The method of obtaining 3-{2-/4-(6-toranzo [d] isoxazol-3-yl) piperidine-1-yl /ethyl}-2-methyl-6,7,8,9-tetrahydro-4h-pyrido /1,2-a/ pyrimidine-4-she and intermediate compounds to obtain

 

(57) Abstract:

The invention relates to a method for 3-{ 2-[4-(6-toranzo[d]isoxazol-3-yl) piperidine-1-yl] ethyl} -2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a] pyrimidine-4-it (I) interaction of 3-(2-amino-ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a] pyrimidine-4-it (II) isoxazol derivative of the formula (III)where Y and Z represent the deleted group, such as halogen or alkyl - or arylsulfonate, in the presence of a suitable solvent and base. The proposed method allows to simplify the process of obtaining the compound (I) through the use of a more available source of reagents. The invention relates also to compounds of the formula (II) and (III). 3 S. and 4 C.p. f-crystals.

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Connection f-crystals (III).

The invention relates to a method for 3-{2-[4-(6-toranzo[d]isoxazol-3-yl)piperidine-1-yl] -ethyl} - 2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-it formula I

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which has a pharmaceutical application, due to its antipsychotic properties, as well as to new compounds which are intermediates for the receipt of the compounds, namely 3-(2-amino-ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a] pyrimidine-4-ONU formula II

Compounds II and III, along with some of their predecessors, not described in previous literature, the present research.

Known (patent EP 196123) different ways of obtaining 3-{2-[4-(6-toranzo[d] isoxazol-3-yl)piperidine-1-yl] -ethyl} - 2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a] pyrimidine-4-it. Three of them lie in the formation of 2-methyl-6,7,8,9-tetrahydro - 4H-pyrido[1,2-a]pyrimidine-4-it using various methods of condensation and cyclization. The fourth method consists in the reaction of N-alkylation of 6-fluoro-3-(4-piperidine)benzo[d]isoxazol-3-(2-chloroethyl)- 2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one or in a similar way with other deleted groups.

Patent ES 2006888 and ES 2006889 described the ways in which use different types of final cyclization core isoxazol.

Obtaining N-alkyl or N-arylpiperazines, based on the present invention, described in the chemical literature. Get them as interaction 1,5-dehalogenation with primary amines (J. von. Braun, Chem.Ber., 37, 3210 (1904); 39, 4351 (1906); 40, 3914 and 3930 (1907); 42, 2048 2052 (1909)), and the interaction of 1,5-bialkin or arylsulfonamides with primary amines (K. Rey of compound I, consisting in the use of new original products.

The method of obtaining 3-{2-[4-(6-toranzo[d]isoxazol-3-yl)piperidine-1-yl] -ethyl} -2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-it formula I is in the interaction of 3-(2-amino-ethyl)-2-methyl-6,7,8,9 - tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-it formula II with compounds of General formula III, in which Y and Z are deleted groups, for example halogen or alkyl - or arylsulfonate, and Y and Z may be the same or different, in accordance with the following scheme:

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The reaction is carried out in a polar solvent, such as alcohol, low molecular weight, such as methanol, ethanol, isopropanol or n-butanol, preferably ethanol, or in polar aprotic solvents such as acetonitrile, N,N-dimethylformamide or N-an organic, preferably in acetonitrile, in the presence of organic bases such as triethylamine, or inorganic bases such as hydroxide, carbonate or bicarbonate of an alkali metal, at a temperature between 40 and 120oC, preferably about 80oC. the resulting product I produce by conventional means and purified by recrystallization.

The compounds of formula II and III, it is STI and are also the aim of the present invention.

3-(2-amino-ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a] pyrimidine - 4-one receive in accordance with the following synthesis scheme:

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The substitution reaction of the chlorine in the 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a] pyrimidine-4-Ohe (IV) (JP 52005797; H. Fujita, Ann. Rep. Sankyo Res. Lab 29, 75-98 (1977)) dibenzylamino to obtain 3-(2-dibenzylamino)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a] pyrimidine - 4-it (V) is carried out in a suitable solvent, for example acetonitrile, N,N-dimethylformamide, N-organic or methanol, in the presence of inorganic bases such as hydroxide, carbonate or bicarbonate of an alkali metal or organic base, such as triethylamine, at temperatures between 50 and 100oC, preferably between 70 and 90oC. Optionally in a reaction medium can be entered as a catalyst iodide of an alkali metal.

The hydrogenation of 3-(2-dibenzylamino)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a] pyrimidine-4-it (V) to obtain 3-(2-amino-ethyl)-2-methyl - 6,7,8,9-tetrahydro-4H-pyrido[1,2-a] pyrimidine-4-it formula II is carried out in an inert solvent, for example methanol, ethanol, isopropanol or mixtures of these alcohols with water in various proportions at a temperature of between 20 and 60oC, preferably between 45 is considerable higher than atmospheric pressure, in the presence of a catalyst of palladium on coal, used in amounts of between 5 and 15% by weight of the original product V Products V and II produce by conventional methods and do not require further treatment.

The compounds of formula III can be obtained, respectively platitudinous scheme of synthesis.

4-Tetrahydroprotoberberine (VI) (J. Gibson, J. Chem.Soc., 25255 (1930)) and 1,3-differental (VII) interact in the presence of anhydrous aluminum trichloride, forming the product of alkylation Friedel -, (2,4-differenl)-(tetrahydropyran-4-yl)methanol of formula VIII, in an environment suitable solvent, such as dichloromethane or 1,2-dichloroethane, or in the presence of an excess of 1,3-diferente, acting also as a solvent. The reaction is carried out at a temperature between 40 and 85oC, preferably about 80oC. the Product produce by conventional methods and purified by recrystallization.

The oxime is produced from compound VIII by reaction with hydroxylamine hydrochloride in accordance with the classical methods (see, for example, "Advanced organic Chemistry", J. March, 4th edition, p.406). Formed mixture (75:25) SYN - and anti-isomers of the oxime (2,4-differenl)-(tetrahydropyran-4-yl)methanol of formula IX. EMU mixture of isomers produce by conventional methods.-the oxime can be distinguished column chromatography on silica gel.

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The cyclization mixture Asimov IX or the corresponding SYN-isomer 6-fluoro-3-(tetrahydropyran-4-yl)benzo[d] isoxazol formula X is carried out in a suitable solvent and in the presence of a base, such as methanol, ethanol and the hydroxide, carbonate or bicarbonate of an alkali metal or tetrahydrofuran or dioxane and hydride or alkoxide of an alkali metal. Preferably the use of methanol and sodium hydroxide. The reaction is carried out at a temperature between 50 and 100oC, preferably at the boiling temperature of the reaction mixture. Product X emit the usual ways. It should be separated from directionspanel isomer source oxime IX column chromatography on silica gel, if the original product using a mixture of Asimov.

Disclosure tetrahydropyranyloxy engine 6-fluoro-3-(tetrahydropyran-4-yl)benzo[d] isoxazol (X), make use of a variety of reagents in accordance with the nature of the groups Y and Z, which should be in the compounds of General formula III. So, for example, using trichromate phosphorus in the presence of Hydrobromic acid or phosphoric acid at 140oC (P Volynskii, Jzv. Akad. Nauk. SSSR Ser.Khim. 11, 2528 (1979), C. A. 92, 128341 (1980)) is obtained directly connection III 272-6 (1989)) or anhydrous magnesium bromide in acetic anhydride (D. J. Goldsmith, J. Org.Chem. 40, 3571 (1975)) and subsequent saponification of the resulting bromoacetate potassium carbonate in methanol at room temperature get brombert XI (Y = Br). Similarly compound XI (Y = I) receive treatment X idestam by acetyl in acetonitrile boiling under reflux (A. Oku, Tetrahedron Lett 23, 681 (1982)) with subsequent saponification of the obtained intermediate iodoacetate.

Halogenerte General formula XI in turn dihalogenoalkane products of General formula III by treatment of the classical halogenocarboxylic alcohols reagents, for example chloride tiomila, trichloride and with phosphorus pentachloride, chloroxylon phosphorus or tribromide phosphorus (see , for example, "Advanced Organic Chemistry", J. March, 4th edition, p. 433). Similarly, processing halogenation XI-alkylhalogenide or arylsulfonate, for example methanesulfonyl - or a-toluensulfonate, respectively, received halogenated.sulphonated or halogen-p-toluensulfonate.

Experimental part

Example 1. 3-(2-Dibenzylamino)-2-methyl-6,7,8,9-tetrahydro - 4H-pyrido[1,2-a]pyrimidine-4-one (V).

14 g (0,1666 mole) of sodium bicarbonate and 24 g (0,1218 mole) of dibenzylamine added to a solution of 25 g (0,1104 mole) of 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetr is, then cooled to 5oC and shaken for 30 min at the same temperature. The mixture is then filtered with suction. The hard part is suspended in 125 ml of water and the mixture is heated to 60oC with shaking for 1 hour. The suspension is left to cool to room temperature and shaken for 30 minutes the Solid part was filtered with suction and dried in vacuum at 40oC, getting to 35.7 g of white solid product. Yield 84%.

Melting point: 110-111oC.

IR-spectrum (KBr), cm-1: 3020, 2980-2800, 1655, 1588, 1533, 1444, 1188, 744, 694.

The NMR spectrum (CDCl3), (ppm): 7,40-7,15 (SC., 10H; aromatic), 3,80 (t, J=6, 2H; CH2pyridopyrimidines), the 3.65 (s, 4H; CH2of benzyl), 2,85 (t, J=6, 2H; CH2pyridopyrimidines), 2,70 (SC., 2H; CH2ethylene), 2,60 (SC., 2H; CH2ethylene), 2,10 (s, 3H; CH3), 1,90 (SC., 4H; CH2pyridopyrimidines).

Elemental analysis: C25H29N3O (mol. mass. 387,53)

Calculated (%): C 77,49, H rate of 7.54, N 10,84,

Found (%): C 77,36, H To 7.59, N 10,77.

Example 2. 3-(2-amino-ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a] pyrimidine-4-one (II).

2 g of Pd/C (10%) with a humidity of 50% added to a suspension of 20 g (0,0517 mole) of 3-(2-dibenzylamino)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-he is hladiny to room temperature, the catalyst is separated by filtration and the solvent is removed in vacuum, obtaining oily residue, which crystallized upon treatment with heptane. The crystals are dried in vacuum at room temperature, receiving 9.3 g of white solid product. Yield 88%.

Melting point: 126oC.

IR-spectrum (KBr), cm-1: 3322, 2944, 1655, 1588, 1527, 1322, 1194.

NMR spectrum (ppm): 3,90 (t, J=6, 2H; CH2pyridopyrimidines), 2,85 (t, J= 7, 4H; CH2pyridopyrimidines and CH2ethylene), 2,70 (t, J=7, 2H; CH2ethylene), is 2.30 (s, 3H; CH3), 1,90 (SC., 4H; CH2pyridopyrimidines), 1,70 (sa, 2H; NH2, deuterium).

Elemental analysis: C11H17N3O (molecular weight 207,28)

Calculated (%): C 63,74, H 8,27, N 20,27,

Found (%): C 63,69, H Compared To 8.26, N 20,35.

Example 3. (2,4-Differenl)-(tetrahydropyran-4-yl)methanon (VIII).

Dropwise to 34.1 g (0,229 mole) of 4-tetrahydroprotoberberine add in agitated suspension is 61.3 g (0,460 mole) of anhydrous aluminum trichloride in 113 ml of 1,3-diferente. The mixture is refluxed for 20 hours, allowed to cool to room temperature and the reaction mass is then poured onto 500 g of ice and 50 ml of concentrated hydrochloric acid. The mixture is extracted three times the same sodium sulfate. The solvent is evaporated in vacuum, obtaining salt, which crystallizes. It is recrystallized from heptane. Get to 41.4 g of white solid product. Yield 80%.

Melting point: 50-51oC.

IR-spectrum (KBr), cm-1: 3054, 2964, 2845, 1680, 1605, 1485, 1421, 1093.

The NMR spectrum (CDCl3), (M. D.): a 7.85 (DDD, 1H; aromatic), 6.90 to (m, 2H; H; aromatic), of 4.05 (dt, 2H; H-EQ--O-Tgp), a 3.50 (m, 2H; H=CCF--O-TBM), 3,30 (m, 1H; CH-C=O), 1,85 (SK, 4H; TBM).

Elemental analysis: C12H12F2O2(molecular weight 226,22)

Calculated (%): C 63,71, H 5,35, F LS 16.80,

Found (%): C 63,65, H 5,38, F X 16.75.

Example 4. The oxime(2,4-differenl)-(tetrahydropyran-4-yl)methanone (IX).

10 g (0,144 mole) of hydroxylamine hydrochloride dissolved in 50 ml of water, and 20 g (0,147 mole) digidratirovannogo sodium acetate added to a solution of 31 g (0,137 mole) of (2,4-differenl)-(tetrahydropyran-4-yl)methanone in 100 ml of ethanol. The resulting solution was refluxed for 10 hours. The mixture is cooled and the ethanol is evaporated in a vacuum. Add 100 ml of water, the resulting suspension is cooled to 5oC and a solid portion was separated by filtration, washed with ice water and dried at 40oC. Get 32,24 g of white solid product, p is STI-isomer by chromatography on silica gel, using as eluent a mixture of heptane/ethyl acetate (7:3).

Melting point: 115-116oC.

IR-spectrum (KBr), cm-1: 3323, 2936, 2850, 1617, 1505, 1421, 1110, 969, 845.

The NMR spectrum (CDCl3), (ppm): 8,10 (s, 1H, N-OH, the date is.), to 7.15 (DDD, 1H; aromatic), to 6.95 (m, 2H; aromatic), 4,00 (dt, 2H; H-EQ--O-TBM), 3,40 (m, 2H; H=ACS--O-TBM), 2,70 (m, 1H; CH-C=O), 1,70 (SK, 4H; TBM).

Elemental analysis: C12H13F2NO (molecular weight 241,22)

Calculated (%): C 59,65, H 5,42, F 13,24, N 5,80,

Found (%): C 59,61, H 5,48, F 13,19, N Of 5.82.

Example 5. 6-Fluoro-3-(tetrahydropyran-4-yl)benzo[d]isoxazol (X).

10 g (0,0415 mole) of SYN-oxime(2,4-differenl)-(tetrahydropyran-4-yl)methanone added to a solution of 3 g (0,0454 mole) sodium hydroxide at 85% in 100 ml ethanol. The mixture is refluxed one hour, cooled to room temperature and the solvent is evaporated to dryness. Add 50 ml of water. The resulting suspension shaken for 15 min and the solid portion was separated by filtration, washed thoroughly with water. The obtained white product is dried in vacuum at 40oC receives 9.0 g of 6-fluoro-3-(tetrahydropyran-4-yl)benzo[d]isoxazol. The release of the 98%.

Melting point: 86-87oC.

IR-spectrum (KBr), cm-1: 2926, 2858, 1612, 1498, 1240, 1123, 840.<�cue), 4,10 (dt, 2H; H-EQ--O-TBM), 3,60 (DDD, 2H; H=ACS--O-Tgp), the 3.35 (m, 1H; CH-C=N), 2,10 (SK, 4H; TBM).

Elemental analysis: C12H12FNO2(molecular weight 221,23)

Calculated (%): C 65,15, H 5,47, F 8,59, N 6,33,

Found (Percent): C, 65.22 Per, F 8,65, N 6,29.

Example 6. 3-(6-Toranzo[d]isoxazol-3-yl)-5-iodopentane-1-ol (XI, Y=I).

8,147 g (0,054 mole) iodine sodium and 3.3 ml (0,0462 mole) acetyl chloride added sequentially to a solution of 3.4 g (0,0154 mole) of 6-fluoro-3-(tetrahydropyran-4-yl)benzo[d] isoxazol in 20 ml of dry acetonitrile. The mixture is refluxed in an atmosphere of dry nitrogen for 8 hours. The reaction mixture is allowed to cool to room temperature and then poured into a solution of 20 g of sodium metabisulfite in 60 ml of water. The acetonitrile is evaporated under vacuum and the residue extracted three times with 50 ml of saturated aqueous salt solution and dried on anhydrous sodium sulfate. The solvent is evaporated in vacuum and the oily residue is dissolved in 20 ml of methanol. Add to 2.13 g (0,0154 mole) of anhydrous potassium carbonate and the mixture is shaken at room temperature for 30 minutes Add to 7.8 ml of 3 N hydrochloric acid, the methanol is evaporated in vacuo and the residue partitioned between 20 ml of water and 20 ml of dichloromethane. The organic phase is separated, saxar-3-yl)-5-iodopentane-1 (XI, Y=I). Yield 66%.

The product can be cleaned column chromatography on silica gel, using a mixture of heptane/ethyl acetate (7:3) as eluent.

IR-spectrum (KBr), cm-1, 3400, 3100, 2950, 1615, 1500, 1280, 1120, 1050, 960, 840.

The NMR spectrum (CDCl3) (million e): of 7.75 (DD, 1H; aromatic), 7,25 (MTS, 1H; aromatic), 7,10 (DDD, 1H; aromatic), 3,65 (SK, 3H; CH-C=H and CH2-OH) and 3.15 (m, 2H; CH2I) to 2.40 (m, 2H; CH2-CH2-OH), 2,10 (m, 2H; CH2CH2I) to 1.70 (s, 1H; OH, the date.).

Elemental analysis: C12H13FINO2(molecular weight 349,14)

Calculated (%): C around 41.28, 3,75 H, F 5,44, I 36,35, N 4,01,

Found (%): C 41,32, H 3,82, F 5,39, I 36,24, N 3,95.

Example 7. Meanswhat-3-(6-toranzo[d] isoxazol-3-yl)-4-Identica (III, Z=1, Y=-O-SO2-CH3).

2 ml (0,0143 mole) of triethylamine and 1.1 ml (0,0143 mole) of methanesulfonamide in 10 ml of dichloromethane added sequentially to a solution of 3,533 g (0,01 mol) of 3-(6-toranzo[d]isoxazol-3-yl)-4-iodopentane-1-ol in 20 ml of dry dichloromethane, pre-cooled to 0oC. the Mixture is shaken at 0-5oC for 1 hour. Add 20 ml of water, then it is decanted and the aqueous phase is extracted with twice 20 ml of dichloromethane. The combined organic phase is washed successively with 20 ml is the spruce of it is evaporated to dryness, getting 3,48 g oil methansulfonate-3-(6-toranzo[d]isoxazol-3-yl)-4-Identica. Yield 81%.

IR-spectrum (KBr), cm-1: 3090, 2930, 1615, 1350, 1175, 955, 820.

The NMR spectrum (CDCl3), (ppm): of 7.75 (DD, 1H; aromatic), 7,30 (DD, 1H; aromatic), to 7.15 (DDD, 1H; aromatic), 4,20 (m, 2H; CH2-O3S), of 3.60 (m, 1H; CH-C=N) and 3.15 (m, 2H; CH2-I) 2,95 (s, 3H; CH3-SO3-), 2,35 (SK, 4H; CH2CH2-I and CH2CH2-O3S-).

Elemental analysis: C13H15FINO4(molecular weight 426,73)

Calculated (%): C 36,59, H 3,54, F 4,45, I 29,74, N 3,28, S 7,51,

Found (%): C 36,62, Of 3.60 H, F 4,50, I 29,69, 3,33 N, S 7,60.

Example 8. 3-{2-[4-(6-Toranzo[d]isoxazol-3-yl)piperidine-1-yl]ethyl}-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one (I).

20 g (of 0.08 mole) of 3-(2-amino-ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a] pyrimidine-4-it and 34.2 g (of 0.08 mole) of metasulfite 2-(6-toranzo[d] isoxazol-3-yl)-4-Identica dissolved in 300 ml of acetonitrile. Then add 17 g (0.2 mole) of sodium bicarbonate and the resulting solution was kept at boiling temperature for 6 hours. The solution is cooled to room temperature and the solvent is evaporated from it in a vacuum. Add 300 ml water and the suspension was kept at boiling temperature for 30 min without vesbaltarve, washed with water and dried at 50oC. After recrystallization from ethanol 26,3 g 3-{2-[4-(6-toranzo[d]isoxazol-3-yl)piperidine-1-yl] ethyl}-2-methyl - 6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-it is in the form of a white solid product. Yield 80%.

Melting point: 170oC.

IR-spectrum (KBr), cm-1: 3060, 2944, 2800, 1650, 1527, 1122.

The NMR spectrum (CDCl3), (ppm): of 7.75 (DD, 1H; aromatic), 7,25 (DD, 1H; aromatic), 7,05 (DDD, 1H; aromatic), of 3.95 (t, 2H; CH2pyridopyrimidines), 3,15 (SK, 3H; Pieper.), to 2.85 (t, 2H; CH2pyridopyrimidines), 2,75 (SC. , 2H; ethylene), 2,55 (SK, 2H; ethylene), is 2.30 (s, 3H; CH3), 2,10 (SK, 4H, Pieper., periderm.), 1,90 (SC., 6H; Pieper., periderm.).

Elemental analysis: C23H27FN4O (molecular weight 410,49)

Calculated (%): C 67,30, H 6,63, F 4,63, I 13,65,

Found (%): C 67,16, H 6,70, F 4,57, I 13,72.9

1. The method of obtaining 3-{2-/4-(6-toranzo [d] isoxazol-3-yl)piperidine-1-yl/ethyl} -2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a] -pyrimidine-4-it formula I

< / BR>
characterized in that it includes the interaction of 3-(2-amino-ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-4-it formula II derived from benzo [d] isoxazol formula III

< / BR>
where Y and Z represent the deleted group, such to the AI of a suitable solvent and base.

2. The method of obtaining 3-{2-/4-(6-toranzo [d] isoxazol-3-yl/piperidine-1-yl)ethyl}-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]-pyrimidine-4-p. 1, characterized in that the reaction is performed in a polar solvent such as an alcohol with a low molecular weight such as methanol, ethanol, isopropanol or n-butanol, preferably ethanol, or in polar aprotic solvents, such as acetonitrile, N,N-dimethylformamide or N-an organic, preferably in acetonitrile.

3. The method of obtaining 3-{2-/4-(6-toranzo [d] isoxazol-3-yl)piperidine-1-yl/ethyl}-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-PP. 1 and 2, characterized in that the reaction is carried out in the presence of organic bases, such as tertiary or heterocyclic amine, preferably triethylamine, or inorganic bases such as hydroxide, carbonate or bicarbonate of an alkali metal or mixtures thereof, preferably sodium bicarbonate.

4. The method of obtaining 3-{2-/4-(6-toranzo [d] isoxazol-3-yl)piperidine-1-yl/ethyl}-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-PP. 1 and 3, characterized in that the reaction is carried out at 40-120oC, preferably about 80oC.

5. The method of obtaining 3-{2-/4-(6-toranzo [d, that in the compounds of General formula III are two of the deleted group Y, and Z represent preferably an iodine atom and methysulfonylmethane.

6. 3-(2-amino-ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a] pyrimidine- -4-one of formula II

< / BR>
as an intermediate product to obtain 3-{2-/4-(6-toranzo [d] isoxazol-3-yl)piperidine-1-yl/ethyl} - 2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-it.

7. Derivatives of benzo [d] isoxazol General formula III

< / BR>
in which Y and Z are deleted groups, such as halogen or alkyl - or arylsulfonate, and Y and Z may be the same or different,

as intermediate products for the preparation of 3-{2-/4-toranzo[d] isoxazol-3-yl)piperidine-1-yl/ethyl} -2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-it.

 

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< / BR>
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< / BR>
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m is 1 or 2;

represents a C1-C4-alcander; B is an R2CH2, O, SO or SO2where R2is hydrogen or C1-4-alkyl;

n is 0, 1 or 2;

L represents hydrogen; C1-2-alkyl; C3-6-cycloalkyl; C3-C6alkenyl, optionally substituted by aryl; C1-C6-alkylsulphonyl; C1-C6-алкилоксикBR>
-Alк-Y-R4(o-2);

-Alк-Z1-C X-2-R5(o-3); or

-CH2-CHOH-CH2-O-R6(o-4); where R3represents cyano, aryl or Het; R4represents hydrogen, aryl, Het, or1-C6-alkyl, optionally substituted aryl or Het; R5represents hydrogen, aryl, Het or1-C6-alkyl, optionally substituted aryl or Het; R6represents aryl or naphthalenyl; Y represents O, S, NR7where R7is hydrogen, C1-C6-alkyl or C1-C6-alkylcarboxylic;

Z1and Z2each independently represents O, S, NR8or a simple link, where R8is hydrogen or C1-C6-alkyl; X represents O, S or NR9where R9is hydrogen, C1-C6-alkyl or cyano; Alк each independently is a C1-C6-Alcantara; each Het represents: (i) optionally substituted heterocyclic ring with 5 or 6 members containing 1, 2, 3 or 4 heteroatoms selected from oxygen, sulfur and nitrogen, provided that there is not more than 2 oxygen atoms and/or sulfur; (ii) optionally substituted heterocyclic ring with 5 or 6 members which of substituted five - or six-membered ring through 2 carbon atoms or 1 nitrogen atom; and that in the rest of the condensed ring contains only carbon atoms; (iii) optionally substituted heterocyclic ring with 5 or 6 members, which contains 1 or 2 heteroatoms selected from oxygen atoms, sulfur and nitrogen, and optionally substituted five - or six-membered ring through 2 carbon atoms or 1 carbon atoms and 1 nitrogen atom; and which in the rest of the condensed ring contains 1 or 2 heteroatoms selected from oxygen atoms, sulfur and nitrogen; and, if Het is a monocyclic ring system, it is not necessary to have up to 4 substituents; and if Het is a bicyclic ring system, it may not necessarily be up to 6 substituents, which are selected from halogen, amino, mono - and di(C1-C6-alkyl)amino, aryl WITH1-C6-amino, nitro, cyano, aminocarbonyl,1-C6-alkyl, C1-C6alkyloxy,1-C6-alkylthio,1-C6-allyloxycarbonyl,1-6-alkyloxy-FROM1-6-alkyl, C1-6-allyloxycarbonyl1-6-alkyl, hydroxy, mercapto, hydroxy1-C6-alkyl, C1-C6-alkylcarboxylic aryl, Rilc1-C6-alkylamino is whether 3 substituents, each of which is independently selected from halogen, hydroxy, nitro, cyano, trifloromethyl,1-C6-alkyl, C1-C6-alkyloxy,1-C6-alkylthio, mercapto, amino, mono - and di-(C1-C6-alkyl)amino, carboxyl,1-6-allyloxycarbonyl, and C1-C6-alkylcarboxylic

The invention relates to 9-amino-1,2,3,4-tetrahydropyridines and related compounds of the formula I

< / BR>
in which Y is C= O or CHOH; R1is hydrogen or lower alkyl; R2is hydrogen, lower alkyl or phenyl-lower alkyl; R3is hydrogen, OR4in which R4is hydrogen, COR5in which R5is lower alkyl, X is hydrogen, lower alkyl, halogen, lower alkoxy-, hydroxy-group or trifluoromethyl, their geometric or optical isomers, N-oxides, or their pharmaceutically acceptable salts and accessions acids (acid additive salts), which are useful in reducing dysfunction in memory and are thus indicative for the treatment of disease Allgamer
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