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Dimers of pyrrol[2,1-c][1,4]benzodiazepine as antitumoral agents and method of their obtaining
Dimers of pyrrol[2,1-c][1,4]benzodiazepine as antitumoral agents and method of their obtaining
IPC classes for russian patent Dimers of pyrrol[2,1-c][1,4]benzodiazepine as antitumoral agents and method of their obtaining (RU 2338747):
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Pyperidine derivatives and method of their obtaining, application, pharmaceutical composition based on them and method of treatment Pyperidine derivatives and method of their obtaining, application, pharmaceutical composition based on them and method of treatment / 2336276
Claimed invention relates to pyperidine derivatives of formula (I) , where R represents galogen or C1-4alkyl; R1 represents C1-4alkyl; R2 or R3 independently represent hydrogen or C1-4alkyl; R4 represents trifluorinemethyl or galogen; R5 represents hydrogen, C1-4alkyl or C3-7cycloalkyl; R6 represents hydrogen, R7 represents radical of formula (W), or R7 represents radical of formula (W) and R7 represents hydrogen; X represents CH2, NR5 or O; Y represents nitrogen, and Z represents nitrogen; or Y represents CH, and Z represents nitrogen; A represents C(O), m is zero or whole number from 1 to 3; t is whole number from 1 to 3; and p and q are whole number from 1 to 2; or to their pharmaceutically acceptable salts and solvates. Claimed invention also relates to method of obtaining said derivatives and to their application for treating condition with tachyquininamia.
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Pyrrolopyramidines, with inhibiting properties to catepsin k and method of obtaining them (versions) Pyrrolopyramidines, with inhibiting properties to catepsin k and method of obtaining them (versions) / 2331644
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Pyrazolopyrimidines and medium, with fungicidal and bactericidal activity for fighting harmful organisms, based on them Pyrazolopyrimidines and medium, with fungicidal and bactericidal activity for fighting harmful organisms, based on them / 2331643
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Using flumazenil in production of drug for treatment of cocaine abuse / 2322985
Invention proposes using flumazenil representing 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazol[1,5-a][1,4]benzodiazepine-3-carboxylic acid ethyl ester for production of drug used in treatment of cocaine abuse, abstinence syndrome from cocaine and relapse of cocaine abuse. Agent is administrated in time periods from 1 to 15 min providing administration of from 0.1 to 0.3 mg of flumazenil that represents the therapeutically effective dose for treatment of cocaine abuse (variants), corresponding drugs (variants) of flumazenil and methods for treatment (variants). In this regimen in the dose 2 mg of flumazenil for less 1 h above 55% of gamma-glutamic acid receptors are occupied. Invention provides attenuation or removing symptoms of cocaine abuse and rapid recovery of psychophysiological functions.

FIELD: medicine.

SUBSTANCE: new derivatives of pyrrol[2,1-c][1,4]benzodiazepine of the general formula where n=2-10 are described. A pharmaceutical composition, containing them, and the method of obtaining are also described.

EFFECT: compounds possess antitumoral activity and can be applied in medicine.

18 cl, 3 ex, 2 tbl, 1 dwg

 

The technical field to which the invention relates

The present invention relates to new pyrrolo[2,1-C][1,4]benzodiazepines useful as potential anticancer agents. This invention relates to a method of obtaining new pyrrolo[2,1-C][1,4]benzodiazepines useful as anticancer agents. More specifically, the invention provides a method of obtaining 1,1'-{[(misalkan-1,N-diyl)piperazine]dioxy}bis[(11aS)-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-ones] with the changing length of the aliphatic chain, and also describes antineoplastic (anticancer) activity. The structural formula of the new pyrrolo[2,1-C][1,4]benzodiazepines is as follows, where n=2-10.

Prior art

Pyrrolo[2,1-C][1,4]benzodiazepine antitumor antibiotics commonly known as connection class astromicin. In the last few years is increasing interest to develop new pyrrolo[2,1-C][1,4]benzodiazepines (PBB). These antibiotics covalently interact with DNA, forming N2-guanine adducts, which lie within the minor groove of double-stranded DNA by eminalley connection, resistant to acids, with the electrophilic Eminem in position N10-C11. (S. Kunimoto et al., J. Antibiot., 1980, 33, 665; K.W. Kohn and C.L. Speous, J. Mol. Biol., 1970, 51, 551; L.H. Hurley et al. Biochem. Biophys. Acta., 1977, 475, 521; D.J. Kaplan and L.H. Hurley, Biochemistry, 1981, 20, 7572). Molecules have the right spiraled, which allows them to follow the curvature of the minor groove of b-form double-stranded DNA, covering three pairs of bases. Recently developed dimers PBB containing two C2-Exo-methylindoline subunit DC-81 connected in position C-8 inert propanediamine linker (S.J. Gregson et al., J. Med. Chem., 2001, 44, 737). A recent development has been the combination of two units of PBB in positions C-8 with the formation of bifunctional alkylating reagents that can bind DNA. (D.E. Thruston et al., J. Org. Chem., 1996, 61, 8141-8147). Recently been synthesized unstitched mixed Imin-amide dimers PBB, with significant ability to bind DNA and strong antitumor activity (A. Kamal et al., US Pat. 636233, 26.03.2002; A. Kamal et al., J. Med. Chem., 2002, 45, 4679).

Natural pyrrolo[2,1-C][1,4]benzodiazepines belong to the group of antitumor antibiotics produced byStreptomyces. Recently there are many compelling reasons for synthesis PBB systems, as they can recognize and bind to certain DNA sequences. Examples of natural PBB include astromicin, DC-81, Dominican, liberalizing and neutralized.

.

However, the clinical efficacy of these antibiotics interfere with several limitations, such as poor solubility of the water, if present, the development of resistance to the drug and metabolic inactivation.

The purpose of the invention

The main purpose of the present invention is to offer new pyrrolo[2,1-C][1,4]benzodiazepines useful as anticancer agents.

Another objective of the present invention is the pharmaceutical compositions containing the new pyrrolo[2,1-C][1,4]benzodiazepines useful as anti-cancer tools.

Another objective of the present invention is a method of obtaining new pyrrolo[2,1-C][1,4]benzodiazepines.

The invention

Thus, the present invention provides new pyrrolo[2,1-C][1,4]benzodiazepines of the formula VI, where n=2-10, and the way they are received.

Detailed description of the invention

Accordingly, the present invention provides analogues of 1,1'-{[(misalkan-1,N-diyl)piperazine]dioxy}bis[(11aS)-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-it] of the formula (VI)

where n=2-10.

Another variant embodiment of the invention relates to new pyrrolobenzoxazepines structural formula shown below (n=2)

Another variant embodiment of the invention relates to new pyrolobus is azepino structural formula, below (n=3)

Another variant embodiment of the invention relates to new pyrrolobenzoxazepines structural formula shown below (n=4)

Another variant embodiment of the invention relates to new pyrrolobenzoxazepines structural formula shown below (n=5)

Another variant embodiment of the invention relates to new pyrrolobenzoxazepines structural formula shown below (n=6)

Another variant embodiment of the invention relates to new pyrrolobenzoxazepines structural formula shown below (n=7)

Another variant embodiment of the invention relates to new pyrrolobenzoxazepines structural formula shown below (n=8)

Another variant embodiment of the invention relates to new pyrrolobenzoxazepines structural formula shown below (n=9)

Another variant embodiment of the invention relates to new pyrrolobenzoxazepines structural formula shown below (n=10)

In one embodiment, the invention relates what I way to obtain analogues of 1,1'-{[(misalkan-1,N-diyl)piperazine]dioxy}bis[(11aS)-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-it] of the formula (VI), moreover, the method involves the following stages:

a) interaction of the compounds of formula (I) of 1,2-dibromethane in miscible with water, an organic solvent in the presence of a base at the boiling point under reflux for 20-48 hours,

b) pouring the reaction mixture of stage (a) into water, extraction with ethyl acetate, separating an ethyl acetate layer and discard the aqueous layer,

c) the process of evaporation of an ethyl acetate layer stage (b), to obtain the residue, which is then purified to obtain pure compound of formula (II)

d) maintaining the solution of the compounds of formula (II) in the ketone solvent in the presence of a base at the boiling point under reflux for 20-48 hours,

e) pouring the reaction mixture of stage (d) in water, extraction with ethyl acetate, separating an ethyl acetate layer, the process of evaporation of an ethyl acetate layer to form a residue, cleaning residue, to obtain a compound of formula (IV)

f) dissolving the compounds of formula (IV) in alcohol, adding dihydrate chloride tin(II) and boiling under reflux for 0.5-1.5 hours,

g) bringing the pH of the reaction mixture of stage (f) to 8.0 with a solution of bicarbonate of an alkali metal,

h) extraction of the solution with pH 8.0 stage (g) with ethyl acetate, the separation of an ethyl acetate extract, drying an ethyl acetate extract over anhydrous sodium sulfate, filter, the Finance and the process of evaporation of an ethyl acetate solution, to get the crude compound of formula (V),

i) dissolving the compounds of formula (V) phase (h) in a mixture of acetonitrile-water, adding mercury chloride, mercury oxide and stirring for 6-12 hours at ambient temperature,

j) evaporation of the organic layer stage (i), dilution of the residue with ethyl acetate, adding a saturated solution of bicarbonate at room temperature, filtered through a layer of celite, washing the layer with ethyl acetate, to obtain a clear filtrate; and

k) evaporation of the filtrate stage (j), to obtain the residue, which is purified by passing through a column of silica gel, to obtain the pure compounds of formula (VI).

In another embodiment of the invention used a base selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate.

In another embodiment of the invention used ketonic solvent is selected from the group consisting of acetone, methyl ethyl ketone and isobutyl ketone.

In another embodiment of the invention used alcohol selected from the group consisting of methanol, ethanol and isopropanol, preferably methanol.

Another variant of the invention provides a pharmaceutical composition, useful as antitumor agents, and composition content is t an effective amount of one or more analogues of 1,1'-{[(misalkan-1,N-diyl)piperazine]dioxy}bis[(11aS)-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-it] of the formula (VI).

In yet another embodiment of the invention, the composition optionally contain pharmaceutically acceptable additives.

In yet another embodiment of the invention the composition is administered to mammals, including humans.

In yet another embodiment of the invention the composition may be administered orally, systemically, or by any other known methods.

The method of obtaining pyrrolo[2,1-f][1,4]benzodiazepines of the formula VI is represented on the drawing and accompanying description, where n=2-10; the method includes: interaction of diethylthiourea (2S)-N-[4-hydroxy-5-methoxy-2-nitrobenzoyl]-2-carboxaldehyde formula I with dibromethane in aprotic miscible with water, an organic solvent, such as acetone, THF and DMF, in the presence of a weak inorganic bases, such as2CO3, CsCO3and VASO3at a temperature up to the boiling temperature under reflux for up to 48 hours, the interaction of diethylthiourea (2S)-N-[4-(n-romancoke)-5-methoxy-2-nitrobenzoyl]pyrrolidine-2-carboxaldehyde formula II with a piperazine of formula III in the presence of a weak inorganic bases, such as K2CO3, CsCO3and VASO3and in the presence of aprotic miscible with water and organic solvents at temperatures up to the boiling temperature under reflux for is about 48 hours, the selection of diethylthiourea 1,1'-{[(misalkan-1,N-diyl)piperazine]dioxy}bis[(11aS)-7-methoxy-2-nitrobenzonitrile-2-carboxaldehyde] formula IV where n=2-10, conventional methods, the recovery of the nitro compounds of formula IV SnCl2·2H2O in the presence of an organic solvent at a temperature up to the boiling temperature under reflux, the selection of diethylthiourea 1,1'-{[(misalkan-1,N-diyl)piperazine]dioxy}bis[(11aS)-7-methoxy-2-aminomethylpyrrolidine-2-carboxaldehyde] formula V where n=2-10, conventional methods, the interaction of the amino compounds of formula V with known reagents that remove protection, obtaining new pyrrolo[2,1-f][1,4]benzodiazepines of the formula VI, where n has the values listed above.

Predecessor, diethylthiourea (2S)-N-(4-hydroxy-2-methoxy-2-nitrobenzoyl)pyrrolidine-2-carboxaldehyde formula I (intermediate DC-81), produced by the method described in the literature (D.E. Thurston et al., Synthesis, 1990, 81).

Some typical compounds of formula VI of the present invention is given below.

1) of 1,1'-{[(bicutan-1,N-diyl)piperazine]dioxy}bis[(11aS)-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-it].

2) of 1,1'-{[(beproven-1,N-diyl)piperazine]dioxy}bis[(11aS)-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-it].

3) of 1,1'-{[(bisutun-1,N-diyl)piperazine]dioxy}bis[(11aS)-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[,1-c][1,4]benzodiazepine-5-it].

These new analogues of dimers pyrrolo[2,1-c][1,4]benzodiazepine, linked through piperazine in positions C-8, has shown promising anticancer activity in various cell lines. The synthesized molecules are of great biological importance because of the possible consequences of selective DNA binding. This has led to the development and synthesis of new representatives of the same class, as shown in figure 1, which includes:

1. Education simple essential link in position C-8 intermediate compounds DC-81 with piperazine.

2. Boiling of the reaction mixture within 24-48 hours.

3. The synthesis of C-8-linked dimer of Iminov PBB activity of antitumor antibiotics.

4. Purification of column chromatography using various solvents such as ethyl acetate, hexane, dichloromethane and methanol.

Way to generate new unstitched pyrrolo[2,1-c][1,4]benzodiazepines disclosed and claimed in co-pending application of applicants.

The following examples are provided for illustration and therefore should not be construed as limiting the scope of the invention.

A brief description of the drawing which is a schematic diagram of obtaining compounds of General formula VI(a-i).

Example 1

The solution diethylthiourea (2S)-N-(4-hydroxy-5-methoxy-2-nitrobenzoyl)pyrrolidine-2-carboxaldehyde is ormula I (800 mg, 2 mmol), 1,2-dibromethane (940 mg, 2.5 mmol) and K2CO3(828 mg, 3 mmol) in dry acetone (40 ml) was boiled under reflux for 48 hours. After completion of the reaction as evidenced by TLC (EtOAc-hexane (7:3)), the reaction mixture was poured into water and then extracted with ethyl acetate. Evaporation of the organic layer gave the crude product which was further purified column chromatography on silica gel, elwira a mixture of EtOAc-hexane (1:1)and received net diethylthiourea (2S)-N-[4-(2-bromoethoxy)-5-methoxy-2-nitrobenzoyl]pyrrolidine-2-carboxaldehyde formula II.

1H-NMR: (CDCl3) δ 1,20-1,4 (m, 6N), a 1.75-2,2 (m, 4H), 2,6-2,9 (m, 4H), 3,20-to 3.33 (m, 2H) to 3.67 (t, 2H), 3,95 (s, 3H), 4,37 (t, 2H), 4,62-4,78 (m, 1H), around 4.85 (d, 1H), PC 6.82 (s, 1H), to 7.67 (s, 1H).

The solution diethylthiourea (2S)-N-[4-(3-bromoethoxy)-5-methoxy-2-nitrobenzoyl]pyrrolidine-2-carboxaldehyde formula II (507 mg, 1 mmol), piperazine (0,043 mg, 0.5 mmol) formulas III and2CO3(414 mg, 3 mmol) in dry acetone (20 ml) was boiled under reflux for 48 hours. After completion of the reaction as evidenced by TLC (EtOAc), the reaction mixture was poured into water and then extracted with ethyl acetate. Evaporation of the organic layer gave the crude product which was further purified column chromatography on silica gel, elwira a mixture of EtOAc-hexane (9:1)and received net diethylthiourea 1,1'-{[(bicutan-1,N-diyl)piperazine]dioxy}b is[(11aS)-7-methoxy-2-nitrobenzonitrile-2-carboxaldehyde].

1H-NMR: (CDCl3) δ 1,29-of 1.41 (m, 12H), 1,7-2,39 (m, 8H), 2,60-2,90 (m, 20H), 3,17-3,3 (m, 4H), to 3.92 (s, 6H), 4,2 (t, 4H), 4,60-4,70 (m, 2H), 4,81 (d, 2H), 6,8 (s, 2H), and 7.7 (s, 2H).

Mass spectrometry with fast atom bombardment (FAB-MS): 939 (M+N)+.

Diethylthiourea 1,1'-{[(bicutan-1,N-diyl)piperazine]dioxy}bis[(11aS)-7-methoxy-2-nitrobenzonitrile-2-carboxaldehyde] formula IV (939 mg, 1.0 mmol) was dissolved in methanol (10 ml), was added SnCl2·2H2O (1,124 g, 5.0 mmol) and boiled under reflux for 1.5 hours. The reaction mixture is then carefully brought to pH 8 with saturated solution of NaHCO3and were extracted with ethyl acetate (3×20 ml). The combined organic phase was dried over Na2SO4, was evaporated under vacuum and obtained crude diethylthiourea 1,1'-{[(bicutan-1,N-diyl)piperazine]dioxy}bis[(11aS)-7-methoxy-2-aminomethylpyrrolidine-2-carboxaldehyde].

The solution diethylthiourea 1,1'-{[(bicutan-1,N-diyl)piperazine]dioxy}bis[(11aS)-7-methoxy-2-aminomethylpyrrolidine-2-carboxaldehyde] formula V (879 mg, 1 mmol), HgCl2(794 mg, at 2.93 mmol), HgO (686 mg, 3,18 mmol) in CH3CN/H2O (3:1, 15 ml) was stirred at room temperature for 12 hours before until TLC (EtOAc) shows complete loss of starting material. Then the organic layer is evaporated in vacuo and the residue diluted with ethyl acetate. To the resulting solution was slowly added saturated NaHCO 3at room temperature and the mixture was filtered through celite and washed with ethyl acetate. The filtrate was evaporated in vacuum and received crude 1,1'-{[(bicutan-1,N-diyl)piperazine]dioxy}bis[(11aS)-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-he] formula VIa, which was further purified column chromatography on silica gel, elwira first with ethyl acetate to remove traces of salts of mercury, then a mixture of CHCl3-methanol (9:1).

1H-NMR: (CDCl3) δ 1,92-to 2.42 (m, 8H), 2,60-2,95 (m, 12H), 3,2-3,88 (m, 6H), to 3.92 (s, 6H), 4,14-to 4.28 (m, 4H), 6,76 (s, 2H), 7,5 (s, 2H), 7,66 (d, 2H).

FAB MS: 631 (M+N)+.

Example 2

The solution diethylthiourea (2S)-N-(4-hydroxy-5-methoxy-2-nitrobenzoyl)pyrrolidine-2-carboxaldehyde formula I (400 mg, 1 mmol), 1,3-dibromopropane (502 mg, 2.5 mmol) and K2CO3(414 mg, 3 mmol) in dry acetone (20 ml) was boiled under reflux for 48 hours. After completion of the reaction as evidenced by TLC (EtOAc-hexane (7:3)), the reaction mixture was poured into water and then extracted with ethyl acetate. Evaporation of the organic layer gave the crude product which was further purified column chromatography on silica gel, elwira a mixture of EtOAc-hexane (1:1)and received net diethylthiourea (2S)-N-[4-(4-bromopropane)-5-methoxy-2-nitrobenzoyl]pyrrolidine-2-carboxaldehyde formula II.

1H-NMR: (CDCl3) δ 1,25-1,4 (m, 6H), of 1.85 to 2.35 (m, 4H), 2,38-2,5 (m, 2H), 2,6-2,9 (who, 4H), 3,18-to 3.33 (m, 2H), to 3.64 (t, 2H), of 3.97 (s, 3H), 4,29 (t, 2H), 4,67-4,78 (m, 1H), a 4.83 (d, 1H), 6,78 (s, 1H), and 7.7 (s, 1H).

The solution diethylthiourea (2S)-N-[4-(4-bromopropane)-5-methoxy-2-nitrobenzoyl]pyrrolidine-2-carboxaldehyde formula II (520 mg, 1 mmol), piperazine (0,043 mg, 1 mmol) formulas III and2CO3(414 mg, 3 mmol) in dry acetone (20 ml) was boiled under reflux for 48 hours. After completion of the reaction as evidenced by TLC (EtOAc), the reaction mixture was poured into water and then extracted with ethyl acetate. Evaporation of the organic layer gave the crude product which was further purified column chromatography on silica gel, elwira a mixture of EtOAc-hexane (9:1)and received net diethylthiourea 1,1'-{[(beproven-1,N-diyl)piperazine]dioxy}bis[(11aS)-7-methoxy-2-nitrobenzonitrile-2-carboxaldehyde] formula IV.

1H-NMR: (CDCl3) δ 1,3-is 1.42 (m, 12H), 1,9 of-2.32 (m, 8H), 2,47 to 2.6 (m, 4H), 2,7-2,9 (m, 24H), 3,2-3,3 (m, 4H), of 3.95 (s, 6H), 4,1-4,2 (t, 4H), to 4.62-4.75 in (m, 2H), 4,82 (d, 2H), 6.75 in (s, 2H), to 7.67 (s, 2H).

FAB MS: 967 (M+N)+.

Diethylthiourea 1,1'-{[(beproven-1,N-diyl)piperazine]dioxy}bis[(11aS)-7-methoxy-2-nitrobenzonitrile-2-carboxaldehyde] formula IV (966 mg, 1.0 mmol) was dissolved in methanol (10 ml), was added SnCl2·2H2O (1,124 g, 5.0 mmol) and boiled under reflux for 1.5 hours. The reaction mixture is then carefully brought to pH 8 with saturated solution of NaHCO3and were extracted atilas what tatom (3× 20 ml). The combined organic phase was dried over Na2SO4, was evaporated under vacuum and obtained crude diethylthiourea 1,1'-{[(beproven-1,N-diyl)piperazine]dioxy}bis[(11aS)-7-methoxy-2-aminomethylpyrrolidine-2-carboxaldehyde] formula V.

The solution diethylthiourea 1,1'-{[(beproven-1,N-diyl)piperazine]dioxy}bis[(11aS)-7-methoxy-2-aminomethylpyrrolidine-2-carboxaldehyde] formula V (907 mg, 1 mmol), HgCl2(794 mg, at 2.93 mmol), HgO (687 mg, 3,18 mmol) in CH3CN/H2O (3:1, 15 ml) was stirred at room temperature for 12 hours before until TLC (EtOAc) shows complete loss of starting material. Then the organic layer is evaporated in vacuo and the residue diluted with EtOAc. To the resulting solution was slowly added saturated NaHCO3at room temperature and the mixture was filtered through celite and washed with ethyl acetate. The filtrate was evaporated in vacuum and received crude 1,1'-{[(beproven-1,N-diyl)piperazine]dioxy}bis[(11aS)-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-he] formula VIb, which was further purified column chromatography on silica gel, elwira first with ethyl acetate to remove traces of salts of mercury, then a mixture of CHCl3-methanol (9:1).

1H-NMR: (CDCl3) δ 1,92-is 2.37 (m, 8H), 2.57 m) and-2.8 (m, 16H), 3,32 of 3.75 (m, 6H), of 3.95 (s, 6H), 4,12 is 4.45 (m, 4H), 6,85 (s, 2H), 7,52 (s, 2H), 7,82 (d, 2H).

FAB MS: 659 (M+N)+.

Example 3

The solution IER is ylthioacetate (2S)-N-[4-hydroxy-5-methoxy-2-nitrobenzoyl]pyrrolidine-2-carboxaldehyde formula I (400 mg, 1 mmol), 1,4-dibromobutane (540 mg, 2.5 mmol) and K2CO3(414 mg, 3 mmol) in dry acetone (20 ml) was boiled under reflux for 48 hours. After completion of the reaction as evidenced by TLC (EtOAc-hexane (7:3)), the reaction mixture was poured into water and then extracted with ethyl acetate. Evaporation of the organic layer gave the crude product which was further purified column chromatography on silica gel, elwira a mixture of EtOAc-hexane (1:1)and received net diethylthiourea (2S)-N-[4-(5-bromoethoxy)-5-methoxy-2-nitrobenzoyl]pyrrolidine-2-carboxaldehyde formula II.

1H-NMR: (CDCl3) δ from 1.3 to 1.45 (m, 6H), 1,88-of 2.38 (m, 4H), 2,69-is 2.88 (m, 8H), 3,20-to 3.33 (m, 2H), 3,51 (t, 2H), of 3.97 (s, 3H), of 4.16 (t, 2H), 4,63 was 4.76 (m, 1H), a 4.86 (d, 1H), 6,79 (s, 1H), to 7.67 (s, 1H).

The solution diethylthiourea (2S)-N-[4-(5-bromoethoxy)-5-methoxy-2-nitrobenzoyl]pyrrolidine-2-carboxaldehyde formula II (53 mg, 1 mmol), piperazine (0,043 mg, 1 mmol) formulas III and2CO3(414 mg, 3 mmol) in dry acetone (20 ml) was boiled under reflux for 48 hours. After completion of the reaction as evidenced by TLC (EtOAc), the reaction mixture was poured into water and then extracted with ethyl acetate. Evaporation of the organic layer gave the crude product which was further purified column chromatography on silica gel, elwira a mixture of EtOAc-hexane (9:1)and received net diethylthiourea 1,1'-{[(bisutun-1,N-diyl)piperazine]diox the}bis[(11aS)-7-methoxy-2-nitrobenzonitrile-2-carboxaldehyde] formula IV.

1H-NMR: (CDCl3) δ 1,30 was 1.43 (m, 12H), 2,74 to 2.35 (m, 12H), of 2.51-of 2.66 (m, 16H), 3,20-3,3 (m, 4H), of 3.97 (s, 6H), of 4.12 (t, 4H), with 4.64 was 4.76 (m, 2H), 4,87 (d, 2H), 6,84 (s, 2H), 7,66 (s, 2H).

FAB MS: 995 (M+N)+.

Diethylthiourea 1,1'-{[(bisutun-1,N-diyl)piperazine]dioxy}bis[(11aS)-7-methoxy-2-nitrobenzonitrile-2-carboxaldehyde] formula IV (730 mg, 1.0 mmol) was dissolved in methanol (10 ml), was added SnCl2·2H2O (1,124 g, 5.0 mmol) and boiled under reflux for 1.5 hours. The reaction mixture is then carefully brought to pH 8 with saturated solution of NaHCO3and were extracted with ethyl acetate (3×20 ml). The combined organic phase was dried over Na2SO4, was evaporated under vacuum and obtained crude diethylthiourea 1,1'-{[(bisutun-1,N-diyl)piperazine]dioxy}bis[(11aS)-7-methoxy-2-aminomethylpyrrolidine-2-carboxaldehyde] formula V.

The solution diethylthiourea 1,1'-{[(bisutun-1,N-diyl)piperazine]dioxy}bis[(11aS)-7-methoxy-2-aminomethylpyrrolidine-2-carboxaldehyde] formula V (935 mg, 1 mmol), HgCl2(794 mg, at 2.93 mmol HgO (687 mg, 3,18 mmol) in CH3CN/H2O (3:1, 15 ml) was stirred at room temperature for 12 hours before until TLC (EtOAc) showed complete disappearance of starting material. Then the organic layer was evaporated in vacuum and the residue was diluted with ethyl acetate. To the resulting solution was slowly added saturated NaHCO3at room temperature the e and the mixture was filtered through celite and washed with ethyl acetate. The filtrate was evaporated in vacuum and received crude 1,1'-{[(bisutun-1,N-diyl)piperazine]dioxy}bis[(11aS)-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-he] formula VIc, which was further purified column chromatography on silica gel, elwira first with ethyl acetate to remove traces of salts of mercury, then a mixture of CHCl3-methanol (9:1).

1H-NMR: (CDCl3) δ 1,78-of 2.24 (m, 8H), 2,30-of 2.75 (m, 20H), 3,4-3,7 (m, 6H), to 3.92 (s, 6H), 4,1-to 4.23 (m, 4H), 6.73 x (s, 2H), of 7.48 (s, 2H), 7,60 (d, 2H).

FAB MS: 687 (M+N)+.

Biological activity: the study ofin vitrobiological activity conducted at the National Cancer Institute (USA).

Cytotoxicity: Connection VIa-d were evaluated byin vitroin relation to sixty neoplastic human cells derived from nine cancer types (leukemia, melanoma, non-small cell lung cancer, colon cancer, CNS, ovarian, prostate and breast cancer). For each compound was measured curves dose-effect for each cell line for a minimum of five concentrations at tenfold dilution. Used Protocol 48-hour continuous action of drugs and the analysis of protein sulforhodamine In (SRB) to assess the viability or cell growth. To calculate the concentration causing 50% inhibition of cell growth (IR), complete inhibition of cell growth (ESW, 0% growth) and 50% cell death (LC50, -50% growth)in comparison with the control. Srednegavanskiy the mid-point value log10Pier and log10LC50 and log10IR are listed in table 1. As demonstrated srednegavanskiy examples, the connection VIc shows an interesting profile of activity and selectivity for different cell lines. Srednegavanskiy the mid-point value log10Pier and log10LC50 showed a picture similar to the picture for srednegavonskog mid-point values log10IR.

Table 1< / br>
Srednegavanskiy the mid-point value log10IR, log10Pier and log10LC50 datain vitrothe cytotoxicity of the compounds VIa the-d lines of human tumor cells
Connection log10IR log10Feast log10LC50
VIa -4,69 -4,16 -4,03
VIb -5,19 -4,22 -4,01
VIc -7,70 -5,95 -4,47
VId -5,14 -4,26 -4,04

Cancerin vitroactivity four members of the soybean is ineni VI is given in table 2. Comparison of the data of table 2 reveals the importance alkangovolo linker. As alkanoyl linker increases from two to four carbon atoms in the cytotoxic activity of moderately growing. Chetyrehoborotnye linker compounds VIc gives a suitable match minor groove of the DNA double helix, and this compound shows a slightly higher activity in a number of soedinenii VIa-d.

td align="center"> -4,00
Table 2< / br>
Values log10LC50 (concentration in mol/l,< / br>
causing 50% mortality) for connections VIa-d
Cancer Connection VIa Connection VIb Connection VIc Connection VId
IR LC50 IR LC50 IR LC50 IR LC50
Leukemia                
HL-60(TB) -5,49 -4,00 -6,66 -4,00 -8,00 -4,00 -5,38 -4,00
K-62 -4,58 -4,00 -5,76 -4,00 -7,63 -4,00 -5,46 -4,20
MOLT-4 -5,68 -4,10 -6,50 -4,08 -8,00 -4,00 -4,79 -4,00
RPMI-8226 -6,08 -4,33 -6,73 -4,00 -7,81 -4,60 -5,59 -4,54
SR -6,68 -5,21 - - -8,00 -5,62 -5,37 -4,00
Non-small cell lung cancer                
A549/ATCC -4,10 -4,00 -4,37 -4,00 -7,23 -4,00 -4,66 -4,00
EKVX -4,00 -4,00 -4,47 -4,00 -6,63 -4,00 -4,33 -4,00
HOP-62 -4,46 -4,00 -5,14 -4,00 -8,00 -4,00 -4,00 -4,00
HOP-92 -4,68 -4,00 -6,81 -4,00 -8,00 -4,00 -5,46 -4,00
HCI-H226 -4,80 -4,00 -4,34 -4,00 -8,00 -4,00 -5,30 -4,00
HCI-H23 -4,76 -4,00 -4,89 -4,00 -8,00 -5,59 -5,18 -4,00
HCI-H322 -4,51 -4,00 -4,57 -4,00 -7,59 -4,00 -4,65 -4,00
HCI-H460 -4,95 -4,00 -5,37 -4,00 -8,00 -4,00 -5,49 -4,00
HCI-H522 -4,94 -4,00 -6,40 -4,00 -8,00 -4,00 are 5.47 -4,00
Colon                
COLO 205 -4,66 -4,00 -5,34 -4,00 -7,99 -6,26 -5,49 -4,00
HCC-2998 - - -4,73 -4,04 -7,95 -4,00 -5,69 -4,29
HCT-116 -4,47 -4,00 -4,92 -4,00 -6,42 -4,00 -4,00 -4,00
HCT-15 -4,39 -4,00 -4,25 -4,00 -7,92 -6,37 -4,25 -4,00
HT-29 -4,58 -4,00 -4,46 -4,00 -7,89 -4,00 -5,02 -4,00
KM-12 -4,70 -4,04 -4,64 -4,00 -7,84 -4,67 -5,25 -4,00
SW-620 -4,68 -4,00 -6,23 -4,00 - - -5,49 -4,00
Central nervous system                
SF-268 -4,95 -4,00 -5,52 4,00 -8,00 -4,00 -5,44 -4,00
SF-295 -5,06 -4,00 -4,99 -4,00 -8,00 -4,69 -5,30 -4,00
SF-539 -4,97 -4,00 -6,21 -4,00 -8,00 -4,00 -5,44 -4,00
SNB-19 -4,75 -4,00 -5,06 -4,00 -8,00 -4,44 -4,00 -4,00
SNB-75 -4,23 -4,00 -4,61 -4,00 -7,94 -4,00 -4,51 -4,00
U251 -4,87 -4,00 -5,41 -4,00 -8,00 -4,41 are 5.47 -4,00
Melanoma                
MALME-3M -5,46 -4,17 -5,39 4,00 -8,00 -7,41 - -
LOXIMVI - - - - - - -5,61 -4,00
M14 -4,61 -4,00 -5,55 -4,00 -7,60 -4,17 -4,76 -4,00
SK-MEL-2 -4,57 4,00 -4,82 -4,00 -7,34 -4,00 - -
SK-MEL-28 -4,22 -4,00 -4,48 -4,00 -7,69 -4,00 -4,71 -4,00
SK-MEL-5 -4,75 -4,00 -5,66 -4,50 -7,86 -6,68 -5,48 -4,00
UACC-257 -4,49 -4,00 -4,45 -4,00 -7,65 - -4,75 -4,00
UACC-62 -4,83 -4,00 -4,68 -4,00 -8,00 -7,35 -5,64 -4,00
Ovaries                
IGROVI -4,21 -4,00 -5,26 -4,00 -6,79 -4,00 -5,13 -4,00
OVCAR-3 -4,68 -4,00 are 5.47 -4,00 -7,91 -4,00 -5,32 -4,00
OVCAR-4 -4,00 -4,00 -4,13 -4,00 -7,11 -4,00 -5,38 -4,00
OVCAR-5 -4,65 -4,00 -5,06 -4,00 -7,92 -4,00 -5,33 -4,00
OVCAR-8 -4,58 -4,00 -4,48 -4,00 -8,00 -4,00 -4,67 -4,00
SK-OV-3 -4,00 -4,00 - - - -4,00 - -
Kidney                
786-0 -4,84 -4,00 -5,30 -4,00 -8,00 -4,00 -5,61 -4,00
A -4,29 -4,00 -5,73 -4,00 -6,89 - -5,00 -4,00
ACHN -4,82 -4,00 -4,47 -4,00 -8,00 -4,00 -4,63 -4,00
CAKI-1 -5,04 -4,65 -4,00 -8,00 -4,28 -5,77 -4,00
RXF 393 -4,23 -4,00 -5,68 -4,09 -7,54 -4,00 -8,00 -5,09
SN12C -4,90 -4,00 -4,44 -4,00 -8,00 -4,00 -5,66 -4,00
TK-10 -4,63 -4,00 -5,10 -4,00 -7,69 -4,00 - -4,00
UO-31 -4,12 -4,00 -4,27 -4,00 -6,65 -4,00 -4,00 -4,00
Prostate                
PC-3 -4,44 -4,00 -5,53 -4,00 -7,02 -4,00 -5,41 -4,00
DU-145 -4,36 -4,00 -5,62 -4,00 -7,60 -4,00 -5,37 -4,00
Mammary gland                
MCF7 -4,88 -4,00 -6,01 -4,00 -8,00 -4,00 -5,69 -4,00
NCI/ADR-RES -4,00 -4,00 -4,00 -4,00 -6,47 -4,00 -4,00 -4,00
MDA-MB-231/ATCC -4,67 -4,00 -4,52 -4,00 -7,47 -4,43 -5,42 -4,00
HS578T -4,34 -4,00 -6,13 -4,00 -7,30 -4,00 -5,12 -4,00
MDA-MB-435 -4,71 -4,08 -5,37 -4,09 -7,87 -7,15 -5,37 -4,00
BT-549 -4,56 -4,00 -5,77 -4,00 -7,68 -4,00 -5,31 -4,00
T-47D -4,57 -4,00 -5,16 -4,00 -8,00 -4,00 -5,00 -4,00

1. Derivatives pyrrolo[2,1-C][1,4]benzodiazepine of formula (VI)

where n=2-10.

2. Method of preparing compounds according to claim 1, which includes stages:

a) interaction of diethylthiourea (2S)-N-(4-hydroxy-5-methoxy-2-nitrobenzoyl)pyrrolidine-2-carboxaldehyde formula I of the formula (I)

with dibromo(C2-C10)alkanol in miscible with water, an organic solvent in the presence of a base at boiling point for 20-48 h,

b) pouring the reaction mixture of stage (a) into water, extraction with ethyl acetate, separating an ethyl acetate layer and discard the aqueous layer,

c) the process of evaporation of an ethyl acetate layer stage (b) to obtain a residue, which is then purified to obtain pure diethylthiourea (2S)-N-[4-(n-romancoke)-5-methoxy-2-nitrobenzoyl]pyrrolidine-2-carboxaldehyde formula (II)

where n=2-10;

d) maintaining the solution of the compounds of formula (II) and

piperazine (III) in the ketone solvent in the presence of a base at boiling point for 20-48 h,

e) pouring the reaction mixture of stage (d) in water, extraction with ethyl acetate, separating an ethyl acetate layer, evaporation

an ethyl acetate layer with obtaining balance, purification of the residue to obtain diethylthiourea 1,1'-{[(misalkan-1,N-diyl)piperazine]dioxy}bis[(11S)-7-methoxy-2-neath benzoylpyridine-2-carboxaldehyde] of the formula (IV)

where n=2-10;

f) dissolving the compounds of formula (IV) in alcohol, adding dihydrate chloride tin (II) and boiling for 0.5-1.5 h,

g) bringing the pH of the reaction mixture of stage (f) to 8.0 with a solution of bicarbonate of an alkali metal,

h) extraction of the solution with pH 8.0 stage (g) with ethyl acetate, the separation of an ethyl acetate extract, drying an ethyl acetate extract over anhydrous sodium sulfate, filtration and evaporation of an ethyl acetate solution to obtain the crude diethylthiourea 1,1'-{[(misalkan-1,N-diyl)piperazine]dioxy}bis[(11S)-7-methoxy-2-aminomethylpyrrolidine-2-carboxaldehyde formula (V),

where n=2-10;

i) dissolving the compounds of formula (V) phase (h) in a mixture of acetonitrile-water, adding mercury chloride, mercury oxide and stirring for 6-12 h at ambient temperature,

j) evaporation of the organic layer stage (i), dilution of the residue with ethyl acetate, adding a saturated solution of bicarbonate at room temperature, filtered through a layer of celite, washing the layer with ethyl acetate to obtain a clear filtrate; and

k) evaporation of the filtrate stage (j) to obtain a residue, which is purified by passing through a column of silica gel, to obtain the pure compounds is ormula (VI) according to claim 1.

3. The method according to claim 2, where at stage (a) used a base selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate.

4. The method according to claim 2, where at stage (d) is used ketonic solvent is selected from the group consisting of acetone, methyl ethyl ketone and isobutyl ketone.

5. The method according to claim 2, where at stage (d) used a base selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate.

6. The method according to claim 2, where at stage (f) used alcohol selected from methanol, ethanol and isopropanol.

7. The method according to claim 6, where used, the alcohol is methanol.

8. Pharmaceutical composition having antitumor activity, containing an effective amount of the compounds of formula (VI) according to claim 1.

9. The composition of claim 8, where the composition optionally contain pharmaceutically acceptable additives.

10. Derived pyrrolo[2,1-C][1,4]benzodiazepine of formula (VIc):

11. The method of obtaining the compound of claim 10, which includes stages:

a) interaction of the compounds of formula (I)

with 1,4-dibromobutane in miscible with water, an organic solvent in the presence of a base at boiling point for 20-48 h,

b) pouring out of the s stage of the reaction mixture (a) in water, extraction with ethyl acetate, separating an ethyl acetate layer and discard the aqueous layer,

c) the process of evaporation of an ethyl acetate layer stage (b) to obtain a residue, which is then purified to obtain pure compounds of formula (II)

where n=4;

d) maintaining the solution of the compounds of formula (II) and piperazine in a ketone solvent in the presence of a base at boiling point for 20-48 h,

e) pouring the reaction mixture of stage (d) in water, extraction with ethyl acetate, separating an ethyl acetate layer, the process of evaporation of an ethyl acetate layer with obtaining balance, purification of the residue by obtaining the compounds of formula (IV)

where n=4;

f) dissolving the compounds of formula (IV) in alcohol, adding dihydrate chloride tin (II) and boiling for 0.5-1.5 h,

g) bringing the pH of the reaction mixture of stage (f) to 8.0 with a solution of bicarbonate of an alkali metal,

n) extraction of the solution with pH 8.0 stage (g) with ethyl acetate, the separation of an ethyl acetate extract, drying an ethyl acetate extract over anhydrous sodium sulfate, filtration and evaporation of an ethyl acetate solution to obtain the crude compound of formula (V),

where n=4;

i) dissolving the compound forms of the crystals (V) phase (h) in a mixture of acetonitrile-water, adding mercury chloride, mercury oxide and stirring for 6-12 h at ambient temperature,

j) evaporation of the organic layer stage (i), dilution of the residue with ethyl acetate, adding a saturated solution of bicarbonate at room temperature, filtered through a layer of celite, washing the layer with ethyl acetate to obtain a clear filtrate; and

k) evaporation of the filtrate stage (j) to obtain a residue, which is purified by passing through a column of silica gel, to obtain the pure compounds of the formula (VIc) item 10.

12. The method according to claim 11, where at stage (a) used a base selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate.

13. The method according to claim 11, where at stage (d) is used ketonic solvent is selected from the group consisting of acetone, methyl ethyl ketone and isobutyl ketone.

14. The method according to claim 11, where at stage (d) used a base selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate.

15. The method according to claim 11, where at stage (f) used alcohol selected from methanol, ethanol and isopropanol.

16. The method according to clause 15, where used, the alcohol is methanol.

17. Pharmaceutical composition having antitumor activity, containing an effective amount of the compounds the formula ia (VIc) item 10.

18. The composition according to 17, where the composition optionally contain pharmaceutically acceptable additives.

 
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