N(hetero)-aryl-n - (hetero)-tetralin-alkyl-piperazines, the method of production thereof

 

(57) Abstract:

The invention is used in the chemistry of heterocyclic compounds and medicine. Offers new N (hetero)-aryl-N - (hetero)-tetralin-alkyl-piperazines with serotonergic, dopaminergic and adrenergic activity, of General formula (I)

< / BR>
where Ar1phenyl or thienyl, condensed with 5 - to 6-membered carbocyclic ring; R1and R2is independently H or C1-5alkoxy; Ar2is phenyl, unsubstituted or substituted by a methoxy group, halogen, trifluoromethyl, or pyridylethyl; group selected from

< / BR>
n is 1 or 2; m is 2 or 3 and their pharmaceutically acceptable salts. The proposed methods allow to obtain the target product based on the compounds of formula (II)

< / BR>
and the corresponding petersenstrasse reagent. 9 C.p. f-crystals, 3 tables.

Example 9. 4-[3-(8-methoxy-1,2-dihydronaphthalene-4-yl)- n-propyl]-1-(2-methoxyphenyl) piperazine.

Here follow the same process as described in example 8, except that in this case, using 1-(2 - methoxyphenyl) piperazine.

MS, m/z (rel. range: 394,25 (M++2; 4,2); 393,25 (M++1; 27,0); 392,25 (M+; 100,0); 205,05 (25,6); 203,15 (24,6).

1H-NMR (200MHz, CDCl3); 5,88 (t, 1H, J = 4,5 Hz, H vin.); 6,75 - 7,20 (m, 7H, arom.).

Hydrochlorot: so pl. 209 - 210oC.

Example 10. 1-(3-chlorophenyl)-4-[3-(8-methoxy-1,2 - dihydronaphthalene-4-yl)-n-propyl] piperazine.

Here follow the same process as described in example 8, except that in this case, using 1-(3-chlorophenyl)- piperazine.

MS, m/z (rel. range: 400,15 (M++4; 1,1); 399,15 (M++3; 8,3); 398,15 (M++2; 34,2); 397,15 (M++1; 30,4); 396,15 (M+; 100,0); 222,00 (23,6); 211,10 (21,2); 209,00 (76,,2); 207,00 (30,4); 166,00 (33,6).

1H-NMR (200MHz, CDCl3), (ppm): 1,66 - of 1.85 (m, 2H, ); 2,13 - of 2.28 (m, 2H, CH2endoc.); 2,39 - 2,80 [m, 10H, CH2benz., ] ; 3,21 [broad t, 4H, (CH2)2NAr]; a 3.83 (s, 3H, CH3); by 5.87 (t, 1H, J = 5,0 Hz, H vin.); of 6.71 - 7,21 (m, 7H, arom.).

Hydrochlorot: so pl. 190 - 192oC.

Example 11. 4-[3-(8-methoxy-1,2-dihydronaphthalene-4-yl) -n-propyl] -1-3-triptoreline) piperazine.

Here follow the same process as described in example 8, except that in this case, using 1-(3 - trifluoromethyl) piperazine.

MS, m/z (rel. range: 432,25 (M++2; 2,9); 431,25 (M++1; 21,5); 430,25 (M+; 79,4); 256,10 (32,0); 243,00 (100,0); 241,00 (35,1); 200,00 (56,4); 172,00 (20,1).

1H-NMR (200MHz, CDCl3), (ppm): 1,73 is 1.91 (m, 2H, ); 2,14 - of 2.28 (m, 2H, CH2endoc.); 2,42 - 2,82 (m, 10H, CH2benz., ] ; 3,20 - 3,37 [m, 4H, (CH2)2NAr]; a 3.83 (s, 3H, CH3); of 5.89 (t, 1H, J =is ronfalin-4-yl)- n-propyl] -1-(2-pyridyl) piperazine.

Here follow the same process as described in example 8, except that in this case, using 1-(2-pyridyl) piperazine.

MS, m/z (rel. range: 365,25 (M++2; 1,8); 364,25 (M++1; 14,3); 363,25 (M+; 53,3); 256,25 (39,0); 244,25,(46,1); 121,10 (34,0); 107,10 (100,0); 79,10 (23,0); 78,10 (20,6); 72,10 (35,9).

1H-NMR (200MHz, CDCl3), (ppm): 1,67 - to 1.86 (m, 2H ); 2,13 - of 2.28 (m, 2H, CH2endoc.); 2,40 - 2,63 [m, 8H, ]; by 2.73 (t, 2H, J = 8 Hz, CH2benz.); 3,50 - 3,62 [m, 4H, ]; is 3.82 (s, 3H, CH3); by 5.87 (t, 1H, J = 4,5 Hz, H vin.); 6,58 - 7,52 (m, 6N arom.); 8,16 - 8,23 (m, 1H, N=CH arom.).

Hydrochlorot: so pl. 218 - 220oC.

Example 13. 4-[3-(1,2-dihydronaphthalene-4-yl)-n-propyl] - 1-(2-methoxyphenyl) piperazine.

Here follow the same process as described in example 8, except that in this case, using 1-(2-methoxyphenyl) piperazine

MS, m/z (rel. range: 364,25 (M++2; 3,4); 363,25 (M++1; 27,1); 362,25 (M+; 100,0); 205,10 (31,3); 203,10 (30,4); 162,10 (22,9).

1H-NMR (200MHz, CDCl3), (ppm): 1,72 of - 1.83 (m, 2H, ); 2,19 - of 2.28 (m, 2H, CH2endoc.); 2,43 is 2.55 (m, 4H, ); 2,62 - 2,78 [m, 6H, CH2benz. , ]; 3,10 [broad t, 4H, ]; of 3.84 (s, 3H, CH3; by 5.87 (t, 1H, J = 4,5 Hz, H vin.); 6,82 - 7,27 (m, 8H, arom.).

Hydrochlorot: so pl. 185 - 187oC.

Example 14. 1-(2-methoxyphenyl)-4-[3-(7-methoxy-1,2,3,4 - tetrahydronaphthalen-1-yl)-n-propyl] piperazine.

Hydrochlorot the example 2, solubilizer in MeOH (30 ml) and hydronaut in the presence of catalytic amount of 10% Pd/C. After 2 hours the mixture is filtered on celite, the solvent is evaporated and get hydrochlorate salt of the desired product as a pale yellow solid which crystallized from MeOH/Et2O (yield 90%).

Hydrochlorot: so pl. 203 - 205oC.

MS, m/z (rel. range: 396,35 (M++2; 3,3); 395,35 (M++1; 23,4); 394,35 (M+; 83,8); 205,10 (100,0); 192,10 (33,4); 150,10 (22,8).

1N-NMR (200MHz, CDCl3), (ppm): 1,54 - 1,90 (m, 8H, CH2CH2endoc,. ); 2,46 [broad t, 2H, ]; 2,62 - 2,84 [m, 7H, CH and CH2benz. , ]; 3,12 [broad s, 4H, (CH2)2NAr]; of 3.78 (s, 3H), 3,86 (s, 3H), (2 CH3); 6,63 - 7,07 (m, 7H, arom.).

Example 15. 4-[3-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)- n-propyl] -1-(3-triptoreline)piperazine.

Here follow the same process as described in example 14, on the basis of hydrochlorate obtained in example 5.

Hydrochlorot: so pl. 150 - 152oC.

MS, m/z (rel. range: 434,25 (M++2; 2,4); 433,25 (M++1; 16,7), 432,25 (M+; 58,6); 243,10 (100,0); 230,10 (36,3).

1N-NMR (200MHz, CDCl3), (ppm): 1,53 - of 1.92 (m, 8H, CH2CH2endoc., ; 2,36 - 2,83 [m, 9H, CH and CH2benz., CH2N(CH2)2]; 3,25 [t, 4H, J = 4,9 Hz, (CH2)2NAr]; of 3.77 (s, 3H, CH3); 6,61 - 7,40 (m, 7H, arom.).

Example 16. 1-phenyl-4-[3-(5-methoxy-1,2,3,iMER 14, based on hydrochlorate obtained in example 8.

MS, m/z (rel. range: 366,30 (M++2; 2,8); 365,30 (M++1; 21,4); 364,30 (M+; 80,5); 175,15 (100,0); 162,05 (35,0).

1N-NMR (200MHz, CDCl3), (ppm): 1,54 - 1,90 (m, 8H, CH2CH2endoc, ); 2,38 - 2,85 [m, N, CH and CH2benz., CH2N(CH2)2]; 3,24 [broad t, 4H, (CH2)2NAr]; 3,81 (s, 3H, CH3); 6,62 - 7,35 (m, 8H, arom.).

Hydrochlorot: so pl. 206 - 207oC.

Example 17. 1-(2-methoxyphenyl)-4-[3-(5-methoxy-1,2,3,4 - tetrahydronaphthalen-1-yl)-n-propyl] piperazine.

Here follow the same process as described in example 14, on the basis of hydrochlorate obtained in example 9.

MS, m/z (rel. range: 396,30 (M++2; 3,3); 395,30 (M++1; 23,0); 394,30 (M+; 82,7); 205,10 (100,0); 192,10 (34,4); 150,10 (21,8).

1N-NMR (200MHz, CDCl3), (ppm): 1,53 - 1,89 (m, 8H, CH2CH2endoc., ; 2,38 - 2,87 [m, N, CH and CH2benz., CH2N(CH2)2]; 3,13 [broad s, 4H, (CH2)2NAr]; 3,81 (s, 3H), 3,86 (s, 3H), (2 CH3); 6,62 - 7,17 (m, 7H, arom.).

Hydrochlorot: so pl. 206 - 207oC.

Example 18. 4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)- n-propyl] -1-(2-pyridyl) piperazine.

Here follow the same process as described in example 14, on the basis of hydrochlorate obtained in example 12.

MS, m/z (rel. range: 367,20 (M++2; 1,9); 366,20 (M++1; 13,8); 365,20 (M+; 50,8); 271,20 (29,5); 2CH2CH2endoc., ; 2,38 - 2,85 [m, 9H, CH and CH2benz., CH2N(CH2)2]; 3,59 [broad t, 4H, (CH2)2NAr]; of 3.80 (s, 3H, CH3); 6,58 - 7,52 (m, 6H, arom.); 8,14 - 8,23 (m, 1H, N=CH arom.).

Hydrochlorot: so pl. 169 - 171oC.

Example 19. 4-[3-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1 - yl)-n-propyl] -1-(2-pyridyl) piperazine.

Here follow the same process as described in example 14, on the basis of hydrochlorate obtained in example 12.

MS, m/z (rei. range: 367,25 (M++2; 1,3); 366,25 (M++1; 9,6); 365,25 (M+; 39,7); 271,15 (21,7); 258,15 (60,1); 121,10 31,7); 107,00 (100,00); 86,10 (24,6); 79,10(20,7); 72,10 (48,0).

1H-NMR (200MHz, CDCl3), (ppm): 1,53 - 1,89 (m, 8H, CH2CH2endoc., ; 2,50 [broad t, 2H, ]; 2,61 - 2,82 [m, 7H, CH and CH2benz., ; 3,63 [broad t, 4H, (]; 3,76 (s, 3H, CH3); 6,58 - 7,52 (m, 6H, arom.); 8,15 - 8,21 (m, 1 N, N=CH arom.).

Hydrochlorot: so pl. 143 - 145oC.

Example 20. 1-(2-methoxyphenyl)-4-[3-(4,5,6,7-tetrahydrobenzo[b] Tien-4-yl)-n-propyl] piperazine.

Here follow the same process as described in example 14, on the basis of hydrochlorate obtained in example 9.

MS, m/z (rel. range: 372,20 (M++2; 7,5); 371,20 (M++1; 25,0); 370,20 (M+; 100,0); 205,05 (59,4); 192,15 (25,0); 150,05 (25,4).

1H-NMR (200z, CDCl3), (ppm): 1,42 is 2.01 (m, 8H, CH2endoc., ; 2,45 [t, 2H, J = 7,3 Hz ; 2,61 - 2,81 [m, 7H, CH and CH2

Here follow the same process as described in example 14, on the basis of hydrochlorate obtained in example 9.

MS, m/z (rel. range: 366,25 (M++2; 2,8); 365,25 (M++1; 21,4); 364,25 (M+; 77,7); 205,5 (100,0); 192,15 (30,7); 150,05 (24,5); 91,05 (21,3).

1H-NMR (200MHz, CDCl3), (ppm): 1,54 - of 1.92 (m, 8H, CH2CH2endoc., ; 2,45 [broad t, 2H, ]; 2,62 - 2,88 [m, 7H, CH and CH2benz. , ]; 3,12 [broad s, 4H, ]; 3,86 (s, 3H, CH3); 6,82 - 7,21 (m, 8H, arom.).

Hydrochlorot: so pl. 223 - 224oC.

Example 22. 4-[4-(6-methoxy-1,2-dihydronaphthalene-4-yl)-n-butyl] -1-(2-methoxyphenyl) piperazine.

7-methoxy-1-tetralone (6 mmol), the solubilized in tetrahydrofuran (10 ml) and added to a solution of 4-chloro-n-butylacrylamide (9 mmol) in tetrahydrofuran. The method is carried out as described in example 2. Through the corresponding intermediate crude product (VI), where p = 2, to get the desired product in the form of oil with a total yield of 60%.

MS, m/z (rel. range: 408,25 (M++2; 4,7); 407,25 (M++1; 29,2); 406,35 (M+; 99,9); 205,10 (22,9).

1N-NMR (200MHz, CDCl3), (ppm): 1,50 - of 1.73 (m, 4H, ; 2,14 - 2,19 (m, 2H, CH2endoc.); 2,38 - of 2.54 (m, 4H, ; 2,61 - 2,80 [m, 6H, CH2benz., ]; 3,12 [broad t, 4H, (CH2)2NAr]; 3,79 (s, 3H), 3,86 (s, 3H), (2 CH3); by 5.87 (t, 1H, J = 5 Hz, H vin.); 2,3,4-tetrahydronaphthalen-1-yl)-n-butyl] piperazine. Following the method described in example 14, and on the basis of the relevant product, described in the previous example 22, to obtain the desired product with a yield of 87%.

The following analyses are conducted on a free basis:

MS, m/z (rel. range: 410,35 (M++2; 2,9); 409, 25 (M++1; 20,9); 408,25 (M+; 75,8); 205,10 (100,0).

1N-NMR (200MHz, CDCl3), (ppm): 1.30 and of 1.92 (m, 10H, CH2CH2endoc., ); 2,44 [t, 2H, J = 7,6 Hz ]; 2,62 - 2,83 [m, 7H, CH and CH2benz., ]; 3,18 [broad s, 4H, (CH2)2NAr]; of 3.78 (s, 3H), 3,86 (s, 3H), (2 CH3); 6,63 - 7,02 (m, 7H, arom.).

Hydrochlorot: so pl. 192 - 193oC.

Example 24. 1-(2-methoxyphenyl)-4-{2-[(7-methoxy-1,2,3, 4-tetrahydronaphthalen-1-yl)-thio]-ethyl}piperazine.

Ethyl-2 - mercaptoacetate (6 mmol) and ZnI2(3 mmol) are added to a solution of 7-methoxy-1-tetralone (6 mmol) (obtained according to the method of 7-methoxy-1-tetralone) in CH2Cl2(12 ml). After 2 h after stirring the reaction mixture was poured into water and extracted with CH2Cl2. Extracted solution was dried over Na2SO4and the solvent is evaporated, thereby obtaining a yellow oil, consisting of almost pure ethyl 2-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-thio] - acetate (yield 98%). This product directly hydrolyzing KOH in an aqueous solution of alcohol podkisst HCl and extracted with Et2O. After evaporation of the solvent receive light yellow solid, which crystallized from cyclohexane.

This way you will be given a product that belongs to the F-type, with a yield of 89%.

2-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)thio] - acetic acid (5 mmol) is treated with 5 - 6 ml SOCl2and heated in a vacuum and evaporated to dryness in a rotary evaporator.

The resulting crude oil is treated with the appropriate acid chloride, dissolved in toluene (20 ml) and allowed to interact by boiling under reflux with a solution of 1-(2-methoxyphenyl) piperazine (8 mmol) in toluene (30 ml) in the presence of trimethylamine (10 mmol). After 2 h the reaction mixture was washed with water and 2N HCl.

The organic phase is dried and evaporated, bring to an oil residue, which clean the chromatographic column, and thereby obtain the corresponding 4-(2-methoxyphenyl) piperazine the above-mentioned acid as a yellow-brown oil with a yield of 47%.

This amide (2 mmol) dissolved in tetrahydrofuran (20 ml) is added dropwise to a suspension of LiAlH4(100 mg) in 30 ml of tetrahydrofuran under stirring. The mixture was kept at boiling point in the most light-yellow oil with a yield of 83%.

The product is then converted into the corresponding hydrochloric and crystallized from CHCl3/petroleum ether; so pl. 200 - 201oC.

The following analyses are conducted on the free base: MS, m/z (rel. range: 414,25 (M++2; 1,4); 413,25 (M++1; 4,7); 412,35 (M+; 17,4); 219,20 (24,0); 205,10 (100,0); 190,10 (29,5).

1N-NMR (200MHz, CDCl3), (ppm): 1,67 - 2,10 (m, 4H, CH2CH2endoc.); 2,56 - 2,85 [m, 10H, CH2benz. , SCH2CH2N(CH2)2]; 3,10 [broad t, 4H, (CH2)2NAr] ; of 3.78 (s, 3H), 3,86 (s, 3H), (2 CH3); 4,12 (t, 1H, J = 4 Hz, CHS); 6,67? 7.04 baby mortality(m, 7H, arom.).

Example 25. 4-[1-(8-methoxy-1,2,3,4-tetrahydronaphthalen-4-yl)-1 - propene-3-yl]-1-(2-methoxyphenyl)piperazine.

8-methoxy-1-tetralone (6 mmol), the solubilized in tetrahydrofuran (10 ml) and added to a solution of cyclopropylmagnesium (9 mmol) in tetrahydrofuran (10 ml) and leave boiling under reflux for 1 hour.

The mixture is cooled, and the solution is saturated by the addition of ammonium chloride. The organic phase is washed with water, removed to dryness and the crude reaction product, consisting mainly of 1-cyclopropyl-8 - methoxy-1,2,3,4-tetrahydronaphthalen-1-ol is obtained in the form of a dark oil. The right mixture is treated with HCl solution in dilute acetic acid. The mixture is maintained at whom the offer and get a dark oil, which clean chromatographic column; the product is marked with the full output 64%, consists of 4-(3-chloro-1-propene-1-yl)-8-methoxy-1,2,3,4 - tetrahydronaphthalene intermediate compound (VI) with p = 1.

1-(2-methoxyphenyl) piperazine (3.5 mmol) are added to a solution of compound (VI-A) (3.5 mmol) in dimethylformamide (10 ml) in the presence of NaI (catalytic amount) and sodium carbonate (3.5 mmol). The mixture was kept boiling under reflux for 1 h, then cooled, and after evaporation of dimethylformamide, the residue diluted with water and extracted with CHCl3. After evaporation of the solvent, the obtained residue is cleaned chromatographic column, thus obtaining the desired product as a pale yellow oil (yield 82%).

MS, m/z (rel. range: 393,25 (M++1; 2,0); 392,25 (M+7,1); 205,10 (100,0).

1N-NMR (200MHz, CDCl3), (ppm): 1,82 (m, 2H, CH2endoc.); 2,42 - to 2.65 (m, 6H, ; 2,67 - 2,85 [m, 6H, CH2benz., ; 3,15 [broad s, 4H ]; 3,81 and 3,86 (2S, 6H, 2CH3); 6,00 (broad, s, 1H, H vin.); 6,65 - 7,22 (m, 7H, arom.).

Hydrochlorot: so pl. 202 - 203oC.

Example 26. 4-[1-(8-methoxy-1,2,3,4-tetrahydronaphthalen-4-yl)-1 - propene-3-yl]-1-(2-pyridyl)piperazine.

Here follow the process described in example 25, based on hydrochlorate, 200MHz, CDCl3), (ppm): 1,82 (m, 2H, CH2endoc.); 2,37 - 2,66 [m, 10H, ]; a 2.71 (t, 2H, J = 6,3 Hz, CH2benz.); 3,49 - 3,62 [m, 4H, ]; 3,81 (s, 3H, CH3, 6,00 (broad t, 1H, H vin.); 6,56 - 7,53 (m, 6H, arom.); 8,14 - of 8.25 (m, 1H, N=CH arom.).

Hydrochlorot: so pl. 221 - 222oC.

Example 27. 1-(2-methoxyphenyl)-4-[1,2,3,4 - tetrahydronaphthalen-4-yl)-1-propene-3-yl]piperazine.

Here follow the process described in example 25, based on hydrochlorate obtained in example 9.

MS, m/z (rel. range: 363,20(M++1; 1,4); 362,20 (M+; 5,5); 205,05 (100,00); 190,05 (21,6).

1H-NMR (200MHz, CDCl3), (ppm): 1,82 (m, 2H, CH2endoc.); 2,40 - 2,60 [m, 6N, ; 2,64 - 2,80 [m, 6N, CH2benz., ]; 3,12 [broad s, 4H, ]; 3,85 (s, 3H, CH3); 6,00 (broad t, 1H, H vin.); 6,83 to 7.62 (m, 8H, arom.).

Hydrochlorot: so pl. 198 - 199oC.

Getting homogenate of cerebral tissue of rats for experiments on receptor binding

Preparation of 1 is used for experiments on binding to receptors

5-HT1A, 5-NTV, 5-NTS, 5-HT2, D-2, D-1, - 1.

Cerebral tissue extracted (asported) of male rats (Sprague Dawley) weighing 180 - 220 g homogenized in Tris. HCl buffer, 50 mmol/l, pH 7,4 c Ultra-Turrax (220 seconds) and centrifuged at 50000g for 10 minutes the precipitate is re-suspended in the same volume of buffer, incubated at 37oC for 10 milestown incubation buffer to test for receptor binding.

Preparation of 2 is used for experiments on binding to the receptor.

Cerebral tissue of male Guinea pigs Hattly cavy (Charles River) weighing 300 - 600 g homogenized of 0.32 M sucrose c Ultra-Turrax (220 ° c) and centrifuged at 900 g for 10 min. the Supernatant centrifuged at 22000 g for 20 minutes the precipitate was dissolved in Tris. HCl buffer pH of 7.4, incubated at 37oC for 30 min, and centrifuged at 22000 g for 20 minutes

The precipitate is dissolved incubated in the appropriate buffer prior to testing.

Working conditions for experiments on receptor binding

5-HT1A receptor. Mostly use the methodology described by J. R. Schlegel, Biochem. Pharmacol. 35, 1943 (1986). In short, the homogenate of cerebral cortical layer rats dissolve incubated in buffer (Tris. HCl 50 mmol, pH of 7.7 containing 10 micromoles of pargyline, 4 mmol CaCl2), with 0.1% ascorbic acid) and incubated in a final volume of 1 ml at 25oC for 30 min in the presence of 3H-80H-DPAT (0.1 nmol). Spetsificheskoe binding assessed using a 5-HT (10 micromoles).

5-NTV receptor. Mostly use the methodology described S. J. Peroutka, J. Neurochem. 47, 529, 1986.

In short, the homogenate polos is 4 mmol CaCl2, of 0.1% ascorbic acid) and incubated in a final volume of 1 ml at 25oC for 30 min in the presence of ZN-NT (2.0 nmol) and 80H-DPAT (0.1 micromoles) as blocking agent for 5-HT1A receptors. Spetsificheskoe binding assessed using a 5-HT (10 micromoles).

5-NTS receptor. Mostly use the methodology described S. J. Peroutka, J. Neurochem. 47, 529, 1986.

In short, the homogenate of cerebral cortical layer rats dissolve incubated in buffer (Tris. HCl 50 mmol, pH of 7.7 containing 10 micromoles of pargyline, 4 mmol CaCl2, of 0.1% ascorbic acid), and incubated in a final volume of 1 ml at 25oC for 15 min in the presence of ZN-NT (2.0 nmol) and 80H-DPAT (0.1 micromoles) and EN-24960 (10 nmol) as a blocking agent, respectively, 5-HT1A and 5-NTV receptors. Spetsificheskoe binding assessed using a 5-HT (10 micromoles).

5-HT2 receptor. Mostly use the methodology described by A. K. Mir, Eur. J. Pharmacol. 149, 107, 1988.

In short, the homogenate frontal cortical rat dissolve incubated in buffer (Tris. HCl 50 mmol, pH of 7.7) and incubated in a final volume of 1 ml at 37oC for 15 min in the presence of 3H-Ketanserina (0.35 nmol). Spetsificheskoe connect is ologie, described by W. C. Billard, Life Science, 35, 1885, 1984.

In short, the homogenate strips of rat tail dissolve incubated in buffer (Tris. HCl 50 mmol, pH of 7.4, containing 120 mmol. NaCl, 5 mm KCl, 2 mm CaCl2, 1 mmol MgCl2), and incubated in a final volume of 1 ml at 37oC for 15 min in the presence of 3H-SCH-23390 (0.3 nmol). Spetsificheskoe linking evaluate the use of SCH-23390 (1 micromoles).

D-2 receptor. Mostly use the methodology described l. Creese, Eur. J. Pharmacol. 49, 201, 1978.

In short, the homogenate strips of rat tail dissolve incubated in buffer (Tris. HCl 50 mmol, pH of 7.4, containing 120 mmol NaCl, 5 mmol KCl, 2 mm CaCl2, 1 mmol MgCl2) and incubated in a final volume of 1 ml at 37oC for 15 min in the presence of 3H-Spiroperidol (0.25 mmol) and Ketanserina (40 nmol) as blocking agent for 5-HT2 receptors. Spetsificheskoe binding estimate using Butaclamol (10 micromoles).

-1 receptor. Mostly use the methodology described by A. K. Mir. Eur. J. Pharmacol. 149, 107, 1988.

In short, the homogenate of cerebral cortical layer rats dissolve incubated in buffer (Tris. HCl 50 mmol, pH of 7.7 containing 10 micromoles of pargyline, 0,1% ASCO,2 nmol). Spetsificheskoe linking evaluate the use of Prazosin (3 micromoles).

the receptor. Mostly use the methodology described E. Weber, Proc. Natl. Acad. Sci. USA. 83, 8784 (1986).

In short, the rat brain without cerebellum, homogenized and then dissolve incubated in buffer (Tris. HCl 50 mmol, pH of 7.4) and incubated in a final volume of 1 ml at 25oC for 90 min in the presence of 3H-DTG (0.9 nmol). Spetsificheskoe linking evaluate the use of Haloperidol (1 micromoles).

Behavioral experiments

Evaluation of 5-HT1A activity "in vivo".

The considered compounds analyzed using the method described Tricklebank (Eur. J. Pharmacol., 106, 271, 1985). The considered compounds is injected subcutaneously to male rats (S. D. ), treated with reserpine (1 mg/Kg) for 18 h before the test. Assessment of behavior begin within 3 min after the introduction of the considered compounds, and continue for the next 30 minutes the intensity of the behaviors assessed every 3 min scale, which considers the following table to two specific behaviors, called "Flat body posture and step to the front legs

0: no behavioral effects;

1: the presence of questionable behavioral signtext.

Possible agonistic activity of the products considered were evaluated every 3 min for 30 min after their administration. Antagonistic activity on the stereotype induced 80H-DPAT (0.125 mg/kg s.c.) assessed every 3 minutes for 30 - 60 minutes after administration of the products considered, starting 3 min after injection N-DPAT.

The results of the above experiments are shown in table.1, 2 and 3.5

1. N(hetero)-aryl-N - (hetero)-tetralin-alkyl-piperazines of General formula (I)

< / BR>
where Ar1is phenyl or thienyl condensed with a 5-6-membered carbocyclic ring;

R1and R2are the same or different and mean hydrogen or C1- C5-alkoxy;

Ar2selected from phenyl, unsubstituted or substituted methoxy group, halogen, triptorelin group, or a pyridyl radical;

group

< / BR>
selected from

< / BR>
< / BR>
n = 1 or 2;

m = 2 or 3,

and its pharmaceutically acceptable salts.

2. The compound of General formula I on p. 1, representing a compound of formula IB

< / BR>
where R1, R2, Ar2and group

< / BR>
has the above values,

n = 2

m = 1 or 3,

and its pharmaceutically acceptable is 2">

4. The compound of formula I according to any one of paragraphs.1 to 3, where Ar2selected from 2-methoxyphenyl, 3-chlorphenyl, 3-triptoreline, 2-pyridyl or 2.5-acid. 5. Connection on p. 2 (General formula IB, where balance

< / BR>
is dihydronaphthalene group and Ar2represents phenyl or substituted phenyl group selected from:

4-[3-(6-methoxy-1,2-dihydronaphthalene-4-yl)-n-propyl] -1-(2-methoxyphenyl)- piperazine;

1-phenyl-4-[3-(8-methoxy-1,2-dihydronaphthalene-4-yl]-n-propyl]-piperazine ;

4-[3-8-methoxy-1,2-dihydronaphthalene-4-yl)-n-propyl] -1-(2-methoxyphenyl)- piperazine;

4-[3-(-1,2-dihydronaphthalene-4-yl]-n-propyl]-1-2-methoxyphenyl)piperazine;

4-[4-(6-methoxy-1,2-dihydronaphthalene-4-yl] -n-butyl] -1-2-methoxyphenyl)- piperazine;

-(3-chlorophenyl)-4-[3-(8-methoxy-1,2-dihydronaphthalene-4-yl] -n-propyl] - piperazine;

-4-[3-(8-methoxy-1,2-dihydronaphthalene-4-yl] -n-propyl] -1-(3-triptoreline)-piperazine,

and their pharmaceutically acceptable salts.

6. Connection on p. 2 (General formula IB, where balance

< / BR>
is tetrahydronaphthalene group and Ar2represents phenyl or substituted phenyl group selected from

1-(2-methoxyphenyl-4-[N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-2 - Amin-phenyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]-piperazine;

1-(2-methoxyphenyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-propyl]-piperazine;

1-(2-methoxyphenyl-4-[3-(4,5,6,7-tetrahydronaphthalen-1-yl)-n-propyl]-piperazine;

1-(2-methoxyphenyl-4-[4-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-butyl]-piperazine;

1-(2-methoxyphenyl-4-[3-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-thio] -ethyl}-piperazine;

4-[1-(8-methoxy-1,2,3,4-tetrahydronaphthalen-4-yl)-1-propene-3-yl] -1-(2-methoxyphenyl)-piperazine;

1-(2-methoxyphenyl-4-[1,2,3,4-tetrahydronaphthalen-4-yl)-1-propene-3-yl] - piperazine;

4-[3-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl-1-3-triptoreline)-piperazine; and their pharmaceutically acceptable salts.

7. Connection on p. 2 (General formula IB, where Ar2is pyridyloxy group, and compounds selected from

4-[3(8-methoxy-1,2-dihydronaphthalene-4-yl)-n-propyl] -1-(2-pyridyl)-piperazine;

4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl] -1-(2-pyridyl)-piperazine;

4-[3-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl] -1-(2-pyridyl)-piperazine; 4-[3-(8-methoxy-1,2,3,4-tetrahydronaphthalen-4-yl)-1-propene-3-yl]-1-(2-pyridyl)-piperazine;

and their pharmaceutically acceptable salts.

8. The method of obtaining the compounds of formula (I) under item 1, where the group is a
<, who then interact ketone of General formula II

< / BR>
Ar1, R1, R2n have the meanings as defined above, with a compound of formula III

< / BR>
where m and Ar2have the meanings as defined above,

in apolar solvent by boiling under reflux in the presence of catalytic amounts of acid, and the compound obtained of General formula IV

< / BR>
where Ar1, R1, R2n, m and Ar2have the meanings as defined above,

subjected to reduction with sodium borohydride in a polar solvent at room temperature.

9. The method of obtaining compounds of General formula I on p. 1, where the group

< / BR>
selected from

< / BR>
< / BR>
Ar1, R1, R2, m, n and Ar2have the meanings as defined above, under item 1,

characterized in that a ketone of General formula II, as defined under item 8, is subjected to the interaction with the Grignard reagent

R3-MgX,

where R3- cyclopropyl or -(CH2)4Cl;

X is a halogen atom,

in ethereal solvent, thereby obtaining a compound of General formula (V)

< / BR>
where Ar1, R1, R2, R3and n have the meanings as defined above,

which is
where Ar1, R1, R2and n have the meanings as defined above, and where either p is equal to 1 if in the compound of the formula V R3is cyclopropyl, or p = 2, if R3represents -(CH2)4-Cl, in turn, process the aryl-piperazine of the formula VII:

< / BR>
where Ar2matter, as defined above, thus obtaining a compound of General formula I, where

< / BR>
represents a group

< / BR>
and, if desired, carry out the interaction of the compounds of formula I, obtained in the previous phase, with hydrogen in the presence of catalysts containing noble metals, in a polar solvent, thereby obtaining a compound of General formula I, where

< / BR>
represents a group

< / BR>
10. The method of obtaining compounds of General formula I on p. 1 and its pharmaceutically acceptable salts, where the group

< / BR>
is

< / BR>
m = 2;

Ar1, R1, R2, n and Ar2have the meanings as defined under item 1, characterized in that interact ketone of General formula II, as defined in paragraphs 8, with a regenerating agent, to obtain the compounds of General formula VIII

< / BR>
Ar1, R1, R2and n have the meanings as unisom the corresponding ester of General formula IX

< / BR>
where Ar1, R1, R2and n have the meanings as defined above,

which sequentially hydrolyzing the corresponding acid and process the acid with thionyl chloride to obtain acylchlorides General formula X

< / BR>
where Ar1, R1, R2and n have the meanings as defined above, which, in turn, is subjected to the interaction with arylpiperazine General formula VII, as defined under item 9, to obtain the compounds of General formula XI

< / BR>
where Ar1, R1, R2, n and Ar2have the meanings as defined above, which is treated with LiAlH4.

 

Same patents:

The invention relates to the field of organic synthesis and relates to new organic compounds, method of their obtaining for several options and pharmaceutical compositions containing these compounds

The invention relates to the field of chemistry, to a method for the chemical substance that manifests anthelminthic properties, and can be used in agriculture to treat animals

The invention relates to piperazinone derivatives, to processes for their production, to their use and to the containing pharmaceutical compositions

The invention relates to a compact, crystalline 3-cyan - 2-morpholino-5-(pyrid-4-yl)-pyridine with high apparent (bulk) density and method thereof

The invention relates to new derivatives of 2-aminobenzothiazole, and to their use in pharmaceutical compositions having activity against convulsions induced by glutamate

The invention relates to pharmaceutical facilities intended for use orally, in particular to the pharmaceutical agent in the form of microcapsules and method thereof

The invention relates to heterocyclic amines of formula I:

,

in which

X represents-CH2-group or-S-group;

B denotes a group selected from a number containing-CO -, - CH2OCO-, -CH2OCS-, -CH2NHCO - CH2NHCS-group;

D represents benzhydryl or phenyl group, optionally substituted by halogen atoms, and heterocyclic group, selected from a number containing 1,3,5-triazine-2-yl, pyridin-2-yl and pyrimidine-4-yl, and optionally substituted by one or two substituents selected from the group comprising amino, mono - or di-(C1C6) alkylamino, mono- (C3-C7)-alkynylamino, mono-(C3-C7)-quinil-amino group and pyrrolidin-1-yl group;

The is a simple carbon-carbon bond or a group of the formula: -CH2CH2or CRaRb-, where Raand Rbis a hydrogen atom, (C1-C3)alkyl, or taken together with the carbon atom to which they are attached, form a (C3-C6) cycloalkyl;

A is selected from the group comprising (a) carboxyl group optionally esterified (C1-C4) Ukrspirt the crystals: -CОNHRgOH, where Rcand Rdidentical or different, represent a hydrogen atom, (C1-C6) alkyl, benzyl, pyridin-2-yl, or taken together with the nitrogen atom to which they are bound, form piperidino, morpholino-, 4-thiomorpholine-, 4,5-diazepino, 4-(C1-C4)alkylpiperazine; Rfis a tolyl; Rgis a (C1-C4) alkyl;

(b) (C1-C3) alkyl;

(c) the group-NRcRdwhere Rcand Rddefined above,

(d) a cyano, if "y" does not mean a simple carbon-carbon bond

in the form of S-enantiomers, diastereomers, in the form of various racemic mixtures and their salts with pharmaceutically acceptable acids and bases

The invention relates to the compounds and their pharmaceutically acceptable salts and methods for treating HIV infections and related viruses and/or treatment of acquired immunodeficiency syndrome (AIDS)

The invention relates to a new use some diphenylmethyl-piperazinecarboxamide, in particular amperozide, 4 [4,4-bis(forfinal)butyl] N-ethyl-1-piperazinecarboxamide and their salts in the treatment of substance abuse

The invention relates to pharmaceutical industry concerns (l)-(-)-2(aminocarbonyl)-N-(4-amino-2,6-dichlorophenyl) -4-[5,6-bis(4-forfinal)pentyl]-1-piperazineethanol, its pharmaceutically acceptable acid additive salt or hydrate and method of its production

Imidazopyridine // 2092487
The invention relates to certain imidazoquinolines that selectively bind to the GABA-a receptors

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

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

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

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

14 cl, 36 ex

FIELD: medicine, oncohematology.

SUBSTANCE: the present innovation deals with treating elderly patients with chronic lympholeukosis accompanied with cardiovascular failure. The method deals with applying chemopreparations and cytoprotector. Moreover, 1 wk before the onset of chemotherapeutic therapy one should prescribe preductal at the dosage of 105 mg daily. At this background one should sample blood out of elbow vein at the volume of 200 ml into a vial with glugicir to centrifuge it, isolate plasma, divide into two portions, add into the 1st vial - cyclophosphan 600-800 mg/sq. m, vincristin 1.4 mg/sq. m, into the 2nd vial - adriamycin 50 mg/sq. m to be incubated for 30 min at 37 C and intravenously injected by drops for patients. Simultaneously, the intake of prednisolone should be prescribed at the dosage of 60 mg/sq. m since the 1st d and during the next 5 d and preductal at the dosage of 105 mg daily during a week, and then 2 wk more at the dosage of 60 mg daily. All the procedures should be repeated in above-mentioned sequence 4-6 times. The method enables to decrease toxic manifestations of chemotherapy while applying adequate dosages of cytostatics, anthracycline antibiotics, among them, at no great manifestations of their toxicity due to preductal's cardioprotective action.

EFFECT: higher efficiency of therapy.

1 ex, 5 tbl

FIELD: medicine, cardiology.

SUBSTANCE: it is suggested to apply cortisol antagonists in addition to clonidine while manufacturing preparation to treat heart failure. Moreover, one should introduce cortisol antagonist or a product that includes cortisol antagonist along with the second medicinal preparation being a combined preparation to be applied either simultaneously, separately or successively. The present innovation provides decreased symptoms of heart failure at decreasing cardiac muscle's fibrosis and heart sizes due to preferable impact upon glucocorticoid receptors in patient's heart and/or kidneys.

EFFECT: higher efficiency of application.

12 cl, 2 ex

Up!