RU2322440C1 - SUBSTITUTED ω-AZOLYLALKANE ANILIDES, METHOD FOR THEIR PREPARING AND USING AS ANTI-AGGREGATING AGENT - Google Patents

Abstract

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to substituted ω-azolylalkane anilides. Invention describes substituted ω-(1H-azol-1-yl)-N-phenylalkaneamides of the general formula (I):

wherein Z and Y mean nitrogen atom of CH-group, or they represent the chain -C-CH=CH-CH=CH-C- simultaneously and forming in common an anellated ring; n means a whole number from 1 to 3; R_m are similar or different and mean hydrogen, halogen atom, alkyl group with number of carbon atoms from 1 to 4, alkoxy group, alkylenedioxy group, benzyloxy group, perfluoroalkyl group with number of carbon atoms from 1 to 4, nitro group, alkoxycarbonyl group, carboxyl group, halogenphenylthio group, halogenbenzoyl group; m means a whole number from 0 to 5, their salts with acids. Also, invention describes methods for synthesis of compounds of the formula (I) and their using as anti-aggregative preparations. Invention provides synthesis of novel compounds possessing the useful biological properties.

EFFECT: valuable properties of compounds, improved method of synthesis.

8 tbl, 11 ex

Description

The invention relates to the chemistry of heterocyclic compounds, namely to substituted ω-azolylalkananilides (ω- (1H-azol-1-yl) -N-phenylalkanamides) of the general formula I:

where Z and Y are a nitrogen atom or a CH group, or are simultaneously a chain C — CH = CH — CH = CH — C, together constituting an annelated ring; n is an integer from 1 to 3; R are identical or different, they mean a hydrogen atom, a halogen atom, an alkyl group with the number of carbon atoms from 1 to 4, an alkoxy group with the number of carbon atoms from 1 to 4, an alkylenedioxy group, a benzyloxy group, a perfluoroalkyl group with the number of carbon atoms from 1 to 4, a nitro group, an alkoxycarbonyl group , carboxyl group, halogenophenylthio group, halogenbenzoyl group, m means an integer number of atoms from 0 to 5; to their salts with acids having anti-aggregation activity.

The compounds of general formula I can find application as medical, veterinary and phytotherapeutic drugs, primarily antiplatelet agents.

The invention also relates to methods for producing compounds of general formula I and the use of these compounds as antiplatelet agents.

Many products with azole rings are known, in particular N-phenyl-N-benzyl 2-heterylacetamides with bactericidal activity, used in agriculture and horticulture, of the general formula II, wherein the X and Y atom represent a hydrogen atom, lower alkyl or a halogen atom; Het means piperidino, methylpiperidino, dimethylpiperidino, hexamethyleneimino, pyrazolyl, imidazolyl or 1,2,4-triazolyl [Japanese Patent No. 4145067, MKI C07D 249/08. - Declared. - 10/04/1990].

Known are 2- (azol-1-yl) -N-phenylacetamides with anticancer activity of the general formula III, where R is a hydrogen atom, a methyl group or a nitro group; R ₁ means a hydrogen atom or a methyl group [Kasai S., Nagasawa H., Yamashita M. New Antimetastatic Hypoxic Cell Radiosensitizers: Desing, Synthesis, and Biological Activities of 2-Nitroimidazole-acetamide, TX-1877, and its Analogues. // Bioorg. Med. Chem. - 2001. - No.9. - P.453-64].

S.Dalkara,

A.Willke. Synthesis of Some N-Arylazole Acetamide Derivatives and Their Anticonvulsant and Antimicrobial Activities. // Arzneim. - Forsch. / Drug Res. - 1994. - Vol.44 (II). - № 8. - P.920-924], которые обладают противосудорожной активностью.Known are 2-azolyl-N, N-diphenylacetamides of the general formula IV, where Z is a nitrogen atom or a CH group

S. Dalkara,

A.Willke. Synthesis of Some N-Arylazole Acetamide Derivatives and Their Anticonvulsant and Antimicrobial Activities. // Arzneim. - Forsch. / Drug Res. - 1994 .-- Vol. 44 (II). - No. 8. - P.920-924], which have anticonvulsant activity.

Closest to the claimed substituted ω- (1H-azol-1-yl) -N-phenylalkanamides in structure and production method are N-phenyl-2- (azol-1-yl) -2-alkanamides of the general formula V, where R ₁ means an alkyl group with the number of carbon atoms from 1 to 10, a phenyl or phenoxy group; R ₂ means a hydrogen atom, an alkyl group with the number of carbon atoms from 1 to 5, an allyl group; R ₃ means an alkyl group with the number of carbon atoms from 1 to 8, an allyl group, a cycloalkyl group, a phenyl group; R ₄ means a hydrogen atom, a lower alkyl group or a halogen atom [Japan patent No. 58052256, MKI C07D 249/10. - Declared. - 09.24.1981], used as bactericides of industrial or agricultural purposes, herbicides or fungicides. Compounds of general formula V are prepared in two stages, first by reacting 2-bromoacyl halides with amines in an inert solvent, for example benzene, toluene or tetrahydrofuran in the presence of an aqueous solution of carbonate or sodium hydroxide at a temperature of -10 - + 10 ° C, 2-bromoacetamides are obtained, which the azoles are alkylated in dimethyl sulfoxide in the presence of 1,8-diazobicyclo [5.4.0] undec-7-ene (DBU) when heated to 60 ° C for 24 hours.

The first place among the causes of death is occupied by diseases of the cardiovascular system. The appointment of antiplatelet drugs (antiplatelet agents) prevents the development of severe vascular complications, reduces the risk of severe vascular outcomes: myocardial infarction, strokes. This group of drugs is an important part of the treatment and prevention of angina pectoris, peripheral arterial atherosclerosis, and manifestations of atherothrombosis.

Antiplatelet agents inhibit platelet aggregation, reduce their ability to glue and adhere (adhesion) to the endothelium of blood vessels. Antiplatelet agents can not only prevent aggregation, but also cause disaggregation of already aggregated blood platelets. They are used to prevent the formation of postoperative blood clots, with thrombophlebitis, retinal vascular thrombosis, cerebrovascular accident, and also to prevent thromboembolic complications in coronary heart disease, including myocardial infarction [Kharkevich D.A. Pharmacology. - M .: GEOTAR Medicine, 2000. - 664 p.].

An important place among antiplatelet agents is occupied by azole derivatives, primarily imidazole, which are thromboxane synthetase inhibitors [Demina OV, Khodonov AA, Shvets VI, Varfolomeev SD Human platelet aggregation: molecular kinetic mechanisms and regulatory pathways. // Biologist. membranes. - 2002. - T.19, No. 2. - S.115-152].

After cell stimulation, arachidonic acid is released from membrane phospholipids and converted as a result of a sequence of enzymatic reactions (arachidonic acid cascade) into many different derivatives of metabolites in two main ways - lipoxygenase and cyclooxygenase. The products of the cyclooxygenase pathway are widespread prostaglandins; both prostacyclin (PGI ₂ ), which is formed in the vascular endothelium, and thromboxane (TxA ₂ ), which is synthesized in platelets, are formed from the stable prostacyclin PGH ₂ . In a number of diseases, an imbalance between these two eicosanoids is observed, the overproduction of thromboxane A _{2 is} detected in many pathological conditions. Inhibitors of thromboxane, e.g. dazoksiben block the biosynthesis of thromboxane, the observed conversion of platelet endoperoxides (PGH ₂₎ into prostacyclin PGI _2, thereby increasing athrombogenic properties of the vascular wall, inhibition of platelet adhesion, aggregation and coagulation, and also may be accompanied by a pressure decrease [Garsia -Szabo RR, Peterson MB, Watkins WD et. al. Thromboxane generation after thrombin. Protective effect of thromboxane synthetase inhibition on lang Huid balance. // Circ. Res. - 1983 .-- Vol. 53, N2. - P.214-222].

Many antiplatelet agents - thromboxane synthetase inhibitors are used as vasodilators, antihypertensive drugs, antianginal drugs, cerebrovasodilators, coronary vasodilators, and bronchial asthma and rhinitis.

Closest to the claimed substituted ω- (1H-azol-1-yl) -N-phenylalkanamides for use as antiplatelet agents are phenoxyalkylimidazoles of the general formula IV, where R is hydrogen or alkyl; with the number of methylene groups n from 1 to 9; m is from 0 to 8; Z means an atom of O, S or NH group [US Patent No. 4632934. - Ann. - 08.21.1979], which inhibit thromboxanesynthetase and, due to this, are used as antihypertensive anti-inflammatory, anti-thrombotic agents [Cross P.E., Dickinson R.P., Parry M.J., Randall M.J. Selective tromboxane synthetase Inhibitors. I. 1 - [(Aryloxy) alkyl] -1H-imidazoles. // J. Med. Chem. - 1985. - Vol. 28. - P.1427-32]

The technical task of this invention is to increase the effectiveness of anti-aggregation drugs and expand the range of hematotropic drugs.

The problem is solved by obtaining compounds of General formula I with antiaggregation activity. According to the present invention, ω-azolylalkananilides (ω- (1H-azol-1-yl) -N-phenylalkanamides) of the formula I are prepared in two ways. According to the first method, the interaction of ω-halogenacyl halides, for example, chloroacetyl chloride with substituted anilines (VII) in an environment of organic solvents, for example, methylene chloride, chloroform, toluene, etc., in the presence of an aqueous solution of alkali or alkaline-earth metal hydroxides or carbonates at a temperature from 0 to 20 ° C, according to the Schotten-Bauman reaction, ω-halogenacylanilides (VIII) were obtained with which alkali metal azolates were alkylated in a polar aprotic solvent, for example acetonitrile, dimethylformamide, dimethyl ulfoxide and others at a temperature of from 40 to 150 ° C.

According to the second method, compounds of the general formula I are prepared by reacting ω-azolylalkanoic acids (IX) with chlorinating agents, for example, phosphorus (V) chloride, phosphorus (III) chloride, thionyl chloride, oxalyl chloride, in an inert solvent, for example, dioxane, tetrahydrofuran, methylene chloride and etc., at a temperature of from 20 to 50 ° C, hydrochlorides of acid chlorides of ω-azol-1-ylalkanoic acids (X) were obtained, which were then reacted with substituted anilines (VII) in a polar aprotic solvent, for example acetonitrile, dimethylformamide, dim ethyl sulfoxide or methylene chloride, dioxane in the presence of bases, for example triethylamine, diazabicyclooctane, DBU, etc. at a temperature of from 20 to 60 ° C.

In the above schemes, R, n, m, Z and Y have the same meanings as in the formula I, X means chlorine, bromine; M means an alkali metal, for example sodium, potassium and the like; : B means base, for example triethylamine, DBU, alkali metal or alkaline earth metal hydroxide or carbonate.

Alkylation of azoles, in particular imidazole and 1,2,4-triazole, is the subject of many articles. An alkali metal 1,2,4-triazolate is initially prepared, for example, by reaction with sodium hydride in DMF or sodium ethoxide in alcohol, to which an alkyl halide is then added and 1-alkyl-1,2,4-triazoles are obtained [Bergtrap M., Larsen P. Alkylation, acylation and silylation of azoles. // Acta Chem. Scand. - 1990. - Vol. 44, No. 10. - P. 1050-1057].

2- (Imidazol-1-yl) -N, N-diphenylacetamide is prepared by reacting 2-bromo-N, N-diphenylacetamide with sodium imidazolate in boiling DMF for 48 hours [F.ÖzkanIi, S. Dalkara, Ü. Çaliş, A .Willke. Synthesis of Some N-Arylazole Acetamide Derivatives and Their Anticonvulsant and Antimicrobial Activities. // Arzneim.-Forsch. / Drug Res. - 1994 .-- Vol. 44 (II). - No. 8. - P.920-924].

S.Dalkara,

A.Willke. Synthesis of Some N-Arylazole Acetamide Derivatives and Their Anticonvulsant and Antimicrobial Activities. // Arzneim.-Forsch. / Drug Res. - 1994. - Vol.44 (II). - № 8. - P.920-924].Substituted 2-haloacetamides (VIII), for example bromoacetamides, are prepared by reacting anilines (VII) with bromoacyl bromide in ether in the presence of an aqueous solution of sodium hydroxide.

S. Dalkara,

A.Willke. Synthesis of Some N-Arylazole Acetamide Derivatives and Their Anticonvulsant and Antimicrobial Activities. // Arzneim.-Forsch. / Drug Res. - 1994 .-- Vol. 44 (II). - No. 8. - P.920-924].

The technical result of the invention is new substances - substituted ω- (1H-azol-1-yl) -N-phenylalkylamides of the general formula I and the method for their preparation. In the specified patent [Japan patent No. 58052256, - Decl. - 09.24.1981] propose to obtain the target 1-substituted azoles in difficult to remove solvents, for example, in dimethyl sulfoxide for a long interaction time. We propose alkylation in easily removable solvents, for example, in acetonitrile, with a significantly shorter reaction time. We have proposed an alternative method for preparing the target compounds from azolylalkanoic acids in two stages. First, by reaction with chlorinating agents, acid chlorides were obtained in high yield, with which anilines were then acylated.

The technical result of the invention is the use of ω- (1H-azol-1-yl) -N-phenylalkylamides of the formula I as antiplatelet agents that surpass the known antiplatelet drug dazoxiben (4- [2- (imidazol-1-yl) ethoxy ] benzoic acid) [J. Med. Chem. - 1985. - Vol. 28. - P.1427-32], which allows to increase the effectiveness of antiplatelet drugs and expand the range of hematotropic drugs. The effect of ω- (1H-azol-1-yl) -N-phenylalkylamides of formula I in in vitro experiments was manifested in the range of pharmacologically acceptable concentrations of 10 ^-4 -10 ^-6 M, while the optical density of the plasma decreased to 7.7-42. 6% The studied compounds, for example, 30, 45, 47 exceeded the dazoxiben standard, both during aggregation caused by ADP and collagen.

Comparing the degree of influence of compound 30 on ADP-induced platelet aggregation in vivo at concentrations of 11, 16, 21 mg / kg, it was found that in all studied concentrations it exerted antiaggregation effects to different degrees, with a maximum of action occurring after 7, 9 and 11 hours depending on the dose used. The degree of suppression of aggregation was also dose dependent, and the absorbance values were 26.5% (11 mg / kg), 18.8% (16 mg / kg) and 16.9% (21 mg / kg), respectively. The duration of the effect of compound 30 at a concentration of 11 mg / kg was observed in the range from 1 to 13 hours, and under the influence of concentrations of 16 and 21 mg / kg, a significant suppression of ADP-induced platelet aggregation was observed 24 hours after administration. While a comparative study of the effect of dazoxibene on ADP-induced platelet aggregation in vivo at concentrations of 11, 16, 21 mg / kg allowed us to establish that the maximum action in the study of all concentrations occurred 1 hour after drug administration, while the values of optical density of plasma accounted for 31% when studying the concentration of 11 mg / kg, 29.4% when studying the concentration of 16 mg / kg and 29.3% when studying the concentration of 21 mg / kg, respectively.

A comparison of the data obtained by studying the effect of compound 30 at concentrations of 11, 16, 21 mg / kg on plasma coagulation factors in vivo revealed that the studied compound in all concentrations increased the time of clot formation. At maximum action, compound 30 at concentrations of 16 and 21 mg / kg (28.9, 29.2 s) showed approximately equal results, and at a concentration of 11 mg / kg (22.7 s) it was slightly inferior to them. Thus, all the studied concentrations (11, 16, 21 mg / kg) of the compound increased the clot formation time when studying the effect on plasma coagulation factors. At the same time, at maximum action, compound 30 at concentrations of 16 and 21 mg / kg (28.9, 29.2 s) equally increased the time of clot formation, and at a concentration of 11 mg / kg (22.7 s) it was slightly inferior to higher concentrations. The effect when using a concentration of 16 and 21 mg / kg lasted more than 12 hours, and under the influence of a concentration of 11 mg / kg up to 8 hours. While a comparative study of the effect of dazoxiben at concentrations of 11, 16, 21 mg / kg on plasma coagulation factors in vivo, it was established that the studied compound in all concentrations increased the APTT. In this case, regardless of the concentration, a significant increase in the time of clot formation was observed 3 hours after administration. Thus, all the studied concentrations (11, 16, 21 mg / kg) of dazoxiben increased the time of clot formation when studying the effect on plasma coagulation factors. At the same time, at the maximum effect, the activity of all concentrations was approximately equal, but the duration of the maximum effect increased with increasing concentration of the studied compound (1 hour at a concentration of 11 mg / kg, 2 hours at a concentration of 16 mg / kg and 4 hours at a concentration of 21 mg / kg) . The effect itself, when using a concentration of 11 and 16 mg / kg, lasted between 1 and 7 hours, and under the influence of a concentration of 21 mg / kg, 2 hours longer (between 1 and 9 hours).

The invention can be illustrated by the following examples.

Example 1. 2-Chloro-N-phenylacetamide (1).

To a mixture of 19.7 ml of a 20% solution of sodium hydroxide, 9.3 g (0.1 mol) of aniline and 100 ml of methylene chloride, cooled in an ice and salt bath to 5 ° C, 13 are added dropwise with stirring. 56 g, 9.6 ml (0.12 mol) of 2-chloroacetyl chloride so that the temperature of the mixture does not exceed 10 ° C, and then stirred at room temperature for another 2 hours. The precipitate formed is filtered off and washed with water, the filtrate is washed with saturated sodium bicarbonate solution (2 × 15 ml), water (3 × 20 ml), brine (15 ml) and dried over magnesium sulfate. After the solvent was distilled off in a vacuum of a water-jet pump, the resulting residue was recrystallized from hexane: toluene (2: 1) to obtain 19.64 g (86%) of 2-chloro-N-phenylacetamide (1), mp 129-131 ° C.

Substituted 2-chloro-N-phenylacetamides are similarly prepared. Table 1.

Table 1 Melting points and yield of synthesized 2-chloro-N-phenylacetamides (n = 1) Compound R m Exit, % Mp. ° C one N 0 86 129-131 2 4-cl one 85 170-172 3 4-obn one 54 139-140 four 3,4-Cl ₂ 2 92 111-113 5 3-CF ₃ one 84 60-62 6 4-CF ₃ one 98 161-162 7 4-i-Pr one 90 130-132 8 4-NO ₂ one 97 159-162 9 4-CO ₂ Et 84 91-93

Example 2. 2- (1,2,4-Triazol-1-yl) -N-phenylacetamide (10).

To a suspension of 2.73 g (0.03 mol) of sodium 1,2,4-triazolate, in 30 ml of acetonitrile, 5 g (0.03 mol) of 2-chloro-N-phenylacetamide (1) is added with stirring, the reaction mixture is boiled within 10 hours, the precipitate formed is filtered off and washed with 5 ml of distilled water and dried. Obtain 5.628 g of a technical product, which is a mixture of isomers of 1- and 4-alkylation of triazole, from which 3.20 g (57%) of 2- are isolated by the method of "dry" flash chromatography using methanol: chloroform 1:10 as an eluent. (1,2,4-triazol-1-yl) -N-phenylacetamide (10) melting point 146-148 ° C.

Example 3. 2- (1,2,4-Triazol-1-yl) -N- (4-trifluoromethylphenyl) acetamide (17).

To 1.61 g (0.01 mol) of 4-1,1,1-trifluoromethylaniline in 20 ml of absolute acetonitrile, 1.82 g (0.01 mol) of 1,2,4-triazole-1- acid chloride hydrochloride are added with stirring sludge of acetic acid and 2.02 g (0.02 mol) of triethylamine. Stirred for two hours. The precipitate formed is filtered off, washed with 2 ml of water and 2 ml of acetonitrile. The precipitate was recrystallized from isopropyl alcohol. 2.16 g (41%) of 2- (1,2,4-triazol-1-yl) -N- (4-1,1,1-trifluoromethylphenyl) acetamide are obtained (17), m.p. 187-188 ° C.

Similarly, substituted 2- (1,2,4-triazol-1-yl) -N-phenylacetamides were prepared (Table 2).

Example 4. 2- (Imidazol-1-yl) -N-phenylacetamide (11).

To a suspension of 2.70 g (0.03 mol) of sodium imidazolate, in 25 ml of acetonitrile, 5 g (0.03 mol) of 2-chloro-M-phenylacetamide (1) is added with stirring, boiled for 10 hours, the precipitate is filtered off and washed with 5 ml of distilled water, dried and recrystallized from isopropyl alcohol, 2.64 g (64%) of 2- (imidazol-1-yl) -N-phenylacetamide (2) were obtained, mp. 138-140 ° C.

Similarly, substituted 2- (imidazol-1-yl) -N-phenylacetamides were obtained (Table 2).

Example 5. Ethyl 4 [(1H-benzimidazol-1-yl acetyl) amino] benzoate (43).

To 1.65 g (0.01 mol) of ethyl 4-aminobenzoate in 10 ml of absolute acetonitrile, 2.37 g (0.01 mol) of hydrochloride chloride (benzimidazol-1-yl) acetic acid and 2.02 g are added portionwise with stirring. (0.02 mol) of triethylamine. Heated to 40 ° C and maintained at this temperature with stirring for eighteen hours. The precipitate formed is filtered off, washed with water (2 × 3 ml), and recrystallized from methyl alcohol. Obtain 1.03 g (32%) of ethyl 4 - [(1H-benzimidazol-1-yl acetyl) amino] benzoate (43) so pl. 222-223 ° C.

Similarly, substituted 2- (1H-benzimidazol-1-yl acetyl) -N-phenylacetamides were prepared (Table 3).

Example 6. 4- (1H-imidazol-1-yl) -N- (3-nitrophenyl) butanamide (26).

To 1.38 g (0.01 mol) of 3-nitroaniline in 10 ml of absolute dimethylformamide, 1.725 g (0.01 mol) of 4- (imidazol-1-yl) butanoic acid hydrochloride and 2.02 g ( 0.02 mol) of triethylamine. The reaction mass is heated to 40 ° C during the day. The precipitate formed is filtered off, washed with 5 ml of water and 1 ml of isopropyl alcohol, the filtrate is evaporated in vacuo of a water-jet pump. 10 ml of water was added to the resulting residue and filtered. The precipitate obtained is recrystallized from isopropyl alcohol. Obtain 0.56 g (26%). 4- (1H-imidazol-1-yl) -N- (3-nitrophenyl) butanamide (26) so pl. 145-7 ° C.

Example 7. Ethyl 3 - ([4- (1H-imidazol-1-yl) butanoyl] amino) benzoate (30).

a) Hydrochloride of 4- (imidazol-1-yl) butanoic acid chloride. To 1.16 g (0.0075 mol) of 4- (imidazol-1-yl) butanoic acid in 5 ml of absolute dioxane, 1.56 g (0.0075 mol) of phosphorus pentachloride are added portionwise with stirring. The reaction mass is heated to 40 ° C for six hours until complete dissolution of the phosphorus pentachloride, cooled to room temperature and stirred for another ten hours. The reaction mass is evaporated in vacuum of a water-jet pump. 1.56 g (99%) of 4- (imidazol-1-yl) butanoic acid hydrochloride are obtained in the form of an oil. According to the results of potentiometric argentometric titration, the chlorine content is determined. Found: Cl 34.35%; C ₇ H ₁₀ Cl ₂ N ₂ O; calculated: Cl 33.97%. Subsequently, the product is used without further purification.

b) To 1.25 g (0.0075 mol) of 3-ethoxycarbonylaniline in 10 ml of absolute dioxane, 1.56 g (0.0075 mol) of 1H-imidazol-1-yl butanoic acid hydrochloride and 1.515 g (1.515 g) are added portionwise with stirring. 0.0075 mol) of triethylamine. The reaction mass is heated for forty-eight hours. The precipitate formed is filtered off, washed with 10 ml of water, and recrystallized from isopropyl alcohol. 0.56 g (26%) of ethyl 3 - {[4- (1H-imidazol-1-yl) butanoyl] amino} benzoate (30) was obtained, mp. 146-148 ° C.

Similarly, substituted ω- (azol-1-yl) -N-phenylalkanamides are obtained.

NMR ¹ H-spectra were recorded on a Bruker AC-200 instrument (operating frequency 200 MHz), the shifts were measured relative to tetramethylsilane, and d ₆ -DMSO was used as a solvent. IR spectra were recorded with NaCl prisms in a thin film in liquid paraffin on a Specord M80 spectrometer.

table 2 Melting points and yield of synthesized ω- (1,2,4-triazol-1-yl) -N-phenylalkanamides and ω- (imidazol-1-yl) -N-phenylalkanamides Compound Z n R m Exit, % Mp. ° C one 2 3 four 5 6 7 10 N one N 0 57 146-148 eleven CH one N 0 64 138-140 12 N one 4-cl one 60 198-199 13 CH one 4-cl one 98 191-192 fourteen N one 4-br one 74 210-211 fifteen CH one 4-br one 64 207-208 16 N one 3,4-Cl ₂ 2 63 207-208 17 N one 3-CF ₃ 2 67 146-147 eighteen CH one 3-CF ₃ one 60 162-165 19 N 2 3-CF ₃ one 38 200-201 twenty N one 4-CF ₃ one 41 187-188 21 CH one 4-CF ₃ one 27 191-192 22 N one 4-i-Pr one 43 193-195 23 CH one 4-i-Pr one 48 188-190 24 N one 4-NO ₂ one 68 230-232 25 CH one 4-NO ₂ one 62 140-144 26 CH 3 3-NO ₂ one 26 145-147 27 N one 4-CO ₂ Et one 57 170-172 28 CH one 4-CO ₂ Et one 51 171-173 29th CH 2 3-CO ₂ Et one 52 120-121 thirty CH 3 3-CO ₂ Et one 26 146-147 31 N one 3,4- (OCH ₂ CH ₂ O) 2 69 205-207 32 CH one 3,4- (OCH ₂ CH ₂ O) 2 46 190-193 33 N one 4-OCH ₂ Ph one 75 184-186 34 CH one 4-OCH ₂ Ph one 83 180-183 35 N one 3-NO ₂ , 5- (4-FPhS) 2 56 180-183 36 CH one 3-NO ₂ , 5- (4-FPhS) 2 51 204-206 37 CH one 2- (2-ClBz), 4-Br 2 58 310-312 Table 3 Melting points and yield of synthesized 2- (benzimidazol-1-yl) -N-phenylacetamides (n = 1, m = 1) Compound R Exit, % Mp, ° C 38 4-cl eleven 247-248 39 4-br 25 260-261 40 4-CF ₃ 38 207-209 41 4-NO ₂ 33 272-273 42 4-OCH ₃ 31 200-201 43 4-CO ₂ Et fifteen 222-223 44 3-CF ₃ eighteen 197-199

Example 8. 2- (Imidazol-1-yl) -N- (4-chlorophenyl) acetamide hydrochloride (45).

To a solution of 0.326 g (1.38 mmol) of 2- (imidazol-1-yl) -N- (4-chlorophenyl) acetamide (13) in 5 ml of methyl alcohol, 1.41 ml (2.08 mmol) of 1 is added with stirring , 47M solution of hydrogen chloride in methanol. The solvent is distilled off in a vacuum of a water-jet pump to dryness. 0.373 g (98%) of 2- (imidazol-1-yl) -N- (4-chlorophenyl) acetamide hydrochloride is obtained (45), m.p. 216-217 ° C.

Hydrochlorides of substituted 2- (azol-1-yl) -N-phenylalkanamides were obtained in the same way: from ethyl 4- [2- (1H-imidazol-1-yl) acetylamino] benzoate (28) ethyl 4- [2- (1H-) hydrochloride imidazol-1-yl) acetylamino] benzoate (46) so pl. 105-106 ° C, from ethyl 4- [2- (1H-1,2,4-triazol-1-yl) acetylamino] benzoate (27) 4- [2- (1H-1,2,4-triazole hydrochloride) -1-yl) acetylamino] benzoate (47) mp. 144-146 ° C.

Example 9. Testing of ω-azol-1-ylalkan anilides for the presence of anti-aggregation activity in vitro.

The methodology of the experiment. Platelet-rich plasma (on average 3 × 10 ⁸ in 1 cm ^{3 of} platelets) was obtained by centrifugation of freshly obtained blood from healthy donors (stabilizer - 3.8% sodium citrate, 9: 1 ratio of blood to citrate solution) for 10 minutes at 1000 rpm at room temperature. Before the experiment and at the end of it, platelet counts were counted in each sample. In that case, if the plasma contained a larger number of blood plates, then it was diluted to the required amount by platelet-free plasma obtained by centrifugation of citrated blood for 10 minutes at 3000 rpm. ADF, collagen (NPO RENAM, Russia) were used as an aggregation inducer. Platelet aggregation was studied by light scattering according to the Born method [Born JVR Aggregation of blood platelets by adenosine diphosphate and its reversal. // Nature - 1962. - V.194, N5. - P.927-929. Born JVR Quantitative investigation into the aggregation of blood platelets. // J. Physiol. - 1962. - V.162, N4. - P.487-511] on an aggregometer of the company "CHRONO-LOG" (USA).

Experimental conditions: 37 ° C, platelet-rich plasma volume 450 μl, test substance volume 50 μl, preincubation time with inhibitor preparation 5 minutes with stirring, aggregation inductor volume 50 μl, final concentration for ADP 1 × 10 ^-5 M, collagen - 0.2 mg / ml. (A platelet-rich plasma in a volume of 450 ml was used as a control). A quantitative characteristic of the degree of aggregation was the relative decrease in optical density at the maximum amplitude of the aggregatogram. During the recording, a change in the optical density of the studied plasma was observed in the range of 100% (platelet-rich plasma) to 0% (platelet-free plasma) (wavelength of the probed light flux of 660 nm). The result was expressed as a percentage of the optical density drop at the maximum amplitude of the agretogram.

Experiments were conducted comparing the antiplatelet properties of substances and the standard, the known drug dazoxiben.

Table 5 Effect of ω- (1H-azol-1-yl) -N-phenylalkylamides and dazoxiben on ADP-induced platelet aggregation in vitro Compound % drop in optical density of plasma The control The concentration of the antiplatelet compound, mol / l 10 ^-3 M 10 ^-4 M 10 ^-5 M 10 ^-6 M 10 ^-7 M thirty 59.1 ± 1.3 16.9 ± 1.5 18.3 ± 1.2 26.4 ± 1.7 30.7 ± 2.2 46.6 ± 2.6 45 59.2 ± 1.2 14.0 ± 1.8 22.2 ± 2.1 42.9 ± 1.3 43.0 ± 2.0 48.0 ± 2.5 47 56.3 ± 2.3 18.0 ± 1.7 18.6 ± 1.6 24.5 ± 2.3 28.4 ± 2.8 46.1 ± 2.3 Dazoxiben 57.9 ± 1.7 40.9 ± 1.3 40.1 ± 1.7 41.0 ± 1.8 46.1 ± 1.9 54.0 ± 2.8 Table 6 Effect of ω- (1H-azol-1-yl) -N-phenylalkylamides and dazoxibene on collagen-induced platelet aggregation in vitro Compound % drop in optical density of plasma The control The concentration of the compound is antiplatelet, mol / l 10 ^-3 M 10 ^-4 M 10 ^-5 M 10 ^-6 M 10 ^-7 M thirty 58.3 ± 1.7 11.4 ± 1.9 15.1 ± 1.6 15.4 ± 1.8 28.1 ± 1.3 49.3 ± 1.7 Dazoxiben 58.7 ± 1.4 27.1 ± 1.7 30.2 ± 1.3 37.8 ± 1.2 46.1 ± 1.6 56.9 ± 2.2

Example 10. Biological testing of ω-azol-1-ylalkan anilides for the presence of anti-aggregation activity in vivo.

The selected compounds were administered intravenously to chinchilla rabbits into the marginal vein of the ear at doses of 11, 16, 21 mg / kg. The first blood sampling for the study was carried out 30 minutes after administration, then after 1 hour, 3, 5, 7, 9, 11 and 24 hours. In that case, if the optical density of the plasma 11 hours after the administration of the test compound was significantly different from the control values, then blood sampling was done 13 and 15 hours after the administration. As an inductor used at the threshold concentration of ADP (1 × 10 ^-5 M).

The results obtained are summarized and presented in table 7.

Example 11. A comparative study of the effects of new derivatives of azolylalkanoic acids and dazoxiben on plasma coagulation factors in vivo.

Compounds were administered intravenously to chinchilla rabbits in the marginal vein of the ear, at doses of 11.16, 21 mg / kg. The results obtained are summarized and presented in table 8. The first blood sampling for the study was carried out before the introduction of the studied compounds (control). Further, 30 minutes after administration, after 1 hour, 3, 5, 7, 9, 11 and 24 hours. In the event that the results obtained significantly differed from the control values 11 hours after the administration of the test compound, blood sampling was done 13 and 15 hours after the administration.

Table 7 The effect of compound 30 and dazoxibene on the maximum amplitude of aggregate patterns in in vivo experiments Substance mg / kg % drop in optical density The control Time after administration 30 minutes 1 hour 3 h 5 h 7 h 9 h 11 h 13 h 15 h 24 h thirty eleven 60.1 ± 1.3 50.9 ± 1.5 39 ± 1.9 33.2 ± 2.1 27.4 ± 1.4 26.5 ± 1.7 29.5 ± 1.6 38.7 ± 2.5 49 ± 1.9 59.8 ± 2.2 60.6 ± 2.9 16 61.1 ± 1.6 49.1 ± 1.8 36.8 ± 1.3 36 ± 1.9 34.6 ± 2.2 21.5 ± 2.1 18.8 ± 1.1 22.1 ± 1.3 30.1 ± 1.5 35.1 ± 2.6 56.2 ± 2.5 21 59.7 ± 1.2 47.2 ± 1.4 32.7 ± 1.1 25.8 ± 1.6 22 ± 2.1 20 ± 1.9 18.1 ± 1.7 16.9 ± 2.3 19.1 ± 1.3 25.2 ± 2.3 54 ± 3.4 Dazoxiben eleven 59.7 ± 1.1 45.7 ± 2.3 31 ± 1.4 33.5 ± 1.8 44.2 ± 2.4 57.5 ± 1.1 59.1 ± 1.5 59.5 ± 2.5 - - 61.2 ± 2.8 16 62.3 ± 2.1 46.3 ± 1.3 29.4 ± 1.1 30.2 ± 1.4 33.2 ± 2.2 51.7 ± 1.8 58.1 ± 1.7 59.2 ± 2.1 - - 60.9 ± 2.5 21 60.6 ± 1.6 48.1 ± 1.4 30 ± 1.7 29.3 ± 1.1 30.3 ± 1.2 40.9 ± 1.6 54.7 ± 2.3 58.7 ± 1.9 - - 59 ± 1.8 Note: * - significantly, compared with the control, at p <0.05 Table 8 The effect of compound 30 and dazoxiben on the APTT of rabbits when administered intravenously (M ± t). Substance mg / kg APTT Values the control Time after administration 30 minutes 1 hour 3 h 5 h 7 h 9 h 11 h 13 h 15 h 24 h thirty eleven 15.7 ± 1.3 15.2 ± 1.5 15.9 ± 1.1 16.4 ± 1.6 18 ± 1.4 21.3 ± 2.3 22.7 ± 2.2 20.3 ± 1.2 18.2 ± 1.9 16.8 ± 2.4 15.4 ± 2.1 16 15.3 ± 1.6 15.7 ± 1.8 15.9 ± 1.1 19.5 ± 2.1 23.5 ± 1.4 26 ± 1.8 28.1 ± 1.3 28.9 ± 1.2 26.1 ± 2.3 24.1 ± 2.5 15.2 ± 1.9 21 16.1 ± 1.1 16.7 ± 1.6 17 ± 2.1 19 ± 1.3 22.9 ± 1.1 26.5 ± 1.8 29.1 ± 1.6 29.2 ± 2.3 29 ± 1.9 27.4 ± 1.5 16.3 ± 2.4 Dazoxiben eleven 14.8 ± 1.4 15.3 ± 1.6 16.6 ± 1.2 23.3 ± 1.9 21.4 ± 1.3 17.5 ± 2.1 15.5 ± 1.2 15.4 ± 1.7 - - 15.1 ± 2.3 16 15.1 ± 1.1 15.2 ± 1.4 16 ± 1.7 24.8 ± 1.3 24 ± 1.9 17 ± 1,2 15.3 ± 2.4 15.4 ± 2.2 - - 15.3 ± 1.8 21 15.5 ± 1.7 15.9 ± 1.3 16.6 ± 1.2 24.3 ± 1.9 23.5 ± 1.5 23.1 ± 2.1 18.3 ± 1.8 16.3 ± 1.6 - - 15.6 ± 2.1

The use of ω- (1H-azol-1-yl) -N-phenylalkylamides of the formula I as antiplatelet agents in medicine can increase the effectiveness of antiplatelet drugs and expand the range of hematotropic drugs. According to the effect manifested both in in vitro and in vivo experiments, some of the studied compounds exceeded the dazoxiben standard, both when aggregated by ADP and collagen, they exerted a dose-dependent effect on plasma coagulation factors. Thus, can these compounds expand the arsenal of drugs? used for diseases of the cardiovascular system.

Claims (4)

1. Substituted ω-azolylalkananilides of the general formula I

where Z and Y denote a nitrogen atom or a CH group, or are simultaneously a chain C — CH = CH — CH = CH — C constituting together an annelated ring, n is an integer from 1 to 3, R is the same or different is a hydrogen atom, halogen, an alkyl group with a number of carbon atoms from 1 to 4, an alkoxy group, an alkylenedioxy group, a benzyloxy group, a perfluoroalkyl group with a number of carbon atoms from 1 to 4, a nitro group, an alkoxycarbonyl group, a carboxyl group, a halogenophenylthio group, a halogenbenzoyl group, and 0 means 5, their salts with to islots. 2. A method of producing substituted ω-azolylalkananilides of the general formula I,

where Z and Y denote a nitrogen atom or a CH group, or are simultaneously a chain C — CH = CH — CH = CH — C constituting together an annelated ring, n is an integer from 1 to 3, R is the same or different is a hydrogen atom, halogen, an alkyl group with a number of carbon atoms from 1 to 4, an alkoxy group, an alkylenedioxy group, a benzyloxy group, a perfluoroalkyl group with a number of carbon atoms from 1 to 4, a nitro group, an alkoxycarbonyl group, a carboxyl group, a halogenophenylthio group, a halogenbenzoyl group, and 0 means 5, concluding The fact is that ω-haloacyl halides acylate substituted anilines in organic solvents in the presence of an aqueous solution of hydroxides or carbonates of alkali or alkaline earth metals at a temperature of 0 to 20 ° C to obtain ω-haloacetanilides of the formula II, where R, m, n have the same values as in formula I, X means halogen, which is reacted with alkali metal azolates in a polar aprotic solvent at a temperature of from 40 to 150 ° C.

3. A method of producing substituted ω-azolylalkananilides of the general formula I,

where Z and Y denote a nitrogen atom or a CH group, or are simultaneously a chain C — CH = CH — CH = CH — C constituting together an annelated ring, n is an integer from 1 to 3, R is the same or different is a hydrogen atom, halogen, an alkyl group with a number of carbon atoms from 1 to 4, an alkoxy group, an alkylenedioxy group, a benzyloxy group, a perfluoroalkyl group with a number of carbon atoms from 1 to 4, a nitro group, an alkoxycarbonyl group, a carboxyl group, a halogenophenylthio group, a halogenbenzoyl group, and 0 means 5, concluding The fact is that ω-azolylalkanoic acids of the formula III, where n, Z and Y have the same meanings as in the formula I, are reacted with chlorinating agents in an inert solvent at a temperature of from 20 to 50 ° С to obtain acid chloride hydrochlorides ω-azol-1-ylalkanoic acids of the formula IV, where n, Z and Y have the same meanings as in the formula I with which substituted anilines are acylated in a polar aprotic solvent in the presence of bases at a temperature of from 20 to 60 ° С

4. The use of substituted ω-azolylalkananilides of the general formula I

where Z and Y denote a nitrogen atom or a CH group, or are simultaneously a chain C — CH = CH — CH = CH — C constituting together an annelated ring, n is an integer from 1 to 3, R is the same or different is a hydrogen atom, halogen, an alkyl group with a number of carbon atoms from 1 to 4, an alkoxy group, an alkylenedioxy group, a benzyloxy group, a perfluoroalkyl group with a number of carbon atoms from 1 to 4, a nitro group, an alkoxycarbonyl group, a carboxyl group, a halogenophenylthio group, a halogenbenzoyl group, and 0 means 5, and their salts with acids as anti-aggregation drugs.