Derivative of aminobenzoic acid or its pharmaceutically acceptable salt

 

(57) Abstract:

Usage: in search of drugs, manifesting as antagonism to serotonin and activity accelerate excretion of acetylcholine. Essence: derived aminobenzoic acid f-crystals , where R1- cianelli, substituted or unsubstituted cycloalkyl, galijasevic lower alkyl, quinil or tetrahydro-4H-Piran, R2- amino or aceraminophen, R3is halogen, X is a group-NH-, Z -, =N-CH3or N(CH3)O. Reagent 1: the corresponding derivative of benzoic acid. Reagent 2: amino bicyclo[3.2.1]octane. Reaction conditions: aqueous solution of sodium hydroxide, at room temperature, in the presence of pyridine. table 4.

The present invention relates to a derivative of aminobenzoic acid, especially derived aminobenzoic acid, useful as pharmaceuticals, and to a process for their preparation.

The number of patients with unidentified complaints, such as the full feeling of the abdomen, heartburn, nausea and vomiting among patients with gastrointestinal diseases in recent times has been growing steadily and now reaches 60% or above.

Most of these newstravel the IDT, patients with epigastric unidentified complaints such as chronic gastritis, are in a state characterized by a slow release of the stomach, while patients with hypogastruridae unidentified complaints such as irritable bowel syndrome (or mucous colitis), including the main symptoms of abnormal emptying and abdominal pain, are able gastrointestinal hyperkinesis.

It is recognized that stress and anxiety are the cause of any unidentified complaints, and in this sense unidentified complaint is one of the modern diseases.

Dopamine antagonists, acting on the muscle agents for regulating the movement of smooth muscles and accelerators selection of acetylcholine currently used to facilitate the above-mentioned gastrointestinal unidentified complaints. However, antagonists of dopamine cause strong negative reactions, such as Parkinson's disease, so they should be used with great caution, acting on the muscle agents for regulating the movement of smooth muscles cause such a negative reaction, as excessive constipation, and accelerators selection of acetylcholine function h is platonically.

Under these circumstances, the present inventors have conducted studies to develop tools that are effective in treating all types of patients with gastrointestinal unidentified or unclear complaints, without causing any severe adverse reactions, and show depressant activity against anxiety or fear, which almost always appears as one of the causal factors of such patients.

As a result of these studies it was concluded that the above requirements can be fulfilled with the help of medicines, manifesting as the antagonism of serotonin (referred to here below abbreviated as "NT3"), and the activity of accelerating the excretion of acetylcholine (referred to hereafter abbreviated as "h"). Therefore, we carried out further research in order to find compounds with both kinds of activity when a well-balanced combination of activities, and it was found that the above objective can be achieved by using a derivative of aminobenzoic acid represented by the following General formula (I) or its pharmacologically acceptable salt. This image is in the quality of medicines, have been described in the patent publications UK A N1593146 (1981) scourge group Ltd. published July 15, 1981 N2125398 (1984). Sandon AG, Indepedent-GMBH and Sandoz And published on 7 March 1984 and N2205095 (1988) Bristol-Myers Squibb To. and Bristol-Myers To. published November 30, 1989, U.S. patent N4797406 (1985) Sandoz-Patent-GMBH and Sandoz And published on March 19, 1991, European patent publication And N189002 (1986) Sandoz AG, published on 30 July 1986 N220011 (1987) scourge group PLC. published on April 29, 1987, and N302699 (1989) Perdonal SA and Valton SA, published on 8 February 1989 and the patent publication In the UK N2169292 (1988) Sandoz-Ltd. published on 21 September 1988, the compounds of the present invention differ from them according to the chemical structure.

The compound of the present invention is a derivative of aminobenzoic acid, represented by the following General formula, or its pharmacologically acceptable salt:

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where A is an oxygen atom,

R1is cianelli, substituted or unsubstituted cycloalkenyl, galijasevic lower alkyl, quinil or tetrahydro-4H-Piran,

R2represents amino or alkylamino,

R3represents the atom acceptable salt according to the present invention includes inorganic salts, such as hydrochloride, bromohydrin, sulfate and phosphate, organic acid salts such as acetate, maleate, tartrate, methanesulfonate, bansilalpet and toluensulfonate, and salts of amino acids such as arginine, asparagine and glutamate.

Further, derivatives of aminobenzoic acid of the present invention may form a metal salt, such as sodium, potassium, calcium or magnesium salt, or may be present in the form of a hydrate. Pharmacologically acceptable salts of the present invention include the metal salts and hydrates.

Although the compound of the present invention may be present in the form of geometrical isomers or optical isomers, needless to say that the present invention includes all isomers.

Experimental example 1.

Antagonism against the induced 2-methylxanthines contraction or systole ileum.

This experiment was carried out according to the method of the authors Sangeret al. (see Eur. J. Pharmacol. 159, 113 124 (1989)). Non-end portion of the ileum of male Hartley Guinea pigs were suspenderbelt in a solution of Krebs-Hensleit (37oC) applying a load of 0.5 g to the end of the ileum, and the gaseous mixture, include isometrically. After leaving the drug ileum stands for one or more hours without stabilization, to the solution was added a solution of the test compound and after 30 minutes decumulative was added 2-methylsilicone. The value of RA2 was calculated on the basis of a right shift of the curve dose-response reduction caused by 2-methylxanthines caused by the test compound, according to the method Possumet al. (see A. cn. Int. Pharmacodyn. 143, 299 (1963)). BRL 24682 was used as a control in this experiment. The results are given in table 1.

Experimental example 2.

Activity against vomiting hound dogs, caused by cisplatin.

Used hounds dogs weighing 7 to 12 kg 3 mg/kg cisplatin (product of Sigma) (1 mg/kg in saline) was administered to each dog through the veins of the front paw. One hour after administration of cisplatin control group was injected with saline (0.2 ml/kg) experienced group of dogs were administered a solution of the test compound in physiological solution, each dog through a vein of the other front paw. The incidence of vomiting observed over the 5-hour period from the time of introduction of cisplatin, has been recorded, and the degree of inhibition of the Sabbath." >

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Experimental example 3.

Activity promotion (evocations) function of gastric emptying.

This experiment was carried out according to the method Decktoret al. (see Eur. J. Pharmacol. 147, 313 316 (1988)). Male rats Fscher (weight: 160 to 180 g) were kept in starvation for 18 hours before orally to each rat was given 3 ml of experienced food, including methylcellulose, beef broth, casein, sugar and cornstarch. An hour after the appointment of food the stomach is completely removed from each rat. The degree of gastric emptying was calculated on the basis of weight experienced food remaining in the stomach. The degree of stimulation of the function of gastric emptying was determined by comparing the degree of gastric emptying in rats subjected to treatment with a degree of control rats, which was not appointed to any of the test compounds. Each test compound was administered orally one hour before the introduction of the experimental feed. As a control in this experiment was used BP 24682.

The results are given in table 3.

Experimental example 4.

The effect of increasing the contractions of the ileum of the Guinea pig induced by stimulation in an electric field.

This experimenral pigs were separated and vertically was suspenderbelt in solution (37oC) in a Magnus tube while applying a load of 0.5 g to the end of the muscle. After the solution was passed mixed gas, comprising 98% oxygen and 5% carbon dioxide. Muscle contraction was determined isometrically. In order to cause muscle contraction, muscle stimulation was applied in the electric field when using a platinum electrode once in 10 seconds. The reduction was caused by releasing acetylcholine. After the muscle has stabilized, the tube Magnus cumulative was added to a solution of the test compound with an interval of 10 minutes. The effect of the tested compounds are presented in percentage on the basis of the initial reduction. The minimum concentration of each test compound at which the reduction was found to increase due to the allocation of acetylcholine, shown in table 4.

From the results of the above pharmacological experiments can be understood that the compounds of the present invention have the antagonism of 5-HT3and activity expedite the disbursement ACh and, therefore, effective in the sense of being able to call functions of the gastrointestinal tract, such as the function of gastric emptying, and are useful as antiemetics.

and allocation of ACh, making it useful as a medicinal product on the basis of these activities.

Activity accelerate excretion of acetylcholine based on 5-HT4antagonistic activity of the compounds according to the present invention.

The compound of the present invention is effective against various diseases, and specific examples of diseases include irritable bowel syndrome, peptic esophagitis, nausea, vomiting, abdominal pain and bloating caused by chronic gastritis, bathygastry, the syndrome of post-gastrectomy or similar, gastrointestinal symptoms and gastrointestinal failure, represented by the diseases caused by the appointment of anticancer funds or irritation during irradiation, anxiety, migraine syndrome of memory loss.

In addition, the compound of the present invention is less toxic and highly safe, being, therefore, valuable in this sense.

When the compounds obtained in the following examples 4 and 43, each was administered orally to rats for one week at a dose up to 30 mg/kg, did not manifest any signs of toxicity.

The compound of the present invention is administered as a therapeutic and prophylactic agent of the above diseases in the form of tablets, powders, granules, capsules, syrups and inhaled drugs. Although the dose of it in an appreciable extent varies depending on the degree of symptoms, age and type of disease, the dose for an adult per day is about 0.01 to 1000 mg, preferably 0.1 to 500 mg, more preferably 0.1 to 100 mg which may be administered in one to several portions a day.

When the compound of the present invention is administered in the form of injection, the dose is usually 1 to 3000 μg-kg, preferably from about 3 to 1000 μg/kg

The preparations according to the present invention are prepared using conventional media in the usual way.

More specifically, the solid preparation for oral administration according to the present invention is prepared by adding a filler and, if necessary, a binder, disintegrator, lubricant agent, coloring matter and/or corrigenda to the active ingredient to forming the resulting mixture into tablets, coated tablets, granules, powders or capsules common ways.

llulose and silicon dioxide, examples of the binder include polyvinyl alcohol, polyvinyl ether, ethylcellulose, methylcellulose, gum acacia, tragacanth, gelatin, shellac, hydroxypropylcellulose, hypromellose, calcium nitrate, dextrin and pectin, examples of lubricants include magnesium stearate, talc, polyethylene glycol, silicon dioxide and utverjdenie vegetable oil, examples of coloring agents include substances permitted authoritative bodies as pharmaceutical additives, and examples corrigentov include powder, cocoa, mint herb, aromatic powder, peppermint oil, borneol and powdered cinnamon bark. Of course, pills and granules can be suitably coated with sugar, gelatin or similar if necessary.

Injecting the drug according to the present invention is prepared by adding to the desired active ingredient pH regulator, buffer, stabilizer and/or solubilizing agent and converting the mixture into injecting drug for subcutaneous, intramuscular or intravenous injection using a conventional process.

Examples.

Now will be described examples according to the present invention, although the present group. ///Example 2 A.

Methyl 4-acetamido-5-chloro-2-(3-pentyn-2-yl)oxy benzoate

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Triphenylphosphine (146,4 g) was dissolved in tetrahydrofuran (500 ml). To the resulting solution at -65oC in a stream of nitrogen, gradually, drop by drop, in this order were added diethylazodicarboxylate (97,2 g), 3-penten-2-ol (33,2 g) and a solution of methyl-4-acetamido-5-chlorosalicylic (80 g) in tetrahydrofuran (1.4 l). The temperature of the reaction mixture was raised to room temperature, and the reaction mixture stirred over night at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (200 ml) and dropwise with stirring was added n-hexane (1: 3 l). The crystals precipitated thereby was filtered off and the filtrate was concentrated in vacuum. The residue was purified using chromatography on a column over silica gel, giving of 74.3 g of target compound.

1H-NMR (400 MHz, CDl3) million dollars.

of 1.65 (d, J 5.5 Hz, 3H), 1,82 (d, J 2.0 Hz, 3H), and 2.26 (s, 3H), 3,86 (c, 3H), 4,85, 4,94 (m, 1H), 7,72 (Shir. C. 1H), 7,88 (s, 1H), 8,46 (s, 1H).

Example Century.

Methyl 4-amino-5-chloro-2-{(3-pentyn-2-yl)}oxy benzoate

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To a suspension of methyl 4-acetamido-5-chloro-2-(3-phenyl-2-yl)-hydroxy benzoate (73,3 g) in methanol (700 ml), pool temperature. After the reaction mixture was stirred over night at room temperature, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution (5 l), gradually. The crystals precipitated thereby was removed by filtration, rinsed with water and dried, giving 66.5 g of the target compound as colorless crystals.

1H-NMR (400 MHz, CDl3) million dollars.

of 1.66 (d, J 6.5 Hz, 3H), of 1.81 (d, J 2.0 Hz, 3H), 3,81 (s, 3H), to 4.41 (Shir. C. 2H), 4,70 4,78 (m, 1H), 6,53 (s, 1H), 7,82 (s, 1H).

Example C.

4-amino-5-chloro-2-{(3-pentyn-2-yl)oxy}benzoic acid

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To a suspension of methyl 4-amino-5-chloro-2-(3-pentyn-2-yl)-hydroxy benzoate (56,0 g) in methanol (1.3 l) was added water 5 standards. a solution of sodium hydroxide (140 ml). The resulting mixture was mixed for 6 hours at 50oC and then 3 days at room temperature. To the mixture was added water (1 l) followed by acidification 2 standards. the hydrochloric acid. The crystals thus obtained were removed by filtration, rinsed with water and dried, giving 51,5 g of the target compound as colorless crystals.

1H-NMR (400 MHz, CDl3) million dollars.

1,50 (D. J 6,50 Hz, 3H), 1,79 (d, J 2.0 Hz, 3H), 4,81, Entin-2-yl)oxy}benzoic acid

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()-4-amino-5-chloro-2-{ (3-pentyn-2-yl)oxy} benzoic acid (15.2 g) was dissolved in ethanol (105 ml) and to the resulting solution at room temperature was added a solution of (+)-dehydroabietylamine (17.1 g) in ethanol (15 ml). The resulting mixture was defended on the table for 2 hours. The crystals thus obtained were removed by filtration and mixed with a small amount of ethanol. Then the crystals were dissolved in water 1 standards. the sodium hydroxide solution, and extraction was carried out with dichloromethane. The aqueous phase was padillas of concentrated hydrochloric acid, then was extracted with chloroform. The organic phase was dried and concentrated in vacuo, giving to 4.23 g of white crystals.

These crystals were dissolved in ethyl acetate (70 ml) and the resulting solution was added (S)-(-)-naphthylethylene or 2.67 ml). The mixture, thus obtained, was defended on the table for 1 hour. The crystals thus obtained were removed by filtration and were washed with a small amount of ethyl acetate. Then the crystals were dissolved in 1 norms. hydrochloric acid and extraction was carried out with chloroform. The organic phase was dried and concentrated in ve (45 ml) and the resulting solution was added (S)-(-)-naphthylethylene (1,41 ml). The mixture, thus obtained, was defended on the table for 1 hour. The crystals precipitated thereby was removed by filtration and were washed with a small amount of ethyl acetate. Then the crystals were dissolved in 1 norms. hydrochloric acid and extraction was carried out with chloroform. The organic phase was dried and concentrated in vacuo, yielding 1.50 g (99,6%) target compound as white crystals.

Example 1.

Endo-4-amino-5-chloro-N-(8-methyl-8-azabicyclo[3.2.1] Oct-3-yl)-{(3-pentyn-yl)oxy}-benzamide

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400 mg of 4-Amino-5-chloro-2-(3-pentyn-2-yl)oxy benzoic acid and 400 mg of endo-3-amino-8-methyl-8-azabicyclo[3.2.1]octane were dissolved in 20 ml of pyridine followed by the addition of 0.38 ml of 5 standards. an aqueous solution of sodium hydroxide under stirring at room temperature. The resulting mixture was mixed for 10 minutes followed by the addition of 650 mg of 1,3-dicyclohexylcarbodiimide. The resulting mixture was stirred at room temperature for 8 hours, followed by adding 30 ml of water. The resulting mixture was filtered to remove insoluble substances and the filtrate was podslushivaet aqueous solution of sodium hydroxide and was extracted with chloroform. Organizea using chromatography through silica gel (10% methanol/chloroform), giving 450 mg of the target compound as white crystals.

1H-NMR (400 MHz, d6-DM) million dollars. 1,56, of 1.65 (m, 5H), 1,75, 1,85 (MS, 5H), 1,95, to 2.13 (m, 4H), to 2.18 (s, 3H), 3.00 and, of 3.13 (m, 2H), 3,93, of 4.00 (m, 1H), of 5.05, 5,13 (m, 1H), of 5.89 (Shir.s, 2H), 6,59 (s, 1H), of 7.70 (s, 1H), 8,87 (d, J 6.0 Hz, 1H).

So pl. 173 175oC.

Example 2.

Endo-4-amino-5-chloro-N-[8-methyl-8-azabicyclo[3.2.1]-Oct-3-yl)-2-{(3-Penta - in-2-yl)oxy}benzamide hydrochloride

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450 mg of endo-4-amino-5-chloro-N-8-methyl-(8-azabicyclo(3.2.1)Oct-3-)-yl-2- (3-pentyn-2-yl)oxy} benzamide was dissolved in 5 ml of ethanol, followed by addition of ethanolic hydrochloric acid and diethyl ether in this order. Besieged thus salt was removed by filtration. Did 320 mg of the target compound as pale yellow crystals.

1H-NMR (400 MHz, d6-DM) million dollars. to 1.60 (d, J 6.5 Hz, 3H), 1,82(D. J 2.0 Hz, 3H), 1,98 2,48 (m, 8H), of 2.64 (d, J 6.0 Hz, 5H), 3.75 to 3,98 (m, 2H), 4,05 3,95 (m, 1H), of 5.05 to 5.13 (m, 1H), 5,95 (Shir.s, 2H), and 6.6 (s, 1H), 7,63 (C. 1H), 7,92 (D. J 5.0 Hz, 1H).

Example 3.

(-)-endo-4-Amino-5-chloro-N-(8-methyl-8-azabicyclo(3.2.1) Oct-3-yl)-2-(3-pentyn-2-yl)oxy}benzamide.

(+)-endo-4-amino-5-chloro-N-(8-methyl-8-azabicyclo(3.2.1)Oct-3-yl)-2- (3-pentyn-2-yl)oxy}benzamide.

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800 mg of racemic modification by swedesplease chiral column (product of the company Daicel chemical industries, Ltd. Chiralcel Ml) and solvent in the mobile phase (ethanol:hexane:triethylamine 20:80:0,1), yielding 370 mg (-)-isomer and 300 mg (+)-isomer; (-)-isomer 1H-NMR (400 MHz, CDl3) million dollars.

1,68 of 1.83 (m, 5H), 1,84 (D. J 3.0 Hz, 3H), 1,85 1,95 (m, 3H), 2,05 2,15 (m, 2H), measuring 2.20 to 2.29 (m, 2H), 2,30 (s, 3H), 3,11 3,18 (m, 2H), 4,17 of 4.25 (m, 1H), 4,35 (Shir. s, 2H), 4,93 (square J 3.0 Hz, 7.0 Hz, 1H), 6,46 (s, 1H), 7,98 (d, J 5.5 Hz, 1H), of 8.09 (s, 1H).

(+)-isomer1H-NMR (400 MHz, CDl3d million dollars.

1,79 1,66 (m, 5H), 1,84 (D. J 3.0 Hz, 3H), 1,85 1,94 (m, 2H), 2.06 to to 2.15 (m, 2H), 2,20 2,3 (m, 2H), 2,32 (s, 3H), 3,10 3,18 (m, 2H), 4.16 the 4,24 (m, 1H), 4,93 (square sq, J 3.0 Hz, 7.0 Hz, 1H), 6,46 (s, 1H), 7,98 (D. J 5.5 Hz, 1H), 8,08 (s, 1H).

So pl. 144 145oC.

Example 4.

(-)-endo-4-Amino-5-chloro-N-(8-methyl-8-azabicyclo-(3.2.1)Oct-3-yl)-2-(3-pentyn-2-yl)oxy}benzamide hydrochloride

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1.85 g of (-)-endo-4-Amino-5-chloro-N-(8-methyl-8-azabicyclo(3.2.1) Oct-3-yl)-2- (3-pentyn-2-yl)oxy}benzamide was dissolved in 9 ml of ethanol followed by the addition of 2.46 ml 2 standards. hydrochloric acid and 90 ml of water, in that order. The resulting mixture was subjected to drying by freezing, giving 1,99 g target hydrochloride (-)-isomer.

Mz m/z(FAB): 376 (M++11H-NMR (400 MHz, d6-DM) million dollars. 1,62 (D. J 6.5 Hz, 3H), 1,84 (D. J 2.0 Hz, 3H), 2,03 at 2.45 (m, 8H), 2,67 (D. J 5.1 Hz, 3H), 3,91 3,82 (m, 2H), 4,00 4,05 (m, 1H), 5,10 5,14 (M. the value was obtained by the method, similar to the method of example 1.

Example 5.

Endo-4-Amino-5-chloro-N-(8-methyl-8-azabicyclo(3.2.1) Oct-3-yl-2- (1-penten-3-yl)oxy}benzamide

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1H-NMR (400 MHz, d6-DM) million dollars. of 1.03 (t, J 8 Hz, 3H), of 1.52 (t, J 12.0 Hz, 2H), 1,68 1,74 (m, 2H), 1,84 2,12 (m 6N), and 2.14 (C. 3H), 3,03 (Shir. C. 2H), 3,93 was 4.02 (m, 1H), 4,94 (so J 4.0 Hz, 1H), 5,94 (C. 2H), 6,60 (s, 1H), to 7.67 (C. 1H), 7,78 (D. J 6.0 Hz, 1H).

So pl. 182 184oC.

Example 6.

Endo-4-Amino-5-chloro-N-(8-methyl-8-azabicyclo(3.2.1)Oct-3-yl)-2 - propargylamine

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1H-NMR (400 MHz, d6-DM) million dollars. of 1.50 to 1.70 (m, 2H), 1,75 1,90 (m, 2H), 1,03 of 2.13 (m, 4H), 2,22 (s, 3H), 3,10 3,20 (m, 2H), 3,81 (so J 2 Hz, 1H), 3,94 to 4.01 (m, 1H), 4,88 (D. J 2 Hz, 2H), 5,99 (Shir.with. 2H), 6,52 (C. 1H), to 7.67 (C. 1H), 7,99 (D. J 5 Hz, 1H).

Example 7.

Endo-4-Amino-2-(2-butenyloxy)-5-chloro-N-(8-methyl-8-azabicyclo (3.2.1)Oct-3-yl)benzamide

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1H-NMR (400 MHz, d6DM) million dollars. 1,51 1,58 (m, 2H), 1,75 1,83 (m, 2H), 1,84 (so J 2.5 Hz, 3H), 1,95 2,10 (m, 4H), 2,15 (C. 3H), 3,03 3,00 (m, 2H), 3,98 3,96 (m, 1H), 4,82 (sq J 2.5 Hz, 2H), 5,97 (C. 2H), 6,50 (C. 1H), 7,69 (C. 1H), 8,06 (D. J 7 Hz, 1H).

So pl. 188 191oC.

Example 8.

Endo-4-Amino-5-chloro-N-(8-methyl-8-azabicyclo(3.2.1)Oct-3-yl)-2-3 - pentyloxy benzamide

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1H-NMR (400 MHz, d6-DM) million dollars. 1,68 1,58 (m, 2H), 1,71 (so J 2.5 Hz, 3H), 1,73 1,80 (m, 2H), 1,90 2CLASS="ptx2">

Example 9.

Endo-4-Amino-3-{ (3-Butin-2-yl)oxy)} -5-chloro-N-(8-methyl-8-azabicyclo (3.2.1)Oct-5-yl)benzamide

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1H-NMR (400 MHz, d6-DM) million dollars.

of 1.52 to 1.60 (m, 2H), 1,64 (D. J 6.5 Hz, 3H), 1,71 of 1.78 (m, 2H), 2,08 1,95 (m, 4H), 2.13 in (C. 3H), 2,97 3,03 (m, 2H), 3,70 (D. J 3.0 Hz, 1H), 3,93 of 3.99 (m, 1H), 5,14 (doctor of square J a 3.0 and 6.5 Hz, 1H), 5,97 (Shir. s, 2H), 6,59 (C. 1H), 7,78 (C. 1H), 7,81 (D. J 6.5 Hz, 1H).

Example 10.

Endo-4-Amino-5-chloro-2-{(4-hepten-3-yl)oxy}-N-(8-methyl-8-azabicyclo(3.2. 1)Oct-3-yl)benzamide

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1H-NMR (400 MHz, CDl3) million dollars.

1,10 (so J 8.0 Hz, 3H), 1.12 in (I. J 8.0 Hz, 3H), 1,71 2,31 (m N), 2,32 (C. 3H), and 3.16 (Shir.s, 2H), 4,20 (DD. J 4,0, and 11.0 Hz, 1H), 4,35 (Shir.s, 2H), 4,73 4,78 (m, 1H), gold 6.43 (C. 1H), 7,98 (Shir.with. 1H), 8,09 (C. 1H).

Example 11.

Endo-4-Amino-5-chloro-2-{(4-heptyn-2-yl)oxy}-N-(8-methyl-8-azabicyclo(3.2. 1)Oct-3-yl)benzamide

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1H-NMR (400 MHz, CDl3) million dollars.

of 1.10 (t, J 7.5 Hz, 3H), 1,52 (D. J 6.0 Hz, 3H), 1,74 of 1.92 (m 6N), of 2.08 to 2.18 (m, 3H), 2.26 and was 2.34 (m, 1H), 2,33 (C. 3H), 2,52 (A2BCX type, J 2,5; 7,5; 16.0 Hz, 1H), 2,64 (A2BX type, J 2,5; 2,5; 16.0 Hz, 1H), 3,20 (Shir.with. 2H), 4.16 the 4,24 (m, 1H), 4,33 (Shir.with. 2N), to 4.52 4,63 (m, 1H), 6,32 (C. 1H), of 7.96 (Shir.with. 1H), 8,10 (C. 1H).

Example 12.

Endo-4-Amino-5-chloro-2-{(2-hexyne-4-yl)oxy}-N-(8-methyl-8-azabicyclo(3.2. 1)Oct-3-yl)benzamide

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1H-NMR (400 MHz, d6-DM) MLM. 1H), 4,88 4,94 (m, 1H), of 5.92 (Shir.with. 2H), 6,58 (C. 1H), 7,68 (C. 1H), 7,85 (D. J 6.0 Hz, 1H).

Example 13.

Endo-4-Amino-5-chloro-2-{(3-hexyne-2-yl)oxy}-N-(8-methyl-8-azabicyclo(3.2. 1)Oct-3-yl)benzamide

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1H-NMR (400 MHz, d6-DM+CDl3) million dollars.

of 1.02 (t, J 7.5 Hz, 3H), 1,55 1,65 (m, 5H), 1,73 1,85 (m, 2H), 1,95 2,10 (m, 4H), 2,15 2,23 (m, 5H), 3,00 3,13 (m, 2F), 4,00 3,93 (m, 1H), 5,12 (square so J 6,5; 2.0 Hz, 1H), 5,93 (Shir.s, 2H), 6,59 (C. 1H), 7,69 (C. 1H), 7,89 (D. J 6.0 Hz, 1H).

So pl. 144 145oC.

Example 14.

Endo-4-Amino-5-chloro-2-{ (1-hexyne-3-yl)oxy} -N-(8-methyl-8-azabicyclo (3.2.1)Oct-3-yl)benzamide

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1H-NMR (400 MHz, d6-DM) million dollars.

of 0.93 (t, J 7.5 Hz, 3H), 1,40 -1,60 (m, 4H), of 1.6 to 1.75 (m, 2H), 1,80 2,22 (m 6N), 2,15 (C. 3H), 3.00 and (Shir.with. 2H), 3,70 (C. 1H), 3,90 4,00 (m, 1H), 4.95 points (so J 4.0 Hz, 1H), 5,94 (Shir.with. 2H), 6,60 (C. 1H), 7,69 (C. 1H), 7,76 (D. J 6.0 Hz, 1H).

Example 15.

Endo-4-Amino-5-chloro-2-(2-floratone)-N-(8-methyl-8-azabicyclo(3.2.1) Oct-3-yl)benzamide

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1H-NMR (400 MHz, d6-DM) million dollars.

of 1.50 to 1.60 (m, 2H), 1,62 of 1.75 (m, 2H), 1,90 of 2.18 (m, 4H), 2.13 in (C. 3H), 2,98 3,03 (m, 2H), 3,95 4,00 (m, 1H), 4,25 to 4.28 (m, 1H), 4,32 of 4.35 (m, 1H), 4,75 of 4.77 (m, 1H), 4,88 of 4.90 (m, 1H), of 5.92 (Shir. s, 2H), 6,55 (C. 1H), 7,68 (C. 1H), to 7.77 (D. J 7.0 Hz, 1H).

Example 16.

Endo-4-Amino-5-chloro-2-(3-cyanopropyl)-N-(8-methyl-8-azabicyclo (3.2.1)Oct-3-yl)benthami the,66 (so J 7.0 Hz, 2H), 2,97 to 3.02 (m, 2H), 3,94 to 3.99 (m, 1H), 4,14 (so J 6.0 Hz, 2H), 5,90 (Shir. s, 2H), 6,50 (C. 1H), 7,66 (C. 1H), 7,80 (D. J 7.0 Hz, 1H).

Example 17.

Endo-4-Amino-5-chloro-2-(1-cyclopentyloxy)-N-(8-methyl-8-azabicyclo (3.2.1)Oct-3-yl)benzamide

< / BR>
1H-NMR (400 MHz, d6-DM) million dollars.

1,18 1,35 (m, 5H), 1,43 of 1.65 (m 6N), from 1.66 to 1.83 (m, 4H), 1.93 and - of 2.23 (m, 8H), 3,01 of 3.13 (m, 2H), 4,00 3,93 (m, 1H), 4,22 or 4.31 (m, 1H), of 5.84 (C. 2H), 6,56 (C. 1H), 7,70 (C. 1H), of 7.96 (D. J 5.5 Hz, 1H).

Example 18.

Endo-4-Amino-5-chloro-N-(8-methyl-8-azabicyclo(3.2.1) Oct-3-yl)-2-tetrahydro-4H-Piran-4-hydroxy-benzamide

< / BR>
1H-NMR (400 MHz, d6-DM) million dollars.

1,53 of 1.80 (m 6N), 1,93 2,13 (m 6N), 2,17 (C. 3H), 3,00 3,13 (m, 2H), 3,38 -3,48 (m, 2H), 3,88 3,98 (m, 3H), 4,51 br4.61 (m, 1H), 5,85 (Shir.with. 2H), 6,62 (C. 1H), 7,68 (s, 1H), 7,85 (D. J 6.0 Hz, 1H).

Example 19.

Endo-4-Amino-5-chloro-2-(4-methoxycyclohexyl)-N-(8-methyl-8-azabicyclo(3.2.1)Oct-3-yl)benzamide

< / BR>
1H-NMR (400 MHz, d6-DM) million dollars.

of 1.20 to 1.35 (m, 1H), 1,43 by 1.68 (m, 4H), 1,69 1,81 (m, 3H), 1,82 is 1.91 (m, 1H), 1,95 2,25 (m, 10H), 3,23 (C. 3H), 3,26 to 3.36 (m, 2H), 3,39 to 3.50 (m, 1H), 3,91 of 4.00 (m, 1H), 4,30 4,43 (m, 1H), of 5.83 (Shir.with. 2H), 6,57 (C. 1H), 7,68 (C. 1H), 7,85 (D. J 5.0 Hz, 1H).

Examples 20 to 34.

The following compounds were obtained in a manner analogous to that presented in example 2.

BR>
1H-NMR (400 MHz, d6-DM) million dollars.

of 1.02 (t, J 8 Hz, 3H), 1,82 2,12 (m 6N), 2,24 2,21 (m, 2H), 2,44 2,40 (m, 2H), 2,62 (D. J 6.0 Hz, 3H), and 3.72 (C. 2H), 3,82 (Shir.with. 2H), 3,93 a 4.03 (m, 1H), is 4.93 (t, J 4.0 Hz, 1H), 6,62 (C. 1H), 7,60 (C. 1H), 7,86 (D. J 5.0 Hz, 1H).

MC m/z (FAB), 376 (M++1.

Example 21.

Endo-4-amino-5-chloro-(8-methyl-8-azabicyclo(3.2.1) Oct-3-yl) -2-propargylamines hydrochloride

< / BR>
1H-NMR (400 MHz, d6-DM) million dollars.

1,90 2,10 (m, 2H), 2,11 2,30 (m, 4H), 2,41 of 2.53 (m, 2H), 2.63 in (C. 3H), and 3.72 (t, J 2.0 Hz, 1H), 3,78 of 3.85 (m, 2H), 3,94 a 4.03 (m, 1H), 4,86 (D. J 2.0 Hz, 1H), 6,01 (Shir. s, 2H), 6,53 (C. 1H), 7.62mm (C. 1H), 8,00 (D. J 5.0 Hz, 1H).

So pl. 242 245oC.

Example 22.

Endo-4-Amino-2-(2-butenyloxy)-5-chloro-(8-methyl-8-azabicyclo(3.2.1)Oct-3-yl) benzamide hydrochloride

< / BR>
1H-NMR (400 MHz, d6-DM) million dollars.

1,86 (Shir. s, 3H), from 2.00 to 2.06 (m, 2H), 2,15 2,31 (m, 4H), 2,36 of 2.45 (m, 2H), 2,65 (C. 3H), 3,80 3,88 (m, 2H), 3.96 points of 4.04 (m, 1H), 4,8 (Shir. C. 2H), 6,00 (Shir. C. 2H), 6,50 (C. 1H), 7,63 (C. 1H), 8,05 (D. J 7.0 Hz, 1H).

MC m/z (FAB), 362 (M++1.

So pl. 263 265oC.

Example 23.

Endo-4-Amino-5-chloro-N-(8-methyl-8-azabicyclo(3.2.1)Oct-3-yl)-2- (3-pentyloxy)benzamide hydrochloride

< / BR>
1H-NMR (400 MHz, d6-DM) million dollars.

1,74 (so to 2.5 Hz, 3H), 2.06 to to 2.15 (m, 2H), 2,20 2,30 (m

MC m/z (FAB), 376 (M++1).

Example 24.

Endo-4-Amino-2-{ (3-Butin-2-yl)oxy} -5-chloro-N-(8-methyl-azabicyclo (3.2.1)Oct-3-yl)benzamide hydrochloride

< / BR>
1H-NMR (400 MHz, d6-DM) million dollars.

1,63 (D. J 6.5 Hz, 3H), 1,97 2,30 (m 6N), 2,46 to 2.57 (m, 2H), 2,61 (D. J 5.0 Hz, 3H), 3,71 (D. J 3.0 Hz, 1H), 3,78 of 3.85 (m, 2H), 3,95 4,00 (m, 1H), 4,68 (Shir. s, 2H), 5,12 (doctor of square J a 3.0 and 6.5 Hz, 1H), 6,62 (C. 1H), to 7.61 (C. 1H), 7,88 (D. J 6.0 Hz, 1H), is 10.68 (Shir. C. 1H).

MC m/z (FAB), 362 (M++1).

So pl. 154 158oC.

Example 25.

Endo-4-Amino-5-chloro-2-[(4-hepten-3-yl)oxy] -N-(8-methyl-8-azabicyclo (3.2.1)Oct-3-yl)benzamide hydrochloride

< / BR>
1H-NMR (400 MHz, d6-DM) million dollars.

0,98 1,08 (m 6N), 1,78 of 2.30 (m, 10H), 2,58 2,50 (m, 2H), 2.63 in (D. J 5.0 Hz, 3H), 3,83 (Shir. C. 2H), 4,00 3,93 (m, 1H), 4,90 4,96 (m, 1H), 6,63 (C. 1H), to 7.64 (C. 1H), 7,94 (Shir. C. 1H).

Example 26.

Endo-4-Amino-5-chloro-2-{ (4-heptyn-2-yl)oxy} -N-(8-methyl-8-azabicyclo (3.2.1)Oct-3-yl)benzamide hydrochloride

< / BR>
1H-NMR (400 MHz, d6-DM) million dollars.

0,99 (so J 7.5 Hz, 3H), 1,40 (D. J 4.0 Hz, 3H), 2,00 2,16 (m 6N), 2,30 2,18 (m, 2H), 2.40 a of 2.54 (m, 2H), 2.57 m) to 2.66 (m, 2H), 2.63 in (D. J 5.0 Hz, 3H), 3,84 (Shir. s, 2H), 3,94 to 3.99 (m, 1H), 4.53-in to 4.62 (m, 1H), 6,56 (C. 1H), 7,66 (C. 1H), 7,92 (D. J 5.0 Hz, 1H), the 10.40 (Shir. C. 1H).

Example 27.

Hydrochloride endo-4-amino-5-chloro-2-{ (2-hexyne-4-tx2">

a 1.01 (t, J 7.5 Hz, 3H), 1,84 (D. J 2.0 Hz, 3H), 1,85 2,10 (m 6N), 2,23 of 2.33 (m, 2H), 2,39 2,50 (m, 2H), 2,65 (D. J 6.0 Hz, 3H), 3,81 3,88 (m, 2H), 3.96 points of 4.04 (m, 1H), 4,88 of 4.95 (m, 1H), 5,95 (Shir. C. 2H), 6,61 (C. 1H), 7,63 (C. 1H), 7,92 (D. J 6.0 Hz, 1H).

So pl. 137 141oC.

Example 28.

Hydrochloride endo-4-amino-5-chloro-2-{(3-hexyne-2-yl)-oxy}-N-(8-methyl-8-azabicyclo (3.2.1)Oct-3-yl)benzamide

< / BR>
1H-NMR 400 MHz, d6-DMO) million dollars.

1,04 (so J and 7.6 Hz, 3H), 1,60 (D. J 6.5 Hz, 3H), 1,98 of 2.33 (m, 8H), 2,38 of 2.58 (m, 2H), 2,65 (D. J 5.0 Hz, 3H), 3,80 3,90 (m, 2H), 3.96 points of 4.04 (m, 1H), 5,11 (square so J of 6.5, 2.0 Hz, 1H), 5,98 (Shir.with. 2H), 6,61 (C. 1H), to 7.64 (C. 1H), 7,94 (D. J 5.0 Hz, 1H).

So pl. 134 136oC.

Example 29.

Hydrochloride-endo-4-amino-5-chloro-2-{ (1-hexyne-3-yl)oxy}-N- (8-methyl-8-azabicyclo(3.2.1)Oct-3-yl)benzamide

< / BR>
1H-NMR (400 MHz, d6-DM) million dollars.

of 0.93 (t, J 7.5 Hz, 3H), 1,42 1,55 (m, 2H), 1,67 of 2.15 (m 6N), 2,20 2,30 (m, 2H), 2,40 2,50 (m, 2H), 2.63 in (D. J 5.0 Hz, 3H), 3,70 (C. 1H), 3,78 of 3.85 (m, 2H), 3,95 was 4.02 (m, 1H), 4,96 (so J 4.0 Hz, 1H), 5,20 (Shir.with. 2H), 6,62 (C. 1H), 7,60 (C. 1H), 7,82 (D. J 6.0 Hz, 1H).

MC m/z (FAB), 390 (M++1).

So pl. 138 140oC.

Example 30.

Hydrochloride endo-4-amino-5-chloro-2-(2-floratone)-N-(8-methyl-8-azabicyclo (3.2.1)Oct-3-yl)benzamide

< / BR>
1H-NMR (400 MHz, d6-DM), mln.

1,94-of 2.23 (m 6N), 2,40 2,527,67 (C. 1H), 7,95 (so J 7.0 Hz, 1H).

So pl. 260 262oC.

Example 31.

Hydrochloride endo-4-amino-5-chloro-2-(3-cyclopropane)-N-(8-methyl-8-azabicyclo (3.2.1)Oct-8-yl)benzamide

< / BR>
1H-NMR (400 MHz, d6-DM) million dollars.

2,03 2,13 (m 6N), 2,22 of 2.27 (m, 2H), 2,38 of 2.46 (m, 2H), 2,64 (D. J 5.4 Hz, 3H), 2,68 (so J 7.5 Hz, 2H), 3,82 (m, 2H), 3,94 4,00 (m, 1H), 4,12 (so J 6.8 Hz, 2H), 5,93 (Shir. C. 2H), 6,52 (C. 1H), 7,56 (C. 1H), 7,88 (D. J 4.8 Hz, 1H), 10,14 (Shir. C. 1H).

MC m/z (FAB), 377 (M++H)+.

So pl. 130 132oC.

Example 32.

Hydrochloride endo-4-amino-5-chloro-2-(1-cyclopentyloxy)-N-(8-methyl-8-azabicyclo (3.2.1)Oct-3-yl)benzamide

< / BR>
1H-NMR (400 MHz, d6-DM) million dollars.

1,16 1,33 (m, 5H), 1,43 of 1.65 (m, 4H), 1,66 1,80 (m, 2H), 1,88 - of 2.08 (m, 4H), 2,10 2,18 (m, 1H), 2,20 2,35 (m, 2H), 2,38 to 2.65 (m, 5H), 3,79 3,86 (m, 2H), 3,95 to 4.01 (m, 1H), 4,23 or 4.31 (m, 1H), 6,59 (C. 1H), 7,65 (C. 1H), 7,98 (D. J 5.0 Hz, 1H), 10,55 (Shir.with. 1H).

So pl. 154 156oC.

Example 33.

Hydrochloride endo-4-amino-5-chloro-N-(8-methyl-8-azabicyclo(3.2.1) Oct-3-yl)-2- (tetrahydro-4-Piran-4-oxy)benzamide

< / BR>
1H-NMR (400 MHz, d6-DM) million dollars.

1,55 1,68 (m, 2H), 2,01 2,12 (m 6N), 2,23 of 2.30 (m, 2H), 2,35 at 2.45 (m, 2H), 2,64 (D. J 5.0 Hz, 3H), 3,38 of 3.48 (m, 2H), 3,80 a 3.87 (m, 2H), 3,89 4,00 (m, 3H), 4,50 4,59 (m, 1H), 5,88 (Shir.with. 2H), 6,63 (C. 1H), to 7.61 (C. 1H), of 7.90 (D. J 6,0 is illogically)-N-(8-methyl-8-azabicyclo (3.2.1)Oct-3-yl)benzamide

< / BR>
1H-NMR (400 MHz, d6-DM) million dollars.

1,20 1,30 (m, 1H), 1,38 1,58 (m, 2H), 1,80 1,75 (m, 1H), 1,80 1,90 (m, 1H), 1,95 2,15 (m, 7H), 2,20 2,30 (m, 2H), 2,35 2,45 (m, 2H), 2.63 in (C. 3H), 3,20 3,14 (m, 1H), 3,23 (C. 3H), 3,80 3,88 (m, 2H), 4,00 3,93 (m, 1H), 4,28, however, 4.40 (m, 1H), 5,86 (Shir. C. 2H), 6,58 (C. 1H), to 7.61 (C. 1H), to $ 7.91 (D. J 5.0 Hz, 1H).

Example 35.

(-)-endo-4-Amino-5-chloro-N-(8-methyl-8-azabicyclo(3.2.1) Oct-3-yl)- 2-{ (1-pentyn-3-yl)oxy}benzamide.

(+)-endo-4-Amino-5-chloro-N-(8-methyl-8-azabicyclo(3.2.1) Oct-3-yl)- 2-{ (1-pentyn-3-yl)oxy}benzamide

< / BR>
Named in the title compound was obtained according to the method similar to the method of example 3.

(-) isomer

So pl. 179 182oC

(+) isomer

So pl. 183 184oC.

Examples 36 to 38.

The following compounds were obtained according to the method similar to the method of example 4.

Example 36.

Hydrochloride (-)-endo-4-amino-5-chloro-N-(8-methyl-8-azabicyclo(3.2.1)Oct-3-yl)-2-(3-pentyn-2-yl)oxy}benzamide

< / BR>
1H-NMR (400 MHz, d6-DM) million dollars.

1,60 (D. J 6.5 Hz, 3H), 1,82 (D. J 2.0 Hz, 3H), 2,09 1,95 (m, 2H), 2,10 2,17 (m, 2H), 2,23 2,32 (m, 2H), 2,45 2,33 (m, 2H), 2,65 (D. J 5.0 Hz, 3H), 3,86 3,82 (m, 2H), 3,98 is 4.03 (m, 1H), 5,06 5,14 (m, 1H), 5,98 (Shir. C. 2H), 6,60 (C. 1H), 7,63 (C. 1H), 7,92 (D. J 5.0 Hz, 1H).

MC m/z (FAB), 376 (M++1).

[]2D597,25yl)-2-(1-penten-3-yl)oxy}benzamide

< / BR>
1H-NMR (400 MHz, d6-DM) million dollars.

of 1.02 (t, J 8.0 Hz, 3H), 1,82 2,12 (m 6N), 2,24 2,21 (m, 2H), 2,44 2,40 (m, 2H), 2,62 (D. J 6.0 Hz, 3H), and 3.72 (C. 2H), 3,82 (Shir.with. 2H), 3,93 a 4.03 (m, 1H), is 4.93 (t, J 4.0 Hz, 1H), 6,62 (C. 1H), 7,60 (C. 1H), 7,86 (D. J 5.0 Hz, 1H).

MC m/z (FAB), 376 (M++1).

[]2D5-74,55o(c 1,12, MeOH).

So pl. 144 147oC.

Example 38.

Hydrochloride (+)-endo-4-amino-5-chloro-N-(8-methyl-8-azabicyclo(3.2.1)Oct-3-yl-2-(1-penten-3-yl)oxy}benzamide

< / BR>
1H-NMR (400 MHz, d6-DM) million dollars.

of 1.02 (t, J 8.0 Hz, 3H), 1,82 2,12 (m 6N), 2,24 2,21 (m, 2H), 2,44 2,40 (m, 2H), 2,62 (D. J 6.0 Hz, 3H), and 3.72 (C. 2H), 3,82 (Shir.with. 2H), 3,93 a 4.03 (m, 1H), is 4.93 (t, J 4.0 Hz, 1H), 6,62 (C. 1H), 7,60(C. 1H), 7,86 (D. J 5.0 Hz, 1H).

MC m/z (FAB), 376 (M++1).

[]2D576,36o(c 1,10, MeOH).

So pl. 146 148oC.

Example 39.

Endo-4-Amino-5-chloro-N-(8-methyl-8-azabicyclo(3.2.1) Oct-3-yl)-2- (4-penten-2-yl)oxy}benzamide

< / BR>
10 g of 4-amino-5-chloro-2-{ (4-penten-2-yl)oxy} benzoic acid and 10 g of endo-3-amino-8-methyl-8-azabicyclo(3.2.1)octane were dissolved in 50 ml of pyridine followed by the addition of 9.4 ml of 5 standards. an aqueous solution of sodium hydroxide and 16.1 g of dicyclohexylcarbodiimide in this order. The resulting mixture was mixed the tion was filtered off, and the obtained filtrate was podslushivaet 5 standards. aqueous solution of sodium hydroxide and was extracted with chloroform. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and concentrated in vacuum. The residue was purified using chromatography on silicagel column (10% methanol/chloroform) to give 10.7 g of the target compound as colorless crystals.

1H-NMR (400 MHz, CDl3), mln.

1,54 (D. J 6.0 Hz, 3H), 1,74 of 1.88 (m, 4H), for 2.01 to 2.13 (m, 3H), 2,21 of 2.30 (m, 2H), 2,30 (C. 3H), 2,58 (A2BX type, J 3,0; 7,0; of 17.0 Hz, 1H), 2,58 (A2BX type, J 3,0; 5,0; of 17.0 Hz, 1H), 3,13 3,19 (m, 2H), 4,18 to 4.23 (m, 1H), or 4.31 to 4.38 (Shir. C. 2H), 4,60 4,69 (m, 1H), 6,32 (C. 1H), 7,89 (D. J 3.0 Hz, 1H), 8,10 (C. 1H).

So pl. 208 209oC.

Example 40.

Endo-4-Amino-5-chloro-N-(8-methyl-8-azabicyclo(3.2.1)Oct-3-yl)-2- ((4-penten-2-yl)oxy)benzamide hydrochloride

< / BR>
130 mg of endo-4-amino-5-chloro-N-(8-methyl-8-azabicyclo(3.2.1)Oct-3-yl)-2- (4-penten-2-yl)oxy} benzamide was dissolved in 2 ml ethanol. The resulting solution was pagkilala adding 20% of a mixture of hydrochloric acid/ethanol under cooling with ice, followed by addition of diethyl ether. Fallen thus precipitated crystals were separated by filtration and dried, giving 140 mg CE>/P>1,41 (D. J 6.0 Hz, 3H), 2,03 to 2.14 (m, 4H), 2,29 2,21 (m, 2H), 2.40 a of 2.53 (m, 2H), 2,60 of 2.68 (m, 5H), 3,01 (so J 3.0 Hz, 1H), 3,80 - of 3.85 (m, 2H), 3,98 4,00 (m, 1H), 4,60 of 4.66 (m, 1H), 6,57 (C. 1H), to 7.67 (C. 1H), 7,86 (D. J 3.0 Hz, 1H).

So pl. 139 141oC.

Example 41.

(+)-endo-4-Amino-5-chloro-N-(8-methyl-8-azabicyclo(3.2.1)Oct-3-yl)-2- (4-penten-2-yl)oxy}benzamide

(-)-endo-4-Amino-5-chloro-N-(8-methyl-8-azabicyclo(3.2.1)Oct-3-yl)-2- (4-penten-2-yl)oxy}benzamide

< / BR>
1,65 g racemic modification of the compound was subjected to liquid chromatography high resolution using a chiral column (product Daicel chemical industries, Ltd. Chiracel Ml) and solvent in the mobile phase (ethanol: hexane:triethylamine 20:80:0,1), yielding 480 mg (+)-isomer and 450 mg (-)-isomer.

(+)-isomer1H-NMR (400 MHz, CDl3) million dollars.

1,54 (D. J 6.0 Hz, 3H), 1,83 1,71 (m, 4H), for 2.01 to 2.13 (m, 3H), 2,21 of 2.30 (m, 2H), 2,30 (C. 3H), 2,58 (A2BX type, J 3.0 Hz, 7,0; of 17.0 Hz, 1H), 2,68 (A2BX type, J 3,0; 5,0; of 17.0 Hz, 1H), 3,13 3,19 (m, 2H), 4,18 to 4.23 (m, 1H), 4,35 (Shir. C. 2N), with 4.64 (so sq J 6,0; 6,0 Hz, 1H), 6,32 (C. 1H), 7,89 (D. J 5.5 Hz, 1H), 8,10 (C. 1H).

(-)-isomer1H-NMR (400 MHz, CDl3d million dollars.

1,54 (D. J 6.0 Hz, 3H), 1,71 of 1.88 (m, 4H), 2,05 2,15 (m, 2H), 2,20 2,30 (m, 2H), 2,30 (C. 3H), 2,58 (A2BX type, J 3,0, 7,0; of 17.0 Hz, 1H), 2,68 (A2BX type, J 3,0; 5,0; of 17.0 Hz, 1H), 3,13 3,19 (m, 2H), 4,15-endo-4-amino-5-chloro-N-(8-methyl-8-azabicyclo(3.2.1)Oct-3-yl)-2-(4-penten-2-yl)oxo}benzamide hydrochloride

< / BR>
309 mg (+)-endo-4-amino-5-chloro-(8-methyl-8-azabicyclo(3.2.1)Oct-3-yl)-3-((3-pentyn-2-yl)oxo)benzamide was dissolved in 1.5 ml of ethanol followed by the addition 0,411 ml 2 standards. hydrochloric acid and 15 ml of water, in that order. The resulting mixture was subjected to drying by freezing, giving 333 g of the hydrochloride of (+)-isomer.

1H-NMR (400 MHz, d6-DM) million dollars.

1.44MB (D. J 6.5 Hz, 3H), 2,07 2,17 (m, 4H), 2.26 and is 2.37 (m, 2H), 2,38 2,43 (m, 2H), 2,65 a 2.71 (m, 5H), 3.00 and (so J 2.5 Hz, 1H), 3,82 - 3,93 (m, 2H), 4,01 of 4.05 (m, 1H) and 4.65 (so sq J 6,0; 6,0 Hz, 1H), 5,91 (Shir. C. 2H), 6,59 (C. 1H), 7,69 (C. 1H), 7,88 (D. J 5.0 Hz, 1H), 9,87 (C. 1H).

MC m/z (FAB), 376 (M++1).

Example 43

(-)-endo-4-Amino-5-chloro-N-(8-methyl-8-azabicyclo)-(3.2.1)Oct-3-yl-2-((4 - penten-2-yl)oxy)benzamide hydrochloride

< / BR>
The target compound was obtained according to the method similar to the method of example 42.

1H-NMR (400 MHz, d6-DM) million dollars.

1,42 (D. J 6.0 Hz, 3H), 2,04 of 2.13 (m, 4H), of 2.23 and 2.27 (m, 2H), 2,35 2,43 (m, 2H), 2,67 2,62 (m, 5H), 3,01 (so J 3.0 Hz, 1H), 3,80 - a-3.84 (m, 2H), 3.96 points of 4.00 (m, 1H), with 4.64 (so sq J 6.0 Hz, 1H), 6,57 (C. 1H), 7,66 (C. 1H), 7,87 (D. J 5.0 Hz, 1H).

MC m/z (FAB), 376 (M++1).

[]2D5= -8,88o(c 1.07, and MeOH).

Example 44.

Endo-4-Acetamido-2-(3-butenyloxy)-5-chloro-N-8-methyl-8-azabicyclo (3.2.1)Oct-3-yl)benzamide.1)-octane was dissolved in 5 ml of pyridine followed by the addition of 0.2 ml of 5 standards. an aqueous solution of sodium hydroxide and 300 mg (1,3-dicyclohexylcarbodiimide in this order. The resulting mixture was stirred at room temperature overnight followed by the addition of water. Insoluble matter precipitated thereby was filtered, and the filter was podslushivaet aqueous solution of sodium hydroxide and was extracted with chloroform. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and concentrated in vacuum. The residue was purified using chromatography on silicagel column (10% methanol/chloroform) to give 130 mg of the target compound as colorless crystals.

1H-NMR (400 MHz, CDl3) million dollars.

1,85 1,93 (m, 2H), 2.06 to (so J 3.0 Hz, 1H), 2.13 and to 2.18 (m, 2H), and 2.27 (C. 3H), 2,30 of 2.38 (m, 4H), 2,78 (D. T. J 3,0; 7,0 Hz, 2H), 3,20 of 3.28 (m, 4H), 4,20 4.26 deaths (m, 1H), 4,35 (so J 7.0 Hz, 2H), 7,75 for 7.78 (m, 1H), 8,05 8,9 (m, 1H), 8,23 (C. 1H), 8,33 (C. 1H).

Example 45.

Endo-4-Amino-2-(3-butenyloxy)-5-chloro-N-(8-methyl-8-azabicyclo (3.2.1)Oct-3-yl)benzamide

< / BR>
130 mg of endo-4-acetamido-2-(3-butenyloxy)-5-chloro-N-(8-methyl-8-azabicyclo (3.2.1)Oct-3-yl)benzamide was dissolved in 5 ml of methanol followed by the addition of a solution of 200 mg of sodium hydroxide in 1 ml of water. Obtained Birmingham, distinguished by filtration, rinsed with water and dried, giving 120 mg of the target compound as colorless crystals.

1H-NMR (400 MHz, d6-DM) million dollars.

1,64 1,58 (m, 2H), 1,70 1,75 (m, 2H), 1,94 of 2.09 (m, 4H), 2,12 (C. 3H), 2,72 (D. T. J 3,0; 7,0 Hz, 2H), 2,96 to 3.02 (m, 3H), 3.27 to of 3.32 (m, 2H), 3,92 of 3.96 (m, 1H), 4,17 (so J 7.0 Hz, 2H), 5,88 of 5.92 (m, 2H), 6,50 (C. 1H), 7,70 (C. 1H), 7,88 (D. J 7.0 Hz, 1H).

Example 46.

Endo-4-Amino-2-(3-butenyloxy)-5-chloro-N-(8-methyl-8-azabicyclo (3.2.1)Oct-3-yl)benzamide hydrochloride

< / BR>
20 mg of endo-4-amino-2-(3-butenyloxy)-5-chloro-N-(8-methyl-8-azabicyclo (3.2.1)Oct-3-yl)benzamide was dissolved in a mixture containing 1 ml of ethanol and 7 ml of water, followed by adding 28 μl 2 standards. an aqueous solution of hydrochloric acid. The resulting mixture was subjected to drying by freezing, giving 20 mg of the target compound as colorless crystals.

1H-NMR (400 MHz, d6-DM) million dollars.

to 2.06 of 2.15 (m, 4H), 2,23 of 2.30 (m, 2H), 2,31 is 2.40 (m, 2H), 2,65 (C. 3H), 2,69 (D. T. J 3,0; 7,0 Hz, 2H), 3,01 (so J 3.0 Hz, 1H), 3,81 - 3,86 (m, 2H), 3.96 points to 4.01 (m, 1H), 4,15 (so 7,0 Hz, 2H), 6,51 (C. 1H), 7,65 (C. 1H), to $ 7.91 (D. J 7.0 Hz, 1H).

MC m/z (FAB), 362 (M+++).

So pl. 226 229oC.

Example 47.

(S)-endo-4-Amino-5-chloro-N-(8,8-dimethyl-8-azoniabicyclo(3.2.1)Oct-3-yl)-2-(3-pentyn-2-yl)oxy}be samida was dissolved in 2 ml of ethanol followed by the addition of 0.1 ml under the conditions at room temperature. After stirring the resulting solution for four hours, precipitated crystals were separated by filtration, were washed twice with a small amount of cold ethanol and dried, giving 257 mg of the target compound as white crystals.

1H-NMR (400 MHz, d6-DM) million dollars.

1,59 1,60 (doctor 3H), 1,82 1,83 (doctor 3H), 1,90 a 1.96 (m, 2H), 2,16 - 2,20 (doctor 2H), 2,42 2,38 (m, 2H), 2,50 at 2.59 (m, 2H), 3,01 (C. 3H), 3,12 (C. 3H), 3,84 (Shir. C. 2H), 4,10 to 4.16 (DD. 1H), 5,03 of 5.11 (m, 1H), 5,99 (C. 2H), 6,60 (C. 1H), 7.62mm (C. 1H), 7,92 7,95 (D. 1H). MC m/z (FAB), 390 (M+).

So pl. 195oC (sec.).

Example 48.

(S)-endo-4-amino-5-chloro-N-(8-methyl-8-azabicyclo(3.2.1)Oct-3-yl)-2-(3-pentyn-2-yl)oxy}benzamide 8-oxide

< / BR>
1.13 g (S)-endo-4-amino-5-chloro-N-(8-methyl-8-azabicyclo(3.2.1)Oct-3-yl)-2-{ (3-pentyn-2-yl)oxy} benzamide was dissolved in 50 ml of dichloromethane followed by the addition 0,81 g m-chlormadinone acid under ice cooling. The resulting solution was stirred for half an hour. After completion of the reaction, the reaction mixture thus obtained were washed with saturated aqueous sodium bicarbonate solution and saturated aqueous common salt in this order, dried over magnesium sulfate. After the solvent was evaporated, the residue is about> million.

1,65 1,67 (2 x d, J 6.5 Hz, 3H), 1,83 1,84 (2 x d, J 1.5 Hz, 3H), 1,90 2,40 (m 6N), 2,47 to 2.57 (m, 1H), 2,86 2,79 (m, 1H), 3,27, 3,30 (C. x 2, 3H), 3,43, 3,66 (2 x m, 2H), 4,30 (m, 1H), to 4.41; 4,45 (2 x width.with. 2H), 4,88 (m, 1H), 6.42 per, to 6.43 (C. x 2, 1H), is 3.08; 8,10 (2 x C. 1H), 8,00; 8,14 (- x with Shir. D. J 6.5 Hz, 1H).

MC m/z (FAB), 392 (M++1).

Example 49.

(S)-Enzo-4-Amino-5-chloro-N-(8-methyl-8-azabicyclo(3.2.1)Oct-3-yl)-2- (3-pentyn-2-yl)oxy}benzamide

< / BR>
The target compound was obtained from Exo-3-amyotrophy and (S)-4-amino-5-chloro-2-{ (3-pentyn-2-yl)oxy} benzoic acid by the method similar to the method of example 1.

1H-NMR (400 MHz, CDl3) million dollars.

1,68 (D. J 6.5 Hz, 3H), 1,83 (D. J 2.0 Hz, 3H), 1,73 1,88 (m, 4H), 1,92 2,02 (m, 2H), 2.05 is to 2.14 (m, 2H), 2,38 (C. 3H), of 3.32 (m, 2H), 4,32 (m, 1H), 4,42 (Shir. C. 2H), 4.75 in a 4.83 (m, 1H), 6.48 in (C. 1H), to 7.64 (Shir. D. J 5.0 Hz, 1H), 8,01 (s, 1H).

MC m/z (FAB), 376 (M++1).

Example 50.

Hydrochloride (S)-Exo-4-amino-5-chloro-N-(8-methyl-8-azabicyclo(3.2.1)Oct-3-yl)-2-(3-pentyn-2-yl)oxy}benzamide

< / BR>
The target compound was obtained according to the method similar to the method of example 2.

1H-NMR (400 MHz, d6-DM) million dollars.

1,63 (D. J 6.5 Hz, 3H), 1,81 (D. J 1.5 Hz, 3H), 1,88 2,25 (m, 8H), 2,61 (D. J 6.0 Hz, 3H), 3,85 (m 2N), is 4.21 (m, 1H), to 4.98 (m, 1H), 6,59 (C. 1H), to 7.64 (D. J 5.5 Hz, 1H), 7,65 (C. 1H), 10,94 (Shir.with. 1H).

1. Derivative of aminobenzoic acid of General formula

< / BR>
where And oxygen;

R1cianelli, substituted or unsubstituted cycloalkenyl, galijasevic lower alkyl, quinil or tetrahydro-4H-Piran;

R2amino - or aceraminophen;

R3halogen;

X group-NH-;

Z N CH3N(CH3)2the process(CH3)

or its pharmaceutically acceptable salt.

2. Connection on p. 1, characterized in that it is a racemic mixture, or its pharmacologically acceptable salt.

3. Connection on p. 1, characterized in that it is a (+)isomer or its pharmacologically acceptable salt.

4. Connection on p. 1, characterized in that it is a (-)isomer or its pharmacologically acceptable salt.

5. Connection on p. 1, characterized in that it And the oxygen, R1quinil, R2amino, R is adusei activity of accelerating the release of acetylcholine and antagonistic activity to serotonin.

 

Same patents:

The invention relates to new derivatives of 1-phenyl-3-azabicycloalkanes-2-ones, to a method for producing them, to pharmaceutical compositions containing them and to their use as therapeutic agents

The invention relates to new compounds with pharmacological activity, in particular bicyclic 1-Aza-cycloalkanes General formula

(I) where R is lower alkyl, unsubstituted or substituted furan, thiophene or imidazole; alkenyl with 3-6 carbon atoms; quinil with 3-6 carbon atoms; phenyl, unsubstituted or substituted lower alkyl, alkoxygroup or by halogen; benzyl, unsubstituted or substituted by halogen; pyridyl; pyrimidinyl;

A, b and C independently of one another denote-CH2or a simple bond;

n is 0 or 1, mixtures of isomers, or individual isomers and their pharmacologically tolerable acid additive salts exhibiting holinoliticheskoy properties

The invention relates to medicine, namely to anesthesiology, and can be used in anesthetic ensuring operations on the brain

The invention relates to medicine, and concerns the use of CIS-1-(33-acetylthiophene)-6-methylpiperidine acid, known as compounds having antihypertensive activity, as a means for the treatment of acute and chronic heart failure

The invention relates to a series of new derivatives of 1-[(2-benzhydrylamine)-4-piperidyl]aliphatic acid having excellent antihistaminic, anti-allergic and anti-asthma activity, which do not have side effects that are typical for compounds with activity of this type

The invention relates to the chemistry of physiologically active compounds

The invention relates to compounds of the formula I

(I) or pharmaceutically acceptable salt accession acids him or stereoisomeric form of the compound, where

-A1= AND2- A3= AND4- bivalent radical having the formula

-CH=CH-CH=CH- (a-1)

-N=CH-CH=CH- (a-2)

-CH=CH-CH=N (a-5) or

-N=CH-N=CH- (and-6),

n=1 or 2

IN - NR4or CH2< / BR>
R4is hydrogen or C1-C6alkyl

L is hydrogen, C1-C6alkyl, C1-C6allyloxycarbonyl, or a radical of the formula

-Alk - R5(b-1),

-Alk - Y - R6(b - 2),

-Alk - Z1- C(=X) - Z2- R7(b-3), or

-CH2- SNON - CH2- O - R8(b-4), where R5is cyano, phenyl optionally substituted C1-C6alkyloxy; pyridinyl; 4,5-dihydro-5-oxo-1-N-tetrazolyl; 2-oxo-3-oxazolidinyl; 2,3-dihydro-2-oxo-1-N-benzimidazolyl; or bicycling radical of formula (C-4-a)

Gwhere G2- CH=CH-CH=CH-, -S-(CH2)3,- -S-(CH2)/2-, -S-CH=CH - or-CH=C(CH3)-O-;

R6- C1-C6-alkyl, pyridinyl optionally substituted by nitro; pyrimidinyl; feast
R7- C1-C6-alkyl; halophenol; 1-methyl-1H-pyrrolyl; furanyl, thienyl, or aminopyrazine;

R8- halophenol;

Y is O or NH;

Z1or Z2each independently NH or a direct link X-O

each Аlk independently - C1-C6alcander

The invention relates to new biologically active chemical compounds, in particular to cyclic amino compounds of the formula I

BANwhere In - perederina, piperidinyl or pyrrolidinyl group, each of which may be substituted by a lower alkyl group, lower alkylcarboxylic group, carbobenzoxy, afterburner (lower) accelgroup, phenylketone (lower) alkyl group, phenylcarbamoyl (lower) alkyl group or phenyl (lower) alkyl group, each of which may be substituted by a halogen atom or a lower alkoxygroup; p is 1 or 2; And -- is a bond, or two-, or trivalent aliphatic C1-6hydrocarbon residue which may be substituted by a lower alkyl group, oxo, hydroximino or hydroxy-group;means either simple or double bond, provided that when a represents a bond, thenmeans of a simple bond; R2and R3independent means ATO condition, both R2and R3are not hydrogen atoms, or R2and R3together with the adjacent nitrogen atom form piperidino, hexamethyleneimino, morpholino, pyrolidine, pieperazinove or 1-imidazolidinyl group, each of which may be substituted by a lower alkyl group, a phenyl (lower) alkyl group, a lower alkylcarboxylic group or diphenyl (lower) alkyl group or a physiologically acceptable salt additive acid

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new sulfur-containing compounds of the formula (I):

their pharmaceutically acceptable salts or solvates, or salt solvates wherein R1 represents (C1-C6)-alkyl, cycloalkyl, aryl, aliphatic or aromatic heterocyclyl substituted with one more basic group, such as amino-, amidino- and/or guanidine-group; R2 represents hydrogen atom (H), alkyl, alkylthio-, alkoxy- or cycloalkyl group; R3 represents COOR5, SO(OR5), SOR5 and others; R4 represents hydrogen atom (H) or (C1-C6)-alkyl; R6 represents hydrogen atom (H); X represents C(Z)2 or NR6CO; Y represents C(Z)2; Z represents hydrogen atom (H), (C1-C6)-alkyl, aryl or cycloalkyl. Indicated compounds inhibit activity of carboxypeptidase U and can be used for prophylaxis and treatment of diseases associated with carboxypeptidase U.

EFFECT: improved preparing method, valuable biochemical and medicinal properties of compounds.

14 cl, 36 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes N-substituted azaheterocyclic carboxylic acids and their esters of the formula (I):

wherein R1 and R2 represent independently hydrogen, halogen atom, NR6R7 or (C1-C6)-alkyl; Y represents >N-CH2 or >C=CH2- wherein only underlined atom is a component of the ring system; X represents -O-, -S-, -CH2CH2- wherein R6 and R7 represent independently (C1-C6)-alkyl; r = 1, 2 or 3; Z represents heterocycle taken among formulas (a), (b), (c), (d), (f), (k), (g) and (j) given in the invention claim. Also, invention relates to a method for their preparing and pharmaceutical composition based on compounds of the formula (I). Invention describes a method for inhibition of neurogenous pain, inflammation and blood glucose level increase to patient by administration to patient the effective dose of compound of the formula (I). Compounds of the formula (I) elicit ability to inhibit the neurogenous pain and blood glucose enhanced level.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

13 cl, 1 tbl, 30 ex

FIELD: organic chemistry, chemical technology, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of sulfonamides of the formula (I) or their pharmaceutically acceptable salts wherein R1 means -OH or -NHOH; R2 means hydrogen atom; R3 means alkyl, alkoxyalkyl, arylalkyl, pyridylalkyl or morpholinylalkyl; A means piperidyl or tetrahydrofuranyl; n = 0; E means a covalent bond; (C1-C4)-alkylene, -C(=O)-, -C(=O)O- or -SO2-; X means hydrogen atom, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl; each among G and G' means -C(R5)=C(R5') wherein R5 and R5' mean hydrogen atom; M means the group -CH-; z means the group -(CR7R7')a-L-R8 wherein a = 0 and each among R7 and R7' means hydrogen atom; L means a covalent bond; R8 means halogen atom or alkoxy-group. Compounds of the formula (I) are inhibitors of metalloproteases and can be used for treatment of arthritis, cancer tumors and other diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indolylpiperidine of the formula (I): wherein A1 means (C1-C7)-alkylene, (C1-C7)-alkyleneoxy-, (C1-C7)-alkylenethio-, (C1-C7)-alkanoyl, hydroxy-(C1-C7)-alkylene; A2 means a single bond, (C1-C7)-alkylene, (C2-C5)-alkenylene; W means a single bond, phenylene, furanylene that is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkoxy- and/or alkyl groups; R1 means hydrogen atom (H), (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C2-C5)-alkoxyalkyl, (C3-C7)-alkenyloxyalkyl, (C3-C7)-alkynyloxyalkyl, (C3-C7)-alkoxyalkoxyalkyl, phenyl-(C1-C7)-alkyl wherein phenyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy- or arylalkoxy- (preferably with phenylalkoxy-) groups, or means (C3-C10)-cycloalkyl-(C1-C7)-alkyl wherein cycloalkyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy-groups; R2 means hydrogen atom (H), halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-; R3 means carboxyl, tetrazolyl, and to their pharmaceutically acceptable salts. Compounds of the formula (I) elicit antihistaminic and anti-allergic activity that allows their using in composition used for treatment of allergic diseases including bronchial asthma, rhinitis, conjunctivitis, dermatitis and nettle rash. Also, invention describes methods for preparing compounds of the formula (I).

EFFECT: valuable medicinal properties of compounds.

15 cl, 2 sch, 3 tbl, 162 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to treatment of patients suffering from diseases associated with pathologic activity of matrix proteases. Treatment involves administration of compounds depicted by general formula (I).

EFFECT: increased treatment efficiency.

136 cl, 448 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-aminopyridine derivatives of formula I , wherein R1 is cyano, carboxyl or carbamoyl; R2 is hydrogen, hydroxyl, C1-C6-alkoxy or phenyl; R3 and R4 are aromatic hydrocarbon such as phenyl or naphthyl, 5-14-membered 5-14-membered optionally substituted aromatic group, excepted cases, when (1) R1 is cyano, R2 is hydrogen, and R3 and R4 are simultaneously phenyl;(2) R1 is cyano, R2 is hydrogen, R3 is 4-pyridyl, and R4 is 1-pyridyl; (3) R1 is cyano, R2 is 4-methylphenyl, and R3 and R4 are simultaneously phenyl;(4) R1 is cyano, R2, R3 and R4 are simultaneously phenyl, or salts thereof. Derivatives of present invention have adenosine receptor antagonist activity and are useful in medicine for treatment of irritable bowel syndrome, constipation, and defecation stimulation.

EFFECT: 2-aminopyridine derivatives as adenosine receptor antagonists useful in medicine.

34 cl, 2 tbl, 179 ex

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