WO1993025542A1

WO1993025542A1 - Benzoxazinone and benzothiazinone derivatives having cardiovascular activity

Info

Publication number: WO1993025542A1
Application number: PCT/EP1993/001377
Authority: WO
Inventors: Silvio Levi; Francesca Benedini; Giorgio Bertolini; Giancarlo Dona; Gianni Gromo; Alberto Sala
Original assignee: Italfarmaco S.P.A.
Priority date: 1992-06-10
Filing date: 1993-06-01
Publication date: 1993-12-23
Also published as: ITMI921423A0; IT1256023B; ITMI921423A1

Abstract

Benzoxazinone and benzothiazinone derivatives having cardiovascular activity and the salts thereof with pharmaceutically acceptable acids and bases are of formula (I), wherein Y is methylene, optionally branched (C3-C6) alkylene or cyclopentylene, cyclohexylene or cycloheptylene; X and Z are independently S or O.

Description

BENZOXAZINONE AND BENZOTHIAZINONE DERIVATIVES HAVING CARDIOVASCULAR ACTIVITY

The present invention relates to 2,3-dihydro-4H- 1,3-benzoxazin- and -benzothiazin-4-one 2-oxo and 2- thioxo derivatives of general formula (I)

wherein R is hydrogen; halogen; hydroxy; (C,-C₈)alkyl; nitro; sulfo; cyano; R₃OCONH-, R₃C0NH-, wherein R₃ is

⁽C^-Cg)alkyl, phenyl or benzyl; (C₁-C₄)alkoxy; amino, mono- and di-(C₁_c₆)alkylamino; formyl; trifluoro- methyl;

Y is methylene, ethylene, optionally branched (C₃

Cg)alkylene, or cyclopentylene, cyclohexylene or cycloheptylene;

X and Z are independently S or 0; and the salts thereof with pharmaceutically acceptable acids and bases.

As herein intended, the alkyl groups are prefera¬ bly methyl, ethyl, propyl, i-propyl, butyl, 2-methyl- propyl, n-pentyl, 3-methylbutyl, i-pentyl, n-hexyl and the like, whereas the alkoxy groups are preferably selected from methoxy, ethoxy, propoxy, i-propoxy, butoxy, 2-methylbutoxy and t-butoxy. Straight or branched (C^-Cg)alkylene means, for example, 2-me- thylethylene, 1,3-propylene, 1,4-butylene, 2-ethylethy- lene, 3-methylpropylene, 1,5-pentylene, 2-ethylpropy- lene, 2-methylbutylene, 1,6-hexylene, 1-ethyl-l-methyl- propylene, 3-methylpentylene and the like.

2,3-Dihydro-4H-l,3-benzoxazin-4-ones unsubstituted on the nitrogen were described by B.W. Horrom et al., J. Org. Chem. , 72., 721 (1950) to have analgesic activity. Other 2,3-dihydro-4H-l,3-benzoxazin-4-ones were described by R.B. Gammil, J. Org. Chem., 4_6_, 3340 (1981). Derivatives from the same heterocycle, but with the nitrogen atom substituted, were described by J. Finkelstein et al. , J. Med. Chem., 11, 1038 (1968) as compounds likely to have antiinflammatory activity. Analogue derivatives having an amino group at the 6- position, also having antiinflammatory activity, were reported by F. Fontanini et al. , Riv. Farmacol. Ter., 4(1) , 119 (1973) (Chem. Abs. 73745n, Vol. 79, page. 40, 1073).

The compounds of the invention are prepared by known processes. For example, compounds of formula (I) wherein X is oxygen can be prepared as follows. A molar amount of an acid of formula (Ila)

wherein R is as defined above, R, is an hydroxy- protecting group, for example (C__c₄)acyl or trialkylsilyl , or of a reactive derivative thereof, such as a halide or a symmetric or mixed anhydride, is reacted with a substantially equimolar amount of an amino-alkanol nitric ester of formula (III)

H₂N-Y-ON0₂ (III) wherein Y is as defined above, or of a salt thereof, such as a halide or a nitrate, to obtain the amide of formula (IV)

wherein R, R^ and Y are as above defined. The reaction is carried out in water or in an organic solvent such as an halogenated aliphatic hydrocarbon, or in water/organic solvent mixtures, at a temperature ranging from about 0°C to room temperature, and it is over in a time from about 1 hour to about 3 hours. When a compound of formula (III) is used in form of a salt thereof, the reaction is preferably carried out also in the presence of an organic or inorganic base. Generally, for this purpose a molar excess of an alkali or alkaline-earth metal carbonate or bicarbonate is used, or of a nitrogenated organic base, such as trimethy1amine , triethylamine, pyridine and analogues, said excess being calculated on compound of formula (Ila).

Subsequently the hydroxy-protecting group R.. is removed (see, for example, T.W. Greene and P.G.M. Wuts, "Protective groups in organic synthesis", 2° Ed., J. Wiley & Son, 1991) to obtain the compound of formula (V)

wherein R and Y are as above defined, which is used for the subsequent cyclization reaction to give the corresponding compound of formula (I). For this purpose, said compound is treated with an equimolar amount of 1,1'-carbonyldiimidazole or another carbonic acid derivative, such as phosgene, or 1,1'- thiocarbonyldiimidazole or another thiocarbonic acid derivative, such as thiophosgene, at a temperature from about -50°C to about 50°C, in a solvent such as tetrahydrofuran, benzene, toluene, a polyhalogenated aliphatic hydrocarbon, dimethy1formamide, mixtures thereof and analogs. The reaction is carried out in the presence of a base such as sodium, sodium methoxide, sodium ethoxide and the like. The reaction times ranges from about 30 minutes to about 5 hours.

Alternatively, a compound of formula (lib) is converted into a corresponding ester of formula (lie)

wherein R is as defined above, and R,, is a group selected from (C^CgJalkyl, such as methyl, ethyl, i- propyl, t-butyl, n-pentyl, benzyl, substituted benzyl or nitrophenyl, which compound is then treated with a substantially equimolar amount of an amino-alkanol of formula (VII)

NH₂_γ-0H (VII) wherein Y is as defined above , optionally in an inert organic solvent , such as an halogenated aliphatic hydrocarbon , at a temperature from about 50 °C to about

200 ^βC .

The resulting amide of formula (VI)

wherein R and Y are as above defined, is reacted with an equimolar amount of 1 , 1 ' -carbonyldiimidazole or another carbonic acid derivative such as phosgene , or of 1 , 1 ' -thiocarbonyldiimidazole or another thiocarbonic acid derivative such as thiophosgene , according to the procedure de scribed above for the steps from compound of formula (V) to compound of formula (I). The resulting compound of formula (VIII)

10 wherein R, Y and Z are as defined above, is then converted into the desired compound of formula (I) as shown in the following reaction scheme.

wherein R, Y and Z are as defined above, and halo is a halogen atom. According to this scheme, the free OH

30 group of the compound of formula (VIII) is substituted with a halogen atom by means of a common halogenating agent such as thionyl chloride, sulfuryl chloride, phosphorous trichloride, phosphorous pentachloride, phosphorous oxytrichloride, phosphorous tribromide, sulfuryl bromide and the like. The reaction proceeds in an organic solvent, preferably in an inert organic solvent such as benzene, toluene, nitrobenzene or chlorobenzene, halogenated aliphatic hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane or 1,1,2-trichloroethane, cyclohexane, tetrahydrofuran, dimethylformamide and the like, at a temperature ranging from about room temperature to the reflux temperature of the reaction mixture. The resulting compound of formula (IX) is subsequently converted into the desired compound of formula (I) through suitable procedures to introduce the -NO- group, for example by treatment with silver nitrate in the presence of an organic solvent such as acetonitrile. Preferably, a silver nitrate molar excess is used calculated on compound of formula (IX), and the reaction is carried out at a temperature from the reflux temperature of the reaction mixture to room temperature; the reaction is over in a time ranging from about 2 to about 6 hours. The resulting compound of formula (I) wherein X is oxygen is recovered according to known techniques. Alternatively, compound of formula (VIII) can be transformed directly into the compound of formula (I) by reacting said compound with 2 molar equivalents of tetrabutylammonium nitrate, of a nitrogenated organic base such as pyridine, and trifluoromethanesulfonic anhydride, at a starting temperature ranging from about -60°C to about -40°C. The reaction proceeds in solvents such as an halogenated organic solvent or dimethylfor¬ mamide or mixtures thereof. After about two hours, the reaction temperature is brought to a range from about 25°C to about 50°C and it is left to this temperature for a time ranging from about 1 to about^" 4 hours. The resulting compound of formula (I) is worked up with the conventional techniques.

When compound of formula (I) is desired in which X is sulfur, the procedure indicated below can, for example, be followed.

An acid of formula (lid)

wherein R is as defined above, is reacted with an equimolar amount of 1,1'-carbonyldiimidazole or another carbonic acid derivative such as phosgene, or of 1,1'- thiocarbonyldiimidazole or another thiocarbonic acid derivative such as thiophosgene, in an inert solvent such as tetrahydrofuran, benzene, toluene, a polyhalo- genated aliphatic hydrocarbon, dimethylformamide, mixtures and analogues, at a temperature from about

10°C to about 50°C and for times ranging from about 10 minutes to about 1 hour. Subsequently, said reaction mixture is added with a substantially equimolar amount, on compound of formula (lid), of an a amino-alkanol nitric ester of formula (III), wherein Y is as defined above, or of a salt thereof, in a inert solvent and in the presence of a base such as triethylamine, trimethylamine, pyridine and the like, at a temperature from about 10°C to about 40°C, preferably at room temperature, and for times ranging from about 1 to 8 hours, to obtain the desired compound of formula (I).

This procedure can also be applied starting from the compound of formula (lie), to give compounds of formula (I) in which X is an oxygen atom. The starting compounds (Ila), (lib) and (lid) are commercially available products or they can be prepared by conventional techniques.

The following examples further illustrate the present invention. EXAMPLE 1

2,3-Dihydro-3-(2'-nitrooxyethyl)-1,3-benzoxazin-2,4- dione

A. 2-Acetoxy-N-(2'-nitrooxyethyl)benzamide

A solution of 40.7 g (0.485 mole) of sodium bicarbonate in 150 ml of water and 120 ml of chloroform was added with 18.6 g (0.11 mole) of 2- nitrooxyethylamine nitrate, at 0°C. After 10 minutes, 22.5 g (0.113 mole) of 2-acetoxybenzoic acid chloride were dropped therein and the resulting solution was left for 2 hours at 0°C.

After warming the solution to room temperature, the phases were separated. The organic phase was dried over sodium sulfate and 21 g of the title product were obtained. M.p.: 88°C (ethanol)

B. 2-Hydroxy-N-(2 '-nitrooxyethyl)benzamide A solution of 18 g (0.067 mole) of the compound prepared in A, in 300 ml of methanol and 60 ml of water, was added with 1.37 g (0.02 mole) of imidazole. The solution was left to stand for 12 hours at room temperature, then concentrated. The resulting residue was taken up into water and extracted with methylene chloride. The organic phase was dried over sodium sulfate to obtain 12.7 g of the title product. M.p.: 78°C (methanol)

C. 2,3-Dihydro-3-(2 '-nitrooxyethyl)-1,3-benzoxazin- 2 ,4-dione

A solution of 9.7 g (0.041 mole) of the product prepared under B, in 500 ml of tetrahydrofuran, was added with 0.219 g (0.004 mole) of sodium methoxide and 6.62 g (0.041 mole) of 1,1'- carbonyldiimidazole. The solution was left to stand at room temperature for 4 hours, then concentrated, and the residue was taken up into water and extracted with chloroform, then dried over sodium sulfate, to give 9.5 g of the title product.

M.p.: 89°C (n-hexane) Elemental analysis C H N Calculated 47.63 3.20 11.11

Found 47.62 3.20 11.01

¹H-NMR (DMSO): 8.01 (dd, 1H) ; 7.85 (dt, 1H) ; 7.5U7.43 (m, 2H) ; 4.78 (m, 2H) ; 4.28 (m, 2H).

¹³C-NMR (DMSO): 160.81; 152.55; 148.09; 136.68; 127.63; 125.71; 116.63; 114.36; 70.71; 39.36. EXAMPLE 2

2,3-Dihydro-3-(2'-nitrooxyethyl)-1,3-benzoxazin-2- thion-4-one

A solution of 13 g (0.054 mole) of the compound prepared in example IB, in 500 ml of tetrahydrofuran, was added with 0.295 g (0.005 mole) of sodium methoxide and 9.73 g (0.054 mole) of 1,1'-thiocarbonyldiimida¬ zole. The solution was left to stand for 6 hours at room temperature, then concentrated, and the residue was taken up into water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, to obtain 6.3 g of the title product.

M.p.: 121°C (ethyl acetate) Elemental analysis C H N S Calculated 44.78 3.01 10.04 11.95

Found 44.79 3.01 10.48 12.01

^^■H-NMR (DMSO): 8.03 (dd, 1H) ; 7.91 (dt, 1H) ; 7.58^7.49 (m, 2H); 4.91 (m, 2H) ; 4.75 (m, 2H). ¹³C-NMR (DMSO): 182.61; 157.53; 154.25; 137.14; 127.67; 126.72; 116.42; 115.24; 70.04; 44.87.

EX.AMPLE 3 2,3-Dihydro-3-(2 '-nitrooxyethyl)-1,3-benzothiazin-2,4- dione

A suspension of 5 g (0.032 mole) of thiosalicylic acid in 100 ml of chloroform, was added with a solution of 10.52 g (0.064 mole) of 1,1'-carbodiimidazole in 50 ml of chloroform. The solution was left at room temperature under stirring for 30 minutes, then a solution of 5.48 g (0.032 mole) of 2-nitrooxyethylamine nitrate in 50 ml of chloroform and 6.3 ml (0.048 mole) of triethylamine was added dropwise. After 5 hours the solution was washed with water, the organic phase was dried over sodium sulfate, to obtain 2.9 g of the title product.

M.p.: 108-110°C (n-hexane) Elemental analysis C H N S

Calculated 44.78 3.01 10.44 11.95

Found 44.75 3.03 10.34 12.03

¹H-NMR (DMSO): 8.29 (dd, 1H) ; 7.79 (dt, 1H) ; 7.65 (d, 1H); 7.56 (t, 1H) ; 4.78 (m, 2H) ; 4.43 (m, 2H). ¹³C-NMR (DMSO): 164.72; 163.18; 134.79; 131.82; 131.26; 128.00; 125.38; 122.36; 70.95; 40.28.

EXAMPLE 4 2,3-Dihydro-6-methoxy-3-(2'-nitrooxyethyl)-1,3- benzoxazin-2,4-dione A. Methyl 2-hydroxy-5-methoxybenzoate

A solution of 15 g (0.089 mole) of 2-hydroxy-5- methoxybenzoic acid in 150 ml of methanol and 14 ml of concentrated sulfuric acid was refluxed for

24 hours. The mixture was then poured into ice and brought to pH - 11 with 5N sodium hydroxide and extracted with ethyl acetate. 15.1 g of the title product were obtained, which were used directly in the subsequent step.

^B _* 2-Hydroxy-N-(2 '-hydroxyethyl)-5-methoxy-benzamide A suspension of 15 g (0.084 mole) of the product prepared in A, in 57.6 g (0.96 mole) of ethanolamine was heated to 170^βC for 2 hours, distilling off the formed methanol. The resulting solution was poured into water acidified to pH - 2 with hydrochloric acid, and extracted with ethyl acetate, then dried over sodium sulfate. 14 g of the title product were obtained. C. 2,3-Dihydro-3-(2 '-hydroxyethyl)-6-methoxy-l,3- benzoxazin-2,4-dione

A solution of 10.5 g (0.05 mole) of the product prepared in B, in 100 ml of methylene chloride, was added with 0.274 g (0.005 mole) of sodium methoxide and subsequently with 8.2 g (0.05 mole) of l,l'-carbonyldiimidazole dissolved in 80 ml of methylene chloride. The resulting solution was left at room temperature for 3 hours, washed with water, and dried over sodium sulfate. The obtained crude product was dissolved in 430 ml of 2:1 tetrahydrofuran/IN hydrochloric acid, and left under stirring for 2 hours. The solution was concentrated to small volume, diluted with water and extracted with methylene chloride, then dried over sodium sulfate. 1.25 g of the title product were obtained.

M.p.: 130-132°C (methylene chloride). D. 2,3-Dihydro-6-methoxy-3-(2'-nitrooxyethyl)-1,3- benzoxazin-2,4-dione

A solution of 1.6 ml (0.001 mole) of trifluoro- methanesulfonic anhydride in 17 ml of methylene chloride was dropped into a solution of 1.2 g (0.005 mole) of the product obtained in C, 3.05 g (0.01 mole) of tetrabutylammonium nitrate, 0.809 ml (0.01 mole) of pyridine in 28.7 ml of methylene chloride and 28.7 ml of dimethylformamide, cooled to -50°C. When the addition was over, the temperature was brought to 40°C and the mixture was left under stirring for 30 minutes, then was poured into water. The organic phases were separated and washed with 1% HCl, with a sodivim bicarbonate saturated solution and with water, finally dried over sodium sulfate. The resulting crude product was purified through silica gel eluting with methylene chloride. 950 mg of the title product were obtained.

M.p.: 141-142°C (n-hexane).

¹H-NMR (DMSO): 7.43÷7.36 (m, 3H) ; 4.78 (m, 2H) ; 4.28 (m, 2H); 3.86 (s, 3H) .

¹³C-NMR (DMSO): 160.74; 156.55; 148.11; 146.76; 124.46; 118.14; 114.70; 108.81; 70.72; 56.20; 39.43.

EXAMPLE 5 2,3-Dihydro-5-methyl-3-(2'-nitrooxyethyl)-1,3- benzoxazin-2,4-dione

A. Methyl 2-hydroxy-6-methylbenzoate The product was prepared starting from 18.7 g (0.123 mole) of 2-hydroxy-6-methylbenzoic acid according to the procedure described in example 4A. 18.8 g of the title product were obtained, which was used directly in the subsequent step. B. 2-Hydroxy-N-(2 '-hydroxyethyl)-6-methyl- benzamide

The product was prepared starting from 18.8 g (0.113 mole) of the product obtained in A, following the procedure reported in example 4B. 19.3 g of the title product were obtained.

M.p.: 134-135°C (n-hexane) C. 2,3-Dihydro-3-(2 '-hydroxyethyl)-5-methyl-l,3- benzoxazin-2,4-dione

The product was prepared starting from 9.9 g (0.05 mole) of the product prepared in B, following the procedure described in example 4C. 3 g of the title product were obtained, which were used directly in the subsequent step.

D. 2,3-Dihydro-5-methyl-3-(2 '-nitrooxyethyl)-1,3- benzoxazin-2,4-dione The product was prepared starting from 2 g (0.009 mole) of the product obtained in C, following the procedure described in example 4D. 1 g of the title product was obtained.

M.p.: 75-76^βC (n-hexane) Elemental analysis C H N

Calculated 49.62 3.79 10.52

Found 49.59 3.77 10.50

^Ε-NMR (DMSO): 7.68 (t, 1H) ; 7.27 (d, 2H) ; 4.77 (m, 2H); 4.25 (m, 2H) ; 2.69 (s, 3H). ¹³C-NMR (DMSO): 161.11; 153.58; 147.95; 141.66; 135.59; 128.35; 114.64; 70.75; 39.19; 21.73.

EXAMPLE 6 7-Chloro-2,3-dihydro-3-(2'-nitrooxyethyl)-1,3- benzoxazin-2,4-dione A. Methyl 4-chloro-2-hydroxybenzoate

The product was prepared starting from 15 g (0.087 mole) of 4-chloro-2-hydroxybenzoic acid, according to the procedure described in example 4A. 15.2 g of the title product were obtained, which was used directly in the subsequent step.

B. 4-Chloro-2-hydroxy-N-(2 '-hydroxyethyl)benzamide The product was prepared starting from 15 g (0.080 mole) of the product obtained in A, following the procedure reported in example 4B. 16.1 g of the title product were obtained which was used directly in the subsequent step.

C. 7-Chloro-2,3-dihydro-3-(2 '-hydroxyethyl)-1,3- benzoxazin-2,4-dione

The product was prepared starting from 12.3 g (0.057 mole) of the product prepared in B, following the procedure described in example 4C. 1.5 g of the title product were obtained, which was used directly in the subsequent step.

D. 7-Chloro-2,3-dihydro-3-(2'-nitrooxyethyl)-1,3- benzoxazin-2,4-dione The product was prepared starting from 1.23 g (0.005 mole) of the product obtained in C, following the procedure described in example 4D. 0.71 g of the title product was obtained. M.p.: 105°C (n-hexane) Elemental analysis C H N Cl Calculated 41.90 2.46 9.78 12.37

Found 41.86 2.43 9.77 12.33

^■"^■H-NMR (DMSO): 8.01 (d, 1H) ; 7.73 (d, 1H) ; 7.53 (dd, 1H); 4.77 (t, 2H) ; 4.27 (t, 2H). ¹³C-NMR (DMSO): 160.18; 153.02; 147.76; 140.72; 129.22; 126.06; 116.88; 113.54; 70.61; 39.40.

EXAMPLE 7 2,3-Dihydro-3-(2 '-nitrooxypropyl)-1,3-benzoxazin-2,4- dione A. 2-Hydroxy-N-(3'-hydroxypropyl)benzamide

The product was prepared starting from 20 g (0.131 mole) of methyl 2-hydroxybenzoate and 13.2 ml (0.157 mole) of 3-amino-propanol, following the procedure reported in example 4B. 25 g of the title product were obtained which was used directly in the subsequent step.

B. 2,3-Dihydro-3-(2 '-hydroxy ropyl)-l,3-benzoxazin- 2,4-dione

The product was prepared starting from 7 g (0.036 mole) of the product prepared in A, following the procedure described in example 4C. 6.9 g of the title product were obtained.

M.p.: 80-81°C (n-hexane).

C. 2,3-Dihydro-3-(2 '-nitrooxypropyl)-1,3- benzoxazin-2,4-dione The compound was prepared starting from 6.8 g (0.030 mole) of the product obtained in B, following the procedure described in example 4D. 1.3 g of the title product were obtained. M.p.: 72-73°C (n-hexane) Elemental analysis C H N

Calculated 49.63 3.79 10.53

Found 49.66 3.75 10.52 l-H-NMR (DMSO): 8.00 (dd, IH) ; 7.83 (dt, IH) ; 7.46 (t, IH); 7.44 (d, IH) ; 4.61 (t, 2H) ; 4.00 (t, 2H) ; 2.06 (q, 2H).

¹³C-NMR (DMSO): 160.96; 152.62; 148.15; 136.42; 127.53; 125.52; 116.62; 114.62; 71.97; 38.96; 26.64.

The compounds of the invention have cardiovascular activity. Particularly, they showed interesting vasorelaxing properties iji vitro and an effective antianginal activity in the test animals. These favourable biological properties are accompanied by a negligible hypotensive effect; on the contrary such an undesired side-effect is marked in the known nitroderi- vatives used nowadays in therapy. Therefore, the compounds of the invention can be used as medicaments having a specific antianginal activity. Moreover, they also proved to have antiarrhytmic activity, which is another favourable property, since the angina attacks are often accompanied by more or less marked arrhythmias.

The vasorelaxing activity of the compounds of the invention was evaluated by means of the test on rabbit aorta strip contracted by noradrenalin. The test was effected according to the method described by K. Murakami et al., Eur. J. Pharmacol., 141, 195, 1987.

The EC^_QS, i.e. the concentrations (expressed in μmoles) of active product inhibiting by 50% the contraction of the aorta strip, were evaluated. The results obtained for some representative compounds of the invention are reported in the following Table 1.

TABLE 1

Compound of example Vasorelaxing activity in vitro EC_5Q (μmoles/1)

1 0.17 2 0.16 3 0.18 4 0.09 5 0.16 6 0.03 7 0.06

The antianginal activity in. vivo was determined on Sprague Dawley anaesthetized rats, meanly weighing 350-

400 g, according to the procedure of M. Leitold et al.,

Arzneim. Forsch. , 3_6, 1454, 1986. The test is effected administering intravenously the animal with 1 I.U./kg, equal to 3 mg/kg of Arg-vasopressin, inducing a coronary spasm which can be reproduced and evidenced electrocardiographycally as an increase in the T-wave.

Then the animals were treated intravenously with four increasing doses of the compounds of the invention in order to measure the ED_5Qs thereof, i.e. the doses capable to inhibit by 50% the increase in the T wave.

The results obtained for some representative compounds of the invention are reported in Table 2. TABLE 2

Compound of example Antiischemic activity

ΞΞ ^{vivo ED}5o ⁽ μg ^kg ⁾

1 27.9 2 102.0 3 611.0

The present invention also relates to the use of the compounds of the invention as antianginal agents, as well as to all the industrially applicable acts and aspects thereof, including the pharmaceutical compositions containing them. Examples of said pharmaceutical compositions are tablets, sugar-coated pills, syrups and vials, the latter suitable for both the oral and the intramuscular or intravenous administrations. They will contain the active principle alone or in admixture with the common, pharmaceutically acceptable carriers and excipients, the active principle being at least one of the compounds of the present invention.

The dosages of the active ingredient used to counteract the angina attacks can range within wide limits, depending on the nature of the used compound, and they are selected to give the most effective therapeutic action on the patient, during 24 hours.

Claims

1. A compound of general formula (I)

⁽C-^-Cg)alkyl, phenyl o benzyl; ( ^~ι~~4)alkoxy; amino, mono- and di-(C^-CgJalkylamino; formyl; trifluoro- methyl;

Y is methylene, ethylene, optionally branched (C,-

Cg)alkylene, or cyclopentylene, cyclohexylene or cycloheptylene;

2. Pharmaceutical compositions useful in the antianginal therapy, which comprise a therapeutically effective amount of at least one compound as defined in claim 1, together with at least a pharmaceutically acceptable excipient.

3. The use of a compound according to claim 1 as an antianginal agent.

4. The use of a compound according to claim 1, for the preparation of a medicament useful in the cardiovascular disorders.