N-cyano-n'-pyridylamine, or their n-oxides, or their pharmaceutically acceptable non-toxic salts, methods for their preparation, pharmaceutical composition and method of inhibiting proliferation of cancer cells

 

(57) Abstract:

N-cyano-N'-pyridylamine formula I,

< / BR>
where R, R', R" is hydrogen or halogen;

WITH1-8-alkylen, possibly substituted by hydroxyl;

X is oxygen, -S(O)n-, n = 1 or 2, or NH;

its tautomeric forms, or their N-oxides, or their pharmaceutically acceptable non-toxic salts, are antagonists of serotonin (NT), and some of them inhibit the proliferation of tumor cells. 7 C. and 10 C.p. f-crystals, 3 tables.

The invention relates to a series of compounds, their pharmaceutically acceptable salts and their N-oxides, a process for the production of the above-mentioned compounds, salts or N-oxides, to pharmaceutical preparations containing the said compounds, dosage units of drugs and to methods of treating patients using the mentioned preparations and dosage units.

New connections or their tautomeric forms, which are suitable in the treatment of human and veterinary medicine, have the General formula (I):

< / BR>
while joining the pyridine ring is carried out in a 3 - or 4-position, in which

R', R" are the same or different and mean hydrogen, halogen or trifluoromethyl, hydroxy, C1-C4-alkyl, s chain, which may be substituted by hydroxy or by halogen, nitro or cyano groups.

X means an oxygen, - S(O)n-, where n means an integer from 0 to 2, or =N-R1where R1is hydrogen or C1-C4-alkyl.

R means hydrogen or one or more C1-C4is alkyl or alkoxy, hydroxy, halogen, triptorelin, cyano, carboxamido, sulfamoyl or microradians.

When these compounds contain one or more asymmetric carbon atoms, these compounds can form optical isomers or diastereoisomers. The present invention also includes all such isomers and mixtures thereof.

Pharmaceutically acceptable salts of compounds of formula I include hydrochloride, hydrobromide, phosphates, sulfates, nitrates, arylsulfonate, citrates, tartratami, maleate, these examples should be considered as limiting the invention.

Preferred compounds of the invention are those compounds of formula I, in which the connection to the pyridine ring is 4-ilozhenii, and/or in which alkylene means straight C3-C6hydrocarbon chain and/or in which X represents oxygen.

86Rb of potassium channels in comparison with the established effects of compounds, protected above by a patent in the UK. Among the compounds represented by formula (I) of the present invention, some unexpectedly turned out to be antagonists of serotonin (5HT), as was clearly shown on separate strips of the bottom of the body of the rat and swelling of the paws of rats caused NT, which makes these compounds potentially suitable for treatment of diseases in which NT involved in the pathological reaction, for example, asthma, allergies and disorders of CNS.

To study the affinity of these compounds for the serotonin receptors2(NT) was determined by inhibition of binding of [3H]ketanserina in specific receptors NC2on charities ligand for binding sites serotonin2the receptor. Molecular pharmacology 21: 301-314 (1982). The results are presented in table 1.

These results show that the compounds of the present invention inhibit the binding of ketanserin in T2receptors and, therefore, have high affinity for these receptors.

Some representatives of this class also inhibit the proliferation of tumor cells during cultivation and prolong the lifespan of rats with a tumor, which makes them potentially useful in cancer chemotherapy.

Suppressing the proliferation of tumor cells was studied using saranovic cells Yoshida, originally derived from hepatic tumors in rats induced by carcinogen o-aminoazotoluene.

Cells were cultured in vitro for 24 hours in the presence of the tested compound. The DNA synthesis was assessed by incorporation of [3H] thymidine and calculated the average, the generally hopeless concentration [IC50] compounds.

Cytotoxicity of compounds in normal lymphocytes was evaluated by the method of excluding the dye, and were expressed as concentrations, the use of which received 50% viability (VC50)lovanii a variety of human cancer cells. The results showed that the compounds of the present invention is able to suppress the proliferation of tumor cells in vitro at concentrations that are approximately 100 times less than concentrations that are cytotoxic to normal cells.

The prolongation of the existence of rats with tumors studied in inbred rats infected narkomanii cells Yoshida (identical to the cells described above) in the number 2107cells. Rats with a tumor, they dosaged orally once a day for one to three days after the transfer of tumor cells to death or until until the mixture Tola was increased by 10% as a result of proliferation of the tumor. The time required for the death of 50% of the animals were evaluated by linear regression analysis. The results are shown in table 3.

These results show that the compounds of the present invention can prolong the lifespan of rats with sarcomatous tumor Yoshida.

The antagonistic effect of the compounds of the invention on NT can be compared with the desired antiemetic effect, compensating known emetic effects of other anticancer agents that can be used in which ossicini, a beneficial effect on the activity, but this impact or minimal impact on the overall blood pressure.

In General, they can be administered orally, intravenously, administered intraperitoneally, through the nose or intradermally.

The present invention also relates to methods of obtaining the desired compounds of formula (I).

One option pyridylcarbonyl formula (II),

< / BR>
in which the substituents are as defined above in formula (I), interacts with an equivalent amount or an excess of cyanamide with or without using conventional inert solvent at room or near room temperature. The reaction can be catalysed by bases, such as triethylamine. Alternatively thiourea of the formula (III),

< / BR>
in which the substituents are as defined above in formula (I), interacts with one or more equivalents of N,N-dicyclohexylcarbodiimide (into) and cyanamide in an inert solvent, for example acetonitrile, at room or higher room temperature, which leads to the release of the compounds of formula (I) and N,N'-dicyclohexylcarbodimide (DCTU). Can be used DOS is>in which the substituents R' and R" are as defined above and Y is halogen, preferably chlorine, or C1-C4-alkylthiomethyl, communicates with the appropriate amine where the symbols have the same meanings as in the formula (I). The amine can be used in excess in an inert solvent, for example pyridine, at room temperature or above room temperature, for example in boiling pyridine. In the case where Y represents halogen, it may be preferable to use the equivalent agent, a binder acid, for example a tertiary amine.

According to another variant, the compound of formula (V),

< / BR>
in which the substituents are as defined above, interacts with equivalent or slightly excess amount of the required amine, where the symbols have the same meanings as in the formula (I), in the presence of one equivalent or slightly more into in an inert solvent, for example dimethylformamide, at 0oC or at room temperature, which leads to the formation of compound (I) and DCTU.

In the methods described above, can be obtained the stereoisomer of formula (I) using the corresponding isomer soo is.

An alternative can be used racemic starting material, then the resulting mixture can be subjected to repeated dissolution of the racemate, for example, by crystallization of the corresponding salts with optically active acid or by chromatography in asymmetric column.

The compounds of formula (II) can be obtained from the desired thiourea (III) or the corresponding urea conventional methods, for example by treatment with triphenylphosphine, tetrachloride-carbon and triethylamine in dry methylene chloride.

The compounds of formula (IV) can be obtained by the interaction with the corresponding cyanamide peregrinationes in the presence of a tertiary amine and then the processing of C1-C4-alkylation, in the case when Y represents C1-C4-alkylthiomethyl. When Y represents halogen, the compound (IV) can be obtained by reacting the compounds of formula (V), for example, with phosgene in an inert solvent in the presence of a tertiary amine.

Educt of the formula (V) can be obtained from the required pyridinethione and cyanamide, using one equivalent of a tertiary amine, in an inert solvent. Alternatively, pyridylmethylamine KIS is nami of cyanamide and one equivalent of a tertiary amine, for example in methanol, to yield amine salt desirable pyridylcarbinol acid (V).

N - and S-oxides of the formula (I) can be conveniently obtained by oxidation of the parent compounds such as m-chloroperbenzoic acid, in an inert solvent, for example chloroform.

Another purpose of this invention is the provision of medicinal products (I) which are suitable for the treatment of the aforementioned diseases.

The required amount of the compounds of formula (I) (hereinafter referred to as active ingredient) for therapeutic effect will, of course, vary depending on the characteristics of the compound and the route of administration and mammal undergoing treatment. A suitable dose of a compound of formula (I) for systemic treatment is from 0.1 to 400 mg per kilogram of body weight, the most preferred dose is from 0.1 to 100 mg per kg of body weight of the mammal, for example from 5 to 20 mg/kg, administered once or several times a day.

The term "dosage unit" is meant a unitary, i.e. a single dose which you can enter the patient and that is easy to apply and easy to pack while it remains in the form of Fizicheskii or liquid pharmaceutical diluents, or the media.

The preparations of the present invention for veterinary and treatment of a person contain the active ingredient in combination with pharmaceutically acceptable carrier and possibly other treatment(s) ingredient(s). The carrier(s) need(s) to be "acceptable" in the sense of compatibility with other ingredients of the product and must be harmful to the recipient.

The drugs make it to a form suitable for oral, rectal, parenteral (including subcutaneous, intramuscular, intravenous and intraperitoneal).

Drugs may suitably be present in the form of dosage units and may be obtained by any of the methods well known in the field of pharmacy. All methods include the stage of bringing the active ingredient into Association with a carrier which consists of one or more additional ingredients. In General, the drugs produced by homogeneous and uniform of bringing the active ingredient into Association with a liquid carrier or a finely powdered solid carrier, or both, and then, if necessary, by forming the product in a desirable drug.

The preparations of the present invention, suitably the th of which contains a predetermined amount of the active ingredient; in the form of powder or granules; in the form of a solution or suspension in an aqueous liquid or non-aqueous liquid, or in the form of an emulsion of the "oil-in-water or emulsion water in oil. The active ingredient can also be entered in the form of beads, medicinal porridge or pasta.

The tablet can be obtained by extrusion or molding of the active ingredient may be one or more extension(s) ingredient(s). Molded tablets can be obtained by pressing in a suitable press active ingredient in free flowing form such as powder or granules, possibly mixed with a binder, lubricant, inert diluent, surface-active agent or dispersing agent. Molded tablets can be obtained by molding in a suitable machine a mixture of the powder of the active ingredient and the carrier moistened inert liquid diluent.

Preparations for rectal injection can be in the form of suppositories comprising the active ingredient and a carrier such as cocoa butter, or in the form of an enema.

Preparations suitable for parenteral administration, are eligible include oil or water composition of the active ingredient, which prepost which this invention may include one or more additional ingredients, for example diluents, buffers, chemicals, improves taste, binders, surfactants, thickeners, lubricants, preservatives tools, such as methoxybenzoate (including antioxidants), emulsifiers, etc.

The compositions may also contain other therapeutically active compounds usually used in the treatment of the above mentioned pathological conditions, for example anti-asthma remedies and anti-cancer drugs, which can lead to synergistic effects on tumor cells.

In accordance with the invention the present compounds is administered to a patient suffering from one of the above pathological conditions, the daily dose (for an adult) from 7 to 28000 mg, preferably from 70 to 7000 mg, and in veterinary practice accordingly daily dose comprising from 0.1 to 400 mg/kg body weight.

Hereinafter the invention will be described in the following non-restrictive examples.

Example 1.

N-cyano-N'-(3-phenoxypropan)-N"-3-pyridylacetic

N-(3-phenoxypropan)-N'-3-pyridylamino (1.73 g) suspended in acetonitrile (10 ml) and added cyanamide (0.50 g) and N,N ' -dicyclohexylcarbodiimide (2,47 g), then triethylamine (0,14 ml)Wali, was washed with acetonitrile and simple ether to obtain a solid mixture of the crude product and N,N'-dicyclohexylcarbodimide, which was removed by extraction with chloroform (25 ml). The product was collected by filtration and washed with chloroform.

Then carried out the purification by dissolving the obtained residue in 0.5 N hydrochloric acid (20 ml), filtered and the resultant deposition rates using a 9 N sodium hydroxide. The melting point 180o-187oC.

NMR (DMSO; -scale) 1.99 (m, 2H), 3.42 (m, 2H), 4.02 (t, 2H), 6.93 (m, 3H), 7.27 (m, 2H), 7.36 (dd, 1H), 7.51 (bt, 1H), 7.67 (m, 1H), 8.34 (m, 1H), 8.47 (m, 1H), 9.15 (bs, 1H).

Example 2.

N-cyano-N'-(2-phenyliminomethyl)-N"-4-pyridylacetic.

N-cyano-N'-4-pyridylamine (1,80 g) suspended in dimethylformamide (5 ml). With stirring in a bath of ice was added N-phenylethylenediamine (1,4 ml) and N,N'-dicyclohexylcarbodiimide (2.50 g), which resulted in obtaining a clear solution. The mixture was left at room temperature for 3 days, when formed suspension, it boiled away under high vacuum. The residue is repeatedly rubbed into powder with simple ether (portion 15 ml) and the residual solid was extracted with 1N hydrochloric acid (50 ml). After filtration of the filtrate by adding 9 N sodium hydroxide solution and transfer into ethyl acetate (CH ml) besieged the people of acetone and simple ether in a ratio of components in a mixture of 1:1 to obtain pure compounds. Melting point: 167-170oC.

NMR (DMSO; -scale): 3.23 (m, 2H), 3.44 (m, 2H), 5.72 (bt, 1H), 6.54 (t, 1H), 6.60 (d, 2H), 7.08 (dd, 2H), 7.21 (d, 2H), 7.86 (bs, 1H), of 8.37 (m, 2H), 9.48 (bs, 1H).

Example 3.

N-cyano-N'-(I-phenoxy-2-propyl)-N"-pyridylacetic

N-(1-phenoxy-2-propyl)-N'-4-pyridylcarbinol (2,53 g) was dissolved in a simple ether (5 ml). Added cyanamide (0.55 g) and triethylamine (0.04 ml) and the mixture is left under stirring overnight in an open flask at room temperature.

Rejected the residue was mixed with simple ether (20 ml) and the suspension was filtered washed in simple ether to obtain a crude product, which was dissolved in 0.5 N hydrochloric acid (30 ml), filtered, and perioadele by adding 9N sodium hydroxide, then collected by filtration and washed with water to obtain pure compounds. Melting point: 164o-166oC.

NMR (DMSO; -scale): 1.24 (d, 3H), 4.01 (d, 2H), 4.31 (m, 1H), 6.97 (m, 3H), 7.20 (bs, 2H), 7.31 (dd, 2H), 7.96 (bd, 1H), 8.35 (bs, 2H), 9.58 (bs, 1H).

Example 4.

N-cyano-N'-(2-phenylthiomethyl)-N"-3-pyridylacetic

S-methyl-N-cyano-N'-pyridinediamine (1.92 g) was dissolved in pyridine (10 ml) and added 2-politiecellen (a 3.06 g). The mixture was left at room temperature for 4 days, then it was boiled away into the vacuum. The remainder RAH">

The crude product was purified by dissolving in excess of 0.5 N hydrochloric acid, filtering and precipitating by adding water to the filtrate 9N sodium hydroxide.

Melting point: 126o-128oC.

NMR (DMSO; -scale): 3.14 (m, 2H), 3.42 (m, 2H), 7.20 (m, 1H), 7.35 (m, 5H), 7.57 (bt, 1H), 7.67 (m, 1H), 8.36 (m, 1H), 8.47 (m, 1H), 9.25 (bs, 1H).

Example 5.

N-cyano-N'-(3-phenoxypropan)-N"-pyridylacetic

Following the procedure of example 1, but substituting N-(3-phenoxypropan)-N'-pyridylacetic N-(3-phenoxypropan)-N'-4-pyridylamino got the desired connection.

NMR (DMSO; -scale): 2.00 (m, 2H), 3.45 (q, 2H), 4.03 (t, 2H), 6.93 (m, 3H), 7.21 (bd, 2H), 7.28 (m, 2H), 7.91 (bt, 1H), 8.37 (bd, 2H), 9.43 (very b, 1H),

Example 6.

N-cyano-N'-(2-phenoxyethyl)-N"-3-pyridylacetic

Following the procedure of example 1, but substituting N-(3-phenoxypropan)-N'-3-pyridylamine N-(2-phenoxyethyl)-N'-3-pyridylamino got the desired connection.

Melting point: 182o-184oC.

NMR (DMSO; -scale): 3.62 (m, 2H), 4.11 (t, 2H), 6.96 (m, 3H), 7.31 (m, 2H), 7.37 (dd, 1H), 7.60 (bt, 1H), 7.67 (m, 1H), 8.35 (m, 1H), 8.48 (m, 1H), 9.25 (bs, 1H).

Example 7.

N-cyano-N'(2-phenoxyethyl)-N"-4-pyridylacetic

Following the procedure of example 1, but substituting N-(3-phenoxypropan)-N"-3-the feast of the P>o-170oC.

Melting point: 167o-170oC.

NMR (DMSO; -scale): 3.67 (m, 2H), 4.13 (t, 2H), 6.95 (m, 3H), 7.24 (m, 2H), 7.30 (dd, 2H), 8.04 (bs, 1H), 8.38 (m, 2H), 9.55 (bs, 1H).

Example 8.

N-cyano-N'-(1-phenoxy-2-propyl)-N"-3-pyridylacetic

Following the procedure of example 1, but substituting N-(3-phenoxypropan)-N'-3-pyridylamine N-(1-phenoxy-2-propyl)-N'-3-pyridylamino got the desired connection.

Melting point: 130odepression -133oC.

NMR (DMSO; -scale): 1.23 (d, 3H), 3.98 (m, 2H), 4.29 (m, 1H), 6.97 (m, 3H), 7.30 (m, 2H), 7.34 (dd, 1H), 7.45 (bd,1H), 7.65 (m, 1H), 8.31 (m, 1H), 8.46 (m, 1H), 9.25 (bs, 1H).

Example 9.

N-cyano-N'-(2-phenylthiomethyl)-N"-4-pyridylacetic

Following the procedure of example 1, but substituting N-(3-phenoxypropan)-N'-3-pyridylamine N-(2-phenylthiomethyl)-N'-4-pyridylamino got the desired connection.

Melting point: 161o-163oC.

NMR (DMSO; -scale): 3.17 (m, 2H), 3.46 (m, 2H), 7.21 (m, 3H), 7.35 (m, 4H), 8.00 (bs, 1H), 8.39 (d, 2H), 9.56 (bs, 1H).

Example 10.

N-(3-p-chlorophenoxy-2-hydroxypropyl)-N'-cyano-N"-4-pyridylacetic

Following the procedure of example 2, but substituting N-phenylethylenediamine 3-p-chlorophenoxy-3-hydroxypropylamino got the desired connection.

That is), 4.5-10.5 (very b, 1H).

Example 11.

N-(2-p-chlorophenoxide)-N'-cyano-N"-3-pyridylacetic

N-(2-p-chlorophenoxide)-N'-3-pyridylamino (1,05 g) suspended in acetonitrile (10 ml) and added cyanamide (285 mg), N,N'-dicyclohexylcarbodiimide (1.40 g) and triethylamine (0.04 ml). The mixture was maintained under stirring at room temperature for weeks, then it was filtered, washed with acetonitrile and simple ether. A solid mixture of the crude product and N, N'-dicyclohexylcarbodimide was extracted with chloroform (15 ml) to obtain pure product, which was collected by filtration and washed with chloroform in a simple ether.

Melting point: 174o-176oC.

NMR (DMSO; -scale): 3.61 (bs, 2H), 4.10 (t, 2H), 7.00 (d, 2H), 7.35 (d, 2H), 7.37 (m, 2H), 7.37 (m, 1H), 7.59 (bs, 1H), 7.66 (m, 1H), 8.34 (dd, 1H), 8.47 (d, 1H), 9.25 (bs, 1H).

Example 12.

N-(2-p-chlorophenoxide)-N'-cyano-N"-4-pyridylacetic

Following the procedure of example II but replacing 3-peredelanaja N-(2-p-chlorophenoxide)-N'-4-pyridylamino got the desired connection.

Melting point: of 174.5o-177oC.

NMR (DMSO; -scale): 3.66 (bt, 2H), 4.13 (t, 2H), 6.99 (d, 2H), 7.22 (bd, 2H), 7.34 (d, 2H), 8.01 (bs, 1H). 8.38 (d, 2H), 9.57 (bs, 1H).

Example 13.

N-cyano-N'-(Ile (10 ml) and added cyanamide (400 mg), N,N'-dicyclohexylcarbodiimide (1,95 r) and triethylamine (0,08 ml). The mixture is left for 3 days at room temperature, then it was filtered, washed with acetonitrile and simple ether to obtain a solid mixture of the crude product and N,N'-dicyclohexylcarbodimide. A pure compound is obtained by extraction of the mixture of 0.5 N hydrochloric acid (16 ml), filtration and the resultant deposition rates additions to the filtrate 9N sodium hydroxide.

Melting point: 137,5o-138oC.

NMR (DMSO; -scale): 1.71 (m, 4H), 3.30 (q, 2H), 3.98 (t, 2H), 6.92 (m, 3H), 7.28 (m, 2H), 7.37 (dd, 1H), 7.48 bt, 1H), 7.67 (bd, 1H), 8.34 (dd, 1H), 8.47 (d, 1H), 9.10 (bs, 1H).

Example 14.

N-cyano-N'-(4-phenoxybutyl)-N"-4-pyridylacetic

Following the procedure of example 13, but substituting 3-peredelanaja N-(4-phenoxybutyl)-N'-4-pyridylamino got the desired connection.

Melting point: 131oC.

NMR (DMSO; -scale): 1.72 (m, 4H), 3.34 (m, 2H), 3.99 (t, 2H), 6.92 (m, 3H), 7.22 (bs, 2H), 7.27 (m, 2H), 7.90 (bt, 1H), 8.38 (bd, 2H), 9.42 (bs, 1H).

Example 15.

N-(5-bromo-3-pyridyl)-N'-cyano-N - (2-phenylthiomethyl)guanidine

S-methyl-N-(5-bromo-3-pyridyl)-N'-zionization (650 mg) and 2-phenylethylamine (740 mg) in pyridine (0.5 ml) was heated to 50oC for 5 hours. To the resulting clear solution was added p is as melting point: 168oC.

NMR (DMSO; -scale): 3.16 (t, 2H), 3.43 (bs, 2H), 7.20 (m, 1H), 7.35 (m, 4H), 7.77 (m, 1H), 7.96 (t, 1H), 8.47 (t, 2H), 9.34 (bs, 1H).

Example 16.

N-cyano-N'-(2-phenylthiomethyl)-N"-3-pyridylamine, S-oxide

N-cyano-N'-(2-phenylthiomethyl)-N"-3-pyridylamine (example 4) (595 mg) suspended in chloroform (40 ml) and portions over 15 minutes was added m-chloroperbenzoic acid (520 mg) at 0oC and stirring. The obtained transparent solution was boiled away in vacuum and the residue was mixed with simple ether (50 ml), filtered, and washed by a simple ether to obtain a crude product. Thin-layer chromatography in silicagel column using as eluent a mixture of methylene chloride and methanol at a ratio in a mixture of 90:10 achieved a net connection. Melting point: 167,5oC.

NMR: (DMSO; -scale): 3.00 (m, 1H), 3.24 (m, 1H), 3.45 (m, 1H), 3.58 (m, 1H), 7.39 (dd, 1H), 7.47-7.75 (m, 7H), 8.36 (dd, 1H), 8.47 (d, 1H), 9.32 (bs, 1H).

Example 17.

N-cyano-N'-(2-phenylthiomethyl)-N"-4-pyridylamine, S-oxide.

Following the procedure of example 16, but substituting 3-peredelanaja N-cyano-N'-(2-phenylthiomethyl)-N"-pyridylamine (example 9), was obtained the desired compound.

Melting point: KZT 166.5o-167oC.

NMR (DMSO; -scale): 3.05 (m, 1H), 3But-N'(5-phenoxyphenyl)-N"-4-pyridylacetic

Following the procedure of example 14, but substituting N-(4-phenoxybutyl)- N'-4-pyridylamine N-(5-phenoxyphenyl)-N'-4-pyridylamino got the desired connection.

Melting point: 188o-189oC.

NMR (DMSO; -scale): 1.46 (m, 2H), 1.59 (m, 2H), 1,74 (m, 2H), 3.31 (m, 2H), 3.96 (t, 2H), 6.91 (m, 3H), 7.21 (bd, 2H), 7.27 (t, 2H), 7.87 (bs, 1H), 8.38 (d, 2H), 9.42 (bs, 1H).

Example 19.

N-cyano-N'-(3-phenoxypropan)-N"-4-pyridylamine, S-oxide

N-cyano-N'(3-phenoxypropan)-N"-4-pyridylamine (example 5) (1.20 g) suspended in methylene chloride (20 ml) and the portions within 2 hours was added m-chloroperbenzoic acid (990 mg) at 0oC and stirred. The resulting solution was boiled away in vacuum and the residue was mixed with two portions of simple ether (20 ml), which was removed by decantation. Added methylene chloride (20 ml) and portions over one hour at 0oC and stirring was added an additional amount of m-chloroperbenzoic acid (990 mg). The mixture is boiled away in vacuum and the residue finally was twice extracted with simple ether (20 ml) to obtain a crude product. Thin-layer chromatography on silicagel column using as eluent a mixture of methylene chloride, methanol and 25% aqueous ammonia at a ratio is SUP>oC.

NMR (DMSO; -scale): 2.00 (m, 2H), 3.50 (q, 2H), 4.03 (t, 2H), 6.92 (t, 1H), 6.93 (d, 2H), 7.27 (m, 2H), 7.45 (bd, 2H), 8.08 (t, 1H), 8.28 (d, 2H), 9.98 (bs, 1H).

Example 20.

N-(5-bromo-3-pyridyl)-N'-cyano-N"-(3-phenoxypropan)guanidine

Following the procedure of example 15, but substituting 2-phenylethylamine 3-phenoxypropylamine got the desired connection.

Melting point: 129o-130oC.

NMR (DMSO; -scale): 1.98 (m, 2H), 3.42 (q, 2H), 4.01 (t, 2H), 6.92 (m, 3H), 7.28 (m, 2H), 7.68 (bt, 1H), 7.95 (t, 1H), 8.44 (d, 1H), 8.47 (d, 1H), 9.23 (bs, 1H).

Example 21.

N-cyano-N'-(6-phenoxyethyl)-N"-4-pyridylacetic

Following the procedure of example 14, but substituting N-(4-phenoxybutyl)-N'-4-pyridylamine N-(6-phenoxyethyl)-N'- 4-pyridylamino got the desired connection.

Example 22.

Tablet

Production of 10,000 tablets:

I. N-cyano-N'(5-phenoxyphenyl)-N"-4-pyridylamine (active connection) - 10000 kg

Nitrocresols - 0.300 kg

II. The low viscosity hypromellose - 0,200 kg

Sorbitanoleat - 0,010 kg

Purified water, a sufficient quantity of

III. Nitrocresols - 0,200 kg

Colloidal anhydrous silica - 0,050 kg

Magnesium stearate - 0,050 kg

I one>Wet granules were dried in a fluidized bed dryer at a temperature of inlet air 60oC up until the dried granulate had a water activity of 0.3-0.4 (= in equilibrium with air with a relative humidity of 30-40%).

The dried granules pass through a sieve with openings of 850 μm.

The sifted granules were finally mixed with III in a conical mixer. The treated granules were pressed into tablets weighing 1071 mg with sufficient hardness.

1. N-cyano-N'-pyridylamine General formula I

< / BR>
and their tautomeric forms, thus joining the pyridine ring is presented in a 3 - or 4-position,

where R', R" are identical or different and denote hydrogen or halogen;

alkylene means a straight or branched C1- C8-alkylene, which may be substituted by a hydroxy-group;

X is oxygen, -S(O)n-, where n means an integer of 0 or 1, or NH group;

R means hydrogen or halogen; or their N-oxides; or their pharmaceutically acceptable non-toxic salt.

2. Connection on p. 1, characterized in that the attachment to the pyridine ring represented in the 4-position.

3. Connection on p. 1, characterized in that h is m what X means oxygen.

5. Salt p. 1, characterized in that it is chosen from the group consisting of the salts formed with hydrochloric acid, Hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, arylsulfonate, citric acid, tartaric acid and maleic acid.

6. Connection on p. 1, characterized in that it is chosen from the group consisting of

N-cyano-N'-(3-phenoxypropan)-N"-4-pyridylamine,

N-cyano-N'-(4-phenoxybutyl)-N"-4-pyridylamine,

N-cyano-N'-(5-phenoxyphenyl)-N"-4-pyridylamine

and their salts and N-oxides, which are defined in paragraph 1.

7. The pharmaceutical composition inhibiting the proliferation of tumor cells, characterized in that as the active component contains an effective amount of a compound according to any one of PD.1 to 6 and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition according to p. 7, characterized in that it contains other necessary auxiliary agents.

9. A method of treating patients by inhibiting the proliferation of tumor cells, characterized in that the active ingredient is administered one or more compounds according to any one of paragraphs.1 - 6 in a daily dose of 7 m is repitions active components.

11. The method of obtaining the compounds of formula I on p. 1, characterized in that pyridylcarbonyl formula II

< / BR>
in which the substituents are as defined above, is subjected to reaction with an equivalent or excess Zinaida at room temperature or close to room temperature.

12. The method according to p. 11, characterized in that it is carried out in the presence of an inert solvent.

13. The method of obtaining compounds of formula I on p. 1, wherein the thiourea of formula III

< / BR>
in which the substituents are as defined above, is subjected to reaction with one or more equivalents of N, N'-dicyclohexylcarbodiimide (into) and cyanamide in an inert solvent, for example acetonitrile, at room temperature or above room temperature, which leads to the formation of compounds of formula (1) and N,N'-dicyclohexylcarbodimide (DCTV).

14. The method of obtaining compounds of formula I on p. 1, characterized in that the compound of formula 1V

< / BR>
in which the substituents R1and R" are as defined above, and where Y is halogen, preferably chlorine, or C1- C4alkylthiomethyl, communicates with the appropriate treatment of compounds of formula I on p. 1, characterized in that the compound of formula V

< / BR>
in which the substituents are as defined above, interacts with the equivalent or slight excess of the required amine, where the symbols have the same meanings as in formula I, in the presence of one equivalent or slightly more into, in an inert solvent, for example dimethylformamide, at 0oC or at room temperature, which leads to the formation of I and DCTV.

16. Connection on p. 1 with antitumor activity.

17. Connection on p. 1 with inhibiting the proliferation of tumor cells activity.

 

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