PL164216B1 - Method for manufacturing new benzopiran derivatives - Google Patents

Abstract

1. The method of producing new derivatives a benzopyran of the formula I or a pharmaceutical thereof or pharmaceutically acceptable salts thereof solvates, wherein the formula is one of A1 or A2 is hydrogen and the other is a group of formula C2F5-, Y1 is -O-, R1 and R2 independently represent a hydrogen atom or a C1-6 group alkyl or R1 and R2 together form C2-7 polymethylene the rest R3 is hydrogen, a group hydroxy, C1-6 alkoxy or C1-7 acyloxy, and R4 is water or R3 and R4 together represent a bond; R5 is an oxopyrrolidinyl group, oxopiperidinyl or pyridonyl, characterized in that the compound of formula 2, wherein A1, A2, R1, R2 and Y1 are as defined above, and a and b together represent epoxy oxygen, is reacted with pyrrolidone or piperidone or pyridone and optionally produces is a pharmaceutically acceptable addition salt a compound of formula 1 and / or is produced pharmaceutically an acceptable solvate of the compound of Formula 1 or a pharmaceutically acceptable salt thereof.

Description

The subject of the invention is a process for the preparation of new benzopyran derivatives.

European Patent Applications, published under the numbers 76075, 93 535, 95 316, 107 423, 120426, 126311, 126350, 126367, 138 134, 250 077, 273262 and 298452, describe benzopyran derivatives with antihypertensive activity, among others. In addition, European patent application No. 176689 discusses certain benzopyran derivatives used in the treatment of, inter alia, the respiratory system.

European patent application published under No. 314446 also describes benzopyran derivatives used in the treatment of hypertension.

New benzopyran derivatives have now been developed with unexpected smooth muscle relaxant activity and therefore potentially useful as bronchodilators for the treatment of respiratory disturbance such as reversible airway obstruction and asthma, and for the treatment of asthma. These compounds have also been shown to be potentially useful for the treatment of disturbances associated with smooth muscle function in the gastrointestinal, genital and renal systems, including the ureters. These disturbances include respectively the intestinal irritation syndrome; premature birth; inability to keep urine or stools; disturbances in the work of the kidneys and accompanying kidney stones. They also have potential utility in the treatment of non-hypertensive cardiovascular disorders such as right ventricular circulatory failure with edema, angina, peripheral vascular disease, and cerebrovascular disease, as well as in the treatment and / or prevention of pulmonary hypertension and disorders associated with acute heart failure. . These compounds also have utility as anticonvulsants in the treatment of epilepsy.

The present invention provides compounds of formula I, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein one of A1 or A2 is hydrogen and the other is C2F 5-, Y1 is -O-; R1 and R2 independently represent H or C1-6 alkyl, or R1 and R2 together form a C2-7 polymethylene moiety; R3 is hydrogen, hydroxy, C1-6 alkoxy or C1-7 acyloxy and R4 is hydrogen, or R3 and R4 together represent a bond; R5 is oxopyrrolidinyl, oxopiperidinyl or pyridonyl.

Preferably A1 is C2F 5- and A2 is hydrogen.

R5 is preferably a 2-oxopiperidinyl group.

R 1 and R 2 are preferably a methyl group.

Preferably, both R5 and R3 are in the trans position.

The process according to the invention consists in reacting the compound of formula II, wherein A1, A2, R1, R2 and Y1 are as defined above, and together b are epoxy oxygen, is reacted with a pyrrolidone or piperidone or pyridone optionally followed by preparing a pharmaceutically acceptable addition salt of a compound of formula 1 and / or forming a pharmaceutically acceptable solvate of a compound of formula 1 or a pharmaceutically acceptable salt thereof.

Suitable pharmacologically acceptable salts of compounds of Formula 1 include acid addition salts and salts of carboxy groups.

An example of pharmacologically acceptable addition salts of compounds of formula 1 are addition salts of optionally substituted amino groups such as hydrochlorides and hydrobromides. The salt-forming groups may be part of the R5 group.

Examples of pharmacologically acceptable salts of carboxyl groups are metal salts such as alkali metal salts or optionally substituted ammonium salts.

The compounds of formula I may also exist in the form of solvates, in particular hydrates, and these hydrates are also included within the scope of the invention.

Compounds of formula I can exist as optical isomers. For example, chirality is presented in those compounds wherein R3 is hydrogen, hydroxy, alkoxy or acyloxy, and R4 is hydrogen, and R1 and R2 have different meanings. It is within the scope of the invention to prepare all optical isomers of the compounds of formula 1 either as individual isomers or as mixtures thereof such as racemates.

If R 3 is hydroxy, alkoxy or acyloxy and R 4 is hydrogen, one of the isomers has 4S, 3R and the other 4R, 3S.

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Compounds of formula 1 may also exist in geometric isomeric forms which are also within the scope of the invention, including those compounds wherein R 5 and R 3 are either trans to each other or cis to each other, preferably trans to others.

Preferably, R1 and R2 are both 'C1-6 alkyl, especially methyl.

When R3 is alkoxy and R4 is hydrogen, a preferred example of R3 is methoxy and ethoxy, especially methoxy. If R3 is acyloxy and R4 is hydrogen, preferably R3 is an unsubstituted carboxy acyloxy group such as an unsubstituted aliphatic acyloxy group. However, preferably R3 and R4 together are a bond, or R3 and R4 together are hydrogen, in particular R3 is hydroxy and R4 is hydrogen.

The compounds according to the invention have pharmacological effects. When "disturbances associated with the smooth muscle function of the gastrointestinal, genital or urinary tract, including the urinary tract, are discussed, this means that they include the intestinal irritation syndrome and vascular disease; premature birth; inability to keep urine and stools; disturbances in the work of the kidneys and accompanying kidney stones.

Where "cardiovascular disturbances" is referred to, this means diseases other than hypertension, such as right ventricular circulatory failure, angina, peripheral vascular disease.

When referred to herein "pulmonary hypertension" means peripheral hypertension, capillary hypertension, venous hypertension, especially peripheral hypertension.

Moreover, pulmonary peripheral hypertension includes hypertension of primary arteries and arteries of secondary origin to pulmonary diseases such as chronic bronchitis, emphysema, lateral curvature of the spine, and environmental diseases such as chronic mountain sickness, aviation.

The term "heart failure" refers to disorders such as the lung and heart malfunction that sometimes arise from chronic bronchitis and emphysema.

Cardiac interaction abnormalities include disorders such as atrial septal defects, phallot defects, ventricular septal defects, and permanent arterial defects.

The compounds of the formula I, their pharmacologically acceptable salts or their pharmacologically acceptable solvates have bronchial and / or blood pressure lowering effects. Therefore, they are used to treat respiratory disorders such as reversible airflow obstruction, vascular disease and asthma, as well as hypertension. Furthermore, they can also be used to treat other disorders described above.

The novel compounds are also used in the preparation of pharmaceutical compositions containing an effective, non-toxic amount of a compound of formula I or a pharmacologically acceptable salt or a pharmacologically acceptable solvate thereof and a pharmacologically acceptable carrier.

The compositions containing the novel compounds are preferably used for oral administration. Although, they may be used for administration by other routes, e.g. in the form of aerosols, spray or inhalation for the treatment of the respiratory tract, or for parenteral administration in patients suffering from cardiac disorders. Other alternative routes of administration include sublingual or transdermal administration. These agents may be administered in the form of tablets, capsules, powders, granules, lozenges, suppositories, powders for reconstitution, liquid preparations such as oral or sterile parenteral solutions or suspensions.

The agents of the invention are preferably used in unit dosage form to control administration.

Unit doses for oral administration are in the form of tablets and capsules and may also contain known excipients such as binders, e.g., syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers, e.g., lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; disintegrants, e.g., starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or pharmacologically acceptable wetting agents, or sodium lauryl sulfate.

Oral solids are prepared by known methods, e.g., by mixing, filling, or tabletting. The remixing process can be used to distribute the active ingredient by using larger amounts of fillers. These processes are known in the art. The tablets may be coated by known methods customary in pharmacy.

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Liquid preparations can be, for example, in the form of emulsions, syrups or elixirs, or in the form of a dry product for reconstitution with water or other carriers. Liquid preparations may contain known additives such as suspending agents, e.g. sorbitol, syrup, methyl cellulose, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate or acacia; non-aqueous vehicles (including edible oils), e.g. almond oil, fractionated coconut oil, oily esters such as glycerin esters, propylene glycol or ethyl alcohol; preservatives, for example ethyl or methyl p-hydroxybenzoate or sorbic acid and, if desired, flavoring or coloring agents.

For parenteral use, fluid dosage units are made using the novel compounds and sterile vehicles and, depending on the concentration, may be suspended or dissolved in the vehicle. For solution preparation, the compound is dissolved in water for injection and sterile filtered before being filled into a suitable vial or ampoule and sealed. Preferably, adjuvants such as analgesics, preservatives, and buffers are dissolved in the vehicle. For added stability, the agent may be frozen after filling into the vials and the water removed under vacuum. Parenteral suspensions are prepared in essentially the same except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilized with ethylene oxide before suspending in the sterile vehicle. Preferably, surfactants or wetting agents are added to the agent to uniformly distribute the compound.

Compounds containing the compounds of the invention, especially for the treatment of reversible airway obstruction and asthma, can be used in a form suitable for the treatment of the respiratory tract, such as sniffing powder or aerosol or spray solution, or microscopic absorbable powder, or in combination with an inert carrier such as lactose. In this case, the particles of the active compound have a diameter of less than 50 microns, preferably less than 10 microns, e.g. 1-50 microns, 1-10 microns or 1-5 microns. Optionally, they may also include small amounts of other anti-asthmatic and anti-inflammatory agents, for example sympathomimetic amines such as isoprenaline, isoetarin, salbutamol, phenylephrine and ephedrine; xanthine derivatives such as theophylline and aminofilin; and corticosteroids such as prednisolone and adrenaline stimulants such as ACTH.

These compositions may contain 0.1-99% by weight, preferably 10-60% by weight of the active ingredient, depending on the route of administration. A preferred range of administration is 10-99, especially 60-99, e.g. 90, 95 or 99% of the active ingredient.

In a preferred aspect, the process of the invention produces compounds of formula 1, their pharmaceutically acceptable salts or their pharmaceutically acceptable solvates in the form of a microcrystalline powder. As indicated above, such a powder is especially valuable for sniffing administration.

The pharmaceutical, especially in inhalable form, comprises a compound of formula I or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof in the form of a microcrystalline powder, and optionally a pharmaceutically acceptable carrier. Suitable carriers are known in the art and include, for example, lactose.

Microcrystalline powder formulations are suitable for aerosol administration at marked doses or in dosing devices.

Aerosol formulations include suitable known propellants, co-solvents such as methanol, surfactants such as oleic alcohol, a drier such as calcium sulfate, and density modifiers such as sodium chloride.

Solutions suitable for absorption are isotonic sterilized solutions, optionally buffered, eg. Of pH 4-7 containing compound generally in an amount of 20 mg ml ^_ 1, and preferably 0.1-10 mg ml ^_ 1 for use in the standard apparatuses absorption.

Also within the scope of the invention is a method of treating respiratory disorders such as reversible obstruction of the airways associated with smooth muscle function, gastrointestinal disorders, cardiovascular disorders, and / or treatment and / or prevention of pulmonary hypertension disorders, and / or treatment of epilepsy in mammals. including humans, which comprises administering an effective, non-toxic amount of a compound of formula 1 or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof to mammals as needed.

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The effective amount of the compound depends on the effectiveness of the compound of the invention, the disorder being treated and the weight of the patient. A suitable unit dose of the pharmaceutical agent contains 0.001-100 mg of a compound of the invention (0.001-10 mg in the case of inhalation), typically 0.01-50 mg, e.g. 0.05-25 or 0.5-25 mg, particularly 0, 1, 12, 5, 10, 15 or 20 mg. These agents may be administered 1-6 times a day, most often 2-4 times, in the usual daily dosage of an adult human weighing 70 kg from 0.002-200 mg, preferably 0.005-100 mg. These doses are therefore in the range of from about 2,5-10- ⁵ mg / kg / cbtień to 3 mg / kg / day, in particular in the range of about 5 · 10-5 mg / kg / day to 1.5 mg / kg / day.

Thus, it is within the scope of the invention to provide a method for preparing a compound of Formula 1, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, for use in a therapeutically active form.

In particular, the invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof for the treatment of respiratory disorders or hypertension or disorders associated with smooth muscle function in the gastrointestinal system or cardiovascular disorders and / or treatment and / or prophylaxis. disorders associated with pulmonary hypertension and disorders associated with cardiac activity and / or treatment of epilepsy.

As pharmacological data illustrating the effect of the compounds according to the invention are presented.

1. Bronchodilator effect.

(a) In vitro bronchodilation in tracheal preparations.

Male guinea pigs weighing 300-600 g have their heads dissected and trimmed through an arterial vein. The trachea was isolated and inserted into an oxygenated Krebs solution at 37 ° C. Thereafter, the spirals (2 per trachea) were prepared by counter-axial and split length. Each preparation was placed in a 10 ml organic bath containing 10 ml of Krebs solution at 37 ° C and bubbled with 5% Co2 in O2. The resting tension of the formulation was 2 g and changes in muscle tension were monitored isometrically with a UFI (2 oz) apparatus from Ormed Ltd coupled to sand. All preparations were allowed to equilibrate for 60 minutes. During this period, the slides were washed at an interval of 15 minutes and, if necessary, the tension was adjusted to 2 g using a mechanical micromanipulator.

Once the test stress was obtained, then the test compound ^- 8 -5-3 (10 -2 X 10 M) was added, and finally maximum relaxation was obtained with the addition of 10 M isopremaline. Test compound stress is expressed as percentage of total relaxation induced in the presence of 10 ³ M isoprenaline.

The corresponding relaxation concentration curves were plotted and the potency value (IC50) and intrinsic activity coefficient (J. A) were evaluated.

Krebs solution consisted of: 118.07 mM sodium chloride, 26.19 mM sodium bicarbonate, 4.68 mM potassium chloride, 1.18 mM potassium orthophosphate, 1.8 mM magnesium sulfate septohydrate, and 2.52 mM calcium chloride, and showed pH around 7.45. The obtained results are summarized in Table 1.

Table 1

The relationship of example no in vitro lCsc (M) I. A. II 1.9Χ10 ⁷ 0.88 IV 3.7 XM) -7 0.89 V 6.3 X10 ' ^e 0.90 VI 1.5 X10- ⁷ 0.97 VII 1.9 X 10 ' ⁸ 0.93 VHI 1 9x10 '7 0.88 IX 7.15X10-8 0.84

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2. Action of antihypertension.

Kiwi pressure-lowering effect.

Systolytic blood pressure was measured by a modified method described by JM Claxton, MG Palfreyman, RH Pyser, RL Whiting in European Journal of Pharmacology, 37,179 (1976). A W + WBP model 8005 device was used to determine the pulses. Before measurement, the rats were placed in a heated room (33.5 ± 0.5 ° C) and then transferred to a cage. Each blood pressure measurement was read at least 6 times. Spontaneous hypertension in rats (age 12-18 weeks) with systolytic blood pressure> 240 · 10 ² Pa was determined as hypertension. The obtained results are summarized in Table 2.

Table 2

The relationship of example no n Initial pressure (B. P.) Oral dose. mg / kg % change in systemic B. P 1h 2h 3h II 4 284 ± 4 0.1 -I9 ± 3 -30 ± 2 -28 ± 2 III 3 230 ± 3 1 0 -38 ± 2 -24 ± 10 -18 ± 6 IV 3 240 ± 0.7 0.3 -40 ± 10 -29 ± 7 -25 ± 7 V 3 228 ± 1 0.3 -36 ± 3 -30 ± 1 -26 ± 2

Toxicity.

No toxicity was found in the above-mentioned studies.

The following Examples illustrate the subject matter of the invention, with Example 1 illustrating the preparation of the starting compounds.

Example Trans-3-bromo-3,4-dihydro-2,2-dimethylene-6-pentafluoroethylene-2H-1lbenzOl pyrann2-3 of formula 8.

To a solution of 0.419 g (1.51 mmol) of 2,2-dimethyl-16pen-afluoroethyl-2H-1lbenzopyran in 5 ml of dimethylsulfoxide (DMSO) containing 5 drops of water, 0.56 g (3.15 mmol) (3.15 mmol) of N-bromosuccinimide. The solution was stirred for 4 hours, then poured into 30 ml of water. The mixture is extracted with 50 ml of ethyl acetate. The organic layers are washed with 4 X 30 ml of water, dried (MgSO 4) and evaporated in vacuo to yield 0.50 g (88%) of a white solid. A sample of the analysis, after thin-layer chromatography on silica (eluent ethyl acetate / hexane 1: 1), indicates that tranSl3-bromoI3,4-dihydro-2,2-dimethyl-6-pentafluoroethniOl2H-ylbenzopyranl4lOl with a melting point of 86 ° C was obtained.

¹ H NMR (CDCl) δ: 1.45 (s, 3H); 1.65 (s, 3H); 2.7 (d, J = 4 Hz, 1H); 4.15 (d, J = 9 Hz, 1H); 4.95 (dd, J = 9.4 Hz, 1H); 6.9 (d, J = 9 Hz, 1H); 7.4 (dd, J = 9.2 Hz, 1H), 7.75 (d, J = 2 Hz, 1H).

Analysis for C13Hi2BrF ₅ O2: Found: C, 41.71; H - 3.35%;

Calcd C, 41.62; H-3, ^ 3% ₀ .

Example II. TranSl3,4-dihydro-2,2L-1-methyl-6-pentafluoroethylOl4- (2-oxopyΓolidin-1-yl) 2H-1-benzopyan-11Ol of formula 3.

To a solution of 0.52 g (4.64 mmol) of potassium t-butoxide in 5 ml of pyrrolidinone is added 0.35 g (0.93 mmol) of trans-3-bromo-1,3,4-dihndro-2,2-dimethyl-6-pentaffuoroethylene- 2H-1lbenzopyl ran-2ol. The solution was stirred for 3.5 h, then diluted with 50 ml of ethyl acetate and 30 ml of 2M hydrochloric acid. The organic layers are separated, washed with 4X60mL of water, dried (MgSO4) and concentrated to give 0.35 g (99%) of tranS-3,4-dihydro-1,2,2-dimethylene-6-pentafluoroethyl-4- (2L-oxopyrrolidin-1-yl) -2H -1-benzopyran-3-ol, m.p. 172-173 ° C (ether / hexane).

1H NMR (CDCl3) δ: 1.3 (s, 3H); 1.55 (s, 3H); 2.1 (m, 2H); 2.6 (m, 2H); 3.0 (m, 1H); 3.3 (m, 2H, 1H disappears from D2O) 3.75 (d, J = 10 Hz, 1H); 5.3 (d, J = 10 Hz, 1H); 6.9 (d, J = 8 Hz, 1H); 7.1 (br. S, 1H); 7.4 (br. D, H = 8 Hz, 1H).

Analysis for C17H 1eF 5NO 3:

Found: C, 53.76; H - 4.62; N - 3.77%;

calcd C, 53.85; H - 4.79; N - 3.69%.

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Example III. 2,2-Dimethyl-6-pentafluoroethyl-4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran of formula 9.

To a solution of 0.60 g (1.58 mmol) of trans-3,4-dihydro-2,2-dimethyl-6-pentafluoroethyl-4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran-3-ol and 0.24 ml (1.71 mmol) of triethylamine in 10 ml of tetrahydrofuran are added 0.14 ml (1.81 mmol) of methanesulfonyl chloride. The solution is stirred for 4 h, 0.39 g (3.48 mmol) of potassium t-butoxide is added and stirring is continued for a further 0.5 h. The mixture is poured into 50 ml of ethyl acetate (20 ml, 2M) hydrochloric acid. and the organic layers were separated, washed with sodium bicarbonate solution, dried (MgSO4 and evaporated in vacuo to an oily product which was chromatographed on silica. Eluting with ethyl acetate / hexane (2: 1), 0.28 g (49%) was obtained 2,2-dimethyl-6-pentafluoroethyl-4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran as a solid white, m.p. 94-95 ° C.

¹ H NMR (CDCl) δ: 1.5 (s, 6H); 2.2 (m, 2H); 2.55 (app. T, J = 8 Hz, 2H); 3.55 (t, J = 7 Hz, 2H); 5.7 (s. 1H); 6.9 (d, J = 8 Hz, 1H), 7.1 (d, J = 2 Hz, 1H); 7.35 (dd, J = 8.2 Hz, 1H).

Analysis for C17H16F 5NO2:

found: C, 57.36; H - 4.55 - N - 3.95%;

calcd: C - SO 4 O; H - 4.47; N - 3.88%.

Example IV. Trans-3,4-dihydro-2,2-dimethyl-6- (1-hydroxy-2,2,2-trifluoroethyl-4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran-3-ol formula 4.

To a solution of 0.48 g (0.43 mmol) of potassium t-butoxide in 5 ml of 2-pyrrolidinone, 0.306 g (0.86 mmol) of trans-3-bromo-3,4-dihydro-2,2-dimethyl- 6- (1-hydroxy-2,2,2-trifluoroethyl) 2H-1-benzopyran-1-ol and the solution was stirred for 3 h, diluted with 50 ml of ethyl acetate and poured into 20 ml of 2M hydrochloric acid. The organic layers are separated, washed 3X50ml of water, dried (MgSO4) and concentrated to an oily product which is crystallized from chloroform to give 0.246 g (79%) of trans-3,4-dihydro-2,2-dimethyl-6- (1 -byroxy-2,2,2-trifluoroethyl-4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran-3-ol as a 3: 2 mixture of diastereoisomers, m.p. 212-214 ° C.

¹ H NMR (de-DMSO / CDCl) δ: 1.2 (s, 3H); 1.45 (s, 3H); 2.0 (m, 2H); 2.45 (m, 2H); 2.95 (m, 1H); 3.3 (m, 1H); 3.65 (dd, J = 10.6 Hz, 1H) 4.85 (m, 1H); 5.1 (d, J = 10 Hz, 1H); 5.3 (d, J = 6 Hz, 1H); 6.45 (1H), [6.75 (d, J = 8 Hz) and 6.78 (d, J = 8 Hz total 1H]; [6.95 (br.s) and 7.05 (br.s) - 1H total]; [7.2 (d, J = 8 Hz) and 7.25 (d, J = 8 Hz) - 1H total].

Found mass 359, 1340, C 17 H 20 F 3 NO 4 calculated 359, 1344

ExampleV. Trans-3,4-dihydro-2,2-dimethyl-4 (2-oxopiperidin-1-yl) -6-pentafluoroethyl 2H-1-benzopyran-3-ol of formula 5.

0.434 g (1.16 mmol) of trans-3-bromo-3,4-dihydro-2,2-dimethyl-6-pentafluoroethyl-2H-1-benzopyran-4-ol is added to the solution 0.651 g (8.81 mmol) ) potassium t-butoxide and 0.584 g (8.9 mmol) of piperidene in 5 ml of sulfoxide. The solution was stirred for 6 h, poured into 30 ml of water and extracted with ethyl acetate. The organic layers are separated, washed 4X50mL of water, dried and concentrated.

Chromatography on silica (ethyl acetate) gives 0.409 g (90%) of trans-3,4-dihydro-2,2-dimethyl-6-pentafluoroethyl-4- (2-oxopiperidin-1-yl) -2H-1-benzopyran- 3-ol, m.p. 159-160 ° C (165.5-166.5 ° C after recrystallization from hexane (ethyl acetate).

¹ H NMR (CDCl3) δ: 1.3 (s, 3H); 1.5 (s, 3H); 1.8 (m, 4H); 2.55 (m, 2H); 2.8 (m, 1H); 3.05 (m, 1H); 3.6 (br. S, 1H); 3.8 (d, J = 10 Hz, 1H); 5.95 (d, J = 10 Hz, 1H); 6.9 (d, J = 8.5 Hz, 1H); 7.2 (br. S, 1H), 7.4 (br d, J = 8.5 Hz, 1H).

Analysis for C isH 20NO 3F 5:

Found: C, 54.79, H, 5.16, N, 3.63, _O ;

calcd: C 54.95 H 5.13 N 3.56%.

Example VI. Trans-3,4-dihydro-2,2-dimethyl-6-pentafluoroethyl-4-2 (1H) -pyridon-1-yl) -2H-1-benzopyran-3-ol of formula 6.

To a solution of 0.448 g (4 mmol) of potassium t-butoxide and 0.387 g (4.1 mmol) of 2-pyridone in 5 ml of dimethylsulfoxide are added 0.30 g (0.8 mmol) of trans-3-bromo-3,4- dihydro-2,2-dimethyl-6-pentafluoroethyl-2H-1-benzopyran-4-ol. The solution is stirred for 6 hours and then diluted

164,216 ml ethyl acetate / 30 ml water. The organic layers are separated, washed 4 X 50 ml of water, dried and concentrated. Preparative thin layer chromatography (3: 1, ethyl acetate / hexane) gives 0.124 g (40%) of trans-3,4-dihydro-2,2- <dit ^^ ll ^ t ^ ffl ^ c ^ 1H / -pyridone- 1-yl) -2H-1-benzopyran-3-ol as a solid white, m.p. 156-157 ° C.

1H NMR (CDCl5) δ: 1.4 (s, 3H); 1.55 (s, 3H); 3.85 (dd, J = 9.5 and 4.5 Hz, 1H); 4.2 (d, J = 4.5 Hz, 1H); 6.25 (t, J = 6.5 Hz, 1H); 6.35 (d, J = 9.5 Hz, 2H); 6.65 (d, J = 9.5 Hz, 1H); 6.65 (d, J = 9.5 Hz, 1H); 6.9 (m, 3H); 7.4 (m, 2H).

Analysis for CieH 16NO3F 5:

Found: C, 55.77; H - 4.2; N - 3.55%;

Calculated C - 55.522 H - 4.15; N - 3.66%.

Example VII. (-) - Trans-3,4-iihydro-2,2Hiimethyl-4- (2-oxopiperidin-1-yl) -6-pentafluoroethyl-2H-1-benzopyran-3-ol of formula 11.

850 mg (1.6 mmol) of trans-3,4-dihydro-2,2-dimethyl-4- (2-oxopiperidin-1-yl) N-1- (S) -phenylethylcarbamate are added to 20 ml of dry tolulene. 6-pentafluoroethyl-2H-1-benzopyran-3-ol, 540 mg (0.42 mL, 4 mmol) of trichlorosilane, and 400 mg (0.55 mL, 4 mmol) of triethylamine under nitrogen. The mixture was stirred overnight at 40 ° C, then cooled and the toluene was evaporated under reduced pressure. The residue is partitioned between ethyl acetate and water. The organic layer is washed, dried and evaporated to give 871 mg of glass product which is chromatographed on silica (EtOAc then CH 2 Cl (EtOAc) to give 161 mg (31%) of the title compound, mp 143 ° C (hexane) .

1 H NMR (CDCl 3) δ: 1.2 (s, 3H); 1.53 (s, 3H); 1.87 (m, 4H); 2.63 (m, 2H); 2.89 (m, 1H); 3.08 (m, 1H), 3.55 (d, 1H, J = 5.3Hz); 3.79 (dd, 1H, J1 = 0.2, J ₂ = 5.3Hz); 5.96 (d, 1H, J = 10.2Hz), 6.92 (d, 1H, J = 8.3Hz), 7.17 (s, 1H), 7.38 (dd, 1H, J1 = 8 8, J ₂ = 1.9Hz).

Analysis for C18H20F3NO3:

found: C - -55 ^^^; H - 5.14; N - 3.51%;

calcd C - 55.52 H - 5.13; N - 3.56%.

mass spectrum observed: 393, 1359

C18H20F 3NO3 calculated: 393, 1364 [a] ² 5 D (EtOH, C = 0.9) = -56.2 °.

Example VIII. (+) -Trans-3,4-dihydro-2,2-dimethyl-4- (2-oxopiperidin-1-yl) -6-pentafluoroethyl-2H-1-benzopyran-3-ol of formula 10.

The title compound (240 mg, 34%) m.p. 142-3 ° C was prepared and purified analogously to Example 7 for the (-) enantiomer but using 910 mg (1.87 mmol) of the diastereomer (faster crop). in the chromatogram) trans-3,4-dihydro-2,2-dimethyl-4- (2-oxopiperidin-1-yl) -6-pentafluoroethyl-2H-1-benzopyran3 (1- (S) -phenylethyl) carbamate -ol.

1 H NMR (CDCl 3) 0: 2.28, 5, 3H); 5 2 2, s, 3) 1); 1.88 (m, 4) 12; 5.59, s.2) 1); 2.88 (m, 1H); 3.08 (m, 1H); 3.75 (m, 2H), 5.96 (d, 1H, J = 9.9Hz); 6.92 (d, 1H, J = 8.5Hz); 7.14 (bs, 1H); 7.38 (dd, 1H, J1 = 8.8, J2 = 1.9Hz).

Analysis for C18H 20F 5NO 3:

found: C, 55.10; H - 5.11; N, 3.62%, Calculated: C, 54.95; H - 5.13; N - -. 55%.

mass spectrum observed: 393, 1359

C18H20F3NO3 calcd: 393.1364 [α] D25 (EtOH, C = 1.04) = + 57.9 °.

Example IX. 2,2-Dimethyl-6-pentafluoroethyl-4- (2-oxopiperidin-1-yl) -2H-1-benzopyran of formula 7.

Under a nitride atmosphere, 6.0 g (16 mmol) of trans-3-bromo-2,2-dimethyl-6-pentafluoroethyl-2H-1-benzopyran-4-ol are added to the solution of piperidone anion (prepared from 7.9 g (80 mmol) ) piperidone and 8.96 g (72 mmol) of potassium t-butoxide) in 70 ml of DMSO. The mixture was stirred for 6 h, then poured into 500 ml of water and left overnight. The product is filtered off, washed and

164,216 is dried to obtain the title compound and its corresponding chromanol (Example 5). The mixture is crystallized from hexane / EtAc to obtain 3.75 g of chromanol. The residue is chromatographed on silica (EtAc and 20% EtO (CHCl) to give an additional amount (70 mg) of chromanol and 38 mg of the title compound, m.p. 121-2 ° C (hexane).

1H NMR (CDCls) δ: 1.52 (bs, 6H); 1.94 (bs, 4H); 2.56 (m, 2H); 3.42 (bs, 2H); 5.64 (s. 1H); 6.90 (d, 1H, J = 8.5Hz); 7.15 (d, 1H, J = 2.2Hz); 7.35 (dd, 1H, J = 8.5, J ₂ = 2.2).

Analysis for C wH-TSF 5NO2:

Found: C, 57.63; H - 4.82; N - 3.80%;

calcd C, 57.60; H - 4.83; N - 3.73% _O.

mass spectrum observed: 375, 1256

C 1sH18F5NO3 calcd: 375, 1258.

Example X. 2,2-Dimethyl-6-pentafluoroethyl 4- (2- (1H) -pyridon-1-yl) -2H-1-benzopyran of formula 12.

To a solution of 0.307 g (0.79 mmol) of trans-3,4-dihydro-2,2-dimethyl-6-pentafluoroethyl-4- (2 (1H) pyridonyl-1-yl) -2H-1-benzopyran-3- ol and 0.12 ml (0.88 mmol) of triethylamine in 10 ml of tetrahydrofuran, 0.66 ml (0.88 mmol) of methanesulfonyl chloride are added. The solution was stirred for 5 h followed by t.-analysis. c. is alcohol-free. Then 0.22 g (1.96 mmol) of potassium t-butoxide was added and the solution was stirred for a further 30 minutes, then diluted with 30 ml of ethyl acetate and washed with water. The organic layers are separated, dried and concentrated to a white solid. Preparative t. -. c. (3 and 2 ethyl acetate / hexane) gives 0.132 g (45%) 2,2-dimethyl-6-pentafluoroethyl-4- (2- (1H) pyridon-1-yl) -2H-1-benzopyran as solid white, mp 128-129 ° C.

¹ H NMR (CDCl3) δ: 1.55 (s, 6H); 5.8 (s. 1H); 6.25 (m, 1H); 6.68 (d, J = 9 Hz, 1H); 6.8 (d, J = 2 Hz, 1H); 6.9 (d, J = 7 Hz, 1H); 7.2 (dd, J = 7 Hz, 1H); 7.45 (m, 2H).

mass spectrum observed: 371, 0945

C w H 14 NO 2 F 5 calc'd: 371.0945.

16 ^ 4216

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MODEL 5

MODEL 6

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Publishing Department of the UP RP. Circulation of 90 copies. Price: PLN 10,000

Claims (10)

Patent claims A process for the preparation of new benzopyran derivatives of formula I or their pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, wherein one of A1 or A2 is hydrogen and the other is C2F5-, Y1 is -O-, Ri and R2 independently represent a hydrogen atom or a Ci-β alkyl group, or Ri and R2 together form a C2-7 polymethylene residue; R3 is hydrogen, hydroxy, Ci-β alkoxy or C1-7 acyloxy and R4 is hydrogen, or R3 and R4 together represent a bond; R5 is an oxopyrrolidinyl, oxopiperidinyl or pyridonyl group, characterized in that the compound of formula 2, wherein A1, A2, Ri, R2 and Yi are as defined above, and together b are epoxide oxygen, is reacted with a pyrrolidone, or With piperidone or pyridone, optionally forming a pharmaceutically acceptable addition salt of a compound of Formula 1 and / or preparing a pharmaceutically acceptable solvate of a compound of Formula 1 or a pharmaceutically acceptable salt thereof. 2. The method according to p. A compound according to claim 1, characterized in that the compound of formula 2 is used, in which A1 is C2F5- group, A2 represents a hydrogen atom, and the other symbols have the meaning given in claim 1. The compound of formula 1 in which all symbols are as defined above is prepared. 3. The method according to p. A compound according to claim 1 or 2, characterized in that a compound containing a 2-oxopiperidinyl group is prepared, wherein a compound of formula I is prepared in which R 5 is a 2-oxopiperidinyl group and the other symbols are as defined above. 4. The method according to p. A compound of formula 1 or 2 or 3, characterized in that a compound of formula 2 is used in which R1 and R2 are both methyl and the other symbols have the above meanings, producing a compound of formula 1 in which R1 and R2 are both represent a methyl group and the other symbols have the meanings given above. 5. The method according to p. A compound of formula 1 in which R5 and R3 are in the trans position is prepared by using a substrate in which R5 and R3 are in the trans position. The method according to p. A process as claimed in claim 1, characterized in that the trans-3-bromo-3,4-dihydro-2,2-dimethyl-6-pentafluoroethyl-2H-1-benzopyran-4-ol is reacted with pyrrolidinone, producing trans-3,4 -dihydro-2,2-dimethyl- (6-pentanoylOethyl-4-2-oxopyrrolidin-11-yl) -2H-1-benzopyran-3-ol. 7. The method according to p. A process as claimed in claim 1, characterized in that the tranSl3-bromOl3,4-dihndro-2,2-dimethyl-6- (1-hydroxy-l2,2,2-trifluoroethylene) -2H-lbenzopyran13lOl is reacted with 2l-pyrrolidinone, producing trans-3,4 -dihndrOl2,2ldimethylOl ^ (1Hndroxnl2,2,2ltrifluoroethylene) l4l (2lOxopyrrolidin-1-yl) -2H-1-benzopyran-3-ol. 8. The method according to p. A process as claimed in claim 1, characterized in that the trans-3-bromo-3,4-dihydro-1,2,2-dimethnlOl6-pentafluorOl2H-1-benzoplranl4-ol is reacted with piperidone to produce trans-3,4ldihndro-2,2-dimimethnlOl6-pentaf'luoroethyl-4. - (2-oxopyrrolidin-1-yl) -2H-1lbenzOl pyran-1-ol. 9. The method according to p. The process of claim 1, wherein tranSl3lbromOl3,4ldihydro-2,2-dimethylOl6l pentafluoroethnlO12H-1lbenzopyranl4-ol is reacted with 2l-pyrndone, producing tranSl3,4ldihydroOl2,2ldimethyl-6-pentafluoroethyl ) -2H-1-benzOl pyran-4-ol. 10. The method according to p. A process according to claim 1, characterized in that the tranSl3lbromOl2,2-dimethnl-6-pentafluorOl 2H-1lbenzopyran-4-ol is reacted with piperidone, 2.2-dlmethylOl6pentafluoroethyl-4- (2-oxopiperndnnl 1-yl) -2H -1-benzopyran. 164 216