-4- / N-methyl-4- / N-methyl-4- (3-methyl-3-nitrosoureido) pyrrole-2-carboxamido) pyrrole-2-carboxamido [pyrrole-2-carboxamido] / pyrrole-2-carboxamido / propyldimethylamine hydrochloride NMR / DMSO-d6 / δ: 1.90 (2H, m), 2.73 (6H, s), 3.19 (3H, s), 3.82 (3H, s), 3.84 (3H, s), 3.85 (3H, s), 3.86 (3H, s), 6.90-7.30 (8H, m), 8 13 (1H, t), 9.88-10.70 (4H, m)

3- (N-methyl-4- / N-methyl-4- (N-methyl-4-) N-methyl-4- (3- (2-chloroethyl) -3-nitrosoureido) pyrrole-2-carboxamido) pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyldimethylamine hydrochloride

NMR / DMSO-d ₆ / CDCl ₃ δ:

1.90 (2H, m), 2.60 (6H),

3.15-4.00 (16H, m),

6.80-7.30 (8H, m), 8.00 br s, 9.70 (1H),

10.48 (1H, s / s), 2.85 (2H, t),

4.22 (2H, t), (1H, t), 9.63 (1H, s), 9.77 (1H, s),

Example 6

To a solution of 765 mg of (2R, 3R) -3-methyloxiranecarboxylic acid in 20 ml of dry tetrahydrofuran cooled to -20 ° C was added 0.825 ml of N-methylmorpholine and then 0.920 ml of pivaloyl chloride.

The resulting suspension was stirred at -20 ° C for 20 minutes, then added to a cooled solution of 2.6 g of 3- (N-methyl-4-) N-methyl-4 / N-methyl-4-aminopyrrole-2-ol. carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyldimethylamine hydrochloride in 50 ml of dimethylformamide and 0.4 g of sodium bicarbonate. The mixture was stirred at 0 ° C for 30 minutes and then at room temperature for 4 hours. The solvents are evaporated to dryness in vacuo and the residue is chromatographed on silica gel using a solvent mixture of chloroform, methanol, 2-normal hydrochloric acid (100: 100: 1).

1.4 g of 3- (N-methyl-4- (N-methyl-4-) N-methyl-4- (3-methyl) 2R, 3R) -oxiranecarboxamido / pyrrole-2-carboxamido / pyrrol-2 are obtained. -carboxamido / pyrrole-2-carboxamido / propyldimethylamine hydrochloride.

NMR / DMSO-d / δ: 1.25 / 3H, d /, 3.3 / 1 H, m /, 3.60 / 1H, d /, / J = 4.7 H _z / cis //.

The following compounds can be obtained in an analogous manner:

N-deformyl-N- (N-methyl-4-) oxirancarboxamido / pyrrole-2-carboxamido / distamycin A hydrochloride

NMR (DMSO-d6): 2.64 (2H, t), 2.89 (2H, m), 3.51 (2H, m), 3.55 (1H, dd), 3.80 (6H), s /, 3.83 (6H, s), 6.90-7.30 (8H, m), 8.21 (1H, t), 8.90 (2H, broad signal), 9.40 (2H), broad signal /, 9.90 (3H, broad signal), 10.28 (1H, broad signal)

3- (N-methyl-4-) N-methyl-4- (N-methyl-4-) N-methyl-4- (oxirankarboxamido) pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2- carboxamido (pyrrole-2-carboxamido) propyldimethylamine hydrochloride NMR / DMSO-d6 / δ: 1.90 (2H, m), 2.72 (6H, s), 2.85-3.40 (4H, m) ,

2.88 (2H, m), 3.54 (1H, dd), 3.82 (3H, s), 3.83 (3H, s), 3.84 (3H, s), 3.85 (3H) s, 6.9-7.3 (8H, m), 8.15 (1H, broad t), 9.88 (1H, broad s), 9.93 (1H, broad s), 10.25 (1H, wide signal)

3- (N-methyl-4- / N-methyl-4- (N-methyl-4-) oxirancarboxamido) pyrrole 2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyldi17 methylamine

NMR (DMSO-d ₆ ) δ: 1.90 (2H, m), 2.70 (6H, s), 2.85-3.42 (4H, m),

2.88 (2H, m), 3.53 (1H, dd), 3.81 (3H, s), 3.86 (3H, S), 3.89 (3H, s), 6.9-7 , 3 (6H, m), 8.17 (1H, broad t), 9.88 (1H, broad s), 9.93 (1H, broad s), 10.25 (1H, broad signal)

N-deformyl-N- (N-methyl-4- (2-chloroethylcarboxamido) pyrrole-2-carboxamido) distamycin A hydrochloride

NMR (DMSO-d6) δ: 2.66 (2H, broad t), 2.74 (2H, t), 3.52 (2H, m), 3.79 (3H, s), 3.81 (3H) , s /, 3.85 / 6H, s /,

3.87 (2H, t), 6.85-7.3 (8H, m), 8.21 (1H, broad t), 8.75 (2H, broad signal), 9.05 (2H, broad signal) 9.90 (3H, broad s), 10.1 (1H, broad s).

3- (N-methyl-4- / N-methyl-4- (N-methyl-4-) - 1- (aziridine) carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyldimethylamine -hydrochloride

NMR (DMSO-d6) δ: 1.90 (2H, m), 2.08 (4H, s), 2.71 (6H, s),

2.83-3.40 (4H, m), 3.81 (3H, s), 3.85 (3H, s),

3.87 (3H, s), 6.9-7.3 (6H, m), 8.20 (1H, t),

9.87 (1H, s), 9.91 (2H, s)

N-deformyl-N- (N-methyl-4- (1-aziridine) carboxamido) pyrrole-2-carboxamido / distamycin A hydrochloride

NMR (DMSO-d6): 2.08 (4H, s), 2.62 (2H, t), 3.54 (2H, m), 3.81 (6H, s), 3.83 (6H), s /, 6.8-7.3 (8H, m), 8.20 (1H, t), 8.80 (4H, broad signal), 9.70 (1H, broad signal), 9.88 (3H) , wide signal /

3- (N-methyl-4- (N-methyl-4-) N-methyl-4- (N-methyl-4- (1-aziridine) carboxamido) pyrrole-2-carboxamido / pyrrole-2-carboxamido) pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyldimethylamine hydrochloride NMR / DMSO-d6 / δ: 1.91 (2H, m), 2.07 (4H, s), 2.82-3.42 / 4H, m /,

3.81 (3H, s), 3.84 (3H, s), 3.85 (3H, s), 3.87 (3H, s), 6.9-7.3 (8H, m), 8 , 19 (1H, broad t),

9.88 (1H, broad s), 9.91 (2H, broad s), 9.96 (1H, broad s)

Example 7

To a stirred aqueous solution of 2.3 g of 3- (N-methyl-4-) N-methyl

4- (N-methyl-4-aminopyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido) propyldimethylamine dihydrochloride in 200 ml of water and sodium bicarbonate (1.5 g) was added at room temperature solution 1 1.0 g of N-methyl-4-nitropyrrole-2-carboxylic acid chloride in 25 ml of tetrahydrofuran.

The resulting mixture was refluxed for 2 hours with stirring. The reaction mixture is evaporated in vacuo, the residue is taken up in water and the pH is adjusted to 13 by addition of 2N sodium hydroxide solution and extraction is carried out with a mixture of chloroform and methanol (70:30). The dried organic extracts are evaporated in vacuo and the residue purified by column chromatography using chloroform, methanol and ammonium hydroxide in a ratio of 70: 30: 1. 2.6 g of 3- (N-methyl-4-) N-methyl-4- (N-methyl-4-) N-methyl are obtained. -4-nitropyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyldimethylamine as a yellow solid of m.p. 195 DEG C. (decomposition).

NMR (DMSO-d6) δ: 1.64 (2H, m), 2.13 (6H, s), 2.27 (2H, t), 3.20 (2H, dt), 3.80 (3H), s /, 3.85 (3H, s), 3.88 (3H, s), 3.98 (3H, s), 6.82 (1H, d), 7.04 (2H, m),

7.18 (1H, d), 7.26 (2H, d), 7.58 (1H, d), 8.18 (1H, d), 8.02 (1H, t), 9.86 (1H) , s /, 9.94 (1H, s), 10.25 (1H, s)

The following compounds can be obtained in an analogous manner:

3- (N-methyl-4- / N-methyl-4) N-methyl-4- (N-methyl-4-) N-methyl-4-nitropyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole -2-carboxamido [pyrrole-2-carboxamido] pyrrole-2-carboxamido / propyldimethylamine NMR (DMSO-d6): 1.68 (2H, m), 2.32 (6H, s), 3.81 (3H) , s /, 3.88 / 9H, broad s /, 3.97 / 3H, s /, 6.8-7.3 (8H, m),

7.60 (1H, d), 8.04 (1H, broad t), 8.18 (1H, d), 9.85-10.27 (4H) broad, ss, NH / z and

3- (N-methyl-4- (N-methyl-4-) N-methyl-4- (N-methyl-4-) N-methyl-4- (N-methyl-4-nitropyrrole-2-carboxamido)) pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyldimethylamine

NMR (DMSO-d6) δ: 1.68 (2H, m), 2.32 (6H, s), 3.81 (3H, s), 3.88 (9H, broad s), 3.97 / 3H , s /, 6.8-7.3 (8H, m),

7.60 (1H, d), 8.04 (1H, broad t), 8.18 (1H, d), 9.85-10.27 (4H, broad, ss, NH).

Example 8

800 mg of 3- (N-methyl-4- / N-methyl-4- / N-methyl-4- / N-methyl-4-nitropyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamines [pyrrole-2-carboxamido] propyldimethylamine is dissolved in a mixture of 70 ml of methanol, 30 ml of water and 3 ml of 1N hydrochloric acid and reduced on a palladium catalyst (10% on activated carbon) under a hydrogen pressure of 0.34 MPa. The catalyst was filtered off, the resulting solution was evaporated in vacuo and the residue was crystallized from ethyl acetate / ethanol. 760 mg of 3- (N-methyl-4- (N-methyl-4-) N-methyl-4- (N-methyl-4-aminopyrrole-2-carboxamido) pyrrol-2-carboxamido) pyrrol-2 are obtained. -carboxamido (pyrrole-2-carboxamido) for pyldimethylamine dihydrochloride

NMR (DMSO-d6) δ: 1.88 (2H, m), 2.72 (6H, s), 3.81 (3H, s), 3.85 (3H, s), 3.86 (3H), s /, 3.90 (3H, s), 6.9-7.3 (8H, m), 8.13 (1H), broad t /, 8.87 (1H, broad s), 9.91 (1H) , broad s /, 10.09 / 1H, broad s /,

10.2 (3H, broad, N ⁺ H)

The following compounds can be obtained in an analogous manner:

3- (N-methyl-4-) N-methyl-4-aminopyrrole-2-carboxamido / pyrrole-2-carboxamido / propyldimethylamine dihydrochloride

NMR (DMSO-d6) δ: 1.70-2.10 (2H, m), 2.73 (6H, s), 2.90-3.40 (4H, m), 3.81 (3H, s) (3.89 / 3H, s), 6.85-7.20 (4H, m), 8.18 (1H, t), 10.40 (1H, s), 10.20 (4H), broad signal /

3- (N-methyl-4-) N-methyl-4- (N-methyl-4-aminopyrrole-2-carboxamido) pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyldimethylamine dihydrochloride NMR / DMSO-dg /

1.85 (2H, m), 2.73 (6H, s), 2.9-3.7 (4H, m),

3.81 (3H, s), 3.84 (3H, s), 3.86 (3H, s),

6.9-7.4 (6H, m), 8.15 (1H, t), 9.88 (1H, s),

10.02 (1H, s)

Example 9

To a solution of 2 g distamycin A hydrochloride in 60 ml methanol was added 0.5 ml aminoacetaldehyde dimethyl acetal and allowed to stand at room temperature for 5 hours. A further 10% of the aminoacetaldehyde dimethylacetal was added and the solution was refluxed for 16 hours. The solvent was removed under reduced pressure and the crude product was dissolved in 100 ml of 1 N aqueous oxalic acid and allowed to stand at 70 ° C for 4 hours.

The aqueous solution was evaporated to dryness and the solid residue was washed several times with acetone and then treated with an excess of 3.5N alcoholic hydrochloric acid solution. The solvent was removed in vacuo and the crude product was dissolved in acetone and filtered. 1.1 g (52.5%) of β- (N-methyl-4-) N-methyl-4- (N-methyl-) 4 formylamino / pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole are obtained. -2 carboxamido / ethyl- (2-imidazole) hydrochloride

NMR (DMSO-d6) δ: 2.83 (2H, broad t), 3.50 (2H, m), 3.82 (3H, s), 3.85 (6H, s), 6.80-7 25 / 8H, m /, 8.10 (1H, broad t), 8.13 (1H, broad s), 9.87 (2H, broad s), 10.00 (1H, broad s)

Example 10

To a solution of 200 mg of distamycin A hydrochloride in 4 ml of methanol was added 0.1 ml of ethylenediamine. The resulting solution was allowed to stand overnight at room temperature and evaporated in vacuo. The residue is taken up in 30 ml of acetone, stirred for 30 minutes and filtered. 20 mg of β- (Ν-β-β-β-β-β-β-γ-4-β-β-β-6-β-β-4-β-β-β-β-β-pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / ethyl) 2- (2-imidazoline) hydrochloride

NMR (DMSO- d 6): 2.68 (2H, broad t), 3.52 (2H, broad d), 3.76 (4H, broad s), 3.80 (3H, s), 3.83 / 6H, s /,

6.8-7.3 (6H, m), 8.12 (1H, d), 8.27 (1H, broad t), 9.90 (2H, broad s), 10.11 (1H, broad s) /

The following compounds can be obtained in an analogous manner:

β- / Ν-ϊϊΐθ ^ γ1-4- / Ν-ιηβ ^ γ1-4- / Ν-πιβί1ιγ1-4- οπηγΐ3ΐηίηοργΓΓθ1-2 ^ 3ΛΛχamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / ethyl- / 2 - / 3,4,5,6-Tetrahydropyrimidine // hydrochloride

NMR (DMSO-d6) δ: 1.75 (2H, m), 2.60 (2H, t), 3.00-3.70 (6H, m), 3.81 (3H, s), 3, 84 / 6H, s /, 6.80-7.30 (6H, m),

8.12 (1H, d), 8.25 (1H, t), 9.90 (2H, s), 10.15 (1H, s)

Example 11

Solution 1.5 g of β- (N-methyl-4-) N-methyl-4- (N-methyl-) - 4-formyl amino / pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carbox amido of ethyl (2-imidazole) hydrochloride in 70 ml of methanol was treated with 50 ml of 1N hydrochloric acid and allowed to stand at room temperature for 48 hours. The solvent was evaporated under reduced pressure and the crude product was taken up in acetone, filtered and collected. 1.2 g of β- (Ν-ιιΐθ ^ γ1-4- / Ν-ιηβί1ιγ1-4-) Ν-ΐηβΐ1ιγ1 -4-aminopyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido are obtained. ethyl- (2-imidazole) dihydrochloride @ 1 H-NMR (DMSO-d6): 3.10 (2H), broad t, 3.52 (2H, m), 3.78 (3H, s), 3.88 (6H, s), 6.70-7.30 (6H, m), 7.47 (2H, s), 8.20 (1H, broad t), 9.85 (1H, broad s), 9, 90 ppm (1H, broad s)

The following compounds can be obtained in an analogous manner:

p- (N-methyl-4-) N-methyl-4- (N-methyl-4-aminopyrrole-2-carboxamido) pyrrole-2-carboxamido / pyrrole-2-carboxamido / ethyl- (2-) - 2-imide zine / (-dihydrochloride) @ 1 H-NMR (DMSO-d6): 2.67 (2H, broad t), 3.52 (2H, m), 3.75 (4H),

Wide s, 3.75 (3H, s), 3.82 (6H, s).

6.75-7.30 (6H, m), 8.20 (1H, broad t), 9.81 (1H, broad s), 9.85 ppm (1H), broad s (p-) N-methyl- 4- (N-methyl-4- / N-methyl-4-aminopyrrole-2-carboxamido) pyrrole-2-carboxamido / pyrrole-2-carboxamido / ethyl- [2-] 3,4,5,6-trahydropyrimidine // - dihydrochloride ¹ H-NMR (DMSO-d6) δ: 1.75 (2H, m), 2.61 (2H, t), 3.10-3.75 (6H, m), 3.76) 3H, s /, 3.85 (6H, s), 6.70-7.30 (6H, m), 8.21 (1H, broad t), 9.80 (1H, broad s), 9.89 ppm (1H, broad s)

Example 12

To a solution of 760 mg of carbohydrate in 20 ml of dry tetrahydrofuran, cooled to -20 ° C, is added 0.825

Of N-methylmorpholine and then 0.920 ml of pivaloyl chloride are added. The resulting suspension was stirred at -20 ° C for 20 minutes, then added to a cold solution of 2.64 g of p- (N-methyl-4-) N-methyl-4- (N-methyl-4-aminopyrrole). -2-carboxamido / pyrrole-2-carboxamido / pyrrol-2-carboxamido / ethyl- (2-imidazole) dihydrochloride in 50 ml of dimethylformamide and 0.4 g of sodium bicarbonate. 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, the residue was taken up in acetone, filtered and collected. 1.45 g of O- (N-methyl-4) -N-methyl-4- (N-methyl-4-) oxirancarboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / ethyl acetate are obtained. - (2-imidazole) -hydrochloride 1 H-NMR (DMSO-d 6): 2.83 (2H, broad t), 2.89 (2H, m), 3.49 (2H, m), 3, 55 (1H, dd), 3.82 (3H, s), 3.85 (6H, s), 6.80-7.25 (8H, m), 8.12 (1H, broad t), 87 (2H, broad s), 10.20 (1H, broad s)

The following compounds can be obtained in an analogous manner:

p- (N-methyl-4-) N-methyl-4- (N-methyl-4-) oxiranecarboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / ethyl- (2) 2- imidazoline // hydrochloride 1 H-NMR (DMSO-d 6): 2.68 (2H, broad t), 2.87 (2H, m), 3.50 (2H, broad d), 3.57 (1H) , dd /, 3.75 (4H), broad

S), 3.80 (3H, s), 3.83 (6H, s), 6.8-7.3 (6H, m), 8.28 (1H, broad t), 9.90 (2H), broad s /, 10.18 (1H, broad signal)

3- (N-methyl-4- / N-methyl-4- (N-methyl-4-) oxirancarboxamido) pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / ethyl- (2 -) 3,4,5,6-tetrahydropyrimidine // - hydrochloride ¹ H-NMR / DMSO-d / δ: 1.75 / 2H, m /, 2.62 / 2H, t /, 2.85 / 2H, m / 3.00-3.70 (7H, m), 3.80 (3H, s), 3.84 (6H, s), 6.80-7.30 (6H, m), 8.23 (1H) , t /, 9.91 (2H, broad signal), 10.20 (1H, broad signal)

Example 13

To a solution of 380 mg of 1,1'-carbonyldiimidazole in 5 ml of dimethylformamide is added a solution of 1 g of p- (N-methyl-4-) N-methyl-4- (N-methyl-4-aminopyrrole-2-carboxamido) pyrrole. -2-carboxamido [pyrrole-2 carboxamido] ethyl- (2-imidazole) dihydrochloride in 15 ml of dimethylformamide and 160 mg of sodium bicarbonate.

Allow to stand at room temperature for 30 minutes and add

0.12 ml of aziridine. The mixture was kept at room temperature for 1 hour and then the solvent was evaporated to dryness. The crude product was taken up in acetone, filtered and collected. 0.5 g of p- (N-methyl-4) -N-methyl-4- (N-methyl-4- (1-aziridine) carboxamido) pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole is obtained. 2-carboxamido / ethyl / 2-zol imidazole / hydrochloride ¹ H 'NMR / DMSO-d / δ: 2.07 / 4H, s /, 2.82 / 2H, br t /, 3.50 / 2H, m / 3.80 (3H, s), 3.84 (6H, s), 6.80-7.25 (2H, m), 8.15 (1H, broad t), 9.71 (1H), broad signal /, 9.92 ppm (2H, broad signal)

The following compounds can be obtained in an analogous manner:

p- (N-methyl-4-) N-methyl-4- (N-methyl-4- (1-aziridine) carboxamido) pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / ethyl - [2- (2-imidazoline) - hydrochloride @ 1 H-NMR (DMSO-d6): 2.08 (4H, s), 2.67 (2H, mt), 3.50 (2H, broad d), 3.75 (4H, broad s), 3.75 (3H, s), 3.80 (6H, s), 6.8-7.30 (6H, m), 8.27 (1H, broad t) , 9.72 (1H, s), 9.91 (2H, s) p- (N-methyl-4-) N-methyl-4- (N-methyl-4- [1- (aziridine) carboxamido] pyrrole -2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / ethyl / 2- / 3,4,5,6-tetrahydropyrimidine // hydrochloride - ^X H-NMR / DMSO-d ₆ / δ 1 74 (2H, m), 2.10 (4H, s), 2.60 (2H, t),

3.05-3.70 (6H, m), 3.80 (3H, s), 8.83 (6H, s), 6.80-7.30 (6H, m), 8.24 (1H), t /, 9.69 (1H, s), 9.85 (2H, s)

Example 14

With external cooling in an ice bath with an ethanolic solution of 200 mg of 3- (N-methyl-4- / N-methyl-4- / N-methyl-4- (3-methyl-) 2R, 3R) oxiranecarboxamido / pyrrole-2- Carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyldimethylamine is bubbled with gaseous hydrochloric acid. After 30 minutes, the precipitate was filtered off under nitrogen and the resulting solid was dried in vacuo. 180 mg of 3- (N-methyl-4-) N-methyl-4- (N-methyl-4- (3-methyl) - (2R, 3R) -oxiranecarboxamido / pyrrole-2-carboxamido / pyrrole-2- are obtained. carboxamido / propyldimethylamine hydrochloride

/DMS.O-dg/ NMR δ: 1.25 / 3H, d /, 3.3 / 1 H, m /, 3.60 / 1H, d /, / J = 4.7 H _z / cis //.

Example 15

N-deformyl-N- (N-methyl-4- (N, N-bis- / 2-chloroethylamino) -pyrrole-2-carboxamido) distamycin A-hydrochloride is bubbled through an ethanolic solution of 100 mg of N-deformyl-N- (N-methyl-4-) gaseous hydrochloric acid.

After 30 minutes, the precipitate was filtered off under nitrogen and the resulting solid was dried in vacuo. 80 mg of N-deformyl-N- (N-methyl-4- (N, N-bis- / 2-chloroethylamino) pyrrole-2-carboxamido / distamycin A hydrochloride are obtained.

NMR (DMSO-d6) δ: 2.63 (2H, t), 3.20-3.9 (1OH, m), 3.80-3.85 (3H, s), 6.46 (1H, d) /, 6.58 / 1H, d /, 6.90 to 7.30 / 6H, m /, 8.20 / ΙΗ t /, 8.73 / 2H, broad signal ^R /.

9.00 (2H, broad signal), 9.70 (1H, broad s),

9.90 (2H, s)

Example 16

Tablets, each weighing 0.250 g and containing 50 mg of active ingredient, may be prepared as follows:

Composition / for 10 000 tablets /

3- (N-methyl-4-) N-methyl-4- (N-methyl-4-) N-methyl-4-nitropyrrole-2 carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2 carboxamido / propyldimethylamine 500 g lactose 1 400 g corn starch 500 g talcum powder 80 g magnesium stearate 20 g

3- (N-methyl-4- (N-methyl-4-) N-methyl-4- (N-methyl-4-nitropyrrole-2-carboxymido) pyrrole-2-carboxamido (pyrrole-2-carboxamido) was mixed). pyrrole-2-carboxamido / propyldimethylamine, lactose and half corn starch. The mixture is passed through a 0.5 mm sieve. Corn starch (10 g) is suspended in 90 ml of warm water and the resulting paste is used to granulate the powder. The granulate is dried, milled on a 1.4 mm sieve, then the remaining amount of starch, talc and magnesium stearate is added, mixed thoroughly and processed into tablets.

Claims (12)

Poly-4-aminopyrrole-2-carboxamide derivatives of the general formula I (1), n is zero or an integer from 1 to 4, R is a (-NHR ₃₎ , wherein R ₃ is α '(-CON) NO / R Unsubstituted halogen, or H nr _{2 4} , wherein R ₄ is alkyl or substituted with 1 to ranyl, methyloxiranyl and m is zero, 1 or 2, b '(-CO) (C 1-4) v-R 1 is halogen, oxi- ⁿ - or - n - aziridinyl group b / -NR ₆ R _{7 group} , where R ₆ and R _{6 ?} have the same meaning and each C 2 -C 4 alkyl is 2-substituted with halogen, each of R 1. denotes independently from each other hydrogen or alkyl of 1 to 4 carbon atoms, R ₂ is an alkyl group having 1 to 6 carbon atoms terminated by a basic group, with the proviso that when n is 1, R _{2 is} not a group of the formula X ^NH -CH ₉ -CH ₉ -CT ^{2 2 x} nh ₂ . and pharmaceutically acceptable salts thereof. A compound of formula I according to claim 1, wherein n is zero, 1 or 2, R is a (-NHR-) wherein R ₃ is a '(-CON / NO) R ₄ wherein R ₄ is C 1 -C 4 alkyl substituted by halogen, or b' (-CO (CH ₂ )) _ip -R ₅ , wherein R ₅ is halogen, oxiranyl, 1-aziridinyl amino, zero or 1, or b) -NR ₆ R ₇ , wherein R 8 and R ₇ are the same and represent each alkyl of 2; and up to 4 carbon atoms 2-substituted with a halogen atom, each of R1 being independently C1-C4alkyl, R ₂ is alkyl of 1 to 6 carbon atoms terminated by a basic group, and its salts with pharmaceutically acceptable acids. The compound of formula I or a salt thereof according to claim 2, wherein the terminal basic group of the substituent R ₂ is selected from the group consisting of amino, mono- or dialkylamino of 1 to 6 carbon atoms in the alkyl moiety, amidino, a group of the formula -N = N-N and a nitrogen-containing heterocyclic ring. ^x ch ₃ 4. A compound selected from the group consisting of: p- (N-methyl-4-) N-methyl-4- (3-methyl-3-nitrosoureido) pyrrole-2 carboxamido / pyrrole-2-carboxamido / propionamidine, p- (N-methyl-4-) N- methyl 4- (3- (2-chloroethyl) -3-nitrosoureido) pyrrole-2-carboxamido / pyrrole-2-carboxamido / propionamidine, 3- (N-methyl-4-) N-methyl-4- / 3 -methyl-3-nitrosoureido / pyrrole-2 carboxamido / pyrrole-2-carboxamido / propyldimethylamine, 3- (N-methyl-4- / N-methyl-4- (3- (2-chloroethyl) -3-nitrosoureido) pyrrole 2-carboxamido / pyrrole-2-carboxamido / propyldimethylamine, 3- (N-methyl-4- / N-methyl-4- / N-methyl-4- (3-methyl-3-nitrosoureido) -pyrrole-2-yl) carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyldimethylamine, 3- (N-methyl-4- / N-methyl-4- / N-methyl-4- [3- (2-chloroethyl) -3-nitro] pyrrolidine / pyrrole-2-carboxamido / pyrrole-2 -carboxamido / pyrrole-2-carboxamides / propyldimethylamine, N-deformyl-N- (N-methyl-4- (3-methyl-3-nitrosoureido) pyrrole-2 carboxamido) distamycin A, N-deformyl-N- (N-methyl-4- (3- (2-chloroethyl) -3-nitrosoureido) pyrrole-2-carboxamido) distamycin A, 3- (N-methyl-4-) N-methyl-4- (N-methyl-4-) N-methyl-4- (3-methyl-3-nitrosoureido) pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole 2-carboxamido / pyrrole-2-carboxamido / propyldimethylamine, 3- (N-methyl-4- / N-methyl-4- / N-methyl-4- / N-methyl-4- / 3- / 2-chloro) rethyl / -3-nitrosoureido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyldime thylamine, 3- (N-methyl-4- / N-methyl-4- (N-methyl-4-) oxiranecarboxamido) pyrrol-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyldimethylamine, N-deformyl-N - N, N-methyl-4- (oxiranecarboxamido) pyrrole-2-carboxamido / distamycin A, 3- (N-methyl-4-) N-methyl-4- (N-methyl-4-) N-methyl-4- (oxirankar boxamido) pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2 carboxamido (pyrrole-2-carboxamido) propyldimethylamine, N-deformyl-N- (N-methyl-4- / 2-chloroethylcarboxamido) pyrrole-2 carboxamido / distamycin A hydrochloride, 3- (N-methyl-4- / N-methyl-4- / N-methyl-4- (3-methyloxiranecarboxamido) pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido) propyldimethylamine, 3- (N-methyl-4-) N-methyl-4- (N-methyl-4- (1-aziridine) carboxamido) -pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carbo xamido / -propyldimethylamine, N-deformyl-N- (N-methyl-4- (1-) aziridine / carboxamido) pyrrole-2 carboxamido / distamycin A, 3- (N-methyl-4-) N-methyl-4- (N-methyl-4-) N-methyl-4- (1-aziridine) carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido (pyrrole-2-carboxamido) pyrrole-2-carboxamido / propyldimethylamine, p- (N-methyl-4-) N-methyl-4- (N, N-bis) 2-chlorethylamino // pyrrol-2 -carboxamido / pyrrole-2-carboxamido / propionamidine, 3- (N-methyl-4- / N-methyl-4- (N, N-bis) 2-chloroethylamino) pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido propyldimethylamine, 3- (N-methyl-4-) N-methyl-4- (N-methyl-4-) N, N-bis / 2-chloroethyl amino // pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole- 2-carboxamido / propyldimethylamine, N-deformyl-N- (N-methyl-4- (N, N-bis) 2-chloroethylamino) pyrrole-2-carboxamido / distamycin A, 3- (N-methyl-4- / N-methyl-4- / N-methyl-4- / N-methyl-4- (N, N-bis) 2-chloroethylamino) pyrrole-2-carboxamido / pyrrole-2- carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyldimethylamine and their pharmaceutically acceptable salts, especially the hydrochlorides. The pharmaceutically acceptable salt of the compound of claim 4, wherein the salt is the hydrochloride. 6. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 which is reacted A) a compound of formula (V), wherein R 1, R ₂ and _n are as defined in claim 1, or a salt thereof, with a compound of formula (VI) II z'-cn (no) -r ₄ (VI), wherein R ₄ is as defined in claim 1 and Z is a leaving group, to form a compound of formula I wherein R is -NHR ₃ and R ₃ is - CON / NO / R _4, where R ₄ has the meaning given in claim 1, or B) a compound of formula V wherein R ₃ , R ₂ and _n are as defined in claim 1 with a compound of formula VII Z-CO- (CH ₂ ) _m -R ₅ (VII), wherein R ₅ and _m are as defined in claim 1 and Z is as defined above, to give a compound of formula I wherein R is -NHR ₃ and R ₃ represents a group -CO ₂ / CH / _m -R _5, wherein R ₅ and m have the meaning given in claim 1, or C) a compound of formula V, wherein R 1, R 1 and n are as defined in claim 1, or a salt thereof, with a compound of formula VIII X-CH-CH, \ / VIII (VIII), wherein X may be hydrogen or C 1 -C 2 alkyl, to form a compound of formula IX wherein R f, R ₂ and _n are as defined in claim 1 and each of X has a meaning corresponding to X in compound of formula VIII and formula IX compound is halogenated to give a compound of formula I wherein R is -NR ₆ R ₇ wherein R _g and R? are given in claim 1 above, and if desired, modifying the substituent R ₂ in the compound of the formula I with or without reservation as described above to give a compound of formula I with a different value for R ₂ and / or optionally converting a compound of formula I into a salt and / or optionally separating a mixture of isomers of formula I into individual isomers. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and / or diluent and, as active ingredient, a compound of formula (I) according to claim 1. A process for the preparation of a pharmaceutical composition according to claim 7, characterized in that the active ingredient is treated with a pharmaceutically acceptable carrier and / or diluent. A compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof, for use as an antiviral and antitumor agent. Use of a compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition according to claim 7 having an antiviral and antitumor effect. 11. A compound of formula I according to claim 1 wherein n is zero or an integer from 1 to 3, R, R and R ₂ are as defined in claim 1 and pharmaceutically acceptable salts thereof. Process according to claim 6, for the preparation of compounds according to claim 11, characterized in that compounds of the general formulas (V), (VI), (VII) and (VIII) are used as starting materials, where n is zero or an integer from 1 to 3. of claim 6 as defined above.