WO1993021163A1 - Quinazolones having cardiovascular activity - Google Patents

Abstract

Compounds of general formula (I), the pharmaceutically acceptable salts thereof, a process for the preparation and the use thereof as antianginal agents.

Description

QUINAZOLONES HAVING CARDIOVASCULAR ACTIVITY

The present invention relates to quinazolones having cardiovascular activity and pharmaceutical compositions containing them.

The compounds of the invention have the following general formula (I):

wherein:

Z is one of the groups of formula

in which the nitrogen atom is

directly bound to the aromatic ring, wherein:

R₁ and R₂ are independently hydrogen, C₁-C₆ alkyl, C₅-C₇ cycloalkyl, phenyl, phenyl optionally substituted with 1 or 2 groups selected independently from OH, halogen, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, carboxy, carbo(C₁-C₄) alkoxy, substituted carbamoyl, cyano, formyl, C₂-C₆ aliphatic acyl;

or, R₁ and R₂ taken together with the carbon atom they are linked to, can form a cycloaliphatic group of 5 to 7 carbon atoms;

R₃ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, phenyl, phenyl optionally substituted with 1 or 2 groups selected independently from OH, halogen, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkyl thio, carboxy, carbo(C₁-C₄) alkoxy, substituted carbamoyl, cyano, formyl, C₁-C₆ aliphatic acyl; or R₃ is , ,

, -NR_aR_b, ' . -SR_a, ,

, halogen, CN;

R₄ and R₅ are independently hydrogen, halogen, hydroxy, C₁-C₆ alkoxy, , , formyl, C₂-C₆

aliphatic acyl, ,

carbo(C₁-C₄) alkoxy, carboxy, cyano, substituted carbamoyl, -CF₃, -NR_aR_b, , C₁-C₆ alkyl,

-N=CH-NR_aR_b' , , ,

-N=CH-Ph, -SR_a, . ;

R₆ is hydrogen, C₁-C₆ alkyl, C₅-C₆ cycloalkyl, phenyl, phenyl optionally substituted with 1 or 2 groups selected independently from OH, halogen, NO-, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, carboxy, carbo(C₁-C₄)alkoxy, substituted carbamoyl, formyl, C₂-C₆ aliphatic acyl; COR_d, COOR_d, CONR_dR_d,;

Y is C₂-C₆ alkylene, cyclopentylene, cyclohexylene, cycloheptylene;

R_a, R_b and R_c, which can be the same or different from each other, are hydrogen, C₁-C₆ alkyl,. C₅-C₇ cycloalkyl, phenyl, phenyl optionally substituted with 1 or 2 groups selected independently from OH, halogen, N0₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, carboxy, carbo(C₁-C₄)alkoxy, substituted carbamoyl, cyano, formyl, C₂-C₆ aliphatic acyl;

R_d and R_d, have the same meanings as R_a, R_b and R_c, except for hydrogen, R_e is hydrogen or C₁-C₅ alkyl;

X is O or S.

The invention also comprises the pharmaceutically acceptable salts of the compounds of formula (I), the diastereomers, the enantiomers and the mixtures thereof.

As herein intended, the alkyl groups are preferably methyl, ethyl, propyl, isopropyl, butyl, 2-methylbutyl, pentyl, 3-methylbutyl, isopentyl, hexyl and analogues, whereas the alkoxy groups are preferably selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-methylbutoxy, ter-butoxy. A C₁-C₆ alkylene chain can be straight or branched and it can be ethylene, 2- methylethylene, 1,3-propylene, 1,4-butylene, 2-ethylethylene, 2-methylpropylene, 1,5-pentylene, 2-ethylpropylene, 2-methylbutylene, 1,6-hexylene, 1-ethyl-1- methylpropylene, 3-methylpentylene and analogues.

US 3,908,011 discloses 6,7,8-trialkoxy-4-aminoquinazolines having antianginal activity, WO 89/05808 discloses nitric acid organic heterocyclic esters having muscle-relaxant activity.

The compounds of the invention have cardiovascular activity.

The compounds of the invention can be prepared according to the following general Scheme 1

Scheme 1

wherein Z, Y, R₄ and R₅ have the meanings reported above, Hal is halogen, for example chlorine, bromine and iodine.

The free OH group of the compounds of formula (II) is replaced by a halogen atom by the action of conventional halogenating agents such as, thionyl chloride, sulforyl chloride, phosphorous trichloride, phosphorous pentachloride, phosphorous oxytrichloride, phosphorous tribromide, sulforyl bromide and the like. The reaction is carried out in an inert organic solvent at temperatures from about room temperature to the reflux temperature of the reaction mixture. The compounds of formula (III) are thus obtained, which are then converted into the desired products of formula (I) by means of suitable procedures to insert the -ONO₂ group, for example by treatment with silver nitrate in the presence of an inert organic solvent such as acetonitrile. A silver nitrate molar excess is preferably used, calculated on the compound of formula (III), and the reaction is carried out at a temperature from the boiling temperature of the reaction mixture and room temperature. The reaction is completed within a time varying from about 2 to about 6 hours. The desired final products of formula (I) are then recovered according to conventional techniques.

Alternatively, the compounds of formula (I) can be obtained directly from the compounds of formula (II) by reaction with a molar excess of trifluoromethanesulf nic anhydride and of a tetraalkylammonium nitrate, at a starting temperature from about -60° to about 0°C. Even though the amounts of trifluoromethanesulfonic anhydride and of tetraalkylammonium nitrate are not critical to the progress of the reaction, about 2 or more molar equivalents of these reagents are preferably used per mole of the starting anhydride.

The reaction is carried out in a number of organic solvents, both polar and apolar. Thus, for example, aliphatic halogenated hydrocarbons containing from 1 to 4 carbon atoms, benzene, toluene, cyclohexane, dioxane, tetrahydrofuran, lower alkyl esters of lower aliphatic acids, di -(C₁-C₄) alkylethers, pyridine, dimethylsulfoxide, dimethylformamide, dimethylacetamide, acetonitrile, and the mixtures thereof can advantageously be used.

After about 2 hours, the reaction temperature is brought to a range from about 25 to about 50ºC and it is left at this temperature for a time varying from about 1 to about 4 hours. After that, it is worked up according to the conventional techniques.

The compounds of formula (IIa) corresponding to the compounds of formula (II) in. which Z is

R₃ is hydrogen, C₁-C₈ alkyl, phenyl, phenyl optionally substituted with 1 or 2 groups selected independently from OH, halogen, NO₂, C₁-C₈ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, carbo(C₁-C₄) alkoxy, substituted carbamoyl, cyano, formyl, C₂-C₆ aliphatic acyl, can be prepared according to the reaction Scheme 2.

Scheme 2

Compound (V) is obtained by heating compound (IV) in acetic anhydride or thionyl chloride or phosphoryl chloride from about 25° to about 100ºC for 1-4 hours.

Compound (IIa) is obtained by heating from about 30° to about 130ºC for 1-5 hours the compounds (V) with H₂NYOH, wherein Y is as defined above, in the absence of solvents or in the presence of inert solvents such as benzene, toluene, nitrobenzene, aliphatic halogenated hydrocarbons, tetrahydrofuran, tetrahydropyran, dimethylformamide.

Particularly, the compounds of formula (IIa), in which R₃ is H, Y is as defined in formula (I), can be prepared according to Scheme 3 .

Scheme 3

Anthranylamides (VI), wherein R₆ is H, are condensed with triethyl orthoformate in the absence of solvents, at a temperature from about 50° to about 140°C for about 4-12 hours.

Compounds of formula (IIIc) corresponding to compounds of formula (III) in which Z is

wherein R₁ is as defined above except for C₅-C₇ cycloalkyl , R₂ is hydrogen R₆ is selected from COR_a , COOR_d, CONR_aR_b, are prepared according to the followin g Scheme :

Scheme 4

wherein Y and Hal are as defined above, R₄ and R₅ are as defined in Scheme 1, except for the groups ,

-N=CHNR_aR_b, , -N=CH-Ph.

Compounds (IIIa) are transformed into (IIIb) either with boron hydrides such as sodium borohydride, sodium cyanoborohydride, potassium borohydride in alcohol solvents such as methanol, ethanol at temperatures of about 0º-70ºC for about 2-8 hours, or by hydrogenation in alcohol solvents such as methanol, ethanol in the presence of acids such as trifluoroacetic acid, acetic acid using Pd/C, Pt/C, PtO₂ as catalyst for about 5-72 hours, at room temperature and under a pressure from about 1 to 5 atm.

Compounds (IIIb) are acylated with acyl halides, carboxylic acid anhydrides, substituted halogen carbonates, disubstituted carbamoyl halides in inert solvents such as halogenated hydrocarbons, tetrahydrofuran, in the presence of bases such as triethylamine, pyridine or in diphasic systems such as halogenated hydrocarbons and aqueous solutions of inorganic bases such as NaOH, KOH, Na₂CO₃ at a temperature of about 0°-50ºC for about 2-10 hours.

Compounds of formula (IIb), corresponding to compounds of formula (II) in which Z is ,

wherein R₆ is hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, phenyl, optionally substituted with 1 or 2 groups selected independently from OH, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, carboxy, ester, amide, nitrile, R₁ and R₂ and Y are as defined in formula (I), can be prepared according to Scheme 5.

Scheme 5

Compounds (IIb) are obtained starting from suitably substituted anthranylamides (VI) by reaction with carbonyl compounds in diluted acids (The Chemistry of Heterocyclic Compounds, Vol. 25, p. 392-393, Interscience publishers (1967)).

Compounds of formula (IIc), corresponding to compounds of formula (II) in which Z is -,

X is S, R₆ is defined as in Scheme 5, R₄, R₅ and Y are as defined in formula (I), can be prepared starting from anthranylamides (VI) and subsequently, if R₆ is H, they can be transformed into the compounds of formula (IId) corresponding to compounds of formula (II) in which Z is and R₃ is halogen, -SR_a,

; which, if R₃ is halogen or -SH,

can be transformed into (IIe), wherein R₃ is as defined in formula (I), except for hydrogen, halogen and the groups containing sulfur, according to Scheme 6.

Scheme 6

Said compounds (IIc) are obtained by condensation of the anthranylamides (VI) with CS₂ in alcohol solvents and inorganic bases such as NaOH, KOH at a temperature of about 25°-100°C, or with thiocarbonyldiimidazole in inert solvents such as benzene, tetrahydrofuran, halogenated hydrocarbons at a temperature of about 0°-50°C for about 1-5 hours.

Compounds (IId) wherein R₃ is Cl are obtained from the compounds (IIe) by reaction with halogenating agents such as chlorine, bromine, sulforyl chloride, in solvents such as halogenated hydrocarbons, glacial acetic acid.

Compound (lid) with R₃=Cl, R₄=R₅=H can be obtained as described in The Chemistry of Heterocyclic Compounds Vol. 25, p. 244-245, Intersσience publishers (1967).

Compounds (lid) wherein R₃ is SR

are obtained by alkylating compounds (IIc) with alkyl halides in the presence of inorganic bases such as K₂CO₃, or metal hydrides such as NaH, KH, in aprotic dipolar solvents such as acetone or dimethylformamide, or alternatively by acylation with acyl halides, carboxylic acids anhydrides, alkyl or aryl halogen carbonates, dialkyl o diarylcarbamoyl halides, in inert solvents such as benzene, toluene, halogenated hydrocarbons, tetrahydrofuran in the presence of organic bases such as triethylamine, pyridine or in diphasic systems of halogenated hydrocarbons and aqueous solutions of inorganic bases such as NaOH, KOH, Na₂CO₃.

Finally, the compounds of formula (IIc) in which X is O, R₄, R₅, R₆ and Y are as defined in formula (I) can be prepared according to Scheme 7.

Scheme 7

Anthranylamides (VI) are treated with alkyl or arylhalogen carbonates to give compounds (VII) which, by treatment with inorganic bases, such as NaOH, KOH in alcohol solvents such as methanol, ethanol at a temperature of about 20°-100°C for about 1-10 hours, give compounds (IIc).

As stated above, the compounds of the invention have cardiovascular activity. Particularly, they show remarkable vasorelaxing properties in vitro, and a remarkable antianginal activity in the animal.

These favourable biological properties are accompanied by a negligible hypotensive effect, whereas such a side-effect is known to be marked in the known nitro derivatives used in therapy.

Therefore, the compounds of the invention can be considered as potential medicaments having a specific antianginal activity. They also proved to have antiarrhythmic activity, which is a further favourable property, since angina attacks are often accompanied by more or less marked arrhythmias.

In vitro vasorelaxing activity

The vasorelaxing activity (VSRL) was evaluated in the test of the rabbit aorta strip, contracted by the action of noradrenalin. The test was performed according to the method described by K. Murakami et al.

Eur. J. Pharmacol., 141, 195, 1987. The IC₅₀s were determined, i.e. the concentrations, expressed in umol./l, of active substance inhibiting by 50% the contraction of the aorta strip.

The results obtained for some representative compounds of the invention are reported in the following Table 1.

Table 1

Compound IC₅₀ (μmol/l)

ITF 1427 2.8

ITF 1428 0.078

ITF 1437 0.19 In vivo antianginal activity

The antianginal activity was evaluated in vivo on anaesthetized Sprague Dawley rats, weighing 350-400 g, according to the procedure by M. Leitold et al., Arzneim. Forsch. 36, 1454, 1986. The test was effected administering the animal intravenously with 1 U.I/kg of 3 mg/kg of Arg-vasopressin, which induces a coronary spasm which can be reproduced and evidenced electrocardiographically with an increase in the width of the T wave. The compounds of the invention were administered intravenously at 4 increasing doses, one hour before the administration of Arg-vasopressin. The antianginal effect was expressed as ED₅₀, i.e. the dose inhibiting by 50% the increase in the T-wave versus controls.

As an example, the compound, described hereinafter in example 2, proved to have an ED₅₀ of 0.18 mg/kg.

The present invention also relates to the use of the novel compounds as antianginal agents, to all the industrially applicable aspects of the use thereof, as well as to the use thereof for the preparation of pharmaceutical compositions. Examples of said pharmaceutical compositions are tablets, sugar-coated tablets, syrups and vials, the latter both for the oral and the intramuscular or intravenous administrations. They contain the active ingredient alone or in combination with pharmaceutically acceptable conventional carriers and excipients.

The dosages of the active ingredient used for the treatment of angina attacks will vary within wide ranges according to the nature of the compound used and they are selected to achieve the most effective therapeutic effect in the patient during 24 hours.

The following examples further illustrate the invention.

The H-NMR spectra were effected in DMSO with a Varian Gemini 200 spectrometer. The ¹³C-NMR were performed using a Varian Gemini 200 spectrometer, taking the DMSO peak at 39.5 ppm as the reference peak. EXAMPLE 1

A. N-(2-Hydroxyethyl)anthranylamide

A mixture of 29 g (0.191 moles) of methyl anthranylate and 100 ml (1.66 moles) of ethanolamine was heated to 170°C and kept at said temperature until complete distillation of the formed methanol The reaction mixture was brought to room temperature, taken up with methylene chloride and washed with a NaCl aqueous saturated solution. The organic phase was dried over sodium sulfate and evaporated under vacuum.

25 g of the title product were obtained as an oil which was used directly for the subsequent step.

B. 3-(2'-Hydroxyethyl)-3,4-dihydroquinazolin-4-one

A mixture of 25 g (0.138 moles) of the product prepared under 1A and 127 ml (0.763 moles) of triethyl orthoformate was heated to 130ºC for 8 hours. By cooling the obtained solution, the title product precipitated. 8 g of product were obtained (m.p. = 120°-122ºC, n-hexane).

C. 3-(2'-Chloroethyl)-3,4-dihydroquinazolin-4-one

The product obtained under 1B (7.7 g, 0.040 moles) was dissolved in 250 ml of chloroform, and the resulting solution, cooled to 0°C, was added dropwise with 3.57 ml (0.048 moles) of thionyl chloride. The obtained solution was heated to 70°C for 5 hours, then washed with water, dried over sodium sulfate and the solvent was evaporated off to obtain 6 g of the title product (m.p. = 122°-123°C; ethyl acetate).

D. 3-(2'-Nitroxyethyl)-3,4-dihydroquinazolin-4-one

The product obtained under 1C (5.2 g, 0.025 moles) was dissolved in 100 ml of acetonitrile and the resulting solution was added with 12.8 g (0.075 moles) of silver nitrate.

The mixture was heated to 85ºC for 10 hours. After cooling, the formed salts were removed by filtration and the solvent was evaporated off. The obtained crude product was taken up with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated to dryness, to obtain 4.4 g of the title product (m.p. = 109°-110°C hexane).

1HNMR (DMSO) (200 MHz) δ: s, 1H, 11.53; dd, 1H, 7.91; dt, 1H, 7.65; t, 1H, 7.19; d, 1H, 7.17; m, 2H, 4.76; m, 2H, 4.29.

¹³CNMR (DMSO) (50.3 MHz) ppm : 162.34; 150.42; 139.66; 135.36; 127.62; 122.82; 115.44; 113.80; 71.17; 37.76. EXAMPLE 2

A. 3-Methylbenzoxazin-3,1-one-4

A solution of N-acetylanthranylic acid ( 15 g , 0.083 moles ) in 100 ml of acetic anhydride was heated to 130 °C for 1 hour . The mixture was evaporated to dryness to obtain 13.5 g of the title product which was used directly for the subsequent reaction . B. 3-(2'-Hydroxyethyl)-2-methyl-3,4-dihydroquinazolin-4-one

A solution of 13.5 (0.083 moles) of the product prepared under 2A in 170 ml (2.83 moles) of ethanolamine was heated to 130°C for 2 hours. The resulting mixture was poured into water and extracted with methylene chloride. The organic phase was dried over sodium sulfate and the solvent was evaporated off. The obtained crude product was crystallized from ethyl acetate to obtain 8.5 g of the title product (m.p. 155°-157ºC).

C. 3-(2'-Chloroethyl)-2-methyl-3,4-dihydroquinazolin- 4-one

The product was prepared from 7.5 g (0.036 moles) of the product prepared under 2B, following the procedure described in 1C. 4.7 g of the title product were obtained (m.p. = 130°-131ºC hexane).

D. 3-(2'-Nitroxyethyl)-2-methyl-3,4-dihydroquinazolin-4-one

The product was prepared from 4.3 g (0.019 moles) of the product prepared under 2C following the procedure described in 1D. 3.7 g of the title product were obtained (m.p. = 102°-104°C hexane).

1HNMR (DMSO) (200 MHz) δ : dd, 1H, 8.11; dt, 1H, 7.82; d, 1H, 7.60; t, 1H, 7.50; t, 2H, 4.88; t, 2H, 4.47; s, 3H, 2.63.

¹³CNMR (DMSO) (50.3 MHz) ppm : 161.79; 155.09; 147.27; 134.76; 126.80; 126.65; 126.46; 120.05; 71.22; 41.62. EXAMPLE 3

A. N-(2-Ethoxycarbonyloxyethyl)-2'-ethoxycarbamoylbenzamide A solution of N-(2-hydroxyethyl)anthranylamide (25 g, 0.1387 moles) in ethyl chloroformate (125 ml) was slowly added at 0°C with triethylamine (36 ml, 0.2774 moles). The reaction mixture was refluxed for 8 hours, then was evaporated to dryness. The resulting crude product was taken up with water and extracted with ethyl acetate. The combined organic phases were washed with water, dried over anhydrous sodium sulfate and evaporated under vacuum to obtain 43 g of title product as an oil which was used directly for the subsequent step.

B. 3-(2'-Hydroxyethyl)-quinazolin-2,4-dione

A mixture of product 3A (43 g, 0.1387 moles) and potassium hydroxide (16 g, 0.2774 moles) in ethanol (350 ml) was refluxed for 3 hours . The solvent was evaporated off and the resulting crude product was taken up with water. The pH was adjusted to about 7 with acetic acid, and the obtained solid was filtered, washed with water and dried to obtain 5.5 g of the title product (m.p. = 247-249ºC water).

C. 3-(2'-Nitroxyethyl)-quinazolin-2,4-dione

A solution of the compound prepared under B (4.7 g, 24.7 mmoles) and tetrabutylammonium nitrate (15 g, 49.42 mmoles) in methylene chloride (140 ml), dimethylformamide (140 ml) and pyridine (4 ml), cooled to -50°C, was added dropwise with trifluoromethanesulfonic anhydride (8 ml, 49.42 mmoles) dissolved in methylene chloride (94 ml). The reaction mixture was stirred at this temperature for 15 minutes, then brought to room, temperature, stirred at this temperature for 30 minutes and subsequently washed with water, 0.5% aqueous hydrochloric acid, 5% aqueous sodium bicarbonate and again with water, and finally dried over anhydrous sodium sulfate. After evaporation of the solvent, a crude product was obtained which was purified on a silica gel column. Yield 1.6 g of the title compound (m.p. = 192°-193°C, ethyl acetate).

1HNMR (DMSO) (200 MHz) δ : s, 1H, 8.41; dd, 1H, 8.18; dt, 1H, 7.86; d, 1H, 7.71; t, 1H, 7.58; t, 2H, 4.89; t, 2H, 4.40.

1³CNMR (DMSO) (50.3 MHz) ppm: 160.70; 148.13(2); 134.75; 127.49; 127.43; 126.35; 121.72; 71.40; 43.60. EXAMPLE 4

1-Acetyl-3-(2'-nitroxyethyl)-1,2,3,4-tetrahydroquinazolin-4-one

A. 1-Acetyl-3-(2'-chloroethyl)-1,2,3,4-tetrahydroquinazolin-4-one

A solution of 3-(2'-chloroethyl)-3,4-dihydroquinazolin-4-one prepared as described in example 1C (8.6 g, 0.412 moles) in ethanol (300 ml) and trifluoroacetic acid (1.5 ml), was added with 10% palladium on carbon (860 mg). The reaction mixture was hydrogenated at room temperature, under 2 atm for 24 hours. The catalyst was filtered off and the solvent evaporated. The obtained crude product was redissolved in tetrahydrofuran (200 ml) and pyridine (30 ml), then acetyl chloride (29.3 ml, 0.338 moles) was slowly added at 0°C. The reaction mixture was stirred at room temperature for 4 hours, then more pyridine (15 ml) and acetyl chloride (15 ml, 0,1731 moles) were added at 0°C, after that the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate; the combined organic phases were washed with a sodium bicarbonate saturated solution, then with a 1M hydrochloric acid solution, dried over anhydrous sodium sulfate and evaporated to obtain 10.5 g of the title product which was used directly for the subsequent step.

B. 1-Acetyl-3-(2'-nitroxyethyl)-1,2,3,4-tetrahydro- quinazolin-4-one

A solution of the product obtained under 4A (6.3 g, 0.0251 moles) and silver nitrate (8.4 g) in acetonitrile (140 ml) was refluxed for 2 hours. After cooling, the formed salts were filtered off and the solvent was evaporated. The resulting crude product was taken up with water and extracted with ethyl acetate.

The organic phases were dried over anhydrous sodium sulfate and evaporated to obtain 6.5 g of a crude product, which was purified by chromatography on a silica gel column, the eluent being ethyl acetate/hexane 3:2, to obtain 4.5 g of the title product (m.p. = 85-86ºC, hexane).

¹H-NMR (DMSO) (200 MHz) δ : d, 1H, 7.90; m, 2H, 7.69- 7.57; t, 1H, 7.38; s, 2H, 5.23; t, 2H, 4.73; t, 2H, 3.99; s, 3H, 2.30.

1³C-NMR (DMSO) (50.3 MHz) ppm: 169.29; 162.77; 140.43;

132.58; 127.98; 125.87; 123.91; 123.54; 71.60; 58.33; 42.42; 22.38.

Claims

1. Compounds of general formula (I)

wherein:

Z is one of the groups of formula

in which the nitrogen atom is

directly bound to the aromatic ring, wherein:

R₁ and R₂ are independently hydrogen, C₁-C₆ alkyl, C₅-C₇ cycloalkyl, phenyl, phenyl optionally substituted with 1 or 2 groups selected independently from OH, halogen, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁_C₆ alkylthio, carboxy, carbo(C₁-C₄) alkoxy, substituted carbamoyl, cyano, formyl, C₂-C₈ aliphatic acyl;

or, R₁ and R₂ taken together with the carbon atom they are linked to, can form a cycloaliphatic group of 5 to 7 carbon atoms;

R₃ is hydrogen, C₁-C₈ alkyl, C₁-C₆ alkoxy, phenyl, phenyl optionally substituted with 1 or 2 groups selected independently from OH, halogen, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, carboxy, carbo(C₁-C₄) alkoxy, substituted carbamoyl, cyano, formyl, C₂-C₆ aliphatic acyl; or R₃ is , -NR_aR_b, , ,

-SR_a, halogen, CN;

R₄ and R₅ are independently hydrogen, halogen, hydroxy, C₁-C₆ alkoxy, , , formyl, C₂-C₈ aliphatic

acyl, , carbo(C₁-C₄)alkoxy , carboxy, cyano,

substituted carbamoyl, -CF₃, -NR_aR_b, , C₁-C₈ alkyl.

-N=CH-NR_aR_b, . ,

-N=CH-Ph, -SR_a, , , ;

R₆ is hydrogen, C₁-C₈ alkyl, C₅-C₇ cycloalkyl, phenyl, phenyl optionally substituted with 1 or 2 groups selected independently from OH, halogen, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, carboxy, carbo(C₁-C₄)alkoxy, substituted carbamoyl, formyl, C₂-C₆ aliphatic acyl; COR_d, COOR_d, CONR_dR_d';

Y is C₂-C₆ alkylene, cyclopentylene, cyclohexylene, cycloheptylene; R_a, R_b and R_c, which can be the same or different from each other, are hydrogen, C₁-C₆ alkyl, C₅-C₇ cycloalkyl, phenyl, phenyl optionally substituted with 1 or 2 groups selected independently from OH, halogen, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, carboxy, carbo(C₁-C₄)alkoxy, substituted carbamoyl, cyano, formyl, C₂-C₈ aliphatic acyl;

R_d and R_d' have the same meanings as R_a, R_b and R_c, except for hydrogen, R_e is hydrogen or C₁-C₅ alkyl;

X is O or S;

the pharmaceutically acceptable salts thereof as well as the diastereomers, the enantiomers and the mixtures thereof.

2. Pharmaceutical compositions containing a therapeutically effective amount of at least one compound of claim 1 in admixture with a pharmaceutically acceptable carrier.

3. The use of the compounds according to claim 1 for the preparation of a medicament for the antianginal therapy.

4 . The use of the compounds according to claim 1 as antianginal agents .