Derivatives oxa - or thiadiazole, the retrieval method (variants), pharmaceutical composition

 

(57) Abstract:

Describes new compounds of formula I, where R1represents a C1-C6alkyl, halo-(C1-C6alkyl), C2-C6quinil, hydroxy-(C2-C6quinil), phenyl, naphthyl, heteroaryl selected from the group comprising thienyl, pyridyl, thiazolyl, benzothiazolyl, R2represents N or C1-C4alkyl, R3represents naphthyl or phenyl, possibly substituted by one or two1-C4by alkyl, halogen, C1-C4alkoxyl, hydroxyl, heteroaryl selected from the group comprising thienyl, 2,3-dihydrobenzofuranyl, X is oxygen, and Y represents a direct bond, -CH2- or-CH2O-, or a pharmaceutically acceptable salt. These compounds are antagonists at the muscarinic receptor, which can be used in the treatment of, for example, irritable bowel syndrome, and incontinence. These compounds can also be used as enhancers of recognition. 5 C. and 13 C.p. f-crystals, 1 table.

The technical field

This invention relates to substituted derivatives of oxadiazole and thiadiazole. The compounds according to izobreteny is ulatory through cardiac muscarinic sites and do not have any significant antihistaminic activity.

Description

These compounds may be used in the treatment of diseases associated with changes in motility and/or tone of smooth muscles, which can be, for example, found in the intestine, trachea, and urinary bladder. Such diseases include irritable bowel syndrome (mucous colitis), diverticulitis, urinary incontinence, the esophageal achalasia and chronic obstruction of the respiratory tract.

These compounds can also be used as enhancers recognition and, thus, for the treatment of diseases that cause memory impairment, such as Alzheimer's disease and age-related memory disorders.

In accordance with this invention provides compounds of formula:

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where R1represents a C1-C6alkyl, halo- (C1-C6alkyl), C3-C7cycloalkyl, C2-C6quinil, hydroxy-(C2-C6quinil), (C1-C4alkoxy) - (C2-C6quinil), aryl, aryl- (C1-C4alkyl), heteroaryl or heteroaryl- (C1-C4alkyl);

R2represents H or C1-C4alkyl;

R3represents aryl, heteroaryl, 2,3 - digidrive the>, -(CH2)2or-CH2O-;

and their pharmaceutically acceptable salts.

Under the "halo" refers to chlorine, bromine, fluorine or iodine.

Preferred aryl groups are phenyl and naphthyl, each of which optionally has up to three substituents independently selected from C1-C4of alkyl, C1-C4alkoxyl, hydroxyl, halogen and trifloromethyl.

More preferably, the aryl group selected from phenyl, optionally substituted by one or two substituents, each of which is independently selected from C1-C4of alkyl, C1-C4alkoxyl, hydroxyl, halogen and trifloromethyl, and naphthyl.

Most preferably, the aryl group represents a phenyl, forfinal, dichlorophenyl, hydroxyphenyl, methoxyphenyl or naphthyl.

Preferred heteroaryl groups are thienyl, pyridyl, thiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl and pyrimidinyl, each of which is optionally substituted by one or two substituents independently selected from C1-C4of alkyl, C1-C4, alkoxyl, hydroxyl and halogen.

More preferred heteroaryl groups is ethyl and ethyl. Preferred CNS groups are methoxy and atoxyl. Preferred halogen groups are chlorine, bromine and fluorine. Preferred cycloalkyl groups are cyclobutyl, cyclopentyl and cyclohexyl, especially cyclobutyl. Preferred alkenylphenol group is ethinyl. Preferred hydroxy-(C2-C6quinil) groups are HO-CH2CC - HO-(CH2)4-CC-. Preferred haloalkyl groups are trifluoromethyl and pentafluoroethyl.

R1preferably represents C1-C6alkyl, pentafluoroethyl, C4-C6cycloalkyl, ethinyl, -CC-CH2OH, - CC-(CH2)4OH, phenyl group, optionally substituted by one or two substituents, each of which is independently selected from halogen, C1-C4of alkyl, C1-C4alkoxyl and hydroxyl; naphthyl or heterocyclic group selected from tanila, pyridyl, thiazolyl and benzothiazolyl, each of which is optionally substituted with halogen, C1-C4the alkyl, C1-C4alkoxyl or hydroxyl.

R2preferably represents H or CH3.

R3preferably before the IMO selected from halogen, C1-C4of alkyl, C1-C4alkoxyl and hydroxyl; 2,3-dihydrobenzofuranyl; C4C7cycloalkyl or thienyl.

X preferably represents 0.

Y preferably represents a direct bond, -CH2- or-CH2O-.

Pharmaceutically acceptable salts of the compounds of formula (I) include acid salts of joining, such as hydrochloride, hydrobromide, hydrohloride, sulfates or bisulfate, phosphates or hydrogen phosphates, acetates, besylate, citrates, fumarate, gluconate, lactate, maleate, mesylates, succinate and tartratami. A more detailed list of pharmaceutically acceptable salts are described, for example, in the Journal of Pharmaceutical Sciences, I. 66, No. 1, January 1977, pp. 1-19. These salts can be obtained in the usual way, for example by mixing a solution of the free base and acid in a suitable solvent, for example ethanol, and recovering the acid salt of accession or in the form of sediment, or by evaporation of the solution.

The compound (I) can contain one or more optically active centers, and the invention includes both divided and undivided form. Divided forms may be obtained by conventional means, for example a liquid is eating through education suitable salts or derivatives thereof.

One way of preparing compounds (I) include ketones (II):

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where X, Y, R2and R3have the meanings specified for formula (I), by reaction with a Grignard reagent, an organolithium or thereorganization reagent of the formula:

R1MgHal, R1Li or R1CeCl2< / BR>
where Hal represents Cl or Br, in a suitable organic solvent.

When using organolithium or areorganized reagent reaction is usually carried out at low temperature, i.e. at 0oC or below, preferably at about -78oC.

The preferred organic solvent is tetrahydrofuran.

The preferred Grignard reagents are bromide of magnesium.

The Grignard reagents can be produced in situ, for example by the addition of a halide of formula R1Hal dropwise to the suspension under rotation of magnesium in an organic solvent, such as diethyl ether, at a rate sufficient to maintain reflux distilled. After stirring for approximately 30 minutes at room temperature the resulting solution containing the Grignard reagent, added dropwise to a solution of ketone (II) in a suitable body is n from the reaction mixture in the usual way.

New intermediate compounds (II) are also included in the scope of this invention.

The intermediate compound (II) in which X = O, get the usual ways, such as the following:

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An alternative way to obtain the intermediate compounds (IIA) is the following:

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Ways of obtaining thiadiazoline intermediate compounds are the following:

(a)

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or (b)

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Another way is to obtain the compounds (I) of hydroxyacetamido compound (III) or a basic salt:

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where R1and X have the meanings indicated for formula (I) or (a) by reaction with a compound of formula (IV):

Q-CH(R2)-Y-R3(IV)

where Q is tsepliaeva group, such as tosyloxy, mesilate, tripterocalyx, Cl or Br, a R2, R3and Y have the meanings indicated for formula (I);

or (b) reaction with an aldehyde or ketone of the formula V

(V)

where R2, R3and Y have the meanings indicated for formula (I), in the presence of a reducing agent, such as triacetoxyborohydride or cyanoborohydride sodium, in a suitable organic solvent, for example tetrahydrofuran, and usually at room temperature.

When used in (the sodium carbonate or ethyldiethanolamine.

The compounds of formula (III) can be obtained by removing the benzyl group in which-CH(R2)-Y-R3represents benzyl, from compounds of the formula (III), usually by reaction with a suitable chloroformate, for example, chloritisation, in a suitable organic solvent, for example dichloromethane or toluene, and preferably with delegacia.

The selectivity of the compounds (I) as antagonists of muscarinic receptor can be defined as follows.

Male Guinea pigs kill and remove the terminal ileum, trachea, urinary bladder and the right atrium, which is suspended in physiological saline at a residual voltage of 1 g 32oC, saturated with 95% O2and 5% CO2. Ileal contractions, bladder and trachea record with isotonic (the ileum) or isometric (bladder and trachea) of the sensor. The frequency of contractions spontaneously beating right atrium determined on the basis of isometrically recorded contractions.

Curves corresponding to doses of acetylcholine (the ileum) or carbachol (trachea, bladder and right atrium), determined on the basis of 1-5 minutes Comte is ideologicheskim salt solution, containing the lowest vine test connection. Test connection provide an opportunity to balanced with tissues for 20 minutes and repeat the curve corresponding to the dose of the agonist, to obtain maximum response. Bath agencies drain and re-fill with physiological saline solution containing the second concentration of the test compound, and repeat the above procedure. Typically, each tissue 4 determine the concentration of test compounds.

Determine the concentration of test compound that causes a doubling of the concentration of agonist, to obtain an initial reaction (value pA2- Arunlakshana and Schild. (1959), Brit. J. Pharmacol., 14, 48-58). Using the above analytical instruments, determine the selectivity of the fabric against the antagonists of muscarinic receptor.

Activity against narrowing of the bronchi, as well as reducing bowel or bladder caused by the agonist, compared with changes in heart rate are determined with the help of the dog under anesthesia. Oral activity set using dogs in consciousness, determining the effect of compounds on, for example, heart rate, pupil diameter and peristalsis.

Oral dosages of the compounds enter the human for the treatment or prevention of diseases associated with changes in motility and/or tone of smooth muscle, such as irritable bowel syndrome, diverticular disease, urinary incontinence, oesophageal achalasia and chronic obstruction of the respiratory tract, typically range from 3.5 to 350 mg per day for the average patient age (70 kg). Thus, for a typical adult patient, individual tablets or capsules usually contain from 1 to 250 mg of active compound in a suitable, pharmaceutically acceptable excipient or carrier for one-time or repeated administration (once or several times per day). If necessary, the dosage for intravenous typically range from 0.35 to 35 mg per dose. In practice, the physician determines the appropriate dosage, the most suitable for each individual patient, which varies depending on the age, weight and response of the patient. The above dosages are intended for medium cases, however, bezuslovno the tion of the invention.

The people of the compounds of formula (I) can be introduced in pure form, but usually they are administered in a mixture with a pharmaceutical carrier selected with regard to the proposed route of administration and conventional pharmaceutical practices. For example, they can be administered orally in the form of tablets containing such excipients as starch or lactose, in the form of capsules or ovules, either pure or in a mixture with excipients, or in the form of elixirs or suspensions containing corrigentov or dyes. They can be introduced by injection parenterally, for example intravenously, intramuscularly or subcutaneously. In the case of parenteral administration it is best to use them in the form of a sterile aqueous solution which may contain other substances, for example salts or glucose to ensure isotonicity of the solution with blood.

Another aspect of this invention provides a pharmaceutical composition comprising a compound of formula (I) or its pharmaceutically acceptable salt together with a pharmaceutically acceptable diluent or carrier.

The invention also includes the use of compounds of formula (I) or its pharmaceutically acceptable salts as a drug of the invention includes the use of compounds of formula (I) or its pharmaceutically acceptable salt for a medicinal product, used in the treatment of diseases associated with changes in motility and/or tone of smooth muscle, such as irritable bowel syndrome, diverticular disease, urinary incontinence, oesophageal achalasia and chronic obstruction of the respiratory tract.

Further, this invention includes all new intermediate compounds cited in this description.

The synthesis of compounds of formula (I) and some of the intermediate compounds is illustrated in the following Examples and Preparations, respectively.

The purity of the compounds was determined in the usual way using thin-layer chromatography using plates Merck Kieselgei 60 F254. Spectra1H nuclear magnetic resonance (nmr) were recorded using a spectrometer Bruker AC-300 and Varian Unity 300 and in all cases consistent with the proposed structures. Chemical shifts are given in parts per million () down field from tetramethylsilane using standard abbreviations for designation of major peaks, such as singlet (s), doublet (d), doublet of doublets (dd), triplet (t), Quartet (q), multiplet (m) and broad (b). LRMS means the mass spectrum of the low resolution. Room temperature refers to 20-25oC.

oC (IPA-ethyl acetate), n(300 MHz, COCl3) 1,7 (2H, m), and 2.0 (2H, m), 2,2 (3H, s), 2,6 (1H, m), 2,85 (1H, m), and 3.2 (1H, m), and 3.8 (1H, m), and 4.4 (1H, m).

DRUG 2

1-Acetylpiperidine-4- (2-oxo-2-phenylethyl) carboxamide

< / BR>
Carbonyldiimidazole (GDI) (212,0 g, 1,31 mol.) add portions to stir a suspension of 1-acetylpiperidine-4-carboxylic acid (200,0 g, 1,17 mol. ) in dry dichloromethane under nitrogen atmosphere at room temperature (you should pay attention to the allocation of CO2). The resulting solution was then stirred at room temperature under nitrogen atmosphere for 2 hours. Add-aminoacetophenone hydrochloride (210 g, 1,22 mol.), and then triethylamine (170 cm3, 1,22 mol.), causing a small exothermic reaction. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere anhydrous sodium sulfate and concentrated under reduced pressure, receiving the target compound in the form of a solid orange substance (300 g, the 1.04 mol., 79%). Rf of 0.15 (95:5 CH2Cl2:MeOH), so pl. 161-162oCn(300 MHz, CDCl3) 1,7 (2H, m), 1,9 (2H, m), 2,1 (3H, s), 2,5 (1H, m), 2,7 (1H, t), 3,1 (1H, t), 3,9 (1H, d), 4,6 (1H, d), and 4.8 (2H, d), and 6.6 (1H, s), and 7.5 (2H, m), and 7.6 (1H, t), and 7.9 (2H, d).

DRUG 3

3-Benzoyl-5- {4- (1-acetylpiperidine)}-1,2,4-oxadiazol

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1-Acetylpiperidine-4-(2-oxo-2-phenylethyl) carboxamide 294 g of 1.02 mol.) dissolved in glacial acetic acid (1.5 l) with gentle heating. Then dropwise within 2 hours add a solution of sodium nitrite (100 g) in deionized water (120 cm2) with a gentle cooling in an ice-water bath. The resulting reaction mixture was stirred at room temperature for 144 hours, continuing to add sodium nitrite (100 g) and deionized water (120 cm3) every 48 hours. The contents of the flask is then rinsed with nitrogen and concentrated under reduced pressure, obtaining a solid residue, which was dissolved in dichloromethane (2.5 l) and washed sequentially with deionized water (500 cm), aqueous sodium hydroxide (200 cm310% of the weight. /about. ) and deionized water (500 cm3). The organic fraction is dried over anhydrous sodium sulfate and concentrate, 7%), Rf 0.26 (95:5 CH2Cl2:MeOH), so pl. 97 - 100oC n(300 MHz, CDCl3) 1,9 (2H, m), 2,1 (3H, s), 2,2 (2H, m), 2,9 (1H, t), 3,3 (2H, m), 3,9 (1H, d), 4,5 (1H, d), and 7.5 (2H, t), and 7.6 (1H, t), and 8.2 (2H, d); m/z LRMS) 322 (MNa+), 317 (MNH4+) and 300 (MH+).

THE DRUG 4

3-Benzoyl-5-(4-piperidinyl) -1,2,4-oxadiazole hydrochloride

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3-Benzoyl-5-{4-(1-acetylpiperidine)}-1,2,4-oxadiazol (230 g of 0.77 mol. ) is dissolved in methanol saturated with HCl (2.5 l) and heated at reflux distilled within 24 hours. Then the contents of the flask and allow to cool and add concentrated hydrochloric acid (10 cm3). The reaction mixture was then heated under reflux distilled for 20 hours, after which TCX does not show residues of starting materials. The flask contents are then cooled in a bath of ice and acetone, obtaining a white solid, which was filtered and washed with ethyl acetate to obtain the target compound (175 g, of 0.58 mol. , 75%), so pl. 224-227oCn(300 MHz; CDCl2) to 2.1 (2H, m), 2,3 (2H, m), 3,1 (2H, m), (3,3 2H, m), and 3.6 (1H, m), and 7.6 (2H, m), and 7.8 (1H, m), and 9.1 (1H, s); m/z LRMS) 258 (MH+).

THE DRUG 5

3-Benzoyl-5-4-(1-benzylpiperidine)-1,2,4-oxadiazol

< / BR>
Benzyl bromide (67 cm3, of 0.56 mol.) add to a mixture of 3-benzoyl-5-(4-piperidinyl)-1,2,4-oxadiazole hydrochloride (165 anatoy temperature in a nitrogen atmosphere for 48 hours. Then add deionized water (1.3 l) and the mixture vigorously stirred for 1 hour. The organic layer is collected, and the remaining aqueous fraction extracted with ethyl acetate (500 cm3). Then the combined organic fractions dried over anhydrous sodium sulfate and concentrated, obtaining a pale yellow oil. Elwira flash chromatography (1 kg silica "Kieselgel 60) using 8% methanol in dichloromethane, to obtain a colorless oil, which is subjected to azeotropic toluene to obtain the target compound as white solid (177 g of 0.51 mol., 91%,) Rf of 0.6 (95:5 CH2Cl2: MeOH), so pl. 67-69oCn(300 MHz, CDCl3) to 2.1 (6H, m), 2,9 (2H, d) and 3.1 (1H, m), 3,6 (2H, s), and 7.3 (5H, m), and 7.5 (2H, t), and 7.7 (1H, t), and 8.3 (2H, d); m/z (LMRS) 348 (MH+).

THE DRUG 6

2-tert-Butyldimethylchlorosilane

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Mandelonitrile (50 g of 0.38 mol.) and imidazole (64 g of 0.94 mol.) dissolved in dimethylformamide (100 cm3) and the resulting solution cooled in an ice-water bath. Then within 20 minutes servings add tert-butyldimethylsilyl chloride (68 g of 0.45 mol.). The contents of the flask are heated to 35oC and stirred at this temperature for 18 hours. Then the reaction mixture is cooled and divided between tilasivat brine (100 cm3), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crude product as a yellow oil. Elwira flash chromatography (600 g silica "Kieselgel 60" using 20% dichloromethane in pentane, get the target compound in the form of oil (77 g, 0.31 in mol. , 82%),n(300 MHz, COCl3) 0,1 (3H, s), 0,2 (3H, s), and 1.0 (9H, s), and 5.5 (1H, s), 7.4 (5H, m).

PREPARATION 7

-tert-Butyldimethylchlorosilane

< / BR>
Solid potassium carbonate (54 g, 0.39 to say.) add to a mixture of 2-tert-butyldimethylchlorosilane (45 g of 0.18 mol.) and hydroxylamine hydrochloride (25 g, of 0.36 mol.) in ethanol (450 cm3) and the resulting mixture is heated under reflux distilled in a nitrogen atmosphere for 2 hours. Then the contents of the flask are cooled and concentrated under reduced pressure. The remainder is divided between dichloromethane (3 x 150 cm3) and deionized water (100 cm3). Then the combined organic fractions washed with brine (100 cm3), dried over anhydrous magnesium sulfate and concentrated under reduced pressure, obtaining the target compound in the form of hard yellow substance cases (53.2 g of 0.18 mol., 100%).n(300 MHz, CDCl3) 0,1 (3H, s), 0,2 (3H, s), and 1.0 (9H, s), and 4.8 (2H, bs), 5,3 (1H, bs), and 7.3 (3H, m) and 7.5 (2H, m).


-tert-Butyldimethylchlorosilane cases (53.2 g of 0.18 mol.) dissolved in tetrahydrofuran (400 cm3) and add 10 g of crushed and sifted through a sieve the mixture is heated under reflux distilled in a nitrogen atmosphere for 15 minutes, and then cooled in an ice bath. The portions add sodium hydride (8.0 g, 60% dispersion, 0.2 mol.) and the contents of the flask give the opportunity to slowly warm to room temperature so as to control the Fizz. When the evolution of hydrogen ceases, added dropwise a solution of ethyl N-benzylpiperidine-4-carboxylate (45 g of 0.18 mol.) in tetrahydrofuran (125 cm3). The flask contents are stirred at room temperature for 30 minutes and then heated under reflux distilled in a nitrogen atmosphere for 1.5 hours. After cooling, the reaction mixture was separated between ethyl acetate (2 x 200 cm3) and deionized water (200 cm3). Then the combined organic fractions washed with brine (100 cm3), dried over anhydrous magnesium sulfate and concentrated under reduced pressure, obtaining the target compound in the form of a yellowish-brown oil (62 g, 0,13 mol. , 72%),n(300 MHz, CDCl1) 0,1 (3H, s), 0,2 (3H, s), and 1.0 (9H, s), and 2.0 (6H, m), 2,9 (3H, m), 3,5 (2H, s), 6,0 (1H, s), and 7.3 (8H, m) and 7.5 (2H, m)or ammonium fluoride (237 cm3, 1M in tetrahydrofuran) is added dropwise to a stirred solution of 3 - (tert-butyldimethylsiloxy) -5-{ 4-(1- benzylpiperidine)} -1,2,4-oxadiazole (62 g of 0.13 mol.) in tetrahydrofuran (200 cm3) at 0oC. Then the resulting solution was allow to warm to room temperature and stirred for further 30 minutes. The contents of the flask are divided between ethyl acetate (3 x 200 cm3) and deionized water (200 cm3), and the combined organic fractions washed with brine (100 cm3), dried over anhydrous magnesium sulfate and concentrated under reduced pressure, obtaining the target compound in the form of a yellow solid substance (45,0 g) (Found C, and 70.5; H, 6.5; the N 11,8. C21H23N3O2. 1/2 H2O requires C,70,4; H, 6.8; the N 11,7%;n(300 MHz; CDCl3) of 2.0 (6H, m), 2,9 (4H, m), 3,5 (2H, s), 5,9 (1H, d), 7.3 (10H, m); m/z LRMS) 350(MH+).

THE DRUG 10

3-Benzoyl-5-4-(1-benzylpiperidine)-1,2,4-oxadiazol

< / BR>
The manganese dioxide (206 g, 2,37 mol.) add in portions to a mechanically stirred solution of 3- (-hydroxybenzyl) -5-{4-(1-benzylpiperidine)}- 1,2,4-oxadiazole (45,0 g at 0.19 mol.) in dry tetrahydrofuran (300 cm3) at room temperature for 2 hours. The resulting mixture was then stirred the pressure, getting sticky substance. The residue is again dissolved in a minimum quantity of hot diisopropyl ether, the resulting solution is filtered, and then cooled in an ice-water bath to obtain the target compound as a beige crystalline solid (26 g, 75 mmol, 58%). This material is in all respects identical to the material obtained in accordance with the Drug 5.

PREPARATION 11

3-(1,1-Diphenyl-1-hydroxymethyl)-5-(4-piperidinyl)-1,2,4 - oxadiazol

< / BR>
-Chloroethylphosphonic (0,27 cm3, 2.5 mmol.) added dropwise to a stirred solution of 3-(1,1-diphenyl-1-hydroxymethyl) -5-{4-(1-benzylpiperidine)} -1,2,4-oxadiazole (1,00 g, 2,30 mmol.) in dry dichloromethane (10 cm3) at 0oC in nitrogen atmosphere. The resulting solution was stirred at 0oC for 40 minutes and then concentrated under reduced pressure. The resulting residue is dissolved in methanol (20 cm3) and heated at reflux distilled for 40 minutes. Then the contents of the flask are cooled, concentrated under reduced pressure and separated between dichloromethane (100 cm3) and saturated aqueous sodium bicarbonate (50 cm3). The organic fraction is dried over anhydrous sodium sulfate, and then close the eat 5-15% methanol in dichloromethane, get the target compound as a white foam (0.68 g, 2.0 mmol, 80%), Rf of 0.05 (90:10 CH2Cl2:MeOH),n(300 MHz, CDCl3) 1,9 (2H, m) and 2.2 (2H, m), 2,8 (2H, t), and 3.1 (1H, m), 3,3 (2H, m), 4.2V (1H, b), and 7.4 (10H, m); m/z LRMS) 336 (MH+).

PREPARATION 12

3-(1-Cyclobutyl-1-phenyl-1-hydroxymethyl)-5-(4-piperidinyl)-1,2,4 - oxadiazol

< / BR>
Claritinclaritin (3,30 g, 23,0 mmol.) added dropwise to a stirred solution of 3-(1-cyclobutyl-1-phenyl-1 - hydroxymethyl)-5-{ 4-(1-benzylpiperidine)} -1,2,4-oxadiazole (charged 8.52 g, 21,0 mmol.) in dry toluene (100 cm3). Then the resulting solution is heated under reflux distilled in a nitrogen atmosphere for 90 minutes. The contents of the flask allow to cool, and the reaction mixture is concentrated under reduced pressure. The resulting residue is dissolved in methanol (50 cm3) and heated at reflux distilled for 40 minutes. Then the contents of the flask are cooled, concentrated under reduced pressure and separated between dichloromethane (100 cm2) and saturated aqueous sodium bicarbonate (50 cm3). The organic fraction is dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Elwira flash chromatography (25 g silica "Kieselgel 60) using 5-15% methanol in dichloromethane, Paul (1H, m), and 3.2 (2H, m), and 3.3 (1H, m), and 7.3 (3H, m), 7.5 (2H, d); m/z LRMS) 315 (MH+).

EXAMPLE 1

3-(1,1-Diphenyl-1-hydroxymethyl)-5-4-(1-benzylpiperidine)- 1,2,4-oxadiazol

< / BR>
Finality (5.0 cm31.8 M in cyclohexane, 9.0 mmol.) added dropwise to a stirred solution of 3-benzoyl-5-{4-(1 - benzylpiperidine)}-1,2,4-oxadiazole (3.0 g, 8.6 mmol) in dry tetrahydrofuran (40 cm3) at -78oC in nitrogen atmosphere. Then the resulting solution was allow to warm to room temperature for two hours and is divided between ethyl acetate (3 x 50 cm3) and brine (20 cm3). The combined organic fractions dried over anhydrous sodium sulfate and concentrated under reduced pressure. Elwira flash chromatography (30 g silica "Kieselgel 60) using 35% ethyl acetate in hexane, to obtain the target compound (2.9 g, 6.8 mmol. , 76%) Rf of 0.8 (ethyl acetate), (Found C, 75,45, H, 6,4, N, 9,8. C27H27N3O2. 1/2 H2O requires C, 75,4, H, 6,45, N, 9.8 per cent);n(300 MHz, CDCl3) of 2.0 (6H, m), 2,9 (2H, m), 3,5 (2H, s), and 3.7 (1H, s) and 7.3 (15H, m); m/z LRMS) 426 (MH+).

EXAMPLE 2

3-(1-butyl-1-phenyl-1-hydroxymethyl)-5-4-(1-benzylpiperidine) -1,2,4-oxadiazol

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The target compound is obtained by a method described in Example 1, adnano With, 73,5, H, 7,8, N, 10,0. C25H31N3O2requires, 74,0, H, 7,7, 10.4 per cent);n(300 MHz, CDCl3) to 0.8 (3H, m), 1,3 (4H, m), and 2.1 (8H, m), 2,9 (3H, m), 3,2 (1H, s), 3,5 (2H, m), and 7.3 (8H, m), 7.5 (2H, d); m/z LRMS) 406 (MH+).

EXAMPLE 3

3-{ 1-(2-Thienyl)-4-phenyl-1-hydroxymethyl}-5-{4-(1- benzylpiperidine)}-1,2,4-oxadiazol

< / BR>
n-Utility (1.3 cm3, 2.5 M in hexane, 3.25 mmol) added dropwise to a stirred solution of thiophene (0.3 cm3, 3.0 mmol) in dry tetrahydrofuran (30 cm3in nitrogen atmosphere at -78oC and the resulting solution was stirred at -78oC for 10 minutes to obtain 2-titillate. Then one portion add a solution of 3-benzoyl-5-{4-(1-benzylpiperidine)}-1,2,4-oxadiazole (1.0 g, 2.9 mmol.) in dry tetrahydrofuran (10 cm3) and the resulting mixture stirred at -78oC for one hour. The cooling bath is removed and the contents of the flask and allow to warm to room temperature for one hour. Then the reaction mixture was separated between ethyl acetate (3 x 50 cm3) and brine (20 cm3). The combined organic fractions dried over anhydrous sodium sulfate and concentrated under reduced pressure. Elwira flash chromatography (30 g silica "Kieselgel 60) using 40% of etelaat the>S. 1/4 H2O requires C, 68,9, H, 5,9, N, 9.6 per cent);n(300 MHz, CDCls) to 2.1 (6H, m), 2,9 (3H, m), 3,5 (2H, s), 3,95 (IH, s), 6,9 (2H, m), and 7.3 (9H, m), 7.5 (2H, m); m/z LRMS) 432 (MH+).

EXAMPLES 4-9

Compounds of examples 4-9 (see end of description) has indicated General formula, obtained by reaction of 3-benzoyl-5-4- (1-benzylpiperidine)-1,2,4-oxadiazole with the corresponding connection orginality using the method described in Example 3.

< / BR>
EXAMPLE 10

3-(1-Cyclobutyl-1-phenyl-1-hydroxymethyl)-50{ 4- (1-benzylpiperidine)}-1,2,4-oxadiazol

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Cyclobutylamine (21.7 cm3, 0,23 mol.) added dropwise to the suspension under rotation magnesium (5.7 g, 0,23 mol.) in dry diethyl ether (50 cm3with such a rate as to maintain dephlegmation. The resulting mixture was stirred at room temperature for 30 minutes and then added dropwise to a stirred solution of 3-benzoyl-5-{4-(1 - benzylpiperidine)} -1,2,4-oxadiazole (40,0 g, 0,115 mol. ) in diethyl ether (400 cm3) and tetrahydrofuran (100 cm3) at -10oC in nitrogen atmosphere. The mixture allow to warm to room temperature for 2 hours. Then the contents of the flask are cooled and carefully add saturated aqueous ammonium chloride (30 cm). The combined organic fractions then dried over anhydrous sodium sulfate and concentrated under reduced pressure. Elwira flash chromatography (500 g silica "Kieselgel 60) using 40-70% ethyl acetate in pentane, obtain the target compound (31.5 g, 0,78 mol., 68%) (Found C, 73,0, H, 7,4, N, 10,1. C25H29N3O2. 1/4 H2O requires C, 73,5, H, 7,3, N, 10.3 per cent);n(300 MHz, CDCl3) to 1.9 (12H, m), 2,9 (3H, m), 3,2 (1H, s), and 3.3 (1H, m), 3,5 (2H, s), and 7.3 (8H, m) and 7.5 (2H, d); m/z LRMS) 403 (MH+).

Elwira GHUR (column Chiralpak AD" 2.5 x 25 cm) using 20% isopropanol, 0,06% triperoxonane acid, 0.03% diethylamine in hexane with a speed of 7 cm3/min, receive (-)-3-(1-cyclobutyl-1-phenyl-1-hydroxymethyl-5-{ 4-(1 - benzylpiperidine)}-1,2,4-oxadiazol, []D-480.1, dichloromethane; and (+)-3-(1-cyclobutyl-1-phenyl-1-hydroxymethyl)-5-(4- (1-benzylpiperidine)-1,2,4-oxadiazole, []D-51, 0.1, dichloromethane (Found From 74.3, H, 7,2, N, 10,4. WITH25H29N3O2requires, 74,4, H, 7,2, N,10,4%).

EXAMPLES 11-15

Compounds of examples 11-15 (see the end of the description), having the following General formula is obtained by reaction of 3-benzoyl-5-4-(1-benzylpiperidine)-1,2,4-oxadiazole with the appropriate Grignard reagent, ispolzuete)-piperidinyl} ]-1,2,4-oxadiazol

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Solid sodium bicarbonate (0.20 g) is added to a stirred solution of 3-(1,1-Diphenyl-1-hydroxymethyl)-5-(4-piperidinyl)-1,2,4-oxadiazole (0.20 g, 0.6 mmol. 4 - performer chloride (0,075 cm30.6 mmol) in dry dimethylformamide (1 cm3). The resulting mixture was stirred in nitrogen atmosphere at room temperature for 24 hours, and then separated between ethyl acetate (3 x 20 cm3) and saturated aqueous sodium carbonate (20 cm3). Then the combined organic fractions dried over anhydrous sodium sulfate and concentrated under reduced pressure. Elwira flash chromatography (40 g silica "Kieselgel 60) using 30-50% ethyl acetate in hexane, to obtain the target compound (0.07 g, 0.16 mmol, 26%) (Found C, 72,6, H, 5,95, N, And 9.4. C27H26N3O2F requires C, 73,1, H, 5,9, N, 9.5 per cent);n(300 MHz, CDCl3) to 2.1 (6H, t), 2,9 (3H, t), 3,5 (2H, s in), 3.75 (1H, s), to 6.95 (2H, d.) and 7.4 (12H, t); m/z LRMS) 444 (MH+).

EXAMPLES 17 and 18

The compounds of examples 17 and 18 (see the end of the description), having the following General formula is obtained by reaction of 3- (1,1-diphenyl-1-hydroxymethyl)-5-(4-piperidinyl)-1,2,4-oxadiazole with the corresponding haloalkyl using the method described in Example 16.

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EXAMPLE 19

3-(1-the lot (0.04 g, 0.6 mmol) add to the mix a solution of 3-(1-cyclobutyl-1-phenyl-1-hydroxymethyl)-5- (4-piperidinyl)-1,5,4-oxadiazole (0.16 g, 0.5 mmol.) in dry tetrahydrofuran (15 cm3) at room temperature under nitrogen atmosphere. Then added 4-methoxybenzaldehyde (0,082 g, 0.6 mmol) and sodium triacetoxyborohydride (0,212 g, 1.0 mmol) and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 6 hours. Then the contents of the flask are divided between dichloromethane (100 cm3) and saturated aqueous sodium bicarbonate. The organic fraction is collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure, obtaining a brown oil. Elwira flash chromatography (silica "Kieselgel 60) using 30-50% ethyl acetate in hexane, to obtain the target compound (0.125 g, 0.28 mmol, 56%) (Found C, 71,1, H 7,25, N, 8,6. C25H31N3O3. 1/3 H2O requires C, 71,7, H, 7,2, N, 9.6 per cent);n(300 MHz, CDCl3) 1,6-2,2 (12H, m), 3,2 (1H, s), and 3.3 (1H, t), 3,4 (2H, s), and 3.8 (3H,.S), to 6.95 (3H, m), and 7.3 (4H, m), 7.5 (2H, m); m/z LRMS) 434 (MH+).

EXAMPLES 20-25

Compounds of examples 20-25 (see the end of the description), having the following General formula is obtained by reaction of 3-(1-cyclobutyl-1-phenyl-1-hydroxymethyl)-5- (4-piperidinyl)-1,2,4-ox
3-(1-Cyclobutyl-1-phenyl-1-hydroxymethyl)-5- [4-{1-(2-phenoxyethyl)piperidinyl}]-1,2,4-oxadiazol

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2-Phenoxypropane (0.10 g, 0.5 mmol.) added to a solution of 3- (1-cyclobutyl-1-phenyl-1-hydroxymethyl)-5-(4-piperidinyl)- 1,2,4-oxadiazole (0.16 g, 0.5 mmol. ) in dry tetrahydrofuran at ambient temperature under nitrogen atmosphere. Then add ethyldiethanolamine made (0.13 g, 1.0 mmol) and the resulting solution was stirred at ambient temperature for 7 days. Then the contents of the flask are divided between ethyl acetate (3 x 30 cm3) and saturated aqueous sodium bicarbonate (10 cm3). Then the combined organic extracts dried and concentrated under reduced pressure. Elwira flash chromatography (silicon dioxide ("Kieselgel 60) using 3% methanol in dichloromethane, to obtain the target compound (of 0.022 g, 0.05 mmol, 10%)n(300 MHz, CDCl3) 1,6-2,2 (10H, m), 2,3 (2H, t), 2,8 (2H, t), 2,9 (1H, m), and 3.0 (2H, m), 3,2 (1H, s), and 3.3 (1H, q), 4,1 (2H, t), and 6.9 (3H, m), and 7.3 (5H, m), 7.5 (2H, m); m/z LRMS) 434 (MH+).

EXAMPLE 27

3-(1-Cyclobutyl-1-phenyl-1-hydroxymethyl)-5-[4-{1- (-methyl-benzyl) - piperidinyl}]-1,2,4-oxadiazol

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The above compound is obtained by reaction of 3-(1-cyclobutyl-1 - phenyl-1-hydroxymethyl)-5-(4-piperidinyl)-1,2,4-oxadiazole with-meta N3O2. 1/3 H2O requires C, 73,8, H, and 7.5; N, 9.9 per cent);n(300 MHz, CDCl3) 1,3 (3H, s), 1,6-2,2 (12H, m), 2,8 (2H, m), and 3.0 (1H, m), 3,2 (1H, s), and 3.3 (1H, t), 3,5 (1H, m), 7,2 (8H, m) and 7.5 (2H, m); m/z LRMS) 419 (MH+).

The activity indicators muscarinic antagonists, see table.1.

Presented in table. 1 data show that the claimed compounds are useful in the treatment of urinary incontinence and other diseases, such as irritable bowel syndrome, requiring treatment with antagonist muscarinic receptor.

1. Derivatives oxa - or thiadiazole of the General formula I

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where R1represents a C1-C6alkyl, halo-(C1-C6alkyl), C3-C7cycloalkyl, C2-C6quinil, hydroxy-(C2-C6quinil), phenyl, naphthyl, heteroaryl selected from the group comprising thienyl, pyridyl, thiazolyl, benzothiazolyl;

R2- H or C1-C4alkyl;

R3- naphthyl or phenyl, possibly substituted by one or two C1-C4by alkyl, halogen, C1-C4alkoxyl, hydroxyl, heteroaryl selected from the group comprising thienyl, 2,3-dihydrobenzofuranyl, C4-C7cycloalkyl;

X is oxygen;

Y is a direct bond, -CH2- or-CH2O is phenyl, optionally substituted by one or two substituents, each of which is independently selected from1-C4of alkyl, C1-C4alkoxyl, hydroxyl or halogen.

3. Connection on p. 2, in which R3represents phenyl, forfinal, dichlorophenyl, hydroxyphenyl, methoxyphenyl or naphthyl.

4. The compound according to any one of the preceding paragraphs, in which R1represents a C1-C6alkyl, pentafluoroethyl, C4-C6cycloalkyl, ethinyl, -CC-CH2OH, -CC-(CH2)4-OH; phenyl group.

5. The compound according to any one of the preceding paragraphs, in which R2represents H or CH3.

6. The compound according to any one of the preceding paragraphs, in which Y represents a direct bond or-CH2O-.

7. Connection on p. 1, representing 3-(1-cyclobutyl-1-phenyl-1-hydroxymethyl)-5-[4-(1-benzylpiperidine)] -1,2,4-oxadiazol or (+)-3-(1-cyclobutyl-1-phenyl-1-hydroxymethyl)-5-[4-(1-benzylpiperidine)]-1,2,4-oxadiazol.

8. The pharmaceutical composition exhibiting properties antagonist muscarinic receptor, characterized in that it includes the compounds of formula I or its pharmaceutically acceptable salt according to any of formulas II

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where X, Y, R2and R3have the values listed in paragraph 1.

10. The method of obtaining the compounds of formula I on p. 1 or its pharmaceutically acceptable salts, characterized in that it comprises the reaction of compounds of formula II by p. 9 with a Grignard reagent, an organolithium or thereorganization compound of the formula

R1MgHal, R1Li or R1CeCl2,

where Hal Is Cl or Br, and R1matter specified in paragraph 1,

in an organic solvent, with this method also optionally includes the transformation of the product of formula I in a pharmaceutically acceptable salt.

11. The method according to p. 10, characterized in that the use of the reagent of formula R1MgBr or R1Li, R1matter specified in paragraph 10.

12. The method of obtaining the compounds of formula I on p. 1 or its pharmaceutically acceptable salts, characterized in that it comprises the reaction of compounds of formula III or its underlying salt

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where R1and X have the meanings specified in paragraph 1,

either (a) with the compound of the formula IV

Q-CH(R2)-Y-R3,

where Q is tsepliaeva group;

R2, R3and Y have the values listed in paragraph 1;

or (b) with an aldehyde or ketone of the formula V

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where varicela, while this method also optionally includes the transformation of the product of formula I in a pharmaceutically acceptable salt.

13. The method according to p. 12, characterized in that tsepliaeva group Q is tosyloxy, mesilate, tripterocalyx, Cl or Br, in which the reducing agent is triacetoxyborohydride or cyanoborohydride sodium.

14. The method according to p. 12 or 13, characterized in that (a) use the free base of compound III and the reaction is carried out in the presence of an acid acceptor.

15. The method according to p. 14, wherein the acid acceptor is a sodium bicarbonate or ethyldiethanolamine.

16. The method according to any of paragraphs.10 to 15, characterized in that the receive connection according to any one of paragraphs.2 - 7.

17. The method according to p. 12 to obtain the compound 3-(1-cyclobutyl-1-phenyl-1-hydroxymethyl)-5[4-(1-benzylpiperidine)] -1,2,4-oxadiazole, characterized in that the bromide cyclobutylamine reacts with 3-benzoyl-5-[4-(1-benzylpiperidine)]-1,2,4-oxadiazole, optionally with subsequent separation of the compounds on its (+) and (-) enantiomers.

18. The method according to p. 17, characterized in that the separation is carried out using GHUR.

 

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