HUT74587A - Benzoxazinones and benzothiazinones and pharmaceutical compositions containing them - Google Patents

Description

EP-A-0 490 183 and EP-A-0 359 627; in the synthesis of compounds claimed in European Patent Application, they are therapeutically effective, especially in the cardiovascular field.

Thus, the present invention relates to compounds of formula (I) wherein

X is O or S;

Y is a methylene group, an ethylene group, an optionally branched (? 3-5) alkylene group, a cyclopentylene group, a cyclohexylene group or a cycloheptylene group, the latter three groups being optionally substituted with (0-4) alkyl;

A is hydroxy; (C1-g) alkoxy, formyloxy; (C2-g) acyloxy; SH; (C 1-8) alkyl mercapto; a mesyl group; (C2-g) alkylsulfonyloxy; tosyloxy group; phenylsulfonyloxy, which may be optionally substituted with (C 1-8) alkyl; -OS-O-R3 or -OCOR3 wherein

II II o

R3 is (C ^ g) alkyl group, a methylene group, an ethylene group or a 2,3-dihydro-4H-l, 3-benzoxazin-4-one N and q is ω-substituted (C3_ ₆₎ alkylene;

R is hydrogen, (C1-C6) alkyl or phenyl;

R, and R ₂ is hydrogen, halogen, (Ci_g) alkoxy, trifluoromethyl or (Ci_g) alkyl and 3 is concerned with a pharmaceutically acceptable acid or basic salts, which are pharmaceutically active materials independently.

The invention further relates to the use of compounds of formula I as active ingredients in the cardiovascular field.

In the compounds detailed below, alkyl groups are essentially methyl, ethyl, propyl, isopropyl, butyl, 2-methylpropyl, η-pentyl, 3-methylbutyl, isopentyl, n-hexyl and the like. while the alkoxy groups are preferably selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-methylbutoxy and tert-butoxy. Examples of linear or branched (C 3-8) alkylene groups are 2-methylethylene,

1,3-propylene, 1,4-butylene, 2-ethyl-ethylene, 3-methyl-propylene, 1,5-pentylene, 2-ethyl-propylene, 2-methyl-butylene, 6-hexylene, 1-ethyl-1-methylpropylene, 3-methylpentylene and the like. The (C 2-6) acyloxy group is e.g. acetyloxy, propionyloxy, butyryloxy, hexanoyloxy, oxalyloxy, malonyloxy and succinyloxy.

The compounds of the invention are prepared according to methods known to those skilled in the art. For example, a (I), compounds of formula I, wherein X, Y, R, and R 2 is A is hydroxy, (C ^ _g) alkoxy forrni1 alkyloxy or (C ₂ -6) are as defined above, acyloxy, EP-A-0 490 183; can be prepared by reacting a salicylamide or thiosalicylamide of formula II wherein R1, R2, X and Y are phen4 and R4 is hydrogen, (C1-C6) alkyl. or (C 1-8) acyl, with an aldehyde of formula (III) wherein R is as defined above, or a derivative or precursor thereof. The condensation is generally carried out in an acidic medium such as a system formed by a strong mineral acid and acetic acid to give compounds of formula I wherein R4 is an acetyl group or in a system formed by molecular sieves sulfonic acids such as p-toluenesulfonic acid, methanesulfonic acid, α- and β-naphthalenesulfonic acid, phosphoric acids, phosphoric esters and the like. The condensation may be carried out in an organic solvent, preferably an inert organic solvent such as ethyl acetate, acetonitrile, benzene, nitrobenzene or chlorobenzene, halogenated aliphatic hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane or In the presence of 1,2-trichloroethylene, cyclohexane, tetrahydrofuran, tetrahydropyran, dimethylformamide, dimethylacetamide. The reaction temperature can vary over a wide range without adversely affecting the course of the reaction. The preferred temperature range is from about -10 ° C to the reflux temperature of the reaction, and the reaction is carried out for about 10 minutes. 2 hours and approx. Finish within 30 hours.

The molar amounts of the reagents (II) and (III) are not critical to the favorable cyclization and can be used in the widest stoichiometric ratios. When it is desired to produce compounds of formula I wherein R is hydrogen or methyl, precursors of compounds of formula III such as paraformaldehyde and paraldehyde may be advantageously used.

Compounds of formula (I) wherein Y, X, R, R 1 and R ₂ are as defined above and A is hydroxy may be used as reagents for the preparation of other compounds of formula (I).

For example, when desired to produce (I) compounds of formula I, wherein X, Y, R, R and R ₂ are as defined above, and A represents formyloxy group, (C ₂ _g) acyloxy group, mesyl alkyloxy group, (C ₂ _g) alkylsulfonyloxy group, a tosyloxy group, phenylsulfonyl-oxy group which may be substituted (C ₂ _g) -alkyl, -OS-O-R 3 or -OCOR 3, wherein R 3 is o (C 1-4 g) alkyl, methylene, ethylene or one

A (C 3-8) alkylene group substituted with a 2,3-dihydro-4H-1,3-benzoxazin-4-one-N-yl group, a compound of formula (I) wherein A is hydroxy, anhydride, halide or excess of the corresponding carboxylic acid or sulfonic acid activated in the form of an imidazole is preferably treated in the presence of an organic base such as pyridine. Suitable solvents for such synthesis are, for example, chloroform or methylene chloride, while the reaction temperature is approximately -10 ° C to room temperature and the reaction time is about 1 to 20 hours. When A is -OS-O-R 3 or

SHE

-OCOR3 group, at the end of the reaction add the appropriate amount of the desired R3OH alcohol O.

Compounds of formula (I) wherein A is hydroxy may also be used to prepare compounds of formula (I) wherein A is a mercapto group or (C 1-8) alkyl mercapto, a compound of formula (IV) via an intermediate in which X, Y, R, R 1 and R 2 are as defined above, and Halo is halogen, preferably chloro. Such an intermediate can be prepared by treating the hydroxyl group with a halogenating agent such as thienyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, sulfuryl bromide and the like. Said halogenation reaction is carried out in an organic solvent, preferably an inert organic solvent, wherein the solvent is selected from those used for the synthesis of the compounds of formula (I) described above at a reaction temperature between room temperature and the reflux temperature of the reaction mixture. The compound of formula (IV) can be converted to the compound of formula (I) by reaction with thiourea, wherein A is a mercapto group, at a reflux temperature of the reaction mixture for about 5-12 hours followed by a strong inorganic base such as an alkali metal hydroxide. hydrolysis at reflux for about 2 to 10 hours. The compound of formula (I) wherein A is a mercapto group can then be converted to a compound of formula (I) wherein A is a (C 1-8) alkylmercapto, a suitable acyl halo

With Ί nide in the presence of an organic base such as diazabicycloundecene as taught by Patai (Part 2, pages 721-735).

Compounds of formula (I) wherein A is hydroxy can also be prepared from compounds of formula (I) wherein A is (C 1 -C 6) alkoxy, with a suitable acyl halide. Williamson reaction.

In general, compounds of formula (I) may be converted to other compounds of formula (I) by suitable methods known to those skilled in the art for converting a substituent to a R 2 substituent. Conversion of R 1 or R 2 to another R 1 or R 2, where R 1 and R 2 are as defined above, can be accomplished by methods well known to those skilled in the art. These processes are within the scope of the present invention, together with obvious modifications to the methods described above for the preparation of the compounds of the invention.

The following examples illustrate the preparation of the compounds of the present invention. Unless otherwise noted, 1 H-NMR spectra were recorded in dimethylsulfoxide (DMSO).

EXAMPLE 1

2,3-Dihydro-3- (2'-hydroxyethyl) -4H-1,3-benzoxazin-4-one

A) N- (2'-hydroxyethyl) salicylamide is described in Aust. J. Chem., 25, 1797 (1972).

B) 5.5 g (0.03 mol) and 0.57 g of compound A)

- 8 (0.003 mol) of p-toluenesulfonic acid was dissolved in 100 ml of benzene and 2.7 g of vapor formaldehyde was added. The reaction mixture was heated at 90 ° C for 3 hours, then the resulting water was distilled off, and after cooling to room temperature, the residue was washed with water. The organic phase was recovered and the solvent was evaporated to give 4.7 g of a residue which was dissolved in 150 ml of tetrahydrofuran and 14 ml of 1 N hydrochloric acid. The reaction mixture was refluxed for 8 hours, cooled to room temperature and extracted with ethyl acetate. The organic phase was dried and concentrated in vacuo. 3.76 g of the expected product are obtained.

59-61 ° C (after recrystallization from 1: 9 methylene chloride / acetone).

1 H-NMR (200 MHz): 7.82 (1H, dd); 7.54 (1H, dt); 7.18 (1H, t); 7.07 (1H, d); 5.34 (2 H, s); 3.57 (4H, s).

EXAMPLE 2

3- (2'-Acetoxyethyl) -2,3-dihydro-4H-1,3-benzoxazin-4-one

To a solution of 10 g (0.05 mol) of the compound of Example 1 in 200 ml of chloroform and 4.18 ml (0.05 mol) of pyridine was added 19.6 ml (0.207 mol) of acetic anhydride. The solution was allowed to stand at room temperature for 12 hours, then washed with water, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography (hexane: ethyl acetate = 6: 4). 2.4 g of the expected product are obtained.

67 DEG C. (after recrystallization from ethyl acetate-hexane).

1 H-NMR (200 MHz): 7.82 (1H, dd); 7.55 (1H, dt); 7.15 (2H,

m); 5.35 (2 H, s); 4.17 (2 H, t); 3.79 (2 H, t); 2.00 (3H, s).

EXAMPLE 3

3- (2-Acetoxyethyl) -2,3-dihydro-6-methyl-4H-1,3-benzoxazin-4-one

A) 8.5 g of methyl 5-methyl salicylate [J. Chem. Soc. 661, (1961)] in 3.7 ml of 2-aminoethanol was heated at 170 ° C for 3 hours. After cooling to room temperature, the reaction mixture was taken up in ethyl acetate, washed with 5% hydrochloric acid and dried over sodium sulfate to give 9 g of N- (2'-hydroxyethyl) -5-methylsalicylamide.

M.p. 73-75 ° C (after recrystallization from hexane).

B) 8 grams (0.041 mol) of the compound obtained in A)

To a solution of 500 ml of chloroform and 11 ml of glacial acetic acid was added 4 g of paraformaldehyde. The reaction mixture was cooled to 0 ° C and 10 g of gaseous hydrochloric acid was added over 30 minutes, and the resulting solution was stirred at room temperature for 24 hours. The oily layer was removed and the chloroform layer was washed with water and dried over sodium sulfate. After evaporation of the solvent, the resulting crude residue was purified on a silica gel column using a 85:15 by volume mixture of methylene chloride and acetone. 6 g of the expected product are obtained.

ί

- 10 Mp: 53-55 ° C after recrystallization from hexane.

1 H-NMR (80 MHz): 7.61 (1H, d); 7.30 (1H, dd); 6.92 (1H, d);

5.30 (2H, S); 4.15 (2 H, t); 3.71 (2 H, t); 2.02 (3H, S).

EXAMPLE 4

2,3-Dihydro-3- (2'-hydroxyethyl) -6-methyl-4H-l, 3-benzoxazin-4-one

To a solution of 6 g (0.024 mol) of the compound of Example 3 in 120 ml of methanol was added 1.4 g (0.013 mol) of sodium carbonate and the resulting mixture was allowed to stand for 12 hours at room temperature. After evaporation of the solvent, the resulting crude product was taken up in methylene chloride and the resulting organic phase was washed with water and dried over sodium sulfate. After removal of methylene chloride, 4.2 g of the expected product are obtained.

59-61 ° C after recrystallization from diethyl ether. 1 H-NMR (80 MHz): 7.60 (1H, d); 7.30 (1H, dd); 6.90 (1H, d);

5.30 (2 H, s); 4.83 (1H, t); 3.56 (4 H, m); 2.30 (3H, S).

EXAMPLE 5

3- (2'-acetoxyethyl) -7-chloro-2,3-dihydro-4H-l, 3-benzoxazin-4-one

A) Following the procedure of Example 3A, 4-chloro-N- (2-hydroxyethyl) salicylamide was prepared from 20 g of methyl 4-chlorosalicylate (Chem. Abs. 81, 3624q) and ml of 2-aminoethanol. Yield: 11 g.

95-97 ° C after recrystallization from chloroform.

B) 11 g (0.051 mol) of compound A) and 4.5 g of paraformaldehyde gave 9 g of the title compound in the same manner as in Example 3B.

92-94 ° C, after recrystallization from hexane.

1 H-NMR (80 MHz): 7.82 (1 H, d); 7.30-7.08 (2 H, m); 5.35 (2 H, s); 4.15 (2 H, t); 3.70 (2 H, t); 2.00 (3H, s.).

EXAMPLE 6

7-Chloro-2 ₁ 3-dihydro-3- (2 ·-hydroxyethyl) -4H-1,3-benzoxazin-4-one

From 8 grams (0.03 mol) of the compound of Example 5 a

Example 4 gave 6.1 g of the title compound. 104-106 ° C after recrystallization from hexane.

1 H-NMR (80 MHz): 7.83 (1 H, d); 7.30-7.10 (2 H, m); 5.36 (2 H, s); 4.86 (1H, t); 3.60 (4 H, m).

EXAMPLE 7

3- (2'-acetoxyethyl) -2,3-dihydro-7-methyl-4H-l _/ 3-benzoxazin-4-one

A) N- (2'-Hydroxyethyl) -4-methylsalicylamide was prepared according to the procedure of Example 3A, from 20 g of methyl 4-methyl salicylate (Chem. Abs. 64, 6568d) and 9 ml. Starting from 2-aminoethanol. Yield: 16.7 g.

78-80 ° C after recrystallization from hexane.

B) From the compound (A) (16 g, 0.081 mol) and paraformaldehyde (4.5 g) obtained in Example 3B (13), the title compound was obtained as an oil.

1 H-NMR (200 MHz): 7.59 (1H, d); 6.98 (1H, d); 6.91 (1H, s);

5.19 (2 H, s); 4.18 (2 H, t); 3.68 (2 H, t); 2.01 (3H, s).

EXAMPLE 8

2,3-Dihydro-3- (2'-hydroxyethyl) -7-methyl-4H-1,3-benzoxazin-4-one

From 12 g of the compound of Example 7, following the procedure of Example 4, 9 g of the title compound were obtained as an oil.

¹ H-NMR (80 MHz): 7.73 (1H, d); 6.96-6.63 (2 H, m); 5.20 (2H, S); 3.96-3.56 (4 H, m); 2.36 (3H, s).

EXAMPLE 9

3- (2'-acetoxyethyl) -2,3-dihydro-2-methyl-4H-l, 3benzoxazin-4-one

Starting from 18.4 g (0.101 mol) of the compound of Example 1A) and 8.13 ml (0.061 mol) of paraformaldehyde,

Following the procedure of Example 3B, the title compound was obtained as an oil (6.7 g).

¹ H-NMR (200 MHz): 7.74 (1H, dd); 7.52 (1H, dt); 7.17 (1H, t); 7.02 (1H, d); 5.70 (1H, q); 4.22 (2H, t); 4.63 to 3, 83 (1H m); 3.56 to 3.23 (1H, m); 2.05 (3H, s); 1.56 (3H, d).

EXAMPLE 10

2,3-Dihydro-3- (2'-hydroxyethyl) -2-methyl-4H-l, 3benzoxazxn-4-one

Starting from 6 grams (0.029 mol) of the compound of Example 9, the procedure of Example 4 was followed. This gave 3.8 g of the title compound as an oil.

¹ H-NMR (200 MHz): 7.74 (1H, dd); 7.52 (1H, dt); 7.17 (1H,

t); 7.01 (1H, d); 5.50 (1H, q); 3.90-3.57 (4 H, m); 1.52 (3H,

d).

EXAMPLE 11

3- (2-Acetoxyethyl) -2,3-dihydro-2,7-dimethyl-4H-1,3-benzoxazin-4-one

Starting from 6 grams (0.03 mol) and 2.4 ml (0.018 mol) of paraformaldehyde from Example 7A,

Example 3B. 2.5 g of the title compound are obtained in the form of an oil.

¹ H-NMR (200 MHz): 7.63 (d, 1H); 6.92 (d, 1H); 6.88 (s, 1H);

5.66 (q, 1H); 4.28 (t, 2H); 4.08-3.78 (m, 1H); 3.52-3.22 (m, 1H); 2.35 (S, 3H); 2.02 (s, 3H); 1.52 (s, 3H).

EXAMPLE 12

2,3-Dihydro-2,7-dimethyl-3- (2 '-hydroxyethyl) -4H-1,3-benzoxazin-4-one

Starting from 2.3 grams (0.009 mole) of the compound of Example 11 and following the procedure of Example 4. 2.1 g of the title compound are obtained in the form of an oil.

¹ H-NMR (80 MHz): 7.63 (1H, d); 7.00-6.76 (2 H, m); 5.66 (1H, q); 4.86 (1H, t); 3.70-3.43 (4 H, m); 2.36 (3H, s); 1.50 (3H,

d).

EXAMPLE 13

3- (2 · Acetoxy-ethyl) -6-chloro-2,3-dihydro-4H-4-one 3benzoxazin

A) 5-Chloro-N- (2'-hydroxyethyl) salicylamide was prepared according to the procedure of Example 3A, 19 g of methyl 5-chloro-14

from salicylate [Arch. Pharm. 296 (10), 714 (1963)] and 7.5 ml of 2-aminoethanol. Yield: 13.8 g.

M.p. 100-102 ° C after recrystallization from hexane.

B) From 13 grams (0.06 mol) of the compound obtained in A) and

Starting from 4.5 g of paraformaldehyde, proceed as in Example 3B. 11 g of the expected product are obtained. 93-95 ° C after recrystallization from hexane.

¹ H-NMR (80 MHz): 7.73 (1H, d); 7.53 (1H, dd); 7.10 (1H, d);

5.35 (2H, S); 4.16 (2 H, t); 3.71 (2 H, t); 2.02 (3H, s).

EXAMPLE 14

6-Chloro-2,3-dihydro-3- (2'-hydroxyethyl) -4H-1,3-benzoxazin-4-one

Starting from 10 grams (0.037 mol) of the compound of Example 13 and proceeding as in Example 4. 7 g of the expected product are obtained.

M.p. 88-90 ° C after recrystallization from diethyl ether. ¹ H-NMR (80 MHz): 7.73 (1H, d); 7.53 (1H, dd); 7.10 (1H, d);

5.36 (2 H, S); 3.56 (4 H, m).

EXAMPLE 15

N- (5'-Acetoxypentyl) -2,3-dihydro-4H-1,3-benzoxazin-4-one

A) N- (5'-hydroxypentyl) salicylamide was prepared by

Using the procedure of Example 3A starting from 17.6 g of methyl salicylate and 8.5 ml of 5-aminopentanol. Yield: 11 g.

The compound obtained as an oil was used in the next step without modification.

• · · ·

B) Starting from 11.4 grams (0.051 mol) of compound A) and 4.5 grams of paraformaldehyde and proceeding as in Example 3B. This gave 9 g of the title compound as an oil.

1 H-NMR (200 MHz): 7.79 (1H, dd); 7.51 (1H, dt); 7.14 (1H, t); 7.04 (1H, t); 5.29 (2 H, s); 4.03 (2 H, t); 3.44 (2 H, t); 2.04 (3H, s); 1.60-1.19 (6 H, m).

EXAMPLE 16

2.3-Dihydro-3- (5'-hydroxypentyl) -4H-1,3-benzoxazin-4-one

Starting from 8.5 grams (0.031 mol) of the compound of Example 15, proceeding as in Example 4. 5.3 g of the title compound are obtained in the form of an oil. 1 H-NMR (200 MHz): 7.79 (1H, dd); 7.51 (1H, dt); 7.14-7.04 (2 H, m); 5.29 (2 H, s); 3.44 (4 H, m); 1.60-1.19 (6 H, m).

EXAMPLE 17

2.3-Dihydro-3- (2'-hydroxyethyl) -7-methoxy-4H-1,3-benzoxazin-4-one

A) N- (2'-Hydroxyethyl) -4-methoxysalicylamide was prepared according to the procedure of Example 3A from 16.9 g of methyl 4-methoxysalicylate [J. Org. Chem. 23, 756 (1958)] and 7 ml

Starting from 2-aminoethanol.

Yield: 9.5 g.

92-94 ° C after recrystallization from hexane.

B) 9 grams (0.042 mol) of compound A) and 0.81 g (0.004 mol) of p-toluenesulfonic acid were dissolved in 130 ml of

In a solution of 4 µm molarcula sieve and 1.55 g of paraformaldehyde was added to the resulting solution. The mixture was refluxed for 2 hours and then, after cooling to room temperature, ethyl acetate (300 mL) was added. The molecular sieve was filtered off, the solution was washed with water and the organic layer was separated and dried over sodium sulfate. Evaporation of the solvent gave a residue (10.3 g) which was purified by silica gel column chromatography (ethyl acetate: hexane = 8: 2). Yield: 2.1 g of the title compound as an oil.

1 H-NMR (200 MHz): 7.83 (1H, d); 6.63 (1H, dd); 6.42 (1H, d);

5.36 (2H, S); 4.88 (1H, t); 3.62-3.47 (4 H, m); 3.81 (3H, S).

EXAMPLE 18

2,3-Dihydro-N- (2-hydroxyethyl) -4H-1,3-benzothiazin-4-one

A) A solution of 5 g (0.03 mol) of methylthiosalicylate (Synthesis, 59, 1974) in ethanolamine (0.06 mol) was heated to 140 'Con while methanol was distilled off. After 2 hours, the solution was poured onto ice and extracted with ethyl acetate. The organic phase was dried and evaporated in vacuo. 4.2 g (0.01 mol) of bis [2- (2-hydroxyethyl) carboxamidophenyl] disulfide are obtained, which is dissolved in 32 ml of ethanol. The resulting solution was heated at 65 ° C and 0.4 g (0.01 mol) of sodium borohydride in 21 ml of ethanol was added dropwise. The solution was heated at 65 ° C for 1 hour and then cooled to room temperature. Residue obtained after evaporation of the solvent, ··· ··· • ·•

• »· ί ·· ··

17 columns were chromatographed on a silica gel column using ethyl acetate as the eluent. 1.4 g of N- (2-hydroxyethyl) -2-mercaptobenzamide were obtained in the form of an oil, which was used in the next step without modification.

B) To a solution of 3.5 grams (0.017 mol) of compound A in 50 ml of dioxane was added 1.59 g (0.053 mol) of paraformaldehyde. The solution was cooled to 0 ° C and then saturated with gaseous hydrochloric acid. The temperature was then raised to room temperature and stirred for 3 days. After dilution with water, the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuo. The resulting residue was chromatographed on a silica gel column using ethyl acetate / hexane (8: 2) as the eluent. 1.5 g of the expected product are thus obtained in the form of an oil.

¹ H-NMR (80 MHz): 7.93-7.80 (1H, m); 7.50-7.13 (3 H, m); 4.83 (2 H, s); 3.63 (4 H, m).

EXAMPLE 19

2,3-Dihydro-trans-3- (2H-hydroxycyclohexyl) -4H-1,3-benzoxazin-4-one

A) Trans-N- (2'-hydroxycyclohexyl) salicylamide was prepared according to the procedure of Example 3A from 16 g of methyl salicylate and 12 g of trans-2-aminocyclohexanol. Yield:

9.1 g.

91-96 ° C, after recrystallization from hexane.

eee · «·« · * • · * * • e · · · ·· ··

- 18 B) The title product was prepared according to the procedure of Example 17B starting from 8.1 grams (0.0319 mol) of compound A. Yield: 1.5 g.

87-89 ° C after recrystallization from hexane.

¹ H-NMR (80 MHz): 7.90 (1H, dd); 7.33 (1H, dt); 7.0-5.70 (2 H, m); 3.56 (2 H, m); 2.10-1.15 (8 H, m).

EXAMPLE 20

2.3-Dihydro-3- (1'-methyl-2'-hydroxyethyl) -4H-1,3-benzoxazin-4-one

A) N- (1'-Methyl-2'-hydroxyethyl) salicylamide was prepared according to the procedure of Example 3A, from 18 g (0.118 mol) of methyl salicylic acid and 18.8 ml of 2 starting from amino-1-propanol. Yield: 19 g. The compound obtained as an oil was used in the next step without modification.

B) Following the procedure of Example 1B, starting from 19 grams (0.973 mol) of compound A). 7.76 g of the expected product are obtained in the form of an oil.

¹ H-NMR (200 MHz): 7.82 (1H, dd); 7.52 (1H, dt); 7.17 (1H, t); 7.05 (1H, d); 5.30 (2 H, m); 4.50 (1H, m); 2.50 (2 H, m); 1.20 (3 H, d).

EXAMPLE 21

2.3-Dihydro-N- (2'-hydroxyethyl) -6-methoxy-4H-1,3-benzoxazin-4-one

A) N- (2'-Hydroxyethyl) -5-methoxysalicylamide was prepared according to the procedure of Example 3a, from 259 g (0.137 mol) of 519 methoxysalicylic acid methyl ester and 9.94 ml. Starting from 2-aminoethanol. Yield: 25 g. The compound was used in the next step without modification.

B) The title product was prepared as in Example 1B starting from 20 grams (0.094 mol) of compound A). Yield: 17.2 g of product in the form of an oil.

1 H-NMR (80 MHz): 7.30-6.90 (3H, m); 5.30 (2 H, s); 3.80 (3 H, s); 3.60 (4H, s).

EXAMPLE 22

2,3-Dihydro-N- (2'-hydroxyethyl) -7-trifluoromethyl-4H-1,3-benzoxazin-4-one

A) N- (2'-Hydroxyethyl) -4-trifluoromethylsalicylamide was prepared according to the procedure of Example 3A from 26 g (0.118 mol) of 4-trifluoromethylsalicylic acid methyl ester. [J. Chem. Soc. 76, 1051-4 (1954)] and starting from 100 ml of 2-aminoethanol. Yield: 24 g. The resulting compound was used in the next step without modification.

B) The title product was prepared according to the procedure of Example 1B starting from 20 grams (0.08 mol) of the compound of A). Yield: 13 g.

M.p. 63-65 ° C after recrystallization from hexane.

1 H-NMR (80 MHz): 7.92 (1H, d); 7.40 (1H, d); 7.36 (1H, S);

5.36 (2 H, s); 3.53 (4H, s).

EXAMPLE 23

N- (2'-Acetoxyethyl) -2,3-dihydro-7-trifluoromethyl-4H-1,3-benzoxazin-4-one

Example 2 was carried out starting from 5.1 grams (0.019 mol) of the compound of Example 22. so

4.7 g of the expected product are obtained.

1 H-NMR (200 MHz): 8.00 (1H, d); 7.50 (1H, d); 7.48 (1H, s); 5.43 (2 H, s); 4.17 (2 H, t); 3.72 (2 H, t); 2.00 (3H, s).

EXAMPLE 24

2.3-Dihydro-3- (2'-hydroxyethyl) -8-methyl-4H-1,3-benzoxazin-4-one

A) N- (2'-Hydroxyethyl) -3-methylsalicylamide was prepared according to the procedure of Example 3A, 24.2 g (0.145 mol).

Starting from methyl 3-methylsalicylic acid and 100 ml of 2-aminoethanol. Yield: 28.9 g. The compound was used in the next step without modification.

B) The title product was prepared according to the procedure described in Example 1B starting from 28.3 grams (0.145 mol) of compound A). Yield: 15 g of product in the form of an oil.

¹ H-NMR (80 MHz): 7.59 (1H, d); 7.34 (1H, d); 7.00 (1H, t);

5.33 (2 H, s); 3.58 (4 H, m); 2.23 (3H, s).

EXAMPLE 25

2.3-Dihydro-3- (2H-hydroxyethyl) -5-methyl-4H-1,3-benzoxazin-4-one

A) N- (2H-hydroxyethyl) -6-methylsalicylamide was prepared according to the procedure of Example 3A from 18.8 g (0.113 mol) of methyl 6-methylsalicylic acid and starting from 2 ml of 2-aminoethanol. Yield: 19.3 g.

134-135 ° C after recrystallization from hexane.

B) The title product was prepared according to the procedure described in Example 1B starting from 13.6 grams (0.069 mol) of compound A). Yield: 6.6 g of product as an oil.

¹ H-NMR (80 MHz): 7.30 (1H, t); 6.86 (2 H, m); 5.23 (2 H, s); 3.56 (4 H, m); 2.63 (3H, s).

EXAMPLE 26

2,3-Dihydro-N- (3'-hydroxypropyl) -4H-1,3-benzoxazin-4-one

A) N- (3'-Hydroxypropyl) salicylamide was prepared by

Using the procedure of Example 3A starting from 20 g (0.131 mol) of methyl salicylic acid and 13.2 ml of 3-aminopropanol. Yield: 24 g of product in the form of an oil which was used in the next step without modification.

B) The title product was prepared according to the procedure described in Example 1B starting from 17 grams (0.087 mol) of the compound A). 7.75 g of the expected product are obtained in the form of an oil.

¹ H-NMR (80 MHz): 7.76 (1H, dd); 7.50 (1H, dt); 7.10 (2 H, m);

5.33 (2 H, s); 3.52 (4 H, m); 1.73 (2 H, m).

EXAMPLE 27

2,3-Dihydro-N- (2H-hydroxy-1 * -methyl-1H-propyl) -4H-1,3-benzoxazin-4-one

A) 31.24 g (0.146 mol) of methyl salicylic acid and 13 g (0.146 mol) of 3-amino-2-butanol were heated at 80 ° C for 4 hours and then cooled to room temperature. The crude product was washed with hexane and purified by silica gel column chromatography (eluent: chloroform: acetone = 10: 1). 12 g of N- (1'-methyl-2'-hydroxy-1'-propyl) salicylamide were obtained in the form of an oil which was used in the next step without modification.

B) The title compound was prepared according to the procedure described in Example 1B starting from 11 grams (0.052 mol) of compound A). 8.13 g of the expected product are obtained in the form of an oil.

¹ H-NMR (80 MHz): 7.76 (1H, dd); 7.46 (1H, dt); 7.10 (2 H, m);

5.33 (2 H, s); 4.30 (1H, m); 3.76 (1H, m); 1.30 (6H, dd).

EXAMPLE 28

2 _# 3-Dihydro-3- (2'-hydroxy-1 H -propyl) -4 H -1,3-benzoxazin-4-one

A) N- (2'-Hydroxy-1'-propyl) salicylamide was prepared according to the procedure of Example 3A, from 18 g (0.118 mol) of salicylic acid methyl ester and 18.3 ml of l-amino- Starting from 2-propanol. Yield: 24 g of product in the form of an oil which was used in the next step without modification.

....... 'f

- 23 B) The title product was prepared according to the procedure of Example 1B starting from 20 grams (0.102 mol) of the compound A). 18 g of product are obtained in the form of an oil.

¹ H-NMR (200 MHz): 7.83 (1H, dd); 7.50 (1H, dt); 7.33-7.00 (2 H, m); 5.40 (2 H, s); 4.00-3.10 (3 H, m); 1.10 (3 H, d).

EXAMPLE 29

2,3-Dihydro-3- (2'-hydroxyethyl) -7-isopropoxy-4H-l, 3-benzoxazin-4-one

A) N- (2'-Hydroxyethyl) -4-isopropoxysalicylamide was prepared according to the procedure of Example 3A starting from 25.3 g (0.166 mol) of 4-isopropoxysalicylic acid methyl ester. (prepared 4-isopropoxysalicylic acid from Synthesis (1984, 758-760) treated with methanol and sulfuric acid) and 100 ml of 2-aminoethanol. Yield: 22 g. The compound was used in the next step without modification.

B) The title compound was prepared according to the procedure described in Example 1B using 5 grams (0.028 mol) of the compound A as starting material. 3.1 g of product are obtained in the form of an oil.

¹ H-NMR (200 MHz): 7.70 (1H, d); 6.69 (1H, dd); 6.58 (1H, d);

5.31 (2 H, s); 4.88 (1H, bs); 4.71 (1H, m); 3.53 (4 H, m);

1.29 (6H, d).

Example 30

2,3-Dihydro-3- (2'-mercaptoethyl) -4H-1,3-benzoxazin-4-one

A) To a solution of 9 g (0.046 mol) of the compound of Example 1 in 70 ml of chloroform was added 3.54 ml (0.048 mol) of methylene chloride. The resulting solution was heated at 70 ° C for 3 hours and then cooled to room temperature, washed with 5% sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and evaporated. 9.3 g of 2,3-dihydro-3- (2-chloroethyl) -4H-1,3-benzoxazin-4-one are obtained.

B) To a solution of 15 g (0.071 mol) of compound A in 500 ml of ethanol was added 16.1 g (0.2 mol) of thiourea. The mixture was refluxed for 8 hours, cooled to room temperature, treated with 10% sodium hydroxide solution (42 mL) and refluxed for 5 hours. The solution was evaporated to dryness and the residue was taken up in water and extracted with chloroform. The organic phase was dried over sodium sulfate and evaporated. The crude product was purified by flash chromatography using chloroform as eluent. 2.3 g of the expected product are obtained.

M.p .: 44-46 ° C after recrystallization from chloroform. ¹ H-NMR (200 MHz): 7.82 (1H, dd); 7.54 (1H, dt); 7.17 (1H, t); 7.07 (1H, d); 5.38 (2 H, s); 3.63 (2 H, t); 2.72 (2H, q); 2.46 (1H, t).

EXAMPLE 31

2,3-Dihydro-3- (2'-methoxyethyl) -4H-1,3-benzoxazin-4-one

A) To a solution of 10 g of methyl salicylate in 15 ml of acetonitrile was added 5.5 ml of 2-methoxyethylamine and the mixture was refluxed for 24 hours. At the end of reflux, the solution was evaporated to dryness in vacuo, taken up in ethyl acetate and washed with 1N hydrochloric acid and water. The organic phase was dried over sodium sulfate and concentrated to a small volume. The solid thus formed was filtered off and dried in vacuo. 9 g of N- (2'-methoxyethyl) salicylamide were obtained.

B) Following the procedure of Example 1B, starting from 9 grams of compound A (0.046 mol), 8.3 g of the expected product are obtained.

¹ H-NMR (200 MHz, DMSO): 7.82 (1H, dd); 7.55 (1H, dt); 7.17 (1H, t); 7.07 (1H, d); 5.32 (2 H, s); 3.67 (2 H, m); 3.51 (2 H, m); 3.29 (3H, s).

EXAMPLE 32

2,3-Dihydro-3- (2'-tosyloxyethyl) -4H-1,3-benzoxazin-4-one

To a solution of 3 g (0.015 mol) of the compound of Example 1 in chloroform (3.7 ml) was added pyridine (3.7 ml, 0.046 mol) and tosyl chloride (8.88 g, 0.046 mol). After 2 hours, the reaction mixture was washed with 1 N hydrochloric acid. The organic layer was dried over sodium sulfate and evaporated, and the crude product was purified by flash chromatography (98: 2 methylene chloride: ethyl acetate). 3.34 g of the expected product are obtained.

122-124 ° C after recrystallization from methylene chloride.

¹ H-NMR (200MHz): 7.77-7.71 (3H, m); 7.55 (1H, dt); 7.33 (2 H, m); 7.17 (1H, t); 7.06 (1H, d); 5.20 (2 H, s); 4.23 (2H, t); 3.72 (2 H, t); 2.32 (3H, s).

EXAMPLE 33

2,3-Dihydro-3- (2'-mesyloxyethyl) -4H-1,3-benzoxazin-4-one

A solution of 5 g (0.026 mol) of the compound of Example 1 in chloroform and 5.8 ml (0.072 mol) of pyridine was cooled to 0 ° C and then added.

5.6 ml (0.072 mol) of mesyl chloride in 20 ml of chloroform. After 6 hours, the solution was washed with 1N hydrochloric acid, water, 5% sodium bicarbonate, and finally water. The organic phase was dried over sodium sulfate and concentrated in vacuo. 2.7 g of the expected product are obtained.

76-78 ° C after recrystallization from methylene chloride.

¹ H-NMR (200 MHz): 7.83 (1H, dd); 7.55 (1H, dt); 7.18 (1H, t9; 7.09 (1H, d); 5.36 (2H, d); 4.39 (2H, t); 3.83 (2H, d); 3.22 (3H, s).

EXAMPLE 34

Methyl-2- (2 ', 3'-Dihydro-4'-oxo-1', 3 · · benzoxazin-3-yl) ethyl sulfite

10 grams (0.05 mol) of the compound of Example 1

A solution of chloroform (200 mL) was cooled to -15 ° C and methylene chloride (3.77 mL, 0.051 mol) was added. After 1 h, methanol (2.1 mL) was added and the reaction mixture was warmed to room temperature and evaporated after 5 h. The crude product thus obtained was purified by flash chromatography (hexane: ethyl acetate = 1: 1). This gave 4 g of the title compound as an oil.

¹ H-NMR (200 MHz): 7.82 (1H, dd); 7.54 (1H, dt); 7.17 (1H, t); 7.07 (1H, d); 5.35 (2 H, s); 4.14 (2 H, m); 3.77 (2 H, m); 3.59 (3H, S).

EXAMPLE 35

Bis-2 · - (2,3-dihydro-4-oxo-l, 3-benzoxazin-3-yl) ethyl carbonate

4 grams (0.02 mol) of the compound of Example 1

To a solution of 200 ml of methylene chloride was added 120 mg (0.002 mol) of sodium methylate and 1.92 g (0.012 mol) of carbonyldiimidazole. The solution was allowed to stand at room temperature for 23 hours and then washed with water. The organic phase was dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography (hexane: ethyl acetate = 6: 4) to give 2.5 g of the title compound.

74-75 ° C after recrystallization from hexane / ethyl acetate (1: 1).

1 H-NMR (200 MHz): 7.82 (2H, dd); 7.54 (2H, dt); 7.18 (2 H, t); 7.07 (2 H, d); 5.30 (4H, s); 4.25 (4H, t); 3.70 (4 H, t).

EXAMPLE 36

2,3-Dihydro-3- (2'-ethoxyethyl) -4H-1,3-benzoxazin-4-one

Following the procedure of Example 31, starting from 12 g of 2-ethoxyethylamine, 1.4 g of the title compound are obtained. 1 H-NMR (200 MHz): 7.83 (1H, dd); 7.52 (1H, dt); 7.15 (1H, t); 7.05 (1H, d); 5.32 (2 H, s); 3.65 (2 H, m); 3.54 (2 H, m); 3.45 (2H, q); 1.10 (3 H, t).

EXAMPLE 37

Isopropyl-2- (2 ·, 3 · dihydro-4'-oxo-1 ·, · 3'-benzoxazin-3-yl) ethyl sulfite

The title compound was prepared according to the procedure of Example 34 starting from 10 g (0.051 mol) of the compound of Example 1 followed by 3.78 ml (0.051 mol) of thionyl chloride and 398 ml (5.17 mol) of isopropyl -alcohol. 1.2 g of the expected product are thus obtained in the form of an oil.

¹ H NMR (200 MHz) : 7.82 (1H, dd); 7.55 (1H, dt); 7.17 (1H, t); 7.08 (1H, d) ; 5.35 (2 H, s); 4.71 (1H, m); 4.13 (2 H, m); 3.78 (2 H, m); 1 24 (3H, d); 1.21 (3H, d).

EXAMPLE 38

6,8-Dichloro-2,3-dihydro-3- (2'-hydroxyethyl) -4H-1,3-benzoxazin-4-one

A) 3,5-Dichloro-N- (2'-hydroxyethyl) salicylamide was prepared according to the procedure of Example 3A starting from 20.9 g (0.094 mol) of methyl 3,5-dichloro. salicylate and 6.85 ml (0.113 mol) of 2-aminoethanol. Ho4

- 29 zam: 14 9.

137-139 ° C after recrystallization from hexane.

B) Starting from 14 g (0.055 mol) of the compound of Step A and 3.07 g of paraformaldehyde, 2.7 g of the title compound is obtained according to the procedure of Example 3B.

98-100 ° C after recrystallization from hexane. 1 H-NMR (200 MHz): 7.88 (1H, d); 7.72 (1H, d); 5.47 (2 H, s);

4.91 (1H, t); 3.57 (4 H, m).

EXAMPLE 39

2,3-Dihydro-4,5-dimethoxy-3- (2'-hydroxyethyl) -4H-1,3-benzoxazin-4-one

A) 4,5-Dimethoxy-N- (2-hydroxyethyl) salicylamide was prepared by 23 g (0.108 mol) of 4,5-dimethoxysalicylic acid methyl ester [prepared by Synthesis. (758, 1984) was treated with 100 ml of 2-aminoethanol at 170 ° C for 3 hours. After cooling to room temperature, the mixture was taken up in ethyl acetate, washed with 5% aqueous hydrochloric acid and dried over sodium sulfate. Yield: 18 g. The compound was used in the next step without modification.

B) The title compound was prepared according to the procedure of Example 17B using 15 grams (0.062 mol) of the compound of Step A as starting material. Yield: 13 g.

1 H-NMR (200MHz): 7.21 (1H, s); 6.67 (1H, s); 5.27 (2 H, s);

4.84 (1H, 7); 3.81 (3H, s); 3.76 (3H, s); 5.52 (4 H, m).

i

I 1.

i.

EXAMPLE 40

2.3-Dihydro-6-fluoro-3- (2-hydroxyethyl) -4H-1,3-benzoxazin-4-one

A) 5-Fluoro-N- (2'-hydroxyethyl) salicylamide was prepared according to the procedure of Example 3A starting from 4.9 g (0.03 mol) of 5-fluoro-salicylic acid methyl. ester and 2.08 mL (0.034 mol) of 2-aminoethanol. Yield:

5.29 g.

B) The title compound was prepared according to the procedure of Example 17B starting from 5.2 g (0.026 mol) of the compound of Step A and 2.37 g of paraformaldehyde. Yield: 3.1 g.

128-130 ° C after recrystallization from hexane. ¹ H-NMR (200 MHz): 7.52 (1 H, dd); 7.42 (1H, dt); 7.15 (1H, dd); 5.32 (2 H, s); 4.90 (1 H, t); 3.57 (4 H, m).

EXAMPLE 41

2.3-Dihydro-6-ethyl-3- (2'-hydroxyethyl) -4H-1,3-benzoxazin-4-one

A) 5-Ethyl-N- (2-hydroxyethyl) salicylamide was prepared by the procedure of Example 3A starting from 26.8 g (0.148 mol) of 5-ethylsalicylic acid methyl ester. (prepared by the method described in Synthesis, 758 (1984)) and 10.7 ml (0.178 mol) of 2-aminoethanol. Yield: 29.8 g.

B) The title product was prepared according to the procedure described in Example 17B, starting from 25 g (0.119 mol) of the compound of Step A and 10.7 g of the title compound.

g using paraformaldehyde. Yield: 11.9 g.

1 H-NMR (200 MHz): 7.62 (1H, d); 7.37 (1H, dd); 6.97 (1H, d);

5.32 (2H, S); 4.87 (1H, t); 3.57 (4 H, m); 2.62 (2H, q); 1.20 (3 H, t).

EXAMPLE 42

2 ₁ 3-Dihydro-6,7-dimethyl-3- (2'-hydroxyethyl) -4H-1,3-benzoxazine-4-one

A) 4,5-Dimethyl-N- (2-hydroxyethyl) -salicylamide was prepared according to the procedure of Example 3A, starting from 4,5,6-dimethylsalicylic acid (33.6 g, 0.186 mol). methyl ester (prepared by the method described in Synthesis, 758 (1984)) and 13.5 ml (0.223 mol) of 2-aminoethanol. Yield: 34.4 g.

B) The title compound was prepared according to the procedure of Example 17B using 30.5 grams (0.146 mol) of the compound of Step A and 13.14 g of paraformaldehyde as starting material. Yield: 17.7 g.

89-91 ° C after recrystallization from hexane.

1 H-NMR (200 MHz): 7.55 (1H, S9; 6.85 (1H, s); 5.27 (2H, s); 4.87 (1H, t); 3.55 (4H) m, 2.25 (3H, s), 2.20 (3H, s).

EXAMPLE 43

6-Bromo-2,3-dihydro-3- (2 ·-hydroxyethyl) -4H-1,3-benzoxazin-4-one

A) 5-Bromo-N- (2 * -hydroxyethyl) salicylamide was prepared according to the procedure of Example 3A starting from 5.2 g (0.022 mol) of 5-bromo-salicylic acid methyl ester. 32 vol and 1.63 ml (0.027 mol) of 2-aminoethanol. Yield: 5.53 g.

B) The title compound was prepared according to the procedure of Example 17B using 5.4 grams (0.021 mol) and 1.87 g of paraformaldehyde as starting material in the compound of Step A). Yield: 1.84 g.

M.p. 78-81 ° C after recrystallization from hexane. ¹ H-NMR (200 MHz): 7.87 (1H, d); 7.70 (1H, d); 7.07 (1H, d);

5.37 (2 H, s); 4.90 (1H, t); 3.57 (4 H, m).

As mentioned above, the compounds of the present invention have cardiovascular efficacy and, in particular, exhibit remarkable antianginal and anti-ischemic efficacy in experimental animals. These favorable biological properties are usually accompanied by a negligible antihypertensive effect. Thus, the compounds of the invention can be used as medicaments with specific antianginal efficacy.

In vivo antianginal efficacy was determined in anesthetized Sprague Dawley rats (mean weight 350-400 g) according to the method described by Leitold M. et al., Arzneim. Forsch. 36, 1454 (1986)]. The assay was performed by intravenously administering to the animals 1 international unit of a compound of formula (I), equivalent to 3 mg / kg Argvasopressin; the latter compound is reproducible and causes coronary cramps with detectable T-wave growth. The animals were then intravenously treated according to the present invention. ························•

With four incremental doses of 33 compounds to measure their ED5Q, the dose that produces 50% inhibition of T-wave growth. The measured ED5Q values of the compounds of the invention ranged from about 1 Mg / kg to about 300 Mg / kg. The compounds of Examples 1, 2, and 34 have ED5Q values of 87 mg / kg, 215 pg / kg, respectively. Was 10.5 Mg / kg. Some of the compounds of the invention were tested as described above, but were administered orally. so e.g. the compound of Example 1 showed an ED5Q of 0.23 mg / kg.

The antianginal efficacy of the claimed compounds is described in Sakai, K. et al., Pharmacol. Met. 5, 325336 (1981)], also tested with a methacholine-induced angina probe. The percent inhibition of ST-wave growth induced by methacholine (0.8 pg / kg i.v.) was measured after intravenous administration of the compounds of the invention. The results are shown in Table 1.

Table 1

Example% Inhibition at 3 pg / kg Serial Number after 1 min 10 min 30 min

4th 60.0 45.0 6th 57.1 51.0 28.6 8th 31.1 14th 71.4 54.7 73.8 17th 45.1 39.2 18th 37.2 28.0

«·» · *

- 34 Continued from Table 1

The serial number of the example % inhibition at a dose of 3 gg / kg 1 minute After 10 minutes 30 minutes 21st 25.0 38.6 34.1 22nd 29.3 22.0 34.1 30th 30.2 48.8 37.2 31st 30.0 20.4 38th 40.6 39th 23.0 52.3

By the same method, the compound of Example 1 was determined to have an ED 50 of 73.5 µg / kg.

The above assay was repeated with 0.3 mg / kg orally of the claimed compounds. The results are shown in Table 2.

Table 2

Example is% inhibition

number 30 minutes 120 minutes expiration after 4 52.6 14 71.2 73.1 34 46.8 21.8 21 28

• * ··· w

- 35 I ί

The same assay showed that the compounds of the invention exhibit an oral ED59 of between about 100 mg / kg and about 0.01 mg / kg.

The above favorable biological properties are combined with low toxicity. By the method of Lichtfield and Wilcoxon [J. Pharm. Expt. Ther. 96, 99 (1949)] are actually higher than 500 mg / kg in mice and 800 mg / kg in rats, i.p. dosing.

The invention also encompasses the use of the claimed compounds as anti-anginal agents and in the treatment of ischemic cardiopathies, taking into account all industrial aspects of the application, including use in pharmaceutical compositions. Examples of such compositions include tablets, sugar-coated and film-coated tablets, syrups and vials, where the latter are suitable for oral, intramuscular or intravenous administration. These formulations may contain the active ingredient alone or in association with carriers and excipients generally accepted in medicine. The dosage of active ingredient used for anti-anginal therapy or for the treatment of ischemic cardiopathies may vary widely depending on the compound employed and is selected to provide the patient with an effective therapeutic dose. so e.g.

Unit doses of 0.01 to 1 mg may be administered 1 to 4 times daily, depending on the needs of the patient, that is, for the prevention, treatment or emergency use of the active ingredient.

Claims (5)

Claims Compounds of formula (I): wherein X is O or S; Y represents a methylene group, an ethylene group, an optionally branched (C 3-8) alkylene group, a cyclopentylene group, a cyclohexylene group or a cycloheptylene group, the last three of which may be substituted with (C 1-4) alkyl; A is hydroxy; (C1-8) alkoxy, formyloxy; (C2-g) acyloxy; SH; ( _C1-6 ) alkyl mercapto; a mesyl group; _(C2-g) alkylsulfonyloxy group; tosyloxy group; phenyl-sulfonyloxy group which may be substituted _{(C2 sixth)} alhilceoporttal; -OS-OR, except _gy -OCOR ₃ , where 0 is 0 R 3 is (C 1-8) alkyl, methylene, ethylene or (C 3-8) alkylene substituted at a ω position with a 2,3-dihydro-4H-1,3-benzoxazin-4-one-N-yl; R is hydrogen, (C 1 -C 6) alkyl or phenyl; R1 and R2 are independently hydrogen, halogen, (C1-C6) alkoxy, trifluoromethyl or (C1-C6) alkyl, and the pharmaceutically acceptable acid and base salts thereof which are useful as pharmaceutically active agents. Use of compounds according to claim 1 for the preparation of medicaments useful in the cardiovascular field. Use of the compounds according to claim 1 for the preparation of medicaments useful in antianginal therapy. A pharmaceutical composition comprising a compound of claim 1 together with a pharmaceutically inactive excipient. A composition for use in cardiovascular therapy comprising a compound of claim 1 together with a pharmaceutically inert excipient. f ITALFARMACO S.P.A.