3-(1,2,5-oxadiazol-3-yl)-3-(1,2,5-thiadiazole-3-yl)-1,2, 5,6-tetrahydropyridine derivatives or their pharmaceutically acceptable salts, and pharmaceutical composition exhibiting muscarinic cholinergic receptor agonistic activity

 

(57) Abstract:

Usage: as substances exhibiting muscarinic cholinergic receptor agonistic activity. The inventive product 3-(1,2,5-oxadiazol-3-yl)- 3-(1,2,5-thiadiazole-3-yl)-1,2,5,6-tetrahydropyridine derivatives of the following formula, where Z is oxygen or sulfur; R is hydrogen or C1-3-alkyl; when Z is oxygen, R1is a halogen, amino group, acetylamino or-O-R2where R2-C4-6-alkyl or C4-6-quinil; when Z is sulfur, R1means halogen, C1-8-alkyl, C6alkenyl straight chain, cyclopropylmethyl, benzyloxy, morpholino-, 4-methylpiperidino - or 4-hexylamino or a group-O-R2where R2- linear or branched C1-8alkyl, C3-6alkenyl, C3-6-quinil, cyclopropylmethyl, or a group-R3-O-R4or-R3-O-R4-O-R5where each R3-R5means C1-4-alkyl; or R1means the group of S-R2where R2linear C2-8alkyl, or their pharmaceutically acceptable salts, and pharmaceutical composition. (see below). 1 Il. table 2.

The invention relates to new compounds 1,2,5,6-tetrahydropyridinium, R1is a halogen, amino group, acetylamino or-O-R2where R2is4-6-alkyl or C6-quinil; Z, meaning sulfur, R1is halogen, C1-8-alkyl, C6-alkenyl straight chain, cyclopropylmethyl, benzyloxypropionic, morpholino-, 4-methylpiperidino - or 4-hexylamino or a group-O-R2where R2linear or branched C3-6alkenyl,3-6-quinil, cyclopropylmethyl, -R3-O-R4or-R3-O-R4-O-R5where each of R3, R4and R5means1-4-alkyl, or R1represents a group S-R2where R2linear C2-8-alkyl, or their pharmaceutically acceptable salts.

In addition, this invention relates to a pharmaceutical composition for oral administration of expressing muscarinic cholinergic receptor agonistic activity.

Pharmacological properties of the compounds according to this invention (formula I) can be illustrated by determining their ability to inhibit specific binding of 3H-oxotremorine-M (3H)-oxo).

3H-Oxo marks muscarinic receptors in the CNS (preferably agonistic domains re is 0 nm. In these experimental conditions are determined only centers with medium and high affinity. The inhibitory effect of the compounds on the binding of 3H-oxo reflects the affinity to muscarinic acetylcholine receptors.

Except where otherwise indicated, all operations carried out at 0-4aboutC. Fresh cortex (0.1 to 1 g) of male Wistar rats (150-250 g) homogenized with 5-10 10 ml of 20 mm s, pH 7.4, in a homogenizer Ultra-Turcax. The homogenizer was washed with 10 ml of buffer and the United suspensions centrifuged 15 min at 40,000 g. The precipitate washed three times with buffer. At each stage of the homogenized sediment, as indicated above, 2 x 10 ml of buffer and centrifuged 10 min at 40,000 g. The resulting precipitate homogenized in 20 mm s with pH 7.4 (100 ml/g of original tissue) and used in the analysis of binding. To an aliquot of 0.5 ml was added 25 μl of the test solution, 25 μl of 3H-oxotremorine (resulting concentration 1 nm), mixed and incubated for 30 min at 25aboutC. Nonspecific binding thrice determined using Arecoline (1 μg/ml, the resulting concentration) as the test compounds. After incubation the sample was added 5 ml ice buffer, immediately poured on a glass filter define a conventional liquid scintillation counter. Specific binding is the total binding minus nonspecific binding. Compound dissolved in 10 ml of water (if necessary, by heating the first bath in less than 5 min) at a concentration of 2.2 mg/ml Before calculating IR50you need to get 25-75% inhibition of specific binding.

The test results are expressed as IR50(concentration, ng/ml, the test compounds inhibiting the binding of 3H-oxo 50%).

IR50= (introduced concentration tested.connection) x ng/ml where Caboutspecific binding in control analysis; Cxspecific binding in the test. The calculations assume normal kinetics according to the law of mass action.

The test results of some compounds according to this invention are presented in table.1, and comparative analyses of the compounds of formula I with compounds of similar structure in the table. 2.

Compounds according to this invention together with a conventional auxiliary agents, carriers or diluents, for example in the form of their acid additive salts can enter into pharmaceutical compositions and unit dosage forms, which may be solid, as tablets or filled cap is doing, in the form of suppositories for rectal administration, or in the form of sterile injectable solutions for parenteral, including subcutaneous, administration. Such pharmaceutical compositions and unit dosage forms may include conventional ingredients in conventional proportions, with an additional active compounds or without them. These forms may contain any effective muscarinic cholinergic agonist amount of the active ingredient corresponding to the intended interval daily dose. Examples of suitable dosage forms are tablets containing 10 mg of active ingredient or 1-100 mg per pill.

Compounds according to this invention can be used for pharmaceutical formulations, such as oral and parenteral introduction mammals, including humans, in accordance with conventional ways of galenobismutite.

Conventional carriers are pharmaceutically acceptable organic or inorganic carriers suitable for parenteral or enteral administration, inert to active compounds. Examples of such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyalkane and diglycerides of fatty acids, pentaerythritol esters of fatty acids, hydroxymethylcellulose and polyvinylpyrrolidone.

Pharmaceutical formulations can be sterilized and mixed, if necessary, with auxiliary agents, emulsifiers, salts for regulating the osmotic pressure, buffers and/or coloring agents, etc., inert to active compounds.

For parenterale introduction is especially suitable injectable solutions or suspensions, preferably aqueous solutions of the active compounds dissolved in polyhydroxyalkane castor oil.

Ampoules are conventional unit dosage forms.

For oral administration is particularly suitable tablets, granules or capsules having talc and/or carbohydrate carrier binder, etc., where the carrier is preferably lactose and/or corn starch and/or potato starch. Syrups, elixirs, etc. can be used where used sweet media.

As a rule, the compounds of this invention receive in a single form containing 1-100 mg of the pharmaceutically acceptable carrier in a single dose.

The dose of the compounds according to this invention is 1-na tablet, you can get conventional tabletting methods, contains: the Active connection, mg 5.0 mg Lactose Ph Eur. 67,8 Avicl, 31,5 mg Amberlite, 1.0 mg Stearate, mg Ph.Eur 0.25

Due to the high muscarinic cholinergic receptor agonistic activity of the compounds according to this invention is very useful for the treatment of symptoms associated with decreased cognitive functions of the mammalian brain, with the introduction in the amount effective for stimulating the cognitive functions of the forebrain and hippocampus. Important stimulating activity of the compounds according to this invention includes activity against pathophysiological diseases of Alzheimer and normal fading brain function.

Compounds according to this invention it is possible to introduce the subject, for example the body of a living animal, including humans, to stimulate cognitive functions of the forebrain and hippocampus in the form of a pharmaceutically acceptable acid salt additive, such as a hydrobromide, hydrochloride, or sulfate, obtained by conventional means, for example by evaporation of a solution of the free base and acid to the dry residue, usually in parallel, simultaneously, or together with a pharmaceutically acceptable carrier or a parenteral, including subcutaneous, by the number of effectively stimulating the forebrain and hippocampus and improves poznavalny function of a mammal, due to the muscarinic cholinergic receptor agonistic activity.

Compounds according to this invention can be used as analgesics and therefore can be used for the treatment of severe painful conditions. In addition, these compounds are suitable for the treatment of glaucoma.

Suitable spacing of doses is 1-100 mg daily, for example, 10-100 mg / day and especially 30-70 mg/day, depending on the exact way of introduction, forms of administration, purpose of administration, the patient and the weight of his body and from the opinions and experience of the attending physician or veterinarian.

Preferred methods of obtaining active compounds of this invention are illustrated in more detail by the following examples.

P R I m e R 1. A. 3-(4-Chloro-1,2,5-thiadiazole-3-yl)pyridine.

To a solution of monochloride sulfur (2.4 ml, 30 mmol) in N,N-dimethylformamide (5 ml) is slowly added alpha-amino-al - f (3-pyridyl)acetonitrile (1.7 g, 10 mmol). The reaction mixture was stirred 18 h at room temperature, add water (20 ml), the aqueous phase is extracted with ether and efiro the AZ extracted with ether, the ether phase is dried and evaporated. The residue is purified column chromatography (SiO2eluent a mixture of ethyl acetate/methylene chloride 1: 1). The target compound is obtained in yield of 45% (880 mg). M+: 197.

B. 3-(4-Methoxy-1,2,5-thiadiazole-3-yl)pyridine.

To a solution of sodium (460 mg, 20 mmol) in methanol (10 ml) was added 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (750 mg, 3.8 mmol). The mixture is stirred for 1 h at 50aboutWith and evaporated. The residue is dissolved in water and extracted with methylene chloride. The combined organic phase is dried, evaporated, and recrystallized from petroleum ether and obtain the target compound with a yield 630 mg (86%).

Century 3-(4-Methoxy-1,2,5-thiadiazole-3-yl)-1-methylpyridinium.

Mixture under the conditions (of 0.37 ml, 6 mmol) and 3-(4-methoxy-1,2,5-thiadiazole-3-yl)pyridi (500 mg, 2.5 mmol) in acetone (10 ml) is stirred for 18 h at room temperature. The desired product precipitated from solution and is collected by filtration. Yield: 1 g (100%).

, 1,2,5,6-Tetrahydro-3-(4-methoxy-1,2,5-thiadiazole-3-yl)-1 - methylpyridine oxalate.

Sodium borohydride (460 mg, 12 mmol) was added to a solution of 3-(4-methoxy-1,2,5-thiadiazole-3-yl)-1-methylpyridinium (1 g, 3 mmol) in ethanol (99.9% of the 20 ml) and the reaction mixture was stirred 1 h at countriesa phase is evaporated and the residue purified column chromatography (SiO2, eluent a mixture of ethyl acetate/methanol 4:1). The target product is recrystallized in the form of oxalate from acetone. Yield: 390 mg So pl. 150aboutS; M+: 211; connection 1.

P R I m m e R 2. A. 3-(4-Ethoxy-1,2,5-thiadiazole-3-yl)pyridine.

To a solution of sodium (440 mg, 17 mmol) in ethanol (10 ml) was added 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (540 mg, 3.3 mmol). The mixture is stirred for 10 h at 40aboutWith and evaporated. The residue is dissolved in water and extracted with methylene chloride. The combined organic phase is dried, evaporated and obtain 520 mg (76%) of target compound.

B. 3-(4-Ethoxy-1,2,5-thiadiazole-3-yl)-1-methylpyridinium.

Mixture under the conditions (0.3 ml, 5 mmol) and 3-(4-ethoxy-1,2,5-thiadiazole-3-yl)pyridine (520 mg, 2.5 mmol) in acetone (10 ml) is stirred for 18 h at room temperature. The desired product precipitated from solution, collected by filtration and receive 0,72 g (83%).

Century 3-(4-Ethoxy-1,2,5-thiadiazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine oxalate.

Sodium borohydride (300 mg, 8 mmol) was added to a solution of 3-(4-ethoxy-1,2,5-thiadiazole-3-yl)-1-methylpyridinium (0,72 g, 2 mmol) in ethanol (99.9% of the 20 ml) and the reaction mixture stirred for 1 h at room temperature. After evaporation the residue is dissolved in water and extrage the SiO2, eluent a mixture of ethyl acetate (methanol 4:1). The target product is crystallized in the form of the oxalate salt from acetone, recrystallized from methanol and receive 190 mg. So pl. 137aboutS; M+: 225 connection 2.

P R I m e R 3. A. 3-(4-Propoxy-1,2,5-thiadiazole-3-yl)pyridine.

To a solution of sodium (440 mg, 17 mmol) in 1-propanol (10 ml) was added 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (650 mg, 3.3 mmol). The mixture is stirred for 2 h at 50aboutWith and evaporated. The residue is dissolved in water and extracted with methylene chloride. The combined organic phase is dried, evaporated and get 700 mg (96%) of target compound.

B. 3-(4-Propoxy-1,2,5-thiadiazole-3-yl)-1-methylpyridinium.

Mixture under the conditions (of 0.37 ml, 6 mmol) and 3-(4-propoxy-1,2,5-thiadiazole-3-yl)pyridi (700 mg, 3.1 mmol) in acetone (10 ml) is stirred for 18 h at room temperature. The desired product precipitated from solution, collected by filtration and receive 0,98 mg (88%).

Century 1,2,5,6-Tetrahydro-1-methyl-3-(4-proporsi-1,2,5-thiadiazole-3)- pyridineacetic.

Sodium borohydride (380 mg, 10 mmol) was added to a solution of 3-(4-propoxy-1,2,5-thiadiazole-3-yl)-1-methylpyridinium (980 mg, 2.7 mmol) in ethanol (99.9% of the 20 ml) and the reaction mixture was stirred 1 h at 0aboutC. After viparita the up column chromatography (SiO2eluent a mixture of ethyl acetate/methanol 4:1). The target product is crystallized in the form of oxalate from acetone and receive 440 mg. So pl. 148aboutS; M+: 239; connection 3.

P R I m e R 4. A. 3-(4-Butoxy-1,2,5-thiadiazole-3-yl)pyridine.

To a solution of sodium (290 mg, 12.5 mmol) in n-butanol (10 ml) was added 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (490 mg, 2.5 mmol). The mixture is stirred for 18 h at 25aboutWith and evaporated. The residue is dissolved in water and extracted with methylene chloride. The combined organic phase is dried, evaporated and obtain 580 mg (100%) of target compound.

B. 3-(4-Butoxy-1,2,5-thiadiazole-3-yl)-1-methylpyridinium iodide.

Mixture under the conditions (0.3 ml, 5 mmol) and 3-(4-butoxy-1,2,5-thiadiazole-3-yl)pyridine (580 mg, 2.5 mmol) in acetone (5 ml) is stirred for 18 h at room temperature. The target compound precipitated from the solution, collected by filtration and gain of 0.60 g (64%).

Century 3-(4-Butoxy-1,2,5-thiadiazole-3-yl)-1,2,5,6-tetrahydro-1 - methylpyridinium.

Sodium borohydride (240 mg, 6.4 mmol) are added to a solution of 3-(4-butoxy-1,2,5-thiadiazole-3-yl)-methylpyridinium (of 0.60 g, 1.6 mmol) in ethanol (99.9% of the 20 ml) and the reaction mixture was stirred 1 h at 0aboutC. After evaporation the residue is dissolved in water and extracted with e is NT a mixture of ethyl acetate/methanol 4:1). The target product is crystallized in the form of the oxalate salt from acetone and receive 280 mg. So pl. 158aboutS; M+: 253; compound 4.

P R I m e R 5. A. 3-(4-Isopropoxy-1,2,5-thiadiazole-3-yl)pyridine.

To a solution of sodium (290 mg, 12.5 mmol) in isopropanol (10 ml) is added 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (490 mg, 2.5 mmol). The mixture is stirred for 18 h at 25aboutWith and evaporated. The residue is dissolved in water and extracted with ethyl acetate. The combined organic phase is dried, evaporated and get 540 mg (98%) of target compound.

B. 3-(4-Isopropoxy-1,2,5-thiadiazole-3-yl)-1-methylpyridinium.

Mixture under the conditions (0.3 ml, 5 mmol) and 3-(4-isopropoxy-1,2,5-thiadiazole-3-yl)PI-ridin (540 ml, 2.4 mmol) in acetone (5 ml) is stirred for 18 h at room temperature. The target compound precipitated from the solution, collected by filtration and gain of 0.68 g (77%).

Century 1,2,4,5-Tetrahydro-3-(4-isopropoxy-1,2,5-thiadiazole-3-yl)-1 - methylpyridine)- oxalate.

Sodium borohydride (280 mg, 7.2 mmol) are added to a solution of 3-(4-isopropoxy-1,2,5-thiadiazole-3-yl)-1-methylpyridinium - Yes (650 mg, 1.8 mmol) in ethanol (99.9% of the 20 ml) and the reaction mixture was stirred 1 h at 0aboutC. After evaporation the residue is dissolved in water and extracted with ethylacetoacetate/methanol 4:1). The target product is crystallized in the form of the oxalate salt from acetone and receive 280 mg. So pl. 164aboutS; M+: 239; connection 5.

P R I m e R 6. A. 3-(4-Pentyloxy-1,2,5-thiadiazole-3-yl)pyridine.

To a solution of sodium (230 mg, 10 mmol) in 1-pentanol (20 ml) is added 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (490 mg, 2.5 mmol). The mixture is stirred for 3 h at 50aboutWith and evaporated. The residue is dissolved in water and extracted with methylene chloride. The combined organic phase is dried, evaporated and get the target product.

B. 3-(4-Pentyloxy-1,2,5-thiadiazole-3)-1-methylpyridinium.

Mixture under the conditions (0.3 ml, 5 mmol) and 3-(4-pentyloxy-1,2,5-thiadiazole-3-yl)Piri - DIN (620 mg, 2.5 mmol) in acetone (5 ml) is stirred for 18 h at room temperature. The target compound precipitated from the solution, collected by filtration and receive 0,81 g (84%).

Century 1,2,5,6-Tetrahydro-1-methyl-3-(4-pentaoxa-1,2,5-thiadiazole-3-yl) peridiniaceae.

Sodium borohydride (300 mg, 8 mmol) are added to a solution of 3-(4-pentyloxy-1,2,5-thiadiazole-3-yl)-1-methylpyridinium (0,81 g, 2 mmol) in ethanol (99.9% of the 20 ml) and the reaction mixture was stirred 1 h at 0aboutC. After evaporation the residue is dissolved in water and extracted with ether. The dried organic phase wuct crystallized in the form of the oxalate salt from acetone and receive 220 mg. So pl. 150aboutS; M+:267; connection 6.

P R I m e R 7. A. 3-(4-Isobutoxy-1,2,5-thiadiazole-3-yl)pyridine.

To a solution of sodium (230 mg, 10 mmol) in isobutyl alcohol (10 ml) is added 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (490 mg, 2.5 mmol). The mixture is stirred for 3 h at 50aboutWith and evaporated. The residue is dissolved in water and extracted with methylene chloride. The combined organic phase is dried, evaporated and get the target connection.

B. 3-(4-Isobutoxy-1,2,5-thiadiazole-3-yl)-1-methylpyridinium.

Mixture under the conditions (0.6 ml, 10 mmol) and 3-(4-isobutoxy-1,2,5-thiadiazole-3-yl)Piri - DIN (588 mg, 2.5 mmol) in acetone (5 ml) is stirred for 18 h at room temperature. The target compound precipitated from the solution, collected by filtration and obtain 0.88 g (87%).

Century 1,2,5,6-Tetrahydro-3-(4-isobutoxy-1,2,5-thiadiazole-3-yl)-1 - methylpyridinium.

Sodium borohydride (160 mg, 4.3 mmol) are added to a solution of 3-(4-isobutoxy-1,2,5-thiadiazole-3-yl)-1-methylpyridinium (of 0.82 g, 2.2 mmol) in ethanol (99.9% of the 20 ml) and the reaction mixture was stirred 1 h at 0aboutC. After evaporation the residue is dissolved in water and extracted with ethyl acetate. The dried organic phase is evaporated and the residue purified column chromatography (SiO2,0 mg. So pl. 135aboutS; M+: 253; connection 7.

P R I m e R 8. A. 3-(4-Isopentane-1,2,5-thiadiazole-3-yl)pyridine.

To a solution of sodium (230 mg, 10 mmol) in isopentanol (20 ml) is added 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (490 mg, 2.5 mmol). The mixture is stirred for 2 h at 50aboutWith and evaporated. The residue is dissolved in water and extracted with ether. The combined organic phase is dried, evaporated and get the target connection.

B. 3-(4-Isopentane-1,2,5-thiadiazole-3-yl)-1-methylpyridinium.

Mixture under the conditions (0.5 ml, 10 mmol) and 3-(4-isopentane-1,2,5-thiadiazole-3-yl) -pyridine (622 mg, 2.5 mol) in acetone (5 ml) is stirred for 18 h at room temperature. The desired product precipitated from solution, collected by filtration and receive 0,78 g (81%).

Century 1,2,5,6-tetrahydro-3-(4-isopentane-1,2,5-thiadiazole-3-yl)-1 - methylpyridinium.

Sodium borohydride (150 mg, 4 mmol) are added to a solution of 3-(4-isopentane-1,2,5-thiadiazole-3-yl)-1-methylpyridinium (780 mg, 2 mmol) in ethanol (99.9% of the 20 ml) and the reaction mixture was stirred 1 h at 0aboutC. After evaporation the residue is dissolved in water and extracted with ethyl acetate. The dried organic phase is evaporated and the residue purified column chromatography (alwen the L. 152aboutS; M+: 267 connection 8.

P R I m e R 9. A. 3-(4-Hexyloxy-1,2,5-thiadiazole-3-yl)pyridine.

To a solution of sodium (230 mg, 10 mmol) in 1-hexanol (15 ml) is added 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (490 mg, 2.5 mmol). The mixture was stirred at 50aboutC for 2 h and evaporated. The residue is dissolved in water and extracted with ether. The combined organic phase is dried, evaporated and get the target product.

B. 3-(4-Hexyloxy-1,2,5-thiadiazole-3-yl)-1-methylpyridinium.

Mixture under the conditions (0.5 ml, 7.5 mmol) and 3-(4-hexyloxy-1,2,5-thiadiazole-3-yl)Piri - DIN (658 mg, 2.5 mmol) in acetone (5 ml) is stirred for 18 h at room temperature. The desired product precipitated from solution, collected by filtration and receive 0,81 g (80%).

Century 3-(4-Hexyloxy-1,2,5-thiadiazole-3-yl)-1,2,5,6-tetrahydro-1 - methylpyridinium.

Sodium borohydride (230 mg, 6 mmol) are added to a solution of 3-(4-hexyloxy-1,2,5-thiadiazole-3-yl)-1-methylpyridinium (810 mg, 2 mmol) in ethanol (99.9% of the 20 ml) and the reaction mixture stirred for 1 h at room temperature. After evaporation the residue is dissolved in water and extracted with ethyl acetate. Dry the organic phase is evaporated and the residue purified column chromatography (SiO2, alomg. So pl. 148aboutS; M+: 281; connection 9.

P R I m e R 10. A. 3-(4-Benzyloxy-1,2,5-thiadiazole-3-yl)pyridine.

To a solution of sodium (490 mg, 2.5 mmol) in benzyl alcohol (15 ml) is added 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (490 mg, 2.5 mmol). The mixture is stirred for 2 h at 50aboutWith and evaporated. The residue is dissolved in water and extracted with ether. The combined organic phase is dried, evaporated and get the target product.

B. 3-(4-Benzyloxy-1,2,5-thiadiazole-3-yl)-1-methylpyridinium.

Mixture under the conditions (0.5 ml, 7.5 mmol) and 3-(4-benzyloxy-1,2,5-thiadiazole-3-yl)Piri - DIN (673 mg, 2.5 mmol) in acetone (5 ml) is stirred for 18 h at room temperature. The desired product precipitated from solution, collected by filtration and obtain 0.75 g (73%).

Century 3-(4-Benzyloxy-1,2,5-thiadiazole-3-yl)-1,2,5,6-tetrahydro-1 - methylpyridinium.

Sodium borohydride (230 mg, 6 mmol) are added to a solution of 3-(4-benzyloxy-1,2,5-thiadiazole-3-yl)-1-methylpyridinium (750 ml, 1.8 mmol) in ethanol (99.9% of the 20 ml) and the mixture is stirred 1 h at 0aboutC. After evaporation the residue is dissolved in water and extracted with ethyl acetate. Dry the organic phase is evaporated and the residue purified column chromatography (SiO2, eluent ethyl acetate/methane is +: 287; connection 10.

P R I m e R 11. A. 3-[4-(3-Butenyloxy)-1,2,5-thiadiazole-3-yl]pyridine.

To a solution of 3-butene-1-ol (540 ml, 7.5 mmol) and sodium hydride (180 mg, 7.5 mmol) in dry tetrahydrofuran added a solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (490 mg, 2.5 mmol) in dry tetrahydrofuran. The reaction mixture was stirred 1 h at room temperature. Water is added and the mixture extracted with ether. The ether phase is dried, evaporated and obtain 650 mg of the target product.

B. 3-[4-(3-Butenyloxy)-1,2,5-thiadiazol-3-yl]-1-methylpyridinium.

Mixture under the conditions (0.5 ml, 7.5 mmol) and 3-[4-(3-butenyloxy)-1,2,5-thiadiazole-3-yl] -pyridine (583 mg, 2.5 mmol) in acetone (5 ml) is stirred for 18 h at room temperature. The desired product precipitated from solution, collected by filtration and obtain 890 mg (96%).

Century 3-[4-(3-Butenyloxy)-1,2,5-thiadiazole-3-yl] -1,2,5,6-tetrahydro-1 - methylpyridinium.

Sodium borohydride (210 mg, 5.5 mmol) are added to a solution of 3-[4-(3-butenyloxy-1,2,5-thiadiazole-3-yl)-1-methylpyridinium - Yes (1,03 g, 2.8 mmol) in ethanol (99.9% of the 20 ml) and the mixture is stirred 1 h at 0aboutC. After evaporation the residue is dissolved in water and extracted with ethyl acetate. Dry the organic phase is evaporated and the residue purified stake is atoi salt from acetone and receive 380 mg. So pl. 141aboutS; M+: 251; compound 11).

P R I m e R 12. A. 3-[4-(2-Butenyloxy)-1,2,5-thiadiazole-3-yl]pyridine.

To a solution of 2-butyl-1-ol (530 mg, 7.5 mmol) and sodium hydride (180 mg, 7.5 mmol) in dry tetrahydrofuran added a solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (490 mg, 2.5 mmol) in dry tetrahydrofuran. The mixture is stirred for 2 h at room temperature. Water is added and the mixture extracted with ether. The ether phase is dried, evaporated and get the target product.

B. 3-[4-(2-Butenyloxy-1,2,5-thiadiazole-3-yl)-1-methylpyridinium.

Mixture under the conditions (0.5 ml, 7.5 mmol) and 3-[4-(2-butenyloxy)-1,2,5-thiadiazole-3-yl] -pyridine (578 mg, 2.5 mmol) in acetone (5 ml) is stirred for 18 h at room temperature. The desired product precipitated from solution, collected by filtration and obtain 0.88 g (95%).

Century 3-[4-(2-Butenyloxy)-1,2,5-thiadiazole-3-yl] -1,2,5,6-tetrahydro - 1-methylpyridinium.

Sodium borohydride (180 mg, 4.7 mmol) are added to a solution of 3-[4-(2-butenyloxy)-1,2,5-thiadiazole-3-yl]-1-methylpyridinium - Yes (0.88 g, of 2.35 mmol) in ethanol (99.9% of the 20 ml) and the reaction mixture was stirred 1 h at 0aboutC. After evaporation the residue is dissolved in water and extracted with ethyl acetate. Dry the organic phase is evaporated, isout in the form of oxalate from acetone, recrystallized from methanol and receive 140 mg. So pl. 158aboutC. M+: 249; connection 12.

P R I m e p 13. A. 3-(4-Propargyloxy-1,2,5-thiadiazole-3-yl)pyridine.

To a solution of propargilovyh alcohol (420 mg, 7.5 mmol) and sodium hydride (180 mg, 7.5 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (490 mg, 2.5 mmol) in dry tetrahydrofuran. The reaction mixture was stirred 2 h at room temperature. Water is added and the mixture extracted with ether. The ether phase is dried, evaporated and obtain 530 mg (98%) of target compound.

B. 3-(4-Propargyloxy-1,2,5-thiadiazole-3-yl)-1-methylpyridinium.

Mixture under the conditions (0.45 ml, 7.2 mmol) and 3-(4-propargyloxy-1,2,5-thiadiazole-3-yl)- pyridine (430 mg, 2.4 mmol) in acetone (5 ml) is stirred for 18 h at room temperature. The target compound precipitated from the solution, collected by filtration and gain of 0.58 g (67%).

Century 1,2,5,6-Tetrahydro-1-methyl-3-(4-propargyloxy-1,2,5-thiadiazole-3-yl)pyridi - dioxalate.

Sodium borohydride (230 mg, 6 mmol) are added to a solution of 3-(4-propargyloxy-1,2,5-thiadiazole-3-yl)-1-methylpyridinium (0.68 g, 1.9 mmol) in ethanol (99.9% of the 20 ml) and the reaction mixture was stirred 1 h at 0aboutC. After evaporation OST Nochnoi chromatography (SiO2, eluent ethyl acetate/methanol 4:1). The target compound is crystallized in the form of the oxalate salt from acetone and receive 200 mg. So pl. 155aboutS; M+: 235; connection 13.

P R I m e R 14. A. 3-(4-Cyclopropylmethoxy-1,2,5-thiadiazole-3-yl)pyridine.

To a solution of cyclopropanecarbonyl (360 mg, 5 mmol) and sodium hydride (110 mg, 5 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (490 mg, 2.5 mmol) in dry tetrahydrofuran. The reaction mixture is stirred 3 h at room temperature. Add water and the mixture extracted with ether. The ether phase is dried, evaporated and receive 400 mg (69%) of target compound.

B. 3-(4-Cyclopropylmethoxy-1,2,5-thiadiazole-3-yl)-1-methylpyridinium.

Mixture under the conditions (0.25 ml, 4 mmol) and 3-(4-cyclopropylmethoxy-1,2,5-thiadiazole-3-yl)pyridine (400 mg, 1.7 mmol) in acetone (5 ml) is stirred for 36 h at room temperature. The target compound precipitated from the solution, collected by filtration and receive 0,41 g (65%).

Century 3-(4-Cyclopropylmethoxy-1,2,5-thiadiazole-3-yl)-1,2,5,6-tetrahydro - 1-methylpyridinium.

Sodium borohydride (170 mg, 4.4 mmol) was added to a solution of 3-(4-cyclopropylmethoxy-1,2,5-thiadiazole-3-yl)-1-metier - idinindia (410 mg, 1.1 mm is between water and extracted with ethyl acetate. Dry the organic phase is evaporated and the residue purified column chromatography (SiO2, eluent ethyl acetate/methanol 4:1). The target compound is crystallized in the form of the oxalate salt from acetone and receive 130 mg. So pl. 153aboutS; M+: 251; connection 14.

P R I m e R 15. A. 3-(4-Chloro-1,2,5-thiadiazole-3-yl)-1-methylpyridinium.

A solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (1.98 g, 10 mmol) and under the conditions (4,25 g, 30 mmol) in acetone (10 ml) was stirred at room temperature for 16 hours the Precipitate is collected by filtration and receive 3,40 g (100%) specified connection.

B. 3-(4-Chloro-1,2,5-thiadiazole-3-yl)-1,2,5,6-tetrahydro-1 - methylpyridinium.

To a suspension of sodium borohydride (330 mg, 0.6 mmol) in ethanol (20 ml) is added 3-(4-chloro-1,2,5-thiadiazole-3-yl)-1-methylpiperid - iniiated (1,46 g, 4.3 mmol) at 0aboutC. the Reaction mixture was stirred 1 h at 0aboutC. water is Added and the mixture extracted with ethyl acetate. After drying, an ethyl acetate phase is evaporated and the residue purified column chromatography (eluent ethyl acetate/methanol 4:1). Output: 880 mg (95%). Crystallization with oxalic acid from acetone obtain the target product. So pl. 124aboutS; M+: 215 and 217; connection 16.

Century 1,2,5,6-Tetrahydro-3-(4-methoxime (10 ml) is added 3-(4-chloro-1,2,5-thiadiazole-3-yl)-1,2,5,6-Tetra - hydro-1 - methylpyridinium (310 mg, 1 mmol). The mixture is stirred for 18 h at 50aboutWith and evaporated. The residue is dissolved in water and extracted with ethyl acetate. The combined organic phases are dried and evaporated. The target compound is crystallized in the form of the oxalate salt from acetone and receive 270 mg. So pl. 152,1aboutS; M+: 253; connection 15.

G 3-(4-Chloro-1,2,5-thiadiazole-3-yl)-1,2,5,6-tetrahydropyridinium.

To a solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (670 mg, 3.1 mmol) in 1,2-dichloroethane (20 ml) add a solution of 1-chloromethylphosphonate (440 mg, 3.1 mmol) in 1,2-dichloroethane at 0aboutC. the Reaction mixture is heated for 2 hours at 40aboutWith and evaporated. The residue is dissolved in methanol and boiled for 1 h under reflux. After cooling to room temperature the precipitate is collected by filtration and obtain 320 mg (41%). So pl. 224aboutS; M+: 201 and 203; the connection 17.

D. 3-(4-Butoxy-1,2,5-thiadiazole-3-yl)-1,2,5,6-tetrahydropyridines.

To a solution of sodium (150 mg, 6.5 mmol) in 1-butanol (15 ml) is added 3-(4-chloro-1,2,5-thiadiazole-3-yl)-1,2,5,6 - tetrahydropyridinium (240 mg, 1 mmol). The reaction mixture was stirred 1 h at 50aboutC. After evaporation the residue is dissolved in water and extracted with ethyl acetate. E. get the target connection. Yield: 170 mg (52%). So pl. 173-174aboutWITH M+239; the connection 18.

P R I m e R 16. A. 3-(4-Chloro-1,2,5-thiadiazole-3-yl)-1-ethylpyridinium.

A solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (1.13 g, 5.7 mmol) and ethyliodide (22,65 g, 17 mmol) in acetone (15 ml) is stirred for 16 h at 40aboutC. the Precipitate is collected by filtration and receive the target connection. Yield: 510 mg (26%).

B. 3-(4-Chloro-1,2,5-thiadiazole-3-yl)-1-ethyl-1,2,5,6 - tetrahydropyridines.

To a suspension of sodium borohydride (170 mg, 4.5 mmol) in ethanol (10 ml) was added 3-(4-chloro-1,2,5-thiadiazole-3-yl)-1-Etiler - idoneidad (510 mg, 1.5 mmol) at 0aboutC. the Mixture is stirred 1 h at 0aboutC. water is Added and the mixture extracted with ethyl acetate. After drying an ethyl acetate phase is evaporated and the residue purified column chromatography (eluent ethyl acetate/methanol 4:1). Crystallization with oxalic acid from acetone obtain the target compound with a yield 70 mg So pl. 143aboutS; M+: 229 and 231; connection 19.

P R I m e R 17. A. 3-(4-Ethoxy-1,2,5-thiadiazole-3-yl)-1-ethylpyridinium.

A solution of 3-(4-ethoxy-1,2,5-thiadiazole-3-yl)pyridine (0,90 g, 4.3 mmol) and ethyliodide (2,03 g, 13 mmol) in acetone (4 ml) is stirred for 16 h at 40aboutC. the Precipitate is collected and filtered tetrahydropyridines.

To a suspension of sodium borohydride (410 mg, up 10.8 mmol) in ethanol (10 ml) was added 3-(4-ethoxy-1,2,5-thiadiazole-3-yl)-1-atile - reinitiated (1,32 g, 3.6 mmol) at 0aboutC. the Mixture is stirred 1 h at 0aboutWith, add water and extracted with ethyl acetate. After drying an ethyl acetate phase is evaporated and the residue purified column chromatography (eluent ethyl acetate/methanol 4:1). Crystallization with oxalic acid from acetone gain of 0.49 g of the target product. So pl. 120-122aboutS; M+: 239; connection 20.

P R I m e R 18. 3-(4-Heptyloxy-1,2,5-thiadiazole-3-yl)-1,2,5,6-tetrahydro-1 - methylpyridinium.

To a solution of sodium (120 mg, 5 mmol) in 1-heptanol (10 ml) was added 3-(4-chloro-1,2,5-thiadiazole-3-yl)-1,2,5,6-tetrahydro-1 - methylpyridinium (310 mg, 1 mmol). The reaction mixture was stirred 18 h at 50aboutC. After evaporation the residue is dissolved in water and extracted with ethyl acetate. An ethyl acetate phase is dried, evaporated and get the oil. Crystallization in the form of the oxalate salt from acetone receive the target connection. Yield: 270 mg (70%). So pl. 152aboutS; M+: 295; connection 21.

P R I m e R 19. A. 3-[4-(3-Pentyloxy)-1,2,5-thiadiazole-3-yl]pyridine.

To a solution of 3-pentyn-1-ol (750 mg, 9 mmol) and sodium hydride is ear tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h, add water and extracted with ether. The ether phase is dried, evaporated and get the target connection.

B. 3-[4-(3-Pentyloxy)-1,2,5-thiadiazole-3-yl]-1-methylpyridinium.

Mixture under the conditions (0.6 ml, 9 mmol) and 3-[4-(3-pentyloxy)-1,2,5-thiadiazole-3-yl] pyridine (3 mmol) in acetone (10 ml) is stirred for 18 h at room temperature. The desired product precipitated from solution, collected by filtration and gain of 0.68 g (59%).

Century 3-[4-(3-Pentyloxy)-1,2,5-thiadiazole-3-yl] -1,2,5,6-tetrahydro - 1-methylpyridinium.

Sodium borohydride (150 mg, 4 mmol) was added to a solution of 3-[4-(3-pentyloxy)-1,2,5-thiadiazole-3-yl] -1-methylpyridine - iodide (0.68 g, 1.7 mmol) in ethanol (99.9% of the 15 ml) and the reaction mixture was stirred 1 h at -10aboutC. After evaporation the residue is dissolved in water and extracted with ethyl acetate. The dried organic phase is evaporated and the residue purified column chromatography (SiO2, eluent ethyl acetate/methanol 4:1). The target product is crystallized in the form of the oxalate salt from acetone and receive 240 mg So pl. 166-167aboutS; M+: 263; connection 22.

P R I m e R 20. A. 2-[4-(4-Pentyloxy)-1,2,5-thiadiazole-3-yl]pyridine.

To Rast 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (490 mg, 2.5 mmol) in dry tetrahydrofuran. The reaction mixture was stirred 1 h at room temperature, add water and extracted with ether. The ether phase is dried, evaporated and get the target product.

B. 3-[4-(4-Pentyloxy)-1,2,5-thiadiazole-3-yl]-1-methylpyridinium.

Mixture under the conditions (0.5 ml, 7.5 mmol) and 3-[4-(4-pentyloxy)-1,2,5-thiadiazole-3 - yl] pyridine (2.5 mmol) in acetone (10 ml) is stirred for 18 h at room temperature. The target compound precipitated from the solution, collected by filtration and gain of 0.67 g (69%).

Century 3-[4-(4-Pentyloxy)-1,2,5-thiadiazole-3-yl] -1,2,5,6-tetrahydro-1 - methylpyridinium.

Sodium borohydride (150 mg, 4 mmol) was added to a solution of 3-[4-(4-pentyloxy)-1,2,5-thiadiazole-3-yl] -1-methylpyridinium - Yes (to 0.67 g, 1.7 mmol) in ethanol (99.9% of the 15 ml) and the reaction mixture was stirred 1 h at -10aboutC. After evaporation the residue is dissolved in water and extracted with ethyl acetate. Dry the organic phase is evaporated and the residue purified column chromatography (SiO2, eluent ethyl acetate/methanol 4:1). The specified connection is crystallized in the form of the oxalate salt from acetone to yield 150 mg So pl. 141-142aboutS; M+: 265; connection 23.

P R I m e R 21. A. 3-[4-(2-Propenyloxy)-1,2,5-Tiada tetrahydrofuran is added a solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred 1 h at room temperature. Water is added and the mixture extracted with ether. The ether phase is dried, evaporated and get the target product.

B. 3-[4-(2-Propenyloxy)-1,2,5-thiadiazole-3-yl]-1-methylpyridinium.

Mixture under the conditions (0.4 ml, 6 mmol) and 3-[4-(2-propenyloxy)-1,2,5-thiadiazole-3-yl) pyridine (3 mmol) in acetone (5 ml) is stirred for 18 h at room temperature. The target compound precipitated from the solution, collected by filtration and obtain 0.96 g (88%).

Century 3-[4-(2-Propenyloxy-1,2,5-thiadiazole-3-yl)-1,2,5,6-tetrahydro-1 - methylpyridinium.

Sodium borohydride (210 mg, 5.5 mmol) was added to a solution of 3-[4-(2-propenyloxy)-1,2,5-thiadiazole-3-yl] -1-methylpyridin deposits iodide (0.96 g, 2.6 mmol) in ethanol (99.9% of the 25 ml) and the reaction mixture was stirred 1 h at -10aboutC. After evaporation the residue is dissolved in water and extracted with ethyl acetate. Dry the organic phase is evaporated and the residue purified column chromatography (SiO2, eluent ethyl acetate/methanol 4:1). The target product is crystallized in the form of the oxalate salt from acetone to yield 270 mg So pl. 136-137aboutS; M+: 237 connection 24.

P R I m e R 22. A. 3-(4-Octyloxy-1,2,5-thiadiazole-3-and the)pyridine (590 mg, 3 mmol). The mixture is stirred for 1 h at 50aboutWith and evaporated. The residue is dissolved in water and extracted with methylene chloride. The combined organic phase is dried, evaporated and get the target connection.

B. 3-(4-Octyloxy-1,2,5-thiadiazole-3-yl)-1-methylpyridinium.

Mixture under the conditions (1 ml, 15 mmol) and 3-(4-octyloxy-1,2,5-thiadiazole-3-yl)Piri-DIN (3 mmol) in acetone (5 ml) is stirred for 18 h at room temperature. The target compound precipitated from the solution, collected by filtration and receive 0,81 g (62%).

Century 3-(4-Octyloxy-1,2,5-thiadiazole-3-yl)-1,2,5,6-tetrahydro-1 - methylpyridinium.

Sodium borohydride (210 mg, 5.6 mmol) was added to a solution of 3-(4-octyloxy-1,2,5-thiadiazole-3-yl)-1-methylpyridinium (0,81 g of 1.87 mmol) in ethanol (99.9% of the 10 ml) and the reaction mixture was stirred 1 h at -10aboutC. After evaporation the residue is dissolved in water and extracted with ethyl acetate. Dry the organic phase is evaporated and the residue purified column chromatography (eluent ethyl acetate/methanol 4:1). The target compound is crystallized in the form of the oxalate salt from acetone to yield 330 mg So pl. 144-145aboutS; M+: 309; the connection 25.

P R I m e R 23. A. 3-[4-(3-Hexyloxy)-1,2,5-thiadiazole-3-yl]pyridine.

RA is 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred 1 h at room temperature, add water and extracted with ether. The ether phase is dried, evaporated and get the target product.

B. 3-[4-(3-Hexyloxy)-1,2,5-thiadiazole-3-yl]-1-methylpyridinium.

Mixture under the conditions (1 ml, 15 mmol) and 3-[4-(3-hexyloxy)-1,2,5-thiadiazole-3-yl] pyridine (3 mmol) in acetone (5 ml) is stirred for 18 h at room temperature. The target compound precipitated from the solution, collected by filtration and receive 0,85 g (71%).

Century 3-[4-(3-Hexyloxy)-1,2,5-thiadiazole-3-yl] -1,2,5,6-etagere-1 - methylpyridinium.

Sodium borohydride (190 mg, 5 mmol) was added to a solution of 3-[4-(3-hexyloxy)-1,2,5-thiadiazole-3-yl] -1-methylpyridinium - Dida of 0.85 g, 2.1 mmol) in ethanol (99.9% of the 10 ml) and the reaction mixture was stirred 1 h at -10aboutC. After evaporation the residue is dissolved in water and extracted with ethyl acetate. Dry the organic phase is evaporated and the residue purified column chromatography (SiO2, eluent ethyl acetate/methanol 4:1). The target compound is crystallized in the form of the oxalate salt from acetone to yield 350 mg. So pl. 174-175aboutS; M+: 277; connection 26.

P R I m e R 24. A. 3-[4-(3-Methyl-2-butenyloxy)-1,2,5-tedium tetragidrofurane added a solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred for 0.3 h at room temperature. Water is added and the mixture extracted with ether. The ether phase is dried, evaporated and get the target product.

B. 3-[4-(3-methyl-2-butenyloxy)-1,2,5-thiadiazole-3-yl] -1 - methylpyridinium.

Mixture under the conditions (1 ml, 15 mmol) and 3-[4-(3-methyl-2-butenyloxy)-1,2,5-tiava-Zol-3-yl] pyridine (3 mmol) in acetone (3 ml) is stirred for 18 h at room temperature. The desired product precipitated from solution and is collected by filtration with access to 0.92 g (79%).

Century 3-[4-(3-Methyl-2-butenyloxy)-1,2,5-thiadiazole-3-yl]-1,2,5,6 - tetrahydro-1-methylpyridinium.

Sodium borohydride (220 mg, 6 mmol) was added to a solution of 3-[4-(3-methyl-2-butenyloxy)-1,2,5-thiadiazole-3-yl] -1 - methylpyridinium (0,92 g, 2.3 mmol) in ethanol (99.9% of the 15 ml) and the reaction mixture stirred for 0.5 h at -10aboutC. After evaporation the residue is dissolved in water and extracted with ethyl acetate. Dry the organic phase is evaporated and the residue purified column chromatography (SiO2, eluent: ethyl acetate/methanol 4:1). The target compound is crystallized in the form of the oxalate salt from acetone to yield 380 mg So pl. 150-151aboutS; M+: 265; connection 27.

P R I m e R 25. A. 3-[4-(0 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred 18 h at room temperature. Add water and the mixture extracted with ether. The ether phase is dried, evaporated and get the target product.

B. 3-[4-(3-Butenyl-2-oxy)-1,2,5-thiadiazole-3-yl]-1 - methylpyridinium.

Mixture under the conditions (1 ml, 15 mmol) and 3-[4-(3-butenyl-2-oxy)-1,2,5-thiadiazole-3 - yl] pyridine (3 mmol) in acetone (3 ml) is stirred for 18 h at room temperature. The desired product precipitated from solution and is collected by filtration to yield 0.73 g (65%).

Century 3-[-(3-Butenyl-2-oxy)-1,2,5-thiadiazole-3-yl] -1,2,5,6-tetrahydro-1 - methylpyridinium.

Sodium borohydride (190 mg, 5 mmol) was added to a solution of 3-[4-(3-butenyl-2-oxy)-1,2,5-thiadiazole-3-yl] -1-methylpyridinium - Dida (0.73 g, 1.9 mmol) in ethanol (99.9% of the 15 ml) and the reaction mixture stirred for 0.5 h at -10aboutC. After evaporation the residue is dissolved in water and extracted with ethyl acetate. The dried organic phase is evaporated and the residue purified column chromatography (SiO2, eluent ethyl acetate/methanol 4:1). The target compound is crystallized in the form of the oxalate salt from acetone to yield 270 l]pyridine.

To a solution of 4-HEXEN-1-ol (900 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred 1 h at room temperature. Add water and the mixture extracted with ether. The ether phase is dried, evaporated and get the target product.

B. 3-[4-(4-Hexenoate)-1,2,5-thiadiazole-3-yl]-1-methylpyridinium.

Mixture under the conditions (1 ml, 15 mmol) and 3-[4-(4-hexenoate)-1,2,5-thiadiazole-3-yl] pyridine (3 mmol) in acetone (5 ml) is stirred for 18 h at room temperature. The target compound precipitated from the solution and collected by filtration to yield 0.54 g (45%).

Century 3-[4-(4-Hexenoate)-1,2,5-thiadiazole-3-yl} -1,2,5,6-tetrahydro - 1-methylpyridinium.

Sodium borohydride (150 mg, 4 mmol) was added to a solution of 3-[4-(4-hexenoate)-1,2,5-thiadiazole-3-yl] -1-methylpyridinium - Yes (0.54 g, 1.3 mmol) in ethanol (99.9% of the 15 ml) and the reaction mixture stirred for 0.5 h at -10aboutC. After evaporation the residue is dissolved in water and extracted with ethyl acetate. Dry the organic phase is evaporated and the residue purified column chromatography (SiO2, eluent ethyl acetate/methanol 4:1). The target connection ASS="ptx2">

P R I m e R 27. A. TRANS-3-[4-(3-hexenoate)-1,2,5-thiadiazole-3-yl]pyridine.

To a solution of TRANS-3-HEXEN-1-ol (900 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h was Added water and the mixture extracted with ether. The ether phase is dried, evaporated and get targeted product.

B. TRANS-3-[4-(3-hexenoate)-1,2,5-thiadiazole-3-yl] -1 - methylpyridinium.

Mixture under the conditions (1 ml, 15 mmol) and TRANS-3-[4-(4-hexenoate)-1,2,5-thiadiazole-3-yl] pyridine (3 mmol) in acetone (5 ml) is stirred for 18 h at room temperature. The desired product precipitated from solution and is collected by filtration yield of 0.90 g (75%).

Century TRANS-3-[4-(3-hexenoate)-1,2,5-thiadiazole-3-yl] -1,2,5,6 - tetrahydro-1-methylpyridinium.

Sodium borohydride (190 mg, 5 mmol) was added to a solution of TRANS-3-[4-(3-hexenoate-1,2,5-thiadiazole-3-yl)-1-methylpyridin - diiodide (from 0.90 g, 2.2 mmol) in ethanol (99.9% of the 15 ml) and the reaction mixture stirred for 0.5 h at -10aboutC. After evaporation the residue is dissolved in water and extracted with ethyl acetate. Dry the organic phase is evaporated and the mod is comfort in the form of the oxalate salt from acetone to yield 420 mg So pl. 163-164aboutS; M+: 279; connection 30.

P R I m e R 28. A. CIS-3-[4-(2-pentyloxy)-1,2,5-thiadiazole-3-yl]pyridine.

To a solution of CIS-2-penten-1-ol (780 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred 1 h at room temperature. Water is added and the mixture extracted with ether. The ether phase is dried, evaporated and get the target product.

B. CIS-3-[4-(2-pentyloxy)-1,2,5-thiadiazole-3-yl]-1 - methylpyridinium.

Mixture under the conditions (1 ml, 15 mmol) and CIS-3-[4-(2-pentyloxy)-1,2,5-thiadiazole-3-yl] pyridine (3 mmol) in acetone (5 ml) is stirred for 18 h at room temperature. The desired product precipitated from solution and is collected by filtration yield of 0.53 g (46%).

C. CIS-3-[4-(2-pentyloxy)-1,2,5-thiadiazole-3-yl] -1,2,5,6 - tetrahydro-1-methylpyridinium.

Sodium borohydride (150 mg, 4 mmol) was added to a solution of CIS-3-(2-pentyloxy)-1,2,5-thiadiazole-3-yl] -1-methylpyridinium - Dida (of 0.53 g, 1.3 mmol) in ethanol (99.9% of the 15 ml) and the reaction mixture stirred for 0.5 h at -10aboutC. After evaporation the residue is dissolved in water and extracted with ethyl acetate. Ground is anal 4:1). The target compound is crystallized in the form of the oxalate salt from acetone to yield 210 mg So pl. 143-144aboutS; M+: 265; connection 31.

P R I m e R 29. A. CIS-3-[4-(2-hexenoate)-1,2,5-thiadiazole-3-yl]pyridine.

To a solution of CIS-2-HEXEN-1-she (900 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred 1 h at room temperature. Water is added and the mixture extracted with ether. The ether phase is dried, evaporated and get the target connection.

B. CIS-3-[4-(2-hexenoate)-1,2,5-thiadiazole-3-yl]-1 - methylpyridinium.

Mixture under the conditions (0.5 ml, 7.5 mmol) and CIS-3-[4-(2-hexenoate)-1,2,5-thiadiazole - 3-yl]pyridine (3 mmol) in acetone (4 ml) is stirred for 18 h at room temperature. The target compound precipitated from solution and is collected by filtration.

C. CIS-3-[4-(2-hexenoate)-1,2,5-thiadiazole-3-yl] -1,2,5,6 - tetrahydro-1-methylpyridinium.

Sodium borohydride ( 150 mg, 4 mmol) are added to a solution of CIS-3-[4-(2-hexenoate)-1,2,5-thiadiazole-3-yl]-1 - methylpyridinium (0.6 g, 1 mmol) in ethanol (99.9% of the 20 ml) and the reaction mixture stirred for 0.5 h at -10aboutC. PEFC who headed the remainder of the purified column chromatography (SiO2, eluent ethyl acetate/methanol 4:1). The target compound is crystallized in the form of the oxalate salt from acetone to yield 150 mg So pl. 122-123aboutS; M+: 279 connection 32.

P R I m e R 30. A. 3-[4-(5-Hexenoate)-1,2,5-thiadiazole-3-yl]pyridine.

To a solution of 5-HEXEN-1-ol (900 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred 1 h at room temperature. Water is added and the mixture extracted with ether. The ether phase is dried, evaporated and get the target product.

B. 3-[4-(5-Hexenoate)-1,2,5-thiadiazole-3-yl]-1-methylpyridinium.

Mixture under the conditions (0.5 ml, 7.5 mmol) and 3-[4-(5-hexenoate)-1,2,5-thiadiazole-3-yl] pyridine (3 mmol) in acetone (5 ml) is stirred for 18 h at room temperature. The target compound precipitated from the solution and collected by filtration to yield 0.75 g (62%).

Century 3-[4-(5-Hexenoate)-1,2,5-thiadiazole-3-yl] -1,2,5,6-tetrahydro - 1-methylpyridinium.

Sodium borohydride (150 mg, 4 mmol) was added to a solution of 3-[4-(5-hexenoate)-1,2,5-thiadiazole-3-yl]-1 - methylpyridinium (0.75 g, 1.8 mmol) in ethanol (99.9% of the 20 ml) and the reaction mixture peremeshannyj phase is evaporated and the residue purified column chromatography (SiO2, eluent ethyl acetate/methanol 4:1). The target compound is crystallized in the form of the oxalate salt from acetone to yield 250 mg. So pl. 137-138aboutS; M+: 279; compound 33).

P R I m e R 31. A. CIS-3-[4-(3-hexenoate)-1,2,5-thiadiazol-3-yl]pyridine.

To a solution of CIS-3-HEXEN-1-ol (900 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred 1 h at room temperature. Water is added and the mixture extracted with ether. The ether phase is dried, evaporated and get the target connection.

B. CIS-3-[4-(3-hexenoate)-1,2,5-thiadiazole-3-yl] -1 - methylpyridinium.

Mixture under the conditions (0.5 ml, 7.5 mmol) and CIS-3-[4-(3-hexenoate)-1,2,5-thiadiazole-3-yl] pyridine (3 mmol) in acetone (5 ml) was stirred at room temperature for 18 hours the desired product precipitated from solution and is collected by filtration to yield 0.9 g (46%).

C. CIS-3-[4-(3-hexenoate)-1,2,5-thiadiazole-3-yl] -1,2,5,6-tetrahydro - 1-methylpyridinium.

Sodium borohydride (230 mg, 6 mmol) was added to a solution of CIS-3-[4-(3-hexenoate)-1,2,5-thiadiazole-3-yl] -methylpyridinium - Yes (from 0.90 g, 2.2 mmol) in ethanol (99.9% of the 15 ml) and Rea is dilatatum. The dried organic phase is evaporated and the residue purified column chromatography (SiO2, eluent ethyl acetate/methanol 4:1). The target compound is crystallized in the form of the oxalate salt from acetone to yield 300 mg. So pl. 149-150aboutS; M+: 279; connection 34.

P R I m e R 32. A. TRANS-3-[4-(2-hexenoate)-1,2,5-thiadiazole-3-yl]pyridine.

To a solution of TRANS-2-HEXEN-1-ol (900 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran added a solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h was Added water and the mixture was extracted with diethyl ether. The ether phase was dried and evaporated, receiving the specified connection.

B. TRANS-3-[4-(2-hexenoate)-1,2,5-thiadiazole-3-yl] -1 - methylpyridinium.

Mixture under the conditions (0.5 ml, 7.5 mmol) and TRANS-3-[4-(2-hexenoate)-1,2,5-tiava - Zol-3-yl]pyridine (3 mmol) for (5 ml) was stirred at room temperature for 18 hours the Specified connection, precipitated from solution in the precipitate was separated by filtration. The output was 1,09 g (90%).

Century TRANS-3-[4-(2-hexenoate)-1,2,5-thiadiazole-3-yl] -1,2,5,6 - tetrahydro-1-methylpyridinium.

P R I m e R 33. A. 3-(1,2,5-Thiadiazole-3-yl)pyridine.

To a solution of 1-potential (2.7 g, 30 mmol) and sodium hydride (1.2 g, 30 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (1.2 g, 6 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at -10aboutC for 0.5 hours was Added water and the mixture was extracted with diethyl ether. The ether phase was dried and evaporated. The residue was purified through column chromatography (SiO2, eluent ethyl acetate/methylene chloride=1: 1), receiving the specified connection.

B. 3-(1,2,5-Thiadiazole-3-yl)-1-methylpyridinium.

Mixture under the conditions (1 ml, 15 mmol) 3-(1,2,5-thiadiazole-3-yl)-pyridine (6 mmol) in acetone (5 ml) was stirred at room temperature for 18 hours Specified connection 3-yl)-1,2,5,6-tetrahydro-1-methylpyridinium.

Borohydride sodium (380 mg, 10 mmol) was added to a solution of 3-(1,2,5-thiadiazole-3-yl)-1-methylpyridinium (1.2 g, 4.4 mmol) in ethanol (99.9% of the 20 ml), the reaction mixture was stirred at -10aboutC for 0.5 hours After evaporation the residue was dissolved in water and was extracted with ethyl acetate. The dried organic phase was evaporated and the residue was purified through column chromatography (SiO2, eluent ethyl acetate/methanol 4:1). The specified connection crystallized as a salt of oxalic acid from acetone to yield 430 mg So pl. 189-190aboutS; M+: 181; connection 36.

P R I m e R 34. 1,2,5,6-Tetrahydro-3-(3-hexyloxy-1,2,5-thiadiazole-4-yl)pyridine - xalat.

To a solution of 3-(4-hexyloxy-1,2,5-thiadiazole-3-yl)-1,2,5,6-tetrahydro-1 - methylpyridine (0,70 g, 2.4 mmol) in 1,2-dichloroethane (20 ml) was added a solution of 1-chloromethylphosphonate (0.35 g, 2.4 mmol) and 1,2-dichloroethane at 0aboutC. the Reaction mixture was stirred at 40aboutC for 2 h and evaporated. The residue was dissolved in methanol, boiled in a flask with reflux condenser for 1 h and evaporated. The residue was dissolved in dilute sodium hydroxide solution and was extracted with diethyl ether. The combined ether phases were dried and evaporated. Crystallization in the form of a salt of oxalic to the CLASS="ptx2">

P R I m e R 35. A. 3-{4-[2-(2-Methoxyethoxy)ethoxy]-1,2,5-thiadiazole-3-yl}pyridine.

To a solution of sodium (210 mg, 9 mmol) in 2-(2-methoxyethoxy)ethanol (10 ml) was added 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (590 mg, 3 mmol). The mixture was stirred at 50aboutC for 4 h and evaporated. The residue was dissolved in water and was extracted with diethyl ether. The combined organic phase was dried and evaporated, receiving the specified connection.

B. 3-{4-[2-(2-Methoxyethoxy)ethoxy]-1,2,5-thiadiazole-3-yl}-1 - methylpyridinium.

Mixture under the conditions (0.5 ml, 9 mmol) and 3-{4-[2-(2-methoxyethoxy)ethoxy] -1,2,5-thia-diazol-3-yl}pyridine (3 mmol) in acetone (10 ml) was stirred at room temperature for 18 hours the Specified connection, loose precipitated from solution, was separated by filtration. Output ranged from 0.76 g (60%).

Century 3-{ 4-[2-(2-Methoxyethoxy)ethoxy] -1,2,5-thiadiazole-3-yl} -1,2,5,6 - tetrahydro-1-methylpyrrolidinium.

Borohydride sodium (150 mg, 4 mmol) was added to a solution of 3-{2-[2-(2-methoxyethoxy)ethoxy] -1,2,5-thiadiazole-3-yl]-1-methyl - peridiniidae (0,76 g, 1.8 mmol) in ethanol (99.9% of the 20 ml), the reaction mixture was stirred at -10aboutC for 1 h After evaporation the residue was dissolved in water and was extracted with ethyl acetate. Dried PR is Nol:1). The specified connection crystallized as a salt of oxalic acid from acetone to yield 70 mg So pl. 142-143aboutS; M+: 299; compound 38.

P R I m e R 36. A. 3-[4-(3-Ethoxy-1-propoxy)-1,2,5-thiadiazole-3-yl]pyridine.

To a solution of 3-ethoxy-1-propanol (940 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 hours was Added water and the mixture was extracted with diethyl ether. The ether phase was dried and evaporated, receiving the specified connection.

B. 3-[4-(3-Ethoxy-1-propoxy)-1,2,5-thiadiazole-3-yl] -1 - methylpyridinium.

Mixture under the conditions (0.5 ml, 9 mmol) and 3-(4-ethoxy-1-propoxy-1,2,5-thiadiazole-3-yl)pyridine (3 mmol) in acetone (5 ml) was stirred at room temperature for 18 hours the Desired compound precipitated precipitated from solution, was separated by filtration.

Century 3-[4-(3-Ethoxy-1-propoxy)-1,2,5-iadiza-3-yl] -1,2,5,6-tetrahydro - 1-methylpyridinium.

Borohydride sodium (190 mg, 5 mmol) was added to a solution of 3-[4-(3-ethoxy-1-propoxy)-1,2,5-thiadiazole-3-yl] -1 - methylpyridinium (3 mmol) in ethanol (99.9% of the 15 ml), reactioni with ethyl acetate. The dried organic phase was evaporated and the residue was purified through column chromatography (SiO2, eluent ethyl acetate/methanol 4:1). The desired compound crystallized as a salt of oxalic acid from acetone to yield 210 mg So pl. 149-150aboutS; M+: 283; connection 39.

P R I m e R 37. A. 3-[4-(2-Ethoxyethoxy)-1,2,5-thiadiazole-3-yl]pyridine.

To a solution of 2-ethoxyethanol (1.08 g, 12 mmol) and sodium hydride (410 mg, 12 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (790 mg, 4 mmol) in dry tetrahydrofuran. The mixture was stirred at room temperature for 2 hours was Added water and the mixture was extracted with diethyl ether. The ether phase was dried and evaporated, obtaining the desired connection.

B. 3-[4-(2-Ethoxyethoxy)-1,2,5-thiadiazole-3-yl]-1-methylpyridinium.

Mixture under the conditions (0.5 ml, 9 mmol) and 3-[4-(2-ethoxyethoxy)-1,2,5-thiadiazole-3-yl] pyridine (4 mmol) in acetone (3 ml) was stirred at room temperature for 18 hours the Desired compound precipitated precipitated from solution, was separated by filtration. Yield 1.45 g (92%).

Century 3-[4-(2-Ethoxyethoxy)-1,2,4-thiadiazole-3-yl] -1,2,5,6-tetrahydro-1 - methylpyridinium.

Borohydride sodium (350 mg, 9 mmol) was added to the operating mixture was stirred at -10aboutC for 1 h After evaporation the residue was dissolved in water and was extracted with ethyl acetate. The dried organic phase was evaporated and the residue was purified through column chromatography (SiO2, eluent ethyl acetate/methanol 4:1). The desired compound crystallized as a salt of oxalic acid from acetone to yield 640 mg So pl. 153-156aboutS; M+: 269; connection 40.

P R I m e R 38. A. 3-[4-(2-Butoxyethoxy)-1,2,5-thiadiazole-3-yl]pyridine.

To a solution of 2-butoxyethanol (1.06 g, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 hours was Added water and the mixture was extracted with diethyl ether. The ether phase was dried and evaporated, obtaining the desired connection.

B. 2-[4-(2-Butoxyethoxy)-1,2,5-thiadiazole-3-yl]-1-methylpyridinium.

Mixture under the conditions (0.5 ml, 9 mmol) and 3-[4-(2-butoxyethoxy)-1,2,5-thiadiazole-3-yl] pyridine (3 mmol) in acetone (4 ml) was stirred at room temperature for 18 hours the Desired compound precipitated precipitated from solution, was separated by filtration to yield 1.07 g (85%).

Century 3-[4-(2-Butoxyethoxy to a solution of 3-[4-(2-butoxyethoxy)-1,2,5-thiadiazole-3-yl] -1-methylpyridinium-Oded Hagai (1.07 g, 2.5 mmol) in ethanol (99.9% of the 20 ml), the reaction mixture was stirred at -10aboutC for 1 h After evaporation the residue was dissolved in water and was extracted with ethyl acetate. The dried organic phase was evaporated, the residue was purified through column chromatography (SiO2, eluent ethyl acetate/methanol 4:1). The desired compound crystallized as a salt of oxalic acid from acetone to yield 490 mg So pl. 152-153aboutS, M+: 297; a connection 41.

P R I m e R 39. A. 3-{4-[2-(2-Butoxyethoxy)ethoxy]-1,2,5-thiadiazole-3-yl}pyridine.

To a solution of 2-(2-butoxyethoxy)ethanol (1,46 g, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-[4-(chloro-1,2,5-thiadiazole-3-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h was Added water and the mixture was extracted with diethyl ether. The ether phase was dried and evaporated, obtaining the desired connection.

B. 3-{4-[2-(2-Butoxyethoxy)ethoxy]-1,2,5-thiadiazole-3-yl}-1 - methylpyridinium.

Mixture under the conditions (0.5 ml, 9 mmol) 3-{4-[2-(2-butoxyethoxy)ethoxy]-1,2,5-thiadiazole-3-yl} pyridine (3 mmol) in acetone (5 ml) was stirred at room temperature for 18 hours Required joint the azole-3-yl} -1,2,5,6 - tetrahydro-1-methylpyridinium.

Borohydride sodium (230 mg, 6 mmol) was added to a solution of 3-{4-[2-(2-butoxyethoxy)ethoxy] -1,2,5-thiadiazole-3-yl} -1 - methylpyridinium (3 mmol) in ethanol (99.9% of the 20 ml), the reaction mixture was stirred at -10aboutC for 1 h After evaporation the residue was dissolved in water and was extracted with ethyl acetate. The dried organic phase was evaporated and the residue was purified through column chromatography (SiO2, eluent ethyl acetate/methanol 4:1). The desired compound crystallized as a salt of oxalic acid from acetone to yield 340 mg So pl. 90-91aboutS; M+: 341; the connection 42.

P R I m e R 40. A. 3-{4-[2-(2-Ethoxyethoxy)ethoxy]-1,2,5-thiadiazole-3-yl} pyridine.

To a solution of 2-(2-ethoxyethoxy)ethanol (1,21 g, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 hours was Added water and the mixture was extracted with diethyl ether. The ether phase was dried and evaporated, obtaining the desired connection.

B. 3-{ 4-[2-(2-Ethoxyethoxy)ethoxy]-1,2,5-thiadiazole-3-yl}-1 - methylpyridinium.

Mixture under the conditions (0.5 ml, 9 mmol) and 3-{4-[2-(2-ethoxyethoxy)ethoxy]-1,the second connection, precipitated precipitated from solution, was separated by filtration.

Century 3-{4-[2-(2-Ethoxyethoxy)ethoxy]-1,2,5-thiadiazole-3-yl}-1,2,5,6 - tetrahydro-1-methylpyridinium.

Borohydride sodium (230 mg, 6 mmol) was added to a solution of 3-{4-[2-(2-ethoxyethoxy)ethoxy} -1,2,5-thiadiazole-3-yl}-1 - methylpyridinium (3 mmol) in ethanol (99.9% of the 20 ml), the reaction mixture was stirred at -10aboutC for 1 h After evaporation the residue was dissolved in water and was extracted with ethyl acetate. The dried organic phase was evaporated, the residue was purified through column chromatography (SiO2, eluent ethyl acetate/methanol 4:1). The desired compound crystallized as a salt of oxalic acid from acetone to yield 290 mg So pl. 115-116aboutS; M+: 313; connection 43.

P R I m e R 41. A. 3-[4-(4-Methylpyridine)-1,2,5-thiadiazole-3-yl]pyridine.

A solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (10,80 g, 4 mmol) and 4-methylpiperidine (a 1.96 g, 20 mmol) in dimethylformamide (10 ml) was heated at 100aboutC for 3 hours After evaporation the residue was added water and was extracted with diethyl ether. Combined and dried organic phase was evaporated, the residue was purified through column chromatography (SiO2, eluent ethyl acetate/methylene chloride 1:2). The output of elided (0.5 ml, 8 mmol) and 3-[4-(4-methylpiperidino)-1,2,5-thiadiazole-3-yl] pyridine (0.8 g, 3.1 mmol) in acetone (5 ml) was stirred at room temperature for 18 hours the Desired compound precipitated precipitated from solution, was separated by filtration. The output of 1.14 g (92%).

Century 3-[4-(4-Methylpiperidino)-1,2,5-thiadiazole-3-yl]-1,2,5,6 - tetrahydro-1-methylpyridinium.

Borohydride sodium (270 mg, 7 mmol) was added to a solution of 3-[4-(4-methylpiperidino)-1,2,5-thiadiazole-3-yl] -1 - methylpyridinium (1,14 g, 2.8 mmol) in ethanol (99.9% of the 20 ml), the reaction mixture was dissolved in water and was extracted with ethyl acetate. The dried organic phase was evaporated, the residue was purified through column chromatography (SiO2, eluent ethyl acetate/methanol:1). The desired compound crystallized as a salt of oxalic acid from acetone to yield 450 mg So pl. 106-107aboutS; M+: 278; connection 44.

P R I m e R 42. A. 3-(4-Morpholino-1,2,5-thiadiazole-3-yl)pyridine.

A solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (0,59 g, 3 mmol) and research (1.3 g, 15 mmol) in dimethylformamide (5 ml) was heated at 100aboutC for 3 hours After evaporation the residue was added water and was extracted with diethyl ether. Combined and dried organic phase was evaporated, the residue was purified on-(4-Morpholino-1,2,5-thiadiazole-3-yl)-1-methylpyridinium.

Mixture under the conditions (0.5 ml, 8 mmol) and 3-(4-morpholino-1,2,5-thiadiazole-3-yl)Piri - DIN (680 mg, 2.7 mmol) in acetone (5 ml) was stirred at room temperature for 18 hours the Desired compound precipitated precipitated from solution, was separated by filtration. Yield 1.0 g (94%).

Century 3-(4-Morpholino-1,2,5-thiadiazole-3-yl)-1,2,5,6-tetrahydro-1 - methylpyridinium.

Borohydride sodium (380 mg, 10 mmol) was added to a solution of 3-(4-morpholino-1,2,5-thiadiazole-3-yl)-1-methylpyridinium (1,53 g, 39 mmol) in ethanol (99.9% of the 30 ml), the reaction mixture was stirred at -10aboutC for 1 h After evaporation the residue was dissolved in water and was extracted with ethyl acetate. The dried organic phase was evaporated, the residue was purified through column chromatography (SiO2, eluent ethyl acetate/methanol 4:1). The desired compound crystallized as a salt of oxalic acid from acetone to yield 470 mg So pl. 177-178aboutS; M+: 266; connection 45.

P R I m e R 43. A. 3-(4-Hexylamino-1,2,5-thiadiazole-3-yl)pyridine.

A solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (0,59 g, 3 mmol) and hexylamine (1.52 g, 15 mmol) in dimethylformamide (5 ml) was heated at 100aboutWith in 48 hours After evaporation the residue was added water and was extracted with diethyl ether. is amino-1,2,5-thiadiazole-3-yl)-1-methylpyridinium.

Mixture under the conditions (0.9 ml, 9.6 mmol) and 3-(4-hexylamino-1,2,5-thiadiazole-3-yl)PI-ridin (3.2 mmol) in acetone (5 ml) was stirred at room temperature for 18 h and evaporated.

Century 3-(4-Hexylamino-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1 - methylpyridinium.

Borohydride sodium (380 mg, 10 mmol) was added to a solution of 3-(4-hexylamino-1,2,5-thiadiazole-3-yl)-1-methylpyridinium - Dida (4.2 mmol) in ethanol (99.9% of the 25 ml), the reaction mixture was stirred at -10aboutC for 1 h After evaporation the residue was dissolved in water and was extracted with ethyl acetate. The dried organic phase was evaporated, the residue was purified through column chromatography (SiO2, eluent ethyl acetate/methanol 4:1). The desired compound crystallized as a salt of oxalic acid from acetone to yield 490 mg So pl. 102-103aboutS, M+: 280; connection 46.

P R I m e R 44. A. 3-(4-Propylthio-1,2,5-thiadiazole-3-yl)pyridine.

Sodium hydrosulfide (220 mg, 3 mmol) for 30 min was added to a solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (0,59 g, 3 mmol) in dimethylformamide (20 ml) at room temperature, in addition, imposed potassium carbonate (1.24 g, 9 mmol) and iodopropane (0,76 g, 4.5 mmol). The reaction mixture was stirred at room temperature t is rivali, getting the desired compound with a yield of 89% (0,63 g).

B. 3-(4-Propylthio-1,2,5-thiadiazol-3-yl)-1-methylpyridinium.

Mixture under the conditions (0.5 ml, 8 mmol) and 3-(4-propylthio-1,2,5-thiadiazole-3-yl)Piri-DIN (0,63 g, 2.6 mmol) in acetone (5 ml) was stirred at room temperature for 18 h and evaporated.

Century 3-(4-Propylthio-1,2,5-thiadiazole-3-yl)-1,2,5,6-tetrahydro-1 - methylpyridinium.

Borohydride sodium (200 mg, 5 mmol) was added to a solution of 3-(4-propylthio-1,2,5-thiadiazole-3-yl)-1-methylpyridinium (2.6 mmol) in ethanol (99.9% of the 15 ml), the reaction mixture was stirred at -10aboutC for 1 h After evaporation the residue was dissolved in water and was extracted with ethyl acetate. The dried organic phase was evaporated, the residue was purified through column chromatography (SiO2, eluent ethyl acetate/methanol 4:1). The desired compound crystallized as a salt of oxalic acid from acetone to yield 310 mg So pl. 138-139aboutS; M+: 255; connection 47.

P R I m e R 45. A. 3-(4-Butylthio-1,2,5-thiadiazole-3-yl)pyridine.

Sodium hydrosulfide (0.5 g, 6.8 mmol) was added to a solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (0.5 g, 2.5 mmol) in dimethylformamide (20 ml) at room temperature, the reaction mixture was stirred in the flax was stirred for 10 minutes Was added water (50 ml) and was extracted with diethyl ether. The combined ether fractions were dried and evaporated, obtaining the desired connection. The output 0.6,

B. 3-(4-Butylthio-1,2,5-thiadiazole-3-yl)-1-methylpyridinium.

Methyliodide (1 ml, 15 mmol) was added to a solution of 3-(4-butylthio-1,2,5-thiadiazole-3-yl)pyridine (0.6 g, 2.3 mmol), the reaction mixture was stirred at room temperature for 48 h and evaporated.

Century 3-(4-Butylthio-1,2,5-thiadiazole-3-yl)-1,2,5,6-tetrahydro-1 - methylpyridinium.

Borohydride sodium (250 mg, 6.2 mmol) was added to a solution of 3-(4-butylthio-1,2,5-thiadiazole-3-yl)-1-methylpyridinium (2.3 mmol) in ethanol (99.9% of the 20 ml), the reaction mixture was stirred at 0aboutC for 1 h After evaporation the residue was dissolved in water and was extracted with ethyl acetate. The dried organic phase was evaporated, the residue was purified on chromatic column (SiO2, eluent ethyl acetate/methanol 4:1). The desired compound crystallized as a salt of oxalic acid from acetone to yield 300 mg. So pl. 148-150aboutS; M+: 269; connection 48.

P R I m e R 46. A. 3-(4-Methylthio-1,2,5-thiadiazole-3-yl)pyridine.

Sodium hydrosulfide (0.5 g, 6.8 mmol) was added to a solution of 3-(4-chloro-1,2,5-thiadiazole-3-PE for 30 minutes Was added potassium carbonate (2 g, 14.5 mmol) and methyliodide (1 ml, 15 mmol), the reaction mixture was additionally stirred for 10 minutes was Added water (50 ml) and was extracted with diethyl ether. The combined ether phases were dried and evaporated, obtaining the desired connection. The output of 0.5 g

B. 3-(4-Methylthio-1,2,5-thiadiazole-3-yl)-1-methylpyridinium.

Methyliodide (1 ml, 15 mmol) was added to a solution of 3-(4-methylthio-1,2,5-thiadiazole-3-yl)pyridine (0.5 g, 2.3 mmol), the reaction mixture was stirred at room temperature for 48 h and evaporated.

Century 3-(4-Methylthio-1,2,5-thiadiazole-3-yl)-1,2,5,6-tetrahydro-1 - methylpyridinium.

Borohydride sodium (250 mg, 6.2 mmol) was added to a solution of 3-(4-methylthio-1,2,5-thiadiazole-3-yl)-1-methylpyridinium (2.3 mmol) in ethanol (99.9% of the 20 ml), the reaction mixture was stirred at 0aboutC for 1 h After evaporation the residue was dissolved in water and was extracted with ethyl acetate. The dried organic phase was evaporated, the residue was purified through column chromatography (SiO2, eluent ethyl acetate/methanol 4:1). The desired compound crystallized as a salt of oxalic acid from acetone to yield 300 mg. So pl. 169-170aboutS; M+: 227; connection 49.

P R I m e R 47. A. droxia sodium (16 g, 400 mmol) in methanol (100 ml). Methylnitrite, obtained by introducing droplets of a solution of concentrated sulfuric acid (to 12.8 ml) and water (26 ml) to a solution of sodium nitrite (33,2 g, 480 mmol) in water (20 ml) and methanol (20 ml) was passed through a solution of 3-pyridylacetonitrile at 0aboutC. the Reaction mixture was stirred at 0aboutC for 1 h and precipitated precipitate was separated by filtration. The precipitate was washed with a small amount of methanol, obtaining the desired product with a yield of 70% (41,1 g). M+: 147.

B. alpha-oximino-3-pyridylacetonitrile.

A mixture of alpha-oximino-3-pyridylacetonitrile (41,0 g, 279 mmol), hydroxylamine hydrochloride (21,5 g, 310 mmol) and sodium acetate (50,8 g, 620 mmol) in ethanol (99.9% of the 500 ml) was boiled in a flask with reflux condenser for 4 hours After cooling, the precipitate was separated by filtration and dried. The sediment consisted of the desired product and sodium acetate (85 g, 168%). M+: 180.

Century 3-(4-Amino-1,2,5-oxadiazol-3-yl)pyridine.

The crude alpha-oximino-3-pyridylacetonitrile (5 g) and Piatigorsky phosphorus (5 g) was boiled in a flask with reflux condenser in an environment of dry diethyl ether (250 ml) techeye 6 hours Then added water and potassium carbonate to obtain an alkaline environment. The mixture is stratified the air traffic management ethereal fractions was obtained the desired product with a yield of 850 mg; M+: 162.

G 3-(4-Amino-1,2,5-oxadiazol-3-yl)-1-methylpyridinium.

To a solution of 3-(4-amino-1,2,5-oxadiazol-3-yl)pyridine (870 mg, 5.3 mmol) in acetone (20 ml) was added methyliodide (990 μl, 16 mmol), the reaction mixture was stirred over night at room temperature. The desired compound precipitated from the solution precipitates were separated by filtration. Yield 1.1 g (69%).

D. 3-(4-Amino-1,2,5-oxadiazol-3-yl)-1,2,5,6-tetrahydro-1 - methylpyridinium.

Borohydride sodium (262 mg, 6,9 mmol) was added to a solution of 3-(4-amino-1,2,5-oxadiazol-3-yl)-1-methylpyridinium (1,05 g of 3.45 mmol) in methanol (80 ml) at 0aboutC. After 15 min was added water (40 ml) and the mixture was extracted with diethyl ether. The ether phase was dried, evaporated and purified through column chromatography (eluent ethyl acetate/methanol 2:1). Crystallization from acetone with oxalic acid resulted in getting the required connection with the release of 310 mg (50%). So pl. 181-183aboutS; M+:180; the connection 50.

P R I m e R 48. A. 3-(4-Acetylamino-1,2,5-oxadiazol-3-yl)pyridine.

Untreated, hydroxyimino-3-pyridylmethylamine (4.5 g) and phosphoric acid (49 g) was stirred at 100aboutC for 18 h After cooling to room temperature is slow which was agarawala methylene chloride. The organic phase was dried and evaporated, obtaining the desired compound with a yield of 430 mg.

B. 3-(4-Acetylamino-1,2,5-oxadiazol-3-yl)-1-methylpyridinium.

Methyliodide (450 μl, 7.2 mmol) was added to a solution of 3-(4-acetylamino-1,2,5-oxadiazol-3-yl)pyridine (490 mg, 2.4 mmol) in acetone. The reaction mixture was stirred at room temperature for 18 h and the precipitate was separated by filtration. Yield 640 mg (77%).

Century 3-(4-Acetylamino-1,2,5-oxadiazol-3-yl)-1,2,5,6-tetrahydro-1 - methylpyridinium.

Borohydride sodium (140 mg, 3.7 mmol) was added to a solution of 3-(4-acetylamino-1,2,5-oxadiazol-3-yl)-1-methylpyridinium - Oded Hagai (640 mg, of 1.85 mmol) in methanol (15 ml) at 0aboutC. After 15 min was added water ( 10 ml), the reaction mixture was extracted with diethyl ether. The combined ether fractions were dried and evaporated. Crystallization from acetone with oxalic acid resulted in getting the required connection with the release of 140 mg. So pl. 180-184aboutS; M+: 222; connection 51.

P R I m e R 49. A. 3-(1,2,5-Oxadiazol - 3-yl)pyridine and 3-(4-chloro-1,2,5-oxadiazol-3-yl)pyridine.

To a solution of 3-(4-amino-1,2,5-oxadiazol-3-yl)pyridine (1.0 g, 6.2 mmol) in glacial acetic acid (16 ml) and concentrated hydrochloric acid (5.2 ml) we use the ITA sodium (483 mg, 7 mmol) in water (3 ml) and 5aboutC. the Reaction mixture was additionally stirred for 30 min at 0aboutC. For alkalizing medium was added an aqueous solution of sodium hydroxide (2 BC), the mixture was extracted with diethyl ether. The ether fraction was dried and evaporated, obtaining a mixture of the desired compounds. Separation on chromatographically column (SiO2, eluent ethyl acetate) allowed us to obtain chloropropane, top spot, with an output of 230 mg and unsubstituted product, the bottom spot, with the release of 60 mg.

B. 3-(4-Chloro-1,2,5-oxadiazol-3-yl)-1-methylpyridinium.

Methyliodide (1 ml, 15 mmol) was added to a solution of 3-(4-chloro-1,2,5-oxadiazol-3-yl)pyridine (230 mg, 1.2 mmol) in acetone. The reaction mixture was stirred at room temperature for 18 h and evaporated, obtaining the desired connection.

Century 3-(4-Chloro-1,2,5-oxadiazol-3-yl)-1,2,5,6-tetrahydro-1 - methylpyridinium.

Borohydride sodium (119 mg, 3.2 mmol) was added to a solution of 3-(4-chloro-1,2,5-oxadiazol-3-yl)-1-methylpyridinium (1.2 mmol) in methanol (5 ml) at 0aboutC. After 15 min was added water, the mixture was extracted with diethyl ether. The ether fraction was dried and evaporated. Crystallization from acetone with oxalic acid and precrystallization 52.

P R I m e R 50. A. 3-(1,2,5-Oxadiazol-3-yl)-1-methylpyridinium.

Methyliodide (1 ml, 15 mmol) was added to a solution of 3-(1,2,5-oxadiazol-3-yl)pyridine (430 mg, 2.8 mmol) in acetone (20 ml). The reaction mixture was stirred at room temperature for 18 hours the Desired compound precipitated in the form of a precipitate in the solution was separated by filtration. The yield was 82% (700 mg).

B. 3-(1,2,5-Oxadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridinium.

Borohydride sodium (168 mg, 4.4 mmol) was added to a solution of 3-(1,2,5-oxadiazol-3-yl)-1-methylpyridinium (640 mg, 2.2 mmol) in methanol (15 ml) and water (2 ml) at 0aboutC. After 15 min was added water, the mixture was extracted with diethyl ether. The combined ether fractions were dried and evaporated. The residue is crystallized as a salt of oxalic acid from acetone, giving the desired compound with a yield of 100 mg. So pl. 238-240aboutC, decomposed; M+: 165; connection 53.

P R I m e R 51. A. 3-(4-Hexyloxy-1,2,5-oxadiazol-3-yl)pyridine.

To a solution of sodium (100 mg, 4.3 mmol) in 1-hexanol (10 ml) was added 3-(4-chloro-1,2,5-oxadiazol-3-yl)pyridine (180 mg, 1 mmol). The mixture was stirred at 25aboutC for 18 h and evaporated. The residue was dissolved in water and was extracted with diethyl ether. The volumes of the 5-oxadiazol-3-yl)-1-methylpyridinium.

Mixture under the conditions (1 ml, 15 mmol) and 3-(4-hexyloxy-1,2,5-oxadiazol-3-yl)Piri - DIN (1 mmol) in acetone (5 ml) was stirred at room temperature for 18 h and evaporated, obtaining the desired connection.

Century 3-(4-Hexyloxy-1,2,5-oxadiazol-3-yl)-1,2,5,6-tetrahydro-1 - methylpyridinium.

Borohydride sodium (76 mg, 2 mmol) was added to a solution of 3-(4-hexyloxy-1,2,5-oxadiazol-3-yl)-1-methylpyridinium (1 mmol) in methanol (5 ml), the reaction mixture was stirred at 0aboutC for 15 minutes After evaporation the residue was dissolved in water and was extracted with diethyl ether. Dried organic fraction was evaporated, the residue was purified through column chromatography (SiO2, eluent ethyl acetate/methanol 4:1). The desired compound crystallized as a salt of oxalic acid from acetone to yield 60 mg So pl. 143-147aboutS; M+: 265; connection 54.

P R I m e R 52. A. 3-(4-Butylochka-1,2,5-oxadiazol-3-yl)pyridine.

To a solution of sodium (150 mg, 6.5 mmol) in 1-butanol (5 ml) was added 3-(4-chloro-1,2,5-oxadiazol-3-yl)pyridine (350 mg, 1.9 mmol). The mixture was stirred at 25aboutC for 2 h and evaporated. The residue was dissolved in water and was extracted with diethyl ether. The combined organic fractions were dried and CLASS="ptx2">

Mixture under the conditions (1 ml, 15 mmol) and 3-(4-Butylochka-1,2,5-oxadiazol-3-yl)Piri - DIN (1.9 mmol) in acetone (10 ml) was stirred at room temperature for 18 h and evaporated.

Century 3-(4-Butylochka-1,2,5-oxadiazol-3-yl)-1,2,5,6-tetrahydro-1 - methylpyridinium.

Borohydride sodium (148 mg, 3.8 mmol) was added to a solution of 3-(4-Butylochka-1,2,5-oxadiazol-3-yl)-1-methylpyridinium (1.9 mmol) in methanol (20 ml), the reaction mixture was stirred at 0aboutC for 15 minutes After evaporation the residue was dissolved in water and was extracted with diethyl ether. Dried organic fraction was evaporated, the residue was purified through column chromatography (SiO2, eluent ethyl acetate/methanol 4:1). The desired compound crystallized as a salt of oxalic acid from acetone to yield 120 mg So pl. 132-135aboutS; M+: 237; connection 55.

P R I m e R 53. A. 3-[4-(3-Hexyloxy)-1,2,5-oxadiazol-3-yl]pyridine.

To a solution of 3-hexyne-1-it (980 mg, 10 mmol) and sodium hydride (240 mg, 10 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-oxadiazol-3-yl)pyridine (450 mg, 2.5 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 hours was Added water and the mixture of ekstragirovanie)-1,2,5-oxadiazol-3-yl]-1-methylpyridinium.

Mixture under the conditions (1.5 ml, 22 mmol) and 3-[4-(3-hexyloxy)-1,2,5-oxadiazol-3-yl] pyridine (2.5 mmol) in acetone (20 ml) was stirred at room temperature for 18 h and evaporated, obtaining the desired connection.

Century 3-[4-(3-Hexyloxy)-1,2,5-oxadiazol-3-yl]-1,2,5,6-tetrahydro - 1-methylpyridinium.

Borohydride sodium (190 mg, 5 mmol) was added to a solution of 3-[4-(3-hexyloxy)-1,2,5-oxadiazol-3-yl] -1-methylpyridinium - Oded Hagai (2.5 mmol) in methanol (20 ml), the reaction mixture was stirred at 0aboutC for 15 minutes After evaporation the residue was dissolved in water and was extracted with diethyl ether. Dried organic fraction was evaporated and the residue was purified through column chromatography (SiO2, eluent ethyl acetate/methanol 4:1). The desired compound crystallized as a salt of oxalic acid from acetone to yield 50 mg So pl. 159-161aboutS; M+: 261; connection 56.

P R I m e R 54. 3-(4-Pentyl-1,2,5-thiadiazole-3-yl)-1,2,5,6-tetrahydro-1 - methylpyridinium.

To a solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)-1,3,5,6-tetrahydro-1-methylpyridine (450 mg, 1.5 mmol) in tetrahydrofuran (20 ml) at 0aboutWith a slow solution was added interminiband (1.5 mmol) in tetrahydrofuran. The reaction mixture was premesis is a (1.5 mmol) in tetrahydrofuran. The reaction mixture was stirred for 10 min and was added water (20 ml). The product was extracted with diethyl ether (3 x 100 ml) and dried ether fraction was evaporated. The residue is crystallized as a salt of oxalic acid from acetone to yield 300 mg (58%). Recrystallization from ethanol resulted in the obtaining of the desired product with a yield 125 mg (24%). So pl. 156-157aboutS; M+: 251; connection 57.

P R I m e R 55. 3-(4-Heptyl-1,2,5-thiadiazole-3-yl)-1,2,5,6-tetrahydro-1 - methylpyridinium.

To a solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (450 mg, 1.5 mmol) in tetrahydrofuran (20 ml) at 0aboutWith slowly added to the solution heptylamine bromide (1.5 mmol) in tetrahydrofuran. The reaction mixture was stirred for 10 min and was added water (20 ml). The product was extracted with diethyl ether (3 x 100 ml) and dried ether fraction was evaporated. The residue is crystallized as a salt of oxalic acid from acetone to yield 400 mg (73%). So pl. 151-152aboutS; M+: 274; compound 58.

P R I m e R 56. 3-[4-(5-Hexenyl)-1,2,5-thiadiazole-3-yl]-1,2,5,6-tetrahydro-1 - methylpyridinium.

To a solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (450 mg, 1.5 mmol) in tetrahydrofuran (20 m the mixture was stirred for 10 min and was added water (20 ml). The product was extracted with diethyl ether (3 x 100 ml) and dried ether fraction was evaporated. The residue was purified through column chromatography (SiO2, eluent ethyl acetate/methanol 4:1). The desired compound crystallized as a salt of oxalic acid from acetate to yield 340 mg (64%). So pl. 113-115aboutS; M+: 263; connection 59.

P R I m e R 57. 3-(4-Octyl-1,2,5-thiadiazole-3-yl)-1,2,5,6-tetrahydro-1 - methylpyridinium.

To a solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (450 mg, 1.5 mmol) in tetrahydrofuran (20 ml) at 0aboutWith a slow solution was added octylacrylamide (1.5 mmol) in tetrahydrofuran. The reaction mixture was stirred for 10 min and was added water (20 ml). The product was extracted with diethyl ether (3 x 100 ml) and dried ether fraction was evaporated. The residue was purified through column chromatography (SiO2, eluent ethyl acetate/methanol 4:1). Search soedinenie crystallized as a salt of oxalic acid from acetone to yield 430 mg (75%). So pl. 157-158aboutC; M+: 293; connection 60.

P R I m e R 58. 3-(4-Isobutyl-1,2,5-thiadiazole-3-yl)-1,2,5,6-tetrahydro-1 - methylpyridinium.

To a solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (300 mg, 1.5 tetrahydrofurane. The reaction mixture was stirred for 10 min and was added water (20 ml). The product was extracted with diethyl ether (3 x 100 ml) and dried ether fraction was evaporated. The residue was purified through column chromatography (SiO2, eluent ethyl acetate/methanol 4:1). The desired compound crystallized as a salt of oxalic acid from acetone to yield 350 mg (76%). So pl. 148-149aboutS; M+: 237 connection 61.

P R I m e R 59. 3-(4-Cyclopropylmethyl-1,2,5-thiadiazole-3-yl)-1,2,5,6-tetrahydro-1 - methylpyridinium.

To a solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl-1,2,5,6-tetrahydro-1 - methylpyridine (300 mg, 1.4 mmol) in tetrahydrofuran (20 ml) at 0aboutWith a slow solution was added cyclopropylmagnesium (1.5 mmol) in tetrahydrofuran. The reaction mixture was stirred for 10 min and was added water (20 ml). The product was extracted with diethyl ether (3 x 100 ml) and dried ether fraction was evaporated. The residue was purified through column chromatography (SiO2, eluent ethyl acetate/methanol 4:1). The desired compound crystallized as a salt of oxalic acid from Cetona with the release of 380 mg (83%). So pl. 147-148aboutS, M+: 235; connection 62.

P R I m e R 60. 3-(4-Propyl-1,2,5-thiadiazole-3-yl)-1,2,5,6-tetrahydro-1 - methylpyridine is rageragerage (20 ml) at 0aboutWith a slow solution was added propylaniline (1.5 mmol) in tetrahydrofuran. The reaction mixture was stirred for 10 min and was added water (20 ml). The product was extracted with diethyl ether (3 x 100 ml) and dried ether fraction was evaporated. The residue is crystallized as a salt of oxalic acid from acetone to yield 350 mg (75%). So pl. 141-142aboutS; M+: 223; connection 63.

P R I m e R 61. A. 3-(4-Octylthio-1,2,5-thiadiazole-3-yl)pyridine.

Sodium hydrosulfide (0.25 g, 3.3 mmol) was added to a solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (0,59 g, 3 mmol) in dimethylformamide (20 ml) at room temperature, the reaction mixture was stirred for 30 minutes was Added potassium carbonate (1.24 g, 9 mmol) and 1-bromooctane (0,80 ml, 4.5 mmol) and the reaction mixture was additionally stirred for 10 minutes was Added water (50 ml) and was extracted with diethyl ether. The combined ether fractions were dried and evaporated, obtaining the desired connection.

B. 3-(4-Octylthio-1,2,5-thiadiazole-3-yl)-1-methylpyridinium.

Methyliodide (0.5 ml, 7.5 mmol) was added to a solution of 3-(4-octylthio-1,2,5-thiadiazole-3-yl)pyridine (3 mmol) and the reaction mixture was stirred at room temperature for 48 h and evaporated.

g, 7 mmol) was added to a solution of 3-(4-octylthio-1,2,5-thiadiazole-3-yl)-1-methylpyridinium (3 mmol) in ethanol (99.9% of the 20 ml), the reaction mixture was stirred at 0aboutC for 1 h After evaporation the residue was dissolved in water and was extracted with ethyl acetate. Dried organic fraction was evaporated and the residue was purified through column chromatography (SiO2, eluent ethyl acetate/methanol 4:1). The desired compound crystallized as a salt of oxalic acid from acetone to yield 400 mg of T. pl. 121-122aboutS; M+: 325; compound 64.

P R I m e R 62. A. 3-(4-Ethylthio-1,2,5-thiadiazole-3-yl)pyridine.

Sodium hydrosulfide (0.25 g, 3.3 mmol) was added to a solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (0,59 g, 3 mmol) in dimethylformamide (20 ml) at room temperature, the reaction mixture was stirred for 30 minutes was Added potassium carbonate (1.24 g, 9 mmol) and ethyliodide (0,36 ml, 4.5 mmol), the reaction mixture was additionally stirred for 10 minutes was Added water (50 ml) and was extracted with diethyl ether. The combined ether fractions were dried and evaporated, obtaining the desired connection.

B. 3-(4-Ethylthio-1,2,5-thiadiazole-3-yl)-1-methylpyridinium.

Methyliodide (0.5 ml, 7.5 mmol) was added to a solution of 3-(4-ethylthio-1 was evaporated.

Century 3-(4-Ethylthio-1,2,5-thiadiazole-3-yl)-1,2,5,6-tetrahydro-1 - methylpyridinium.

Borohydride sodium (270 mg, 7 mmol) was added to a solution of 3-(4-ethylthio-1,2,5-thiadiazole-3-yl)-1-methylpyridinium (3 mmol) in ethanol (99.9% of the 20 ml), the reaction mixture was stirred at 0aboutC for 1 h After evaporation the residue was dissolved in water and was extracted with ethyl acetate. Dried organic fraction was evaporated and the residue was purified through column chromatography (SiO2, eluent ethyl acetate/methanol 4:1). The desired compound was led in the form of a salt of oxalic acid from acetone to yield 490 mg So pl. 145-146aboutS; M+: 241; compound 65.

P R I m e R 63. A. 3-(4-Pentylthio-1,2,5-thiadiazole-3-yl)pyridine.

Sodium hydrosulfide (0.25 g, 3.3 mmol) was added to a solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (0,59 g, 3 mmol) in dimethylformamide (20 ml) at room temperature, the reaction mixture was stirred for 30 minutes was Added potassium carbonate (1.24 g, 9 mmol) and interbreed (700 mg, 4.5 mmol) and the reaction mixture was additionally stirred for 10 minutes was Added water (50 ml) and was extracted with diethyl ether. The combined ether fractions were dried and evaporated, obtaining the desired connection.

B. 3-(4-Penttila-1,2,5-thiadiazole-3-yl)pyridine (3 mmol) and the reaction mixture was stirred at room temperature for 48 h and evaporated.

Century 3-(4-Pentylthio-1,2,5-thiadiazole-3-yl)-1,2,5,6-tetrahydro-1 - methylpyridinium.

Borohydride sodium (300 mg, 8 mmol) was added to a solution of 3-(4-pentylthio-1,2,5-thiadiazole-3-yl)-1-methylpyridinium (3 mmol) in ethanol (99.9% of the 20 ml), the reaction mixture was stirred at 0aboutC for 1 h After evaporation the residue was dissolved in water and was extracted with ethyl acetate. Dried organic fraction was evaporated and the residue was purified through column chromatography (SiO2, eluent ethyl acetate/methanol 4:1). The desired compound was led in the form of a salt of oxalic acid from acetone to yield 430 mg So pl. 136-138aboutS; M+: 283; compound 66.

P R I m e R 64. A. 3-(4-Hexylthio-1,2,5-thiadiazole-3-yl)pyridine.

Sodium hydrosulfide (0.25 g, 3.3 mmol) was added to a solution of 3-(4-chloro-1,2,5-thiadiazole-3-yl)pyridine (0,59 g, 3 mmol) in dimethylformamide (20 ml) at room temperature, the reaction mixture was stirred for 30 minutes was Added potassium carbonate (1.24 g, 9 mmol) and exelrod (0,63 g, 4.5 mmol) and the reaction mixture was additionally stirred for 10 minutes was Added water (50 ml) and was extracted with diethyl ether. The combined ether fractions were dried and evaporated, obtaining the desired connection.

B. 3-(4-Gex is keltia-1,2,5-thiadiazole-3-yl)pyridine (3 mmol) and the reaction mixture was stirred at room temperature for 48 h and evaporated.

Century 3-(4-Hexylthio-1,2,5-thiadiazole-3-yl)-1,2,5,6-tetrahydro-1 - methylpyridinium.

Borohydride sodium (230 mg, 6 mmol) was added to a solution of 3-(4-hexylthio-1,2,5-thiadiazole-3-yl)-1-methylpyridinium (3 mmol) in ethanol (99.9% of the 20 ml), the reaction mixture was stirred at 0aboutC for 1 h After evaporation the residue rationale in the water and was extracted with ethyl acetate. Dried organic fraction was evaporated and the residue was purified through column chromatography (SiO2, eluent ethyl acetate/methanol 4:1). The desired compound was led in the form of a salt of oxalic acid from acetone to yield 350 mg. So pl. 126-127aboutS; M+: 297; a connection 67.

1. 3-(1,2,5-Oxadiazol-3-yl)- 3-(1,2,5-thiadiazole-3-yl)-1,2,5,6 - tetrahydropyridine derivatives of General formula

< / BR>
where Z is oxygen or sulfur;

R is hydrogen or C1-C3-alkyl;

when Z is oxygen, R1halogen, amino, acetylamino or-O-R2where R2WITH4-C6-alkyl or C6quinil;

when Z is sulfur, R1halogen, C1-C8-alkyl, C6alkenyl straight chain, cyclopropylmethyl, benzyloxy, morpholino-, 4-methylpiperidino - or 4-hexylamino or the group-O-R2where R2linear or RA is>quinil, cyclopropylmethyl, -R3-O-R4or-R3-O-R4-O-R5where each of R3, R4and R5WITH1-C4-alkyl, or R1the group's R2where R2linear C2-C8-alkyl,

or their pharmaceutically acceptable salts.

2. Pharmaceutical composition for oral administration of expressing muscarinic cholinergic receptor agonistic activity, containing the active principle and a pharmaceutically acceptable carrier or diluent, characterized in that it contains as active principle compounds under item 1 in the amount of 1-100 mg per single dose.

Priority signs:

22.02.89 when R2oxygen or sulfur, R2- C1-C4-alkyl, C1-C4alkenyl,1-C4-quinil;

12.05.89 when R2WITH5-alkyl, C6-quinil,R1- halogen or amino group.

 

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(I) where R is a hydrogen atom, a lower alkyl or a group of the formula

orwhere R1means-Cho or - CN, namely, that on-halogenoalkane derivative of the formula:

where R has the above meanings, is subjected to the interaction with R3SH, where R3- benzyl, environment aprotic organic solvent, with the formation of the compounds of formula

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IB R=CHF2O-, R'=CH3O-, Alk=C2H5(K-3);

If R=CH3O-, R'=CF3-CHF-CF2O-, Alk=CH3(K-6);

Iك R=CH3O-, R'=CHF2O-, Alk=CH3(K-7)

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14 cl, 36 ex

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2 cl, 3 ex

FIELD: organic chemistry, biochemistry, medicine, endocrinology.

SUBSTANCE: invention relates to a trans-olefinic activator of glucokinase representing compound taken among the group consisting of olefinic amide of the formula (I): wherein R1 and R2 mean independently of one another hydrogen, halogen atom, nitro-group, perfluoro-(lower)-alkyl, (lower)-alkylsulfonyl or (lower)-alkylsulfonylmethyl; R means -(CH2)m-R3 or lower alkyl comprising from 2 to 4 carbon atoms; R3 means cycloalkyl comprising from 3 to 8 carbon atoms; R4 means the group: or unsubstituted, or monosubstituted five- or six-membered heteroaromatic ring linked by ring carbon atom with indicated amino-group wherein this five- or six-membered heteroaromatic ring comprises from 1 to 2 heteroatoms taken among the group consisting of sulfur or nitrogen atom wherein one heteroatom being as nitrogen atom is arranged near with binding ring carbon atom, and wherein indicated monosubstituted heteroaromatic ring is substituted at ring carbon atom not adjacent with mentioned binding carbon atom with a substitute taken among the group consisting of halogen atom and group of the formula: m = 0 or 1; n = 0, 1, 2, 3 or 4; R7 means hydrogen atom or lower alkyl; Δ means trans-configuration relatively to a double bond; or its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition, method for prophylactic or therapeutic treatment of diabetes mellitus of type II and to methods for preparing compounds of the formula (I). Invention provides preparing activators of glucokinase that enhance insulin secretion in treatment of diabetes mellitus of type II.

EFFECT: valuable medicinal properties of compounds.

25 cl, 29 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I):

wherein X means group of the formula (X-1) wherein R15 means halogen atom, (lower)-alkyl and perfluoro-(lower)-alkyl; R16 means hydrogen, halogen atom and (lower)-alkyl; or X means group of the formula (X-2) wherein Het means 5- or 6-membered heteroaromatic ring comprising 1 or 2 heteroatoms as nitrogen (N) atom; R15 and R16 have values indicated above for (X-1); R30 means hydrogen atom or (lower)-alkyl; p means a whole number from 0 to 1; or X means group of the formula (X-3) wherein R18 means aryl; R19 means unsubstituted arylalkyl or heteroarylalkyl representing 6-membered heteroaromatic ring comprising nitrogen (N) atom as a heteroatom; R20 means unsubstituted (lower)-alkanoyl; Y means group of the formula (Y-1) wherein R22 and R23 mean independently from one another hydrogen atom, (lower)-alkyl, halogen atom or perfluoro-(lower)-alkyl and at least one of radicals R22 and R23 doesn't mean hydrogen atom; R24 means hydrogen atom; or Y means group of the (Y-3) wherein R25 means group of the formula: R26-(CH2)e- wherein R26 means (lower)-alkoxy-group, (lower)-alkylthio-group, (lower)-alkylsulfonyl; or R26 means group of the formula: -NR28R29 wherein R28 means hydrogen atom; R29 means (lower)-alkanoyl or (lower)-alkylaminocarbonyl; Q means -(CH2)f- wherein e means a whole number from 0 to 4; f means a whole number from 1 to 3; a bond denoted as a dotted line can be hydrogenated optionally; and to its pharmaceutically acceptable salts and esters. Also, invention proposes a pharmaceutical composition designated for treatment or prophylaxis of rheumatic arthritis, cerebrospinal sclerosis, intestine inflammatory disease and asthma and containing compound of the formula (I) or its pharmaceutically acceptable salt or ester in combination with a compatible pharmaceutical carrier. Invention proposes derivatives of thioamide inhibiting interaction between α4-comprising integrins and VCAM-1.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

20 cl, 1 tbl, 86 ex

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