Derivatives benzopyran

 

(57) Abstract:

Usage: when you activate potassium channels in the form of anti-ischemic and anti-arrhythmic drugs. The inventive product: (3S-TRANS)-3-(( ((6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H - 1-benzopyran-4-yl)amino) carbonyl)amino)benzocaine acid. B. F. C21H21N3O5O42H20. Output 73,9%, so pl. 135 - 138oC. the Methyl ester of (3S-TRANS)-3-(( ((6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)amino) carbonyl)amino)benzoxazol acid. B. F. O22H23N3O2O21H20. Yield 66%, so pl. 45 - 48oC. for 24 h. p. F.-ly, 1 table.

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.

According to the invention offers a new way to use compounds having activity by activation of potassium channels, as anti-ischemic and anti-arrhythmic drugs. These compounds for use in the method of the present invention in the most paletable a hydrogen or lower alkyl, having 1-4 carbon atoms;

X is oxygen or sulfur;

Y is a group-NR8-, -O-, -S - or a group -

R1arylalkyl, heterocycle or (heterocycle)-alkyl;

R2hydrogen, hydroxy group, -OCH3;

R3and R4each independently is hydrogen, alkyl or arylalkyl, or R3and R4taken together with the carbon atom to which they are attached, form a 5-to 7-membered carbocyclic loop;

R5is selected from hydrogen, alkyl, haloalkyl, alkenyl, quinil, cycloalkyl, arylalkyl, cycloalkyl, -CN, -NO2, -COR, -COOR, -CONHR, -CONR2, -CF3, -S-alkyl, -SO-alkyl, -SO2-alkyl, - (O-alkyl)2halogen, amino, substituted amino, -O-alkyl, -OCF3, -OCH2CF3, -OCO-alkyl, -OCONR-alkyl, -NRCO-alkyl, and-NRCOO-alkyl, NRCON(R)2in which R in each of the above groups can be hydrogen, alkyl, aryl, arylalkyl, cycloalkyl or (cycloalkyl)-alkyl or haloalkyl;

R6is selected from hydrogen, alkyl, halogen, HE, O-alkyl, amino and substituted amino group, O-alkyl, OCO-alkyl, OCONR-alkyl, NRCON(R)2, NRCO-alkyl and NRCOO-alkyl, in which R in each of the above groups can be hydrogen, and is jdy independently selected from hydrogen, of alkyl, arylalkyl;

or R1and R8or R1and R7or R7and R8taken together, may form a 5 to 7-membered saturated or unsaturated cycle which may optionally include aryl group, combined with the two carbon atoms such from 5 to 7-membered cycle;

n is 1, 2 or 3;

R10hydrogen, hydroxy, alkyl or-O-alkyl.

Also disclosed are new compounds, which are compounds of formula I with the proviso that when Y is-NH, R2hydroxy group, R3and R4each is stands, R5hydrogen, R66-cyano-group, R7hydrogen, and a and X each is oxygen, R1must be other than phenyl.

The invention in its broadest features relates to a new method of using compounds of formula I as anti-ischemic and anti-arrhythmic drugs, as well as to new compounds of formula I.

The new compounds of the invention are all compounds of formula I except those in which Y is-NH-, R1the phenyl, R2hydroxy group, R3and R4each is stands, R5hydrogen, R66-cyano-group, R

Known compounds of formulas AND

where X is oxygen or sulfur, and R7is selected and the class consisting of C1-6of alkyl, substituted amino group, optionally substituted by one or two1-6-alkyl groups, which may be the same or different; amino groups optionally substituted C1-6-alkyl or C1-6-alkenylphenol group, or WITH1-6-alkanoyloxy group, optionally substituted with up to three halogen atoms, or phenyl group, optionally substituted C1-6-alkyl, C1-6-alkoxy group or halogen, or C1-6-alkoxy group or phenoxy group, optionally substituted C1-6-alkyl, C1-6-alkoxy group, or halogen; or, when X is oxygen, R7additionally, selected from the class consisting of carboxy groups, WITH1-6-alkoxycarbonyl or aminocarbonyl, optionally substituted by one or two groups WITH1-6-alkyl, which may be the same or different.

These compounds are disclosed as antihypertensive drugs. In fact, at the present time it is found that some of the known compounds have small or does not have, Hypo is ormula

as identified, has little or does not possess hypotensive activity, but has anti-ischemic activity. In addition, all the compounds of formula I are useful as anti-arrhythmic drugs.

The compounds of formula I in which a is oxygen, X is oxygen and Y is NR3can be obtained by treating compounds of formula II

R1- 4-nitrophenyloctyl ether Harborview acid, to obtain the intermediate of formula III

RONO2< / BR>
Intermediate III may then be subjected to reaction with an amine of the formula IV

in an organic solvent, such as dimethylformamide, tetrahydrofuran, acetonitrile or methylene chloride to obtain the compounds of formula I, where a and X each is oxygen and Y is-other8.

The compounds of formula I in which X is oxygen or sulfur, and Y is NR8where R8is hydrogen, can be obtained from compounds of formula IV by treatment with isocyanate or isothiocyanato formula V

R1N C Z O S)

The compounds of formula I, in which X, Y and a are oxygen, can be obtained from compounds of formula IV by treatment of its epitomi amine catalyst.

The compounds of formula I, in which X and a are oxygen and Y is - can be obtained by reaction of the compound of formula IV with an acid of formula VII

R - X (where X' is OH, Cl) and a carbodiimide or with acylchlorides formula VII in an organic solvent and a base such as triethylamine and pyridine.

The compounds of formula I in which X is sulfur, can be obtained by treating compounds of the formula I, in which X is oxygen, reagent Lawesson or R4R10in organic solvents, such as tetrahydrofuran and toluene.

Amerosport formula IV in which R2is TRANS-hydroxy group can be obtained by known methods. Amerosport formula IV in which a is-O-, a R2is a CIS-hydroxy group can be obtained by known methods.

Amine of the formula IV in which R2is hydrogen and a is-O-, can be obtained from the ketone of formula VIII

by a standard method. The ketone of formula VIII can be obtained by known literature methods.

Amine of the formula IV in which a is-O-, and R2is hydrogen, can be obtained from an olefin of the formula IX

the sequence of stages, which includes:
succinimide and light;

C) substitution of bromine azide using sodium azide, followed by a

d) catalytic reduction of azide.

The compound of formula I in which a is CH2, NR9, -S-, -SO - and-SO2- can be obtained in this way from amines of the formula X

in which a is CH2, NR9, -S-, -SO -,- SO2-.

The compounds of formula X, where a is NH, described in the literature, the compounds of formula X in which a is-S-, -SO-, -SO2as well.

The compounds of formula X in which a is CH2can be obtained by known methods.

The compounds of formula I in which R1and R7connect via (through) deep cycle, can be obtained by treating the intermediate of formula XI

4-nitrophenyloctyl ether Harborview acid and a base such as triethylamine in an organic solvent such as methylene chloride, acetonitrile, etc.

The compounds of formula XI in which R2is TRANS-hydroxyl can be obtained by reaction of an epoxide of the formula XII

with an amine of the formula XIII

-R8in an alcohol solvent such as ethanol.

The compounds of formula XI can be obtained also allroy R1and R7are connected via the aryl cycle can be obtained by cyclization of the intermediate of formula XI

using a base such as sodium methoxide in methanol.

The compounds of formula XV can be obtained from the epoxide XII and aniline of formula XVI

(R alkyl/ aryl) in the presence of magnesium perchlorate in an organic solvent such as acetonitrile.

The compounds of formula XVI are known.

To get individual enantiomers of compounds of formula I in which R2H, OH, a a O, compound IV, where R2H, OH, a a 0, turns into diastereomeric amides of the formula formula XVII and XVIII

and processing of chiral prizemistoj almond acid in the presence of dicyclohexylcarbodiimide.

Compounds XVII and XVIII are separated by crystallization or chromatography. Enantiomer almond acid, which gives a crystalline diastereoisomer with desirable 4R-stereochemistry of benzopyrene (as shown in the formula (XV) is preferred in the stage of cleavage.

Compounds XVII and XVIII is then hydrolyzed by heating in the presence of sulfuric acid in dioxane to obtain the enantiomers of formulas XIX and XX

< / BR>
< / BR>
The enantiomers of the nineteenth and twentieth subsequently turn into the existing enantiomers, where And differs from the oxygen.

The proposed compounds may have asymmetric centers at 2-4 carbon atoms benzopyrano cycle. In addition, any one of the radicals R may have an asymmetric carbon atom. Therefore, the compounds of formula I may exist in diastereoisomeric forms or mixtures thereof. The above method can use the racemates, enantiomers or diastereomers as starting materials. When work diastereomers substances, they can be separated by conventional chromatographic methods or methods fractionated crystallization.

The proposed compounds in which R7is hydrogen, Y is NR8, a R8is hydrogen, can exist as a mixture of tautomers represented by the following structures. Tautomeric substances obtained in relative amounts that vary from connection to connection. All forms are included in the scope of formula I.

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< / BR>
The tautomers of formula I, such I' and I" are also possible, in which Y is 0, S, and -, and also included in the scope of the invention.

The compounds of formula I and pharmaceutically acceptable salts act as and what edstam, for example, as anti-arrhythmic drugs and anti-ischemic funds.

As previously described, the compounds of formula I are particularly useful as anti-ischemic funds, as they was found to have low or totally absent hypotensive activity. Thus, the compounds of formula I are useful in the treatment of ischemic conditions such as myocardical ischemia (myocardial ischemia), cerebral ischemia, lower limb ischemia, and the like. Selectivity, i.e., anti-ischemic activity with low or totally absent hypotensive activity, means that in the treatment of, for example, ischemia of the heart, these compounds are less likely to cause coronary syndrome victimize (outflow of blood from more vascularizing area in less vascularization due to narrowing or blockage of coronary arteries), profound arterial hypotension and coronary inadequate perfusion (inadequate coronary circulation). Under low or totally absent activity of vasodilatative (vasodilator activity) it is meant that these compounds has value IC50(aorta rat) greater than any activato is their value IC50(aorta rat) greater than 10 times, compared with those of cromakalim (i.e. have 1/10 vasodilatation actions), and preferably substances having a size IC50greater than 50-fold compared with cromakalim.

The tests were carried out in accordance with the following method. The results are presented in the table.

Test methodology for aorta rats.

After sacrifice of the animals in male rats Wistar Kyoto was removed thoracic aorta, which was placed in chilled saline solution containing mmol NaCl 118,4; KCl 4,7; KH2PO41,2; MgSO41,2; CaCl22,5; NaHCO325,0; glucose 11,7. Each aorta were cut ring and mechanically removed endothelium. Since the rings were made of individual histological sections for registration isometric force and each slice was placed in a separate bath with saline solution temperature 37aboutC, aerated with 95% O2/5% CO2(pH 7.4). During the period balance made the hood rings up to 2 g and repeated stimulation of 24.7 mm KCl in order to determine the airway.

After equilibration in each bath was added propanolol (1 Ám) to block beta-adrenergic receptors. C is s cumulative curve of concentration relaxation. After the solution in the bath reached final concentration, tried to do a "reversal" of relaxation (in the presence of test compound) by adding sufficient quantities of 4 M KCl solution, to obtain a final concentration in the bath at 60 mm KCl.

Presented data are the average data of scanning electron microscopy at least four rings of various animals. Figures IC50was determined from a quadratic approximation to the logical transformation of the concentration curves of relaxation. Concentrated basic solutions of test compounds were prepared daily; they were either aqueous solutions or solutions in DMSO.

Tests the hearts of rats (% reduction in LDH).

Preparation extracted hearts with artificial circulation.

All experiments used male rats Sprague-Dawley (450-550 g). Rats did anesthesia, injecting intraperitoneally 30 mg/kg sodium pentobarbital. Rats were intubated, and then intravenously injected with heparin (1000 u/kg). Simultaneously with artificial ventilation of the lungs with the help of automatic breathing apparatus, spent perfusion of hearts in situ through readily perfusion of these hearts bicarbonate buffer solution of Krebs-Henseleit (112 mmol NaCl2, 25 mmol NaHCO3, 5 mmol KCl, 1.2 mm MgSO4, 1 mmol KH2PO4, 1.25 mmol CaCl2, 11.5 mmol dextrose and 2 mmol of pyruvate, aerated with 95% O2/5% CO2) at constant pressure (75 mm RT.cent.). Then in the left ventricle was injected water-filled rubber balloon attached to a metal cannula and connected to the pressure sensor of Statham to measure the pressure in the left ventricle. Then the heart was left for 15 minutes to trim and during that time brought diastolic blood pressure up to 5 mm RT.article which was maintained for 5 minutes and Then measured the functioning of the heart to ischemic condition and before the introduction of the drug, measured heart rate and coronary blood flow using extracorporeal electromagnetic flow sensor. The functioning of the heart was determined as twice the product of heart rate on the pressure generated by the left ventricle divided by 1000. The natural temperature of hearts in the course of the experiment supported, plunging heart in the buffer solution temperature 37aboutWith that accumulated in a closed heated bath.

The Protocol of the experiment.

After s% DMSO, n 7). Processing of hearts relevant drugs or carriers was carried out for 10 minutes At this time, measurements of the functioning of the heart and blood flow after administration of drugs, and then the heart was put into a state of ischemia, completely stopping the perfusion buffer solution. Ischemia was maintained for 25 min, and then started re-perfusion buffer solution without drugs.

Re-perfusion was carried out for 30 min and at the same time was measured again function reperfusion and blood flows.

Thus, for example, by injection of a composition containing one (or a combination) of the compounds of the invention ischemic condition mammals of the body of the carrier (e.g., human) down. A single dose, or preferably two to four divided daily doses, provided on the basis of the quantities of about 0.001 to 100 mg per kg of body weight per day, preferably from about 0.1 to about 25 mg per kg per day is appropriate to reduce ischemic condition. The substance preferably is administered orally, but can be applied also parenteral route, such as subcutaneous, intramuscular or tubular solutions or transdermal (percutaneous) dressings (plasters). The above doses are suitable also for other cardiovascular and not cardiovascular applications.

In the compounds of the present invention when activated potassium channels, these compounds are also useful in the treatment of cardiovascular diseases. For example, the proposed compounds are useful as drugs for the treatment of congestive heart failure, as protivoateroskleroticheskim funds, as protivodiareynah funds as thrombolytic agents and in limiting myocardial infarction.

Compounds of the invention, as it is expected to be useful in the treatment of disorders of the Central nervous system such as Parkinson's disease, as proteotoxic funds funds against tremor, epilepsy. Compounds of the invention can also be incorporated into the recipe in combination with a diuretic (diuretic), such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichlormethiazide, polythiazide or benzthiazide, as well as ethacrynic acid, ticrynafen, chlorthalidone, furosemide, muzolimine, bumetanide, triamteren, amyloidosis, zofenopril, fosinopril, enalapril, ceronapril, cilazapril, delapril, pentopril, quinapril, ramipril, lisinopril, and salts of such compounds, with thrombolytic agents such as tissue plasminogen activator (PLA), recombinant APT, streptokinase, urokinase, the PUK and complex activator Antilibanus plasminogen and streptokinase (called APSAC, eminase laboratory Vichama) or by blocking the calcium channels, such as nifedipine or diltiazem. This combination of substances, if they are introduced into the composition in the form of a fixed dose, uses of the compounds of the present invention in the dose limits described above, and the other pharmaceutically active agent within the approved doses of it.

The compounds of formula I and their combinations can be introduced into the composition as described above, compositions such as tablets, capsules or elixirs for oral administration, in sterile solutions or suspensions for parenteral administration, and can be introduced percutaneous or solutions for nasal inhalation. About 10 to 500 mg of the compounds of formula I conundrums together with a physiologically acceptable excipient, carrier, excipient, binder, will protect according to accepted pharmaceutical practice. The amount of active material in these compositions or preparations of aleeta so, to get the appropriate dosage is within the specified limits.

Preferred compounds claimed in the invention are the compounds of formula I, where R1represents phenyl or substituted phenyl, phenylalkyl or six-membered heterocycle containing as the heteroatom nitrogen atoms;

R2hydrogen, hydroxy or a group

-O--CH3;

R3and R4each represents alkyl;

R5haloalkyl, cyano;

Y group NR8or -;

R7and R8each represents hydrogen, or

R7+R8form a five-membered nitrogen-containing heterocyclic ring;

R1and R7together form condensed with phenyl five-membered nitrogen-containing heterocyclic ring;

X is oxygen or sulfur;

And oxygen;

R10hydrogen, alkyl, alkoxy or oxygraph.

P R I m e R 1. (TRANS)-1-(6-cyano-3,4-dihydro-3-hydroxy-2,2 - dimethyl-2H-1-benzopyran-4-yl)-3-phenylacetone

A suspension of TRANS-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonic sludge (obtained by Evans and others J. Med.Chem. 1983, 26, 1582 the reaction mixture is heated at boiling temperature with reverse drains phlegmy within 4 hours The reaction product precipitates. The reaction mixture is then concentrate under vacuum and the residue is ground to powder using isopropyl ether, to obtain the above compound as a colourless solid (0.9 g, 63%), so pl. 240-241aboutC, H-NMR (CDCl3) DMSO/ 8,3 (singlet, 1H); 7.7 (singlet, 1H); 7,4 (doublet, J 8.0 Hz, 3H); 7,26 (triplet, J 8.0 Hz, 2H); 7.0 (triplet, J 9.0 and 7.0 Hz, 1H); 6,86 (doublet, J 9.0 Hz, 1H); 6,4 (doublet, J 8.0 Hz, 1H); 5,3 (doublet, J 5.0 Hz, 1H); 4,9 (triplet, J 9.0 and 8.0 Hz, 1H); 3,6 (two doublet, J of 4.0 and 6.0 Hz, 1H); 1.5 (singlet, 3H); 1.3 (singlet, 3H);13C-NMR (CDCl3) DMSO: 157,0, 156,5, 139,1, 132,2, 132,1, 128,4, 123,9, 121,8, 118,2, 117,8, 80,0, 74,3, 49,9, 26,1, 18,4; IR (KBr), cm-1: 1132, 1267, 1491, 1550, 1612, 1645, 2226, 2932, 2978, 3433.

Analysis:

Calculated for C19H19N3O3C 67,64; H OF 5.68; N 12,45

Found, C 67,35; H The 5.45; N 12,35.

P R I m m e R 2. (TRANS)-1-(6-cyano-3,4-dihydro-3-hydroxy-2,2 - dimethyl-2H-1-benzopyran-4-yl)-3-phenyltoloxamine

A suspension of (TRANS)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzop - RAS-6-carbonitrile (obtained by Evans and others J. Med. Chem. 1983, 26, 1582 and J. Med. Chem. 1986, 29, 2194) (1.0 g, 4.6 mmol) in ethanol (4 ml) under a current of argon is treated with phenylisothiocyanate (of 0.62 g, 4.6 mmol) and the reaction mixture is heated at the boiling reverse running off flatprofile-

the first ether, to obtain the above compound as a colourless solid (1.4 g, 85% ), so pl. 183-185about;1H-NMR (CDCl3) : 8,5 (singlet, 1H), and 7.4 (multiplet, 7H), 6,83 (doublet, J 8.0 Hz, 1H), 6,1 (singlet, 1H), 6,0 (singlet, 1H), 4.0 (ice singlet, 1H), 3,67 (doublet, J 10.0 Hz, 1H), 1.5 (singlet, 3H), 1.3 (singlet, 3H),13C-NMR (CDCl3): 182,5, 156,8, 133,3, 131,9, 130,4, 128,2, 126,0, 125,8, 122,2, 118,8, 118,6, 104,0, 80,5, 75,8, 50,0, 26,3, 18,6; IR (KBr) cm-1: 1070, 1265, 1491, 1531, 2226, 2978, 3312, 3362.

Analysis:

Calculated for C19H19N3O2C 64,56; H 5,42; N 11,89; S 9,07;

Found, C 64,50; H 5,41; N 11,64; S 8,76.

P R I m e R 3. TRANS-N-(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) benzoylacetate

To a solution of hydrochloride (TRANS)-4-amino-3,4-dihydro-3-hydroxy-2,2 - dimethyl-2H-1-benzopyran-6-carbonitrile (obtained by Evans and others J. Med. Chem. 1983, 26, 1582 and J. Med. Chem. 1986, 29, 2194) (1.0 g, 3.9 mmol) in 20% aqueous tetrahydrofuran (25 ml) is added phenyl acetate chloride (0,91 g, 5.9 mmol, 0.8 ml) dropwise, the pH of the reaction mixture support between 8,5-9,0 simultaneous addition of 25% aqueous solution of sodium carbonate. After complete addition, the reaction mixture is stirred for more than one hour. The mixture is then diluted with ethyl acetate (200 ml) and the layers of ristuka reaction. The crude solid is recrystallized from chloroform to obtain the above compound (0.7 g) as a white solid, so pl. 204-205aboutWITH:1H-NMR (DMSO-d6) 8,55 (doublet, J 8.0 Hz, 1H), 7,6 (two doublet, J 1.0 and 9.0 Hz, 1H), 7,35 (multiplet, 6N), 6,95 (doublet, J 9.0 Hz, 1H), 5,7 (doublet, J 6.0 Hz, 1H), 4,85 (triplet, J of 10.0 and 9.0 Hz, 1H), 3,6 (multiplet, 3H), 1,4 (singlet, 3H), 1,2 (singlet, 3H):13C-NMR (DMSO-d6) 171,5, 156,5, 136,5, 132,8, 129,3, 128,5, 126,8, 125,4, 119,1, 118,1, 103,0, 80,6, 71,3, 48,8, 43,0, 26,8, 19,1: IR (KBr) cm-1: 1071, 1126, 1268, 1489, 1652, 2225, 2976, 3411.

Analysis:

Calculated for C20H20N2O30,1 H2O, C 71,02; H OF 6.02; N 8,28;

Found, C Is 70.94; H 5,94; N 8,05.

P R I m e R 4. [3R-[3 4 -(S*)]-N-(6-Cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) - hydroxy-benzoylacetone

To a solution of (TRANS)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H - 1-benzopyran-6-carbonitrile (obtained by Evans and others J. Med. Chem. 1983, 26, 1582 and J. Med. Chem. 1986, 29, 2194) (10.0 g, at 45.9 mmol), S-(+)-almond acid (6,98 g, at 45.9 mmol), hydroxybenzotriazole hydrate (6.2 g, at 45.9 mmol) in dimethylformamide (60 ml) at 0aboutWith add dicyclohexylcarbodiimide (9.5 g, at 45.9 mmol). The mixture continued to stir at room temperature for 20 h, and then cooled in an ice bath. Myetanola in chloroform and washed with 1N. a solution of sodium hydroxide, 1N. hydrochloric acid, brine and dried over anhydrous magnesium sulfate. After removal of the drying agent, the solvent is removed under vacuum. The residue is crystallized from ethanol, to obtain the above compound (6.0 g) as a white solid, so pl. 238-240aboutC []D25+94,6about(1, Meon):1H-NMR (CDCl3) : of 7.4 (multiplet, 5H), 7,26 (triplet, J 1.0 Hz, 1H), 6,97 (doublet, J 9.0 Hz, 1H), 6,83 (doublet, J 9.0 Hz, 1H), 5,16 (singlet, 1H), 4,98 (triplet, J9,0 Hz, 1H), 3.8 (doublet, J 5.0 Hz, 1H), 3,55 (two doublet, J 4.0 and 5.0 Hz, 1H), 1,45 (singlet, 3H), 1,2 (singlet, 3H).

Analysis:

Calculated for C20H20N2O4C 68,17; H 5,72; N 7,95;

Found, C 67,92; H 5,49; N 8,05.

P R I m e R 5. [3S-[34 -(R*)]-N-(6-Cyano-3,4-dihydro-3 - hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) - hydroxy - benzoylacetone.

The residual substance from the mother liquor of example 4 purified flash chromatography on silica gel, elwira mixture of hexane ethyl acetate (3:7) and the residue is crystallized from a mixture of methylene chloride-isopropyl ether to obtain the above compound (6.0 g) as a white solid, so pl. 100-102about(Foaming): []D25-26,1about(1, Meon):1H-NMR (DMSO-d6) : 8,4 ubly, J 5.0 Hz, 1H), 5,0 (singlet, 1H), 4,76 (triplet, J 9.0 Hz, 1H), 3,75 (two doublet, J 4.0 and 5.0 Hz, 1H), 1,40 (singlet, 3H), 1,15 (singlet, 3H).

Analysis:

Calculated for C20H20N2O40,25 H2O, C 67,30; H 5,78; N 7,84

Found, C 67,54; H 5,95; N 7,44.

P R I m e R 6. [3S-[3 4 -(S*)]-N-(6-cyano-3,4-dihydro-3 - hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) - hydroxy - benzoylacetone

To a solution of (TRANS)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H - 1-benzopyran-6-carbonitrile (obtained by Evans and others J. Med. Chem. 1983, 26, 1582 and J. Med. Chem. 1986, 29, 2194) (1.64 g, 7.5 mmol), R-(-)-almond acid (1,14 g, 7.5 mmol), hydrate hydroxy-benzotriazole (1.0 g, 7.5 mmol) in dimethylformamide (15 ml) at 0aboutWith add at room temperature dicyclohexylcarbodiimide (1.55 g, 7.5 mmol). The reaction mixture was allowed to mix at room temperature for 20 h, and then cooled it in an ice bath. The solid is removed by filtration and the filtrate concentrated under vacuum. The residue is dissolved in 5% methanol in chloroform and washed with 1N. a solution of sodium hydroxide, 1N. hydrochloric acid, brine, followed by drying over anhydrous magnesium sulfate. After removal of the drying agent, the solvent is removed under vacuum. The residue is crystallized UB>D25-94,9about(1, Meon),1H-NMR (DMSO-d6) : 8,45 (doublet, J 8.0 Hz, 1H), 7,5 (multiplet, 4H), and 7.3 (multiplet, 2H), 7.0 (singlet, 1H), 6,88 (doublet, J 8.0 Hz, 1H), 6,2 (singlet, 1H), 5,57 (doublet, J 5.0 Hz, 1H), 5,0 (singlet, 1H), 4,76 (triplet, J 9.0 Hz, 1H), 3,75 (two doublet, J 4.0 and 5.0 Hz, 1H), 1,40 (singlet, 3H), 1,15 (singlet, 3H).

Analysis:

Calculated for C20H20NO4C 68,17; H 5,72; N 7,95;

Found, C 68,00; H 5,52; N 7,95.

P R I m e R 7. [3R-[34 -(R*)]-N-(6-Cyano-3,4-dihydro-3 - hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) - hydro - cibenzoline.

The residual substance, extracted from the mother liquor of the above example 6, purified flash chromatography on silica gel, elwira with a mixture of hexane-ethyl acetate (3: 7) and the reaction product is crystallized from a mixture of methylene chloride-isopropyl ether to obtain the above compound as a white solid, so pl. 100-102about(Foaming): []D25+25,6about(1, Meon);1H-NMR (CDCl3) : of 7.4 (multiplet, 5H), 7,26 (triplet, J 1.0 Hz, 1H), 6,97 (doublet, J 9.0 Hz, 1H), 6,83 (doublet, J 9.0 Hz, 1H), 5,16 (singlet, 1H), 4,98 (triplet, J 9.0 Hz, 1H), 3.8 (doublet, J 5.0 Hz, 1H), 3,55 (two doublet, J 4.0 and 5.0 Hz, 1H), 1,45 (singlet, 3H), 1,2 (singlet, 3H).

Analysis:

Calculated for C20H20N2
A. 6-Cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran

A solution of 6-cyano-2,2-dimethyl-2H-1-benzopyran (5.5 g, 29.7 mmol, obtained by Evans and others J. Med. Chem. 1983, 26, 1582 and J. Med. Chem. 1986, 29, 2194) in anhydrous ethanol (40 ml) is treated with palladium on coal (0.35 g) and stirred under a pressure of hydrogen gas for 2 hours, the Catalyst was filtered through Celite and pressed the precipitate washed with ethyl acetate. The filtrate is concentrated under vacuum, in order to obtain 5,71 g yellow oil. The crude reaction product is dissolved in ethyl acetate (60 ml) and washed successively with 5% hydrochloric acid (60 ml), saturated sodium bicarbonate solution (60 ml), saturated sodium chloride solution (60 ml) and dried over anhydrous magnesium sulfate. The solvent was recovered under vacuum to obtain 5,14 g of the above compound in the form of a yellow solid, which is used in the next stage without additional purification.

1H-NMR (CDC3) : 7,37 (singlet, 1H), 7,34 (singlet, 1H), 6,80 (doublet, J 8,8 Hz, 1H), 2,78 (two doublet, 2H), 1,80 (two doublet, 2H), 1.35 (singlet, 6N),13C-NMR (CDCl3) : 157,95, 133,82, 131,34, 122,07, 119,53, 118,24, 102,66, 75,76, 32,13, 26,81, 22,06.

B. 4-Bromo-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran

To a solution of natwanman, 1.1 EQ.). The solution is rinsed with argon. The solution azobisisobutyronitrile (0.4 g, of 3.42 mmol) in carbon tetrachloride (10 ml) is added; the reaction mixture is heated at the boiling reverse drains phlegmy within a half-hour exposure (high intensity visible light). The reaction mixture is concentrated under vacuum and the residue is dissolved in ethyl acetate (75 ml). The solution is washed successively with distilled water (4 x 75 ml), saturated sodium bicarbonate solution (75 ml), saturated sodium chloride solution (75 ml) and dried over anhydrous magnesium sulfate. The solvent extract under vacuum to obtain 9,51 g orange waxy solid that is ground to powder with cold pentane to obtain 7,19 g solid beige color. This substance is crystallized from 10% ethyl acetate in hexane (25 ml), to obtain 4,60 g of the above compound B in the form of off-white needles. The Queen cells are combined and chromatographic on silica gel, elwira with a mixture of hexane/ethyl acetate (19:1) to obtain additional of 2.26 g of the reaction product, 1H-NMR (CDCl3) : 7,86 (doublet, J1,17 Hz, 1H), 7,42 (two doublet, J 1,76 and 8,79 Hz, 1H), 6,82 (doublet, J 8,80 Hz, 1H), 5,35 (two doublet, 1H), 2,45 (multiplet, NH">

Century 4-Azido-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran

The solution of the above compound B (of 6.73 g, 25,29 mmol) in dry N, N-dimethylformamide (100 ml) is treated with sodium azide (3,29 g, 50,57 mmol, 2 EQ.) and stirred at room temperature under a current of argon for 4 h, the Reaction mixture was divided into parts between layers ethyl acetate (100 ml) and distilled water (200 ml). The organic layer is separated and the aqueous layer extracted with ethyl acetate (100 ml). The combined organic layers are washed successively with distilled water, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under vacuum to obtain 5,62 g orange resin, which is ground to powder using pentane to obtain 4,50 g of the above compound In the form of a not-quite-white solid.

1H-NMR (CDCl3) : 7,69 (singlet, 1H), 7,46 (doublet, J 8,80 Hz, 1H), 6,86 (doublet, J 8,21 Hz, 1H), 4,59 (two doublet, J 6,45 and of 2.34 Hz, 1H), 2,24 (multiplet, 1H), 2,01 (multiplet, 1H), 1,49 (singlet, 3H), 1,36 (singlet, 3H),13C-NMR (CDCl3) : 157,66, 133,79, 133,41, 121,20, 119,24, 104,21, 76,80, 53,73, 38,30, 28,97, 26,29.

, 4-Amino-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran
angle (0.25 g) and stirred under a pressure of hydrogen gas within 1.25 h at room temperature. The reaction mixture is filtered to remove the catalyst. The filtrate is acidified to pH 1-2 with concentrated hydrochloric acid (0,85 ml) and concentrate under vacuum to a white solid. Crude hydrochloric acid amine dissolved in distilled water (100 ml) and extracted with ethyl acetate (discarded). The aqueous layer was adjusted to pH 11-12 50% sodium hydroxide solution and extracted with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent is evaporated under vacuum to obtain 1,542 g of the above compound D as a yellow oil, which solidified upon standing. The reaction product used in the next stage without additional purification,1H-NMR (DMSO-d6) : 8,01 (singlet, 1H), 7,51 (doublet, J 8,21 Hz, 1H), 6,82 (doublet, J 8,21, 1H), 3,86 (two doublet, 1H), 2,07 (two doublet, J by 5.87 and 13,49 Hz, 1H), and 1.56 (multiplet, 1H), 1,39 (singlet, 3H), 1.24 (the singlet, 3H),13C-NMR (DMSO-d6) : 156,82, 132,51, 131,59, 129,40, 119,47, 117,45, 101,70, 76,99, 43,13, 42,47, 29,39, 24,70.

D. N-(6-Cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)-N'- phenylacetone.

The solution of the above compound G (0,70 g, 3.46 mmol) in phenylisocyanate (0,41 g, 3.46 mmol) in anhydrous ethanol (11.5 ml) is heated at the boil precipitated from the solution. It is collected by filtration by suction, washed with diisopropyl ether and dried under vacuum to obtain 0,743 g of the above compound in the form of a white solid substance, so pl. 214-215aboutS.1H-NMR (CDCl3) : 8,60 (singlet, 1H), to 7.67 (singlet, 1H), 7.62mm (doublet, J 8,80 Hz, 1H), of 7.48 (singlet, 1H), 7,45 (singlet, 1H), 7,26 (multiplet, 2H), 6,94 (multiplet, 2H), 6,64 (doublet, J 8,21 Hz, 1H), 5,00 (multiplet, 1H), 2,19 (multiplet, 1H), 1,76 (multiplet, 1H), 1,44 (singlet, 3H), 1,32 (singlet, 3H).13C-NMR (CDCl3) : 157,31, 155,23, 140,20, 132,46, 132,11, 128,68, 125,37, 121,34, 119,18, 118,14, 117,86, 102,10, 77,22, 41,86, 38,87, 28,96, 24,56.

Analysis: Calculated for C19H19N3O2C 71,01; H 5,96; N 13,07;

Found, C 71,14; H 5,97; N 12,91.

P R I m e R 9. N-(6-Cyano-3,4-dihydro-2,2-dimethyl-2H-1 - benzopyran-4-yl)-N'-(phenylmethyl)-urea

The solution of the above compound G from example 8 (0.50 g, 2,47 mmol) and benzylisothiocyanate (0.33 g, 2,47 mmol) in anhydrous ethanol (4 ml) is heated at boiling reverse drains phlegmy for 3 h and cooled to room temperature. The reaction product precipitates from solution. It is collected by filtration by suction: solid ground to powder using diisopropyl ether and dried under vacuum to obtain the SUB>) : to 7.59 (singlet, 1H), 7,56 (singlet, 1H), 7,38-7,24 (multiplet, 5H), 6.89 in (doublet, J 8,21 Hz, 1H), 6,56 (triplet, J by 5.87 Hz, 1H), 6,50 (doublet, J 8,21 Hz, 1H), 4,94 (multiplet, 1H), 4,30 (doublet, J 5,86 Hz, 2H), 2,10 (multiplet, 1H), 1,74 (multiplet, 1H), 1,41 (singlet, 1H), of 1.28 (singlet, 3H).13C-NMR (DMSO-d6) : 158,11, 157,19, 140,78, 132,25, 132,08, 128,22, 126,93, 126,61, 126,12, 119,18, 118,03, 102,02, 77,28, 43,01, 41,95, 38,81, 29,08, 24,42.

Analysis:

Calculated for C20H21N3O2C 71,62; H OF 6.31; N 12,53;

Found, C 71,56; H 6,40; N 12,29.

P R I m e R 10. (TRANS)-1-(6-cyano-3,4-dihydro-3-hydroxy-2,2 - dimethyl-2H-1-benzopyran-4-yl)-3-(phenylmethyl)-urea

A suspension of (TRANS)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzop - RAS-6-carbonitrile (1.0 g, 4.6 mmol) (obtained by Evans and others J. Med. Chem. 1983, 26, 1582 and J. Med. Chem. 1986, 29, 2194) in ethanol (4 ml) under a current of argon is treated benzylisothiocyanate (0.6 g, 4.6 mmol) and the reaction mixture is heated at the boiling reverse drains phlegmy for 4 hours the reaction Product precipitates from solution. Then the reaction mixture is concentrated under vacuum and the residue is ground to powder using diisopropyl ether, to obtain the above compound as a colourless solid (1.3 g), so pl. 147-148aboutS.1H-NMR (DMSO) : 7,60 (doublet, J 2.4 Hz, blet, J 5,9 Hz, 1H), with 4.64 (triplet, J of 9.3 and 8.8 Hz, 1H), 4,3 (multiplet, 2H), 3,52 (two doublet, J a 3.5 and 5.9 Hz, 1H), 1,40 (singlet, 3H), 1,17 (singlet, 3H):13C-NMR (DMSO) : 158,8, 156,2, 140,8, 132,7, 132,3, 128,2, 126,9, 126,6, 119,1, 117,8, 102,5, 80,3, 71,7, 49,5, 43,0, 26,5, 18,8: IR (KBr) cm-1: 1266,5, 1305,8, 1489,5, 1566,1, 1611,5, 1634,8, 2226,4, 2979,3, 3355,0.

Analysis:

Calculated for C20H21N3O3C 68,36; H OF 6.02; N 11,96;

Found, C 68,38; H Of 6.02; N 11,89.

P R I m e R 11. (TRANS)-N-[3-(atomic charges)-6-cyano-3,4-dihydro - 2,2-dimethyl-2H-1-benzopyran-4-yl]-N'-prilocaine

The solution of the above compound of example 1 (2.70 g, 8.0 mmol) and acetic anhydride (2,04 g, 20.0 mmol) in pyridine (30 ml) was stirred at room temperature for four days. The reaction mixture is separated into pieces between layers of 10% aqueous hydrochloric acid and ethyl acetate. The organic phase is washed with distilled water, followed by washing with a saturated solution of sodium chloride. The solvent was remove under vacuum: the obtained white solid (2,78 g, so pl. 263-264aboutC) dried joint evaporation with ethanol. 1H-NMR (DMSO-d6) : 8,65 (singlet, 1H), 7,66 (multiplet, 2H), 7,46 (singlet, 1H), 7,43 (singlet, 1H), 7,26 (multiplet, 2H), 7,02 (doublet, J 7.62MM, 1H), 6,94 (multiplet, 1H), 6,67 (doublet, J 8,79 Hz), 4,96 (triple is of 5.84, 155,18, 140,11, 132,86, 132,66, 128,65, 124,62, 121,43, 118,84, 118,17, 117,94, 103,2, 78,35, 72,42, 47,16, 25,65, 20,64, 20,15.

Analysis:

Calculated for C21H21N3O4C 66,48; H 5,58; N 11,07;

Found, C 66,32; H 5,52; N 11,06.

P R I m e R 12. (TRANS)-1-(6-Acetyl-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzo - Piran-4-yl)-3-phenylacetone

A. 6-Acetyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran

To a solution of 95% 4-hydroxyacetophenone (to 13.6 g, 100 mmol), 3-chloro-3-methyl-butyne (17,4 g, 170 mmol) in methylene chloride (75 ml) is added water (75 ml), sodium hydroxide (6.4 g, 160 mmol) and Triton B (40% in methanol, 23,0 g, 52 mmol). The reaction mixture was stirred at room temperature for 6 days. The organic layer is separated, the aqueous phase is re-extracted with methylene chloride (2 x 200 ml). The combined extracts are concentrated under vacuum, the residue is transferred into ethyl acetate (500 ml), washed with 1N, a solution of sodium hydroxide (3 x 250 ml), brine (200 ml) and dried over magnesium sulfate. The solvent is evaporated under vacuum and the residue is dissolved in 1,2-dichlorobenzene (40 ml) and heated at boiling reverse drains phlegmy for 4 hours the Solvent is removed by distillation at atmospheric pressure using a column in the Game, and the residue is distilled under poniatowa solids. 1H-NMR (CDCl3) : 7,75 (two doublet, J of 2.3 and 8.8 Hz, 1H), 7,73 (doublet, J 2.4 Hz, 1H), 6,78 (doublet, J 8,8 Hz, 1H), 6.35mm (doublet, J 10.0 Hz, 1H), 5,66 (doublet, J 9.9 Hz, 1H), 2,53 (singlet, 3H), 1,45 (singlet, 6N):13C-NMR (CDCl3) : 196,7, 157,4, 131,1, 130,2, 126,8, 121,6, 120,6, 116,0, 77,5, 28,3, 26,2. the room (2 x 200 ml). The combined extracts are concentrated under vacuum, the residue is transferred into ethyl acetate (500 ml), washed with 1N. a solution of sodium hydroxide (3 x 250 ml), brine (200 ml) and dried over magnesium sulfate. The solvent is evaporated under vacuum and the residue is dissolved in 1,2-dichlorobenzene (40 ml) and heated at boiling reverse drains phlegmy for 4 hours the Solvent is removed by distillation at atmospheric pressure using a column in the Game, and the residue is distilled under reduced pressure (so Kip. 140-150aboutWith 2.0 mm), to obtain the above compound (7.0 g) as a pale yellow solid.1H-NMR (CDCl3) : 7,75 (two doublet, J of 2.3 and 8.8 Hz, 1H), 7,73 (doublet, J 2.4 Hz, 1H), 6,78 (doublet, J 8,8 Hz, 1H), 6.35mm (doublet, J 10.0 Hz, 1H), 5,66 (doublet, J 9.9 Hz, 1H), 2,53 (singlet, 3H), 1,45 (singlet, 6N):13C-NMR (CDCl3) : 196,7, 157,4, 131,1, 130,2, 126,8, 121,6, 120,6, 116,0, 77,5, 28,3, 26,2.

B. 6-Acetyl-3,4-dihydro-2,2-dimethyl-3-bromo-4-hydroxy-2H - benzopyran

To a solution of the above marrying at room temperature. The reaction mixture was stirred for 30 min at room temperature. It was then poured into water (50 ml) and extracted with ethyl acetate (2 x 100 ml). The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrate under vacuum to obtain a colorless residue, which is ground to powder using a mixture of diisopropyl ether/hexanol to obtain the above-mentioned compound B (2.5 g) as a white solid, so pl. 84-86aboutS.1H-NMR (CDCl3) : 8,15 (singlet, 1H), 7,83 (two doublet, J 2,3 and 6.5 Hz, 1H), 6,85 (doublet, J 8.7 Hz, 1H), 4.95 points (doublet, J 9.4 Hz, 1H), 4,14 (doublet, J 9.4 Hz, 1H), and 3.0 (multiplet, 1H), 2,56 (singlet, 3H), 1,64 (singlet, 3H), 1,43 (singlet, 3H): 13C-NMR (CDCl3) : 197,1, 156,5, 131,0, 130,5, 129,5, 122,4, 117,5, 80,2, 70,0, 62,1, 28,9, 26,7, 20,6.

Century 6-Acetyl-3,4-dihydro-2,2-dimethyl-3-hydroxy-4-amino-2H-1 - benzopyran

To a solution of the above compound B (2.5 g, 8.4 mmol) in ethanol (20 ml) is added a concentrated solution of ammonium hydroxide (20 ml). The reaction mixture is heated in a thick-walled (closed) bottle for reactions under pressure for 4 hours Then concentrated under vacuum and ground to powder with ether to obtain the above compound (1.9 g) as a colourless twardosz, 1H), 4,10 (doublet, J 9.4 Hz, 1H), 3,64 (doublet, J 9.4 Hz, 1H), 2.49 USD (singlet, 3H), 1,41 (singlet, 3H), 1,10 (singlet, 3H),13C-NMR (CDCl3) : 195,7, 156,3, 129,8, 129,0, 122,4, 118,0, 117,2, 79,1, 70,8, 50,4, 26,3, 26,2, 17,9.

, (TRANS)-1-(6-Acetyl-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1 - benzopyran-4-yl)-3-phenylacetone

A suspension of the above compound (0.1 g, 0.42 mmol) in methylene chloride (5 ml) under a current of argon is treated with triethylamine (0.04 g, 0.42 mmol), followed by adding phenylisocyanate (0.05 g, 0.42 mmol). The reaction mixture was stirred at room temperature for 4 h the reaction Product precipitates from the reaction mixture. It is filtered and washed with methylene chloride to obtain the above compound (0.15 g), so pl. 210-211aboutS.1H-NMR (DMSO) : 8,6 (singlet, 1H), 7,82 (multiplet, 3H), 7,44 (doublet, J 9.0 Hz, 2H), 7,25 (multiplet, 2H), 6,95 (multiplet, 1H), 6,86 (doublet, J9,0 Hz, 1H), 6,55 (doublet, J 9.0 Hz, 1H), 5,6 (doublet, J 8.0 Hz, 1H), 4,7 (multiplet, 1H), 3.5 (multiplet, 1H), 3,4 (multiplet, 1H), 2,4 (singlet, 3H), 1,4 (singlet, 3H), 1,2 (singlet, 3H): IR (KBr) cm-1: 3340,9, 2980,2, 1653,1, 1601,0, 1550,9, 1498,8, 1442,8, 1357,9, 1371,5, 1271,2, 1130,4.

Analysis:

Calculated for C20H22N2O40,44 H2O, C 66,31; H 6,36; N 7,73;

Found, C 66,28; H Between 6.08; N 7,76.

P R I m e p 13. is)-2-nitroaniline

To a solution of 2-nitroaniline (6,9 g, 50.0 mmol) in pyridine (6 ml) and methylene chloride (25 ml) is added at 0aboutWith under a current of argon, ethyl ether of Harborview acid (7.3 ml, 75,0 mmol) via addition funnel. After complete addition, the cooling bath removed and the reaction mixture was allowed to mix at room temperature over night. The reaction mixture was poured into 2n. hydrochloric acid and extracted with ethyl acetate. The combined extracts washed with water, saturated sodium bicarbonate solution and saline. After drying over anhydrous magnesium sulfate the solvent is evaporated to obtain the above-mentioned compound a as a yellow solid (7.7 g).1H-NMR (CDCl3) : 8,55 (doublet, J 8.0 Hz, 1H), 8,2 (doublet, J 8.0 Hz, 1H), 7,6 (triplet, J 8.0 Hz, 1H), 7,1 (triplet, J 7.5 Hz, 1H), 4,25 (Quartet, J 6.0 Hz, 2H), 1.3 (triplet, J 6.0 Hz, 3H):13C-NMR (CDCl3) : 153,0, 135,8, 135,4, 125,7, 122,1, 120,5, 63,6, 14,3 M. D.

B. 2-[(Etoxycarbonyl)-amino]-aniline

The solution of the above compound A (2.0 g, 9.5 mmol) in absolute ethanol (25 ml) hydronaut at atmospheric pressure in the presence of 10% palladium hydroxide/carbon catalyst (200 mg). The catalyst is filtered off, using a Packed layer of celite, and the filtrate is de colorless solid (820 mg).1H-NMR (CDl3) : 7,2 (doublet, J7,0 Hz, 1H), 7.0 (triplet, J 6.5 Hz, 1H), 6,7 (multiplet, 3H), 4.2V (Quartet, J 6.0 Hz, 2H), 3,75 (broadened singlet, 2H), 1.3 (triplet, J 6.0 Hz, 3H), 13C-NMR (CDCl3) : 158,2, 140,0, 126,3, 124,9, 124,0, 119,3, 117,3, 61,3, 14,4 M. D.

Century (TRANS)-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-[2- [((etoxycarbonyl)-amino)-phenyl]-amino]-2H-1-benzopyran-6 - carbonitrile.

The reaction mixture containing the above-mentioned compound B (900 mg, 5.0 mmol), 6-cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1 - benzopyran (1.0 g, 5.0 mmol) (obtained by Evans and others J. Med. Chem. 1983, 26, 1582 and J. Med. Chem. 1986, 29, 2194) and magnesium perchlorate (1.12 g, 5.0 mmol) in acetonitrile (5.0 ml), stirred under a current of argon at room temperature for 48 hours the Reaction mixture was diluted with ethyl acetate and washed with water, saturated sodium bicarbonate solution and saline. After drying over anhydrous magnesium sulfate the solvent is evaporated to obtain the above compound In the form of a colorless foamy substance (2,02 g),1H-NMR (CDCl3) : EUR 7.57 (singlet, 1H), 7,30 (two doublet, J 8.8 and 2.3 Hz, 1H), 7.0 (multiplet, 2H), 6.75 in (doublet, J 8.2 Hz, 2H), 6,60 (multiplet, 3H), 4,3 (multiplet, 2H), 4,05 (multiplet, 3H), 3,60 (doublet, J 8,8 Hz, 1H), 1,4 (singlet, 3H), 1,2 (singlet, 3H), 1,16 (triplet, J 7.0 Hz, 3 is="ptx2">

, (TRANS)-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(2,3-dihydro-2-oxo-1H-Benzema - Gasol-1-yl)-2H-1-benzopyran-6-carbonita - Rhyl

To a solution of above compound (1,15 g, to 3.02 mmol) in methanol (6.0 ml) is added a methanol solution of sodium methoxide (1,04 ml, 4.4 solution, 9.0 mmol) and the reaction mixture is refluxed under a current of argon for 4 hours Add a further quantity of a solution of sodium methoxide (1,04 ml) and heating continued for an additional 4 h, the Reaction mixture was cooled to ambient temperature and diluted with ethyl acetate. It was washed with 10% citric acid solution, saturated sodium bicarbonate solution and saline. After drying over anhydrous magnesium sulfate the solvent is evaporated and the residue purified on a flash chromatography (20% acetone in methylene chloride). The resulting reaction product is crystallized from isopropyl alcohol in two steps to obtain the above compound (605 mg), so pl. 255-257aboutC. IR (KBr) cm-1: 2225, 1682, 1491,1H-NMR (DMSO-d6) : 7,60 (two doublet, J8,4 and 1.8 Hz, 1H), 7,55, 7,38 (doublet, J 8,8 Hz, 1H), 7,18 (singlet, 1H), 7,06 (multiplet, 2H), 6,95 (triplet, J 8.1 Hz, 1H), 6,77, (triplet, J and 7.6 Hz, 1H), 6,16 (doublet, J 7.7 Hz, 1H), 5,91 (doublet, J 6.3 Hz, 1H)t doubling of the signals due to the presence in solution of two rotamers.

Analysis:

Calculated for C19H17N3O3C 66,05; H 5,11; N 12,53

Found, C 67,95; H Of 5.05; N 12,37.

P R I m e R 14. (TRANS)-1-(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzo - Piran-4-yl)-(3-pyridinyl)-urea

A. 4-Nitrophenyl-(3-pyridinyl)-carbamate

A solution of 3-aminopyridine (5.0 g, 5.3 mmol) in methylene chloride (40 ml) is treated with a solution of 4-nitrophenyl ether Harborview acid (10.7 g, 5.3 mmol) in methylene chloride (40 ml) followed by addition of pyridine (4,2 g, 5.3 mmol) under a current of argon, and the reaction mixture was allowed to mix at room temperature for 24 hours, the Solid is filtered and washed with methylene chloride to obtain the above-mentioned compound a (13,0 g) as a pale yellow solid.1H-NMR (DMSO) : 8,14 (doublet, J 7,1 Hz, 2H), 8,02 (doublet, J 1.8 Hz, 1H), 7,9 (multiplet, 1H), 7,5 (multiplet, 2H), 6,98 (doublet, J 7.0 Hz, 2H).

B. (TRANS)-1-(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)- (3-p

A solution of (TRANS)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1 - benzopyran-6-carbonitrile (1.0 g, 4.6 mmol) (obtained by Evans and others J. Med. Chem. 1983, 26, 1582 and J. Med. Chem. 1986, 29, 2194) in acetonitrile (20 ml) under a current of argon is treated with the above connection, the filtrate concentrated under vacuum. The residue is diluted with ethyl acetate and washed with water (3 x 200 ml), saturated sodium bicarbonate solution, water and concentrated under vacuum. The residue is ground to powder using ethyl acetate to obtain the above compound (1.4 g) as a colourless solid, so pl. 225-227aboutC.

1H-NMR (DMSO) : 9,0 (singlet, 1H), 8,42 (doublet, J of 4.7 Hz, 1H), 8,25 (doublet, J 8.2 Hz, 1H), 7,80 (multiplet, 1H), 7,79 (multiplet, 2H), 7,38 (doublet, J 8,8 Hz, 1H), 6,95 (doublet, J 8,8 Hz, 1H), 4,74 (triplet, J 8,8 Hz, 1H), 3,65 (doublet, J 9.4 Hz, 1H), 1,44 (singlet, 3H), 1,21 (singlet, 3H);13C-NMR (DMSO) : 156,3, 155,3, 139,5, 135,8, 132,6, 132,3, 130,9, 126,4, 125,5, 119,1, 117,9, 102,7, 80,4, 71,2, 49,5, 26,5, 18,9: IR (KBr) cm-1: 1265,4, 1369,5, 1487,2, 1548,9, 1610,7, 1697,5, 2222,1, 1769,9, 2986,0, 3068,9, 3296,6.

Analysis:

Calculated for C18H18N4O31,53 H2O, C 59,07; H 5,80; N 15,31.

Found, C 59,07; H 6,12; N 15,12.

P R I m e R 15. (TRANS)-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(2-oxo-3-phenyl-1-they - diazolidinyl)-2H-1-benzopyran-6-Carboni - home to the thrill

A. (TRANS)-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-phenyl-ethylendiamine-2H-1-Ben - superan-6-carbonitrile

A solution of 6-cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1 - benzopyran (1.0 g, 5.0 mmol) (obtained by Evans and others J. Med. Chem. 1983, 26, 1582 and J. Med. Chem. 29, 2194) in ethanol (10 ml) thereof, the temperature within 24 hours The reaction mixture is concentrated under vacuum, to obtain the above-mentioned compound a (1.5 g) as a colourless solid.

B. (TRANS)-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(2-oxo-3-phenyl - 1-imidazolidinyl)-2H-1-benzopyran-6-carbonitrile

The solution of the above compound And (1,67 g, 5.0 mmol) in methylene chloride (20 ml) under a current of argon at 0aboutTo process a solution of 4-nitrophenyloctyl ether Harborview acid (1.3 g, 6.4 mmol) in methylene chloride (10 ml), followed by adding triethylamine (0.65 g, 6.4 mmol). The reaction mixture was allowed to mix at room temperature for 16 hours Then diluted with methylene chloride and washed with 10% hydrochloric acid and water. The organic layer is dried over anhydrous magnesium sulfate and concentrate under vacuum to obtain the crude reaction product, which is recrystallized from a mixture of ether in ethyl acetate, to obtain the above compound (0.7 g) as a colourless solid, so pl. 205-206aboutS.1H-NMR (CDCl3) : 7,52 (multiplet, 7H), 7,24 (triplet, J and 7.6 Hz, 1H), 7,02 (doublet, J 6,7 Hz, 1H), and 5.30 (doublet, J 10.5 Hz, 1H), 3,88 (doublet, J 5.8 Hz, 1H), a 3.87 (multiplet, 1H), 3,57 (multiplet, 1H), 3.27 to (multiplet, 1H), 1,71 (SYN is 18,5: IR (KBr) cm-1: 1269,2, 1429,3, 1487,2, 1599,1, 1684,0, 2224,1, 2895,3, 2978,3, 3445,1.

Analysis:

Calculated for C12H21N3O3C 69,40; H OF 5.83; N TO 11.56;

Found, C 69,08; H 5,70; N 11,54.

P R I m e R 16. (CIS)-1-(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzo - Piran-4-yl)-3-phenylacetone

A. (TRANS)-4-acetylamino-8-cyano-3,4-dihydro-2,2-dimethyl-3 - hydroxy-2H-1-benzopyran

To a solution of (TRANS)-4-amino-6-cyano-3,4-dihydro-2,2-dimethyl-3 - hydroxy-2H-1-benzopyran (3.0 g, of 13.8 mmol) (obtained by Evans and others J. Med. Chem. 1983, 26, 1582 and J. Med. Chem. 1986, 29, 2194) in 20% water in tetrahydrofuran (40 ml) are added simultaneously, dropwise) acetyl chloride (1.66 g, 21,1, mmol) and 20% aqueous sodium bicarbonate solution with rapid stirring. pH support to 9.0. The reaction mixture is stirred for another 15 min at room temperature and evaporated under vacuum. The remainder is divided into parts between layers of ethyl acetate and 5% aqueous solution of hydrogen chloride. The organic layer was washed with saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent generate to get 3,30 g of the above compound As a white solid.1H-NMR (DMSO-d6) : 8,28 (doublet, J 68 Hz, 1H), 1,99 (singlet, 3H), 1,42 (singlet, 3H), 1,18 (singlet, 3H).13C-NMR (DMSO-d6) : 170,50, 156,27, 132,74, 132,57, 125,28, 119,06, 117,88, 102,80, 80,22, 71,23, 48,54, 38,58, 26,54, 22,94.

B. (CIS)-4-acetylamino-6-cyano-3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran.

To a solution of above compound (3.25 g, 12.5 mmol) in methylene chloride (30 ml) under a current of argon add TRIFLUORIDE to diethylaminosulfur (2,21 g, 13.7 mmol, 1.1 EQ.) at room temperature. The reaction mixture was stirred for 18 h, the solvent was remove under vacuum. The remainder is divided into parts between layers of ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and evaporated under vacuum to get to 3.02 g of a colorless resin. The crude oxazoline is dissolved in dioxane (30 ml), treated with 0.25 N. aqueous solution of sulfuric acid (1 ml) and stirred for 18 h at room temperature. The reaction mixture is separated into pieces between layers of ethyl acetate and distilled water. The organic phase is washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, dried over magnesium sulfate and evaporated under vacuum, what is the Etat, to obtain 1.08 g of the above compound B as a white solid.1H-NMR (DMSO-d6) : 8,12 (doublet, J 8,79 Hz, 1H), 7,58 (doublet, J8,21 Hz, 1H), of 7.48 (singlet, 1H), 6,88 (doublet, J 8,21 Hz, 1H), 5,67 (doublet, J at 5.27 Hz, 1H), 5,20 (doublet, J by 5.87 Hz, 1H), 3,60 (multiplet, 1H), 2,02 (singlet, 3H), 1.39 in (singlet, 3H), 1,25 (singlet, 3H).13C-NMR (DMSO-d6) : 170,12, 157,29, 132,51, 132,25, 122,75, 119,32, 117,42, 101,93, 79,58, 67,66, 45,17, 24,90, 24,04, 22,65.

Century (CIS)-4-amino-6-cyano-3,4-dihydro-2,2-dimethyl-3-hydroxy-2H - 1-benzopyran live under vacuum. The remainder is divided into parts between layers of ethyl acetate and 5% aqueous solution of hydrogen chloride. The organic layer was washed with saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent generate to get 3,30 g of the above compound As a white solid. 1H-NMR (DMSO-d6) : 8,28 (doublet, J 8,80 Hz, 1H), to 7.59 (doublet, J becomes 9.97 Hz, 1H), 7,49 (singlet, 1H), 6,92 (doublet, J 8,21, 1H), 4,82 (triplet, J 8,80 Hz, 1H), 3,55 (two doublet, J 5,57 and 9,68 Hz, 1H), 1,99 (singlet, 3H), 1,42 (singlet, 3H), 1,18 (singlet, 3H).13C-NMR (DMSO-d6) : 170,50, 156,27, 132,74, 132,57, 125,28, 119,06, 117,88, 102,80, 80,22, 71,23, 48,54, 38,58, 26,54, 22,94

B. (CIS)-4-acetylamino-6-cyano-3,4-dihydro-2,2-dimethyl-3-hydroxy energized argon add TRIFLUORIDE to diethylaminosulfur (2,21 g, 13.7 mmol, 1.1 EQ.) at room temperature. The reaction mixture was stirred for 18 h, the solvent was remove under vacuum. The remainder is divided into parts between layers of ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and evaporated under vacuum to get to 3.02 g of a colorless resin. The crude oxazoline is dissolved in dioxane (30 ml), treated with 0.25 N. aqueous solution of sulfuric acid (1 ml) and stirred for 18 h at room temperature. The reaction mixture is separated into pieces between layers of ethyl acetate and distilled water. The organic phase is washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, dried over magnesium sulfate and evaporated under vacuum to obtain 2,53 g crude cosmicopia. The crude reaction product chromatographic on silica gel, elwira with ethyl acetate to obtain 1.08 g of the above compound B as a white solid.1H-NMR (DMSO-d6) : 8,12 (doublet, J 8,79 Hz, 1H), 7,58 (doublet, J8,21 Hz, 1H), of 7.48 (singlet, 1H), 6,88 (doublet, J 8,21 Hz, 1H), 5,67 (doublet, J at 5.27 Hz, 1H), 5,20 (doublet, J by 5.87 Hz, 1H), 3,60 (multiplet, 1H), 2,02 (singlet, 3H)0, 24,04, 22,65.

Century (CIS)-4-amino-6-cyano-3,4-dihydro-2,2-dimethyl-3-hydroxy-2H - 1-benzopyran

The solution of the above compound B (0,80 g, 3.1 mmol) in dioxane (9 ml) and 1.5 M aqueous sulfuric acid (6.4 ml) is heated at 75aboutC for 48 hours the Reaction mixture is concentrated under vacuum and separated into pieces between layers 2n. of sodium hydroxide and ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated under vacuum to obtain 0.65 g not quite white solid. Crude amerosport chromatographic on silica gel, elwira 5% methanol in ethyl acetate to obtain 0.54 g of the above compound In the form of a pure white solid.1H-NMR (DMSO-d6) : 8,00 (singlet, 1H), 7,52 (doublet, J 8,79 Hz, 1H), 6,80 (doublet, J 8,21 Hz, 1H), 5,31 (broadened singlet, 1H), 3,92 (doublet, J to 3.52 Hz, 1H), 3,50 (broadened singlet, 1H), 3.33 and (broadened singlet, 1H), 1,38 (singlet, 3H), 1,20 (singlet, 3H).13C-NMR (DMSO-d6) : 156,93, 133,06, 131,56, 127,36, 119,61, 116,85, 101,61, 79,41, 70,43, 46,64, 25,07, 24,32.

G. of (CIS)-1-(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)-3 - FeNi

A solution of above compound (0.18 g, 0.10 mmol) and phenylisocyanate (0.10 g, 0.84 mmol, of 1.05 equiv.) in ethanol (2 ml)ground into powder using diisopropyl ether, to obtain 0.26 g of the above compound in the form of a white solid substance, so pl. 226-227 of theaboutC.

1H-NMR (DMSO-d6) : 8,89 (singlet, 1H), 7,58 (doublet, J to 8.20 Hz, 1H), 7,54 (singlet, 1H), 7,45 (doublet, J a 7.62 Hz, 2H), 7,26 (multiplet, 2H), 6,92 (multiplet, 2H), 6,58 (doublet, J 8,79 Hz, 1H), of 5.84 (doublet, J 5,86 Hz, 1H), 5,0 (multiplet, 1H), 3,66 (multiplet, 1H), 1,41 (singlet, 5H), 1.28 (in the singlet, 3H).

Analysis:

Calculated for C19H19N3O30,26 H2O, C 66,71; H OF 5.75; N TO 12.28;

Found, C 66,90; H 5,77; N 12,09.

P R I m e R 17. (TRANS)-N-[3,4-dihydro-3-hydroxy-2,2-dimethyl-6-(trifluoromethyl)-2H - 1-benzopyran-4-yl]-N'-prilocaine

A suspension of (TRANS)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-6 - trifluoromethyl-2H-1-benzopyran (0.5 g, 1.9 mmol) (obtained according to Buckley and others [D. R. Buckle et al] J. Med. Chem. 1990, 33, 3028) in ethanol (5 ml) under a current of argon is treated with phenylisocyanate (0,23 g, 1.9 mmol) and the reaction mixture is heated at boiling point with reverse drains phlegmy for 4 hours the reaction Product precipitates from the reaction mixture. The mixture is then concentrated under vacuum and the residue is ground to powder using diisopropyl ether and hexanol to obtain the above compound as a colorless solid (0.5 g), so dps 1H), 6,77 (doublet, J 8.2 Hz, 1H), 5,22 (broadened doublet, 1H), 4,80 (broadened triplet, 1H), 3.45 points (doublet, J 9.4 Hz, 1H), 1,37 (singlet, 3H), 1,12 (singlet, 3H):13C-NMR (CDCl3) : 157,0, 156,5, 139,1, 137,3, 129,4, 126,5, 125,0, 124,7, 122,0, 121,7, 118,0, 79,6, 76,4, 51,4, 26,3, 18,2: IR (KBr) cm-1: 1118,5, 1362,1, 1443,4, 1500,9, 1558,3, 1598,8, 1647,8, 2981,4, 3391,3.

Analysis:

Calculated for C19H19H3N2O3C 59,99; H TO 5.03; N 7,37; F 14,99;

Found, C 59,78; H 5,08; N 7,39; F 15,13.

P R I m e R 18. (TRANS)-1-(6-cyano-3,4-dihydro-3-hydroxy-2,2 - dimethyl-2H-1-benzopyran-4-yl)-(2-pyridinyl)-urea

A. 4-Nitrophenyl-(2-pyridinyl)-carbamate

A solution of 2-aminopyridine (2.0 g, is 21.3 mmol) in methylene chloride (20 ml) is treated with a solution of 4-nitrophenylamino ether Harborview acid (4.3 g, is 21.3 mmol) in methylene chloride (30 ml) followed by addition of pyridine (1.7 g, is 21.3 mmol) under a current of argon. The reaction mixture was allowed to mix at room temperature for 24 hours, the Solid is filtered and washed with methylene chloride to obtain the above compound (4.8 g) as a pale yellow solid.

B. (TRANS)-1-(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)- (2-p

A solution of (TRANS)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-banter the e (10 ml) under a current of argon is treated with the above compound (1.8 g, 6,9 mmol) and the reaction mixture is heated at 80aboutC for 4 h, the Reaction mixture was concentrated under vacuum and the residue diluted with ethyl acetate. It is washed with water (3 x 200 ml), saturated sodium bicarbonate solution, water and concentrated under vacuum. The residue is crystallized from a mixture of ether-hexanol to get solid (0.84 g). This solid is recrystallized from a mixture of diisopropyl ether methylene chloride, to obtain the above compound as a colorless solid (0.5 g), so pl. 192-194aboutWITH:1H-NMR (CDCl3) : 9,2 (singlet, 1H), 8,17 (doublet, J of 4.1 Hz, 1H), 7,83 (singlet, 1H), 7,71 (triplet, J 6.5 Hz, 1H), EUR 7.57 (doublet, J 8,8 Hz, 1H), 6,99 (multiplet, 3H), 5,20 (triplet, J 8.2 Hz, 1H), 5,0 (singlet, 1H), 3,91 (doublet, J 8,8 Hz, 1H), 1,64 (singlet, 3H), 1,42 (singlet, 3H):13C-NMR (CDCl3) : 158,4, 156,9, 152,6, 146,0, 138,8, 133,1, 132,3, 123,1, 119,0, 118,6, 117,7, 112,2, 104,1, 80,2, 75,7, 51,2, 26,4, 18,7: IR (KBr) cm-1: 1268,2, 1305,5, 1489,9, 1556,1, 1584,2, 1679,1, 224,8, 2979,7, 3063,6, 3411,1.

Analysis:

Calculated for C18H18N4O30,66 H2O, C, 63.47 PER; H OF 5.40; N 16,45;

Found, C 63,37; H 5,31; N 16,55.

P R I m e R 19. (TRANS)-1-(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzo - Piran-4-yl)-(4-pyridinyl)-urea

A. 4-Nitrophenyl-(4-pyridinyl)-calonego ether Harborview acid (4.3 g, of 21.3 mmol) in methylene chloride (30 ml, followed by addition of pyridine (1.7 g, is 21.3 mmol) under a current of argon. The reaction mixture was allowed to mix at room temperature for 24 hours, the Solid is filtered and washed with methylene chloride to obtain the above-mentioned compound a (5.0 g) as a pale yellow solid.

B. (TRANS)-1-(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)- (4-p

A solution of (TRANS)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1 - benzopyran-6-carbonitrile (1.0 g, 4.6 mmol) (obtained by Evans and others J. Med. Chem. 1983, 26, 1582 and J. Med. Chem. 1986, 29, 2194) in dimethylformamide (10 ml) under a current of argon is treated with the above compound (1.8 g, 6,9 mmol) and the reaction mixture is heated at 50aboutC for 16 h, the Reaction mixture was concentrated under vacuum and the residue diluted with ethyl acetate. The solution was washed with water (3 x 200 ml), saturated sodium bicarbonate solution, water and concentrated under vacuum. The residue is subjected to flash chromatography on silica gel, elwira mixture of acetone/ethyl acetate (1:1) to obtain solid (0.21 g). This solid is ground to powder using ethyl acetate to obtain the above compound (0.18 g) in the form bestv the(singlet, 1H), 7,35 (multiplet, 3H), 6,79 (doublet, J 9.8 Hz, 1H), 6,52 (doublet, J 7.7 Hz, 1H), from 5.29 (singlet, 1H), 4,80 (triplet, J9,4 Hz, 1H), 3,53 (doublet, J 10.0 Hz, 1H), 1,44 (singlet, 3H), 1,22 (singlet, 3H);13C-NMR (CDCl3) : 156,0, 155,7, 149,6, 146,5, 132,1, 124,1, 117,7, 102,9, 79,9, 73,0, 49,6, 26,0, 18,3: IR (KBr) cm-1: 1267,0, and 1334,0 1490,6, 1532,8, 1594,3, 1699,5, 2226,9, 2979,9, 3365,4.

Analysis calculated for C18H18N4O3x x 0,72 H2O, C 61,53; H 5,58; N 15,94

Found, C 61,94; H 5,15, N 15,53.

P R I m e R 20 (-)-N-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1 - benzopyrene-4-yl)-N'-(phenylmethyl)urea

A. N-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)--hydroxybenzeneacetic

In a solution of R-(-)-almond acid (22.1 g, 0.14 mol) and 1-hydroxybenzotriazole hydrate (19.6 g, 0.14 mol), cooled to 0aboutC was added sequentially N-methylmorpholine (16.2 g, 0.16 mol), 4-amino-5-cyano-3,4-dihydro-2,2-dimethyl-2H-1 - benzopyran (29,4 g, 0.14 mol, example 8, part D) and 1-(3-dimethyl+aminopropyl)-2-ethylcarbodiimide, HCl (27.9 g, 0.14 mol).

The reaction mixture was aged for 0.5 h at 0aboutC and 2 h at room temperature. The solvent was removed under vacuum and the residue was divided between 5% aqueous HCl and ethyl acetate. The organic fraction was washed with saturated restore, it was obtained 52 g yellow unreacted residue. Untreated diastereomer mixture was cromatografierea on the silicon dioxide, Luterana 1:1 hexane/ethyl acetate, resulting 23,2 g (47,7%) of isomer A. T. pl. 120-121aboutC []D25-39,5about. 1H NMR (CDCl3) 7, 7,43-7,34 (m, 7H), for 6.81 (D, J to 8.20 Hz, 2H), 5,23, (m, 1H), 5,13 (d, J3,52 Hz, 1H), 4,27 (m, 1H), 2,08 (dd, J 5,86 N, 13,78 Hz, 1H), 1,71 (d, J 12,31 Hz, 1H), 1,42 (S, 3H), of 1.36 (S, 3H),13C-NMR (CDCl3) 173,26, 158,09, 139,60, 133,30, 132,46, 129,27, 129,18, 126,88, 123,39, 19,62, 118,99, 103,64, 77,00, 74,50, 42,33, 39,59, 29,77, 25,05, MS: (M+H)+337.

C. (-)-4-amino-6-cyano-3,4-dihydroxy-2,2-dimethyl-2H-1-benzopyran

A solution of N-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)--hydroxybenzeneacetic (22,3 g, 66,2 mmol isomer from example 19, part a) in a mixture of dioxane (195 ml) and 1.5 M H2SO4(140 ml) was heated at 75-85aboutC for five days. The reaction mixture was concentrated under vacuum and the concentrate was divided between the distillated water and ethyl acetate. The aqueous phase was washed with ethyl acetate, which has an alkaline reaction (pH > 12) adding 50% NaOH solution and the dedicated diethyl ether. The ether extracts were washed with a saturated solution of chloride NAT is I, kristallicheskogo when defending []D25-CHCl3-95,8o. 1H NMR (CDCl3) : 7,86 (S, 1H), 7,40 (dd, J2,35 and 8,80 Hz, 1H), 6,80 (d, J to 8.20 Hz, 1H), was 4.02 (dd, J 5,86 and of 11.14 Hz, 1H), 2,13 (dd, J by 5.87 and 13,49 Hz, 1H), of 1.66 (d, J 11,73 Hz, 1H), (S, 3H), of 1.30 (S, 3H),13C NMR (CDCl3) : 157,14, 132,09, 132,00, 127,48, 119,50, 118,01, 102,96, 76,83, 44,06, 43,77, 29,63, 24,94.

C. (-)-N-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl-N'-(phenylmethyl) urea

A solution of (-)-4-amino-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1 - benzopyran (2.0 g, 9.9 mmol, from example 19, part b) and benzyl isocyanate (1,32 g, 9.9 mmol) in ethanol (15 ml) under argon was heated under irrigation within 2 hours the Solvent was removed under vacuum and the crude product was grinded into powder with isopropyl ether to obtain 2,98 g (89,7%) indicated in the title of a pure white solid connections, so pl. 140-141aboutWITH

[D25, DMF -41,2o,1H NMR (DMSO-d6) : to 7.59 (S, 1H), 7,56 (d, J 1,76 Hz, 1H), 7,38-7,22 (m, 5H), 6.89 in (d, J 8,21 Hz, 1H), 6,56 (t, J by 5.87 Hz, 1H), of 6.49 (d, J 8,79 Hz, 1H), 4,94 (m, 1H), 4,30 (d, J by 5.87 Hz, 1H), 2,11 (dd, J 6,16 and 13.1 Hz, 1H), 1,74 (d, J 12,32 Hz, 1H), 1,41 (S, 3H), of 1.28 (S, 3H).13C NMR (DMSO-d) : 158,19, 157,27, 140,80, 132,25, 132,15, 128,31, 126,98, 126,69, 126,18, 119,28, 118,13, 102,06, 77,37, 43,08, 42,01, 37,80, 29,15, 24,47, MS: (M+S)+G 336

Chemical composition:

Calculated for C20H21N3O2, )% C 71,62; H of 6.31; N 12,53; ylmethyl) urine

A. N-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)--hydroxybenzeneacetic

In a solution of R-(-)-almond acid (22.1 g, 0.14 mol), and 1-hydroxybenzotriazole (19.6 g, 0.14 mmol), cooled to 0aboutC was added sequentially N-methylmorpholine (16.2 g, 0.16 mmol), 4-amino-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1 - benzopyran (29,4 g, 0.14 mmol, from example 8, part D) and 1-(3-dimethylaminopropyl)-2-ethylcarbodiimide, HCl (27.9 g, 0.14 mol).

The reaction mixture was aged for 0.5 h at 0aboutC and 2 h at room temperature. The solvent was removed under vacuum and the residue was divided between 5% aqueous HCl and ethyl acetate. The organic fraction was washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo, there was obtained 52 g yellow unreacted residue. Untreated diastereomer mixture was cromatografierea on the silicon dioxide, buyowner 1:1 hexane/ethyl acetate, resulting 19,8 g (40,6%) of isomer (isomer As discussed in example 19, part a), so pl. 135-136aboutC. []D25-60,8about,1HNMR (CDCl3) : 7,51-7,30 (m, 6H), 7,27 (d, J 1,76 Hz, 1H), 6,80 (m, 2H), by 5.18 (m, 1H),) 172,59, 157,53, 139,13, 133,07, 132,81, 131,98, 128,92, 126,38, 122,86, 118,97, 118,56, 103,25, 76,83, 74,26, 41,81, 38,96, 29,15, 24,62, MS: (M+H)+G 337.

C. (+)-4-amino-6-cyano-3,4-dihydroxy-2,2-dimethyl-2H-1-benzopyran

A solution of N-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)- -hydroxybenzamide (18,8 g of 55.9 mmol isomer, from example 20, part a) in a mixture of dioxane (163 ml) and 1.5 M H2SO4(116 ml) was heated at 75-85aboutC for 5 days. The reaction mixture was concentrated under vacuum and the concentrate was divided between distilled water and ethyl acetate. The aqueous phase was washed with ethyl acetate, which has an alkaline reaction (pH > 12) adding 50% NaOH solution and the dedicated diethyl ether. The ether extracts were washed with saturated salt solution, dried over sodium sulfate and evaporated in vacuum to obtain 8.90 g (72%) of a yellow oily compound, kristallicheskogo when defending.

[]D25CHCl3+95,4o, 1HNMR (CDCl3) : 7,86 (S, 1H), 7,40 (dd, J 2.35 and 8,80 Hz, 1H), 6,80 (d, J to 8.20 Hz, 1H), was 4.02 (dd, J 5,86 and of 11.14 Hz, 1H), 2,13 (dd, J by 5.87 and 13,49 Hz, 1H), of 1.66 (d, J 11,73 Hz, 1H), 1,46 (S, 3H), of 1.30 (S, 3H);13CNMR (CDCl3) 157,14, 132,09, 132,00, 127,48, 119,50, 118,01, 102,97, 76,83, 44,06, 43,77, 29,63, 24,94.

C. (+)-N-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)-N'-(phenylmethyl) urine

A solution of (+is, 9.9 mmol) in ethanol (15 ml) under argon was heated under irrigation within 2 hours the Solvent was removed under vacuum and the crude product was rubbed with isopropyl ether to obtain and 2.79 g (84%) of pure white solid compound mentioned in the title. So pl. 135-137aboutC []D25-DMF +41,9o.1HNMR (DMSO-d6) : to 7.59 (S, 1H), 7,56 (d, J 1,76 Hz, 1H), 7,38-7,22 (m, 5H), 6.89 in (d, J 8,21 Hz, 1H), 6,56 (t, J by 5.87 Hz, 1H), of 6.49 (d, J 8,79 Hz, 1H), 4,94 (m, 1H), 4,30 (d, J by 5.87 Hz, 1H), 2,11 (dd, J 6,16 and 13.19 Hz, 1H), 1,74 (d, J 12,32 Hz, 1H), 1,41 (S, 3H), of 1.28 (S, 3H),13CNMR (DMSO-d) : 158,19, 157,27, 140,80, 132,25, 132,15, 128,31, 126,98, 126,69, 126,18, 119,28, 118,13, 102,06, 77,37, 43,08, 42,01, 37,80, 29,15, 24,47; MS: (M+H)+G 336.

Chemical composition:

Calculated for C20H21N3O2C 71,62; H OF 6.31; N 12,53

Found, C 71,67; H 6,30; N 12,32. 128,31, 126,98, 126,69, 126,18, 119,28, 118,13, 102,06, 77,37, 43,08, 42,01, 37,80, 29,15, 24,47, MS: (M+S)+G 336

Chemical composition:

Calculated for C20H21N3O2C 71,62; H OF 6.31; N 12,53;

Found, C 71,60; H 6,28; N 12,21.

P R I m e R 21. (+)-N-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)-N'-(phenylmethyl) urine

A. N-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)--hydroxybenzeneacetic

In a solution of R-(-)-almond acid (22.1 g, 0.14 mol), and 1-hydroxybenzotriazole is, -amino-6-cyano-3,4-dihydro-2,2-dimethyl - 2H-1 - benzopyran (29,4 g, 0.14 mmol, from example 8, part D) and 1-(3-dimethylaminopropyl)-2-ethylcarbodiimide, HCl (27.9 g, 0.14 mol).

The reaction mixture was aged for 0.5 h at 0aboutC and 2 h at room temperature. The solvent was removed under vacuum and the residue was divided between 5% aqueous HCl and ethyl acetate. The organic fraction was washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo, there was obtained 52 g yellow unreacted residue. Untreated diastereomer mixture was cromatografierea on the silicon dioxide, buyowner 1:1 hexane/ethyl acetate, resulting 19,8 g (40,6%) of isomer (isomer As discussed in example 19, part a), so pl. 135-136aboutC. []D25-60,8about,1H NMR (CDCl3) : 7,51-7,30 (m, 6H), 7,27 (d, J 1,76 Hz, 1H), 6,80 (m, 2H), by 5.18 (m, 1H), 5,08 (d, J 2,93 Hz, 1H), 3,97 (d, J 2,93 Hz, 1H), 2,12 (dd, J 6,15 and 13.19 Hz, 1H), 1.69 in (dd, J 11,43 and 13,20 Hz, 1H), 1,40 (S, 3H), of 1.30 (S, 3H),13C NMR (CDCl3) : 172,59, 157,53, 139,13, 133,07, 132,81, 131,98, 128,92, 126,38, 122,86, 118,97, 118,56, 103,25, 76,83, 74,26, 41,81, 38,96, 29,15, 24,62, MS: (M+H)+G 337.

C. (+)-4-amino-6-cyano-3,4-dihydroxy-2,2-dimethyl-2H-1-benzopyran

A solution of N-(6-cyano-3,4-digits dioxane (163 ml) and 1.5 M H2SO4(116 ml) was heated at 75-85aboutC for 5 days. The reaction mixture was concentrated under vacuum and the concentrate was divided between distilled water and ethyl acetate. The aqueous phase was washed with ethyl acetate, which has an alkaline reaction (pH > 12) adding 50% NaOH solution and the dedicated diethyl ether. The ether extracts were washed with saturated salt solution, dried over sodium sulfate and evaporated in vacuum to obtain 8.90 g (72%) of a yellow oily compound, kristallicheskogo when defending.

[]D25CHCl3+95,4o,1H NMR (CDCl3) : 7,86 (S, 1H), 7,40 (dd, J 2.35 and 8,80 Hz, 1H), 6,80 (d, J to 8.20 Hz, 1H), was 4.02 (dd, J 5,86 and of 11.14 Hz, 1H), 2,13 (dd, J by 5.87 and 13,49 Hz, 1H), of 1.66 (d, J 11,73 Hz, 1H), 1,46 (S, 3H), of 1.30 (S, 3H);13C NMR (CDCl3) 157,14, 132,09, 132,00, 127,48, 119,50, 118,01, 102,97, 76,83, 44,06, 43,77, 29,63, 24,94.

C. (+)-N-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)-N'-(phenylmethyl) urea

A solution of (+)-4-amino-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1 - benzopyran (2.0 g, 9.9 mmol, from example 20, part b) and benzyl isocyanate (1,32 g, 9.9 mmol) in ethanol (15 ml) under argon was heated under irrigation within 2 hours the Solvent was removed under vacuum and the crude product was rubbed with isopropyl ether to obtain and 2.79 g (84%) SUP>1H NMR (DMSO-d6) : to 7.59 (S, 1H), 7,56 (d, J 1,76 Hz, 1H), 7,38-7,22 (m, 5H), 6.89 in (d, J 8,21 Hz, 1H), 6,56 (t, J by 5.87 Hz, 1H), of 6.49 (d, J 8,79 Hz, 1H), 4,94 (m, 1H), 4,30 (d, J by 5.87 Hz, 1H), 2,11 (dd, J 6,16 and 13.19 Hz, 1H), 1,74 (d, J 12,32 Hz, 1H), 1,41 (S, 3H), of 1.28 (S, 3H),13C NMR (DMSO-d) 158,19, 157,27, 140,80, 132,25, 132,15, 128,31, 126,98, 126,69, 126,18, 119,28, 118,13, 102,06, 77,37, 43,08, 42,01, 37,80, 29,15, 24,47; MS: (M+H)+G 336.

Chemical composition:

Calculated for C20H21N3O2C 71,62; H OF 6.31; N 12,53;

Found, C 71,67; H 6,30; N 12,32.

P R I m e R 22. 3,4-Dihydro-2,2-dimethyl-4-(2-oxo-3-phenyl-1-imidazolidinyl)-2H-1 - benzopyran-6-carbonitrile

A. N-(6-cyano-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl)-N'-phenylethylene - min

A solution of 4-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-2H-benzopyran (0.75 g, 2.82 mmol, from example 8, part b) and N-phenylethylenediamine (8,84 g, 10%) containing NaHCO3(2,40 g, 5%) in N,N-dimethylformamide (15 ml) was maintained for 48 h at room temperature.

The reaction mixture was partitioned between ethyl acetate and distilled H2O. the Organic phase was washed with distilled water, saturated NaCl solution, dried over Na2SO4and evaporated in vacuum to obtain 3,71 g orange neproreagirovavshikh balance. The crude product was chromatographia dioxide of silicon, e is the melting.

1H NMR (CDCl3) : to $ 7.91 (S, 1H), 7,38 (dd, J 2,34 and 8,79 Hz, 1H), 7,19 (m, 2H), 6,79 (d, J8,21 Hz, 1H); 6,70 (m, 3H), a 3.87 (dd, J 5,86 and of 11.14 Hz, 1H), 3,26 (m, 2H), 3,10 (m, 1H), 2,86 (m, 1H), measuring 2.20 (dd, J by 5.87 g and 12,90 Hz, 1H), 1,58 (d, J 12,30 Hz, 1H), 1,45 (S, 3H), of 1.27 (S, 3H);13C NMR (CDCl3) : 157,63, 148,16, 132,40, 132,09, 129,21, 125,32, 119,56, 118,09, 117,52, 112,97, 102,89, 76,83, 49,24, 44,89, 44,00, 39,25, 29,69, 24,96; MS: (M+H)+G 332.

C. 3,4-dihydro-2,2-dimethyl-4-(2-oxo-3-phenyl-1-imidazolidinyl)- 2H-1-benzopyran-6-carbonitrile

To a solution of N-(6-cyano-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4 - yl)-N'-phenylethylenediamine (0.36 g, 1.12 mmol, from example 21, part a) and triethylamine (0.12 g, 1.18 mmol) in methylene chloride (4 ml) cooled to 0aboutC, was added a solution of 4-nitrophenyl chloroformate (0.24 g, 1.18 mmol), dissolved in methylene chloride (3 ml). The reaction mixture was maintained at room temperature for 4 hours the Solvent was evaporated in vacuum and the residue was divided between ethyl acetate and 5% aqueous HCl solution. The organic phase was washed with 2n. NaOH solution, saturated NaCl solution, dried over MgSO4and the solvent evaporated to obtain 420 mg orange unreacted residue. The crude product was chromatographia on the silicon dioxide, buyowner hexane/ethyl acetate (4:1) to obtain a 0.30 g of pure white solid which, 1H), 3,88 (m, 2H), 3,36 (m, 1H), 3,14 (m, 1H), 2,03 (m, 2H), 1,47 (S, 3H), of 1.33 (S, 3H);13C NMR (DMSO-d6) : 158,08, 157,13, 140,58, 132,86, 131,56, 128,63, 121,86, 121,63, 119,15, 118,52, 117,05, 102,54, 77,31, 44,68, 42,06, 36,56, 34,06, 29,36, 24,01; MS: (M+H)+G 348.

Chemical composition:

Calculated for C21H21N3O20,2 H2O, C 71,87; H 6,14; N OF $ 11.97;

Found, C 71,97; H 6,04; N, 11.87 Per.

P R I m e R 23. 3,4-Dihydro-2,2-dimethyl-4-(2-oxo-3-phenylmethyl)-1-imidazolidinyl-2H-1-benzop Iran

A. N-(6-Cyano-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl)-N - benzylethanolamine

A solution of 4-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (1.50 g, 5,64 mmol, from example 8, part b) and N-benzylethanolamine (8,48 g, 10%) containing NaHCO3(4,80 g, 5%) in N,N-dimethylformamide (30 ml) was maintained for 48 h at room temperature. The reaction mixture was partitioned between ethyl acetate and distilled water. The organic phase was washed with distilled water, saturated NaCl solution, dried over Na2SO4and evaporated in vacuum to obtain 4,10 g of an orange oily substance. The crude product was chromatographia on the silicon dioxide, buyowner 9: 1 methylene chloride/methanol (traces of NH4OH) to obtain 0,91 g (48%) of colorless compounds.

1H NMR (CDCl313C NMR (CDCl3) : 157,66, 139,89, 132,52, 132,03, 128,43, 128,14, 127,05, 126,55, 119,65, 118,06, 102,89, 76,86, 53,77, 49,38, 49,01, 45,32, 39,25, 36,40, 29,72, 25,02; MS: (M+H)+G 334.

C. 3,4-Dihydro-2,2-dimethyl-4-(2-oxo-3-(phenylmethyl)-1 - imidazolidinyl)-2H-1-benzopyran-6-carbonitrile

To a solution of N-(6-cyano-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4 - yl)-N'-benzylideneaniline (0,91 g, a 2.71 mmol, from example 22, part a) and 4-nitrophenyl chloroformate (0,57 g, to 2.85 mmol) in methylene chloride (22.5 ml), cooled to 0aboutC, was added pyridine (0.27 g, 3,39 mmol). The reaction mixture was maintained at room temperature for 24 h, was diluted with methylene chloride and washed with 5% HCl, 2N NaOH solution and saturated NaCl solution. The extract was dried over MgSO4and evaporated in vacuum to obtain 1,32 g orange unreacted residue. The crude product was chromatographia on the silicon dioxide, buyowner hexane/ethyl acetate (3:2) to obtain 0.65 g (66%) of compound as a colorless amorphous solid. So pl. 45-48aboutC,1H NMR (CDCl3) : 7,51-7,39 (m, 7H), 6,93 (d, J 9,38 Hz, 1H), 5,43 (dd, J7,03 and of 11.14 Hz, 1H), 4,55 (m, 2H), 3,36-3,20 (m, 3H), 3,05 (m, 1H), 1,99 (m, 2H), 1,59 (S, 3H), 1,45 (S, 3H).

13C NMR (CDCl3) : 160,77, 158,29, 136,70, 132,49, 131,66, 128,60, 128,03, 127,48, 121,38, 119,16, 118,61, 103,29, 76,94, 48,17, 45,15, 41,90, 37,26, 34,96, 34,67, 29,75, 24,012
O, C 72,35; H 6,46; N 11,50;

Found, C 71,55; H Of 6.31; N 11,30.

P R I m e R 24. Methyl ester of (3S-TRANS)-3-((((6-cyano-3,4 - dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)amino) carbonyl)amino)benzoxazol acid.

A. Hydrochloride methyl ester 3-amino phenylacetic acid.

A suspension of 3-amino phenylacetic acid (5.0 g, 33 mmol) in methanol (50 ml) at 0aboutWith under argon was slowly treated with thionyl chloride (19,4 g, 165 mmol). After adding the reagent, the mixture was left to warm to room temperature and incubated 16 hours the Solvent was evaporated, and the residue was ground into powder with a complex of ethyl ether to obtain the hydrochloride of the methyl ester of 3-amino phenylacetic acid as colorless solid (5.3 g, 96.8 per cent).

1H NMR (CDCl3) : 10,6 (S, 2H), 7,42 (m, 4H), 3,68 (S, 3H), 3,66 (S, 2H),13C NMR (CDCl3) 172,5, 137,3, 133,1, 131,2, 130,8, 125,9, 123,7, 53,5, 41,5.

Century Methyl ester 3((((4-nitrophenyl)oxy) carbonyl)amino)-benzooxazol acid

In a suspension of the hydrochloride of the methyl ester of 3-aminophenylacetic acid (1.7 g, 10 mmol) in methylene chloride (30 ml) was added pyridine (0,79 g, 10 mmol), followed by adding a solution of 4-nitrophenylphosphate (4.3 g, is 21.3 mmol) in m which was washed with water (100 ml), 10% sodium hydroxide (100 ml), water (1100 ml) and dried over anhydrous magnesium sulfate and concentrated in vacuum. The residue was powdered with complex isopropyl ether to obtain methyl ester 3((((4-nitrophenyl)oxy)-carbonyl)-amino)benzoxazol acid (1.8 g, 53%) as a yellow, low-viscosity solids.

C. the Methyl ester of (3S-TRANS)-3-((((6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl - 2H-1-benzopyran-4-yl)amino)-carbonyl)AMI - no - benzoxazol acid

A solution of (TRANS)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1 - benzopyran-6-carbonitrile (1.0 g, 4.6 mmol) in acetonitrile (30 ml) under argon was treated with methyl ether 3((((4-nitrophenyl) oxy)-carbonyl)-amino)benzoxazol acid (1.7 g, 5.2 mmol) and the reaction mixture was heated at 80aboutC for 16 h, the Reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate. It was washed with 10% hydrochloric acid (100 ml), water (100 ml) and concentrated in vacuo. The residue was instantly chromatographia on silica gel, buyowner acetone/methylene chloride (2: 8) to obtain methyl ester of (3S-TRANS)-3-((((6-cyano-3,4-dihydro-3-hydroxy - 2,2-dimethyl-2H-1-benzopyran-4-yl)amino)carbonyl)amino) benzoxazol acid 2H), 7,34 (m, 1H), was 7.08 (d, J 8.2 Hz, 1H), 6,99 (m, 1H), 6.75 in (d, J 8.2 Hz, 1H), 5,85 (d, J 5.3 Hz, 1H), a 4.83 (m, 1H), 3,76 (S, 4H), and 3.5 (S, 2H), 1.57 in (S, 3H), of 1.35 (S, 3H);13C NMR (CDCl3) 171,9, 156,6, 156,0, 140,7, 135,1, 132,9, 129,0, 126,3, 122,6, 119,4, 118,9, 116,7, 102,9, 80,6, 71,7, 51,9, 49,7, 26,8, 19,2; 1R (KBr) 1132,2, 1267,4, 1491,6, 1559,5, 1611,4, 1659,3, 1734,3, 2226,2, 2980,1, 3385,0 cm-1. []D25= -4,4about(0,525, DMF).

Chemical composition:

Calculated for C22H23N3O5C 64,54; H 5,66; N 10,26;

Found, C 64,36; H Of 5.84; N 10,01.

P R I m e R 25. (3S-TRANS)-3-((((6-cyano-3,4-dihydro-3-hydroxy - 2,2-dimethyl-2H-1-benzopyran-4-yl)amino)carbonyl)amino) benzocaine acid

A solution of methyl ester of (3S-TRANS)-3-((((6-cyano-3,4-dihydro-3 - hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)amino)-Carbo - nil)amino) benzoxazol acid (0.7 g, 1.7 mmol, compound of example 24) in methanol (15 ml) under argon was treated with hydrate of lithium hydroxide (0.14 g, 3.4 mmol) and the reaction was maintained at room temperature for 16 hours After adding a small amount of lithium hydroxide (2 EQ.), the reaction mixture was maintained 48 hours It was concentrated in vacuo, the residue was diluted with water (50 ml) and extracted with ethyl acetate. The organic layer was discarded and the aqueous layer was acidified to rn% hydrochloric acid and extracted atilas the n on silica gel, buyowner methylene chloride (methanol/acetic acid (1800:200:5) to obtain (3S-TRANS)-3-((((6-cyano-3,4-dihydro - 3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)- amino)carbonyl)amino) benzoxazol acid as a colorless solid (0.5 g, 73,9%), so pl. 135-138about(With foaming):1H NMP (DMSO-d6) : 8,76 (S, 2H), 7.62mm (m, 2H), 7,42 (m, 2H), 7,25 (m, 2H), of 6.96 (d, J8,3 Hz, 1H), make 6.90 (d, J 7.0 Hz, 1H), 6,70 (d, J 8.2 Hz, 1H), 4,77 (m, 2H), 3,76 (m, 2H) and 1.51 (S, 3H), of 1.28 (S, 3H); 13C NMR (CDCl3) 172,8, 156,3, 155,9, 140,3, 135,6, 132,7, 132,4, 128,6, 126,0, 122,4, 119,1, 118,8, 117,9, 116,2, 102,7, 80,3, 71,6, 49,4, 26,5, 18,9; 1R (KBr) 1132,1, 1267,2, 1491,3, 1491,3, 559,3, 1611,2, 1659,3, 1713,2, 2228,1, 2980,1, 3379,0 cm-1; []D25-6,7about(0,683, DMF).

Chemical composition:

Calculated for C21H21N3O50,42 H2O, C 62,59; H 5,46; N 10,43;

Found, C 62,97; H 5,46; N Of 10.05.

1. DERIVATIVES BENZOPYRAN General formula

< / BR>
where R1is phenyl or substituted phenyl, phenylalkyl or six-membered heterocycle containing as the heteroatom nitrogen atoms;

R2hydrogen, hydroxy or the group

< / BR>
R3and R4each alkyl;

R5haloalkyl, cyano;

Y group N R8or

< / BR>
R7and R8each hydrogen or R7+ R8- membered nitrogen-containing, heterotic is ASEE heterocyclic ring;

X is oxygen or sulfur;

R10hydrogen, alkyl, alkoxy or oxygraph.

2. Connection on p. 1, representing (TRANS)-1-6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl - 2H-1-benzopyran-4-yl)-3-phenylacetone.

3. Connection on p. 1, representing (TRANS)-1-(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran - 4-yl)-3-phenyltoloxamine.

4. Connection on p. 1, representing TRANS-N-(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)-benzoylacetone.

5. Connection on p. 1 representing [3R-[3,4-(SW)]] -N-(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) -- hydroxyindolacetic.

6. Connection on p. 1 representing [3S-[3,4 - (RW)] -N- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl - 2H-1-benzopyran-4-yl)- -hydroxyindolacetic.

7. Connection on p. 7, predstavlyayuschee a [3S-[3,4- (SW)]-N- (6-cyano-3,4-dihydro-3-hydroxy - 2,2-dimethyl-2H - 1-benzopyran-4-yl)- hydroxyindolacetic.

8. Connection on p. 1 representing [3R-[3,4(RW)]]- -(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) -- hydroxyindolacetic.

9. Connection on p. 1, representing N-(6-cyano-3,4-dihydro - 2,2-is-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl) -N- (phenylmethyl)-urea.

11. Connection on p. 1, representing (TRANS)-1- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)-3-(phenylmethyl)-urea.

12. Connection on p. 1, representing (TRANS) -N-[3-(atomic charges)-6 - cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl] -N - phenylacetone.

13. Connection on p. 1, representing (TRANS)-1-(6-acetyl-3,4 - dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)-3-phenylacetone.

14. Connection on p. 1, representing (TRANS)-3,4-dihydro-3-hydroxy-2,2-dimethyl - 4-(2,3-dihydro-2-oxo-1H-benzimidazole-1 - yl)-2H-1-benzopyran-6-carbonitrile.

15. Connection on p. 1, representing (TRANS)-1-(6-cyano-3,4-dihydro-3-hydroxy - 2,2-dimethyl-2H-1-benzopyran-4 - yl)-(3-pyridinyl)-urea.

16. Connection on p. 1, representing (TRANS)-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(2-oxo-3-phenyl-1-imidazolidinyl) -2H-1-benzopyran-6-carbonitrile.

17. Connection on p. 1, representing (CIS)-1-(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-3-hydroxy-2,2-dimethyl-2H-1 - benzopyran-4-yl)-3-phenyl-urea.

18. Connection on p. 1, representing (TRANS)-N-[3,4-dihydro-3-hydroxy-2,2 - dimethyl-6-(trifluoromethyl)-2H-1-benzopyran-4-yl]-N - phenylacetone.

19. Link)-urea.

20. Connection on p. 1, representing (TRANS)-1-(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)-(-4-pyridinyl)-urea.

21. Connection on p. 1, representing a [-]-N-[6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl] -N -[phenylmethyl]-urea.

22. Connection on p. 1, representing the (+)-N-(6-cyano-3,4-dihydro-2,2 - dimethyl-2H-1-benzopyran-4-yl] -N- [phenylmethyl)-urea.

23. Connection on p. 1, which represents a 3,4-dihydro-2,2-dimethyl-4-[2-oxo-3-phenylmethyl]- 1-imidazolidinyl-2H-1-benzopyran-6-carbonyl.

24. Connection on p. 1 represents methyl ether [3S-TRANS]-3- [[[[6-cyano-3,4-dihydro-3 - hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl]amino] carbonyl]amino]benzoxazol acid.

25. Connection on p. 1 representing [3S-TRANS]-3-[[[[6-cyano-3,4-dihydro-3-hydroxy-2,2 - dimethyl-2H-1-benzopyran-4-yl] amino]carbonyl] amino]benzoxazol acid.

 

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FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzopyrane of the formula (I): wherein each R1 and R2 represent independently (C1-C6)-alkyl group; R3 represents hydroxyl group; R4 represents hydrogen atom; R6 represents hydrogen atom; R7 represents hydrogen atom; X is absent or represents C=O; R8 represents hydrogen atom or (C1-C6)-alkyl group; R9 represents nitro-group; Y represents (C3-C8)-alkylene group, group -(CH2)m-CR11R12-(CH2)n- wherein M and n are equal and each means independently 0, 1, 2, 3 or 4; m + n = 2 or above; when m = 0 then each R11 and R12 represents independently (C1-C6)-alkyl group or hydroxyl group; Y represents group -(CH2)o-O-(CH2)p- wherein o and p are equal and each means independently 2, 3 or 4; R5 represents hydrogen atom, amino-group, (C1-C6)-alkoxy-group, (C3-C8)-cycloalkyl group, (C1-C6)-alkylthio-group, (C1-C6)-alkylamino-group, di-(C1-C6)-alkylamino-group, (C1-C6)-alkoxycarbonylamino-group, and to their pharmaceutically acceptable salts, and to an anti-arrhythmic agent.

EFFECT: valuable medicinal properties of derivatives.

7 cl, 1 tbl, 9 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to derivatives of benzopyrane of the formula (1)

or the formula (2) ,

wherein each R1 and R2 means independently of one another hydrogen atom; R3 means hydroxyl group; R4 means hydrogen atom; R5 means (C1-C6)-alkyl group substituted with (C6-C14)-aryl group wherein indicated (C1-C6)-group can be substituted optionally with hydroxyl, methyl group and indicated (C6-C14)-aryl group can be substitute optionally with 1-3 radicals R7 (wherein R7 represents halogen atom or amino-group) or linear (C5-C8)-alkyl group; R6 means (C1-C6)-alkyl group (wherein indicated alkyl group can be substituted optionally with hydroxyl or amino-group), halogen atom, nitro-group or -C(O)NH2 but excluding compound of the formula (1) wherein R means -NO2 at position 6; R5 means -CH2CH2Ph, and R1 and R2 mean methyl group, and compound of the formula (1) wherein R6 means bromine atom at position 6; R5 means benzyl and R1 and R2 mean methyl group, or their pharmaceutically acceptable salts, and a pharmaceutical preparation based on thereof. Proposed compounds are useful as anti-arrhythmic agents.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 7 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: invention concerns novel amidomethyl-substituted derivatives of 2-(4-sulfonylamino)-3-hydroxy3,4-dihydro-2N-chromen-6-yl of the general formula (I) where R1 is C1-C4alkyl, R2 is C1-C4alkyl, R3 is phenyl optionally once or twice substituted or substituted by halogen, C1-C4alkyl, C1-C4alkoxy group or trifluoromethyl, naphthyl or biphenyl, R4 is hydrogen, C1-C6alkyl or C3-C7cycloalkyl-C1-C4alkyl, R5 is hydrogen, and R6 is C1-C6 alkyl, phenyl-C1-C4alkyl, phenyl group optionally substituted by halogen, furyl-C1-C4alkyl or tetrahydronaphthyl, or R5 and R6 together with nitrogen atom linking them form piperazine ring optionally substituted by phenyl.

EFFECT: also invention claims method of obtaining claimed compounds, and intermediary products used in method implementation, as well as medicines containing compounds of the formula (I) with antiarrhythmic effect, and application of these medicines.

11 cl, 6 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention refers to the new benzopyran derivatives of formula (I) whereat X is NR6, R6 is hydrogen atom r C1-4-alkyl group; Y is bond SO, SO2; Z is C1-4-alkyl group (whereat C1-4-alkyl group can be arbitrary substituted with 1-5 atoms of halogen) or phenyl group (whereat phenyl group can be arbitrary substituted with C1-4-alkyl group); W is hydrogen atom, halogen atom, hydroxy group, C1-6-alkoxygroup, C1-4-alkyl group, C1-6-alkyl sulphonylamino group; R1 and R2 independently of each other represent C1-3-alkyl group; R3 is hydrogen atom, hydroxy group or methoxy group; m is integer number from 0 to 4; n is integer number from 0 to 4; V is ordinary bond; R4 is hydrogen or C1-6-alkyl group; and R5 is - hydrogen atom,- C1-6-alkyl group,- C3-8-cycloalkyl group or C3-8-cycloalkenyl group or - C6-14-aryl group (whereat every C6-14-aryl group can be arbitrary substituted with 1-3 R12 whereat R12 is halogen atom) and pharmaceutical composition thereof.

EFFECT: compounds are applicable as antiarrhythmic drug.

27 cl, 60 tbl, 20 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new chroman derivatives of formula I: , or to their pharmaceutically acceptable salts where m has a value of 0; p has a value of 2; q has a value of 2; Ar represents phenyl optionally substituted with halogen atom; R2 represents ; X represents -NR9-; n has a value of 2 or 3; each R3, R4, R5 and R6 independently represents hydrogen or C1-12alkyl; each R7 and R8 independently represents either hydrogen, or C1-12-alkyl, or R7 and R8 together with nitrogen whereto attached, can form 4-6-members ring, or one of R7 and R8 and one of R5 and R6 together with atoms whereto attached can form 4-6-members ring; and R9 represents hydrogen or C1-12-alkyl, or when R7 represents hydrogen or methyl, R9 together with R8 and atoms whereto attached can form 6-members ring.

EFFECT: preparation of chroman new derivatives and the pharmaceutical composition containing compounds of formula (I).

22 cl, 1 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of general formula in which R1 stands for C1-C4-alkyl; R2 stands for C1-C4-alkyl; R3 stands for phenyl, which optionally contains 1-3 any substituents, selected from the group, including halogen, C1-C6-alkyl and C1-C4-alkoxygroup; R4 stands for hydrogen; C1-C6-alkyl or C3-C7-cycloalkyl -C1-C4-alkyl, R5 stands for hydrogen; and R6stands for hydrogen; and R7 stands for hydrogen; and R9 stands for C1-C4-alkyl; and R10 stands for C1-C6-alkyl, phenyl-C0-C4-alkyl or pyridinyl-C0-C4-alkyl; on condition that R10 does not stand for phenyl, if R5 and R9 together form C2-alkylene; or R5 R9 together form C1-C3-alkylene; or R6 and R9 together form C1-C3-alkylene; or R7 and R9 together form C2-C4-alkylene or C1-C3-alkyleneoxygroup; or R8 and R9 together form C3-C5-alkylene; or R9 and R10 together form C4-C6-alkylene; and n equals 0 or 1, or its any physiologically compatible salts. In addition, the invention relates to pharmaceutical composition, containing formula I compounds and intended for treatment of cardio-vascular diseases, to application of said compounds for preparation of medication, as well as to method of obtaining formula I compounds.

EFFECT: obtained and described are novel compounds, possessing cardio-vascular activity.

16 cl, 8 ex, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: given invention refers to arylamines of formula (I) and their pharmaceutically acceptable salts which are active in relation to 5HT receptors, particularly show 5-HT6 modulating activity, and can be used for treating a number of diseases, such as obesity, or the other diseases, for treating 5-HT-associated condition selected from a group containing Alzheimer's disease, Hundington's disease, obesity, obesity-related disorder, insulin-independent diabetes, Alzheimer's disease related cognitive disorders, schizophrenia related cognitive disorders, reflux gastroesophagitis, non-ulcer dyspepsia, depression, anxiety, migraine, gastritis, gastric emptying disorder, eating disorders, gastrointestinal disorders, constipations, panic attacks, memory impairment, disturbed sleep, alcohol-use disorders, anorexia, bulimia, obsessive-compulsive disorders, psychosis, Parkinson's disease, Hundington's chorea, and/or schizophrenia, drug abuse and attention deficit/hyperactivity disorder (ADHD). In the compound of formula (I) n means 1; A means C1-C3alkylene; R1 means hydrogen or C1-C10alkyl; R2 means C1-C10alkoxy, C(O)CF3 or SO2R6, where R6 can be C1-C4 alkyl R3 and R4 independently means hydrogen, substituted or unsubstituted C1-C7alkyl, where a substituted is selected from dihydrobenzodioxidine or benzodioxole, probably substituted by halogen; phenyl, probably substituted by C1-C4alkyl, C1-C4alkoxy, halogen, trifluoromethyl; aryl selected form naphthyl or tetrahydronaphthyl, optionally substituted by C1-C4alkyl, C1-C4alkoxy; heteroaryl, 5-members heteroaryl condensed with the benzoic ring with sulphur atom as a heteroatom, chromanyl probably substituted by halogen; B means a bound; and X and Y means -CH-.

EFFECT: preparing pharmaceutically acceptable salts which are active in relation to 5HT receptors.

59 cl, 9 dwg, 1 tbl, 57 ex

FIELD: color-forming compositions and recording material.

SUBSTANCE: claimed composition includes developer containing urea-urethane compound and colorless or light colored leuco dye. Recording material based on this composition also is proposed.

EFFECT: color-forming compositions with improved image conservation ability and increased image intensity.

21 cl, 14 tbl, 153 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 1-arenesulfonyl-2-arylpyrrolidine and piperidine of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C7)-alkyl; R2 means furyl, thienyl, pyridyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, cyano-group, CF3 or -N(R4)2; R3 means naphthyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, acetyl, cyano-group, hydroxy-(C1-C7)-alkyl, -CH2-morpholine-4-yl, (C1-C7)-alkyloxy-(C1-C7)-alkyl, (C1-C7)-alkyl-N(R4)2 or CF3; R4 means independently of one another hydrogen atom (H), (C1-C7)-alkyl with exception for (RS)-2-phenyl-1-(toluene-4-sulfonyl)pyrrolidine, (RS)-1-(toluene-4-sulfonyl)-2-p-tolylpyrrolidine, N-tosyl-cis-3-methyl-2-phenylpyrrolidine, 3-[1-(toluene-4-sulfonyl)pyrrolidine-2-yl]pyridine and N-tosyl-2-(3,4-dimethoxyphenyl)pyrrolidine, and their pharmaceutically acceptable salts also. Compounds of the formula (I) elicit the effect of agonists or antagonists of metabotropic glutamate receptors that allows their using in pharmaceutical agent useful for treatment or prophylaxis of acute and/or chronic neurological disturbances.

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 3 sch, 94 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: 5-aryl-1H-1,2,4-triazole derivatives of general formula I

, pharmaceutically acceptable salts thereof or pharmaceutical composition containing the same are described. In formula R1 is C1-C6-alkyl, C1-C6-haloalkyl or phenyl; R2 is C3-C8-cycloalkyl; phenyl optionally substituted with one or more substituents selected from C1-C4-alkyl; halogen, hydroxyl, C1-C4-alkoxy, nitro, di-(C1-C4)-alkylamino, C1-C4-alkylsulphonyl, C1-C4- alkylsulphonylamino, and methylenedioxy; phenyl-(C1-C4)-alkyl, wherein phenyl is substituted with C1-C4-alkoxy; or pyridil. New compounds are effective and selective cyclooxygenase-2 (COX-2) inhibitors and useful in treatment of inflammations.

EFFECT: new compounds for inflammation treatment.

10 cl, 36 ex, 1 tbl

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new stable crystalline forms of derivative of pyrimidine nucleoside of the formula (I) eliciting the excellent anti-tumor activity. Also, invention relates to pharmaceutical composition eliciting an anti-tumor effect, applying crystalline form for preparing medicinal agent and to a method for prophylaxis or treatment of tumor diseases.

EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of derivative.

10 cl, 2 tbl, 4 dwg, 9 ex

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