Acryloyldimethyl derivatives of pyrrole and their pharmaceutically acceptable acid additive salts, pharmaceutical composition and the method of production thereof

 

(57) Abstract:

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

,

in which n is an integer from 1 to 5; each of R1and R2which may be identical or different, is hydrogen, halogen, -CN, -NO2C1-C4the alkyl, or the group: , R3is hydrogen, halogen, -CN or-NO2. Each R4is independently hydrogen or C1-C4the alkyl, a is a bond, the group or the group-NH - Het-Co -, in which Het is a saturated or unsaturated pentabasic or setiathome heterogenities ring and in which 1, 2 or 3, P5- C1-4alkyl, and pharmaceutically acceptable salts. Compounds used as antineoplastics agents. 3 S. and 3 C.p. f-crystals.

The invention relates to acryloyl-substituted perroleum derivatives, method for their production and to their containing pharmaceutical compositions.

Pyrrolone derivatives that are the subject of the present invention may be considered as derived distamycin a, which is a known compound having the following formula:

< / BR>
the invention provides acryloyl-substituted derivatives, having the following formula (I):

< / BR>
in which n is an integer from 1 to 5; each of R1and R2which may be identical or different, is hydrogen, halogen, -CN, -NO2C1-C4, alkyl or the group:

< / BR>
R3is hydrogen, halogen, -CN, or-NO2each R4is, independently of one another, hydrogen or C1-C4-alkyl, a is a bond, the group or the group Het-CO, in which Het is substituted or not substituted pentabasic or setiathome heterogenities ring, and

< / BR>
in which m is 1, 2 or 3, and each of R5independently from each other, is C1-C4alkyl group.

The present invention also includes acceptable from a pharmaceutical point of view salts of the compounds of formula (I), as well as possible isomers described by formula (I), both separately and in mixture. In the above formula (I) n in the preferred embodiment is 3, 4 or 5; in A preferred embodiment, is a bond or a group-NH-, Het-CO, B in the preferred embodiment, is a group of people or which is in the preferred embodiment 1, and each R5is stands.

When a is the flax version unsubstituted pentabasic or setiathome heterogenities ring, containing at least one, in the preferred embodiment, one or two heteroatoms selected from O, S and N. Examples of the above-mentioned heterological include thiophene, thiazole, pyridine, isoxazol, furan, triazole and midazol.

When R1and R2are the same, in the preferred embodiment, are hydrogen. When R1and R2various, R1is in a preferred embodiment, hydrogen, and R2is in the preferred embodiment, the halogen, the halogen in the preferred embodiment is chlorine or bromine.

When R3is halogen, it is preferred variant of chlorine or bromine. In the preferred embodiment, each group R4independently is C1-C4the alkyl, in particular, stands, and in the preferred embodiment, all of the group R4are the stands.

As mentioned previously, the present invention also includes acceptable from a pharmaceutical point of view salts of compounds of formula (I). Such salts are salts with acceptable from a pharmaceutical standpoint acids, either inorganic acids such as, for example, hydrochloric Hydrobromic, nitric and sulfuric, or arganine/ acid.

A preferred class of compounds are the subject of this invention are the compounds of formula (I) in which n is 3, 4 or 5,

A is a bond or a group

B is a group of people or

R1and R2is hydrogen,

R3is chlorine or bromine, and R4is stands, in particular in the form of a salt with hydrochloric acid.

Special examples of preferred compounds which are the subject of the present invention, in particular, in the form of salts with hydrochloric acid are the following:

N-diformyl-N-/ -chlorocresol/Distamycin AND,

b-N-methyl-4-/N-methyl-4/N-methyl-4-/N-methyl-4/a-chloro-acrylamide/pyrrol-2-carboxamido/pyrrol-2-carboxamido/pyrrol-2-carboxamido/propionamide,

N-diformyl-N/a-bromocresol/Distamycin AND,

b-/N-methyl-4-/N-methyl-4-/N-methyl-4/N-methyl-4/-a-bromoacrylic/pyrrol-2-carboxamido/pyrrol-2-carboxamido/pyrrol-2-carboxamido/pyrol-2-carboxamido/propionamide,

b-/N-methyl-4/N-methyl-4-/N-methyl-4-/N-methyl-4-/N-methyl-4-/a-bromoacrylic/pyrol-2-carboxamido/pyrrol-2 - carboxamido/pyrrol-2-carboxamido/pyrrol-2-carboxamido/ pyrrol-2-carboxamido/propionamide,

N-diformyl-N-/4-/a-bromoacrylic/benzoyl who amido/pyrrol-2-carboxamido/pyrrol-2-carboxamido/propyl-dimethylamine

The compounds of formula (I) is obtained using the procedure containing:

A) interaction of the compounds of formula (II)

< / BR>
in which n, R4and B have already been defined above, or its salt with the compound of the formula (III)

< / BR>
in which R1, R2, R3and A have already been defined above and X is hydroxy or substituted by the group, thus obtaining the compound of formula (I) or its salt, or

B) interaction of the compounds of formula (IV)

< / BR>
in which Z is either H2N-Het-CO-, and n, R4, B and Het have already been defined above, or its salt with the compound of the formula (V)

< / BR>
in which R1, R2, R3and X has already been defined above, thus obtaining a compound of formula (I) in which a is the group or its salt.

Substituted by a group X in the compounds (III) and (V) may be, for example halogen, in particular chlorine or other substituted group such as, for example, 2,4,5-trichlorophenoxy, 2,4-dinitrophenoxy, succinimido-N-hydroxy, imidazolyl, pivaloyloxy, or acyloxy formate or isopropoxy formate

The resulting compound of formula (I) can be converted into acceptable from a pharmaceutical standpoint salt, if necessary.

The reaction between the compound nom relation (II): (III) from 1:1 to 1:2 in an organic solvent such as, for example, dimethylsulphoxide, hexamethylphosphoramide, dimethylacetamide or, in a preferred embodiment, dimethylformamide, or their aqueous mixtures in the presence of an organic base such as triethylamine or aminobutiramida ethylamine; or inorganic bases such as, for example, sodium bicarbonate and a condensing agent such as, for example, N-ethyl-N'-/3-dimethylaminopropyl/carbodiimide, or in a preferred embodiment, N,N'-dicyclohexylcarbodiimide. The reaction temperature varies in the range from about 10oC to about 50oC, and the reaction time is from about 1 to about 12 o'clock

The reaction between the compound of formula (II) and the compound of the formula (III) in which X is a substituted group, for example, 2,4,5-trichlorophenoxy or succinimido-N-hydroxy, or imidazolyl in General carried out in a molar ratio (II): (III) in the range from 1:1 to 1:2 in an organic solvent such as, for example, dimethylformamide or pyridine in the presence of organic bases, for example, diisopropylethylamine at a temperature of from about 0oC to approximately 25oC for from about two hours to about ten hours. Similar reaction conditions can be used when the X connection which can be performed under conditions similar to those that were described above for the reaction between compounds of formula (II) and the compound of the formula (III) with the appropriate sense for X.

The compounds of formula (I) obtained according to the process described above, can be treated using known techniques such as, for example, chromatography on silica gel or aluminum oxide, and/or recrystallization from organic solvents such as, for example, lower aliphatic alcohols or dimethylformamide.

The compounds of formula (II) are known compounds or can be obtained by known methods from known compounds, see for example, Argamon and other Gazzetta Chim. Ital. so 97, S. 1097/1967/.

The compounds of formula (IV) can be obtained using the following procedures, which are well known in organic chemistry. In particular, for example, the compounds of formula (IV) in which Z is a group may be obtained through the interaction of the compounds of formula (II) with para-nitrobenzene chloride and recovering the resulting nitro compounds using known methods.

The compounds of formula (III) are known compounds or can be obtained using known methods, for example, PR is I can be obtained by interaction of para-aminobenzoic acid with activated derivatives of acrylic acid using a known technique.

Compounds of the present invention possess cytotoxic properties relative to the tumour cells, so they can be used as antineoplastics agents, for example, in order to inhibit a variety of tumors such as, for example, a carcinoma, for example, carcinoma of the breast, carcinoma of the lung, carcinoma of the bladder, carcinoma of the colon, tumors of the ovaries and uterus. Other neoplasms that may find the use of the compounds of the present invention are, for example, sarcoma, for example, sarcoma of soft tissue and bone, and hematological malignant diseases such as, for example, leukemia.

Tested the cytotoxicity of the compounds that are the subject of the present invention, for example, the cells of leukemia L 1210 mice, using the following procedure. Cells were obtained from in vivo tumors and transferred into cell culture. Cells were used up to ten repetitions. Cytotoxicity was determined by counting live cells after 4 h treatment and 48 h of cultivation in medium without drug. Cell growth in percent in the treated cultures were compared with the growth control of crops. ID50values (dose inhibiting 50% of cell growth cf the hydrate -/N-methyl-4/N-methyl-4-/N-methyl-4-/N-methyl-4-/a-bromoacrylic/pyrrol-2-carboxamido-/pyrrol-2-carboxamido/pyrrol-2-carboxamido/pyrrol-2 - carboxamido/ propionamide, which is the subject of the present invention, EID50-the value determined in accordance with the above described test was 0,003 g /ml.

Compounds that are the subject of the present invention can be applied using known methods, for example, parenterale, for example, by intravenous injection or infusion, intramuscularly, subcutaneously, local way or tematicheskie.

The dosage depends on age, weight and condition of the patient and the method of application. For example, the appropriate dose to be applied to the adult patient can vary from about 0.05 to about 100 mg per dose 1-4 times a day.

The pharmaceutical composition which is the subject of the present invention includes compounds of formula (I) as the active material together with one or more acceptable from a pharmaceutical point of view fillers.

The pharmaceutical compositions of the present invention in the General case is obtained using the following well-known techniques and apply them in acceptable from a pharmaceutical point of view the form.

For example, solutions for intravenous injection or infusion may contain as carrier, naprimer salt solutions.

The suspensions or solutions for intramuscular injections may contain, together with the active compound is acceptable from a pharmaceutical point of view, the carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and, if necessary, an appropriate amount of hydrochloride lidocaine.

Forms for application, for example, creams, lotions or pastes for use in dermatological treatment active ingredients can be mixed with oily known fillers.

Solid tematicheskie forms, e.g. tablets and capsules, may contain together with the active compound diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch and potato starch, and lubricating agents, for example, silicon dioxide, talc, stearic acid, magnesium stearate or calcium, and/or polyethylene glycols, binding agents, e.g. starches, gum Arabic, gelatin, methylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, loosening agents, for example starch, elganowo acid, alginate, starch glycolate, sodium, foaming mixture, colorants, flavoring agents, wetting agents, for example lecithin, poliurethane pharmaceutical forms. The above-mentioned pharmaceutical or spooling can be obtained using known methods, for example, by mixing, granulation, compaction of tablets, the formation of the sugar shell or skinning.

In addition, in accordance with the present invention features a method of treating virus infections and tumors in a patient in need of the section containing the application to the aforementioned patient compositions are the subject of this review.

The following examples illustrate but do not limit the present invention.

Abbreviations DMF and TF denote, respectively, dimethylformamide and tetrahydrofuran.

Example 1. In the solution a-bromocresol acid (226 mg) in dry DMF (5 ml) was added N, N'-dicyclohexylcarbodiimide (228 mg) and the resulting suspension was stirred at room temperature for 20 minutes the Mixture was added into a solution of cordigera N, deformed Distamycin A (526 mg) in DMF (10 ml) and sodium bicarbonate (84 mg). The suspension was stirred at room temperature for 4 h, after filtering, the solvent is evaporated under vacuum until dry. The residue was subjected to chromatography on silica gel with metranil is on A (310 mg), D & F. lmax/EtOH 95o/ / / 242/ /23772/, 312/33961/nm,

FD-M. C. m/z 586, M++ 1; 586, M+NH3505, M+- HBr, J. M. R. /DMSO-d6/:d 2,62/2H, triplet/, 3,45/2H, multiplet/, 3,81/3H, singlet/, 3,85/6N, singlet/, 6,20/1H, doublet/, 6,70/1H, doublet/, 6,9-7,3/6N, multiplet/, 8,18/1H, triplet/ 8,6/2H broad singlet/ 8,96/2H broad singlet/, 9,88/1H singlet/ to 9.93/1H singlet/, 10,29/1H, singlet/.

Using a similar procedure was obtained the following compounds: hydrochloride-N-diformyl-N/a-chlorocresol/Distamycin A U. F. lmax/EtOH 95%/ /E/: 242 /23080/, 310 /32972/ nm, FD-m C: m/z: 542, M++1, 505, M+-HCl, 542, M+-NH3The NMR /DMSO-d6/:: 2,65/2H, triplet/, 3,50/2H, multiplet/, 3,80/3H, singlet/, 3,83/3H, singlet/, 3,84/3H, singlet/, 5,98 /1H, doublet/, 6,40/1H, doublet/, 6,90-7,30/6N, multiplet/, 8,20/1H, triplet/, 8,75/2H, broad singlet/, 9,04/2H, broad singlet/, 9,89/1H, singlet/, 9,95/1H, singlet/, 10,32/1H, singlet/.

Hydrochloride b-/N-methyl-4-/N-methyl-4-/N-methyl-4-/N-methyl-4/a-chloraniline/pyrrol-2-carboxamido/pyrrol-2-carboxamido/pyrrol-2 - carboxamido/pyrrol-2-carboxamido/propionamide.

U. F. lmax/EtOH/ 95o/ /E/: 244 /30 055/, 314 /46 098/ nm,

FAB-M. C. m/z:644, M++ 1, 602 M+CH2CCl-

J. M. R. /DMSO-d6/: 2,62/2H, triplet/, 3,2-4,00/14N, multiplet/, 5,99/1H, doublet/, 6,39/1H, doublet/, 6,90-7,30/8H, Mulet/,

Hydrochloride b/N-methyl-4-/N-methyl-4-/N-methyl-4-/N-methyl-4-/a-bromoacrylic/pyrrol-2-carboxamido/pyrrol-2 - carboxamido/pyrrol-2-carboxamido/pyrrol-2 - carboxamido/propionamide,

U. F. lmax/EtOH 95o/ /E/242 /29876/, 314 /45224/ nm,

FAB-M. S. m/z 708, M+-1,628 M+Br,

J. M. R. /DMSO-d6/ 2,63/2H, triplet/, 3,50/2H, triplet/, 3,80/3H, singlet/, 3,84/3H, singlet/, 3,85/6N, singlet/ to 6.19/1H, doublet/, 6,69/1H, doublet/, 6,90-7,25/8H, multiplet/, 8,12/1H, triplet/, 8,63/2H, broad singlet/, 8,89/2H, broad singlet/, 9,80/1H, singlet/, 9,83/1H, singlet/, 9,86/1H, the singlet/, 10,30/1H, singlet/.

3-/N-methyl-4-/N-methyl-4-/N-methyl-4-/N-methyl-4-a-chloracetamide/pyrrol-2-carboxamido/pyrrol-2-carboxamido/ pyrrol-2-carboxamido/pyrrol-2-carboxamido/propyl-dimethylamine,

U. F. lmax/EtOH 95o/ 239 /29707/, 313 /43738/,

FAB-M. C. m/z 679, M + 1, 589, M + -CH2CCl-CO-;

J. M. R. /DMSO-d6/ 1,66/2H, multiplet/, 2,17/6N, singlet/, 2,25/2H, triplet/, 3,20/H, multiplet/, 3,80/3H, singlet/, 3,83/N, the singlet/, 5,99/1H, doublet/, 6,37/1H, doublet/, 6,75-7,30/8H, multiplet/, 8,03/1H, triplet/, 9,83/1H, singlet/, 9,90/1H, singlet/, 9,92/1H, singlet/, 10,23/1H, the singlet/.

Hydrochloride b-/N-methyl-4-/N-methyl-4-/N-methyl-4-/N-methyl-4-/N-methyl-4-/a-bromoacrylic/pyrrol-2-carboxamido/pyrrol-2 - carboxamido/pyrrol-2-carboxamido/pyrrol-2-carbono-d6/: 2,61 /2H, triplet/, 3,48/2H, multiplet/, 3,82/15H, broad singlet/, 6,21/1H, doublet/, 6,80/1H, doublet/, 6,9-7,3/10H, multiplet/, 8,19/1H, triplet/, 8,73/2H, broad singlet/, 8,93/2H, broad singlet/, 9,90/4H, broad singlet/, 10,28/1H, broad singlet/.

Example 2. In the solution /E/ b-/para-b-or-acrylic acid (428 mg) obtained according to J. O. C. T. 26, S. 755, /1961/, in dry DMF (10 ml), cooled to 0owas added N,N'-dicyclohexylcarbodiimide (288 mg) and the resulting solution was stirred at 0owithin 20 minutes

Was added N-diformyl-Distamycin A-hydrochloride (526 mg) and the mixture was stirred for 30 minutes at 0oand then for 4 h at room temperature. After filtration the solvent is evaporated under vacuum until dry and the residue was subjected to chromatography on silica gel using methylene chloride:methanol 80:20 as eluent, providing hydrochloride N-diformyl-N-/E/- b-/para-methoxybenzoyl-b-bromocresol/ distamycin A /265 mg/.

U. F. lmax/EtOH 95oC/ /E/ 225 /33007/, 304 /32704/ nm

FAB-MS m/z 720, M++ 1, 511, 389, 267

J. M. R. /DMSO-d6/: 2,62/2H, triplet/ 3,48/2H, multiplet/, 3,71/3H, singlet/, 3,74/3H, singlet/, 3,79/3H, singlet/, 3,81/3H, singlet/, 6,68/1H, singlet/, 6,75-7,20/6N, multiplet/, 6,88, ,90 /1H, singlet/, 10,30/1H, singlet/.

Using a similar procedure has been the following link:

Hydrochloride N-diformyl-N-/4/-/a-bromoacrylic/benzoyl/Distilleria A,

U. F. lmax/EtOH 95o/ /E/ 241, /31387/, 311, /48156/ nm,

J. M. R. /DMSO-d6/: 2,62/2H, triplet/, 3,45/2H, multiplet/, 3,81/3H, singlet/, 3,85/3H, singlet/, 3,86/3H, singlet/, 6,34/1H, doublet/, 6,84/1H, doublet/, 6,9-7,4/6N, multiplet/, 7,7-8,1/4H, multiplet/, 8,20/1H, triplet/, 8,72/2H, broad singlet/, 9,90/2H, broad singlet/, 9,90/1H, singlet/, 9,96/1H, singlet/, 10,30/1H, singlet/, 10,56/1H, singlet/.

Example 3. In a solution of acrylic acid (245 mg) in dry TTF (10 ml), cooled to -10oadded (0,47 ml), and then a pivaloyl chloride (0,41 ml).

The resulting suspension was stirred at -10oC for 20 min, then it was added to the cooled solution of cordigera N-diformyl Destigmatizing A (526 mg) in DMF (10 ml) and NaHCO3.

The mixture was stirred for 30 min at 0oand then for 4 h at room temperature.

The solvent is evaporated under vacuum, and the residue was subjected to chromatography on silica gel using methylene chloride: methanol 80:20 as eluent, giving the hydrochloride of N-diformyl-N-acryloyl-Distiller is, 37.

J. M. R. /DMSO-d6/: 2,63/2H, triplet/, 3,50/2H, multiplet/, 3,81/3H, singlet/, 3,85/3H, singlet/, 3,89/3H, singlet/, 5,66/1H, double doublet/, to 6.19/1H, double doublet/, 6,46 /1H, double doublet/, 6,90-7,30/6N, multiplet/, 8,20/1H, triplet/, 8,60-9,20/4H, broad/ 9,88 /1H, singlet/, 9,90 /1H, singlet/, 10,18 /1H, singlet/.

Using a similar procedure was obtained the following compounds:

Hydrochloride-N-diformyl-N//Z/- b-chlorocresol/Distamycin A,

U. F. lmax/EtOH 95o/ /E/ 243 /23254/, 311 /35288/ nm,

FD-M. C. m/z 541, M+, 505, M+HCl, 478,

J. M. R. -/DMSO-d6/: 2,64/2H, triplet/, 3,50/2H, multiplet/, 3,80/3H, singlet/, 3,86/6N, singlet/, 6,52/1H, doublet/, 6,89/1H, doublet/, 6,9-7,3/6N, multiplet/, by 8.22/1H, triplet/, cent to 8.85/4H, broad triplet/, 9,89/1H, singlet/, to 9.93/1H, singlet/, to 9.93/1H, singlet/, 10,28/1H, singlet/.

Hydrochloride N-diformyl-N-/E/ -b-chlorocresol Distamycin A,

U. F. lmax/EtOH 95o/ /E/ 241 /24584/, 312 /35517/ nm,

FDMC m/z 505, M+HCl, 478.

J. M. R. /DMSO-d6/: 2,64/2H, triplet/, 3,50/2H, multiplet/, 3,80/3H, singlet/, 3,86/6N, singlet/, 6,70/1H, doublet/, 7,30/1H, doublet/, 6,9-7,3 /6N, multiplet/, by 8.22/1H, triplet/, cent to 8.85/4H, broad triplet/, 9,89/1H, singlet/, to 9.93/1H, singlet/, 10,5/1H, singlet/.

Example 4. In the mixed solution of the hydrochloride of N-diformyl Distamycin 5oC and then for 1 h with vigorous stirring solution was added para-nitrobenzoyl chloride (2.5 g) in dioxane (25 ml).

The reaction mixture was stirred for one hour, acidified with 2 N HCl solution to pH 4, and then evaporated until dry under vacuum. The residue was treated with acetone (200 ml) was stirred for 1 h and filtered, resulting in a received hydrochloride N-diformyl-N-/para-nitrobenzoyl/Distamycin A (2.6 g).

Example 5. Connection hydrochloride N-diformyl-N-/para-nitrobenzoyl/Distamycin A (2.6 g) was dissolved in a mixture of CH3OH (150 ml) and 2N HCl solution (10 ml) and was restored over a Pd catalyst(10% on carbon) at a pressure of H2/50 psi, 3.5 kg/cm2within 4 hours the Catalyst was separated by filtration, and the resulting solution was concentrated under vacuum until dry.

The residue was treated with ethanol (10 ml) was stirred for 1 h and filtered to obtain the hydrochloride of N-diformyl-N-/para-aminobenzoyl/Distamycin A (2 g).

J. M. R. /DMSO-d6/: d 2,62/2H, triplet/, 3,45/2H, multiplet/, 3,81/3H, singlet/, 3,85/3H, singlet/, 3,86/3H, singlet/, 6,90-7,40/6N, multiplet/, 7,10-7,70/4H, multiplet/, 8,20/1H, triplet/, charged 8.52/3H, broad singlet/, 8,72/2H, broad Shin is injection 20 mg/ml

Pharmaceutical composition for injection can be obtained by dissolving 20 g of the hydrochloride b-/N-methyl-4-/N-methyl-4-/N-methyl-4-/N-methyl-4-/a-bromoacrylic/-pyrrol-2 - carboxamido/pyrrol-2-carboxamido/pyrrol-2-carboxamido/pyrrol-2-carboxamido/propionamide in water for injection (1000 ml) and filling vials 1-5 ml, which was then sealed.

1. Acryloyldimethyl derivatives of pyrrole General formula I

< / BR>
where n is 3, 4, 5;

R1and R2the same or different, are each hydrogen, halogen or a group

< / BR>
R3hydrogen or halogen;

R4methyl;

A bond or a group

< / BR>
B group

< / BR>
and

< / BR>
where m 1;

R5each independently C1C4is an alkyl group,

and their pharmaceutically acceptable acid additive salt.

2. Compounds of General formula I on p. 1, where n is 3, 4 or 5, A relationship or group

< / BR>
B group

< / BR>
or

< / BR>
R1and R2hydrogen, R3chlorine or bromine, R4is methyl, and their pharmaceutically acceptable acid additive salt.

3. Compounds of General formula I on p. 1, selected from the group of N-diformyl-N-(alpha-chloroacrylic)-Distamycin A, beta-(N-methyl-4-(N-methyl-4-(N-methyl-4-(N-methyl-4-(alveopalatal, N-diformyl-N-(alpha-bromocresol)-Distamycin A, beta-(N-methyl-4-(N-methyl-4-(N-methyl-4-(N-methyl-4-(N-bromoacrylic)pyrrol-carboxamido)-pyrrole-2-carboxamido)pyrrol-2-carboxamido)pyrrol-2-carboxamido)propionamide, beta-(N-methyl-4-(N-methyl-4-(N-methyl-4-(N-methyl-4-(N-methyl-4-(alpha - bromoacrylic)-pyrrole-2-carboxamido)pyrrol-2-carboxamido)-pyrrole-2-carboxamido)-pyrrole-2-carboxamido)pyrrol-2-carboxamido)propionamide, N-diformyl-N-(4-(alpha-bromoacrylic)-benzoyl-Distamycin A, 3-(N-methyl-4-(N-methyl-4-(N-methyl-4-(N-methyl-4-(alpha-chloracetamide)- pyrrole-2-carboxamido)-pyrrole-2-carboxamido)pyrrol-2-carboxamido)pyrrol-carboxamido)propylpiperonyl, and their pharmaceutically acceptable acid additive salt.

4. The compound of General formula I according to any one of paragraphs. 1 to 3, representing salt chloride-hydrogen acid.

5. Pharmaceutical composition having antitumor activity and containing an active component based on a derivative of the substituted pyrrole and a pharmaceutically acceptable carrier and/or diluent, characterized in that the active agent contains an effective amount of compounds of General formula I on p. 1 or its pharmaceutically acceptable acid-additive conditionig salts, characterized in that interact compounds of General formula II

< / BR>
where n, R4and B have the above values,

or its salt with a compound of General formula III

< / BR>
where R1, R2, R3and A have the above meanings;

X is hydroxyl or delete group

obtaining the target product in free form or in pharmaceutically acceptable acid salt additive.

 

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