Dihydropyridine derivatives or their pharmaceutically acceptable salts and pharmaceutical compositions on their basis

 

(57) Abstract:

Dihydropyridine derivatives of the formula /1/, where Het is a group or a designated direct bond, -CH2-, -CH2-CH2or, when Het is group b , the symbol A can also be marked by the group-CH=CH-; R is a hydrogen atom or the halogen, alkyl (C1-C3or alkoxygroup C1-C3; one of R3and R4marked alkyl, C1-C3possibly omega-substituted alkoxygroup C1-C3and the other regardless of the first - alkyl, C1-C3possibly replaced by alkoxygroup C1-C3or a group of /g/; R5hydrogen atom or alkyl (C1-C6possibly substituted by a group-N/RcRd; one of R1and R2refers to a group - OR', where R' is alkyl (C1-C6possibly replaced by alkoxygroup C1-C3or cyano, and the other independently of the first means a/ alkyl (C1-C3b/ group - OR', c/ group /psi/ or d/ group-ORIVwhere RIVhydrogen atom or a Deputy chosen from /I/, /II/, /III/ IV/, can be used as agents that enhance antitumor activity. 4 C. and 4 h.p. f-crystals, 1 PL.

The invention otoya and containing pharmaceutical compositions.

The main purpose of the invention is to provide new compounds of the formula I

< / BR>
where Het group of the formula

;

A denotes a direct bond or a group-CH2-;

R is a hydrogen atom;

one of the symbols R3and R4C1-C3-alkyl, and the other independently of the first means C1-C3-alkyl, unsubstituted or omega-substituted C1-C3-alkoxygroup, -amino(C1-C3)alkoxy group or phthalimido(C1-C3)-alkoxy group;

R5hydrogen atom, a C1-C3-alkyl or w-morpholine-(C1-C3)-alkyl;

one of R1and R2represents C1-C4-alkoxy, and the other independently represents C1-C4-alkoxy, C1-C3-alkyl or 2-cyanoethoxy;

and their pharmaceutically acceptable salts, provided that:

A) in the case when each of the symbols R3and R4denotes unsubstituted C1-C3-alkyl; one of R1and R2represents C1-C4-alkoxy and the other represents C1-C4-alkoxy or 2-cyano, ethoxy, then R5does not mean a hydrogen atom;

In the case where the communication or-CH2group, Het-1H-imidazol-1-yl or pyridin-3-yl, one of R is Teal, methoxymethyl or aminoethoxymethyl or ethyl and the other is methyl, ethyl, methoxymethyl or aminoethoxymethyl, and R is a hydrogen atom, then R5does not denote a hydrogen atom or methyl;

(C) when And communication, Het represents 3-(1H - imidazol-1-yl), R is a hydrogen atom, R1ethoxypropan, R2a methoxy group, R3methyl, R4is (2-trimethicone)-methyl, then R5does not mean a hydrogen atom.

The framework of the invention are also covered all the possible isomers and stereoisomers of the compounds of formula I and their mixtures. In addition, a part of the invention covered pharmaceutically acceptable biological precursors (also known as predicate) compounds of the formula I, i.e. compounds of formula non-formula I, above, but which nevertheless when introduced into the human body are subjected to conversion directly or indirectly as a result of human activity in the compounds of formula I, and their metabolites.

Pharmaceutically acceptable salts of the compounds of formula I are in particular acid adducts of mineral acids such as nitric, hydrochloric, Hydrobromic, sulfuric, perarnau and phosphoric acids, or org, what imoney, benzoic, cinnamic, almond, fumaric acid, methanesulfonate and salicylic acid.

The framework of the invention are also salts of the compounds of formula I with pharmaceutically acceptable bases, which are either inorganic bases, for example hydrates, oxides of alkali metals, particularly sodium and potassium, or alkaline earth metals, particularly calcium and magnesium, or organic bases such as alkylamines followed, it is preferably triethylamine, or basic amino acids occurring in nature, preferably arginine, as well as internal salts, i.e., zwitterionic.

Alkyl groups can be branched or straight chains.

Preferred alkyl groups are C1-C3are methyl, ethyl and n-through. The preferred alkyl group is C1-C6represents an alkyl group, a C1-C4in particular methyl, ethyl, n-sawn, ISO-propyl or isobutylene. Preferred alkoxy groups C1-C3represent methoxy and ethoxypropan, in particular a methoxy group.

Preferred alkalinous group C2-C5is is Yes, the substituent R is not a hydrogen atom, the preferred option it must be in the ortho-position to the carbon atom of the phenyl ring, which has a 1,4-dihydropyridine Deputy. A typical example of group values RIVcan serve as a group

.

Typical examples of the group RIVcan serve as the radicals of the following formulae

< / BR>
< / BR>
< / BR>
< / BR>
Typical examples of the group RIVcan serve as the radicals of the following formula:

< / BR>
< / BR>
< / BR>
The preferred value of R5is C1-C3-alkyl.

Specific examples of preferred compounds of formula I in accordance with the invention are diethyl ether 1,4-dihydro-1-(N-morpholinoethyl)-2,6-dimethyl-4-[3-(1H-imidazol-1-yl)-phenyl] -3,5-pyridinedicarboxylic acid; diethyl ester of 1,4-dihydro-1-(N-morpholinoethyl)-2,6 - dimethyl-4-[4-(1H-imidazol-1-yl)-phenyl]-3,5-pyridinedicarboxylic acid; diisobutenyl ether 1,4-dihydro-1,2,6-trimethyl-4-[3-(pyridin-3-yl)-phenyl]-3,5-pyridinedicarboxylic acid; diethyl ester of 1,4-dihydro-1-(N-morpholinoethyl)-2,6-dimethyl-4-[3-(pyridin-3-yl)-phenyl]-3,5-pyridinedicarboxylic acids and their pharmaceutically acceptable salts.

An additional aim of the invention are: what rmulas (see International patent application W0 90/06923) and in this description as a specific chemical of interest not illustrated: diethyl ether 1,4-dihydro-2,6-diethyl-4-[4-(1H-imidazol-1-yl)-phenyl]-3,5-pyridinedicarboxylic acid; dimethyl ester of 1,4-dihydro-2,6-dimethyl-4-[4-(1H-imidazol-1-yl)-phenyl]-3,5-pyridinedicarboxylic acid and utilizability ether 1,4-dihydro-2,6-dimethyl-4-[4-(1H-imidazol-1-yl)-phenyl] -3,5-pyridinedimethanol acid.

New connections are proposed in accordance with the invention, namely compounds of formula I, as defined above, and their salts, can be obtained by the method in the implementation which provides

a) reaction of compounds of formula

< / BR>
where the values of R, A, Het, R2and R3defined above, with a compound of the formula

< / BR>
where the values of R1, R4and R5defined above, or

b) reaction of compounds of formula II with the compound of the formula

< / BR>
where the symbols R1and R4defined above, in the presence of ammonium salt or hydroxide, resulting in the formation of the proposed connection, where the values of R, A, Het, R1R4defined above, and R5hydrogen atom, or

C) reaction of the compound of formula V

< / BR>
the action of the compounds of formula V with the compound of the formula IV, where R2group-OR', as defined above, in the presence of a salt or hydroxide of ammonia, resulting in a proposed connection, where the values of R, A, Het, R3R5defined above, and each of R1and R2indicated group-OR', where R' is defined above, with values of R1equal values of R2and the values of R3equal values of R4or

e) alkylation of the proposed connection, where R5hydrogen atom, to obtain the corresponding proposed connection, in which R5alkyl-C1C6, unsubstituted or substituted in accordance with defined above, or

f) conversion of the proposed connection, in which the values of Raand Rbdefined above, and these radicals together with the nitrogen atom to which they are bound, form phthalimido group, in another proposed connection, in which Raand Rbrepresent hydrogen atoms, and, if desired, conversion of the proposed connection to another of the proposed connection and/or, if desired, conversion of the proposed connection at its pharmaceutically acceptable salt and/or, if desired, the conversion of a salt into a free compound, and/or if Gelateria, covered by the description of the application for international patent W0 90/06923, and their salts can be obtained by carrying out the method, according to which is provided by

a) reaction of the compound of formula IIa, IIb, IIc or IId

< / BR>
where Het 1H-imidazol-1-yl, with the compound of the formula accordingly IIIa, IIIb, IIIc or IIId

< / BR>
or b) reaction of the compound of formula IIA, IIb, IIc or IId, where Het - 1H-imidazol-1-yl, with the compound of formulas, respectively, IVa, IVb, IVc or IVd

< / BR>
in the presence of a salt or hydroxide of ammonium or

C) reaction of compounds of formula VA

< / BR>
where Het 1H-imidazol-1-yl, taken together with the compounds of formulas IIIa and IVa, IIIb and IVb, IIIc and IVc or IIId and IVd or

d) reaction of compounds of formula VA, where Het 1H - imidazol-1-yl, with the compound of formula IV, IVb, IVc or IVd in the presence of a salt or hydroxide of ammonia and, if desired, conversion of the compound, thus obtained, its pharmaceutically acceptable salt or, if desired, the conversion of a salt into a free compound, and/or, if desired, separating a mixture of isomers of the proposed connection on the individual isomers.

Reactions, which are described in sections a), b), c) and d) can be carried out in accordance with methods which are well known in organic chemistry, in astrostart and E. I. Meyers. Chem. Rev. 82, 223, 1982). Thus, in particular, reactions, which are described in sections a), b), c) and d) can be performed basically in accordance with the following procedure, which includes, for example, exposure of the reagents at a temperature of about 50 150oC in an inert organic solvent, such as methanol, ethanol, isopropanol, dioxane, tetrahydrofuran, dimethylformamide, acetonitrile, dimethylsulfoxide, pyridine and mixtures thereof. In the implementation of the methods (b) and (d) the hydroxide ammonium can be used, for example, in the form of a concentrated aqueous solution of ammonia, whereas as ammonium salt, in particular, to use ammonium acetate.

The alkylation process of the proposed compounds in which R5hydrogen atom, in accordance with option e) of the method can be carried out by reaction with an appropriate possibly substituted by alkylhalogenide C1-C6preferably with iodide, in the presence of dry alkali metal hydroxide, preferably of potassium hydroxide, at room temperature, in an atmosphere of inert gas, for example nitrogen, in an inert solvent, such as dimethyl sulfoxide.

The conversion offer connections in druid methods, which are known in the art as methods of removal phthalimide group. In a preferred variant spend the reaction phthalimide derived from metaluminous solution in water or an acceptable dialkylated simple ether such as diisopropyl ether, or with an aqueous solution of hydrazine, preferably at room temperature. Additional options for the possible conversion of the proposed connection to another connection may include, for example, the following: conversion of the proposed connection, the molecule of which contains esterified carboxyl group, in the proposed compound the molecule of which contains a group-CONR"R", where the symbols R" and R"', defined above, in accordance with known methods. So, for example, conversion of esterified carboxy group into the corresponding amide can be performed by direct reaction with ammonia or the appropriate amine in an environment acceptable solvent, for example diethyl ether or benzene, or in an environment of excess amine as solvent, at a temperature which is in the range from room temperature to the boiling point.

Intermediate reactive derivatives may be an act which, predpochtitelno the acid chlorides, mixed anhydrides, for example etoxycarbonyl - or tert.- BUTYLCARBAMATE, or reactive intermediates obtained at the place of use of the reaction of the acid with dicyclohexylcarbodiimide or carbodiimides. Conducting the reaction of the reactive intermediates obtained in accordance with conventional methods, such as those typically used in peptide synthesis, with ammonia or the appropriate amine in an environment acceptable solvent or with an excess of the amine at a temperature in the preferred range from about -10 to 50oC.

Possible obtain the salt of the proposed connection, as well as the conversion of a salt into a free compound and the separation of a mixture of isomers into the individual isomers can be performed by conventional methods. So, for example, separation of a mixture of geometric isomers, such as CIS - and TRANS-isomers, may be carried out by fractional crystallization from a suitable solvent or chromatographic processing either through column chromatography, or liquid chromatography under high pressure.

The compounds of formula II can be obtained by reaction of the compound of formula V with the compound tooversee obviously, values of R1and, respectively, R4to connect IV must be such that desirable for R2and, respectively, R3the compounds of formula II. The process is preferably carried out by reaction of compounds IV and V in the presence of a suitable base, such as diethylamine or pyridine, in an environment suitable solvent, such as ethanol or benzene, at a temperature in the range from about room temperature up to the boiling point.

Compounds of formulas III and IV are known compounds or those which can be obtained according to conventional procedures from known compounds. The compounds of formula V are known compounds or those which can be obtained according to known methods from known compounds, for example, the recovery of the corresponding complex alilovic esters of the formula

,

where the values of R, A and Het are defined above, and RVIalkyl, C1-C6. The reduction can be carried out in the presence of an appropriate reducing agent, such as diisobutylaluminium, in an environment suitable solvent, for example diethyl ether or tetrahydrofuran, at a temperature in the range of approximately eat a corresponding alcohol of the formula

< / BR>
where the values of R, A and Het are defined above. The oxidation process can be carried out in accordance with well known procedures for the conversion of the primary alcohol to the corresponding aldehyde (see, for example, J. March. Advanced Organic Chemistry. 1985. Publishing House "By G. Puccini. Willy publ.", C. 1057-1060).

In addition, the compounds of formula V, in which a direct link can be obtained by oxidation of compounds of the formula

< / BR>
where the symbols R and Het are defined above. The oxidation process can be carried out in accordance with known procedure, for example, using chromium trioxide in acetic anhydride. Compounds of formulas VI, VII, VIII are well known compounds or those that can be obtained according to known procedures (see, for example, I. Med. Chem. 1981, 24, 1475; I. Med. Chem, 1981, 24, 1149; European patent application N 173172 A2). Thus, in particular, the compounds of formulas VI and VII, in which Het - imidazolidinyl radical can be obtained, for example, the reaction of imidazole or its salts such as sodium salt, respectively, with the compound of the formula IX or X

< / BR>
where the values of R, A and RVIdefined above, and X is acceptable tsepliaeva group, such as a suitable halogen atom, preferably chlorine or bromine, totilo the Russian literature. Compounds IX and X are known compounds.

The new compounds of formula I and new chemical facilities covered by the proposal for the international patent WO 90/06923 and also constitute an additional objective of the invention is able to enhance the action of antitumor agents against tumor cells of various types, including those resistant to many drugs cells, resulting in their use in chemotherapy of cancer in mammals, including humans. The ability to enhance antitumor activity was also detected in imidazolinone and piridinovykh derivatives (see Application for international patent WO 90/06923). These new compounds in accordance with the invention and previously known (see Application for international patent WO 90/06923) in this description is defined as "proposed connection", all of which together correspond to the formula IA as defined in this specification.

Due to its ability to potentiate the antitumor effects of the proposed compounds may be used in accordance with the method of the combined antitumor treatment by means of by using combinations of anticancer agents in relatively low the e clinical chemotherapeutic treatment. Thus, an additional aim of the invention is the use of compounds of formula

< / BR>
where Het group or

And a direct link, -CH2-, -CH2-CH2or, in the case where Het group And may also indicate the group-CH=CH-;

R is a hydrogen atom or the halogen, alkyl (C1C3or alkoxyalkyl C1-C3;

one of the symbols R3and R4denotes alkyl, C1-C3, unsubstituted or omega-substituted alkoxygroup C1-C3and the other independently of the first means:

(a) alkyl, C1-C3, unsubstituted or omega-substituted alkoxygroup C1-C3or

b) -(CH2)m-O-(CH2)n-NRaRbwhere each of m and n, which may be identical or different, denotes a positive integer of 1 to 3, and each of Raand Rbwhich may be identical or different, denotes a hydrogen atom or alkyl (C1-C3or Raand Rbtogether with the nitrogen atom to which they are bound, form phthalimido group;

R5hydrogen atom or alkyl (C1-C6, unsubstituted or substituted by a group-N(RcRd), in which each of Rcand Rd, with which they are associated, Rcand Rdform morpholino or piperidino group;

one of R1and R2indicated group-OR', where R' is alkyl-C1-C6or unsubstituted, or omega-substituted by cyano or lexigraphy C1-C3and the other independently of the first means:

(C) alkyl (C1-C3; or

d) a group-OR', as defined above, or

(e) the group-NR"R"', where each of R" and R"', which may be identical or different, denotes a hydrogen atom or alkyl (C1-C3; or

f) a group-ORIVwhere RIVhydrogen atom or a Deputy chosen from the class that includes:

(I) -(CH2)m'-CH=CH-Rh, where m' is a positive integer of 1 to 3, and Rh phenyl group, either unsubstituted or substituted with one to three substituents selected from Akilov C1-C3alkoxyalkyl C1-C3and halogen atoms;

(II) -O-NRV-(CH2)n'-CHRV- Ph, where the values of combinations of Ph defined above; O alkalinity radical C2-C5; n is 0, 1 or 2; and each of RVindependently denotes a hydrogen atom, alkyl-C1-C3or Ph, where the values of combinations of Ph defined above;

< / BR>
where p is 2 or 3, and the values of combinations of Ph defined above,

or its pharmaceutically acceptable salts in the preparation of pharmaceutical compositions intended for use to enhance the antitumor agent.

Specific examples of preferred compounds of formula IA include the following products: diethyl ether 1,4-dihydro-2,6-dimethyl-4-[4-(1H-imidazol-1-yl)-phenyl]-3,5 - pyridinedicarboxylic acid; diethyl ester of 1,4-dihydro-1,2,6-trimethyl-4-[4-(1H-imidazol-1-yl)-phenyl] -3,5-pyridinedicarboxylic acid; diethyl ester of 1,4-dihydro-1-(N-morpholinoethyl)-2,6-dimethyl-4-[3-(1H-imidazol-1 - yl)-phenyl]-3,5-pyridinedicarboxylic acid; diethyl ester of 1,4-dihydro-1-(N-morpholinoethyl)-2,6-dimethyl-4-[4-(1H-imidazol-1-yl)-phenyl] -3,5-pyridinedicarboxylic acid; diethyl ester of 1,4-dihydro-1,2,6-trimethyl-4-[3-(pyridin-3-yl)-phenyl] -3,5-pyridinedicarboxylic acid; diisobutenyl ether 1,4-dihydro-1,2,6-trimethyl-4-[3-(pyridin-3-yl)-phenyl] 3,5-pyridinedicarboxylic acid; diethyl ester of 1,4-dihydro-1,2,6-trimethyl-4-[4-(pyridin-3-yl)-phenyl] -3,5-pyridinedicarboxylic acid; diethyl ester of 1,4-dihydro-1-(N-morpholinoethyl)-2,6-dimethyl-4-[3-(pyridin-3-yl)-phenyl] -3,5-pyridinedicarboxylic acid; diethyl ether 1,4-dihydro-2,6-diethyl-4-[4-(1H-and is enyl]-3,5-pyridinedicarboxylic acid; utilizability ether 1,4-dihydro-2,6-dimethyl-4-[4-(1H-imidazol-1-yl)-phenyl] -3,5-pyridinedicarboxylic acid; diethyl ester of 1,4-dihydro-1,2,6-trimethyl-4-[3-(1H-imidazol-1-yl)-phenyl]-3,5-pyridinedicarboxylic acid; 3-ethyl-5-methyl ether ()-1,4-dihydro-2-[(2-phthalimidomethyl)-methyl]-6-methyl-4-[3-(1H-imidazol-1-yl)-phenyl]-3,5-pyridinedicarboxylic acid; 3-ethyl-5-methyl ether ()-1,4-dihydro-2-(methoxy)-methyl-6-methyl-4-[3-(1H-imidazol-1-yl)-phenyl] -3,5-pyridinedicarboxylic acid; methyl ester ()-1,4-dihydro-5-acetyl-2,6-dimethyl-4-[3-(1H-imidazol-1-yl)-phenyl] -3-pyridylcarbinol acid; diethyl ester of 1,4-dihydro-2,6-dimethyl-4-[3-(1H-imidazol-1-yl)-phenyl] -3,5-pyridinedicarboxylic acid with a melting point 202 204oC; diethyl ether 1,4-dihydro-2,6-dimethyl-4-[3-(1H-imidazol-1-ylmethyl)-phenyl] -3,5 - pyridinedicarboxylic acid with a melting point 196 -199oC; dimethyl 1,4-dihydro-2,6-dimethyl-4-[3-(1H - imidazol-1-yl)-phenyl]-3,5-pyridinedicarboxylic acid with a melting point of 212 217oC; diethyl ether 1,4-dihydro-2,6-dimethyl-4-[2-(1H-imidazol-1-yl)-phenyl] -3,5 - pyridinedicarboxylic acid with a melting point 208 210oC; diethyl ether 1,4-dihydro-2,6-diethyl-4-[3-(1H-imidazol-1-yl)-phenyl]-3,5-pyridinedicarboxylic acid with temperature plavini the melting point 208 210oC; diethyl ether, 4-dihydro-2,6-diethyl-4-[3-(1H-imidazol-1-yl)-phenyl] -3,5-pyridinedicarboxylic acid with a melting point 171 172oC; utilmately ether 1,4-dihydro-2,6-dimethyl-4-[3-(1H-imidazol-1-yl)-phenyl]-3,5-pyridinedicarboxylic acid with a melting point 197 200oC; 2-cyanoethylation ether 1,4-dihydro-2,6-dimethyl-4-[3-1H-imidazol-1-yl)-phenyl] -3,5-pyridinedicarboxylic acid.

The data of elementary analysis for C23H24N4O4.

Calculated, 65,70, N Of 5.75, N 13,32.

Found, Compared With 65.38, N 5,73, N 13,15.

NMR spectrogram [DMCO-d6, , PM/1000000 hours of 1.10 (3H, T. CH2CH3); 2,28 (6H, c.C-CH3); of 2.58 (2H, T. COOCH2CH2CN); 4,01 (2H, K. CH2CH3); of 4.05 (2H, T. COOCH2CH2CN); is 4.93 (1H, c. CH 4-th position of dihydropyridines); 7,05 of 7.6 (6H, m, phenyl + CH=CH-imidazolyl protons); of 8.09 (1H, D. D. N-CH-N-); 8,88 (1H, c. NH).

Ethyl-2-[methyl-(phenylmethyl)-amino] -ethyl ester 1,4-dihydro-2,6-dimethyl-4-[3-(1H-imidazol-1-yl)-phenyl]-3,5-pyridinedicarboxylic acid.

The data of elementary analysis for C30H34N4O4.

Calculated C 70,02, H 6,66, N 10,89.

Found, C 69,17, H 6,72, N Of 10.72.

Thin layer chromatography: eluent chloroform/methanol in the ratio 95/ is. N(CH3)(CH2Ph)] is 2.37 (6H, s 2C-CH3); 2,69 [2H, T. CH2N(CH3)(CH2Ph)] 3,50 [2H, s N(CH3)(CH2Ph)] of 4.11 (2H, K. CO2CH2CH3); is 4.21 (2H, T. CO2CH2CH2-); 5,11 (1H, s, CH at 4 position of dihydropyridines); of 5.89 (1H, s, NH); 7,10 7,40 (11H, m, CH 2-, 4-, 5 - and 6-positions of the phenyl ring, CH 4 - and 5-positions of the imidazole and phenyl hydrogen atoms of the ether group); for 7.78 (1H, D. D. CH 2 position of the imidazole).

Mass spectrum: m/z 514 M+.

Monohydrate ethyl ester 1,4-dihydro-2,6-dimethyl-4-[3-(1H-imidazol-1-yl)-phenyl]-3,5-pyridinedicarboxylic acid.

The melting point of 117 121oC (decomposition).

Diethyl ether 1,4-dihydro-2,6-dimethyl-4-[3-(3-pyridyl)-phenyl] -3,5-pyridinedicarboxylic acid with a melting point of 183 186oC; Diisobutyl ether 1,4-dihydro-2,6-dimethyl-4-[3-(3-pyridyl)-phenyl]-3,5-pyridineboronic acid with a melting point 97 98oC; ethyl-2-[methyl-(phenylmethyl)-amino] -ethyl ester 1,4-dihydro-2,6-dimethyl-4-[3-(3-pyridyl)-phenyl]-3,5-pyridineboronic acid in the form of a butter-like product.

The data of elementary analysis for C32H35N3O4.

Calculated C 73,12, H Of 6.71, N 7,99.

Found, C 71,90, H 6,85, N 7,75.3
, s, h/1000000 hours of 1.21 (3H, T. CH2CH3); 2,16 [3H, s N(CH3)(CH2Ph)] of 2.35 (6H, s C-CH3); 2,64 [2H, T. CH2N(CH3)(CH2Ph)] 3,45 [2H, s N(CH3)(CH2Ph)] of 4.12 (2H, K. of SOON2CH3) and their pharmaceutical acceptable salts.

Another aim of the invention is a method of combined treatment of cancer in mammals, including humans, in need of such treatment, and in the implementation of this method provided by the introduction into the body:

1) the compounds of formula IA or pharmaceutically acceptable salts and

2) the antitumor agent in quantities and within a close time interval that is sufficient to effect a therapeutically useful interaction.

The aim of the invention is the creation of products that includes the compound of formula IA or pharmaceutically acceptable salt and antitumor agent as a combined preparation for simultaneous, separate or sequential use in anticancer therapy.

The term "anticancer agent" is used to denote both individual anticancer drugs, and "cocktail", i.e. a mixture of such drugs, in soo is predlagaemym connection or alternatively can be introduced into the body in accordance with the method of combined treatment, represent doxorubicin, daunomycin, epirubicin, idarubitsin, etoposide, fluorouracil, mephalan, cyclophosphamide, bleomycin, vinblastine and mitomycin or a mixture of two or more such means.

Thus, the proposed connection can be used for the treatment of cancer with the aim of improving this treatment. You can enter them in the body of a patient suffering from cancer, which is treatable with anti-tumor agent, such as anthracyclinebased, in particular doxorubicin, daunomycin, epirubicin or idarubitsina, as indicated above, together with this anticancer agent. The proposed connection and antitumor agent, in particular anthracyclinebased, you can enter with the aim of improving the condition of a patient suffering from leukemia, particularly myeloid leukemia, lymphoma, sarcoma, neuroblastoma, Wilm tumor or malignant tumor in the bladder, breast, lung or thyroid.

The enhancement of the antitumor action of the proposed connection is confirmed, for example, the fact that they are able to weaken resistance to the effects of doxorubicin, as illustrated below.

oC in humidified atmosphere with 5% carbon dioxide. As the nutrient medium used material F12 ham, to which was added 10 fetal calf serum, 1 vitamins (vitaminosis solution instead of 100 X) and 1 glutamine (200 mm). Cells of both strains were subjected to cycle twice a week.

Drugs.

Doxorubicin company "Farmitalia Carlo Erba was dissolved in sterile water and spectrophotometrically by determining the concentration of the solutions. The solutions proposed compounds in ethanol was prepared immediately before use. The maximum ethanol final concentration to use 1 had no appreciable action on the proliferation of cells.

Cytotoxic evaluation.

To determine the inhibitory colony effectiveness of individual drugs and combinations thereof, used the method of plate seeding isolated cells. The concentration of exponentially growing cells Lovo and Lovo/DX drove up to 300 cells/ml, after which produced sowing in 36-mm Petri dishes (2 ml/Cup). After 48 h incubation amberliedenny both compounds. The duration of treatment drugs accounted for 4 h, after which cells were washed with physiological saline, was added to fresh medium, and then the cups were incubated for 7 days. The number of surviving cells was determined as the percentage in the treated samples relative to untreated samples. For a combination of the proposed connections with doxorubicin number of surviving colonies was calculated in comparison with the number of surviving colonies in samples that were treated only offer connections.

Results.

The proposed compounds were tested on cells Lovo and Lovo/DX in accordance with the above (see "Materials and methods").

The table shows the typical effect of the proposed connection on the cytotoxicity of doxorubicin in cells Lovo and Lovo/DX in comparison with the tool Nifedipine (UK, 1173862), which has a very similar chemical structure. In used to the maximum concentration of the compound, when used individually, had no cytotoxic effect neither on Lovo cells or on cells Lovo/DX. In the case of trials in combination with doxorubicin all proposed is santoshi from 49.1 (only one doxorubicin) to less than 3.2 (proposed connection + doxorubicin). In respect of Lovo cells cytotoxic effect individually doxorubicin and its combination with the test compounds is the same (IR50about 100 ng/ml).

Notes to table:

FCE 24265 diethyl ether 1,4-dihydro-2,6-dimethyl-4- [3-(1H-imidazol-1-yl)-phenyl]-3,5-pyridinedicarboxylic acid.

FCE 26341 3-ethyl-5-methyl ether ()-1,4-dihydro-2-methoxymethyl-6-methyl-4-[3-(1H-imidazol-1-yl)-phenyl]-3,5-pyridinedicarboxylic acid.

FCE 26262 diethyl ether 1,4-dihydro-1,2,6-trimethyl - 4-[3-(1H-imidazol-1-yl)-phenyl]-3,5-pyridinedicarboxylic acid.

FCE 26224 diisobutenyl ether 1,4-dihydro-2,6-dimethyl-4-[3-(pyridin-3-yl)-phenyl]-3,5-pyridinedicarboxylic acid.

FCE 27335 diethyl ether 1,4-dihydro-2,6-dimethyl-4-[4-(1H-imidazol-1-yl)-phenyl]-3,5-pyridinedicarboxylic acid.

FCE 26332 3-ethyl-5-methyl ether 1,4-dihydro-2-[(2-phthalimidomethyl)-methyl]-6-methyl-4-[3-(1H-imidazol-1-yl/-phenyl]-3,5-pyridinedicarboxylic acid.

The toxicity of the proposed connection is negligibly low, making it safe to use in therapeutic treatment. The mice that were not given food for 9 h, oral drove only portions of increasing doses proposed soedinenii (LD50to connect FCE 24265, which was determined on the seventh day after injection into the body, exceed 800 mg/kg. Given the low toxicity of the proposed connection, safe to use for medical purposes.

The mode of therapeutic treatment of various clinical syndromes should be adapted to the type of pathology that is observed, and, as usual, to the path of insertion into the body to form introduced into the body connection, as well as the age, weight and condition of the individual patient. A proposed dose of the compounds, such as diethyl ether, 1,4-dihydro-2,6-dimethyl-4-[3-(1H-imidazol-1-yl)-phenyl]-3,5-pyridinedicarboxylic acid and diethyl ether 1,4-dihydro-2,6-dimethyl-4-[3-(3-pyridyl)-phenyl] -3,5-pyridinedicarboxylic acid, when they are orally administered in the body of adults is in the range of about 5 to 500 mg per serving 1 to 3 times a day. It is obvious that the dosage can be selected for optimal therapeutic results.

As mentioned above a part of the invention kativasti well as pharmaceutical compositions containing the compounds of formula I in combination with pharmaceutically acceptable carriers (the basics) or diluents.

Will complement the carrier and/or diluent and, as activedata framework connection choose from diethyl ether 1,4-dihydro-2,6-diethyl-4-[4-(1H-imidazol-1-yl)-phenyl]-3,5-pyridinedicarboxylic acid, dimethyl 1,4-dihydro-2,6-dimethyl-4-[4-(1H-imidazol-1-yl)-phenyl] -3,5-pyridinedicarboxylic acid and utilisabilito ether 1,4-dihydro-2,6-dimethyl-4-[4-(1H-imidazol-1-yl)-phenyl]-3,5-pyridinedicarboxylic acids and their pharmaceutically acceptable salts. The nature of the pharmaceutical composition depends, what is clear from the desired path of its introduction into the body. Such compositions can be prepared in the usual way using conventional components. So, for example, the proposed compounds can enter the body in the form of aqueous or oily solutions or suspensions, tablets, pills, capsules, syrups, drops or suppositories. For example, for oral ingestion by pharmaceutical compositions containing the proposed connection on preferred options should be a pill or pills with sugar or film coating or capsules that contain activetestsuite substance together with diluents, in particular such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, lubricants such as silicon dioxide, talc, stasera binder materials for example starches, gelatine, methylcellulose, carboxymethylcellulose, Arabian gum, tragakant, polyvinylpyrrolidone, agents, giving friability, in particular starches, alginic acid, alginates, nitroglycol starch, gas-emitting mixture, colorants, sweetening agents, wetting agents, in particular lecithin, Polysorbate, laurylsulfate, and, as a rule, non-toxic and pharmacologically inactive substances that are injected in the form of pharmaceutical preparations.

These pharmaceutical preparations can be manufactured by known means, for example by mixing, granulating, pelletizing, sugar coating or film coating. Liquid dispersions for oral administration can consist, for example, syrups, emulsions and suspensions. Syrups as the carrier may include, for example, sucrose or a combination of saccharose with glycerine and/or mannitol and/or sorbitol. Suspension and emulsion as a carrier can contain, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol.

The suspensions or solutions for intramuscular injections can work together actively with the new oil, etiloleat, glycols, in particular propylene glycol, and, if desirable, acceptable number of lidocaineydrocortisone.

The solutions for intravenous injections and infusions as the carrier may include, for example, sterile water or preferably they can be prepared in the form of a sterile aqueous isotonic salt solutions.

Suppositories together with activedayton substance may contain a pharmaceutically acceptable carrier such as cocoa butter, polyethylene glycol, ether polyoxyethylenesorbitan and fatty acids as surfactant or lecithin.

In this description to reduce ome, OEt, OiPr, Et2O, AcOH denote, respectively, methoxy, ethoxy, isopropoxy, diethyl ether, acetic acid.

Example 1.

A mixture of 0.910 g (from 5.29 mmol) of 3-(1H-imidazol-1-yl)-benzaldehyde, 1,69 g (from 5.29 mmol) ethyl-4-(2-phthalimidomethyl)-acetoacetate and 0,628 g (from 5.29 mmol) methyl-3-aminocrotonate in 30 ml of isopropyl alcohol is refluxed for 12 hours and Then the reaction mixture was concentrated, diluted with water and subjected to extraction treatment with ethyl acetate. The organic layers are combined, dried over betwedn the th environment (chloroform with methanol in the ratio of 98 to 2), receiving in the form of a yellow mass of 2 g (66'th output) butter-like product. After recrystallization from methanol receive 1 g of pale yellow solid, which corresponds to 3-ethyl-5-methyl ether ()-14-dihydro-2-[(2-phthalimidomethyl)-methyl]-6-methyl-4-[3-(1H-imidazol-1-yl)-phenyl]-3,5-pyridinedicarboxylic acid.

Melting point 168 172oC.

The data of elementary analysis for C31H30N4O7.

Calculated C 65,25, 5,30 H, N 9,82.

Found, C 64,87, H 5,31, N To 9.93.

Thin layer chromatography: eluent chloroform with methanol in the ratio of 97 to 3; Rf0,4.

1H-NMR spectrogram [DMCO d6, s, h /1000000 hours of 1.09 (3H, T. COOCH2CH3); of 2.23 (3H, c.C-CH3); of 3.54 (3H, s COOCH3); 3,60 of 3.85 (4H, m,- OCH2CH2N= ); 3,95 (2H, m, COOCH2CH3); 4,50 of 4.67 (2H, 2 D. C-OCH2-); 4,89 (1H, s, CH at 4 position of dihydropyridines); 7,0 8,1 (11H, m, phenyl ring + imidazolone ring); to 8.40 (1H, s, NH).

Mass spectrum m/z: 570 (6, M+); 539 (2); 441 (7); 427 (100); 379 (4); 208 (41); 174 (57); 144 (11).

In accordance with the same procedure can be obtained the following compounds: 3-ethyl-5-methyl ether ()-1,4-dihydro-2-(methoxy)-methyl-6-methyl-4-[3-(1H-imidazol-1-yl)-phenyl] -3,5-pyridylcarbonyl the 25N3O5.

Calculated C 64,22, 6,12 H, N Of 10.21.

Found, C 63,75, H 6,03, N 10,00.

Thin layer chromatography: eluent chloroform with methanol in the ratio of 98 to 2; Rf0,30.

1H-NMR spectrogram [CDCl3, s, h/1000000 hours of 1.21 (3H, T. COOCH2CH2); of 2.38 (3H, c.C-CH3); 3,47 (3H, S.-CH2OCH3); the 3.65 (3H, s COOCH3); to 4.1 (2H, m, COOCH2CH3); 4,58, 4,70 (2H, 2 D.-CH2OCH3); of 5.05 (1H, s, CH at 4 position of dihydropyridines); was 7.08 (1H, BS. NH); 7,1 to 7.35 (6H, m, phenyl ring + CH in the 4th and 5th positions of the imidazole); 7,79 (1H, s-N=CH-N=).

Mass spectrum m/z: 411 (10, M+); 366 (4); 282 (5); 268 (100); 222 (15); 208 (51); 144 (24).

Methyl ether ()-1,4-dihydro-5-acetyl-2,6-dimethyl-4- [3-(1H-imidazol-1-yl)-phenyl]-3-pyridineboronic acid with a melting point of 226oC.

The data of elementary analysis for C20H21N3O3.

Calculated C 68,36, Of 6.02 H, N 11,96.

Found, C 67,76, H 6,04, N 11,74.

Thin layer chromatography: eluent chloroform with methanol in the ratio of 96 to 4; Rf0,30.

1H-NMR spectrogram [CDCl3, s, h/1000000 hours 2,19, 2,31, 2,37 (N, 3 S. COOH3+ 2C-CH3); and 3.72 (3H, s COOCH3); 5,11 (1H, c. CH 4-th position of dihydropyridines); x 6.15 (1H, BS. NH); and 7.1 to 7.4 (6H, m Hairdryer-trimethyl-4-[3-(1H-imidazol-1-yl)-phenyl]-3,5-pyridinedicarboxylic acid.

To 0,144 g (0,0026 mol) of finely powdered potassium hydroxide in 15 ml of DMSO added 0.26 g (0,0066 mol) diethyl ether 1,4-dihydro-2,6-dimethyl-4-[3-(1H-imidazol-1-yl)-phenyl]-3,5-pyridinedicarboxylic acid and the mixture is stirred for 2 h at room temperature in a stream of nitrogen. Then the mixture was added 0.187 g (0,00131 mol) under the conditions. After 2 h stirring the reaction mixture was poured into water and subjected to extraction treatment with ethyl acetate, the organic layer is dried over anhydrous sodium sulfate and evaporated in vacuum. The residue is purified in silikagelevye column with mobile phase (eluent chloroform with methanol in a concentration of from 1 to 2), resulting in a gain of 0.13 g (48-cent yield) of pure product.

The data of elementary analysis for C23H27N3O4.

Calculated C 67,46, H Of 6.65, N 10,24.

Found, C 66,10, H 6,62, N 9,83.

Thin layer chromatography eluent chloroform with methanol in the ratio of 95 to 5; Rf0,35.

1H-NMR spectrogram [CDCl3, s, h/1000000 hours of 1.27 (6H, T. 2 COOH2CH3); 2,49 (6H, c. 2C-CH3); is 3.21 (3H, c.N-CH3); 4,19 (4H, K. 2 COOCH2CH3); 5,12 (1H, c. CH 4-th position of dihydropyridines); 7,0 7,3 (6H, m, phenyl ring + CH 4 - and 5-m position the respective compounds: diethyl ether 1,4-dihydro - 1,2,6-trimethyl-4-[4-(1H-imidazol-1-yl)-phenyl] -3,5 - pyridinedicarboxylic acid with a melting point of 80 83oC; diethyl ether 1,4-dihydro-1-(N-morpholinoethyl)-2,6 - dimethyl-4-[3-(1H-imidazol-1-yl)-phenyl] -3,5-pyridinedicarboxylic acid with a temperature of plavanie 110 112oC; diethyl ether 1,4-dihydro-1-(N-morpholinoethyl)-2,6 - dimethyl-4-[4-(1H-imidazol-1-yl)-phenyl] -3,5-pyridinedicarboxylic acid; diethyl ester of 1,4-dihydro-1,2,6-trimethyl-4-[3-(pyridin-3-yl)-phenyl]-3,5-pyridinedicarboxylic acid; Diisobutyl ether 1,4-dihydro-1,2,6-trimethyl-4-[3-(pyridin-3-yl)-phenyl] -3,5-pyridinedicarboxylic acid; diethyl ester of 1,4-dihydro-1,2,6-trimethyl-4-[4-(pyridin-3-yl)-phenyl] -3,5-pyridinedicarboxylic acid and diethyl ether 1,4-dihydro-1-(N-morpholinoethyl)-2,6-dimethyl-4-[3-(pyridin-3-yl)-phenyl]- 3,5-pyridinedicarboxylic acid.

Example 3. 3-ethyl-5-methyl ether ()-1,4-dihydro-2-[(2-aminoethoxy)-methyl] -4-[3-(1H-imidazol-1-yl)-phenyl] -6-methyl-3,5-pyridinedicarboxylic acid.

A mixture of 0.8 g (0,0014 mol) of 3-ethyl-5-methyl ether ()-1,4-dihydro-2-[(2-phthalimidomethyl)-methyl]-6-methyl-4-[3-(1H-imidazol-1-yl)-3,5-pyridinedicarboxylic acid with 9 ml of 20 aqueous methylamino solution in diisopropyl ether and 10 ml absolute atenolo stirred for 2 days at room temperature. The reaction mixture was then evaporated to dryness, the residue dissolved in ethyl acetate and IER is e and the residue purified in silikagelevye column with mobile phase (eluent chloroform with methanol and hydroxide of ammonia in the ratio of 90 to 10 0,2), resulting in a gain of 0.4 g (65'th output) butter-like product, which is subjected to conversion in his maleato salt.

The data of elementary analysis for C27H33N4O9.

Calculated C 58,27, H 5,79, N 10,07.

Found, C 57,32, H 5,72, N Being 9.61.

Thin layer chromatography: eluent chloroform in the mixture with methanol and hydroxide of ammonia in the ratio of 90 to 10 to 0.2; Rf0,18.

1H-NMR spectrogram [DMCO, s, h/ 1000000 hours of 1.13 (3H, T. COOCH2CH3); to 2.35 (3H, s C-CH3); 3,05 (2H, m ); of 3.56 (3H, c. COOCH3); to 3.64 (2H, m, OCH2CH2NH+3); of 4.05 (2H, m, COOCH2CH3); 4,50, 4,74 (2H, 2D.C-CH2O); 4,96 (1H, c. CH 4-th position of dihydropyridines); 6,03 (2H, c. HOOCCH=CHCOOH); 7,1 8,2 (7H, m, phenyl ring + imidazole ring) 7,80 (3H, BS. ); of 8.47 (1H, c. NH).

Mass spectrum m/z 440 (13, M+); 423 (67); 364 (41); 350 (68); 297 (100); 280 (65); 208 (44); 144 (44).

Example 4. A mixture of 17.2 g (0.1 mol) of 4-(1H-imidazol-1-yl)- benzaldehyde with 26 g (0.2 mol) of ethyl acetate and 5 ml of concentrated hydroxide ammonium in 25 ml absolute ethanol was boiled under reflux for 6 hours Then the mixture was poured into 500 ml of a mixture of ice water and the aqueous solution was subjected to extraction processing methylene chloride. About the ovale of diethyl ether, resulting received of 25.7 g (65-cent yield) of diethyl ether 1,4-dihydro-4-[4-(1H-imidazol-1-yl)- phenyl]-3,5-pyridinedicarboxylic acid with a melting point of 231 - 233oC. In accordance with the same procedure obtained the following compounds: diethyl ether 1,4-dihydro-2,6-diethyl-4-[4-(1H-imidazol-1-yl)-phenyl]-3,5 - pyridinedicarboxylic acid; dimethyl ester of 1,4-dihydro - 2,6-dimethyl-4-[4-(1H-imidazol-1-yl)-phenyl] -3,5 - pyridinedicarboxylic acid and utilizability ether-1,4 - dihydro-2,6-dimethyl-4-[4-(1H-imidazol-1-yl)-phenyl]-3,5 - pyridinedicarboxylic acid.

Example 5. Pills, weight each of which was 150 mg, containing 50 mg activitiesthese substances obtained as follows.

Composition (for 10,000 tablets), g:

Diethyl ether 1,4-dihydro-2,6-dimethyl-4-[3-(1H-imidazol-1-yl)-phenyl] -3,5-pyridinedicarboxylic acid 500

Lactose 710

Corn starch 237,5

Powdered talc 37,5

Magnesium stearate 15

Diethyl ether 1,4-dihydro-2,6-dimethyl-4-[3-(1H-imidazol-1-yl]-3,5-pyridinedicarboxylic acid, the lactose and half the corn starch are mixed, the mixture is then forced through a sieve with mesh size of 0.5 mm 18 g of corn starch are suspended in 180 ml of warm water. Prigotovila then add the remaining quantity of starch, talc and magnesium stearate, carefully mixed and processed into tablets using punches of diameter 8 mm

Example 6. Tablets, each weighing 150 mg and containing 50 mg activitiesthese substances, are manufactured as follows.

Composition (for 10,000 tablets), g:

Diethyl ether 1,4-dihydro-2,6-dimethyl-4-[3-(3-pyridyl)-phenyl]-3,5-pyridinedicarboxylic acid 500

Lactose 710

Corn starch 237,5

Powdered talc 37,5

Magnesium stearate 15

Mix diethyl ether 1,4-dihydro-2,6-dimethyl-4-[3- (3-pyridyl)-phenyl] -3,5-pyridinedicarboxylic acid, the lactose and half the corn starch, the mixture is then forced through a sieve with apertures of 0.5 mm, 18 g of corn starch are suspended in 180 ml of warm water. Cooked pasta is used for granulation of powder. The granules are dried, crushed on the sieve hole size 1.4 mm, then add the remaining quantity of starch, talc and magnesium stearate, are thoroughly mixed and processed into tablets using punches of diameter 8 mm

1. Dihydropyridine derivatives of the General formula I

< / BR>
< / BR>
A direct bond or-CH2-;

R is hydrogen;

R1-alkyl or 2-cyanoethoxy;

R3and R4one WITH1WITH3-alkyl, and the other regardless of the first1WITH3-alkyl, unsubstituted or omega-substituted radical selected from the group comprising FROM1WITH3-alkoxygroup, -amino-C1WITH3-alkoxy or phthalimido-C1WITH3-alkoxy; R5hydrogen, C1WITH3-alkyl or w-morpholine-C1WITH3-alkyl;

or their pharmaceutically acceptable salts, provided that in the case where each of the symbols R3and R4denotes unsubstituted WITH1WITH3-alkyl; one of R1and R2stands WITH1WITH4-alkoxy, and the other WITH1WITH4-alkoxy or 2-cyanoethoxy, then R5not hydrogen; in the case when A bond or-CH2the group Het 1H-imidazol-1-yl or pyridin-3-yl, one of R1and R2denotes methoxy or ethoxypropan, and the other is methyl, methoxy or ethoxy, one of R3and R4denotes methyl or ethyl and the other is methyl, timetokill or aminoethoxymethyl, and R is hydrogen, then R5not hydrogen and is not methyl; when A connection, Het 3-(1H-imidazol-1-yl), R is hydrogen, R1ethoxypropan, R2a methoxy group, R3is methyl, R4(2 phthalimides)methyl, then R5not VOD, R is hydrogen, R1and R2independently1WITH4-alkoxy, and R3, R4and R5defined under item 1, or its pharmaceutically acceptable salt.

3. Connection on p. 1, characterized in that represents a connection selected from a class which includes diethyl ether 1,4-dihydro-1-(N-morpholinoethyl)-2,6-dimethyl-4(3- (1H-imidazol-1-yl)phenyl)-3,5-pyridinedicarboxylic acid, diethyl ether, 1,4-dihydro-1-(N-morpholinoethyl)-2,6-dimethyl - 4-(4-(1H-imidazol-1-yl)phenyl)-3,5-pyridinedicarboxylic acid, di-isobutyl ether 1,4 - dihydro-1,2,6-trimethyl-4-(3-(pyridin-3-yl)phenyl)-3,5 - pyridinedicarboxylic acid, diethyl ether, 1,4-dihydro-1-(N-morpholinoethyl)-2,6-dimethyl-4-(3-(pyridin-3-yl)phenyl)- 3,5-pyridinedicarboxylic acid, or its pharmaceutically acceptable salt.

4. Connection on p. 1, characterized in that it is a compound selected from the group comprising diethyl ether 1,4-dihydro-2,6-diethyl-4-(1H - imidazol-1-yl)phenyl-3,5-pyridinedicarboxylic acid, dimethyl 1,4-dihydro-2,6-dimethyl-4-(4-(1H-imidazol-1-yl)phenyl)-3,5 - pyridinedicarboxylic acid and utilizability ether 1,4-dihydro-2,6 - dimethyl-4-(4-(1H-imidazol-1-yl)phenyl)-3,5-pyridinedicarboxylic acid, or its pharmaceutically acceptable salt.

6. The composition according to p. 5, characterized in that it contains as active component a compound selected from the group comprising diethyl ether 1,4-dihydro-2,6-dimethyl-4-(4-(1H-imidazol-1-yl)phenyl-3,5-pyridinedicarboxylic acid, dimethyl 1,4-dihydro-2,6-dimethyl-4-(4-(1H-imidazol-1-yl)phenyl)-3,5 - pyridinedicarboxylic acid, utilizability ether 1,4-dihydro-2,6-dimethyl-4-(4-(1H-imidazol-1-yl)phenyl)-3,5-pyridinedicarboxylic acid or their pharmaceutically acceptable salts.

7. The compound of General formula II

< / BR>
where

A direct bond or-CH2-;

R is hydrogen;

one of R1and R2is1WITH4- alkoxy, and the other independently1WITH4-alkoxy, C1- C3-alkyl or 2-cyanoethoxy;

one of R3and R4WITH1WITH3-alkyl, and the other nasalises1WITH3-alkoxy, amino-C1WITH3-alkoxy or phthalimido-C1- C3-alkoxygroup;

R5hydrogen, C1WITH3-alkyl or-morpholine-C1WITH3-alkyl, provided that when each of R3and R4unsubstituted WITH1WITH3-alkyl; one of R1and R2WITH1WITH4-alkoxy, and the other WITH1WITH4-alkoxy or 2-cyanoethoxy, then R5not hydrogen, in the case where A bond or-CH2the group Het 1H-imidazol-1-yl or pyridin-3-yl, one of R3and R4methyl or ethyl and the other is methyl, ethyl, methoxymethyl or aminoethoxymethyl, and R is hydrogen, then R5not hydrogen and is not methyl; and when A connection, Het - 3-(1H-imidazol-1-yl), R is hydrogen, R1ethoxypropan, R2a methoxy group, R3methyl, R4(2 phthalimides)methyl, then R5not hydrogen, or its pharmaceutically acceptable salt having a synergistic effect of the antitumor agent activity.

8. The compound of formula I on p. 1, selected from the group consisting of diethyl ether 1,4-dihydro-1-(N-morpholinoethyl)- 2,6-dimethyl-4-(3-(1H-imidazol-1-yl)phenyl)-3,5-pyridinedicarboxylic acid; diethyl ester of 1,4-dihydro-1-(N-morpholinoethyl)- 2,6-dimethyl-4-(4-(1�-3-yl)phenyl)-3,5-pyridinedicarboxylic acid; diethyl ether 1,4-dihydro-1-(N-morpholinoethyl)-2,6-dimethyl-4-(3-(pyridin-3-yl)phenyl)- 3,5-pyridinedicarboxylic acid; diethyl ester of 1,4-dihydro-2,6-diethyl-4-(4-(1H-imidazol-1-yl)phenyl)-3,5-pyridinedicarboxylic acid; dimethyl ester of 1,4-dihydro-2,6-dimethyl-4-(4-(1H-imidazol-1-yl)phenyl)-3,5-pyridinedicarboxylic acid; utilisabilito ether 1,4-dihydro-2,6-dimethyl-4-(4-(1H-imidazol-1-yl)phenyl)-3,5-pyridinedicarboxylic acid or their pharmaceutically acceptable salts, having a synergistic effect of the antitumor agent activity.

 

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< / BR>
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