Benzopyrane, intermediate compounds, pharmaceutical composition and method of treatment

 

(57) Abstract:

Benzopyrane formula I, where X Is O or NH; R, R1and R2- H or C1-ciacil; R3(a) 6-membered heterocyclic ring containing 1 or 2 N, and the specified ring linked to X via a carbon atom in the ring, optionally condensed with a benzene ring and optionally substituted by alkyl, halogen or exography, provided that R3is not - N -(C1-6- alkyl/pyridinoline group, (C) when X is NH, group (i), or (c) when X is NH, a group of the formula (j); R4is phenyl, substituted by 1 or 2 hydroxy groups; R5- C1-6- alkyl; R6- SR5; R7is cyano; R8- OR5or their pharmaceutically acceptable salts. The compounds of formula I possess manifested in relaxation of smooth muscle activity, because they are able to open potassium channel s in this fabric. 5 N. And 17 C.PP. f-crystals, 1 PL.

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The present invention relates to benzopyrene. More specifically, it relates to derivatives of 6-(hydroxyphenyl)sulfonylamino(b) of Piran and compositions containing them, their uses, methods of preparation and intermediate compounds used in obtaining such derivatives.

Predlagaemaya potassium channels. Therefore, they are useful in the treatment or prevention of diseases associated with a change in the tone and/or sokrushitelny the ability of smooth muscle, which may, for example, occur in the lung, urinary bladder, intestine, uterus, or cardiovascular system. Such diseases include chronic obstruction of the respiratory tract, asthma, urinary incontinence, irritable bowel syndrome, a disease associated with the formation of diverticula, achalasia (an impaired ability to relax the smooth muscle sphincter) of the esophagus and hypertension. In addition, derivatives of the present invention may be useful in the treatment of peripheral vascular disease, congestive heart failure, pulmonary hypertension, myocardial ischemia and brain strokes, patchy baldness in men, cardiac arrhythmia, fatigue or paralysis of skeletal muscles (myotonica muscular dystrophy, glaucoma, epilepsy, tinnitus, dizziness, and dysmenorrhea (menstrual disorders).

In the patents EP-A-0547522, EP-A-0351720, EP-A-0450415 and EP-A-0400430 described benzopyrane with pharmacological activity. In the patent EP-A-0553679 described epoxysilane of chromenes.

In accordance with the present invention provides compounds of Formby independently selected from H and C1-C4-alkyl or taken together are C2-C6-alkylen;

R2represents H or C1-C4-alkyl;

R3represents: (a) 6-membered heterocyclic ring containing 1 or 2 heteroatoms of N, and the specified ring linked to X via a carbon atom in the ring, optionally condensed with a benzene ring and optionally substituted (including condensed benzyl parts) C1-C6-alkylene, hydroxy, -OR5, halogen, -S(O)mR5, oxo, amino, -other5, -N(R5)2, cyano, -CO2R5, -CONH2, -CONHR5or CO(R5)2provided that R3is not N-(C1-C6-alkyl)-pyridinoline group, (b) when X is-NH-group of formula

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(c) when X is-NH-group of formula

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R4represents phenyl, substituted hydroxy-group and optionally substituted by 1 or 2 substituents, each of which is independently selected from hydroxy, C1-C6-alkyl, -OR5, halogen, cyano and nitro;

R5- C1-C6-alkyl;

R6is-OR5-THE OTHER5, -N(R5)2, -SR5or other9;

R7is cyano;

R8- -OR5-THE OTHER5, -N (the Roxy, -OR5, halogen, cyano or nitro;

m = 0, 1, or 2.

In the above definitions, the term "halogen" means fluorine, chlorine, bromine or iodine. Alkyl groups containing three or more carbon atoms, can be unbranched or branched.

Preferably, X represents O or NH.

Most preferably X is O.

Preferably R, R1and R2each represents C1-C4-alkyl.

Most preferably R, R1and R2each represents methyl.

Preferably R3represents: (a) 6-membered heterocyclic ring containing 1 or 2 heteroatoms of N, and the specified ring optionally condensed with a benzene ring, and optionally substituted C1-C4-alkyl, hydroxy, halogen or oxo, more preferably the specified ring is not fully saturated, (b) a group of the formula

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or (c) a group of the formula

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More preferably R3is 1,2-dihydro-2 - oxo-1H-pyridin-4-yl, 1,2-dihydro-5,6-dimethyl-2-oxo-1H - pyridin-4-yl, 3-hydroxypyridine-6-yl, 2,3-dihydro-2-methyl - 3-oxopyridine-6-yl, 2,3-dihydro-2-ethyl-3-oxopyridine-6-yl, 1,2-dihydro-1-oxo-2H-phthalazine-4-and Littorina.

Most preferably, R3is 1,2-dihydro - 2-oxo-1H-pyridin-4-yl or 2,3-dihydro-2-methyl-3-oxopyridine-6-yl.

Preferably R4represents phenyl, substituted with one or two hydroxy groups. More preferably R4represents 2-, 3 - or 4-hydroxyphenyl or 3,4-dihydroxyphenyl. Most preferably R is 3-hydroxyphenyl or 4-hydroxyphenyl.

Preferably R6is - SR5. Most preferably, R6is methylthio.

Preferably R8is-OR5. Most preferably, R8is ethoxy.

Pharmaceutically acceptable salts of compounds of formula I include acid-additive and basic salts.

Suitable salts of the accession acid derived from acids which form metaxylene salt, and examples of such salts are the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, phosphate, hydrogen phosphate, acetate, maleinate, fumarate, lactate, tartrate, citrate, gluconate, benzoate, methanesulfonate, bansilalpet and para-toluensulfonate.

Suitable salts of the bases are derived from bases which form non-toxic salts, and the use of the salts is given in Berge et al., J. Pharm. Sci., 1977, 66, 1-19.

The compounds of formula I can contain one or more asymmetric carbon atoms and can therefore exist in two or more stereoisomeric forms. The present invention includes the individual stereoisomers of the compounds of formula I and their mixtures, and where it takes place, all tautomeric forms of compounds of formula I.

Division of diastereoisomers can be carried out by conventional methods, for example by fractional crystallization, chromatography or HPLC stereoisomeric mixtures of compounds of formula I or a suitable salt or derivative. Single enantiomer of compounds of formula I can also be obtained from a corresponding optically pure intermediate or by separation, for example by HPLC of the corresponding racemate using a suitable chiral media or by fractional crystallization diastereoisomeric salts formed by interaction of the corresponding racemate with a suitable optically active acid or base.

A preferred group of compounds of formula I has the formula IA

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where

X, R, R1, R2, R3and R4such as described above for soedinenii:

1) All the compounds of formula I can be obtained by removing the protection of the compounds of formula II

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where

R10is phenyl, substituted by protected hydroxy-group and not necessarily even substituted by 1 or 2 substituents, each of which is independently selected from the protected hydroxy-group, hydroxy, C1-C6-alkyl, -OR5, halogen, cyano and nitro;

X, R, R1, R2, R3and R5such as indicated above for the compounds of formula (I).

Specialists in this field of technology is well known for a variety of acceptable hydroxyamine groups and methods for their removal, for example, see T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Second Edition, Wiley-Interscience, 1991.

Some alkyl groups such as methyl and tert-butyl, can be attributed to hydroxyamine groups. It should be understood that when the phenyl group, R10substituted C1-C4-alkoxy (for example methoxy or tert-butoxy), it can also be turned into hydroxyproline by using some conditions unprotect.

In the usual method of removing methyl hydroxyamino group methoxyphenylacetone formula II handles tribromide boron in the appropriate organic the group can also be used trialkylsilyl group. Preferred is tert-butyldimethylsilyl group which can be removed by treatment with fluorine ions using, for example, tetrabutylammonium or hydrofluoric acid.

When the resulting compound of formula I is 1,2-diode, it can be obtained from compounds of formula II, wherein both of the hydroxy-group secured together, for example, as ketal.

The compounds of formula II, where R3has definition (a) above for R3the compounds of formula I can be obtained from compounds of formula VI conventional technique similar to that described in method (2) obtain the compounds of formula I.

The compounds of formula II, where R3has definition (a) or (C) above for R3the compounds of formula I, can be obtained by first converting the compounds of formula VI to the corresponding derivative of 4-amino-3-hydroxybenzophenone method similar to that described to obtain the compounds of formula VII from the compound of formula III in method (4), followed by additional introduction of the desired 4-substituent method similar to that described in any one or more (any suit) method (4), (5) and (7).

2) Connected, R2and R4such as described above for compounds of formula I can be obtained by the coupling of compounds of formula III

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where

R, R1, R2and R4such as mentioned above for this method, or with the compound of the formula

R3XH

or, where appropriate, with its tautomerism in the presence of a base or basic salt of the compounds of formula

R3XH

where X and R3such as mentioned above for this method.

Preferred basic salts of compounds of formula R3XH include alkali metal salts, for example sodium and potassium salts. When using a basic salt can be formed in situ from the corresponding compounds of formula R3XH using a suitable base such as sodium hydride.

If the basic salt of the compounds of formula R3XH is not used, it is necessary the presence of a suitable base, for example pyridine or triethylamine, though usually need only a catalytic amount.

The reaction can be carried out in a suitable solvent, for example ethanol or 1,4-dioxane, at a temperature ranging from room temperature up to (preferably) the boiling point of the solvent.

1-C6of alkyl, - OR5, halogen, cyano and nitro;

R, R1, R2, R4and R5such as described above for compounds of formula I for method (2).

In the conventional method, the compound of formula VI enter into interaction with the thiol of the formula

R10aSH

where

R10asuch as the one above, for this method,

in the presence of tert-butoxide sodium and tetrakis(triphenylphosphine)-palladium(O) in a suitable solvent (e.g. ethanol) at boiling point.

The resulting compound of formula V can be converted into oxirane (ethylene oxide) of the formula VI by oxidation with sodium hypochlorite in the presence of [(R,R)-or (S,S)-1,2-bis(3,5-di-tert-butylaniline)]cyclohexane-manganese (III) chloride (see, J. A. C. S., 1991, 113, 7063).

Hydroxyamino(s) group(s) can then be removed from the compounds of formula VI in the usual way, with a compound of formula III.

You can obtain the connection formula V from a compound of formula IV, using methyl as hydroxyamino group in R10ato deaccelerate this compound to obtain the corresponding phenol, and ZAT is R.

All the compounds of formula IV and R10aSH can be obtained by known methods.

3) the compounds of formula I, where R3accept is as defined in (a) above for R3the compounds of formula I, and X, R, R1, R2and R4such as described above for compounds of formula I can be obtained by the coupling of compounds of formula VIA

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where

R10bis phenyl, substituted three(C1-C4-alkyl)silyloxy (i.e., three(C1-C4-alkyl)silyl-protected hydroxy-group) and optionally further substituted by 1 or 2 substituents, each of which is independently selected from three(C1-C4-alkyl)silyloxy, hydroxy, C1-C6-alkyl, -OR5, halogen, cyano and nitro, and R, R1, R2and R5such as described above for compounds of formula I, or with the compound of the formula

R3XH

or, where appropriate, its tautomers in the presence of a base or basic salt of the compound of the formula:

R3XH

where

X and R3such as is specified for this method.

The preferred three(C1-C4-alkyl)soliloquizing group is tert-butyldimethylsilyloxy.

Preferred snowlove basic salt can be formed in situ from the corresponding compounds of formula R3XH using a suitable base, such as sodium hydrate.

If the basic salt of the compounds of formula R3XH is not used, it is necessary the presence of a suitable base, for example pyridine or triethylamine, though usually it is only necessary catalytic amount.

In the conventional method, where the basic salt of the compounds of formula R3XH is not used, the reaction is carried out in a suitable organic solvent (such as 1,4-dioxane, ethanol, isopropanol or diethylene glycol) and at elevated temperature, for example at the boiling temperature of the solvent or of a similar temperature.

4) the compounds of formula I where X is NH, R3represents a group of the formula

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R, R1, R2, R4, R5and R7such as described above for compounds of formula I can be obtained by the coupling of compounds of formula VII

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where

R, R1, R2and R4such as mentioned above for this method,

with the compound of the formula:

(R5S)2C=NR7< / BR>
where

R5and R7such as mentioned above for this method.

In the conventional method, the reactants are heated together in the presence of the Oia formula VII can be obtained by treating compounds of formula III ethanol solution of aqueous ammonia is typically at a temperature of from 40 to 50oC.

5) the compounds of formula I where X is NH, R3represents a group of the formula

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where

R6is-OR5-THE OTHER5, -N(R5)2or other9and R, R1, R2, R4, R5, R7and R9such as described above for compounds of formula I can be obtained by the coupling of compounds of formula I, where X, R, R1, R2, R3, R4, R5and R7such as described for the method (4) obtain the compounds of formula I, with a suitable basic salt of the compounds of formula R5OH (i.e., alkoxides derived) or with the compound of the formula R5NH2, (R5)2NH or R9NH2(or, if appropriate, suitable its main salt), where R5and R9such as is specified for this method.

Suitable basic salts of compounds of the formula R5OH, R5NH2, (R5)2NH and R9NH2include alkali metal salts, for example sodium and potassium salts.

The reaction is usually carried out in a suitable solvent, for example tetrahydrofuran, at the boiling point.

6) the compounds of formula I where X is NH, R3represents a 6-membered heterocyclic to the P>3for the compounds of formula I, and R, R1, R2and R4such as described above for compounds of formula I can be obtained by the coupling of compounds of formula VII, R, R1, R2and R4such as indicated above for the compounds of formula VII, with a heterocyclic compound with a 6-chleny nucleus containing 1 or 2 heteroatoms of N, which is substituted at the carbon atom in the ring leaving group, for example, halogen (preferably chlorine or bromine) or a group of formula (C1-C4-alkyl) S(O)n- where n = 0, 1, or 2, and optionally even substituted as indicated above for R3for this method.

In conventional methods where as leaving groups use the halogen, the reaction is carried out in the presence of a suitable acid acceptor (for example, diisopropylethylamine) in a suitable solvent (such as 1,4-dioxane) at a temperature approximately equal to the boiling temperature of the solvent.

7) the compounds of formula I where X is NH, R3represents a group of the formula

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R, R1, R2, R4and R8such as described above for compounds of formula I can be obtained by the coupling of compounds of formula VII where R, R1, R2and R4a suitable leaving group (for example, ethoxy);

R8such as the one above for this method.

In conventional methods of connection are heated together in a suitable solvent (e.g. ethanol) at a temperature approximately equal to the temperature of its boiling point.

The compounds of formula VIII can be obtained by known methods.

All of the above reactions and obtain new raw materials used in the preceding methods, conventional and appropriate reagents and reaction conditions for their execution or receipt, as well as how the selection of target products is well known to experts in the art, including those of the preceding materials and given examples and methods of making.

Pharmaceutically acceptable salt of the compounds of formula I can be easily obtained by mixing together solutions of the compounds of formula I and the desired acid or required basis. Salt can be precipitated from solution and filtered or extracted by solvent evaporation.

The compounds of formula I possess manifested in relaxation of smooth muscle activity, because they are able to open potassium channels in this tissue. They can be checked on kasanakalle rings Guinea pigs.

Adult male Guinea pigs (Porcellus, 500-900 g) were killed by a blow on the head followed by exsanguination. Each trachea was cut and placed in Krebs solution (composition of the Krebs solution was as follows (mmol):

NaCl (119), KCl (4,7), NaHCO3(25), KH2PO4(1,2), MgSO4(1,2), CaCl2(2,5), glucose (11), and to eliminate the effect of endogenous prostanoids added indomethacin (2,8 µm), and the solution was aziraphale a mixture of 95% oxygen - 5% carbon dioxide, and the temperature was maintained constant at 37oC). Cut accrete connective tissue, and opened the tracheal tube through the through-cutting of cartilage on the side opposite to the beam of smooth muscles. The cartilage at one end of the tracheal strips were attached long cotton thread for connection with an isometric transducer and the other thread was attached to the other end of the strip for connection with the electrode for stimulation. The drug is kept under constant tension by the power of 1 g per tub with 15 ml of physiological solution at a temperature of 37oC with saturated gaseous mixture of 95% oxygen and 5 of carbon dioxide. The fabric was washed at intervals of 15 minutes, and allowed her to come to equilibrium within 1 hour.

On ocls 0.1 MS and sirmixalot voltage 25-30 In 10 seconds with intervals of 100 seconds. After stabilization of the contractile responses to the bath was added a single dose of the compounds of formula I or its pharmaceutically acceptable salts, and continued stimulation of tissues within 2 hours.

It was further determined the minimum dose of a compound of formula I, causing the maximum inhibition of cholinergic reduction compared to control.

When applying for a person of compounds of formula I and their salts can be entered separately, but they are usually injected in a mixture with a pharmaceutical carrier selected with regard to the intended route of administration and conventional pharmaceutical practices.

For example, they can be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules, separately or in a mixture with excipients, or in the form of Alexiou, solutions or suspensions containing substances imparting taste and odor, or dyes.

They can be injected parenterally, for example intravenously, intramuscularly or subcutaneously. For parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example enough salts or glucose to make the first dose of the compounds of the formula I is from 0.01 to 20 mg/kg (in single or divided doses), and preferably from 0.1 to 5 mg/kg

Therefore, the tablet or capsule contains from 1 mg to 5 g of active compound for the introduction of one, two or more at a time according to need. In each case, the physician determines the appropriate dose, appropriate for a specific patient, which he varies depending on age, weight and sensitivity of the patient. These doses are given as the average, but in some cases there may be broader or narrower limits dosing, which are included in the scope of the present invention.

The compounds of formula I can also be administered by inhalation is usually the aerosol stream from the vessel (spray) under pressure using a suitable spray substances, such as DICHLORODIFLUOROMETHANE, trichloromethane, dichlorotetrafluoroethane, hydrofluroalkane, carbon dioxide or other suitable gas. In the case of an aerosol under pressure single dose can be provided by using valve permitting metered quantity. Vessel (spray) under pressure may contain a solution or suspension of the active compound. Introduction by inhalation may also be performed by using a nebulizer surfstore may contain a powdery mixture of the compounds of formula I and a suitable powder base, such as lactose or starch.

Aerosol dosage forms preferably performed so that each metered dose or "release" of aerosol contains 20 μg to 1000 μg of the compound of formula I or its pharmaceutically acceptable salt for the patient. The total daily dose, administered by aerosol is in the range from 20 μg to 10 mg may be administered in one single dose or, more usually, separate doses throughout the day.

In accordance with other variants of compounds of formula I can be introduced in the form of a suppository, rectal or vaginal, or topically in the form of a lotion, solution, cream, ointment or spray powder. For example, they can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin, or can be included (at a concentration of from 1 to 10%) in an ointment consisting of a white wax or white vaseline as a basis together with suitable stabilizers and preservatives.

In accordance with the present invention also include:

i) a pharmaceutical composition comprising a compound of formula I or its pharmaceutically acceptable salt together with a pharmaceutically acceptable diluent or sociallearning tools,

iii) the use of the compounds of formula I or its pharmaceutically acceptable salt or composition for the manufacture of a medicinal product for treating or preventing diseases associated with a change in the tone and/or contractile ability of smooth muscle

iv) Applying as specified in III, when the disease is chronic obstruction of the respiratory tract, asthma, urinary incontinence, syndrome level becomes too low colon cancer, a disease associated with the formation of diverticula, achalasia (an impaired ability to relax smooth muscle sphincteral) of the esophagus or hypertension,

v) a Method of treating or preventing human diseases associated with a change in the tone and/or contractility of smooth muscle, including the treatment of a human an effective amount of the compounds of formula I or its pharmaceutically acceptable salt or composition,

vi) method, as specified in V, when the disease is chronic obstruction of the respiratory tract, asthma, urinary incontinence, syndrome level becomes too low colon cancer, a disease associated with the formation of diverticula, achalasia of the esophagus or hypertension, and

vii) intermediate compounds of formulas II, III, VIA and VII.

Following hydro-3 - hydroxy-6-(3-hydroxyphenyl)-sulphonyl-2,2,3-trimethyl-2H-benzo(b) Piran

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(3S, 4R)-4-(2-Chloropyrimidine-4-yl)amino-3,4-dihydro-3 - hydroxy-6-(3-methoxyphenyl)-sulphonyl-2,2,3-trimethyl-2H-benzo(b)Piran (0,23 g) (see getting 19) was dissolved in dichloromethane (25 ml) (vial was equipped with a potassium chloride drying tube), and to the resulting solution was added tribromide boron. The mixture was stirred at room temperature for 24 hours, the resulting precipitate. Decantation dichloromethane, and the solid was dissolved in 1 N. aqueous sodium hydroxide solution and washed with ethyl acetate. Podkolis aqueous phase, obtained resin, which was collected and dried under reduced pressure at 70oC, which resulted in (3S,4R)-4-(2-chloropyrimidine-4-yl)amino-3,4-dihydro-3-hydroxy-6- (3-hydroxyphenyl)sulphonyl-2,2,3-trimethyl-2H-benzo(b)Piran (0,123 g) as a white solid, so pl. > 280oC.

MCHP: m/2 = 475 (m)+.

1H-NMR (d6-DMCO): = and 10.20 (1H, s), 8,15 (1H, d), with 8.05 (1H, d), the 7.65 (1H, m) to 7.50 (1H, d), 7,15-7,40 (3H, m), 7,00 (2H, m), of 6.75 (1H, d), of 5.50 (1H, d), of 1.40 (3H, s) of 1.30 (3H, s), 1,10 (3H, s) M. D.

Example 2. (3S,4R)-3,4-Dihydro-4-(3,4-dioxo-2-amoxicillinum-1 - EN-1-yl)amino-3-hydroxy-6-(3-hydroxyphenyl)sulphonyl-2,2,3-trimethyl - 2H-benzo(b)Piran

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(3S, 4R)-4-Amino-3,4-dihydro-3-hydroxy-6-(3-hydroxyphenyl)sulphonyl - 2,2,3-t is l) (flask equipped with a potassium chloride drying tube), and the mixture was heated under reflux for 90 minutes. The solvent was removed under reduced pressure, then the residue was subjected to azeotropic distillation with dichloromethane, and the crude product was chromatographically on silica using as eluent a mixture (5:95) methanol:dichloromethane, gave (3S,4R)-3,4-dihydro-4-(3,4-dioxo-2-amoxicillinum-1-EN-1-yl) amino-3-hydroxy-6-(3-hydroxyphenyl)sulphonyl-2,2,3-trimethyl-2H - benzo(b)Piran in the form of a yellow solid.

1-H-NMR (d6-DMCO) (found two rotamer): / = 10,20 (1H, W), the 9.25 (0.5 H, W), 9,00 (0.5 H, W), of 7.75 (2H, m), 7,38 (2H, m), 7,25 (1H, s), 7,00 (2H, m), the 5.45 (0.5 H, d), 5,38 (0.5 NS), and 5.30 (0.5 H, s), of 4.95 (1H, d), and 4.75 (1H, HF), 4,60 (1H, W), 1,45 (1,5 H, t) to 1.38 (3H, s), 1,29 (1,5 H, W), 1,22 (3H, s), and 0.98 (3H, s), M. D.

Example 3. (3S, 4R)-4-(3-Cyan-2-methylisothiourea)-3,4-dihydro-3 - hydroxy-6-(3-hydroxyphenyl)sulphonyl-2,2,3-trimethyl-2H-benzo(b)Piran

< / BR>
(3S, 4R)-4-Amino-3,4-dihydro-3-hydroxy-6-(3-hydroxyphenyl) sulphonyl-2,2,3-trimethyl-2H-benzo/b/Piran (0.6 g) (see 20) and dimethyl N-candicemichelle (0.24 g) was dissolved in pyridine (10 ml) (vial equipped with a potassium chloride drying tube, and the mixture was heated at 50-60oC for 24 hours. Solvent was removed under reduced pressure, and the residue chromatog the resulting crude product, which was subjected to azeotropic distillation with ethyl acetate and then dichloromethane, and then triturated with diethyl ether to remove residual pyridine), and the result obtained (3S,4R)-4-(3-cyan-2-methylisothiourea)-3,4-dihydro-3-hydroxy - 6-(3-hydroxyphenyl)sulphonyl-2,2,3-trimethyl-2H-benzo(b)Piran (0,276 g) as a solid.

1H-NMR (d6-DMCO): = of 10.25 (1H, s), and 8.50 (1H, d), of 7.70 (1H, d), to 7.50 (1H, s), 7,30 was 7.45 (2H, m), 7,25 (1H, d), 6,98-7,05 (2H, m), the 5.45 (1H, d), of 5.40 (1H, s), of 2.72 (3H, s) to 1.37 (3H, s), 1,25 (3H, s) of 1.07 (3H, s) M. D.

Example 4. (3S,4R)-3,4-Dihydro-3-hydroxy-6-(4-hydroxyphenyl)sulfonyl - 4-(3-hydroxypyridine-6-yl)oxy-2,2,3-trimethyl-2H-benzo(b)Piran

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(3S, 4R)-6-(4-tert-Butyldimethylsilyloxy)sulphonyl-3,4-dihydro - 3,4-epoxy-2,2,3-trimethyl-2H-benzo(b)Piran (0.35 g) (see getting 14) and 3,6-dihydroxypyridine (0,273 g) suspended in absolute ethanol (3 ml), the resulting suspension was added dry pyridine (0,065 ml), and the mixture was heated under reflux for 4 days. Then removed under reduced pressure, the solvent, and the residue was chromatographically on silica using as eluent a mixture of methanol:ethyl acetate = 1:99, and the result obtained (3S, 4R)-3,4-dihydro-3-hydroxy-6-(4-hydroxyphenyl)-sulfonyl - 4-(3-hydroxypyridine-6-the N 5,57. Calculated for C22H22N2O7S, 0.20 ethyl acetate C 57,50, H 4,99, N 5.88 per cent.

1H-NMR (d6-DMCO): / = 12,38 (1H, s), 7,16 (4H, m), 7,25 (1H, d), 6,80-to 7.00 (4H, m), 5,80 (1H, s) 5,38 (1H, s) to 1.38 (3H, s) of 1.30 (3H, s) and 1.15 (3H, s) M. D.

Example 5. (3S, 4R)-3,4-Dihydro-4-(2,3-dihydro-2-methyl-3-oxopyridine - 6-yl)oxy-3-hydroxy-6-(4-hydroxyphenyl)sulphonyl-2,2,3-trimethyl - 2H-benzo(b)Piran

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(3S, 4R)-6-(4-tert-Butyldimethylsilyloxy)sulphonyl-3,4-dihydro - 3,4-epoxy-2,2,3-trimethyl - 2H-benzo(b)Piran (1,618 g) (see getting 14) and 2,3-dihydro-2-methyl-3-oxo-6-hydroxypyridine (1,33 g) (see J. Org.Chem., 1971, 36, 3372) suspended in dry 1,4-dioxane (15 ml), the resulting suspension was added pyridine (0,275 ml), and the mixture was heated under reflux (flask equipped with a potassium chloride drying tube) for 3 days. The solvent was removed under reduced pressure, and the residue was distributed between ethyl acetate and water. The organic phase was separated and was dried (anhydrous sodium sulfate), the solvent was removed under reduced pressure, and the crude product was chromatographically on silica using as eluent a mixture of methanol:ethyl acetate = 1:99, which gave as a result of (3S,4R)-3,4-Dihydro-4-(2,3-dihydro-2-methyl-3-oxopyridine - 6-yl)oxy-3-hydroxy-6-(4-hydroxyphenyl)with the La C23H24N2O7S C 58,46, H 5,12, N 5,93%.

1H-NMR (d6-DMCO): = the 7.65 to 7.75 (4H, m), 7,27 (1H, d), 6,82-7,05 (4H, m), 5,78 (1H, s), are 5.36 (1H, s) to 3.34 (3H, s) of 1.39 (3H, s) of 1.30 (3H, s) of 1.20 (3H, s) M. D.

Example 6. (3S, 4R)-3,4-Dihydro-4-(2,3-dihydro-2-ethyl-3-oxopyridine - 6-yl)oxy-3-hydroxy-6-(4-hydroxyphenyl)sulphonyl-2,2,3-trimethyl - 2H-benzo(b)Piran

< / BR>
(3S, 4R)-6-(4-tert-Butyldimethylsilyloxy)sulphonyl-3,4-dihydro - 3,4-epoxy-2,2,3-trimethyl-2H-benzo(b)Piran (kzt1.664 g) (see getting 14) and 2,3-dihydro-2-ethyl-3-oxo-6-hydroxypyridine (1.52 g) (see J. Org.Chem., 1971, 36, 3372) suspended in dry 1,4-dioxane (15 ml), the resulting suspension was added pyridine (0,282 ml), and the mixture was heated under reflux (flask equipped with a potassium chloride drying tube) for 3 days. The solvent was removed under reduced pressure, and the residue was distributed between ethyl acetate and water. The organic phase was separated and dried (anhydrous sodium sulfate), the solvent was removed under reduced pressure, and the crude product was chromatographically on silica using as eluent a mixture of methanol:ethyl acetate = 1:99, which gave as a result of (3S,4R)-3,4-dihydro-4-(2,3-dihydro-2-ethyl-3-oxopyridine - 6-yl)oxy-3-hydroxy-6-(4-hydroxyphenyl)sulphonyl-2,2,3-trimethyl - 2H-benzo(b)Piran (0,32O7S, 0.10 ethyl acetate: C 59,16, H of 5.45, N 5,65%.

1H-NMR (d6-DMCO): / =7,52-of 7.70 (4H, m), 7,16 (1H, d), 6,72-6,98 (4H, m), 5,72 (1H, s), and 5.30 (1H, s), equal to 4.97 (1H, m), 4,80 (1H, m) of 1.28 (3H, s) of 1.18 (6H, m) a 1.08 (3H, s) M. D.

Example 7. (3S, 4R)-3,4-Dihydro-4-(2,3-dihydro-2-methyl-3-oxopyridine - 6-yl)oxy-3-hydroxy-6-(3-hydroxyphenyl)sulphonyl-2,2,3-trimethyl - 2H-benzo(b)Piran

< / BR>
(3S, 4S)-6-(3-tert-Butyldimethylsilyloxy)sulphonyl-3,4-dihydro - 3,4-epoxy-2,2,3-trimethyl-2H-benzo(b)Piran (2 g) (see getting 15) and 2,3-dihydro-2-methyl-3-oxo-6-hydroxypyridine (1.5 g) (see J. Org.Chem., 1971, 36, 3372) suspended in ethanol (30 ml), the resulting suspension was added pyridine (0.31 g), and the mixture was heated under reflux (flask equipped with a potassium chloride drying tube) for 100 hours. After cooling, the reaction mixture was filtered, and the filtrate was evaporated, which gave a solid, which was dissolved in a mixture of 0.5% methanol/dichloromethane, and the solution was again filtered. The filtrate was again evaporated, and the residue was chromatographically on silica using as eluent a gradient of methanol:dichloromethane from 0.5: 99,5 up to 3.75:96,25 that resulted in (3S,4R)-3,4-dihydro-4-(2,3-dihydro-2-methyl-3-oxopyridine-6-yl)oxy - 3-hydroxy-6-(4-hydroxyphenyl)sulphonyl-2,2,3-trimethyl-2H-benzo(b)PIR S, 0,75 CH2Cl2: C 53,00, H 4,79, N 5,10%.

1H-NMR (CDCl3): = 8,04 (1H, s), 7,75-a 7.85 (2H, m), 7,30 was 7.45 (3H, m), 6.90 to-7,10 (4H, m), 5,91 (1H, s), and 3.72 (3H, s), 3,32 (1H, s) of 1.45 (3H, s) of 1.40 (3H, s) of 1.30 (3H, s) M. D.

Example 8. (3S, 4R)-3,4-Dihydro-4-(2,3-dihydro-2-methyl-3-oxopyridine - 6-yl)oxy-3-hydroxy-6-(2-hydroxyphenyl)sulphonyl-2,2,3-trimethyl - 2H-benzo(b)Piran

< / BR>
(3S, 4S)-6-(3-tert-Butyldimethylsilyloxy)sulphonyl-3,4-dihydro - 3,4-epoxy-2,2,3-trimethyl-2H-benzo(b)Piran (0.5 g) (see getting 16) and 2,3-dihydro-2-methyl-3-oxo-6-hydroxypyridine (0,41 g) (see J. Org.Chem., 1971, 36, 3372) suspended in dry 1,4-dioxane (8 ml), the resulting suspension was added pyridine (of 0.085 g), and the mixture was heated under reflux (flask equipped with a potassium chloride drying tube) for 20 hours. The solvent is evaporated under reduced pressure, the residue was mixed with dichloromethane (30 ml) and filtered. The filtrate was evaporated, and the residue was chromatographically on silica using as eluent a mixture of hexane: ethyl acetate = 1:1, which gave a mixture of the target product and the epoxy starting material. This mixture was again dissolved in dry 1,4-dioxane (7 ml) was added 2,3-dihydro-2-methyl-3-oxo-6-hydroxypyridine (0.2 g) and pyridine (0.08 g) and the reaction mixture was heated with reverse Ho is dichloromethane and filtered. The filtrate was evaporated, and the residue was chromatographically on silica using as eluent a mixture of methanol: dichloromethane to 2.5:97,5 that resulted in (3S,4R)-3,4-dihydro-4-(2,3-dihydro-2-methyl - 3-oxo-pyridazin-6-yl)oxy-3-hydroxy-6-(2-hydroxyphenyl)sulphonyl - 2,2,3-trimethyl-2H-benzo(b)Piran (0.17 g) as a yellow foam. Found: C To 54.19, H 4,95, N To 5.21. Calculated for C23H24N2O7S, OF 0.625 CH2Cl2: C 54,06, H 4,73, N TO 5.21%.

1H-NMR (CDCl3): / = to 9.15 (1H, s), of 7.90 (1H, d), of 7.75 (1H, DD), a 7.62 (1H, DD), was 7.45 (1H, m), 6,94-7,10 (5H, m), of 5.89 (1H, s), 3,69 (1H, s), 3,48 (1H, s) and 1.51 (3H, s) of 1.42 (3H, s), 1,25 (3H, s) M. D.

Example 9. (3S, 4R)-3,4-Dihydro-4-(1,2-dihydro-1-oxo-2H-phthalazine - 4-yl)-oxy-3-hydroxy-6-(4-hydroxyphenyl)sulphonyl-2,2,3-trimethyl - 2H-benzo(b)Piran

< / BR>
A mixture of (3S, 4S)-6-(4-tert-butyldimethylsilyloxy)sulphonyl - 3,4-dihydro-3,4-epoxy-2,2,3-trimethyl-2H-benzo(b)of Piran (0,81 g) (see getting 14), phthalhydrazide (0.88 g), pyridine (0.5 ml) and diethylene glycol (10 ml) was heated at 120oC for 210 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. The organic extract was dried (anhydrous magnesium sulfate), the solvent evaporated, and the resulting resin was chromatographically on silica using as eluent sigito-1-oxo - 2H-phthalazine-4-yl)-oxy-3-hydroxy-6-(4-hydroxyphenyl)sulphonyl - 2,2,3-trimethyl-2H-benzo(b)Piran (0,091 g) as a solid.

1H-NMR (d6DMCO): = 8,28 (1H, d), 7,80-of 7.95 (4H, m), 7,55-of 7.70 (3H, m), to 6.95 (1H, d), of 6.90 (1H, d), to 6.80 (1H, d), 5,41 (1H, s) of 1.50 (3H, s) to 1.48 (3H, s) of 1.28 (3H, s) M. D.

Example 10. (3S,4R)-3,4-Dihydro-4-(1,2-dihydro-2-methyl - 1-acceptilation-4-yl)oxy-3-hydroxy-6-(4-hydroxyphenyl)sulphonyl - 2,2,3-trimethyl-2H-benzo(b)Piran

< / BR>
A mixture of (3S, 4S)-6-(4-tert-butyldimethylsilyloxy)sulphonyl - 3,4-dihydro-3,4-epoxy-2,2,3-trimethyl-2H-benzo(b)of Piran (0.71 g) (see getting 14), 1,2-dihydro-4-hydroxy-2-methyl-1-oxoproline (0,846 g) (see getting 21), pyridine (0.4 ml) and 1,4-dioxane (10 ml) was heated under reflux for 4 days. The solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate and washed first with dilute aqueous citric acid solution and then brine. The organic phase was dried (anhydrous magnesium sulfate), the solvent was removed and the crude product was chromatographically on silica using as eluent a gradient mixture of dichloromethane:methanol:35% aqueous solution of 100:1:0.15 to 180: 20: 1, the result obtained (3S,4R)-3,4-dihydro-4-(1,2-dihydro-2-methyl-1-acceptilation-4-yl)oxy - 3-hydroxy-6-(4-hydroxyphenyl)sulphonyl-2,2,3-trimethyl-2H-benzo(b)Piran (0.12 g) as a solid.

1H-NMR (CDCl3): Example 11. (3S, 4R)-3,4-Dihydro-4-(1,2-dihydro-2-oxo-1H-pyridin - 4-yl)oxy-3-hydroxy-6-(3-hydroxyphenyl)sulphonyl-2,2,3-trimethyl - 2H-benzo(b)Piran

< / BR>
(3S, 4S)-6-(3-tert-Butyldimethylsilyloxy)sulphonyl-3,4-dihydro - 3,4-epoxy-2,2,3-trimethyl-2H-benzo(b)Piran (0,70 g) (see getting 15) and 2,4-dihydroxypyridine (0,44 g) suspended in ethanol (15 ml), the resulting suspension was added pyridine (0.15 g), and the mixture was heated under reflux (flask equipped with a potassium chloride drying tube) for 5 days. The solvent was removed under reduced pressure, the residue was stirred with a mixture of 5% methanol/dichloromethane and then filtered. The filtrate was evaporated, and the residue was chromatographically on silica using as eluent a mixture of dichloromethane: methanol = 19:1, the result obtained (3S, 4R)-3,4-dihydro-4-(1,2-dihydro-2-oxo-1H-pyridin-4-yl)oxy - 3-hydroxy-6-(2-hydroxyphenyl)sulphonyl-2,2,3-trimethyl-2H-benzo(b)Piran (amount of 0.118 g) as a white foam. Found: C 60,58, H 5,04, N 2,67. Calculated for C23H23NO7S 0,30 diethyl ether: C 60,60, H 5,46, N 2,92%.

1H-NMR (d6-DMCO): = 10,20 (1H, W), 7,71 (1H, DD), a 7.62 (1H, s), 7,30 - 7,40 (2H, m), 7,25 (1H, DD), to 7.15 (1H, d), 6,95 - 7,05 (2H, m), of 6.20 (1H, s), the 6.06 (1H, DD), of 5.45 (1H, s), of 5.40 (1H, s) to 1.48 (3H, s) of 1.34 (3H, s), 1,10 (3H, s) M. D.

Further Alu,2,3-trimethyl-2H-benzo(b)Piran (0,142 g) as a foam.

1H-NMR (d6-DMCO): = 10,50 (1H, W), of 7.96 (1H, d), a 7.62 - 7,72 (2H, m), 7,35 (1H, m), 7,20 (1H, d), 6,94 - 7,00 (2H, m), of 6.65 (1H, DD), of 6.20 (2H, m), of 5.50 (1H, s) of 1.40 (3H, s), 1,32 (3H, s) and 1.15 (3H, s) M. D.

Example 12. (3S, 4R)-3,4-Dihydro-4-(1,2-dihydro-5,6-dimethyl-2 - oxo-1H-pyridin-4-yl)oxy-3-hydroxy-6-(3-hydroxyphenyl)sulphonyl - 2,2,3-trimethyl-2H-benzo(b)Piran

< / BR>
(3S, 4S)-6-(3-tert-Butyldimethylsilyloxy)sulphonyl-3,4 - dihydro-3,4-epoxy-2,2,3-trimethyl-2H-benzo(b)Piran (0,70 g) (see getting 15) and 2,4-dihydroxy-5,6-dimethylpyridin (0,42 g) (see 23) suspended in ethanol (15 ml), the resulting suspension was added pyridine (0.12 g). The mixture was heated under reflux (flask equipped with a potassium chloride drying tube) for 20 days. The solvent was removed under reduced pressure, the residue was stirred in a mixture of 20% methanol/dichloromethane (50 ml), filtered, and the filtrate was evaporated, which gave the crude product, which was chromatographically on silica using as eluent a gradient mixture of dichloromethane:methanol 19 : 1 to 9 : 1, the result obtained (3S, 4R)-3,4-dihydro-4-(1,2-dihydro - 5,6-dimethyl-2-oxo-1H-pyridin-4-yl)hydroxy-3-hydroxy-6- (3-hydroxyphenyl)sulphonyl-2,2,3-trimethyl-2H-benzo(b)Piran (0,143 g) as a solid.

1H-NMR (d6-DM is measures 13. (3S, 4R)-3,4-Dihydro-4-(2,3-dihydro-2-methyl-3 - oxopyridine-6-yl)oxy-6-(3,4-dihydroxyphenyl)sulphonyl-3-hydroxy - 2,2,3-trimethyl-2H-benzo(b)Piran

< / BR>
(3S, 4R)-3,4-Dihydro-4-(2,3-dihydro-2-methyl-3-oxopyridine - 6-yl)oxy-6-(2,4-dihydroxyphenyl)sulphonyl-3-hydroxy-2,2,3-trimethyl - 2H-benzo(b)Piran (0.50 g) (see getting 26) was dissolved in dichloromethane (12 ml) (in nitrogen atmosphere), and to the resulting solution was added tribromide boron (4 ml of 1M solution in dichloromethane). The mixture was stirred at room temperature for one hour, the resulting precipitate. After adding water (20 ml) and dichloromethane (15 ml) was formed insoluble resin, after decantation of the solvent. Then the resin was chromatographically on silica using as eluent a mixture of methanol:dichloromethane = 1:9, and the result obtained (3S, 4R)-3,4-dihydro-4-(2,3-dihydro-2-methyl-3 - oxopyridine-6-yl)oxy-6-(3,4-dihydroxyphenyl)sulphonyl-3-hydroxy - 2,2,3-trimethyl-2H-benzo(b)Piran (0.33 g) as a white foam, which was then triturated with diethyl ether and dried, that gave white solid.

1H-NMR (d6-DMCO): = 10,10 (1H, s), of 9.75 (1H, s), of 7.75 (1H, s), the 7.65 (1H, m), 7,30 (1H, d), to 7.15 (2H, m), 7,05 (1H,d), to 6.95 (1H, d), 6,85 (1H, d), 5,80 (1H, s) 5,72 (1H, s), of 3.60 (3H, s) of 1.40 (3H, s) is 1.31 (3H, C) and 1.15 (3H, s) M. D.

< what in the previous examples.

Example of getting 1. 4-Brompheniramine

4-Bromophenol (259 g) and 4-dimethylaminopyridine (1.5 g) was dissolved in dichloromethane (1000 ml), the resulting solution was cooled in an ice bath, was added thereto triethylamine (219 ml) dropwise, allowing the reaction temperature was kept below 20oC. was Then added within hours propionate (137 ml) and the resulting mixture was stirred at room temperature for 2 hours. The mixture was washed with water and then brine, dried (anhydrous magnesium sulfate), and was removed under reduced pressure, the solvent, resulting in 4-brompheniramine (344 g) as a green oil.

1H-NMR (CDCl3): = the 7.43 (2H, d), 6,94 (2H, d), 2,52 (2H, q), of 1.20 (3H, t) M. D.

Example of getting a 2. 1-(5-Bromo-2-hydroxyphenyl)propane-1-on.

4-Brompheniramine (115 g) (see obtaining 1) and aluminium chloride (150 g) were heated together at approximately 90oC for 15 minutes. The solution was a dark and isolated gaseous chlorodrol. After cooling, the dark mass was carefully added to ice, the resulting brown solid. The mixture was extracted with dichloromethane. The organic phase was separated, washed with brine, was dried (anhydrous magnesium sulfate), and by removing what about the matter.

1H-NMR (CDCl3): = to 12.28 (1H, s), 7,88 (1H, d), 7,55 (1H, DD), 6.89 in (1H, d), to 3.02 (2H, q), of 1.27 (3H, t) M. D.

Example of getting a 3. 6-Bromo-3,4-dihydro-4-oxo-2,2,3-trimethyl - 2H-benzo(b)Piran.

1-(5-Bromo-2-hydroxyphenyl)propane-1-he (375 g) (see getting 2) was dissolved in a mixture of dry toluene (1700 ml) and acetone (2040 ml). To the resulting solution was added piperidine (748 ml), after which the solution was heated under reflux for 7 days. The solvent was removed under reduced pressure, and the residue was dissolved in diethyl ether and washed sequentially with an aqueous solution (x4) citric acid, 0.5 M aqueous solution (x4) of sodium hydroxide and then brine (x3). Separated organic phase, and the solvent was removed under reduced pressure, resulting in 6-bromo-3,4-dihydro-4-oxo-2,2,3-trimethyl-2H-benzo(b)Piran (408 g) as an orange oil. Found: C 53,59, H 1,84.

Calculated for C12H13BrO2: C 53,55, H 4,87%.

1H-NMR (CDCl3): = of 7.90 (1H, d), to 7.50 (1H, DD), 6,79 (1H, d), 2,70 (1H, kV) of 1.50 (3H, s) of 1.28 (3H, s) of 1.17 (3H, s) M. D.

Example 4. 6-Bromo-2,2,3-trimethyl-2H-benzo(b)Piran.

6-Bromo-3,4-dihydro-4-oxo-2,2,3-trimethyl-2H-benzo(b)Piran (407 g) (see 3) was dissolved in ethanol (1500 ml), cooled in an ice bath, and is mperature 3 hours, solvent was removed under reduced pressure, the residue was dissolved in diethyl ether, and the mixture was washed first with water and then brine. The organic layer was dried (anhydrous magnesium sulfate), and by removing the solvent, the obtained crude alcohol. Been dissolving it in toluene (1000 ml), the resulting solution was added para-toluensulfonate (40 g), and the mixture was heated under reflux with removal of water) for 2 hours. Reduced volume of solvent to about 500 ml, and the solution was washed with an aqueous solution of sodium carbonate and then brine. The organic phase was dried (anhydrous magnesium sulfate), and by removing under reduced pressure the solvent, the obtained 6-bromo-2,2,3-trimethyl-2H-benzo(b)Piran (350 g) as an orange oil.

1H-NMR (CDCl3): = 7,10 (1H, DD), of 6.96 (1H, d), 6,59 (1H, d), 5,96 (1H, s) of 1.78 (3H, s) of 1.35 (6H, s) M. D.

Example of getting a 5. 6-(4-Methoxyphenyl)thio-2,2,3-trimethyl - 2H-benzo(b)Piran.

6-Bromo-2,2,3-trimethyl-2H-benzo(b)Piran (9,637 g) (see obtaining 4) was dissolved in absolute ethanol (200 ml), the resulting solution was added tert-butoxy sodium (11,029 g), 4-methoxybenzoyl (4,9 ml) and tetrakis(triphenylphosphine)-palladium(O) (0,454 g), and the mixture was heated under reflux in atmospheres and washed with water. The organic layer was dried (anhydrous sodium sulfate) were removed under reduced pressure, the solvent, and the crude product was chromatographically on silica using as eluent a mixture of hexane:dichloromethane = 1 : 1, resulting in the received 6-(4-methoxyphenyl)thio-2,2,3-trimethyl-2H-benzo/b/Piran (7,823 g) as a yellow oil.

1H-NMR (CDCl3): = 7,28 (2H, d), 7,05 (1H, DD), 6,92 (1H, d), at 6.84 (2H, d), 6,70 (1H, d), 6,00 (1H, s), of 3.80 (3H, s), is 1.81 (3H, s) of 1.40 (6H, s) M. D.

Example of getting a 6. 6-(3-Methoxyphenyl)thio-2,2,3-trimethyl-2H-benzo(b)Piran

6-Bromo-2,2,3-trimethyl-2H-benzo(b)Piran (6.5 g) (see obtaining 4) was dissolved in absolute ethanol (135 ml), the resulting solution was added tert-piperonyl sodium (7.5 g), 3-methoxybenzoyl (3.6 g) and tetrakis(triphenylphosphine) palladium(0) (0.35 g), and the mixture was heated under reflux in nitrogen atmosphere for 48 hours. Next was added tetrakis(triphenylphosphine)palladium(0) (0.3 g) and continued heating for 48 hours. Was removed under reduced pressure, the solvent, and the residue was dissolved in dichloromethane and washed with water. The organic layer was dried (anhydrous sodium sulfate) were removed under reduced pressure, the solvent, and the crude product was chromatographically on the silicon dioxide, ispolnitel-2H-benzo(b)Piran (7.2 g) in the form of butter.

1H-NMR (DCl3): = 7,05 - 7,20 (3H, m), 6,63-of 6.78 (4H, m), equal to 6.05 (1H, c), and 3.72 (3H,c) and 1.83(3H,c), a 1.45(6H, s), M. D.

Example of getting a 7. 6-(2-Methoxyphenyl)thio-2,2,3-trimethyl-2H-benzo(b)Piran.

6-Bromo-2,2,3-trimethyl-2H-benzo(b)Piran (9.6 g) (see obtaining 4) was dissolved in absolute ethanol (200 ml), the resulting solution was added tert-piperonyl sodium (11,0 g), 2-methoxybenzylthio (5.3g) and tetrakis(triphenylphosphine)-palladium(0) (0.45 g), and the mixture was heated under reflux in a nitrogen atmosphere over a period of 74 hours. Was removed under reduced pressure, the solvent, and the residue was dissolved in dichloromethane and washed with water. The organic layer was dried (anhydrous sodium sulfate) were removed under reduced pressure, the solvent, and the crude product was chromatographically first on silica using as eluent a mixture of hexane:dichloromethane = 1: 1, and then on silica using as eluent a mixture of hexane: ethyl acetate = 24: 1, resulting in the obtained 6-(2-methoxyphenyl)thio-2,2,3-trimethyl-2H-benzo(b)Piran (8,12 g) in the form of butter.

1H-NMR (CDCl3): = 7,10-of 7.23 (3H,m), 6,76 - 6,85 (4H,m), equal to 6.05 (1H,s), 3,90 (3H, s) and 1.83 (3H,s) of 1.45 (6H,s) M. D.

Example of getting 8. 6-(4-Hydroxyphenyl)thio-2,2,3-trimethyl-2H-benzo(b)Piran

6-(4-Methoxyphenyl)Toru was added anhydrous lithium iodide (10,04 g), and the mixture was heated under reflux in a nitrogen atmosphere for 48 hours. Then added a further portion of lithium iodide (0.09 g) and continued heating for another 72 hours. After cooling, the mixture was dissolved in dichloromethane and washed 2 N. aqueous solution (x3) hydrochloric acid. Separated organic layer was drained it (anhydrous sodium sulfate) were removed under reduced pressure, the solvent, and the residue was chromatographically on silica using as eluent dichloromethane, resulting in the received 6-(4-hydroxyphenyl)thio-2,2,3-trimethyl-2H-benzo(b)Piran (5,799 g) in the form of butter.

1H-NMR (CDCl3): = of 7.25 (2H, d), 7,05 (1H, DD), 6,92 (1H, d), 6,70-to 6.80 (3H, m), of 6.02(1H,s) to 4.92 (1H, c), of 1.85 (3H,s) of 1.40 (6H,s), M. D.

Example of getting a 9. 6-(3-Hydroxyphenyl)thio-2,2,3-trimethyl-2H-benzo(b)Piran

6-(3-Methoxyphenyl)thio-2,2,3-trimethyl-2H-benzo(b)Piran (3.5 g) (see obtaining 6) was dissolved in dry 2,4,6-collidine (15 ml), the resulting solution was added anhydrous lithium iodide (3 g), and the mixture was heated under reflux in a nitrogen atmosphere for 24 hours. After cooling, the mixture was dissolved in dichloromethane and washed 2 N. aqueous solution (x3) hydrochloric acid. The organic layer was dried (anhydrous sodium sulfate), removed the as eluent gradient, changing from a mixture of hexane: dichloromethane = 1:1 to dichloromethane, resulting in the received 6-(3-hydroxyphenyl)thio-2,2,3-trimethyl-2H-benzo(b)Piran (2.25 g) in the form of butter.

1H-NMR (CDCl3): = 7,05-7,21 (3H,m), 6.75 in (2H, m), 6,60 (2H, m),6,04 (1H, s), 4,60 (1H, W), to 1.86 (3H,s) of 1.45 (6H,s), M. D.

Example 10. 6-(2-Hydroxyphenyl)thio-2,2,3-trimethyl-2H-benzo(b)Piran

6-(2-Methoxyphenyl)thio-2,2,3-trimethyl-2H-benzo(b)Piran (3.5 g) (see obtaining 7) was dissolved in dry 2,4,6-collidine (15 ml), the resulting solution was added anhydrous lithium iodide (9.0 g), and the mixture was heated at 150oC for 40 hours. After cooling, the mixture was dissolved in dichloromethane and washed 2 N. aqueous solution (x3) hydrochloric acid. The organic layer was dried (anhydrous sodium sulfate) were removed under reduced pressure, the solvent, and the residue was chromatographically on silica using as eluent a mixture of hexane:dichloromethane = 1:1, resulting in the obtained 6-(2-hydroxyphenyl)thio-2,2,3-trimethyl-2H-benzo(b)Piran (1.2 g) as oil.

1H-NMR (CDCl3): = 7,50 (1H,d), 7,31 (1H,t), 7,05 (1H, d), of 6.90 (2H, m), of 6.75 (1H, d), of 6.65 (1H,d), 6,55 (1H, s), of 5.99(1H, s), of 1.80 (3H,s) to 1.37 (6H,c) M. D.

Example of getting 11. 6-(4-tert-Butyldimethylsilyloxy)thio-2,2,3-trimethyl-2H-benzo(b)Piramide (12 ml), to the resulting solution were added imidazole (2,768 g) and tert-butyldimethylsilyl (2,923 g). The flask was supplied potassium chloride drying tube and the mixture was stirred at 40oC for 18 hours. Then removed under reduced pressure, the solvent, and the residue was distributed between aqueous sodium bicarbonate solution and dichloromethane. The organic layer was dried (anhydrous sodium sulfate) were removed under reduced pressure, the solvent, and the crude product was chromatographically on silica using as eluent a mixture of hexane: dichloromethane = 1: 1, resulting in the received 6-(4-tert-butyldimethylsilyloxy)thio-2,2,3-trimethyl-2H-benzo(b)Piran (6,681 g) as oil. MCHP: m/z = 413 (+1)+.

1H-NMR (CDCL3): = then 7.20 (2H,d), 7,05 (1H,DD), to 6.95 (1H,d), 6,70-to 6.80 (3H,m), of 6.02 (1H,s), of 1.85 (3H,s) of 1.41 (6H,s) to 0.97( 9H, s) of 0.21 (6H, c) M. D.

Example 12. 6-(3-tert-Butyldimethylsilyloxy)thio-2,2,3-trimethyl-2H-benzo(b)Piran

6-(3-Hydroxyphenyl)thio-2,2,3-trimethyl-2H-benzo/b/Piran (2.2 g), (see 9) was dissolved in dry dimethylformamide (4 ml) and the resulting solution was added imidazole (1.1 g) and tert-butyldimethylsilyl (1.2 g). The flask was supplied potassium chloride drying tube and the mixture was stirred at 40o

1H-NMR (CDCl3): = 7,00-to 7.18 (3H,m), 6,74 (2H, d), to 6.58 (2H,m) 6,00 (1H,s), of 1.80 (3H,s) of 1.40 (6H,s) to 0.88 (9H,s) of 0.10 (6H, s) M. D.

Example of receipt 13. 6-(2-tert-Butyldimethylsilyloxy)thio-2,2,3-trimethyl-2H-benzo(b)Piran

6-(2-Hydroxyphenyl)thio-2,2,3-trimethyl-2H-benzo(b)Piran (1.1 g), (see 10) was dissolved in dry dimethylformamide (2 ml) and the resulting solution was added imidazole (0.55 g) and tert-butyldimethylsilyl (0,61 g). The flask was supplied potassium chloride drying tube and the mixture was stirred at 40oC for 90 minutes. Was added water, and the mixture was extracted with diethyl ether. The organic extract was washed with an aqueous solution (x2) of sodium bicarbonate, dried (anhydrous sodium sulfate) were removed under reduced pressure, the solvent, and the crude product was chromatographically on silica using as eluent a mixture of hexane: dichloromethane - 4:1, result>/P>1H-NMR (CDCl3): = then 7.20 (1H, DD), 7,00 (2H, m), 6,78 (4H, m), equal to 6.05 (1H, s) and 1.83 (3H, s) of 1.45 (6H, s) of 1.05 (9H, s), and 0.28 (6H, s) M. D.

Example of getting a 14. (3S, 4S)-6-(4-tert-Butyldimethylsilyloxy)sulphonyl-3,4-dihydro-3,4 - epoxy-2,2,3-trimethyl-2H-benzo(b)Piran

6-(4-tert-Butyldimethylsilyloxy)thio-2,2,3-trimethyl-2H - benzo(b) Piran (2,182 g) (see 11) and [(S,S)-1,2-bis (3,5-di-tert-butylaniline))cyclohexanemethanol (111)-chloride (see J. Am. Chem. Soc., 1991, 113, 7063) (0,25 g) was dissolved in dichloromethane (10 ml) and the resulting solution was added a 3 M aqueous solution of sodium hypochlorite (50 ml, obtained from 4 M commodity bleach solution). A two-phase system was intensively stirred for 20 hours and then, before the separation of the two layers was diluted with dichloromethane (30 ml). The organic layer was dried (anhydrous sodium sulfate) were removed under reduced pressure, the solvent, and the residue was chromatographically on silica using dichloromethane as eluent, resulting in received (3S,4S)-6-(4-tert-butyldimethylsilyloxy)sulphonyl-3,4 - epoxy-2,2,3-trimethyl-2H-benzo(b)Piran (1,907 g). HPLC confirmed that this product consisted of the same enantiomer.

MCHP: m/z = 478 (M + NH4)+.

1H-NMR (CDCl3): = of 7.90 (1H, d), the et-Butyldimethylsilyloxy)sulphonyl-3,4-dihydro-3,4 - epoxy-2,2,3-trimethyl-2H-benzo(b)Piran.

6-(3-tert-Butyldimethylsilyloxy)thio-2,2,3-trimethyl-2H - benzo/b/Piran (21,0 g) (see obtaining 12), 4-phenylpyridine N-oxide (2.2 g) and [(S, S)-1,2-bis(3,5-di-tert-butylaniline)]cyclohexanamine (111)-chloride (see J. Am. Chem. Soc., 1991, 113, 7063) (2,25 g) was dissolved in dichloromethane (120 ml) and the resulting solution was added a 3 M aqueous sodium hypochlorite solution (500 ml, obtained from 4 M commodity bleach solution). A two-phase system was intensively stirred for 24 hours and then, before the separation of the two layers was diluted with dichloromethane and filtered through cellulose accelerator filtering. Then the organic layer was washed with saline, dried (anhydrous sodium sulfate) were removed under reduced pressure, the solvent, and the residue was chromatographically on silica using dichloromethane as eluent, resulting in received (3S, 4S)-6-(3-tert-butyldimethylsilyloxy) sulphonyl-3,4-dihydro-3,4-epoxy-2,2,3 - trimethyl-2H - benzo(b)- Piran (23,6 g). HPLC confirmed that this product consisted of a single enantiomer.

MCHP: m/z = 461 (M + 1)+.

1H-NMR (CDCl3): = of 7.90 (1H, DD), 7,78 (1H, d), was 7.45 (1H, d), 7,35 (2H, m), 7,00 (1H, DD), to 6.88 (1H, d), 3,70 (1H, s) of 1.55 (3H, s) of 1.50 (3H, s) of 1.30 (3H, s) to 0.97 (9H, s) of 0.21 (6H, s) M. D.

The use of the Russian Academy of Sciences.

6-(2-tert-Butyldimethylsilyloxy)thio-2,2,3-trimethyl-2H - benzo(b)Piran (1.4 g) (see 13), and [(S,S)-1,2-bis(3,5-di-tert-butylaniline)] cyclohexanamine (111)-chloride (see J. Am. Chem. Soc., 1991, 113, 7063) (0,15 g) was dissolved in dichloromethane (7 ml) and the resulting solution was added a 3 M aqueous sodium hypochlorite solution (32 ml, obtained from 4 M commodity bleach solution). A two-phase system was intensively stirred for 24 hours and then, before the separation of the two layers was diluted with dichloromethane. The organic layer was dried (anhydrous sodium sulfate) were removed under reduced pressure, the solvent, and the residue was chromatographically on silica using dichloromethane as eluent, resulting in received (3S, 4S)-6-(2-tert-butyldimethylsilyloxy)sulphonyl-3,4 - dihydro-3,4-epoxy-2,2,3-trimethyl-2H - benzo(b)- Piran (1.2 g),

MCHP: m/z = 461 (M + 1)+.

1H-NMR (CDCl3): = 8,10 (1H, DD), a 7.85 (1H, d), 7,72 (1H, DD), was 7.45 (1H, t), 7,10 (1H, t), PC 6.82 (2H, m), 3,68 (1H,s) of 1.57 (3H, s) of 1.50 (3H, s) of 1.28 (3H, s) of 0.95 (9H, s), 0,30 (6H, c) M. D.

Example of receipt 17. (3S, 4S)-3,4-Dihydro-3,4-epoxy-6-(3-methoxyphenyl)sulphonyl-2,2,3 - trimethyl-2H-benzo(b)Piran.

6-(3-Methoxyphenyl)thio-2,2,3-trimethyl-2H-benzo(b)Piran (4,2 g) (see obtaining 6), and [(S,S)-1,2-bis(3,5-di-tert-butyl and the resulting solution was added a 3 M aqueous sodium hypochlorite solution (130 ml, obtained from 4 M commodity bleach solution). A two-phase system was intensively stirred for 24 hours and then was diluted with dichloromethane. The mixture was filtered through cellulose accelerator filtering to breeding two layers. Then the organic layer was dried (anhydrous sodium sulfate) were removed under reduced pressure, the solvent, and the residue was chromatographically on silica using dichloromethane as eluent, resulting in received (3S,4S)-3,4-dihydro-3,4-epoxy-6-(3-methoxyphenyl)sulphonyl-2,2,3 - trimethyl-2H - benzo(b)- Piran (2.0 g) as a pale yellow foam.

MCHP: m/z = 361 (M + 1)+.

1H-NMR (CDCl3): = of 7.90 (1H, d), 7,78 (1H, DD), 7,40-to 7.50 (3H, m), was 7.08 (1H, DD), 6.89 in (1H, d), of 3.85 (3H, s), and 3.72 (1H, s) of 1.55 (3H, s) of 1.50 (3H, s) of 1.27 (3H, s) M. D.

Example obtain 18. (3S,4R)-4-Amino-3,4-dihydro-3-hydroxy-6-(3-methoxyphenyl)- sulphonyl-2,2,3-trimethyl-2H-benzo(b)Piran.

(3S, 4S)-3,4-Dihydro-3,4-epoxy-6-(3-methoxyphenyl)sulphonyl-2,2,3 - trimethyl-2H-benzo(b)Piran (2.0 g) (see getting 17) was dissolved in ethanol (15 ml) and the resulting solution was added 35% aqueous ammonia solution (10 ml). The mixture was heated at 50oC for 48 hours, after which another solution was added ammonia (5 ml) and was heated for a further 8 hours. Deleted when fluenta mixture of methanol: dichloromethane - 5:95, the result obtained (3S, 4S), 4-amino-3,4-dihydro-3-hydroxy-6-(3-methoxyphenyl)sulphonyl-2,2,3 - trimethyl-2H-benzo(b)Piran (1.9 g) as a foam. Found: C 58,65, H 5,77, N 3,29. Calculated for C19H23NO5S, 0,22 CH2Cl2: C 58,28, H 5,96, N OF 3.53%.

1H-NMR CDCl3): = 8,00 (1H, s), of 7.70 (1H, DD), 7,38-7,52 (3H, m), was 7.08 (1H, DD), 6,85 (1H, d), 3,90 (1H, s), 3,85 (3H, s), 2,60 (1H, Shir), of 1.55 (2H, W), for 1.49 (3H, s) of 1.30 (3H, s) a 1.01 (3H, s) M. D.

Example obtain 19. (3S,4R)-4-(2-Chloropyrimidine-4-yl)amino-3,4-dihydro-3-hydroxy-6- (3-methoxyphenyl)sulphonyl-2,2,3-trimethyl-2H-benzo(b)Piran and (3S, 4R)-4- (4-chloropyrimidine-2-yl)amino-3,4-dihydro-3-hydroxy-6-(3-methoxyphenyl) sulphonyl-2,2,3-trimethyl-2H-benzo(b)Piran.

(3S, 4R)-4-Amino-3,4-dihydro-3-hydroxy-6-(3-methoxyphenyl)sulphonyl-2,2,3-trimethyl-2H-benzo(b)Piran (0.95 g) (see getting 18) was dissolved in dry 1,4-dioxane, to the resulting solution was added 2,4-dichloropyrimidine (0.45 g) and diisopropylethylamine (0.39 g), and the mixture was heated under reflux for 25 hours. Was removed under reduced pressure, the solvent 6 and the residue was subjected to azeotropic distillation with dichloromethane, after which he chromatographically on silica using as eluent a mixture of dichloromethane: ethyl acetate = 4:1, and the result obtained (3S, 4R)-4-(4-chlorine.

MCHP: m/z = 490 (m)+.

1H-NMR (CDCl3): = 8,01 (1H, d), 7,80 (1H, DD), 7,38-to 7.50 (4H, m), 7,05 (1H, DD), of 6.90 (1H, DD), to 6.80 (1H, W), of 5.75 (1H, W), vs. 5.47 (1H, d), of 4.95 (1H, W), of 3.80 (1H, s) of 1.50 (3H, s) of 1.45 (3H, s) of 1.13 (3H, s) M. D.

Further elution with a mixture of dichloromethane:ethyl acetate = 1:1 gave (3S, 4R)-4-(2-chloropyrimidine-4-yl)amino-3,4-dihydro-3-hydroxy-6- (3-methoxyphenyl)sulphonyl-2,2,3-trimethyl-2H-benzo(b)Piran (0.64 g) as a white solid, and so pl. 228-230oC. MCHP: m/z = 490 (m)+.

1H-NMR (CDCl3): = 8,07 (1H, d), a 7.85 (1H, s), of 7.70 (1H, DD), 7,35-7,45 (3H, m), was 7.08 (1H, DD), of 6.90 (1H, DD), is 6.61 (1H, DD), 5,79 (1H, d), of 5.50 (1H, Shir. ) and 4.65 (1H, W), of 3.85 (3H,s) of 1.50 (3H, s) of 1.40 (3H, s) and 1.15 (3H, s) M. D.

An example of obtaining 20. (3R, 4R)-4-Amino-3,4-dihydro-3-hydroxy-6- (3-hydroxyphenyl)-sulphonyl-2,2,3-trimethyl-2H-benzo(b)Piran.

(3S, 4S)-6-(3-tert-Butyldimethylsilyloxy)sulphonyl-3,4 - dihydro-3,4-epoxy-2,2,3-trimethyl-2H-benzo(b)Piran (2.2 g) (see getting 15) was dissolved in ethanol (25 ml) and the resulting solution was added 35% aqueous ammonia solution (25 ml). The mixture was heated at 40-50oC for 24 hours. Was removed under reduced pressure, the solvent, and the residue was chromatographically on silica using as eluent a mixture of methanol:dichloromethane = 7,5:92,5 resulting alucinogeno: C 54,39, H 5,22, N 3,19. Calculated for C18H21NO5S 0,50 CH2Cl2: C 54,57, H 5,46, N OF 3.45%.

1H-NMR (DCl3): = 8,07 (1H, s), of 7.70 (1H, DD), to 7.50 (1H, s), 7,41 (1H, d), 7,30 (1H, d), of 6.99 (1H, DD), for 6.81 (1H, d), 3,99 (1H, s), 3,50 (2H, Shir. ), to 1.48 (3H, s) of 1.28 (3H, s), and 1.00 (3H, s) M. D.

Example of getting a 21. 1,2-Dihydro-4-hydroxy-2-methyl - 1-acceptilation.

Phthalic anhydride (7.4 g) was dissolved in hot acetic acid (50 ml) and the resulting solution was added a solution of methylhydrazine (2.7 ml) in water (50 ml). The mixture was heated under reflux for 15 minutes and left overnight to cool. The resulting precipitate was filtered, washed with water and dried under reduced pressure, obtaining 1,2-dihydro-4-hydroxy-2-methyl-1 - acceptilation (7.6 g) as a white solid, so pl. 243-244oC.

1H-NMR (CDCl3): =8,28 (1H, m), with 8.05 (1H, m), a 7.85 (2H, m), to 4.87 (1H, s), 3,66 (3H, s) M. D.

Example of getting a 22. 1,2-Dihydro-4-hydroxy-1-methyl-2-oxopyridine.

2,4-Dihydroxypyridine (3.0 g) was dissolved in 2 N. aqueous sodium hydroxide solution (30 ml) and the resulting solution was added dropwise over 90 minutes dimethylsulfate (3.7 g). The mixture was stirred at room temperature overnight, acidified with concentrated chloritoid the dichloromethane and filtered. The filtrate was evaporated, and the crude product was chromatographically on silica using as eluent a mixture of methanol:dichloromethane = 7:93, resulting in the obtained 1,2-dihydro-4-hydroxy-1-methyl-2 - oxopyridine (0,77 g) as a yellow solid, so pl. 165 to 169oC. Found: C 57,28, H 5,47, N 10,89. Calculated for C6H7NO2: C 57,59, H 5,64, N 11,19%.

1H-NMR (d6-DMCO): = 10,50 (1H, d), to 7.50 (1H, d), of 5.82 (1H, DD), to 5.55 (1H, d), 3,30 (3H, s) M. D.

An example of retrieving 23. 2,4-Dihydroxy-5,6-dimethylpyridin.

5,6-Dimethyl-4-hydroxy-2-oxo-2H-Piran (11,92 g) (see J. C. S. Perkin Trans 1, 1980, 2272) was dissolved in 1,4-dioxane (80 ml), the resulting solution was added water 35% ammonia solution (40 ml), and the mixture was heated under reflux for 90 minutes. The solution was left overnight to cool, after which the precipitate was filtered and dried under reduced pressure at 90oC for 24 hours, resulting in 2,4-dihydroxy-5,6-dimethylpyridin (3,47 g) as a white solid.

1H-NMR (d6-DMCO): = is 10.75 (1H, W), 5,42 (1H, s), is 2.09 (3H, s) of 1.78 (3H, s) M. D.

Example of getting 24. 6-(3,4-Acid)thio-2,2,3-trimethyl - 2H-benzo(b)Piran.

6-Bromo-2,2,3-trimethyl-2H-benzo(b)Piran (7,4 g) (see the floor,4-dimethoxybenzoyl (5 g) and tetrakis(triphenylphosphine)-palladium(0) (0.5 g), and the mixture was heated under reflux in an atmosphere for 24 hours. Then added an additional portion of tetrakis(triphenylphosphine)-palladium (0) (0.5 g) and continued heating for another 24 hours. Was removed under reduced pressure, the solvent, and the residue was dissolved in dichloromethane and washed with water. The organic layer was dried (anhydrous sodium sulfate) were removed under reduced pressure, the solvent, and the obtained crude product was chromatographically on silica using as eluent a mixture of hexane:dichloromethane = 1:4, resulting in 6-(3,4-acid)thio-2,2,3-trimethyl-2H - benzo(b)Piran (7,4 g) as a yellow oil.

1H-NMR (CDCl3): = then 7.20 (1H, DD), 6,85-to 7.00 (3H, m), to 6.80 (1H, d), 6,72 (1H, d), 6,03 (1H, s), 3,85 (3H, s), of 3.80(3H, s), of 1.85 (3H, s) of 1.41 (6H, s) M. D.

An example of obtaining 25. (3S,4S)-3,4-Digidoc-6-(3,4 - acid)sulphonyl-3,4-epoxy-2,2,3-trimethyl-2H-benzo(b)Piran.

6-(3,4-Acid)thio-2,2,3-trimethyl-2H-benzo(b)-Piran (3.1 g) (see getting 24), 4-phenylpyridine-N-oxide (0.4 g) and [(S, S)-1,2 - bis(3,5-di-tert-butylsilane)]-cyclohexanemethanol (III) chloride (0.4 g) was dissolved in dichloromethane (35 ml) and the resulting solution was added a 3 M aqueous solution of sodium hypochlorite (100 ml, obtained from 4 M commodity bleach is Loya, was diluted with dichloromethane. The organic layer was dried (anhydrous sodium sulfate) were removed under reduced pressure, the solvent, and the residue was chromatographically on silica using as eluent a mixture of dichloromethane:ethyl acetate = 19:1, and the result obtained (3S, 4S)-3,4-dihydro-6-)3,4-acid) sulphonyl-3,4-epoxy-2,2,3-trimethyl-2H-benzo(b)Piran (3.0 g) as a yellow foam.

MCHP: m/z = 408 (m + NH4)+.

1H-NMR (CDCl3): = 7,89 (1H, d), of 7.75 (1H, DD), 7,53 (1H, DD), 7,35 (1H, d), 6,80-7,00 (2H, m) to 3.92 (6H, s), 3,71 (1H, s) to 1.59 (3H, s), of 1.52 (3H, s) of 1.29 (3H, s) M. D.

Example of receipt 26. (3S,4R)-3,4-Dihydro-4-(2,4-dihydro-2-methyl - 3-oxypyridine-6-yl)oxy-6-(3,4-acid)sulfonyl-3-hydroxy - 2,2,3-trimethyl-2H-benzo(b)Piran.

(3S, 4S)-3,4-Dihydro-6-(3,4-acid)sulphonyl-3,4-epoxy - 2,2,3-trimethyl-2H-benzo(b)Piran (3.0 g) (see getting 25) and 2,3-dihydro-2-methyl-3-oxo-6-hydroxypyridine (2.0 g) (see J. Org. Chem., 1971, 36, 3372) suspended in dry 1,4-dioxane (30 ml), the resulting suspension was added pyridine (0,61 g), and the mixture was heated under reflux (flask equipped with a potassium chloride drying tube) for 2 days. Was removed under reduced pressure, the solvent, and the residue was stirred with a mixture of 5% methanol/dichloro-methane and ispolzovaniem as eluent methanol: dichloromethane = 2,5:97,5, the result obtained (3S, 4R)-3,4-dihydro-4-(2,3-dihydro-2-methyl-3-oxopyridine - 6-yl)oxy-6-(3,4-acid)sulfonyl-3-hydroxy-2,2,3-trimethyl - 2H-benzo(b)Piran (1.7 g) as a yellow foam.

1H-NMR (CDCl3): = of 7.90 (1H, d), of 7.75 (1H, DD), 7,52 (1H, DD), 7,35 (1H, s), 7,10 (2H, m), 6.90 to (2H, m) to 3.92 (3H, s), 3,90 (3H, s), 3,70 (3H, s) of 1.50 (3H, s) of 1.40 (3H, s), 1,25 (3H, s) M. D.

Example of getting 27. 6-Bromo-3,4-dihydro-4-oxo-2,2,3-trimethyl - 2H-benzo(b)Piran (Alternative method for obtaining compounds of the preparation of 3)

a) 1-(5-Bromo-2-hydroxyphenyl)propane-1-on.

To a stirred mixture of trichloride aluminum (2.5 kg) in dichloromethane (5000 ml) at room temperature was added within 5 minutes propanolol (864). The mixture was stirred 45 minutes at room temperature, then added to it for 15 minutes a solution of 4-bromoanisole (875 g) in dichloromethane (1000 ml). The reaction mixture was heated under reflux for 6 hours and then cooled and stirred at room temperature overnight.

The reaction mixture was rapidly cooled by slow (over 40 minutes) take it out on the ice (11 kg). The mixture was stirred for 30 minutes followed by separation of the layers. Then the aqueous layer was extracted with dichloromethane (2 1000 ml) and the combined organization is key at atmospheric pressure. Continuing the distillation, was slowly added to methanol (3750 ml). The distillation is continued until then, have not yet been achieved temperature 64oC corps stills and temperature 62oC head part. Then to the solution at this temperature was added water (270 ml), and cooled the reaction mixture and the precipitate discarded non-white solids. After cooling the reaction mixture to 20oC was slowly added water (270 ml) and the mixture was granulated at about 10oC within 2 hours.

The solid was filtered and carefully washed on a soft pad with a mixture of methanol:water (6:1 by volume), then dried under reduced pressure at 50oC, and as a result got mentioned in the title compound (960 g).

b) 6-Bromo-3-dihydro-4-oxo-2,2,3-trimethyl-2H-benzo(b)Piran.

To the mixed solution obtained in stage (a) product (1,46 kg) in acetone (7300 ml) and xylene (6570 ml) was added piperidine (3.04 kg), and the reaction mixture was heated under reflux for 5 days.

The reaction mixture was cooled and washed successively with water (2 3000 ml), and then 2 N. aqueous solution of hydrochloric acid (2 5000 ml) with ice cooling), 2 N. water concrete is the situation, and the result was indicated in the title compound as a brown oil (1,46 kg).

Pharmacological data.

Selected compounds obtained in the foregoing examples were tested for activity, reflected in the relaxation (relaxation) of smooth muscle, the method including the measurement of relaxation in vitro drug electrically stimulated tracheal rings Guinea pigs.

The results presented in this table below, which shows the minimum dose1the compound that causes the maximum inhibition of cholinergic reduction relative to the control.

1. Benzopyrane General formula I

< / BR>
where X is O or NH;

R and R1each independently selected from H and C1-C4-alkyl;

R2- H or C1-C4-alkyl,

R3is: a) 6-membered heterocyclic ring containing 1 or 2 heteroatoms of N, and the specified ring linked to X via a carbon atom in the ring, optionally condensed with a benzene ring and optionally substituted (including condensed benzene portion)1-C6-alkyl, hydroxy, halogen, or oxopropoxy provided that R3not the and X is NH group of the formula

< / BR>
R4represents phenyl, substituted with one or two hydroxy groups;

R5- C1-C6-alkyl;

R6- SR5;

R7is cyano;

R8- OR5.

or their pharmaceutically acceptable salt.

2. Benzopyrane under item 1, in which X represents O or NH; R, R1and R2everyone - FROM1-C4-alkyl; R3represents: (a) 6-membered heterocyclic ring containing 1 or 2 heteroatoms of nitrogen, and the specified ring optionally condensed with a benzene ring and optionally substituted (including condensed benzene portion)1-C4-alkyl, hydroxy, halogen or exography, b) a group of the formula

< / BR>
or (C) a group of the formula

< / BR>
R4is phenyl, substituted by 1 or 2 hydroxy groups;

R6is - SR5;

R8is-OR5;

R5and R7take the values specified in paragraph 1.

3. Benzopyrane under item 2, in which X is represented On; R, R1and R2each is methyl; R3- 1,2-dihydro-2-oxo-1H-pyridin-4-yl, 1,2-dihydro-5,6-dimethyl-2-oxo-1H-pyridin-4-yl, 3-hydroxypyridine-6-yl, 2,3-dihydro-2-methyl-3-oxopyridine-6-yl, 2,3-dihydro-2-ethyl-3-dioxo-2-atomiclevel-1-EN-1-yl or 3-cyano-2-methylisothiourea;

R4- 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl or 3,4-dihydroxyphenyl.

4. Benzopyrane under item 3, in which R3- 1,2-dihydro-2-oxo-1H-pyridin-4-yl or 2,3-dihydro-2-methyl-3-oxopyridine-6-yl, and R4- 3-hydroxyphenyl or 4-hydroxyphenyl.

5. Benzopyrane on PP.1 to 4, which have the General formula IA

< / BR>
where X, R, R1- R4specified in paragraph 1.

6. Benzopyrane under item 1, which is selected from the group consisting of 3,4-dihydro-4-(2,3-dihydro-2-methyl-3-oxopyridine-6-yl)oxy-3-hydroxy-6-(3-hydroxyphenyl)sulphonyl-2,2,3-trimethyl-2H-benzo(b)of Piran and 3,4-dihydro-4-(2,3-dihydro-2-methyl-3-oxopyridine-6-yl)oxy-3-hydroxy-6-(4-hydroxyphenyl)sulphonyl-2,2,3-trimethyl-2H-benzo(b)of Piran, or pharmaceutically acceptable salt of either of these compounds, or (3S, 4R)-stereoisomeric form of any of them.

7. Pharmaceutical composition having activity, relaxing smooth muscle, including an active agent and a pharmaceutically acceptable diluent or carrier, wherein the composition comprises as active agent a compound of formula I or its pharmaceutically acceptable salt according to any one of p. 1 - 6 in an effective amount.

8. Benzopyrane Faure is.

9. Benzopyrane formula I according to any one of paragraphs.1 - 6, with activity, relaxing smooth muscle.

10. The composition according to p. 7, characterized in that it is intended for the treatment of diseases associated with a change in the tone and/or contractility of smooth muscle.

11. The composition according to p. 7, characterized in that it is intended for the treatment of diseases selected from the following groups: chronic obstruction of the respiratory tract, asthma, urinary incontinence, irritable bowel syndrome, a disease associated with the formation of diverticula, achalasia (an impaired ability to relax the smooth muscle sphincter) of the esophagus or hypertension.

12. A method of treating diseases associated with a change in the tone and/or contractility of smooth muscle, characterized in that it is administered an effective amount of the compounds of formula I or its pharmaceutically acceptable salt according to any one of paragraphs.1 - 6.

13. The method according to p. 12, characterized in that said disease is a chronic obstruction of the respiratory tract, asthma, urinary incontinence, irritable bowel syndrome, a disease associated with the formation of diverticula, achalasia (an impaired ability Rackable the BR> where R10is phenyl, substituted by 1 or 2 protective hydroxy groups;

X, R, R1, R2and R3take the values specified in paragraph 1.

15. Benzopyrane General formula VIA

< / BR>
where R10bis phenyl, substituted three(C1-C4-alkyl)silyloxy;

R, R1and R2take the values specified in paragraph 1.

16. Benzopyrane General formula VII

< / BR>
where R, R1, R2and R4takes the values specified in paragraph 1.

17. Benzopyrane formula VIA by p. 15, where three-(C1-C4-alkyl)silyloxy in the symbol definition R10bis tert-butyldimethylsilyloxy.

18. Benzopyrane formula II according to p. 14, where it is protected by a hydroxy-group in the symbol definition R10javljaetsja1-C4-alkoxy, preferably a methoxy group.

19. Benzopyran under item 1, which is (3S, 4R)-3,4-dihydro-4-(2,3-dihydro-2-methyl-3-oxopyridine-6-yl)oxy-3-hydroxy-6-(3-hydroxyphenyl)sulphonyl-2,2,3-trimethyl-2H-benzo(b)Piran, or its pharmaceutically acceptable salt.

20. Benzopyran under item 1, which is (3S, 4R)-3,4-dihydro-4-(2,3-dihydro-2-methyl-3-oxopyridine-6-yl)-oxy-3-hydroxy-6-(4-hydroxyphenyl)sulphonyl-2,2,3 - thee so, that is useful for the treatment of diseases selected from the following group: peripheral vascular disease, congestive heart failure, pulmonary hypertension, ischemia of the myocardium and brain, angina, patchy baldness in men, cardiac arrhythmia, fatigue or paralysis of skeletal muscles (myotonica muscular dystrophy), glaucoma, epilepsy, tinnitus, dizziness, and dysmenorrhea (menstrual disorders).

 

Same patents:

The invention relates to a new method of obtaining the previously described connections of a number of dibenzo[b, e]pyrano[3,2-b]-1-benzopirilievyh salts of General formula (I),

< / BR>
where X 0;

R1a hydrogen atom;

R2-R4the atom of hydrogen or halogen, C1-C6alkyl or C1-C6alkoxygroup, the nitro-group;

R5, R6, R7the atom of hydrogen or C1-C6alkyl,

that exhibit fluorescent properties and are used as dyes for dyeing films and aminomethylating fibers (DOS 2942931 (1980), BASF, Erf

The invention relates to vasoconstrictor /(benzodioxan, benzofuran and benzopyran)-alkylamino/-alkyl-substituted guanidine formula I, their pharmaceutically acceptable salts, or their stereochemical isomers, where X = O, CH2or a direct bond; R1= H, C1-C4alkyl, R2= H, C1-C6alkyl, C3-C6alkenyl, C3-C6quinil, R3= H, C1-C4alkyl; or R2and R1taken together, may form a bivalent radical of the formula/CH2/m-, where m = 4 or 5; or R1and R2taken together may form a bivalent radical of formula-CH=CH -, or the formula/CH2/n-, where n = 2, 3 or 4; or R3may indicate a relationship when R1and R2taken together form a bivalent radical of formula-CH=CH-CH= -, -CH= CH-N= or-CH=N-CH=; where one or two hydrogen atom substituted by a halogen atom, a C1-C6alkoxygroup, C1-C6the alkyl, CN, NH, mono - or di(C1-C6alkyl) amino group, aminocarbonyl, C1-C6alkylaminocarbonyl, R4-H or C1-C6-alkyl; Alk1denotes a divalent C1-C3-ascandilwy radical, A denotes dwuhvalentny a radical of the formula /, lk2represents C2-C15-alcander or C5-C7-cycloalkenyl, and each "R" represents 0, 1, 2, R7and R8each independently is H, a halogen atom, a C1-C6by alkyl, hydroxyl, C1-C6allyloxycarbonyl, C1-C6alkoxygroup, cyano, amino, C1-C6the alkyl, carboxyla, nitro or amino group, aminocarbonyl, C1-C6alkylcarboxylic or mono - or di-(C1-C6)alkylamino, provided that excluded /2-/ (2,3-dihydro-1,4-benzodioxin-2-yl)-methyl/-amino/-ethyl-guanidine

The invention relates to pyrazole derivative of the General formula I, where g2, g3and g6hydrogen; g4- chlorine atom or bromine, WITH1-C3-alkyl, trifluoromethyl, or phenyl; g5is hydrogen or chlorine atom; w2, w3, w5and w6is hydrogen or chlorine atom; w4is hydrogen, a chlorine atom, a C1-C3-alkyl, C1-C3-alkoxy or nitro; X is a direct bond or the group -(CH2)nN(R3)-, where R3is hydrogen or C1-C3-alkyl; n is 0 or 1; R4is hydrogen or C1-C3-alkyl and, when X is a direct bond, R is a group-NR1R2where R1is hydrogen, C1-C6-alkyl or cyclohexyl, and R2- C1-C6-alkyl, non-aromatic carbocyclic radical WITH3-C15possibly substituted by a hydroxyl group, one or more1-C5-alkilani,1-C5alkoxygroup or halogen; amino group WITH1-C4-alkyl in which the amino may dazamide1-C3-alkyl, cyclohexyl1-C3-alkyl; phenyl, unsubstituted or substituted with halogen, or WITH1-C5-alkyl; phenyl WITH1-C3-alkyl, diphenyl1-C3-Olinala, hinokitiol and oxybutylene, unsubstituted or substituted C1-C3-alkyl or benzyl; 1-adamantaneacetic; C1-C3-alkyl, substituted aromatic heterocycle selected from pyrrolyl, pyridyl or indolyl, unsubstituted or substituted C1-C5-alkyl, or R1and R2form together with the nitrogen atom to which they relate, pyrrolidinyl, piperidyl or morpholinyl; or the group R5that represents phenyl WITH1-C3-alkyl, unsubstituted or substituted C1-C5-alkyl; cyclohexyl1-C3-alkyl, or 2-norbornylene; when X represents a group -(CH2)nN(R3)-, R represents a group R2Athat represents a non-aromatic carbocyclic radical WITH3-C15; phenyl substituted by halogen; phenyl WITH1-C3-alkyl, possibly substituted with halogen; indolyl, possibly substituted C1-C5alkoxygroup; anthracene, or group with other2bin which R2b- cyclohexyl, substituted, phenyl, unsubstituted or substituted by one or two halogen atoms, WITH1-C5-alkyl or C1-C5alkoxygroup or their acid additive salts

The invention relates to new derivatives of hinoklidilkarbinola General formula where n is an integer 1, 2, 3, R1-halogen or trihalomethyl, R2is hydrogen, R3-furanyl, tetrahydrofuranyl, DIOXOLANYL, pyranyl, tetrahydropyranyl, optionally substituted by 1, 2 or 3 substituents selected from the group comprising oxoprop and C1-C3-alkyl

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The invention relates to new activators of potassium channels and to a method of use of these and other compounds that have activity in the activation of potassium channels, in the form of anti-ischemic and anti-arrhythmic drugs

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The invention relates to new chemical compound, namely 3-(4-methyl-2-thiazolyl)-6-proper-7-(1-methyl-1-etoxycarbonyl)metaxia - Mona, of the formula I

< / BR>
which has analepticheskih, hypoglycemic and hypolipidemic effect
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