UA62909C2 - Benzopyrans, benzopyran-containing pharmaceutical composition, method for treatment and/or prevention of diseases - Google Patents

Abstract

The invention relates to certain cis and trans benzopyrans having substituted benzamides at position C-4 and to their use in treating and/or preventing certain CNS disorders.

Description

This invention relates to new compounds, to methods of their preparation, and to their use as therapeutic agents.

In the published application for the European Patent Mo. 0126311, substituted benzopyran compounds possessing the ability to reduce blood pressure, including b-acetyl-trans-4-4-(4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1- benzopyran-3-ol.

In documents ER-A-O 376 524, ER-A-O 205 292, ER-A-O 250 077, ER-A-O 093 535, ER-A-O 150 202, ER-A-o 076 075 and MU/0/89/05808 (Bicham Group Plc) also describes some benzopyran derivatives that have antihypertensive activity.

Some benzopyran derivatives believed to have antihypertensive activity are also described in EP-A-O 350 805 (Biersdorf), EP-A-O 277 611, EP-A-O 277 612, EP-A-O 337 179 and ER-A-O 355 565 (Hechst Aktiengesellschaft); ER-A-O 466 131 (Nissan Chemical Industries Ltd.),

EP-A-0339562 (Esytomy Pharmaceuticals), EP-A-415 065 (E. Meryu, EP-A-450415 (Squibb), EP-A-0482934,

ER-A-0296975, 9U0-2004-791 and MUOH8907103.

EP-A-O 430 621 and EP-A-O 385 584 (Bicham Group plc) describe the separation of certain intermediate compounds useful for obtaining the compounds described in the above-mentioned patent applications.

EP-A-O 139,992 (Bicham Group Plc) describes some benzopyran derivatives with cis-isomerism in positions 3 and 4, which have antihypertensive activity. In PCT/5892/01045 (SmithKline

Bycham pls) describe some fluorobenzoylaminobenzopyrans, pyranopyridines! and tetrahydronaphthalenes, in which the substituents in the 3- and 4-positions are in a trans-configuration to each other. The presence of anxiolytic and anticonvulsant activity was also shown for these compounds.

PCT/5893/02512 and PCT/5893/02513 describe an additional group of compounds possessing strong anticonvulsant activity. These patent applications have not been published as of the priority date of this application.

Unexpectedly, it was discovered that some of the following compounds have anticonvulsant activity and, therefore, benefits! in the treatment of epilepsy and, as they also believe, useful for the treatment and prevention of anxiety, manic syndrome, depression, disorders associated with subarachnoid hemorrhage or neural shock, disorders associated with refusal to take a number of harmful substances, Parkinson's disease, psychosis, migraines, accompanied by with or without aura, cerebral ischemia, OSD, i.e. demonomaniacal obsessive-compulsive disorders and/or panic and/or aggressive states.

Accordingly, the present invention provides the following compounds: cis-6-acetyl-45-(2,3-dichlorobenzoylamino)-3,4-dihydro-2H-1-benzopyran-35-ol, trans-6-acetyl-45-(2 ,3-dichloro-4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-ZVA-ol, trans-6-acetyl-45-(3,5-dichlorobenzoylamino)-3, 4-dihydro-2,2-dimethyl-2H-1-benzopyran-ZVA-ol, trans-6-acetyl-45-(3,5-difluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H- 1-benzopyran-ZB-ol, trans-6-acetyl-4-(2--mophencarbonylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol, trans-6-acetyl -45-(3-thiophenecarbonylamino)-3,4-dihydro-2,2-dimethyl-2IN-1-benzopyran-ZVA-ol, trans-6-acetyl-45-(2,5-dichloro-3-thiophenecarbonylamino) -3,4-dimethyl-2H-1-benzopyran-ZVA-ol, cis-6-acetyl-45-(2,5-dichloro-3-thiophenecarbonylamino)-3,4-dihydro-2,2-dimethyl-2H -1-benzopyran-35-ol, trans-6-acetyl-45-(2,3,5-trichlorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-ZVA-ol, trans -6-acetyl-45-(2,3,4-trifluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-ZVA-ol, trans-6-acetyl-4 5-benzoylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-ZB-ol, trans-6-acetyl-45-(3-iodobenzoylamino)-3,4-dihydro-2,2- dimethyl-2H-1-benzopyran-ZB-ol, trans-6-acetyl-45-(5-fluoro-2-methylbenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-ZB- ol, trans-6-acetyl-45-(5-chloro-2-methoxybenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-ZVA-ol, trans-6-acetyl-4- (2,3-dimethylbenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol, cis-6-acetyl-45-(2,3-dichloro-4-fluorobenzoylamino)- 3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-35-ol, cis-6-acetyl-45-(3-chloro-4-fluorobenzoylamino)-3,4-dihydro-2,2- dimethyl-2H-1-benzopyran-35-ol, trans-6-acetyl-45-(2-fluoro-5-pyridinecarbonylamino)-3,4-dihydro-2,2-dimethyl-2|H-1-benzopyran- 3B-ol, trans-6-acetyl-4-(2-phenoxybenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol, trans-7-acetyl-4-(4 -fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol, trans-6-acetyl-45-(2-chloro-5-fluoro-2-thiophenecarbonylamino)-3, 4-dihydro-2,2-dimethyl-2H-1-benzopyran-ZB-ol, cis-6-acet l-45-(2-chloro-5-fluoro-2-iophenecarbonylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-35-ol, and cis-6-acetyl-45- (2,3,4-trifluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-35-ol or their pharmaceutically acceptable salts.

Such compounds will further be called compounds of formula (1).

It should be understood that compounds of formula (I) can have a chiral atom! of carbon in the provisions

Z and 4 can therefore exist in the form of znantiomers. The present invention covers each such znantiomer and their mixtures, including racemat!.

You should also learn that there are preferences for different cases of use! partial or separate znantiomer form!, so, in situations other than subarachnoid hemorrhage or neural shock, it is preferable to use ZK, 45 and 35, 45 znantiomer, and in case of subarachnoid bleeding or neural shock, preferably 35, 45 and ZE, AK znantiomer.

It should also be learned that the compound of formulas (I) or its pharmaceutically acceptable salt also include solvate! of such compounds, for example, hydrate.

The present invention also relates to the compound of formulas (I) or its pharmaceutically acceptable salt within the scope of the above definition, which have predominantly 35, 45 or Э, znantiomeric form, depending on whether the compounds are in cis- or trans-

configuration.

For example, the term "predominantly has the 35, 45 znantiomer form" means that the 35, 45 znantiomer is more than 5095 in comparison with the ZE, AK znantiomer.

It is more preferable that the indicated zantiomer 35, 45 is present in an amount greater than 6095, even more preferably the presence of the zantiomer 35, 45 in an amount greater than 7095, even more preferably the presence of the zantiomer 35, 45 in an amount greater than 8095, and even more preferably the content 35, 45 znantiomer in the amount of more than 9095. It is most preferable that more than 9595 of the 35, 45 znantiomer was present relative to the ZE, 4E znantiomer.

The same is applicable in the case of ZK, 45 znantiomer form". Such compounds and their pharmaceutically acceptable salts are novel and constitute the main aspect of the present invention.

It can be administered to mammals orally, parenterally, sublingually, or transdermally.

The amount effective for the treatment of the disorders described above depends on general factors, such as the nature and severity of the disease to be treated, and the weight of the mammal. However, a unit dose generally contains from 1 to 1000 mg, suitably from 1 to 500 mg, for example, in the range from 2 to 40 mg, in particular, 2, 5, 10, 20, 30, 40, 50, 100, 200, 300 and 400 mg of the active compound.

Single doses are generally prescribed to be taken one or more times a day, for example, 1, 2, 3, 4, 5 or 6 times a day, more often 1 to 4 times a day, so the total daily dose for an adult person weighing 7Okg is generally in the range from 1 to 1000 mg, for example, from 1 to 500 mg, that is, approximately from 0.01 to 15 mg/kg/day, and more often from 0.1 to bmg/kg/day, for example, 1-bmg/kg /day.

It is very preferable that the compound of formulas (I) is prescribed in the form of a single dose of the composition, such as a single oral dose, including a podiazchny form, rectal, local or tonic or parenteral (especially intravenous) composition.

Such compositions are prepared by mixing and suitably adapted for oral or parenteral administration, they can be tablets, capsules, oral liquid preparations, powders, granules, cakes, reconstituted powders, injectable and infused solutions or suspensions or suppositories. Oral compositions are preferred, in particular, compositions having a specific appearance, as they are more convenient for general use.

Tablets and capsules for oral administration are generally presented in the form of a unit dose and contain conventional excipients such as binders, fillers, diluents, substances used for the manufacture of tablets, lubricants, disintegrants!, dyes, flavoring agents and wetting agents. Tablets can also have a coating applied by well-known methods.

Suitable fillers include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycolate. Suitable lubricants include, for example, magnesium stearate.

Suitable pharmaceutically acceptable wetting agents or humectants include sodium lauryl sulfate.

Indication of solid oral compositions can be prepared using traditional methods of mixing, filling, forming in the form of tablets, etc. Repeated mixing procedures can be used to improve the distribution of the active agent throughout the composition in the case when it includes large amounts of fillers. Such operations are well known! in practice.

Oral liquid compositions may take the form, for example, of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be a dry product ready for dilution before use with water or a suitable carrier. Such liquid compositions may contain traditional additives, such as suspending agents, for example, sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, aluminum stearate gel or hydrogenated food fats, emulsifying agents, for example, lecithin, sorbitan monooleate or acacia gum; non-aqueous carriers (which may include dietary fats), for example, almond oil, fractionated coconut oil, oil complex zfiry, such as zfiry! glycerin, propylene glycol or ethyl alcohol; preservatives, for example, methyl or propyl p-hydroxybenzoate or sorbic acid and, if desired, traditional flavors or coloring agents.

Oral preparation form! compositions also include traditional prolonged forms, such as tablets or granules, which have an enteric coating.

For the purposes of parenteral administration, liquid unit dosage forms containing the described compound and a sterile carrier are prepared. The compound can be either suspended or dissolved, depending on the nature! carrier and ego concentration. Parenteral solution! it is usually prepared by dissolving the compound in a carrier and filter-sterilizing it before placing it in a suitable ampoule or vessel and sealing it. It is convenient for adjuvants such as local anesthetics and preservatives! and buffering agent, also dissolved in the carrier. To increase stability, the composition can be frozen after it is introduced into the vessel, and the water is removed under vacuum.

Parenteral suspensions are essentially prepared in the same way, except that the compound is suspended in a carrier instead of being dissolved, and before being suspended in a sterile carrier, it is sterilized by exposure to tylenoxide. It is advantageous to include in the composition a surface-active substance or a moisturizer to facilitate the uniform distribution of the compound of the present invention.

As is customary in practice, the compositions are accompanied by plain written or printed instructions for use in appropriate medical treatment.

The present invention further provides a pharmaceutical composition for use in the treatment and/or prevention of anxiety, manic syndrome, depression, disorders,

associated with subarachnoid hemorrhage or neural shock, disorders associated with withdrawal from the abuse of harmful substances, such as cocaine, nicotine, alcohol, and benzodiazepines, disorders that can be treated and/or prevented with anticonvulsants; such as epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischemia, Alzheimer's disease, schizophrenia and/or an aggressive condition that involves the combination of formulas! (I) or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.

The present invention also provides a method for the treatment and/or prevention of anxiety, manic syndrome, depression, disorders associated with subarachnoid hemorrhage or neural shock, disorders associated with withdrawal from the abuse of harmful substances such as cocaine, nicotine, alcohol, and benzodiazepines, disorders which can be treated and/or prevented by anticonvulsants, such as epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischemia, Alzheimer's disease, schizophrenia, and/or an aggressive condition, which involves administering to a patient suffering from these diseases an effective or prophylactic amount of a compound of the formula ( I) or ego pharmaceutically acceptable salt.

According to an additional aspect, the present invention relates to the use of a combination of formulas! (I) or its pharmaceutically acceptable salt for the production of drugs for the treatment and/or prevention of anxiety, manic syndrome, depression, disorders associated with subarachnoid hemorrhage or neural shock, conditions associated with withdrawal from the use of harmful substances, such as cocaine, nicotine, alcohol and benzodiazepines, disorders that can be treated and/or prevented by anticonvulsants, such as epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischemia, disease. Alzheimer's disease, schizophrenia and/or an aggressive state.

According to one more aspect, the present invention relates to a pharmaceutical composition containing a combination of the formulas! (I) or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.

According to the following aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as a therapeutic agent, in particular, for the treatment and/or prevention of anxiety, manic syndrome, depression, disorders associated with subarachnoid hemorrhage, neural shock, , associated with the refusal to use harmful substances such as cocaine, nicotine, alcohol and benzodiazepines!; disorders that can be treated or prevented by anticonvulsant agents, such as epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischemia, Aldheimer's disease, schizophrenia and/or an aggressive state.

Such compositions can beat the reception! by the method described earlier.

In general, cis compounds of formulas! (I) can be obtained from the corresponding trans-connected, procedure! the receipt of which is described in EP-0126311, EP-0376542, EP-205292, EP-0250077, EP-O093535,

ER-0150202, ER-0076075, UMO/89/05808, ER-0350805, ER-0277611, ER-0277612, ER-0337179, ER-O339562,

ER-0355565, ER-A-415 065 (E. MegsK), ER-A-450 415 (Squibb) ER-0466131, ER-A-0482934, ER-A-0296975, 90-2004-791 and MMOH89х07103.

Cis-compounds of formula (I) can be obtained using the procedures described or analogous to those described in EP-A-0139992.

Cis-compounds of formula (I) can be obtained using the procedures described by Burrell et al. (S. Vyiteiy ei aiYi, Tei Ieitseg5, 31, 3649-3652, 1990) or with the help of procedures described by Kvast and

Vilhausrom (OO. Otsavzi apa E. MiPNatsyeg, Etsg. U. Rnaptasoi, MoiIesshag RNappasoiodu Zesiop 245, 165-171, 1993).

It should be clear what racemat! compounds of the formula (I) can be used for separation or quantitative purification of compounds of the formulas! (I) can be obtained using procedures generally accepted in the art, and especially using the procedures described in EP-0430631 and EP-0355584.

It should also be noted that it is preferable that the compounds of the formula (I) can be obtained in the required enantiomeric form by forming a chirally pure zpoxide using catalysts and conditions described mainly in UMO91114694 or M/093M17026 with subsequent transformation of the zpoxides into the desired compound of the formula! (I) using the procedures described here.

Trans-compounds of formulas (I) can be obtained using the procedures described in

PCT/5892/01045, which is included! in the application for information, or trans-combination of formulas! (I) can be obtained using methods similar to the descriptions in one of the mentioned patents.

Using methods similar to those described in the above-mentioned patent publications and literature sources, the following compounds were obtained.

The following description, examples and results of pharmacological tests illustrate the present invention:

Description 1 2,3-dichloro-4-fluoro-benzoic acid 2,3-dichlorofluorobenzene (5 g), aluminum trichloride (6.917 g) and acetyl chloride (3.85 ml) are heated at a temperature of 130 "C for 20 hours in an argon atmosphere. Black the residue is poured into the mixture with concentrated HCl-ice and sulfur is added. The resulting layers are separated and the organic phase is washed with saturated sodium bicarbonate solution and brine and dried over anhydrous magnesium sulfate. Filtration and evaporation give a black residue, which is treated with n-hexane.

The n-hexane solution was filtered and the solvent was evaporated to give 2,3-dichloro-4-fluoroacetophenone (1.04 g).

The indicated crude material (0.69g), 595 sodium hypochlorite solution (233ml) and dioxane (20ml) are heated at reflux temperature for 16 hours. The solution is cooled and evaporated, and water (20 ml) is added along with conc. НСИ to рННИ!, and the solid substance, which is cooled, filtered and recrystallized from an acetone-water mixture to obtain 2,3-dichloro-4-fluorobenzoic acid! (0.36 Hg).

Description 2 cis 8-acetyl-2-(3-chloro-4-fluorophenyl)-Za,90-dihydro-4,4-dimethyl-4H-benzo|p|pyranoic|4,3-4|oxazole

Solution of trans-6-acetyl-45(3-chloro-4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-benzo|1b|pyran-

ZA-ola (Example 62 in UMO 94, 13656) (3.37g; 8.bmmol) in dry dichloromethane (dOml) and SABT (1.40ml; 10.59mmol) are kept at room temperature for 2 days. Evaporation under vacuum, followed by chromatography of the residue on Kieselgel 60 in a mixture of 2590 ztylate/n-hexane gives the target oxazoline in the form of a colorless gum (2.50 g; 7 895).

IN NMR (SOS z) 6: 1.35 (ZN, s), 1.59 (ZN, s), 2.60 (ZN, s), 4.80 (1Н, d.), 5.35 (1Н , d.), 6.90 (1H, d.), 7.15 (1H, t.), 7.82 (1H, m.), 8.00 (1H, dd.), 8.10 (1H , d.)

Example 1 cis 6-acetyl-45-(2,3-dichlorobenzoylamino)-3,4-dihydro-2|H-1-benzopyran-35-ol

Trans-6-acetyl-45-(2,3-dichlorobenzoylamino)-3,4-dihydro-2H-1-benzopyran-ZB-ol (0.84 g) was dissolved in dichloromethane (50 ml). Distilaminosulphur trifluoride (OABT) (0.325 ml) was added and the solution was stirred overnight. The mixture is evaporated to dryness and chromatographed on Kieselgel 60. Gradient elution using SNeoSiO-ETOAc gives a pale yellow gum (0.71g), which is dissolved in dioxane (20ml) and water (bml) containing 5 standards. H25Ox (Zml), within 2 days. The mixture is alkalized with solid sodium bicarbonate, stirred for 2 hours and evaporated to dryness. The mixture is distributed between ethyl acetate and water, and the organic layer is washed with saline.

The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to obtain a pale yellow gum (0.639 g). Combine the product! of the previous reaction (0.3 g) and chromatographed on

Siselgele 60. Elution with a mixture of dichloromethane-195 methanol gives a white solid (0.47 g), and recrystallization from ethyl acetate-hexane and then from acetone-hexane gives the target compound with T. pl. 104-10776.

IeCho--7.50" (MeOH, c-1.0)

Example 2 trans-6-acetyl-45-(2,3-dichloro-4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-ZA-ol

The compound of this example is obtained by combining 2,3-dichloro-4-fluorobenzoic acid (Description 1) with 0-(-)U-mandelate trans-b-acetyl-45-amino-3,4-dihydro-2,2- dimethyl-2H-1-benzopyran-Z3B-ol according to the method used in Example 1. The target compound is obtained by recrystallization from acetone-hexane in the form of crystals with T. pl. 205-206; (sdbrh 17.67 (MeOH, c-0.44)

Example C trans-6-acetyl-45-(3,5-dichlorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-ZA-ol

T. pl. 2202; ("bo 22.27 (MeOH, p-1.18)

Example 4 trans-6-acetyl-45-(3,5-difluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-ZB-ol

T. pl. 2032; (sCh"brshn28.92 (MeOH, c-1.0)

Example 5 trans-6-acetyl-4-(2-mophencarbonylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol

T. pl. 175.5-177"С;

Example 6 trans-6-acetyl--45-(3-thiophenecarbonylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-ZB-ol

T. pl. 211-213"6;

Example 7 trans-6-acetyl-45-(2,5-dichloro-3-thiophenecarbonylamino)-3,4-dimethyl-2H-1-benzopyran-ZA-ol

T. pl. 19420; (oC"bo--1.02 (MeEON, c-1.03)

Example 8 trans-6-acetyl-45-(2,5-dichloro-3-thiophenecarbonylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-

ZA-al

Yellowish-brown foam.

NMR (SOSI»z) 6: 1.40 (ZN), 1.54 (ZN), 2.06 (1H, d.), 3.84 (1H, dd.), 5.60 (1H, dd. ), 6.92 (1H, d.), 7.22 (1H, shd.), 7.30 (1H), 7.85 (1H, dd.), 7.96 (1H).

Example 9 trans-6-acetyl-45-(2,3,5-trichlorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-ZA-ol

T. pl. 219-223"6;

Example 10 trans-6-acetyl-45-(2,3,4-trifluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-ZA-ol

T. pl. 1672; (od"bozh3.07 (MeeOH, c-0.945)

Example 11 trans-6-acetyl-45-benzoylamino-3,4-dihydro-2,2-dimethyl-2|H-1-benzopyran-3B-ol

T. pl. 188-191260;

Example 12 trans-6-acetyl-45-(3-iodobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-ZA-ol

T. pl. 171-1732C; (sDbro--n15.57 (MeOH, c-1.00)

Example 13 trans-6-acetyl-45-(5-fluoro-2-methylbenzoylamino)-3,4-dihydro-2,2-dimethyl-2IN-1-benzopyran-ZA-ol

T. pl. 194-1967C;

Example 14 trans-6-acetyl-45-(5-chloro-2-methoxybenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-ZA-ol

T. pl. 191-194260;

Example 15 trans-6-acetyl-4-(2,3-dimethylbenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol

T. pl. 188-18920;

Example 16 cis-6-acetyl-45-(2,3-dichloro-4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-35-ol

T. pl. 13070;

Example 17 cis-6-acetyl-45-(3-chloro-4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-35-ol

A solution of oxazoline (02) (2.5 g; bbammol) in 1,4-dioxane (45 ml), water (15 ml) and 5 standards. sulfuric acid (bml) is kept at room temperature for 71 days. An excess of Mansoz is added, and the resulting suspension is stirred at room temperature for 2 hours. The mixture is concentrated under vacuum and then distributed between ethyl acetate and water. The organic layer is washed with water, salt solution and dried (Mag2504).

Evaporation under vacuum gives a pale yellow gum, which is chromatographed on Kieselgel 60 in a mixture of 2595 ethyl acetate/n-hexane. Combining the corresponding fractions with subsequent recrystallization from an acetone/n-hexane mixture gives the target compound in the form of white crystals. (1.20 Gh; 4690).

T. pl. 151-15320;

Found: C - 61.04; H - 4.91; M - 3.86. For SgoNizSIEMO" calculation: C - 61.31; H - 4.89 and M - 3.5795 m tach (KV): 3360, 3310, 2950, 1680, 1640, 1260 and 840cm"

IN NMR (SOSIv) 5: 1.40 (ZN, s), 1.56 (ZN, s), 2.12 (1H, d., ex Ogo), 2.50 (ZN, s), 3.84 (1H, dd.), 5.62 (1H, dd.), 6.91 (1H, d.), 6.95 (1H, sh.d.), 7.23 (1H, t.), 7 .75 (1H, m.), 7.83 (1H, dd.), 7.92 (1H, d.), 7.96 (1H, dd.). t/2: 391 (MU, 196), 37Z (4), 358 (88), 203 (50), 157 (100).

Example 18 cis-6-acetyl-4-(2,3,4-trifluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol

NMR (SOCI3) 6: 1.41 (ZN, s), 1.55 (ZN, s), 2.50 (ZN, s), 3.85 (1H, dd.), 5.67 (1H, dd .), 6.92 (1H, d.), 7.03-7.20 (IN, m.), 7.78-7.90 (2H, m.), 95 (1H, s.).

Example 19 trans-7-acetyl-4-(4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol

T. pl. 189-19320;

Example 20 trans-6-acetyl-45-(2-fluoro-5-pyridinecarbonylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-ZA-ol

T. pl. 847C;

Example 21 trans-6-acetyl-4-(2-phenoxybenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol

T. pl. 20870;

The compounds of the following examples were obtained using procedures similar to those described above.

Example 22 trans-6-acetyl-4-(2-chloro-5-fluoro-2-thiophenecarbonylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-

Z-al

Example 23 cis-6-acetyl-4-(2-chloro-5-fluoro-2-iophenecarbonylamino)-3,4-dihydro-2,2-dimethyl-2IN-1-benzopyran-3-ol

RESULTS OF PHARMACOLOGICAL TESTS

1. Test for social communication of the cross

Compounds of formula (I) or their pharmaceutically acceptable salts may be tested for further use as pharmaceuticals in accordance with the following procedure:

Potential anxiolytic properties are estimated using a procedure that determines the level of social communication of crosses, which is based on the method originally described by File (Rie, 1980, 9U. Mepygozsi. Meiosis, 2, 219-238). In this model, anxiolytic agents selectively increase social interaction, regardless of any influence on motor activity.

Method

Male Sprague-Dola (Zrgadoe-Oameu) crosses (Charles River, Great Britain, 250-300 g) are placed individually in separate cages on the third day before the study. On the day of the test, the animals are randomly assigned to groups! on 8-16 animals, which are administered orally in the amount of 1Tml/kg of various doses of the investigated compound (I) (1-300mg/kg) or the carrier. At the 60th minute after the introduction of the dose, the female is placed in a pair with a male, selected according to his weight and treatment group (that is, the first contact of the animals), in a box used to evaluate social communication under bright light in unusual conditions. The box is filled with white Plexiglas measuring 54x37x26cm with a transparent front wall also made of Plexiglas. The floor is divided into 24 equal squares and brightly lit (115lux). The time spent in active social communication (seconds) (when sniffing, courting, following each other, getting up, climbing up or down, fighting, biting) is estimated by remote monitoring ("blind method") by the number of squares intersected by lines (as an index motor activity).

The average value and standard error for the time spent in social communication, and the number of intersections of the squares is then calculated for each specific group! treatment, and the changes induced by the drug are expressed as a percentage increase or decrease relative to the control values. Statistical comparisons between the groups receiving the carrier and the medicinal product were performed using the Juppei multiple comparison procedure followed by significance assessment by means of variant analysis.

Medicines are suspended in 195 methyl cellulose.

MZP TEST

The test for determining the threshold value for the development of a maximum electroshock seizure (MZP) in rodents is especially sensitive for detecting anticonvulsant activity! In this model, anticonvulsants increase the threshold of induced electrical seizures, whereas proconvulsants! lower the seizure threshold.

Method

Mice (males, Charles River, Great Britain. CO-1 strain, 25-30g) are randomly distributed into groups of 10-20 animals and injected intraperitoneally in the amount of 100 ml/kg of various doses of the compound under study (0.3-300 mg/ kg) or carrier. Then, 30 or 60 minutes after the introduction of the dose, the mice are subjected to a single electroshock (0.1 sec., 50 Hz, sine wave), delivered through a corneal electrode. The average value of the current (and the value of the standard error) required to induce an epileptic seizure in 5095 (СС5о) mice in a specific treatment group is determined using the "up-down" ("prop apa domup") method of Dixon and Mood (Oihop apa Mood) ( 1948)7. Statistical comparison between the groups receiving the vehicle and the drug is performed using the method of Litchfield and Wilcoxon (I yspyleii apa Umisohop) (1949) 3.

For control animals, the SSvo value is generally 14-18tA. At the same time, the first animals in the control group were exposed to a current with a strength of 1 btA. If a tonic seizure does not occur, the value of the current is increased at the next mass under investigation. If a tonic convulsion occurs, the current is reduced and so on, until all the animals in the group are tested. Calculate the percentage of decrease or increase in the value of SSzo for each group! compared to the control.

The studies are carried out using the Hugo Sachs direct current shock generator

Zlektronik (Nido Zaspz EIesigopis Sopeitapi Siggepi ZposkK sepegayog) with a device for controlling the level of shock from 0 to З0бОтA, however, a step value of 2tA is usually used. The drug is suspended in 195 methyl cellulose.

LINKS

1. Gozneg MU. apa 5sptiai 0. (1988), Eriierzu Nezv., 2, 145-181. 2. Oihop MU.). apa Mosa A.M. (1948), 9. Ateg. ziyai Avvp., 43, 109-126.

Z. Peseyia 9.T. apa UMisohop RE. (1949), U. Rpaptasoi. Ex. Tag., 96, 99-113.

THE RESULT

The compound of example 17 increases the shock threshold by 10595 at an oral dose of 1Omg/kg. x- Labyrinth

Compounds of formula (I) or their pharmaceutically acceptable salts can be used for research! with the purpose of further therapeutic use using the procedures below:

Introduction

The fear test using the x-maze (Napaieu apa Miishapu, 1984) makes it possible to determine the "exploratory" reaction of the brain in an environment in which there are both anxiogenic (open passages) and relatively non-anxiogenic (closed passages) areas. A selective increase in the ability to inspect open passages after the introduction of the drug allows one to draw a conclusion about the presence of an axiolytic effect.

The x-maze technique, raised 70 cm above the floor, consists of two closed passages measuring: 45 cm (length) x 15 cm (width) x 10 cm (height) and two open passages measuring: 45x10x1 cm, arranged in such a way that both passages have each type of arrangement ! friend against friend. Passers of both types of markings! into two equal sections. Crosses are placed in the center of the x-maze and observed for 10 minutes, measuring and recording the following parameters: 1) the number of entries and the time spent in the area (a) with an open passage and (b) with a closed passage, (c) at the end of open aisles and (d) at the end of closed aisles; 2) the number of intersecting sections.

The fear of open areas exceeds the fear of closed areas, and rats in a typical case demonstrate a clear preference for closed passages. Anxiolytic agents increase the number of entrances and the time spent on the outer half of the open passages, as well as the percentage of entrance and time spent on the fully open area. There are 4 parameters that estimate the level of fear, and the total number of intersecting sections is calculated for each animal. Medicines are administered intraperitoneally or orally to animals, distributed in groups, including 6 to 12 mice, 30-60 minutes before the test. Statistical comparison between the groups receiving the carrier and the drug is carried out using the Mann-Whitney "O" test (Mapp-UMUnpipeu, "O"-(ezi) (two-sided criterion). 5. Napaieu apa 5. Mipapi, Agop. Rpagtasoi! ., 1984 327 1-5. 4. Delay of cerebral vasospasm in outbred dogs

Compounds of formulas (I) or their pharmaceutical salts can be studied for their pharmaceutical use by means of the procedures given below:

In these studies, 25 male outbred dogs weighing between 9 and 12 kg were used. The animals are placed in cages and cared for in accordance with the guidelines for the care and use of laboratory animals (ONEMU (ОНН5З), publication Mo (MIN) 85-23, revised in 1985). All procedures applied to laboratory animals were approved by the Committee on of animal care and their use, SmithKline Beecham Pharmaceutical

Veespat RPpaptaseshisa!Y. Each animal is anesthetized with pentobarbital (35 mg/kg, IV) and placed on a heated operating table on its back. And then all animals are subjected to tracheotomy, paralyzed (tubocurarine; 0.1 mg/kg, IV) and subjected to artificial ventilation with room air. At the end of free exhalation, a constant assessment of the level of CO" (her COg) is carried out, and arterial blood gas analysis is periodically performed to confirm the stability and adequacy of ventilation during each experiment. In the left external jugular vein and the right femoral artery and vein, polyethylene cannulas are placed for the administration of drugs, while controlling the blood pressure level and taking blood samples. Transfemoral catheterization of the left vertebral artery is carried out through the left femoral artery using the French Lehman Me5 dacron catheter (5 ipspi eptap dakgop saifeieg) (Vaga, Tem/k5rigu MA). Before the start of the experiment, if necessary, anesthesia is maintained by the introduction of pentobarbital (5 mg/kg, IV).

The effect of the compounds of the present invention on acute cerebral vasospasm was evaluated in 15 dogs. For all animals, after intravertebral injection of radiocontrast material (Omnypak 300 (Otpiradne 300)), a control digital angiogram of the anterior spinal artery and the main artery is obtained. In each dog, 4 ml of cerebrospinal fluid is collected with the help of puncture of the mastoid membrane and 4 ml of autologous venous blood is injected. Every 30 minutes repeat angiography after intracavitary blood injection and identify and quantify acute vasospasm in the main and anterior spinal arteries. Infusion of the carrier (1095 polyethylene glycol 200) for 30 minutes does not have an effect on acute vasospasm. The effect of a 30-minute infusion of the investigated compounds on reversible acute vasospasm shown both on the main and anterior spinal arteries.

The effect of the compounds of the present invention was also shown on a model of dogs in which, when administered for a long time, there is a delay in cerebral vasospasm (two models of cerebral vasospasm with hemorrhage). In this model, a control spinal angiogram is obtained and autologous blood is injected intracavitally on the 1st day (as described above). On the third day, the intracavitary injection of blood is repeated, and on the 7th day, severe delayed vasospasm is assessed quantitatively on an angiogram in all animals. Infusion of the carrier (1095 polyethylene glycol) for 60 minutes had no effect on the delayed vasospasm observed in the main and anterior spinal arteries (p-5). The effect of the infusion of the studied compounds on the reversibility of significantly delayed cerebral vasospasm indicates the activity of the compound.

Compounds of formula (I) or their pharmaceutically acceptable salts can be used for research! for pharmaceutical use with the help of procedures listed below: 1) Activity against Parkinson's disease

Rat model with b-hydroxydopamine-induced lesion

Ukazannyi test (pdegzivydiy, I, 1971, Asia RpuzioI. 5sapa 367, 49-68, and/or Opdegzivayi, I, 1971, Asia

Rpuzioi Zsapa 367, 69-93) can be used to determine the presence of formulas in compounds! (I) or their pharmaceutically acceptable salts activity against Parkinson's disease. 2) Anti-psychotic activity

Rat model with amphetamine-induced hypermotor activity

The multiple-indication test (KokkKipai5 I. Apa Apiztap, M, 1980, Rzupoiodisa! VyPep, 88, 551-579) can be used to determine the presence of formulas in compounds! (I) or their pharmaceutically acceptable salts with antipsychotic activity.

C) Anti-migraine activity

Cortical spreading depression and migraine

A multiple-indication test (Umapi et al., 1987, Vgaip Kezeagt, 411, 72-80) can be used to determine the presence of antimigraine activity in compounds of formulas! (I) or their pharmaceutically acceptable salts.

Preparation of animals

Experiment! conducted on female or male cats (2.5-3.0 kg), which were kept without food during the night, but provided with free access to water. Anesthesia was induced with 4-595 halothane and further maintained by intravenous administration of alpha-chloralose (90-110 mg/kg). The value of the rectal temperature and the acid-base level are maintained in the physiological range.

The right femoral artery and vein are catheterized to measure blood pressure, take arterial blood samples, and administer medication. The heart rate is determined based on blood pressure signals and recorded. A left-sided craniotomy of the parietal bone and a durectomy are performed, and the brain is covered with a layer of mineral oil heated to a temperature of 37"C.

Changes in the diameter of blood vessels are determined with the help of real-time video microscopy and the result is recorded! on videotape.

Induction of cortical spreading depression (C50)

C5O was induced by the introduction of a small amount (ZOmg, crystalline) CS! in the region of the suprasylvian gyrus, distant from recording electrodes, observable vessels and other blood vessels. Since the brain is covered with a layer of warm mineral oil, KSI dissolves slowly in the brain within 5 minutes after application. After that, the remaining KSI is removed from the surface of the brain with the help of a tampon soaked in a saline solution.

Changes in extracellular potential and the diameter of arteries and veins are recorded for 120 minutes.

Drug treatment

The compound of example 17 in the form of a suspension (1Omg/kg, in/br) or a carrier (195 labrazol in/br) is administered 90 minutes before the induction of C50O.

During the entire period observed in the control animals (n-4), the reproducible phenomenon of C5O induced KSI was monitored. In contrast to them, in the animals that took the preparation of example 17 (p-3) in response to the introduction of KSI, only initial C5O phenomena were noted. The overall average (minimum-maximum) number of C5O occurrences in the control and test groups was 5.5 (4-9) and 2 (1-2), respectively. The total duration of C5O of similar phenomena was 60.36 minutes (n-:4) in the control and was significantly reduced (p«e0.05) to 13.7240.3 minutes in animals receiving compounds of example 17 (1-3).

Cerebral ischemia a) Test on Mongolian gerbils

Experiment! ip passed the fillings on adult Mongolian gerbils (TitriergookK Ragt (MA)) weighing 60-80 grams. Temporary ischemia of the forebrain was performed by ligation of the bilateral carotid artery under anesthesia with 2.595 isoflurane at 10095 Ohm, and the animals were placed on a heated bed to maintain a body temperature of 37"C degrees. The common carotid arteries are exposed and clamps are placed on both arteries for the period of time specified in the manual , to create an aneurysm.

RVM, dissolved in a saline solution, is administered intraperitoneally as a bolus 30 minutes before occlusion (pretreatment) or immediately after and again at the 6th time of reperfusion, with the subsequent administration of the same dose 2 times a day for two days (subsequent processing). To determine the amount of SA! Neurons of animals are killed on the 7th day after induction of ischemia and perfused with buffered formalin. The brain is removed, fixed in formalin for 3 days, immersed in formalin, cut into a coronal section 7 µm thick (1.5-1.9 mm following the 15th bregma and stained with thionin. The number of intact neurons per 750-µm length of SAI is calculated for each animal layer on both sides of the hippocampus in Z sections b) MSAO method

Three strains of mature male crosses (ZNK) are obtained from commercial suppliers (Takonyk Pharm3z,

Germantown, MU, Charles River, Danvers, MA; and Charles River, respectively) (Tasopis Ragt",

Segtapiomp, Moscow State University; Spazez Kimeg, bapmeg5, MA; apa Spapeh Kimeg)| at the age of 18 weeks (250-300 g in weight) and placed in a cage for 2-4 weeks before use in the indicated studies. To confirm that the strain under investigation! of animals really belong to the hypertensive and normotensive type, groups of animals of each strain are anesthetized with the help of 295 isoflurane (Anaquest Mzdison UM (Apadpievzi, Madivzopg M/I)) and prepared in aseptic conditions for long-term blood pressure control. The femoral artery is catheterized using a polyethylene tube (PE 60; Claoi Adame.

Parsipany, MU (RE 60; Siau Adatv. Ragzirrapu, MU)|, which reaches the descending aorta. The tube is passed subcutaneously from the artery and brought out between the scapula under the back of the neck and cleaned/filled with an isotonic sterile saline solution. The incision is sutured with 2-0 silk thread and treated with 595 lidocaine ointment (Astra Pharmaceuticals, Westboro, MA (Avziga Rpagtaseshisa!5,

Umezirogotsdp, M.A.)). Animals recover after surgery/anesthesia within 5 minutes. 4-5 hours after the operation, the average arterial block pressure is recorded for 5 minutes/cross at the connections of the external tube in each cross! with a Stotham pressure sensor (Ziayat rgezzige igapzdyseg) (P2. 30r; Stotham Medical Instruments. Los Angeles (Ziaiyat Meadis! Ipvipitepiv. 105

Apdeiez, SA)| with access to a polygraph (Model K 711: Beckman Instrumente, Inc. Fullerton. SA (Moae! A 711: Vesktap Ipvigitepiv, Ips., EshShepop, SA)).

Focal stroke procedure

MSAO or imitation surgery is carried out on ZNK rats, 50 under anesthesia with sodium pentobarbital (65 kg/kg, IV, with addition if necessary). All animals are provided with free access to water and food before and after the operation. The body temperature is maintained at the level of 37"С with the help of a heating pad during the entire surgical procedure. The surgery is carried out according to the method described earlier (2-4). The right, dorsal surface relative to the head! is vibrated and treated with providon-iodine, after which the cross is placed in stereotaxic device | Dzvid Kopf Instrumente, Tuyunga, SA (Bbamia Kori Ipzigitepiv, SA), so that the operated (right) side of the head occupies the upper position. An incision of 1-2 cm is made between the eye socket and the external auditory canal. The superior muscle is dissected from the skull and pull, without damaging the auditory conjunctiva or the mandibular nerve. Under microscopic control and irrigated with saline solution, a 2 mm craniotomy is performed, rostral to the zygomatic suture of the skull. The dura mater above the artery is incised using a modified 30 gauge needle tip. In the case permanent right MSAO simultaneously conduct occlusion of the ar teria with the use of electrocoagulation (electrosurgical generator, power 2, CO (Rogse 2

Eiesigozygdisa Sepegaiyug, Maiieu Gab Ips., Voshiadeg, SO)| after that, the indicated artery is cut dorsally in relation to the lateral locations of the olfactory pathways at the level of the lower cerebral veins! big brain A small piece of the indicated artery after immersion in a sterile saline solution

Gelfoam (Upjohn, Kalamazoo, MI (Semyoat Oriopp, Kaiataloo, MI)) is then placed above the level of the craniotomy, and the superior muscle and skin are closed in two layers. Animals are allowed to recover after anesthesia under a heating lamp, after which they are returned to their cages. After 2 hours after conducting MSAO, the animals are killed and the brain is prepared for reactive histological examination.

Measurement of ischemic damage

After the neurological assessment (24 hours after the operation), the rats are killed by administering an overdose! sodium pentobarbital. In the course of 2-3 minutes, the brain is removed and coronal slices are made from the forebrain (2 mm thick) at the level of the olfactory bulbs in the direction of the cortical-cerebellar junction using a brain slicer (59); Tsyvyk-Miller Laboratoriz

Inc., Allison Park (2imis-MiPeg Garogasogiez Ips., Aibzop Ragk, RA)). The indicated section of the forebrain is then immediately immersed in a 195% solution of triphenyltetrazolium chloride (TTX) in a phosphate buffer at a temperature of 37"C for 20-30 minutes (6.78). Then the staining of the tissue is fixed by filtration in 1095% formalin, buffered with phosphate. Both sides of each TTX of the slice is photographed in color using a Polaroid. The resulting photograph is analyzed for the presence of ischemic damage in quantitative terms using systems! image analysis |Amersham

KAB 3000, Louts Associates, Inc. (Ategzpat Nav 3000; Ioaiv Avzosia (evz, Ips.) Morphological changes caused by surgery are evaluated in the entire forebrain (a total of 11 flat surfaces) for each animal. 11 flat images are obtained from each side! 6 slices 2 mm thick, each from which corresponds to approximately 1 mm of a surface slice with fluctuations from "5 mm to -5 mm from the bregma! (97) and include the complete forebrain. Such flat images of the surface (in photographs) are converted into a digital impression and used in the image analysis system for planar determination of necrosis-damaged zones and swelling. For each slice, 2 parameters are determined that characterize ischemic damage associated with MSAO in accordance with the previous definition (2, 4, 98, 122). "Swelling of the hemispheres" is expressed in the form of a percentage increase in the size of the ipsilateral (i.e. on the operated side) of the hemisphere above the contralateral (normal) hemisphere and are calculated as follows:

Zone of the ipsilateral Zone of the contralateral

Percentage - swelling - lolupshearia 0 poluupvriya d/s x100

Zone of the contralateral hemisphere of the hemisphere "Infarct zone" is expressed as the percentage of tissue damaged by necrosis relative to the contralateral (normal) hemisphere and is calculated as follows:

The size of the infarct zone of the infarct zone x 100 of the phalanx, in percent Contralateral zone of the phalanx

Swelling and size! the infarct zone is expressed relative to the contralateral hemisphere (i.e., ipsilaterally located ischemic damage, normalized relative to the normal contralateral hemisphere). This is a parameter! are determined for each section to assess the profile of damage throughout the forebrain (that is, the "profile of the forebrain") and for "full" changes in the forebrain, summing up the data for all sections, obtained with the help of several formulas.

The presence of brain edema associated with swelling of the hemisphere after MSAO is determined by comparing gray/dry weight in accordance with the previous description (45,118). Rats are killed by the introduction of overdoses! sodium pentobarbital 24 hours after simulated surgery or MSAO.

The brain is quickly removed, the forebrain is isolated in the area of the cerebellar-cortical junction and cut into 2 hemispheres, after which each hemisphere of the forebrain is measured within 2 minutes after decapitation using a device for determining the chemical balance (Mesheg Toure5 H5 spetis! raiapse) | Mettler Instrumente Corp, Hightstown, MU (Mesheg Ipzigitepi5 Sogr, Nidpibiomup, MU)). The dry weight is measured using the same scale after drying the hemispheres in a drying cabinet at a temperature of 80"C for 48-72 hours. The water content in each hemisphere is calculated as the difference between the gray and dry weight as a percentage of the dry weight fraction:

Percent

Sroy ves- Su hoyves content (-VBZGHS- - ----- I same - 2 x100

Make your own water

Claims (3)

Y. Compounds of benzopyrans, formulas: і у Со M Ко он Кі К5 Кі юю 0) Кз , where one of Ві and В: is H and the other is acetyl, Нз, Вы, Н5 and Не independently selected from Н and СНз; and VA; vibrane from 2,3-dichlorophenyl, 2,3-dichloro-4-fluorophenyl, 3,5-dichlorophenyl, 3,5-difluorophenyl, 2-thiophenyl, 3-thiophenyl, 2,5-dichloro-3-thiophenyl, 2, 3,5-trichlorophenyl, 2,3,4-trifluorophenyl, phenyl, 3-iodophenyl, 5-fluoro-2-methylphenyl, 5-chloro-2-methoxyphenyl, 2,3-dimethylphenyl, 3-chloro-4-fluorophenyl, 2-fluoro-5-pyridyl, 2-phenoxyphenyl, 4-fluorophenyl, and 2-chloro-5-fluoro-2-iophenyl, and the НМ-СО-Н7 group is a siv or /gapv to the ОН group and is selected from the group , consisting of: cis-6-acetyl-45-(2,3-dichlorobenzoylamino)-3,4-dihydro-2H-1-benzopyran-35-ol, trans-6-acetyl-45-(2,3-dichloro -4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-ZVA-ol, trans-6b-acetyl-45-(3,5-dichlorobenzoylamino)-3,4-dihydro- 2,2-dimethyl-2|H-1-benzopyran-ZB-ol, trans-6b-acetyl-45-(3,5-difluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2nH-1- benzopyran-ZB-ol, trans-6-acetyl-4-(2-thiophenecarbonylamino)-3,4-dihydro-2,2-dimethyl-2|H-1-benzopyran-3-ol, trans-6-acetyl- 45-(3-thiophenecarbonylamino)-3,4-dihydro-2,2-dimethyl-2IN-1-benz opiran-ZV-ol, trans-6b-acetyl-45-(2,5-dichloro-3-thiophenecarbonylamino)-3,4-dimethyl-2H-1-benzopyran-ZVA-ol, cis-6-acetyl-45- (2,5-dichloro-3-thiophenecarbonylamino)-3,4-dihydro-2,2-dimethyl-2IN-1-benzopyran-35-ol, trans-6b-acetyl-45-(2,3,5-trichlorobenzoylamino) )-3,4-dihydro-2,2-dimethyl-2|H-1-benzopyran-ZVA-ol, trans-6b-acetyl-45-(2,3,4-trifluorobenzoylamino)-3,4-dihydro- 2,2-dimethyl-2H-1-benzopyran-ZB-ol, trans-6-acetyl-45-benzoylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-Z3BA-ol, trans- 6-acetyl-45-(3-iodobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-ZVA-ol, trans-6-acetyl-45-(5-fluoro-2-methylbenzoylamino) )-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-ZVA-ol, trans-6b-acetyl-45-(5-chloro-2-methoxybenzoylamino)-3,4-dihydro-2, 2-dimethyl-2H-1-benzopyran-ZB-ol, trans-6b-acetyl-4-(2,3-dimethylbenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3- ol, cis-6-acetyl-45-(2,3-dichloro-4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-35-ol, cis-6-acetyl- 45-(3-chloro-4-fluorobenzoylamino)-3,4-dihydro-2,2-dime tyl-2H-1-benzopyran-35-ol, trans-6-acetyl-45-(2-fluoro-5-pyridinecarbonylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-ZB- ol, trans-6-acetyl-4-(2-phenoxybenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol, trans-7-acetyl-4-(4-fluorobenzoylamino) )-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol, trans-6-acetyl-45-(2-chloro-5-fluoro-2-thiophenecarbonylamino)-3,4- dihydro-2,2-dimethyl-2H-1-benzopyran-ZVA-ol, cis-6-acetyl-45-(2-chloro-5-fluoro-2-thiophenecarbonylamino)-3,4-dihydro-2,2- dimethyl-2H-1-benzopyran-35-ol and cis-6-acetyl-45-(2,3,4-trifluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-35- ol, or their pharmaceutically acceptable salts. 2. Pharmaceutical composition for use as a medicinal product in the treatment and/or prevention of anxiety, manic syndrome, depression, disorders associated with subarachnoid hemorrhage or neural shock, conditions associated with withdrawal from the use of harmful substances, such as cocaine, nicotine , alcohol and benzodiazepines, disorders amenable to treatment and/or prevention with anticonvulsants, such as epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischemia, Alzheimer's disease, schizophrenia and/or an aggressive state characterized by the fact that the compound according to claim 1 or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier. 3. A method of treatment and/or prevention of anxiety, manic syndrome, depression, disorders associated with subarachnoid hemorrhage or neural shock, complex, associated with refusal to use harmful substances, such as cocaine, nicotine, alcohol, and benzodiazepines, disorders amenable to treatment and /or prophylaxis with anticonvulsants, such as epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischemia, Alzheimer's disease, schizophrenia and/or an aggressive state, characterized by the fact that a patient suffering from these diseases is administered as a therapeutic agent an effective or prophylactic amount of the compound claim 1 or its pharmaceutically acceptable salt.