ITMI940355A1 - PHARMACOLOGICAL ACTIVITIES OF CUMARINA, THEIR USE AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM - Google Patents

Description

"DERIVATIVES OF CUMARIN WITH PHARMACOLOGICAL ACTIVITIES, THEIR USE AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM"

The present invention relates to the use of coumarin derivatives with calcium antagonist and antiviral activity.

In particular, the present invention relates to the use of bodies of general formula (I)

needs to:

it is a hydrogen athem or a linear or branched C ^ -C ^ alkyl group; or a group -O-Y-A, in which Y is a linear or branched C-J-C ^ Q alkylene chain,

A is a group of formula (II) or (III)

R, _

5 O _

(II) (III)

J

where is it

Rg is a hydrogen athem, or a linear or branched C-j-C 4 alkyl group;

Rj is a hydrogen atom or a linear or branched C - ^ - C ^ aleoxy group, or together with it forms a 1,2-dioxaethylene group, or an acryloyloxy group, optionally substituted by a hydroxy group and one or more C ^ groups -c 2 linear or branched alkyl;

is a hydrogen atom, or an O-Y-B group, in which

B is a halogen atom, a -OONR ^ Rg * group where

R5 and Rg are independently a hydrogen atom, a linear or branched Cj-C ^ alkyl group, or B is an NR ^ Rg group, where

R7 and Rg are independently a hydrogen atom, a linear or branched C - ^ - C ^ alkyl group, or taken together with the nitrogen atom to which they are bound form a nitrogenous heterocyclic group possibly containing in the heterocyclic ring one or more selected heteroathems between N, 0, S, or B is a group of formula (IV) - (VIII)

R.

where is it

Rg is a hydrogen atom, a linear or branched 3⁄4-C4 alkyl group; R4 a hydrogen atom, or together with R3 it forms a 1,2-dioxaethylene group, optionally substituted by a linear or branched C1-C4 hydroxy group;

their salts with pharmaceutically acceptable acids,

their enantiomeric and diastereoisomeric forms and their mixtures with the exclusion, as regards the use as calcium antagonist agents, of the compounds:

7,7'-ethylenedioxybenzopyran-2,2'-dione,

21,2'-dimethyl-3'-hydroxy-5 ', 6: 6', 7-pyanobezopiran-2-one.

The general formula (I) described above also includes new compounds which constitute another object of the present invention, which therefore refers to the compounds of general formula (I) with the exclusion of:

compounds of general formula (A)

TO

c

2

where RA is a hydrogen atom or a methyl group;

3⁄4 a hydrogen atom, a methyl or ethyl group;

Re is a hydrogen atom;

n is an integer between 1 and 5;

the compound of formula (B)

ίσ, 2> 3

/ s, CB)

and also of:

4-methyl-7- (3- (1-piperidinyl) propoxy) benzopyran-2-one;

4-methyl-7- (2- {1-piperidinyl) ethoxy) benzopyran-2-one;

4-methyl-7- (2- (3-morpholinyl) propoxy) benzopyran-2-one;

4-methyl-7- (2- (1-morpholinyl) propoxy) benzopyran-2-one;

4-methyl-7- (2- (N, N-dimethylamine) ethoxy) benzopyran-2-one;

4-methyl-7- (3- (N, N-diroethylimino) propoxy) benzopyran-2-one;

4-methyl-7- (2- (N, N-diethyl aranino) ethoxy) benzopyran-2-one;

4-me t yl-7- (3- (N, N-diethylamino) propoxy) benzopyr an-2-one;

7— (3— (6-aireninopurin-9-yl) propoxy) benzopyran-2-one;

7- (5- (6-airminopurin-9-yl) pentoxy) benzopyr an-2-one;

7- (1,2-dimethylenebis (oxy)) bis (benzopyran-2-one);

7,7, -ethylenedioxybenzopyran-2,2'-dione;

2 ', 21-dimethyl-31-oxy-5', 6: 6 ', 7-pyanobenzcpyran ^ 2-one.

Examples of linear or branched C1-C4 alkyl groups are methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, terbutyl, preferably methyl and ethyl.

Examples of linear or branched C ^ -C ^ g alkylene chain are methylene, dimethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, decylene, 1-methylethylene, preferably dimethylene, trimethylene, tetramethylene, pentamethylene.

Examples of linear or branched C ^ -C ^ alkoxy groups are methoxy, ethoxy, propoxy, iso-propoxy, butoxy, tert-butoxy, preferably methoxy.

Examples of heterocyclic groups are heterocycles with 6 atoms in the ring, for example pyridine, pyrimidine, pyrazine, 1,3,5-triazine, piperidine, piperazine, morpheline, thiamorpholine, preferably pyridine, piperidine; 5-atom heterocycles in the ring e.g. pyrrole, thiazole, oxazole, imidazole, pyrrolidine, thiazolidine, oxazolidine, imidazolidine, benzimidazole, preferably imidazole, benzimidazole.

Examples of pharmaceutically acceptable acids are halogenhydric acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, fumaric acid.

The compounds of formula (I) in which 3⁄4 is a hydrogen atom or a methyl group are preferred.

The following compounds are particularly preferred:

4-methyl-7- (2- (6-aminopurin-9-yl) ethoxy) benzopyran-2-one, (compound I); 4,4'-ethylenedioxydibenzopyran-2,2'-dione, (compound II);

7- (2- (dibaso1-1-yl) ethoxy) benzopyran-2-one, (compound III);

4,4'-dimethyl-7,7, -ethylenedioxybenzopyran-2,2, -dione, (compound IV);

4-methyl-7- (2- (1-pyridyllium) ethoxy) benzopyran-2-onebromide, (compound V), 4-methyl-7- (2-brchmoethoxy) ben2opyran-2-cne, (compound VI);

7- (2-hromoethoxy) benzopyran-2-one, (compound VII);

4- (2- {6-aimdnopurin-9-yl) ethoxy) benzopyran-2-one, (acnposite VIII);

4-methyl ~ 7- (3- (1-piperidinyl) propoxy) benzopyran-2-one, (compound IX); 4-methyl-7- (4- (1-pyridinium) butoxy) benzopyran-2-chloride, (oonpose X); 4-methyl-7- (2- (1-imidazolinyl) ethoxy) benzopyran-2-cne, (ocherite XI); 4-methyl-7- (2- (1-benzimidazolinyl) ethoxy) benzopyran-2 -cne, (body XII);

7- (2- {1-benzimidazolinyl) ethoxy) benzopyran-2 -one, (compound XIII);

2 ', 21-dimethyl-3 1-hydroxy-5 1, 6: 6 *, 7-pyanobezopiran-2-one, (ocherite XIV);

4-methyl-6,7- (1,2-methylenedio ss i) benzopyran-2 -one, (compound XV); benzodipiran-2, 6-dione, (post XVI);

4-methyl-7- (2- (5-1,2,4-triazolinyl) thioethoxy) benzopyran-2 -one, (compound XVII);

4-methyl-7-carbamoi lanniinonetylbenzcpiran-2-one, (post XVIII);

4-methyl-7- (3- (N, N-diethylamine) propoxis) benzopyran-2 one, (compound XIX); 4-methyl-7- (4- (N, N-diethylainuene) butoxy) benzopyran-2-one, (oonposite XX); 4,4 l-dimethyl-7,7, - (1,3-trimethylened3s (oxy)) bis (benzopyran-2-diane), (compound XXI).

In the last 25 years, the key role of calcium ions in important physiological functions in the animal organism, particularly the human one, has become evident. Disturbances in the binding of calcium ion with cell membranes give rise to vascular hypertension, disturbances in the contractile and chronotropic activity of the heart, development of systemic hypertension and cardiac arrhythmia. Blockers of ionic calcium transport channels (calcium antagonists), which interfere with the intracellular accumulation of calcium, have become valid means for the treatment of hypertension, cardiac ischemia, supraventricular tachyarrhythmia. Disturbances of the homeostatic calcium system are supposed to be a probable cause of diseases such as bronchial asthma, diabetes (Caverò, I., et al., Bull. Soc. Pharm. Lille, 38, (3-4), 1982, 131- 149). Among the other properties of calcium antagonists, their anticonvulsant activity (Pepoli, P.e al., Arch. Int. Pharmacodyn., 292, (1), 1988, 58-67), as well as the ability to fight the syndrome of alcohol abstinence and to carry out therapeutic activities in the treatment of psychic disorders, such as mania and depression (Rabum, D., Trends Pharmacol. Sci., 9, (4), 1988, 117-119).

Calcium antagonists belong to different classes of chemical compounds, including derivatives of 1,4-dihydropyridine and papaverine.

Despite the intense search for new compounds, the number of active ingredients used in the clinic is rather limited. Thus, in the text by Di Gregorio Barbieri, 1990, used as a reference by US doctors, only 5 calcium antagonists are mentioned: finoptina, diltiazem, nifedipine, nicardipine, nimodipine.

It is interesting to note that the Journal of American Medical Associaiion (JAMA) recommended in 1990 only three active ingredients, namely finoptina, diltiazem, nifedipine.

In the reference text by M.D. Mashkovsky (1988) information is found on only 8 compounds: verapamil, fenhidina, defril, sensit, cinnarizine, devincor, cavintone and vinconan; but it should be noted that many of these compounds are no longer used.

From the above it can be concluded that there is a need to supply new compounds with calcium antagonist activity.

It has now been found, and it is the object of the present invention, that the compounds of general formula (I) are endowed with calcium antagonist activity.

7- (3- {6-aminopurin-9-yl) propoxy) benzopyran-2-one and the higher pentoxy homologue have been studied from the photochemical point of view (Wenska and Paszyc, Can. J.Chem. Vol. 62, 1984 , 2006-2010, ibid., Vol.66, 1988, 513-516), but no pharmacological activity is mentioned.

A series of 7-ethoxy / propoxy-substituted 4-methylcoumarins has been prepared and described for their anti-estrogenic activity (Agravai et al., Research Communications, in Chemical Pathology and Pharmacology, vol.3, Nov. 1974, 555-560)

The compound 4,4 '- (1,3-trimethylenebis (oxy)) bis (benzopyran-2-dione) is described as a possible contraceptive agent (Misra et al., J. Indian Chem. Soc., 54 (12), 1977, 1124-6).

Bis (coumarinossi) (C2 “C5) alkanes are described by Thakar et al. in J. Indian Chem. Soc., 57 (1), 1980, 89-91.

Benzopyranes with anti-inflammatory activity are described in the published Japanese patent application JP 9397840 (Toyama Chem.), Filed on 09.02.93.

Benzopyranones with anticonvulsant activity are described in patent application DE 4111861 (Schwabe GmbH) published on 15.10.92.

Derivatives of isochromane with calcium antagonist activity are described in EP 0458387 (Akzo), published on 27.11.92.

The compounds described by the general formula (I), including those already known, are endowed with calcium antagonist activity.

The use of the compounds of formula (I) is therefore an object of the present invention, with the exclusion of the compound 7,7'-ethylenedioxybenzopyran-2,2'-dione, and 2 ', 2'-dimethyl-3' -hydroxy-5 ', 6: 6', 7-piranoezopiran-2-one, as agents with calcium antagonist activity.

The compound 7,7'-ethylenedioxybenzopyran-2,2'-dione, also known by the name Diumancal, has been described by the author of the present invention as a calcium antagonist.

The compound 2 ', 2'-dimethyl-3'-hydroxy-5', 6: 6 ', 7-piranobezopiran-2-one, known as Decursinol, has been described by the author of the present invention as a calcium antagonist useful in the treatment of cardiac ischemic states.

Compounds of formula (I) are prepared with methods known in literature, as described for example in the references cited above.

Briefly, the compound of formula (X)

R.

CX)

R.

where R, R2 and R4 are as defined above, it is reacted with a halogen derivative of formula (XI) X-Y-B, where Y and B are as defined above and X is a halogen atom, preferably chlorine, bromine, iodine. The same procedure is applied with compounds of formula (I) where R is -O-Y-A, starting from the appropriate 4-hydroxycoumarin and treating it with the derived halogen X-Y-A, where the groups are as defined above. there)

R.

(there)

R.

where R and R4 are as defined above, the process is illustrated specifically in Example 2.

The compounds according to the present invention were tested for their calcium antagonist activity according to the experimental model of CaCl2-induced arrhythmia in mice. The compounds of the invention were compared with known calcium antagonists. The following Table 1 shows i

TARKTJA 1

COMPOUND DOSE, SURVIVED AFTER ED50 LD50 WIDTH (mg / Kg) INDUCTION BY CaCl2 (%) THERAPEUTIC

2 min 5 min 15 min

CaCl2 330.0 0.0

Finoptina 0.1 0.0 0.0 0.0

1.0 0.0 0.0 0.0

10.0 50.0 30.0 0.0 10.0 41.0 4.0 Diltiazem 0.01 40.0 40.0 20.0

0.1 60.0 60.0 40.0 0.1 181.0 1810.0 1.0 70.0 80.0 60.0

Nifedipine 0.01 0.0 0.0 0.0

0.1 20.0 20.0 0.0

1.0 10.0 20.0 0.0 1.0 190.0 190.0 I 0.01 0.0 35.0 20.0

0.1 0.0 20.0 0.0

1.0 0.0 50.0 10.0 1.0 800.0 800.0 II 0.01 0.0 0.0 0.0

0.1 40.0 30.0 0.0

1.0 30.0 60.0 40.0 1.0 1000.0 1000.0 Decursinal 0.05 20.0 0.0 0.0

0.1 40.0 30.0 0.0 0.1 370.0 3700.0 1.0 0.0 0.0 0.0

- continued TABLE 1 (continued

COMPOUND DOSE, SURVIVED AFTER ED50 LD50 WIDTH (mg / Kg) INDUCTION BY CaCl2 (%) THERAPEUTIC

2 min 5 min 15 min

Diumancal 0.05 20.0 20.0 0.0

0.1 50.0 100.0 40.0 0.1 2500.025000.0

1.0 0.0 30.0 100.0

III 0.1 0.0 0.0 0.0

1.0 30.0 30.0 10.0

10.0 70.0 60.0 20.0 10.0 1000.0 100.0

V 1.0 30.0 10.0 0.0

10.0 30.0 40.0 10.0 10.0 175.0 17.5

IX 0.1 0.0 20.0 0.0

1.0 20.0 40.0 10.0 1.0 2000.0 2000.0

10.0 0.0 20.0 0.0

X 0.1 0.0 40.0 20.0

1.0 10.0 0.0 0.0

10.0 30.0 50.0 30.0 10.0

XV 0.01 0.0 10.0 10.0

0.1 20.0 50.0 20.0 0.1

1.0 0.0 10.0 0.0

XVI 0.01 10.0 0.0 10.0

0.1 40.0 30.0 60.0 0.1 1000.010000.0

1.0 40.0 30.0 40.0

Quite surprisingly, the compounds according to the present invention have also been shown to possess antiviral activity. The following Table 2 shows the antiviral activity values in experiments on chicken embryos subjected to influenza A / Leningrad / 134/72 virus and on mice subjected to influenza A / Bethesda / 10/63 and influenza A / Aichi viruses. / 2/68.

TABLE 2

Compound Activity index Comparison of

on experimental activity models

chicken white mice

Index of Depression Index of Amantidine Rimantidine Virazole

protection infectivity protection (%) (%) (%)

(%) (lg EID50) (%)

i H XI S / i

37.0 1.1 33.0 52.0 59.0 50.0

XIII 29.0 46.0 52.0 44.0

I 56.0 1.1 41.0 65.0 73.0 62.0 roto HTf II 56.0 1.3 41.0 65.0 73.0 62.0 B »c 3 CL n H. XVII 24.0 0.1 3-0

0) Vili 77.0 2.0 70.0 111.0 125.0 106.0 rf- O rt O H> 3 XXI 54.0 1.0 Φ SD C XIX 57.0 1.2 57.0 90.0 102.0 85.0 c 0) c / l 3 XX 57.0 90.0 102.0 85.0 CD N Ό Di X 43.0 68.0 77.0 65.0 Ό SS DO

3 Amantadine 63.0 100.0 113.0 95.0 SS ss CL <Rimantadina 70.0 1.8 56.0 89.0 100.0 85.0 (D Di r † ► ~ * r + Virazole 66.0 105.0 118.0 100.0 L rt- C 3 B! (D (Λ 3 From the above, the compounds of the present invention are endowed with pharmacological activity, in particular calcium antagonist and antiviral.

Therefore, the use of compounds of formula (I) as calcium antagonist and antiviral agents is a further object of the present invention.

Furthermore, a further object of the present invention is the use of compounds of formula (I) as active principles for the preparation of a medicament with calcium antagonist activity.

A further object of the present invention is the use of compounds of formula (I) as active principles for the preparation of a medicament with antiviral activity.

The present invention also comprises pharmaceutical compositions containing a compound of formula (I) in admixture with pharmaceutically acceptable carriers and excipients. The compositions according to the present invention can be prepared with conventional methods and procedures known to those skilled in the art, as described for example in "Remington's Pharmaceutical Sciences Handbook", XVII ed., Mack Pub., N.Y. USA.

Examples of pharmaceutical compositions are injectable forms, such as sterile solutions or suspensions or reconstitutable lyophilized powders, oral forms, such as tablets, capsules, tablets, dragees, powders, granulates, syrups and solutions; rectal forms, such as suppositories, ovules, glow plugs; topical forms, such as creams, ointments, lotions.

Dosages and posology will be established by the attending physician according to the severity of the pathology to be treated and the patient's condition (age, sex, weight). Dosages will generally be between 0.001 and 100 mg / kg.

The following examples further illustrate the invention.

EXAMPLE 1

7- (2- (Dibasol-1-yl) ethoxy) benzopyran-2-one (compound III).

3.0 g (0.02 mol) of dibasol base, 5.0 g of K2CO3, 50 ml of dimethylformamide and 2.0 g (0.01 mol) of 7- (2- (bromo) ethoxy) benzopyran-2 -one are stirred for 34 hours at a temperature of 130 ° C. The reaction mixture is then cooled and poured into water and ice.

The residue is filtered, dissolved in chloroform and loaded onto a column (3x80) of 40/160 L silica gel and eluted with light petroleum, then with light petroleum / chloroform (1: 3 and 1: 1). 2.0 g (35%) of the title compound are obtained.

C25H20N2 ° 3 ∞η P-f 181-183 “C.

IR (era.-1): 1725 (C = 0 pyranic), 1610, 1590, 1530

(aromatic), 1230-1300 (Ar-O-CF ^).

NMR {CDCI3, cP, m.d.): 6.30 and 7.60

(d.j. = 10.0Hz, H-3 and H-4), 6.60 and 7.50

(d, j. = 8.5 Hz, H-6 and H-5), 6.60 (d, j. = 2.5Hz

H-8), 7.20 - 7.55 (m, aromatic H of dibasol), 3.80

and 4.45 (t, j = 3.5 Hz, -O-CH2-CH2-).

BSBHPTO 2

Benzodipiran-2.6-dione (compound XVI).

A mixture of 37.0 g (0.34 moles) of resorcinol and 57.0 g (0.40 moles) of malic acid in 150 g of concentrated sulfuric acid is heated at a temperature of 130eC for 30 minutes; after which the mixture is poured into water, the residue is filtered, washed with water, then recrystallized from dimethylformanmide. 8.0 g (10%) of the title compound are obtained.

C12H6 ° 4 'ccn P-f * 345eC.

1H (cm-1.): 1700, 1710 (C-O piranico), 1610, 1570, 1550

(aromatic).

NMR (in DMSO, ^, m.d.): 6.50 and 8.60 (d.j.-10.0Hz

H-3, H-31, H-4, H-41),

8.0 (s, H-5), 7.5 (s, H-8).

EXAMPLE 3

4- (2- (6-Anminopurin-9-yl) ethoxy) benzopyran-2-ane (compound VIII). To the sodium salt solution, obtained from 1.35 g (0.01 moles) of adenine in 80 ml of absolute dimethylformanmide, 3.22 g (0.012 moles) of 4- (2- (track) ethoxy) benzopyran are added -2-one, then the solution is left at room temperature for 24 hours. After which the solvent is removed by distillation in vacuum, the residue is washed with water, dried, re-washed with chloroform and recrystallized from ethanol and dried. 2.62 g (81%) of the title compound are obtained.

C17H / l3N4 ° 300.1P * f * 289 ° c

IR (cm. ~ ^): 3300 (NH2), 1710 (C-0 pyranic), 1650, 1610,

1590 (aromatic), 1220 (-C-0-).

NMR (in DMSOjCp, m.d.): 6.10 (s, H-3), 8.40 and

8.60 (adenine s, H-2 and H-8),

7.30 - 8.10 (m, aromatic protons), 4.70 and 4.90

(t, j = 3.5 Hz, -0-CH2-CH2-N-).

EXAMPLE 4

4-Methyl-7- (4- (N.N-diethylamino) butoxy3⁄4benzopyran-2-one UL compound

2.18 g (0.007 moles) of 4-methyl-7 ~ {4-bromobutoxy) benzopyran-2-one, 10 ml of diethylamine and 30 ml of ethanol are boiled for 3 hours. The solvent is then concentrated in vacuum, the residue is dissolved in chloroform and washed a few times with water. Then the chloroform solution is extracted with 1N hydrochloric acid and the extract is concentrated in vacuo. The residue is recrystallized from ethanol. 1.80 g (76%) of the title compound are obtained.

C18H26N03C1 with m.p. 169 * 0.

IR (cm -1): 1730 (C = 0 pyranic), 1615 (aromatic), 1270

(—C — O — C “),

NMR (in DMS0, (/ \ m.d.): 6.20 (s, H-3), 7.05 and 7.70 (d.j. = (, 5 Hz, H -6 and H-5), 7.0 ( s, H-8), 4.20 (t, j = 3.5 Hz, Ar-0-CH2-), 3.10 (m, -N-CH2-), 2.40 (s, = C- CH3), 1.90 (m, CH2 -), 1.30 (t, j = 3.5 Hz,

Claims (1)

CLAIMS 1. Compounds of general formula (I): THERE) where is it: 3⁄4 is a hydrogen atom or a linear or branched O ^ -04 alkyl group; or a -0-Y-A group, in which Y is a linear or branched alkylene chain, A is a group of formula (II) or (III) NH " 5 O No. (II) (III) k.ÀJ where is it R3⁄4 is a hydrogen atom, or a linear or branched alkyl group; R2 is a hydrogen atom or a linear or branched C ^ -C ^ alkoxy group, yet together with R3 it forms a 1,2-dioxaethylene group, or an acryloyloxy group; tetrahydropyranic, optionally substituted by a hydroxy group and one or more linear or branched C ^ -C ^ alkyl groups; R3 is a hydrogen atom, or an O-Y-B group, in which B is a halogen atom, a -CONRgRg group, where R5 and Rg are independently is a hydrogen atom, a C - ^ - C ^ group linear or branched alkyl, o ^ ure B is an NR7Rg / where group R7 and Rg are independently a hydrogen atom, a C1-C4 group linear or branched alkyl, or taken together with the nitrogen atom to which they are bound form a nitrogen-containing heterocyclic group optionally in the heterocyclic ring one or more heteroatoms selected from N, 0, S, or B is a group of formula (IV) - (VIII) R (VII) where Rg is a hydrogen atom, a linear or branched C ^ -C ^ alkyl group; R4 a hydrogen atom, or together with R3 it forms a 1,2-dioxaethylene group, optionally substituted by a linear or branched C1-C4 hydroxy group; their salts with pharmaceutically acceptable acids, their enantiomer, diastereoisomeric forms and their mixtures with the exclusion of: compounds of general formula (A) where R3⁄4 is a hydrogen atom or a methyl group; RB a hydrogen atom, a methyl or ethyl group; R, -. Is a hydrogen atom; n is an integer between 1 and 5; the compound of formula (B) fCH) and of: 4-methyl-7- (3- (1-piperidinyl) propoxy) benzopyran-2-one; 4-methyl-7- (2- (1-piperidinyl) ethoxy) benzopyran-2-one; 4-methyl-7- (2- {3-morpholinyl) propoxy) benzopyran-2-one; 4-methyl-7- (2- (1-morpholinyl-propoxy) benzopyran-2-one; 4-methyl-7- {2- (N, N-dimethylamino) ethoxy) benzopyran-2-one; 4-methyl-7- (3- (N, N-dimethylamino) propoxy) benzopyran-2-one; 4-methyl-7- (2- (N, N-diethylaminino) ethoxy) benzopyr an-2-one; 4-methyl-7- (3- (N, N-diethylamino) propoxy) benzopyran-2-one; 7- (3- (6-aminopurin-9-yl) propoxy) benzopyran-2-one; 7- (5- (6-aminopurin-9-yl) pentoxy) benzopyran-2-one; 7,7'-ethylenedioxybenzopyran-2,2'-dione; 2 ', 2'-dimethyl-3'-hydroxy-5', 6: 6 ', 7-pyanobezopiran-2-one; 7- (1,2-dimethylenebis (oxy)) bis (benzopyran-2-one); 2. Compounds according to claim 1 wherein 3⁄4 is a hydrogen atom or a methyl group. 3. Compounds according to claim 1 or 2 which are: 4-methyl-7- (2- (6-aminopurin-9-yl) ethoxy) benzopyran-2-one, 4,4'-ethylenedioxydibenzopyran-2,2 <1> -dione, 7- {2- (dibasol-1-yl) ethoxy) benzopyran-2-one, 4,4'-dimethyl-7,7'-ethylenedioxybenzppiran-2,2 <1> -dione, 4-methyl-7- (2- (1-pyridinium) ethoxy) benzopyran-2-one bromide, 4-methyl-7- (2-bromoethoxy) benzppiran-2-one, 7- (2-bromoethoxy) benzqpiran-2-one, 4- (2- (6-aminopurin-9-yl) ethoxy) benzopyran-2-one, 4-methyl-7- (3- (1-piperidinyl) propoxy) benzopyran-2-one, 4-methyl-7- (4- (1-pyridinium) butoxy) benzopyran-2-one bromide, 4-methyl-7- (2- (1-iraidazolinyl) and toxy) benzopyr an-2-one, 4-methyl-7- (2- (1-benzimidazolinyl) ethoxy) benzopyr an-2-one, 7 ~ (2- (1-benzimidazolinyl) ethoxy) benzopyran-2-one, 2 ', 2'-dimethyl-3'-hydroxy-5', 6: 6 ', 7-piranobezopiran-2-one, 4-methyl-6,7- (1,2-methylenedioxy) benzopyran-2-one, benzodipiran-2,6-dione, 4-methyl-7- (2- (5-1,2,4-triazolinyl) thioethoxy) benzopyran-2-one, 4-methyl-7-carbamoylaminomethylbenzopyran-2-one, 4-methyl-7- (3- (N, N-diethylamino) propoxy) benzopyran-2-one, 4-methyl-7- (4- (N, N-diethylamino) butoxy) benzopyran-2-one. 4. Use as agents with calcium antagonist activity of the compounds of formula (I), where is it: 3⁄4 is a hydrogen atom or a linear or branched alkyl group; or a group -O-Y-A, in which Y is a linear or branched C ^ -C ^ Q alkylene chain, A is a group of formula (II) or (III) where is it R 5 is a hydrogen atom, or a linear or branched C ± -C 2 alkyl group; R2 is a hydrogen atom or a linear or branched C1-C4 alkoxy group, or together with R3 it forms a 1,2-dioxaethylene group, yet an acryloxy group, possibly replaced by a hydroxy group and one or more C1-C4 alkyl groups linear or branched; R3 is a hydrogen atom, or an O-Y-B group, in which B is a halogen atom, a -CONR5R5 group, R5 and Rg are independently a hydrogen atom, a linear or branched C ^ -C ^ alkyl group, yet B is an NRyRg group, where R7 and Rg are independently a hydrogen atom, a linear or branched C ^ -C4 alkyl group, or taken together with the nitrogen atom to which they are bound form a nitrogenous heterocyclic group possibly containing one or more selected heteroatoms in the heterocyclic ring between N, 0, S, yet B is a group of formula (IV) - (VIII) where is it Rg is a hydrogen atom, a linear or branched C1-C4 alkyl group; R4 is a hydrogen atom, yet together with R3 it forms a 1,2-disooaethylene group, optionally substituted by a linear or branched O2 -04 hydroxy group; their salts with pharmaceutically acceptable acids, their form enantiomers, diastereomers and related mixtures with the exclusion of the compounds: 7,7 * -ethylenedioxybenzopyran-2,2 <1> -dione, e 2 <1>, 2 <1> -dimethyl-3'-hydroxy-5 ', 6: 6', 7-pyanobezopiran-2-one. 5. Use as antiviral agents of the compounds of formula (I), R. where is it: 3⁄4 is a hydrogen atom or a linear or branched 3⁄4-C4 alkyl group; or an -O-Y-A group, in which Y is a 3⁄4-3⁄4o linear or branched alkylene chain, A is a group of formula (II) or (III) where is it R 5 is a hydrogen atom, or a linear or branched CyC ^ alkyl group; R2 is a hydrogen atom or a linear or branched C1-C4 alkoxy group, or together with R3 it forms a 1,2-dioxaethylene group, or an acryloyloxy group; tetrahydropyranic, optionally substituted by a hydroxy group and one or more linear or branched C1-C4 alkyl groups; R3 is a hydrogen atom, or an O-Y-B group, in which B is a halogen atom, a -CONR ^ Rg group, where R5 and Rg are independently is a hydrogen atom, a linear or branched C1 - C4 alkyl group, yet B is a NR7R3 f group where R7 and Rg are independently a hydrogen atom, a linear or branched CyC ^ alkyl group, or taken together with the nitrogen atom to which they are bound form a nitrogenous heterocyclic group containing optionally in the heterocyclic ring one or more heteroatcms selected from N, 0, S, yet B is a group of formula (IV) - (VIII) needs to Rg is a hydrogen athem, a linear or branched C - ^ - C ^ alkyl group; an atom of hydrogen, or together with R3 it forms a 1,2-dioxaethylene group, optionally substituted by a linear or branched C ^ -C ^ hydroxy group; their salts with pharmaceutically acceptable acids, their enantiomer, diastereoisanere forms and related mixtures. 6. Use of the compounds according to claims 1-3 and 4 for the manufacture of a medicament with calcium antagonist activity. 7. Use of the compounds according to claims 1-3 and 5 for the manufacture of a medicament with antiviral activity. 8. Pharmaceutical compositions containing one of the compounds of the preceding claims as an active principle.