Oxycarbonate and oxycarbonate

 

(57) Abstract:

Usage: in medicine. The inventive product oxycarbonate and oxycarbonate total f-ly I: Y-C(R1)N-O-C(O)-R2R- (C3-C5)-alkyl: (C3-C7-cycloalkyl: bicycloheptene, R1C6H4-O-CH2-(CH2)n-lower alkyl or the group; C6H4-(CH2)O R2-amino-, phenylamino-, lower alkylamino-, lower alkoxy-, fenoxaprop: n=1-4; q=1-4. table 2.

The invention relates to new oxycarbonate and oxycarbonate with bronchodilators (bronchodilatory and anti-inflammatory effect and is used to treat asthma.

Asthma is a disease in which respiratory distress syndrome is the result of narrowing of the Airways. This narrowing is caused mainly by: 1) a sharp reduction in respiratory smooth muscle surrounding the Airways; 2) chronic inflammatory process in the lungs. Tools that relieve bronchospasm, and prevent inflammation of the lungs, are effective for soothing symptoms of asthma.

One approach to relieve bronchospasm, and inhibition of inflammation is avelorn muscles and cells of inflammation, respectively. Tools that increase the concentration of camp in smooth muscle, causing rapid bronchodilator effect and inhibit the secretion of inflammatory mediators from activated leukocytes (cm; Hardman, "Smooth musculature; Evaluation of modern knowledge", a Publication of the University of Texas (1981); Nelson, etc. American Review of Respiratory Diease, 1988, 137, 25). Thanks to the dual mechanism of their action, these compounds should be highly effective anti-asthmatic drugs.

The concentration of camp in the cell is determined, on the one hand, the speed of its synthesis under the action of adenylate cyclase, and, on the other hand, the rate of its degradation by phosphodiesterase (PDE-enzymes). Thus, or by stimulating adenylate cyclase activity, or inhibiting PDE-enzyme in lung tissue, it is possible to achieve anti-asthmatic activity. The invention relates to compounds that inhibit specific PDE, often referred to as PDE IV, which selectively metabolizes camp and is insensitive to modulatory influences guanosines 3':5'-monophosphate (cGMP) and calcium. This PDE is found in the cells of the respiratory smooth muscle, and in the cells of inflammation, and it is shown that he is the principal regulator of persons, redlagaemye connections are bronchodilators and anti-inflammatory drugs, and are active in the treatment of allergic and non-allergic asthma in animal models. Since it was found that the compounds inhibit other forms of PDE, it can be expected that they are more selective and safe asthma means than non-selective PDE inhibitors currently used to treat asthma, such as theophylline.

The invention relates to carbamates and carbonates Akimov 1-[3-(Deputy)hydroxy-4-methoxyphenyl]alkanones (lower) with bronchodilators and anti-inflammatory activity of the formula

where R3-C5-alkyl, C3-C7-cycloalkyl, bicycloheptane or Deputy formula

< / BR>
R1lower alkyl or Deputy formula

(CH2)q-

R2amino, phenylamino or lower alkylamino, lower alkoxy - or fenoxaprop;

n takes on the values 1-4;

q takes on the values 1-4.

The terms "lower alkyl", "lower alkoxy" or "lower alkanoyl" refer to fragments containing from 1 to 6 carbon atoms in the carbon chain. The term "aryl" ptx2">

When tested in rats for 6 months. in doses of 100 mg/kg/day connection in accordance with the invention with the title of (E)-O-(aminocarbonyl)the oxime of 1-[3-(cyclopentyloxy-4-methoxyphenyl] ethanone showed neither macro-nor micrococcaceae actions. At this dose was not observed lethal effect. As for this connection bronchodilators ED50for rats is approximately 1 mg/kg (orally), therapeutic index can be preextraction and is >100:1.

The proposed connection can be obtained from the main sequence of reactions in which at the initial stage of isovanillin reacts with derivative containing the desired substituent R, giving isovanillin intermediate containing the desired substituted by a hydroxy-group

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< / BR>
This is followed by a reaction derived from a compound R1or with the appropriate Grignard reagent, followed by oxidation with bichromate of pyridine or manganese dioxide to obtain the corresponding ketone

< / BR>
< / BR>
< / BR>
Then carry out the reaction of this ketone with hydrochloric acid by hydroxylamino, receiving the corresponding oxime

< / BR>
Then carry out the reaction of this ketone is I get N-unsubstituted oxycarbonyl, you can spend the reaction of the intermediate oxime with:

1) chlorosulfonylisocyanate in an environment of dry tetrahydrofuran, or:

2) trichlorotriazine in dry tetrahydrofuran, followed by reaction with ammonia, or:

3) sodium cyanate and triperoxonane acid in the environment methylene chloride, or:

4) cyanate sodium, acetic acid and water

< / BR>
In a similar way one can obtain N-substituted carbamates using appropriately substituted alkyl or arylisocyanate in an environment of dry tetrahydrofuran:

< / BR>
Finally, oxycarbonate can be obtained by reaction of the intermediate reaction with the corresponding alkyl - or arillotta in the environment of pyridine and methylene chloride

< / BR>
To obtain the proposed compounds can be used other known methods.

Source materials used in the described methods, commercially available or can be prepared according to the procedures described in the chemical literature.

Since the compounds according to the invention contain a double bond, they have a CIS-TRANS isomer, and therefore, the range of compounds of the invention include not only the mixture geometrical rules follow.

Due to its ability to inhibit PDE IV, the compounds according to the invention are bronchodilators and anti-inflammatory drugs, and can be used for the treatment of acute and chronic bronchial asthma and related diseases.

When using the compounds according to the invention for the treatment of acute or chronic bronchial asthma on their basis can be prepared dosage forms for oral administration such as, for example, tablets, capsules, and other Compounds can be used single or in combination with known and commonly used substrates such as magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragakant, methylcellulose, carboxymethylcellulose sodium, low melting wax, cocoa butter, etc. Can also be used thinners, corrigentov, soljubilizatory, lubricants, suspendresume agents, binders, disintegrators for tablets and similar components. Connections can also enter parenteral, in this case they are used in the form of sterile solutions containing other dissolved components, for example, saline or glucose, whose role is to comediane it is possible to prepare an aqueous or partially aqueous solutions, which can then be used in the form of aerosols.

Requirements dosages vary depending on what the composition is applied, what is the route of administration selected, what is the severity of the observed symptoms, as well as from the individual patient to be treated. Usually the treatment is started with small doses that are less than optimal for this connection. Then to increase the dosage until then, until you reach the optimal for these conditions result. Usually most desirable to use such concentrations of compounds according to the invention, which give good results without causing harmful or unwanted side effects. The proposed connection, you can enter a single dose, or if desired, you can divide the dose into smaller and enter them at the right times throughout the day.

Typical of the compounds according to the invention is the ability to inhibit PDE IV may be demonstrated by standard pharmacological procedures, which are more fully described in the following examples. These techniques illustrate the ability of the proposed compounds to inhibit PDE IV, isolated from the trachea of the dog.

and m e R 1. 1-[3-(cyclopentyloxy)-4-methoxyphenyl]alanon-(E)-O-(aminocarbonyl)- oxime

A. 3-cyclopentyloxy-4-methoxybenzaldehyde.

To stir on a magnetic stirrer solution isovanillin (0,557 mmol, 85,0 g) in dry dimethylformamide (500 ml) at room temperature in one portion add powdered potassium carbonate (0,558 mol, 77,1 g), then added dropwise net cyclopentyl-bromide (0,614 mol of 91.5 g, 65.9 ml). The resulting suspension is heated to 60aboutWith and monitor the reaction by thin-layer chromatography (TLC) until such time as the reaction does not take place before the end. After completion of the reaction the mixture is cooled to room temperature and vacuum to remove the dimethylformamide. The resulting residue is divided between water and ethyl acetate, the aqueous phase is extracted with ethyl acetate, and the combined organic layers washed with water. Then the organic layers dried over sodium sulfate and concentrated in vacuo, getting alkilirovanny product (MX 0.317 mmol, 70.1 g, 57%) as a viscous oil, which is of sufficient purity to be used further without additional purification.

NMR(DMSO-d6, 300 MHz) 9,83 (s, 1H), 7,52 (DD, J 8,5; 2.0 Hz, 1H), was 7.36 (d, J 2.0 Hz, 1H), 7,16 (d, J 8.5 Hz, 1H), 4,84 (m, 1H), 3,83 (s, 3 is Gnanou stirrer a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (59,0 mmol, 13,0 g) in dry tetrahydrofuran (500 ml) at -78aboutWith dropwise within 30 min add motility (100 mmol, 90,0 ml of 1.4 M solution in ethyl ether). The resulting solution was stirred at -78aboutC for 30 min and quenched the reaction at this temperature, quickly adding a saturated aqueous solution of ammonium chloride (140 ml). After heating to room temperature, water is added to dissolve the solids and vacuum type tetrahydrofuran. The residue is divided between water (500 ml) and ethyl acetate (500 ml), the aqueous phase is extracted with ethyl acetate (500 ml) and the combined organic layers washed with water (500 ml). The organic phase is dried over sodium sulfate and concentrated in vacuo, obtaining the target product as a light yellow oil (58.3 mmol, 13,7 g, 99%). TLC and NMR show that the purity of the product enough to use it without additional purification.

NMR (DMSO-d6, 300 MHz) : 6,91 (d, 1H), 6,84 (m, 2H), 5,00 (d, 1H), amounts to 4.76 (m, 1H), 3,70 (s, 3H), of 1.70 (m, 8H), of 1.27 (d, 3H).

Century 3-cyclopentyloxy-4-methoxyacetophenone.

To stir magnetic stirrer, the solution-methyl-3-cyclopentyloxy-4-methoxybenzamide alcohol (58.3 mmol, of 13.7 g) in dry methylene chloride (400 ml) at room those who live at room temperature over night, after which time TLC shows that there was a complete transformation in the substance that gives fast moving, active in the UV-region of the spot. The reaction mixture is diluted with the same amount of ether and stirred for 1 h the Mixture is filtered through Celite and the filter cake washed with ethyl ether (300 ml) and ethyl acetate (300 ml). The filtrate, having a brown color, concentrated in vacuo and purified by filtration through silica gel (eluent methylene chloride). The organic solvent is removed in vacuum, obtaining the target compound in the form of light solid yellow (58.3 mmol, of 13.6 g, 100%).

NMR (DMSO-d6, 300 MHz) : to 7.59 (DD, J 8.5 Hz; 2.0 Hz, 1H), 7,40 (d, J 2.0 Hz, 1H), 7,03 (d, J 8.5 Hz, 1H), 4,82 (m, 1H), 3,80 (s, 3H), of 2.50 (s, 3H), of 1.70 (m, 8H).

Year 3-cyclopentyloxy-4-methoxyacetophenone.

To stir magnetic stirrer, a solution of 3-cyclopentyloxy-4-methoxyacetophenone (58.3 mmol, 13,6 g) in dry pyridine (300 ml) at room temperature in one portion add hydrochloric acid hydroxylamine (64,0 mmol, of 4.45 g). The resulting suspension slowly becomes homogeneous, and the resulting solution was stirred at room temperature overnight. In vacuum to remove pyridine and the residue is divided between ethylacetate will centerour in vacuum, receiving the target compound in the form of solid, yellowish-brown (56,5 mmol, 14.1 g, 97%). TLC and NMR show that this product is of sufficient purity to use without further purification.

NMR (DMSO-d6, 300 MHz) : 11,0 (s, 1H), 7,24 (d, J 2.0 Hz, 1H), 7,13, (DD, J 8,5; 2.0 Hz, 1H), 6,94 (d, J 8.5 Hz, 1H), 4,77 (m, 1H), 3,75 (s, 3H), 2,10 (s, 3H), of 1.80 (m, 8H).

D. 1-[3-(cyclopentyloxy)-4-methoxyphenyl]alanon(E)-O-(aminocarbonyl)oxime.

To slowly stir the suspension NaOCN (160 mmol, 10.4 g) in methylene chloride (30 ml) at room temperature dropwise within 10 min add triperoxonane acid a (80.0 mmol, 9,12 g, 6,16 ml) and the reaction vessel is tightly closed with a plastic plug. The suspension slowly thickens with the formation of a gelatinous mass, which is periodically stirred, gently shaking by hand. After 2 hours at room temperature, one portion add 3 cyclopentyloxy-4-methoxyacetophenone-oxime (20.0 mmol, to 4.98 g) in methylene chloride (5 ml) and the reaction vessel is again closed. The reaction mixture was periodically stirred manually for 30 min, and then poured into saturated sodium bicarbonate solution (250 ml) and extracted with chloride € in vacuum, receiving a colorless oil. This oil is clear pulse chromatography (silica gel; eluent: 1) 1.25% of ethyl acetate in methylene chloride; 2) 5% ethyl acetate in methylene chloride), triturated with a mixture of ethyl ether/hexane and dried in vacuum at 50aboutWith getting analytically pure target compound in the form of solid white (11.5 mmol, 3,37 g, 58%).

NMR (DMSO-d6, 300 MHz) : 7,39 (d, J 2.0 Hz, 1H), 7,35 (DD, J 8,5; 2.0 Hz, 1H), 7,08 (CL, 2H), 6,85 (d, J 2.0 Hz, 1H), 4.92 in (m, 1H), of 3.78 (s, 3H), to 2.29 (s, 3H), 1,71 (m, 8H).

IR (KBR) (cm-1) 3460, 3250, 2960, 1715, 1600, 1522, 1375, 1265, 1225, 1143, 993, 978.

Mass spectrometry(MS)(EI,m/e) 292/M+,10/, 249 (18), 181(100), 164(20), 124(20).

C15H20N2O4< / BR>
Calculated With 61,63; N 6,90; N 9,58.

Found, 61,66; N 7,06; N 9,60.

Here is a method, alternative stage D: 1-[3-(cyclopentyloxy)-4-methoxyphenyl]alanon(E)-O-(aminocarbonyl)oxime.

To stir magnetic stirrer, a solution of 3-cyclopentyloxy-4-methoxyacetophenone (by 23.4 mmol, of 5.83 g) in dry tetrahydrofuran (200 ml) at 0aboutWith dropwise within 5 min add chlorosulfonylisocyanate from 35.1 mmol, equal to 4.97 g of 3.06 ml). The resulting yellow solution was stirred at 0aboutC for 15 min, tetrahydropyranyl with ethyl acetate (200 ml), and the combined organic layers washed with water (200 ml) and saturated aqueous sodium bicarbonate (200 ml). The organic phase is dried over sodium sulfate and concentrated in vacuo, receiving a dark oil. This substance is clear pulse chromatography (silica gel; eluent: 5% ethyl acetate/methylene chloride) to give a light solid yellow color, which is then triturated with a minimum amount of the mixture of ethyl ether/hexane and collected by suction, obtaining the target compound in the form of solid white. This solid is dried in vacuum at 50aboutWith during the night, getting analytically pure material (to 13.6 mmol, of 3.97 g, 58%).

NMR (DMSO-d6, 300 MHz) : 7,39 (d, J 2.0 Hz, 1H), 7,35 (DD, J 8,5; 2.0 Hz, 1H), 7,08 (CL, 2H), 6,85 (d, J 2.0 Hz, 1H), 4.92 in (m, 1H), of 3.78 (s, 3H), to 2.29 (s, 3H), 1,71 (m, 8H).

IR (KBR) (cm-1) 3460, 3250, 2960, 1715, 1600, 1522, 1375, 1265, 1225, 1143, 993, 978.

MS (EI, m/e) 292(M+,16), 224(18), 182(78), 180(100), 164(35), 140(20) 124(26).

C15H20N2O4< / BR>
Calculated With 61,63; N 6,90; N 9,58.

Found, 61,50; N 6,88; N 9,54.

P R I m m e R 2. 1-[3-(butoxy)-4-methoxyphenyl]alanon(E)-O-(aminocarbonyl)oxime.

A. 3-butoxy-4-methoxybenzaldehyde

According to the method of example 1A from isovanillin dry dimethylformamide (500 ml) receive alkilirovanny product (0,557 mol, 118 g, 100%) as a solid white color with a purity sufficient for further use without additional purification.

NMR (DMSO-d6, 300 MHz) 9,83 (s, 1H), 7,54 (DD, J 8,5; 2.0 Hz, 1H), 7,38 (d, J 2.0 Hz, 1H), 7,16 (d, J 8.5 Hz, 1H), 4,0 (t, 2H), 3,85 (s, 3H), of 1.70 (m, 2H), USD 1.43 (m, 2H), to 0.92 (t, 3H).

B.-methyl-3-butoxy-4-methoxybenzyloxy alcohol.

According to the method of example 1B from 3-butoxy-4-methoxybenzaldehyde (24 mmol, 5.0 g), and metallyte (26,4 mmol, 18,9 ml of 1.4 M solution in ethyl ether) in dry tetrahydrofuran (150 ml) receive alcohol (23,0 mmol, 5,15 g, 96% ); the product obtained according to NMR has a purity of 93% of the Product is used further without additional purification.

NMR (CDCl3MHz) : 6,94 (d, J 2.5 Hz, 1H), cent to 8.85 (m, 2H), 4,82 (K, 1H), 4,01 (t, 2H), 3,85 (s, 3H), 1,82 (p, 2N), 1,50 (m, 3H), of 0.97 (t, 2H).

Century 3-butoxy-4-methoxyacetophenone.

According to the method of example 1B from methyl-3-butoxy-4-methoxybenzylthio alcohol (23 mmol, 5,15 g) and bichromate of pyridine (34,4 mmol, 12,95 g) in dry methylene chloride (150 ml) receive ketone (21.6 mmol, 4,81 g, 94%) as a solid yellow color, the purity of which is sufficient for further use without additional purification.

NMR (CDCl3, 300 MHz) 7,52 (DD, J 8.5 Hz; 2.0 Hz, 1H), 7,51 (d, J 2.0 Hz, 1H), noxim.

According to the method of example 1G from 3-butoxy-4-methoxyacetophenone (15 mmol, 3.33 g) and hydrochloric acid hydroxylamine (16.5 mmol, 1,15 g) in dry pyridine (100 ml) receive acetophenone in the form of light solid yellow (13,17 mmol, 3.12 g, 88%), the purity of which is sufficient to be used further without additional purification.

NMR (CDCl3, 300 MHz) : 11,0 (s, 1H), 7,24 (d, J 2.0 Hz, 1H), 7,13 (DD, J 8,5; 2.0 Hz, 1H), a 4.03 (t, J 7.0 Hz, 2H), 3,86 (s, 3H), of 2.30 (s, 3H), equal to 1.82 (m, 2H), 1,47 (m, 2H), of 0.96 (t, J 7.0 Hz, 3H).

D. 1-[3-(butoxy)-4-methoxyphenyl]alanon(E)-O-aminocarbonyl)oxime.

According to the method of example 1D from 3-butoxy-4-methoxyacetophenone (8,73 mmol, 1,94 g) and chlorosulfonylisocyanate (4,63 mmol, 0,655 g, 0,403 ml) in dry tetrahydrofuran (40 ml) receive a yellow oil, which was purified by impulse chromatography (silica gel: 1) methylene chloride; 2) 2% ethyl acetate/methylene chloride; 3) 5% ethyl acetate/methylene chloride). The resulting residue is triturated with a minimum amount of the mixture of ethyl ether/hexane and collected by suction, obtaining the target compound in the form of solid white. This solid is dried in vacuum at 50aboutWith during the night, getting analytically pure product (1,14 mmol, 0,306 is, ,79 (s, 3H), to 2.29 (s, 3H), 1.69 in (m, 2H), USD 1.43 (m, 2H), 0,53 (t, 3H).

IR (KBR) (cm-1) 3445, 3250, 2970, 1734, 1517, 1370, 1257, 1156, 1023, 975.

MS (EI,m/e) 280(14, M+), 237(100), 181(99), 164(65), 150(48), 125(37), 124(94), 79(30).

C14H20N2O4< / BR>
Calculated From 59,99; N 7,19; N 9,99.

Found, 59,97; N 7,10; N 9,87.

P R I m e R 3. 1-[4-methoxy-3-(3-phenoxypropane)phenyl]alanon(E)-O-aminocarboxylate.

A. 4-methoxy-3-(3-phenoxypropane)-benzaldehyde.

According to the method of example 1A from isovanillin (20 mmol, 3.04 from g), powdered potassium carbonate (22 mmol, 3.04 from g) and 3-phenoxypropylamine (22 mmol, 4,73 g, 3,47 ml) in dry dimethylformamide (100 ml) receive alkilirovanny product (20.0 mmol, 5.75 g, 100%) as a solid, yellowish-brown, the purity of which is sufficient for further use without additional purification.

NMR (DMSO-d6, 300 MHz) 9,84 (s, 1H), 7,56 (DD, J 8,5; 2.0 Hz, 1H), 7,44 (d, J 2.0 Hz, 1H), 7,28 (m, 2H), 7,18 (d, J 8.5 Hz, 1H), 6,94 (m, 3H), 4,20 (t, J 7.0 Hz, 2H), 4,13 (t, J 7.0 Hz, 2H), 3,66 (s, 3H), of 2.20 (m, 2H).

B.-methyl-4-methoxy-3-(3-phenoxypropane)-benzyl alcohol.

According to the method of example 1B from 4-methoxy-3-(3-phenoxypropane)benzaldehyde (8,03 mmol, 2.30 g) and metallyte (a 12.05 mmol, 8,61 ml of 1.4 M solution in ethyl is the first substance of a yellowish-brown color.

NMR (DMSO-d6, 300 MHz) : 7,30 (m, 2H), 6.90 to (m, 6N), 5,02 (d, 1H), 4,63 (m, 1H), 4,12 (t, J 7.0 Hz, 2H), 4.09 to (t, J 7.0 Hz, 2H), 3,70 (s, 3H), 2,15 (p, 2N), of 1.27 (d, 3H).

Century 4-methoxy-3-(3-phenoxypropane)acetophenone.

According to the method of example 1B from-methyl-4-methoxy-3-(3-phenoxypropane)bosilovo alcohol (7,51 mmol, of 2.27 g) and bichromate of pyridine (of 11.26 mmol, to 4.23 g) in dry methylene chloride (75 ml) obtained target compound (7,06 mmol, 2,12 g, 94%) as a light solid yellow color, the purity of which is sufficient to be used for further transformations directly.

NMR (DMSO-d6, 300 MHz) : to 7.61 (DD, J 8,5; 2.0 Hz, 1H), 7,46 (d, J 8.5 Hz, 1H), 7,27 (m, 2H), 7,05 (l, 1H), 6,93 (m, 3H), 4,15 (t, J 7.0 Hz, 2H), 4,10 (t, J 7.0 Hz, 2H), 3,80 (s, 3H), 2,48 (s, 3H), 2,18 (m, 2H).

Year 4-methoxy-3-(3-phenoxypropane)acetophenone.

According to the method of example 1G from 4-methoxy-3-(3-phenoxypropane)acetophenone (7,06 mmol, 2,12 g) and hydrochloric acid hydroxylamine (7,76 mmol, 540 mg) in dry pyridine (70 ml) to obtain the target compound in the form of a whitish solid (6,60 mmol, 2,08 g, 93%), the purity of which is sufficient in order to use it in the further transformation without further purification.

NMR (DMSO-d6300 MHz) : 10,95 (s, 1H), 7,25 (m is-3-(3-phenoxypropane)phenyl]alanon(E)-O-aminocarboxylate.

According to the method of example 1D to slowly stirred suspension of sodium isocyanate (19,02 mmol, 1.24 g) in dry methylene chloride (20 ml) is added anhydrous triperoxonane acid (38,05 mmol, 4,34 g of 2.93 ml) and a solution of 4-methoxy-3-3-phenoxypropylamine (4.76 mmol, 1.50 g) in methylene chloride (6 ml) to give yellow oil, which was purified by impulse chromatography (silica gel: 1) 5% ethyl acetate/methylene chloride; 2) 8% ethyl acetate/methylene chloride; 3) 10% ethyl acetate/methylene chloride). The obtained solid white dried in vacuum, obtaining the analytically pure target compound (3,12 mmol, 1.12 g, 66%).

NMR (DMSO-d6300 MHz) : 7,47 (d, J 2.0 Hz, 1H), was 7.36 (DD, J 8,5; 2.0 Hz, 1H), 7,27 (m, 2H), 7,11 (s, 2H), 6,95 (m, 4H), 4,19 (t, J 7.0 Hz, 2H), 4,12 (t, J 7.0 Hz, 2H), of 3.78 (s, 3H), of 2.28 (s, 3H), of 2.16 (t, 2H).

IR (KBR) (cm-1) 3470, 3250, 2940, 1730, 1605, 1590, 1520, 1370, 1258, 1152, 975, 758.

MS (EI,m/e) 358 (M+, 0,6), 315(55), 164(23), 107(100), 77(75).

C19H22N2O5< / BR>
Calculated With 63,67; N Is 6.19; N Of 7.82.

Found, With 64,01; N Between 6.08; N 7,71.

P R I m e R 4. 1-(3-cyclopentyloxy-4-methoxyphenyl)-2 - phenylethanone(E)-O-(aminocarbonyl)oxime

A. 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-Penilaian-1-ol

To stir the magnetic mesalc the temperature dropwise from a dropping funnel add a solution of benzyl bromide (36,54 mmol, of 4.35 ml) in anhydrous ethyl ether (15 ml). First adding exercise slowly add 2-3 ml of the reagent, and the reaction mixture is heated until then, until the start of the gas. At this point, again dropwise add benzyl bromide, and the reaction mixture is diluted with ethyl ether, preventing dimerization of the Grignard reagent. After the addition of benzyl bromide, the reaction mixture was stirred at room temperature for 1 h, and then at the same temperature is added dropwise a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (30.0 mmol, of 6.61 g) in anhydrous ethyl ether (30 ml). The reaction mixture was stirred at room temperature for 30 min, and then poured into ice water (500 ml) containing concentrated sulfuric acid (7 ml). The aqueous mixture is extracted with ethyl acetate (2 x 300 ml) and the combined organic layers are washed with saturated sodium bicarbonate solution (300 ml). The organic layer is dried over sodium sulfate and concentrated in vacuo, obtaining the target compound in the form of solid white (25,97 mmol, 8.06 g, 86%), the purity of which is sufficient to continue to use it directly.

B. 1-(3-cyclopentyloxy is tan-1-ol (10.0 mmol, 3.12 g) and bichromate of pyridine (15.0 mmol, 5,64 g) in dry methylene chloride (100 ml) receive ketone in the form of light solid yellow (9,05 mmol, 2,81 g, 90% purity which is sufficient in order to use it in the next stage without additional purification.

NMR (CDCl3, 300 MHz) 7,63 (DD, J 8.5 Hz; 2.0 Hz, 1H), 7,54 (d, J 2.0 Hz, 1H), 7,28 (m, 5H), 6,86 (d, J 8.5 Hz, 1H), 4,80 (m,1H), 4,22 (c, 2H), 3,89 (c, 3H), of 1.80 (m, 8H).

C. 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethanone.

According to the method of example 1 from 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenolate-Nona (5.0 mmol, 1.55 g) and hydrochloric acid hydroxylamine (5,50 mmol, 0,382 g) in dry pyridine (25 ml) to obtain the target compound in the form of solid yellow (4.61 mmol, 1.50 g, 93%), the purity of which is sufficient to be used further without additional purification.

NMR (DMSO-d6, 300 MHz) : 11,27 (s, 1H), 7,20 (m, 7H), 6.89 in (m, 8H), 4,70 (m, 1H), 4,12 (s, 2H), 3,70 (s, 3H), of 1.65 (m, 8H).

, 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethanone(E)-O-(aminocarbonyl)oxime

To stir magnetic stirrer, a solution of 1-3 cyclopentyloxy-4-methoxyphenyl-2-phenylethanone (4,51 mmol, 1.48 g ) in dry tetrahydrofuran (45 ml) at 0aboutWith dropwise in t is the temperature during the night slowly rises from 0aboutWith up to room temperature. Then the reaction mixture was cooled to 0aboutC and added dropwise thereto, a saturated solution of ammonia in acetonitrile (25 ml; obtained by propulsiveness gaseous ammonia through acetonitrile at room temperature for 1 h). The solution is stirred, while he slowly heated from 0aboutWith up to room temperature. After 1.5 h, the tetrahydrofuran is removed in vacuo, and the residue is divided between methylene chloride (200 ml) and water (200 ml). The aqueous phase is extracted with ethyl acetate (200 ml) and the combined organic layers washed with water, dried over sodium sulfate and concentrated in vacuo, obtaining a mixture of the product and the oxime (approximately 1:1). The resulting residue is purified by impulse chromatography (silica gel; 1) 2% ethyl acetate/methylene chloride; 2) 5% ethyl acetate/methylene chloride; 3)7% ethyl acetate/methylene chloride) to give a solid white color, which is triturated with a mixture of ether/hexane and dried in vacuum at 50aboutWith getting analytically pure target compound (1,22 mmol, 0,450 g, 27%).

NMR (DMSO-d6, 300 MHz) : 7,38 (m, 2H), 7,24 (m, 2H), 7,17 (m, 5H), 6,94 (d, J 8.5 Hz, 1H), 4,84 (m, 1H), 4,23 (s, 2H), 3,74 (s, 3H), of 1.65 (m, 8H).

IR (KBR) (cm-1) 3925, 3815, 3240, 2950, 2920, 1710, 1588, 1511, 1358, 1252, 1222, 1130, 960, 898.

4< / BR>
Calculated With 68,46, N To 6.57; N 7,60.

Found, C 68,42; N. Of 6.71; N Of 7.48.

P R I m e R 5. 1-(3-cyclopentyloxy-4-methoxyphenyl)-3-phenylpropane(E)- O-(aminocarbonyl)oxime. A. 1-(3-cyclopentyloxy-4-methoxyphenyl)-3-phenylpropane-1-ol.

According to the method of example 4A from magnievyij chips (32,42 mmol, 0,788 g), 2-brahmativartate (32,42 mmol, 6.0 g), 3-cyclopentyloxy-4-methoxybenzaldehyde (32,42 mmol, 7,14 g) obtained in example 1A, and anhydrous ethyl ether (300 ml) to obtain the target compound in the form of solid white (3.4 mmol, 9.60 g, 91%), the purity of which is sufficient for further use without additional purification.

NMR (DMSO-d6, 300 SGC) 7,21 (m, 5H), 6.89 in (d, J 2.0 Hz, 1H), 6.87 in (d, J 8.5 Hz, 1H), 6,80 (DD,J 8,5; 2.0 Hz, 1H), 5,12 (d, 1H), amounts to 4.76 (m, 1H), 4,42 (m, 1H), 3,70 (s, 3H), 2,58 (m, 2H), 2,73 (m, 10H).

B. 1-(3-cyclopentyloxy-4-methoxyphenyl)-3-phenylpropane.

According to the method of example 1B from 1-(3-cyclopentyloxy-4-methoxyphenyl)-3-phenylpro-pan-1-ol (29,41 mmol, 9.60 g) and bichromate of pyridine (44,12 mmol, 16,59 g) in dry methylene chloride (120 ml) receive ketone in the form of light solid yellow color, which, as shown by TLC analysis, contains a small amount of 3-cyclopentyloxy-4-methoxybenzaldehyde. The floor is) to remove traces of aldehyde, remaining after carrying out the Grignard reaction. The aqueous phase is washed with ethyl acetate (500 ml), organic layers combined, dried over sodium sulfate and concentrated in vacuo, obtaining the target compound in the form of solid white (23,74 mmol, of 7.70 g, 89%), the purity of which is sufficient for further use without additional purification.

NMR (DMSO-d6, 300 MHz) of 7.64 (DD, J 8.5 Hz; 2.0 Hz, 1H), 7,43 (d, J 2.0 Hz, 1H), 7,28 (s, 2H), 7,18 (s, 1H),? 7.04 baby mortality (d, J 8.5 Hz, 1H), 4,82 (m, 1H), 3,80 (s, 3H), 3,30 (t, J 7.0 Hz, 2H), 2,90 (t, J 7.0 Hz, 2H), 1.70 to (m, 8H).

C. 1-(3-cyclopentyloxy-4-methoxyphenyl)-3-phenylpropanoate.

According to the method of example 1 from 1-(3-cyclopentyloxy-4-methoxyphenyl)-3-phenylpro-banana (a 9.25 mmol, 3.00 g) and hydrochloric acid hydroxylamine (10,17 mmol, 0,707 g) in anhydrous pyridine (90 ml) receive the oxime as a light solid yellow (8,54 mmol, 2,90 g, 92%), the purity of which is sufficient for further use without additional purification.

NMR (DMSO-d6, 300 MHz) : 11,07 (s,1H), 7,22 (m, 7H), 6,94 (d, J8,5 Hz, 1H), and 4.75 (m, 1H), 3,75 (s, 3H), equal to 2.94 (t, 2H), 1.70 to (m, 8H).

, 1-(3-cyclopentyloxy-4-methoxyphenyl)-3-phenylpropane(E)- O-(aminocarbonyl)oxime.

According to the method, alternative to the method of example 1D, from 1-(3-what, ,12 ml) in dry tetrahydrofuran (80 ml) receive a yellow oil, which was purified by impulse chromatography (silica gel; 1) methylene chloride; 2) 2% ethyl acetate/methylene chloride; 3) 5% ethyl acetate/methylene chloride; 4)10% ethyl acetate/methylene chloride). The resulting residue is triturated with a minimum amount of the mixture of ethyl ether/hexane and collected by suction, obtaining the target compound in the form of solid white. This solid is dried in vacuum at 50aboutWith during the night, getting analytically pure product (2,53 mmol, 0,969 g, 30%).

NMR (DMSO-d6, 300 MHz) : 7,26 (m, 7H), 7,07 (s, 2H), 6,99 (d, J 2.0 Hz, 1H), a 4.86 (m, 1H), of 3.78 (s, 3H), of 3.07 (t, 2H), 2,78 (t, 2H), 1,7 (m, 8H).

IR (KBR) (cm-1) 3480, 3310, 3260, 2940, 1710, 1550, 1515, 1357, 1266, 1218, 1125, 1015, 975, 695.

MS (EI,m/e 382 (0.5 M+), 339(24), 254(60), 213(22), 150(100), 149(31), 105(20), 91(50).

WITH22H26N2ABOUT4< / BR>
Calculated With 69,09; N 6,85; N 7,33.

Found, C 68,81; N 6,82; N? 7.04 Baby Mortality.

P R I m e R 6. 1-[3-cyclopentyloxy)-4-methoxyphenyl]-3-methylbutane(E)- O-(aminocarbonyl)oxime.

A. 1-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylbutane-1-ol.

To stir magnetic stirrer, a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (25.0 mm is billaut isobutylamine (30 mmol, 15 ml of a 2.0 M solution in ethyl ether). The reaction mixture is stirred, while it slowly warmed to room temperature over 1 h Then poured onto a mixture of 1 N. HCl (250 ml) and divide it between the acid solution and ethyl ether (200 ml). The aqueous phase is extracted with ethyl ether (200 ml), the combined organic phases are washed with saturated aqueous sodium bicarbonate (200 ml), saturated aqueous sodium chloride (200 ml) and dried over magnesium sulfate. Concentration in vacuo gives a yellow oil, which was purified by impulse chromatography (silica gel; 1) methylene chloride; 2) 2% ethyl acetate/methylene chloride; 3) 5% ethyl acetate/methylene chloride) to give the target compound in the form of solid white (21.5 mmol, 5,98 g, 86%).

NMR (DMSO-d6, 300 MHz) : PC 6.82 (m, 3H), is 4.93 (d, 1H), amounts to 4.76 (m, 1H), 4,43 (m, 1H), 3,68 (s, 3H), 1,60 (m, 8H), of 1.30 (m, 2H), 0,85 (d, 6N).

B. 1-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylbutane.

According to the method of example 1B from 1-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylbutane-1-ol (21.5 mmol, 5,98 g) and bichromate of pyridine (33.0 mmol, 12.4 g) in dry methylene chloride (125 ml) receive ketone as a light yellow oil (21,0 mmol, 5,80 g, 98%), the purity of which Dodd, J 8,5; 2.0 Hz, 1H), 7,53 (d, J 2.0 Hz, 1H), 6.87 in (d, J 8.5 Hz, 1H), around 4.85 (m, 1H), 3,93 (s, 3H), and 2.79 (d, 2H), 2,30 (m, 1H), 1,80 (m, 8H), 1.00 m (d, 6N).

C. 1-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylbutanoate.

According to the method of example 1 from 1-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylbuta-Nona (10.0 mmol, 2.76 g) and hydrochloric acid hydroxylamine (11.0 mmol, 0,765 g) in dry pyridine (50 ml) to obtain the target compound as a colourless oil, which solidified upon standing (9,51 mmol, 2,77 g, 95%). The degree of purity of the obtained product can be used for further transformation without further purification.

NMR (DMSO-d6, 300 MHz) 10,92 (s, 1H), 7,20 (d, J 2.0 Hz, 1H), 7,13 (DD, J 8,5; 2.0 Hz, 1H), 6,94 (d, J 8.5 Hz, 1H), 4,78 (m, 1H), of 3.73 (s, 3H), 2,60 (d, 2H), 1.70 to (m, 8H), 0,84 (d, 6N).

Year 1-[3-(cyclopentyloxy)-4-methoxyphenyl] -3-methylbutane(E)-O-(aminocarbonyl) ksps.

Following the procedure of example 1D, to slowly stirred suspension of sodium isocyanate (32,0 mmol, 2,08 g) in dry methylene chloride (30 ml) is added anhydrous triperoxonane acid (16.0 mmol, 1,82 g of 1.12 ml) and a solution of 1-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylbutanoate (4.0 mmol, of 1.16 g) in methylene chloride (10 ml); receive a yellow oil, which was purified by impulse chromatography (acetate/methylene chloride). The resulting residue triturated with a mixture of ethyl ether/hexane and dried in vacuum at 50aboutWith getting analytically pure target compound in the form of solid white (2,40 mmol, 0,802 g, 60%).

NMR (DMSO-d6, 300 MHz) : 7,35 (m, 2H), 7,05 (s, 2H), 6,98 (m, 1H), 4,90, (m, 1H), of 3.78 (s, 3H), 2,74 (d, 2H), 1,72 (m, N), 0,86 (d, 6N).

IR (KBR) (cm-1) 3440, 3310, 3200, 2956, 2874, 1722, 1618, 1515, 1360, 1260, 990.

MS (EI, m/e) 334(M+,4), 291(11), 223(13), 206(100), 165(52), 150(65), 149(66).

WITH18H26N2O4< / BR>
Calculated With 64,64; N To 7.84; N Scored 8.38.

Found, 64,97; N A 7.85; N At 8.36.

P R I m e R 7. 1-[3-(cyclopentyloxy)-4-methoxyphenyl]alanon(E)-O-[(methylamino)carbonyl]oxy m

To stir magnetic stirrer, a solution of 3-cyclopentyloxy-4-methoxyacetophenone (2.0 mmol, 0.5 g) obtained in example 1D, in dry tetrahydrofuran (20 ml) at 0aboutWith dropwise over 1 min added methyl isocyanate (2,20 mmol, 0.126 g, 0,130 ml), and then a catalytic amount of 4-dimethylaminopyridine (4 DMAP). The reaction mixture is stirred, while it is within 4 hours slowly heated from 0aboutC to room temperature; during this time the reaction is monitored by TLC analysis. After 4 h domovladenie night. The tetrahydrofuran is removed in vacuo, and the residue is divided between methylene chloride (100 ml) and water (100 ml). The aqueous phase is extracted with methylene chloride (100 ml), the combined organic phases are washed with water (100 ml), dried over sodium sulfate and concentrated in vacuo. The residue is purified by impulse chromatography (silica gel: 1) methylene chloride; 2) 2% ethyl acetate/methylene chloride; 3) 5% ethyl acetate/methylene chloride) and triturated with hexane, obtaining the target compound in the form of a solid substance of white color, which is dried in vacuum at 50aboutWith during the night, getting analytically pure product (1,58 mmol, 0,493 g, 80%).

NMR (DMSO-d6, 300 MHz) 7,39 (DD, J 8,5; 2.0 Hz, 1H), 7,37 (d, J 2.0 Hz; 1H), 6,99 (d, J 8.5 Hz, 1H), 4,90 (m, 1H), of 3.77 (s, 3H), 2,70 (d, 2H), to 2.29 (s, 3H), of 1.70 (m, 8H).

IR (KBR) (cm-1) 3575, 3408, 2960, 1714, 1500, 1427, 1280, 1253, 1233, 1150, 958.

MS (EI, m/e) 306(20,M+), 249(9), 216(19), 185(19), 181(100), 164(20), 86(43), 84(65).

C16H22N2O4< / BR>
Calculated With 62,73; N 7,24; N 9,14.

Found, 62,60; N 7,28; N 9,15.

P R I m e R 8. 1-(3-butoxy-4-methoxyphenyl)alanon(E)-O-[(methylamino)carbonyl]oxime.

According to the method of example 7 from 3-butoxy-4-methoxyacetophenone (2.10 mmol, 0,498 g) obtained in example 2G, and Metelitza is methylaminopropane, receive a yellow oil, which was purified by impulse chromatography (silica gel: 1) methylene chloride; 2) 2% ethyl acetate/methylene chloride). Rubbing with hexane and collecting the suction gives the target compound in the form of a solid substance of white color, which is dried in vacuum at 50aboutWith during the night, getting analytically pure product (1,46 mmol, 0,430 g, 70%).

NMR (DMSO-d6, 300 MHz) : 7,40 (m, 3H), of 6.99 (d, J 8.5 Hz, 1H), Android 4.04 (t, 2H), 3,79 (s, 3H), 2,70 (d, J 3.5 Hz, 2H), 2,30 (s, 3H), 1.69 in (m, 2H), 1,42 (m, 2H), of 0.93 (t, 3H).

IR (KBR) (cm-1) 3355, 2970, 2950, 2883, 1717, 1520, 1464, 1332, 1266, 1234, 1152, 1033, 960.

MS (EI, m/e) 294(31,M+), 150(56), 149(30), 148(23), 237(100), 181(79), 180(30), 165(40), 164(48), 140(42), 135(29), 125(30), 124(56), 79(34).

WITH15H22N2O4< / BR>
Calculated, 61,21; N 7,53; N 9,52.

Found, 60,58; N 7,56; NB 9,41.

P R I m e R 9. 1-(3-butoxy-4-methoxyphenyl)alanon(E)-O-[(phenylamino)carbonyl]oxime.

According to the method of example 7 from 3-butoxy-4-methoxyacetophenone (1.50 mmol, 0,356 g) obtained in example 2G, and phenylisocyanate (1,65 mmol, 0,196 g, 0,179 ml) in dry tetrahydrofuran (15 ml) containing a catalytic amount of 4-dimethylaminopyridine receive a yellow oil, which was purified by impulse chromatography (logo color, which is collected by suction and dried in vacuum at 50aboutWith during the night, getting the analytically pure target compound (0.97 mmol, 0,347 g, 65%).

NMR (DMSO-d6, 300 MHz) 9,78 (s, 1H), 7,53 (DD, J 8,5; 2,0 Hz, 2H), 7,34 (m, 4H),? 7.04 baby mortality (m, 2H), 4.00 points (t, 2H), 3,81 (s, 3H), 2,48 (s, 3H), of 1.70 (m, 2H), 1,44 (m, 2H), of 0.93 (t, 3H).

IR (KBR) (cm-1) 3270, 3140, 3080, 2985, 2965, 1734, 1600, 1552, 1517, 1444, 1320, 1250, 1230, 1210, 1165, 1015, 765.

MS (F, AB, m/e ) 356 (20, M+), 328(7), 312(21), 222(52), 220(100), 164(5), 123(8).

C20H24N2O4< / BR>
Calculated With 67,40; N 6,79; N 7,86.

Found, 67,53; N 6,59; N Of 7.96.

P R I m e R 10. 1-[3-(cyclopentyloxy)-4-methoxyphenyl]alanon(E)-O-(methoxycarbonyl)oxime.

To stir magnetic stirrer, a solution of 3-cyclopentyloxy-4-methoxyacetophenone (190 mmol, 0,474 g) obtained in example 1D, in dry methylene chloride (20 ml) at 0aboutWith added pyridine (3,42 mmol, 0,271 g, 0,277 ml) and then dropwise methylchloroform (2.28 mmol, 0,215 g, 0,176 ml). The resulting yellow solution is stirred, while he for 5 h, slowly warmed to room temperature. The reaction mixture is diluted with methylene chloride (100 ml) and divided between organic solvent and water (100 ml). The aqueous phase is extracted with chloride IU is the atrium and concentrated in vacuo, getting a solid yellow color, which is then triturated with a minimum of a mixture of ethyl ether/hexane and collected by suction, obtaining the target compound in the form of solid white. The solid is dried in vacuum at 50aboutWith during the night, getting analytically pure product (1,19 mmol, 0,365 g, 62.5 per cent).

NMR (DMSO-d6, 300 MHz) : 7,30 (DD, J 8,5; 2.0 Hz, 1H), 7,28 (d, J 2.0 Hz, 1H), 7,02 (d, J 8.5 Hz, 1H), 4,80 (m, 1H), 3,81 (s, 3H), of 3.78 (s, 3H), of 2.30 (s, 3H), of 1.70 (m, 8H).

IR (KBR) (cm-1) 2970, 1790, 1580, 1510, 1540, 1525, 1248, 1150, 1020, 988, 844, 778.

MS (EI m/e) 307 (27, M+), 239(54), 165(35), 164(81), 148(100), 123(32), 122(55).

C16H21NO5< / BR>
Calculated FROM TOTALS 62.52; H 6,89; N 4,56

Found, 62,49; N 6,72; N 4,49.

P R I m e R 11. 1-(3-butoxy-4-methoxyphenyl)alanon(E)-O-(methoxycarbonyl)OK SIM.

According to the method of example 10 from 3-butoxy-4-methoxyacetophenone (1,80 mmol, 0,427 g) obtained in example 2G, pyridine (2.0 mmol, 0,158 g rate £ 0.162 ml) and methylchloroform (2.0 mmol, 0,189 g, 0,154 ml) in dry methylene chloride (20 ml) receive solid whitish color, which purify pulse chromatography (silica gel: 1) methylene chloride/hexane 2: 1; 2) methylene chloride/hexane 4:1; 3) methylene chloride). The obtained substance semesta white (1,59 mmol, 0,470 g, 88%).

NMR (DMSO-d6, 300 MHz) : 7,30 (DD, J 8.5 to 2.0 Hz, 1H), 7,38 (d, J 2.0 Hz, 1H), 7,02 (d, J 8.5 Hz, 1H), a 3.87 (t, 2H), 3,81 (s, 3H), of 3.80 (s, 3H), 2,31 (s, 3H), of 1.70 (m, 2H), 1,44 (m, 2H), 0,93 (m, 3H).

IR (KBR) (cm-1) 3400, 2970, 2950, 1785, 1520, 1442, 1430, 1317, 1245, 1152, 1020, 938, 878, 783.

MS (EI, m/e) 295(51,M+), 220(26), 164(64), 149(33), 148(100), 134(34), 123(37), 122(54), 79(34).

C15H21NO5< / BR>
Calculated With 61,00, N 7,17; N 4,74.

Found, With 60,99; N. Of 7.23; N 4,76.

P R I m e R 12. 1-(3-butoxy-4-methoxyphenyl)alanon(E)-O-(phenoxycarbonyl)oxime.

According to the method of example 10 from 3-butoxy-4-methoxyacetophenone (1.50 mmol, 0,356 g) obtained in example 2G, pyridine (1,65 mmol, 0,130 g of 0.133 ml) and phenylcarbamate (1,65 mmol, 0,258 g, 0,207 ml) in dry methylene chloride (15 ml) has received a yellow oil, which was purified by impulse chromatography (silica gel: 1) methylene chloride/hexane 1:1; 2) methylene chloride/hexane 2: 1). Subsequent rubbing with a minimum of a mixture of ethyl ether/hexane gives the target compound in the form of a solid substance of white color, which is dried in vacuum at 50aboutWith during the night, getting analytically pure product (0.42 mmol, 0,150 g, 28%).

NMR (DMSO-d6, 300 MHz) : 7,47 (m, 2H), 7,33 (m, 5H), 7,05 (d, J 8.5 Hz, 1H), 3,98 (t, 2H), 3,81 (s, 3H), 2.40 A, S="ptx2">

MS (EI, m/e ) 357 (9,1, M+), 221(24), 220(100), 165(19), 150(17), 123(18), 94(19).

C20H23NO5< / BR>
Calculated WITH 67,21; N. OF 6.49; N 3,92

Found, 65,35; N Is 6.54; N Of 3.77.

P R I m e p 13. 1-[3- (bicyclo[2.2.1]hept-2-yloxy)-4-methoxyphenyl] alanon(E)-O-(aminocarbonyl)oxy m

A. 3-(bicyclo[2.2.1]hept-2-yloxy)-4-methoxybenzaldehyde.

To stir magnetic stirrer, the solution isovanillin (10 mmol, 1.52 g) in dry tetrahydrofuran (15 ml) at -10aboutTo add the first indoorpool (10 mmol, 1.12 g), and then triphenylphosphine (14 mmol, 3,67 g). After 5 minutes at -10aboutWith added dropwise a solution of diethylazodicarboxylate (14 mmol, 2,44 g, 2,22 ml) in dry tetrahydrofuran (5 ml) and the resulting solution was allowed to warm to room temperature for 20 hours under vacuum to remove the solvent, and the residue is divided between ethyl acetate and water. The organic phase is dried over sodium sulfate and concentrated in vacuo, obtaining the crude product. This product cleans pulse chromatography (silica gel: 20% ethyl acetate/hexane) to give the target compound as a colourless oil (4.07 mmol, 1.00 m g, 41%).

NMR (DMSO-d6, 300 MHz) 9,82 (s, 1H), 55 (DD, J 8,5; 2.0 Hz, 1H), 7,30 (d, J 2.0 Hz, 1H), 7,18 (d, J 8.5 Hz, 1H), 4,30 (d, J 5.0 Hz, 1H), who oxybenzoyl alcohol.

According to the method of example 1B from 3-(bicyclo- [2.2.1]hept-2-yloxy)-4-methoxybenzamide guide (8,53 mmol, 2.10 g) and metallyte (25,58 mmol, 18,28 ml of 1.4 M solution in ethyl ether) in dry tetrahydrofuran (80 ml) receive the crude alcohol. This product is purified chromatographically (silica gel; methylene chloride) to give the target compound as a colourless oil (4,15 mmol, 1,09 g, 49%).

NMR (CDCl3, 300 MHz) : 6,85 (m, 3H), 4,81 (K, 1H), 4,20 (d, J 5.0 Hz, 1H), 3,81 (s, 3H), 2,50 (d, J 5.0 Hz, 1H), 1,75 (m, 3H), of 1.55 (m, 3H), of 1.46 (d, 3H) and 1.15 (m, 3H).

Century 3-(bicyclo[2.2.1]hept-2-yloxy)-4-methoxyacetophenone.

According to the method of example 1B from methyl-3-(bicyclo[2.2.1]hept-2-yloxy)-4-methoxybenzamido alcohol (4,15 mmol, 1,09 g) and bichromate of pyridine (6,23 mmol, of 2.34 g) in dry methylene chloride (50 ml) receive ketone (3,42 mmol, 0,890 g, 82%) as a solid white color, which has a sufficient purity to use it further without additional purification.

NMR (DMSO-d6, 300 MHz) : 7,60 (DD, J 8,5; 2.0 Hz, 1H), 7,27 (d, J 2.0 Hz, 1H), 7,02 (d, J 8.5 Hz, 1H), 4,25 (d, J 5.0 Hz, 1H), 3,80 (s, 3H), of 2.50 (s, 3H), 2,35 (d, J 5.0 Hz, 1H), 2,25 (s, 1H), of 1.85 (m, 1H), 1,45 (m, 4H), of 1.13 (m, 3H).

, 3-(bicyclo[2.2.1]hept-2-yloxy)-4-methoxyacetophenone.

According to the method of example 1G from 3-(Bicycle dry pyridine (40 ml) receive acetophenone in the form of light solid yellow (3,01 mmol, 0,830 g, 88%), the purity of which is sufficient for further use without additional purification.

NMR (DMSO-d6, 300 MHz) of 11.0 (s, 1H), 7,20 (d, J 2.0 Hz, 1H), 7,14 (DD, J 8,5; 2.0 Hz, 1H), 6,93 (d, J 8.5 Hz, 1H), 4,20 (d, J 5.0 Hz, 1H in), 3.75 (s, 3H), 2,35 (d, J 5.0 Hz, 1H), 2,25 (s, 1H), 2,10 (s, 3H), 1,71 (m, 1H), 1,50 (m, 4H) and 1.15 (m, 3H).

D. 1-[3-(bicyclo[2.2.1] hept-2-yloxy)-4-methoxyphenyl] alanon(E)-O-(aminocarbonyl )oxime.

Following the procedure of example 1D, to slowly stir the suspension (16,56 mmol, 1.08 g) in dry methylene chloride (20 ml) is added anhydrous triperoxonane acid (33,05 mmol, of 3.78 g, 2.55 ml) and a solution of 3-(bicyclo[2.2.1] -hept-2-yloxy)-4-methoxyacetophenone (4.14 mmol, 1,14 g) in methylene chloride (20 ml) to give yellow oil, which was purified by impulse chromatography (silica gel: 1) 5% ethyl acetate/methylene chloride; 2) 8% ethyl acetate/methylene chloride; 3) 10% ethyl acetate/methylene chloride). The obtained solid white dried in vacuum, obtaining the analytically pure target compound (0,99 mmol, 0,316 g, 24%).

NMR (DMSO-d6, 300 MHz) : to 7.35 (DD, J 8,5; 2.0 Hz, 1H), 7,34 (d, J 2.0 Hz, 1H), was 7.08 (s, 2H), 6,98 (d, J 8.5 Hz, 1H), 4,36 (d, J 5.0 Hz, 1H), 3,79 (s, 3H), 2,32 (d, J 5.0 Hz, 1H), to 2.29 (s, 3H), and 2.26 (s, 1H), 1,74 (m, 1H), of 1.59 (d, 1H), USD 1.43 (m, 3H), of 1.33 (m, 3H).

IR (KBR) (cm-117H22N2O4< / BR>
Calculated With 64,13; N 6,97; N 8,80.

Found, With 63,96; 6,67 N; N 8,66.

P R I m e R 14. Analysis to assess the ability of the proposed compounds to inhibit PDE IV.

The solution containing PDE IV, was prepared from the tracheal muscle of the dog as follows.

Shot with Nembutal dog (dose of 33 mg/kg) death. Tracheal muscle removed, cleaned of connective tissue and crush thoroughly. 3-4 g of tissue homogenized in Tris-HCl buffer solution (pH 7,8), using the transmitter station. Then homogenized centrifuged at 25000 (4aboutC) for 30 minutes, the Supernatant decanted, filtered through four layers of gauze and passed through a column filled with DEAE-sepharose (column size: 40 cm x 2 cm, the adsorbent acondicionado Tris-HCl-buffer, pH 7,8). Then the column was washed with 240 ml of buffer to remove unbound proteins. PDE elute using 450 ml of Tris-HCl buffer solution with a linear gradient PA-acetate from 0.0 to 1.0 M (80 ml/h); collect 7.5 ml fractions. Each fraction is analyzed by metabolizing activity of PDE in respect of camp and cGMP. Faction, lamivudine at about 0.6 M Na-acetate and having metabolizing activity against which his actions, provided the proposed connections on PDE IV.

The activity of PDE define (see Thompson and other Advanees Cyclic Nucleotide Research, 1979, 10,69) if 30aboutWith in a reaction mixture containing: 10 mm Tris-HCl (pH of 7.8), 5 mm magnesium chloride, 1 mm-mercaptoethanol, 1 μm 3N-camp, 10 μm Cl-930, uterine solution of PDE IV and the test compound at the desired concentration. Cl-930 performs the role of inhibitor-sensitive cGMP selective in respect of camp PDE (PDE III), which is present in the mother solution of PDE IV, when the latter is prepared in the described manner. The ability of test compounds to inhibit PDE IV determined by measuring the slowing metabolism of camp caused by the test compound, and expressing it as a percentage of deceleration caused by 10 μm of rolipram strong inhibitor of PDE IV (see Beavo, Advances in Second Messenger and Phosphoprotein Research, 1988, 22,1). The values of the IC50calculate for each of the tested compounds as the concentration of test compound that inhibits PDE IV 50%

Testing of the proposed compounds gave results shown in table.1.

Tested in this way compounds exhibit high activity in the inhibition of PDE IV.

Proposed connection classifying the/P> Functional test on the inhibition of phosphodiesterase (PDE) III compared to PDE IV in isolated trachea of the Guinea pig.

Purpose.

Functionally to achieve selectivity of inhibition of PDE III in comparison with PDE IV of the test compound, where PDE III indicates PDE, inhibiting C-GMP and selective for C-AMP and PDE IV denotes PDE, insensitive to C-GMP and selective for C-AMP, which are present in the soft muscles of the trachea.

Samples.Use of male Guinea pigs Hartley (350-400 g).

Animals had free access to food and water.

Procedure. Guinea pigs killed by a blow on the head. Reveal the neck and pull the trachea. The trachea contain aerated DCF, cleaned of connective tissue and fat and cut into rings with a width of approximately 2 mm (usually containing two cartilaginous segment on the ring). Then through the opening in the tracheal rings miss two silk suture thread that is knotted around the cartilage one on each side of the tracheal muscle. Then tracheal ring hung on the suture thread between the glass hook and sensor power shift in the bath for bodies with a volume of 10 ml for measurement of isometric tension.

Fabric is about composition, mm: NaCl 118; KH2PO41,18; KCl 4,74; CaCl22, 5; MgSO47H2O 1,19; NaHCO325; dextrose (11,1 mm), and optionally containing cocaine and hydrocortisone (3 x 10-6M and 1 x 10-5M, respectively, with the aim of blocking mechanisms and intravenous unisntalling absorption), propranolol (1x10-6M block-adrenoceptors), phentolamine (1x10-5M block-adrenoceptors), indomethacin (2,8x10-6M, for the inhibition of spontaneous generation of voltage and calcium disodium add (2,6X10-5M, as an antioxidant). For each tissue sample make stationary tension of 2 g and wait about 30 min with frequent washing and adjustable fixed voltage) to stabilize the fabric. After this stable fabric cut by adding carbachol (1x10-6M), and education voltage measured on a polygraph.

Upon reaching a stable level of reduction (approximately 30 min), in a dish add or 1x10-5M of rolipram (Rolipram, an inhibitor of PDE IV) or 1x10-5M imazodan (Imazodan, S, the inhibitor of PDE III), after which the tissue is incubated until a stable voltage level (usually 45 minutes). The ability to feel connected to the dimension of the finite extent of relaxation. After such a determination based concentration response of each tissue sample was washed with DCF and leave the relaxation to the stationary base voltage.

Measure.

Relaxation, stimulated investigational compound, expressed in percent of the maximum stimulated relaxation. The maximum stimulated relaxation is defined as the difference between the voltage in the tissue after its stabilization in the presence of either of rolipram or imazodan, and the final stationary voltage after washing the fabric of the SDF. The results are presented graphically in the form of the dependence of relaxation (%) versus log concentration of the test compounds. An EC50(concentration of test compound causing 50% of maximum possible relaxation) is determined for each tissue sample by linear regression analysis of points in the series with a concentration of 50% For testing each connection using at least three samples of tissue, each of which is taken from various animals.

Because the concentration of C-AMP from the soft muscles of the trachea are regulated as PDE III and PDE IV, and since the t-AMP is a powerful relaxing agistrate tracheal rings. When the tracheal rings pretreated with imazodan (10-5M), PDE III ingibirovany that allows you to explore the "part" of the voltage of the trachea, which is governed by PDE IV and is sensitive to the inhibitors of PDE IV. When the ring-treated rolipram (10-5M), ingibirovany PDE IV, and can be studied inhibitors PDE III. By comparing the activity of the compounds in relation to the relaxation of the trachea in the presence imazodan with activity in the presence of rolipram, you can determine the selectivity of the inhibitor PDE for PDE IV compared to PDE III.

Calculations.

The percentage of relaxation are calculated according to the following formula:

relaxation 100

For each connection size EU50determine the presence or rolipram or imazodan. The value of EC50is defined as the dose of a compound that causes relaxation equivalent to 50% of the maximum possible relaxation.

The selectivity of the test compounds on the inhibition of PDE IV in comparison with PDE III hope so

overactivity

The ratio of the selectivity significantly smaller than the unit is interpreted as an indication of the selectivity of inhibition of PDE III, while the major is commonly 0.2 to 5) can assume either non-selective inhibition of PDE IV and PDE III, either course of relaxation of the trachea by the mechanism without the participation of the PDE.

Subsequent steps.

If detected that the connection is strong (EC50< 3x10-5or is selective with respect to either PDE III or PDE IV, it can be tested in vivo activity against respiratory or cardiovascular systems.

The required number of connections 50-100 mg.

When these tests for compounds according to the invention obtained the following results:

Example Activity (IC50:M)

1 2.8 x 10-8< / BR>
2 7,9 x 10-8< / BR>
3 5.7 x 10-7< / BR>
4 4.1 x 10-6< / BR>
5 3.3 x 10-6< / BR>
6 3.7 x 10-6< / BR>
7 were Not studied

8 1.2 x 10-5< / BR>
9 1.6 x 10-5< / BR>
10 were Not studied

11 6,1 x 10-6< / BR>
12 1.1 x 10-5< / BR>
13 1.3 x 10-7< / BR>
Examples of results with the reference compounds are given in table. 2.

OXYCARBONATE AND OXYCARBONATE General formula I

< / BR>
where R3WITH5-alkyl, C3WITH7-cycloalkyl, bicycloheptane or a group of the formula

< / BR>
n 1 4;

R1lower alkyl or Gruppo formula

< / BR>
R2amino, phenylamino-, lower alkylamino-, the lowest and the

 

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