Bicyclic nitrogen-containing derivatives or their salts with mineral and organic acids or bases, methods for their preparation and pharmaceutical composition based on them

 

(57) Abstract:

Usage: in medicine as a highly effective antagonists to the receptors of angiotensin II. The inventive products of formula (I), where R2Band R3Bsame or different: hydrogen, lower alkyl, lower foralkyl and thioalkyl, A1B, A2B, A3Band A4Bis carbon or nitrogen, and at least one and maximum two of them represent a nitrogen atom and at least one of them is Metin; R3is hydrogen, hydroxyl, alkyl, hydroxyalkyl, phenyl, alkoxycarbonyl, thioalkyl; R4is hydrogen, hydroxyl, arylalkyl, Allakaket, aryloxy, arylamino. Reagent 1: compound f-crystals (II). Reagent 2: compound of the formula R'4B-CH-(COo2alk-CO-R4Bwhere the values R'2B, R'3Bhave the values of R2Band R3B, R'4B, R4Bhave the values of R4in which reactive groups may be protected, alk - C1- C6-alkyl, the resulting connection f-crystals (III) is subjected to cyclization. Reaction conditions: in a medium of an organic solvent. 5 N. and 2 C.p. f-crystals.

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c

Example 10. 4-[(2-butyl 4-chinoline)oxy]ethylbenzoic.

Enter 0,950 g of the product obtained in stage a is s 170oC. After cooling, the reaction medium is subjected to chromatography on silica (eluant:hexane-ethyl acetate (9:1)). The result of 0.250 g of the target product.

Infrared spectrum (CHCl3):

C=O - 1714 cm-1< / BR>
A heterocycle - 1621, 1609, 1598,

and aromatic compound - 1564, 1498 cm-1< / BR>
Example 11. Hydrochloride 4-[[2-butyl 4-chinoline)oxy]benzoic acid.

a) 4-[(2-butyl 4-chinoline)oxy]benzoic acid

250 mg of the product obtained in example 10, is introduced into 6 cm32 N. sodium hydroxide and 5 cm3ethyl alcohol. Then heated to 80oC for 1 h, evaporated ethanol and collect water.

b) Preparation of the hydrochloride.

In the above solution add 2 N. hydrochloric acid to pH = 1, filtered, washed with water, dried and subjected to product recrystallization from pentane. Then dried at a temperature of 60oC under reduced pressure in the presence of phosphorus pentoxide. Thus obtain 204 mg of the target product.

Chemical composition C20H19NO3,HCl = 357,84

% calculated: C = 67,13; H = 5,63; N = 3,91; Cl = to 9.91;

% obtained: C = 67,1; H = 5,5; N = 3,8; Cl = 9,9.

Infrared spectrum (liquid paraffin)mechanical connection 1538, 1500, 1490 cm-1< / BR>
Example 12. Hydrochloride 4-[(2-butyl 4-chinoline)amino]benzoic acid.

0,840 g of the product obtained in step G preparation of example 3, and 0,640 g aminobenzoic acid injected into 15 cm31 N. hydrochloric acid. Then heated at boiling temperature for 3 h, the precipitate filtered, washed with water and dried at a temperature of 60oC under reduced pressure. So get 0,830 g of the target product.

Chemical composition C20H20N2O3,HCl = 356,85

% calculated: C = 67,32; H = 5,93; N = 7,85; Cl = to 9.93;

% obtained: C = 67,1; H = 5,9; N = 7,7; Cl = 9,6.

Infrared spectrum (liquid paraffin):

The absorption in the region of the OH/NH

C=O - 1710 cm-1< / BR>
Aromatic compound - 1640, 1613, 1591,

+heterocycle - 1554, 1517, 1495 cm-1< / BR>
Example 13. 4'-[(3-butyl 4-indolinyl)methyl](1,1'-biphenyl)-2-methyl carboxylate.

Operations are as in example 1, on the basis of 1.1 g of the product obtained at stage In the preparation of the above example of 1.83 g of 4-(methyl bromide)(1,1'-biphenyl)-2-methyl carboxylate (prepared according to patent EAS 253310), 0.4 g of electrolytic zinc, 700 mg of tetrakis (triphenylphosphine) palladium in 100 cm3Tetra is the comfort with ethyl acetate. The organic phase is washed with water, dried and evaporated. After chromatography on silica (eluant:methylene chloride-acetonitrile (8:2)) to obtain 760 mg of the target product.

Infrared spectrum (CHCl3)

C=0 - 1720 cm-1< / BR>
Conjugated system + - 1614, 1599, 1567,

aromatic compound - 1535, 1515 cm-1< / BR>
Preparation of product used at the beginning of the example 13: 3-butyl-4-carcinosin.

Step A. 2-(1-hexenyl)benzolamide.

In a solution of 4.4 g of 2-iodoaniline 100 cm3of triethylamine added 32 mg of copper iodide, 140 mg of chloride bis(triphenylphosphine) palladium and 2.3 cm31-hexyne. Then shaken for 15 h at room temperature Then evaporated to dryness and taken in ether, filtered insoluble fraction, wash it with ether, then the ether fractions evaporated to dryness. The residue is subjected to chromatography on silica (eluant : hexane-ethyl acetate (9 : 1)). The result of 3.27 g of the target product.

The infrared spectrum

C6H4-NH2- 3486 cm-1< / BR>
NH2deformation or separation. + aromatic compound - 1613, 1570, 1493 cm-1< / BR>
Stage B: 3-butyl 4-hydroxycinnamic

In a suspension with a temperature of 0oC 3.2 g product is collected at a temperature of 0oC a solution of 2 g of sodium nitrite in 60 cm3water, shake for 1 h 30 min at a temperature of 0oC and then for 1 h at a temperature of 100oC. Then the reaction medium was poured into 100 cm3ice-cold water, centrifuged and washed with ice-cold water. The wet product take 100 cm3water and alkalinized with concentrated ammonia. Then centrifuged, washed with water and dried at a temperature of 70oC under reduced pressure. Thus obtain 1.47 g of the target product (pl. t = 180oC).

Infrared spectrum (liquid paraffin):

The absorption in the region of the OH/NH

C=C - 1636 cm-1< / BR>
+ - 1604 cm-1(space)

aromatic compound - 1580 cm-1- 1578 cm-1- 1498 cm-1< / BR>
Step C. 3-butyl 4-carcinosin.

Operations are performed, as in Step E of preparation 1, using 1.2 g of the product obtained in the above step B, using a 10 cm3oxychloride of phosphorus. After chromatography on silica (eluant : hexane-ethyl acetate (6 : 4)) gain of 1.16 g of the target product (pl. t < 50oC).

Infrared spectrum (CHCl3):

C=C+ - 1616, 1558 cm-1< / BR>
aromatic compound -

Example 14. 4'-[(3-butyl 4-Zinal is a, obtained in example 13, 10 cm32 N. sodium hydroxide and 20 cm3ethyl alcohol. The reaction medium is brought to the boiling temperature for 2 h, then poured into water and acidified by adding concentrated hydrochloric acid. The precipitate is washed with water, dried under reduced pressure and subjected to recrystallization from 20 cm3acetonitrile as a result, 0.27 g of the desired product (pl. t = 210oC).

Chemical composition C26H24N2O3, HCl = 396,489

% calculated: C = 78,76; H = 6,1; N = 7,06;

% obtained: C = 78,6; H = 6,0; N = 7,1.

Infrared spectrum (liquid paraffin):

The absorption in the region of the OH/NH

C=0 - 1718 cm-1< / BR>
Conjugated system + - 1622, 1598, 1576,

aromatic compound - 1558, 1522 cm-1< / BR>
Example 15. 4-[[(3-butyl 4-indolinyl)oxy]methyl]benzonitrile.

Operations are performed as in example 6, on the basis of the product obtained at stage B of preparation example 13 and 4-(methyl bromide) benzonitrile.

Example 16. 4-[(3-butyl-4-indolinyl)oxy]methyl]benzoic acid.

Operations are as in example 7, on the basis of the product obtained in example 15.

Example 17. 4'-[[(3-butyl-5-methylthio 4-chinoline)oxy]methyl] the obtained in Step G above preparation, and 1.63 g of 4-(methyl bromide) (1,1'-biphenyl)-2-methyl carboxylate (prepared according to patent EEC 0253310) 50 cm3acetone and add 1.2 g of potassium bicarbonate. The reaction medium is brought to boiling point for 2 hours Then the suspension is centrifuged, and the insoluble fraction was washed with acetone, filtered and dried. After chromatography on silica (eluant : ethyl acetate-hexane (5 : 5)) to obtain 1.8 g of the target product.

Infrared spectrum (CHCl3):

- 1720, 1435 cm-1< / BR>
Aromatic compound - 1600, 1593, 1557,

+ heteroatom - 1505, 1483 cm-1< / BR>
Preparation example 17. 3-butyl-5-methylthio 4-(1H)-hinolan.

Step A. 2-butyl 3-[[3-(methylthio)phenyl]amino]2-butenedioate of diethyl.

In a solution of 4.3 g of 2-butyl-3-oxo of butanedioate of diethyl 2 cm33-(methylthio)analine 100 cm3of toluene are added 50 mg of paratoluenesulfonyl. Then shaken for 4 h at the boiling point, removing the formed water. Then is evaporated to dryness and the residue is subjected to chromatography on silica (eluant : methylene chloride with 30% hexane). The result of 5.1 g of the desired product (pl. t = 55oC).

Infrared SP is s - 1598, 1583, 1488 cm-1< / BR>
Preparation of 2-butyl-3-oxo of butanedioate of diethyl.

In the solution ethylate sodium, obtained by shaking for 1 h at 40oC 2.3 g of sodium and 150 cm3ethanol was added 100 cm3ether, and then 13,55 cm3diethyloxalate. Then heated for 15 min at boiling point, cool slightly and add 50 cm3kaproata ethyl, shaken for 3 h at boiling temperature and for 16 hours at a temperature of 30-35oC. then add 50 cm3water, separating the aqueous phase by the method of sedimentation, washed twice with ether and acidified with 2 N. hydrochloric acid. Then extracted three times using ether, the organic phase is washed with water and then a saturated solution of sodium chloride, dried and evaporated to dryness. After receiving the product 9.5 g use without additional transformations for the next stage.

Step B. 3-butyl 1,4-dihydro 5-(methyltin) 4-oxo-2-quinoline carboxylate ethyl.

Within 45 minutes at a temperature of 250oC heat 1 g of the product obtained in step A. Then, the crude reaction product is cooled and chromatographic on silica (eluant : methylene chloride). In the floor is lexn. - 3330 cm-1(F)

C=O - 1743, 1707 (f) cm-1< / BR>
C=O+C=C+ - 1610, 1596,

aromatic compound - 1559, 1530 cm-1< / BR>
Step C. the Hydrochloride of 3-butyl 1,4-dihydro 5-(methylthio) 4-oxo-2-quinoline carboxylic acid

Within 2 hours at the boiling temperature shaken to 0.63 g of the product obtained in the above step B, 10 cm31 N. sodium hydroxide solution. Then poured into ice water, acidified with concentrated hydrochloric acid, centrifuged, washed with water, dried and concentrated to 100 cm3ethyl acetate. The result is 495 mg of the desired product (tpl.= 240oC).

Infrared spectrum (liquid paraffin):

The absorption in the region of the OH/NH - 3328 cm-1< / BR>
C=O - 1744 cm-1< / BR>
C=O + C=C + - 1610, 1592, 1560,

aromatic compound - 1540, 1516 cm-1< / BR>
Phase, 3-butyl 5-(methylthio) 4(H)-hinolan.

Within 5 min at a temperature of 260oC heated 390 mg of the product obtained at stage C. the result is 300 mg of the target product (pl. t = 144oC).

Infrared spectrum (CHCl3):

=C-NH - 3365 cm-1< / BR>
C=O + C=C+ - 1627, 1609, 1585

aromatic compound - 1560, 1520 cm-1< / BR>
Example 18. Salt diethylamine 4'-[[(3-butyl 1,4-dihydro 5-(matilla a mixture of 1.8 g of product, obtained in example 17, with 20 cm35 n sodium hydroxide solution in 20 cm3ethyl alcohol. Then the solution is poured into water and acidified with hydrogenphosphate sodium, extracted with ethyl acetate, washed with water, dried, and evaporated to dryness. After that, perform chromatography on silica (eluant : methylene chloride-methyl alcohol (9 : 1)). The obtained product is dissolved in 50 cm3ethyl acetate, add 0.15 cm3diethylamine and shaken for 30 minutes After centrifugation and washing twice in 10 cm3ethyl acetate and then 50 cm3simple isopropyl ether is dried at room temperature. The result is 380 mg of the target product (pl. t = 160oC).

Chemical composition C32H38N2O3S = 530,735

% calculated: C = 72,42; H = 7,22; N = 5,28; S = 6,04;

% obtained: C = 71,6; H = 7,1; N = 5,1; S = 5,9.

Infrared spectrum (CHCl3):

Absorption type NH2- - 3100 --> 2200 cm-1< / BR>
and/or-N-H

C=O + - 1624, 1592

aromatic compound - 1558, 1516 cm-1< / BR>
Example 19. 3-butyl 4-[[2'-methoxycarbonyl) (1,1'-biphenyl)4-yl]methoxy] 2-chinainternational ethyl.

Operations are performed, as in the example is the addition of 0.2 g of potassium carbonate. After stirring added 0.21 g of 4-(methyl bromide) (1,1'-biphenyl-2-carboxylate bromide (prepared according to patent EAS 53310). After chromatography on silica (eluent : methyl chloride-methyl alcohol (99:1)) to obtain 180 mg of the target product.

Infrared spectrum (CHCl3):

- 3100 --> 2200 cm-1< / BR>
Conjugated system + - 1618, 1599, 1584,

aromatic compound - 1562, 1492 cm-1< / BR>
Example 20. 3-butyl 4-[[2 methoxycarbonyl (1,1'-biphenyl)4-yl]methoxy]2-quinoline-carboxylic acid.

Operations are as in example 9, on the basis of 0.3 g of the product obtained in example 19, 5 cm3concentrated caustic soda. Then add 2 cm3and 5 cm3ethyl alcohol and heated for 3 hours at boiling point. Ethyl alcohol is evaporated, the solution is cooled to 0oC and acidified with chlorotestosterone acid. The crystals are centrifuged, washed with water and dried. After recrystallization from 10 cm3of dimethylformamide with 1% water get 0,176 g of the target product (tpl.= 162oC).

Chemical composition C28H25NO5=455,52

% calculated: C=73,12; H=5,68; N=3,16;

% obtained: C=72,8; H=5,7; N=3,1.

Infrared spectrum (veselinov< / BR>
Example 21. 4'-[[(3-butyl 4-chinoline)oxy]methyl] (1,1'-biphenyl)-2-carboxylic acid.

Operations are performed on the basis of the product obtained in example 20, by decarboxylation of diphenyl ether with heating to 250oC for 5 minutes

Example 22. 4'-[(2-phenyl 4-hintline) methyl] (1,1'-biphenyl)-2-methyl carboxylate.

Pre-prepare broil [[2'-(methoxycarbonyl)(1,1'-biphenyl)-4-yl] methyl] zinc on the basis of 400 mg per 1 cm3tetrahydrofuran (THF) and 1.53 g of 4'-(methyl bromide) (1,1'-biphenyl)-2-methyl carboxylate (see P. KNOCHEL - J. Org. Chem. 1988, volume 53, pages 5789-5791). In the thus obtained solution is added 240,69 mg 4-chloro-2 phenylindolin and 115 mg of a complex of palladium tetrakis (triphenylphosphine) and leave for 6 hours at a temperature of 50oC. the Reaction medium was poured into a mixture of water-ice-acetic acid. Then the aqueous phase is extracted with ethyl acetate. The organic phase is washed with water, then with water, saturated sodium chloride, dried and evaporated. After chromatography on silica (eluant : ethyl acetate-hexane (1:9), and then (2:8)) to obtain 260 mg of the target product (tpl.= 121-122oC), after recrystallization from simple isopropyl ether.

Infrared range (1< / BR>
Example 23. 4'-[(2-phenyl 4-hintline)methyl] (1,1'-biphenyl)2-carboxylic acid.

240 mg of the product obtained in example 22, give 2 cm3ethyl alcohol and add to 0.55 cm32 N. sodium hydroxide. The solution is shaken for 2 days at room temperature, which is then brought to boiling point for 2 hours Then the solution is evaporated to dryness, taken with water and neutralized with concentrated hydrochloric acid. The precipitate is filtered, dried and subjected to recrystallization from a mixture of water-isopropyl alcohol (10: 90). Thus receive 150 mg of the target product (tpl.= 210oC).

Chemical composition C28H20N2O2=416,48

% calculated: C=80,75; H=4,84; N=6,72;

% obtained: C=80,7' H=4,9; N=6,7.

Infrared spectrum (liquid paraffin):

C=O - 1698 cm-1< / BR>
Aromatic compound- 1618, 1600, 1572, - 1548, 1518, 1498 cm-1< / BR>
Example 24 : 4'-[(2-butyl 4-hintline) methyl] (1,1'-biphenyl)-2-methyl carboxylate.

Operations are as in example 22, on the basis of 4-chloro 2-butylthiazole obtained in stage B the following cooking, and cycloalkanes compounds, prepared as described in example 22.

Th is howling acid.

10 g orthocarolina dissolved in 50 cm3anhydrous pyridine, then add 11.2 cm3chloride of Valerie and bring to boiling point for 2 hours, the Reaction mixture was poured into 100 cm3ice water and acidified with 2 N. aqueous hydrochloric acid solution to pH=7. Then extracted with ethyl acetate, the combined organic phases are washed first 100 cm3water, and then 100 cm3a saturated solution of sodium chloride. Then dehydrate the organic phase with anhydrous magnesium sulfate, filtered and evaporated. The resulting residue is condensed in a simple isopropyl ether, filtered and evaporated. The result of 13.7 g of the desired product (tpl.=76oC).

Infrared spectrum (CHCl3):

-NH - 3416 cm-1< / BR>
-C N - 2222 cm-1< / BR>
Aromatic compound - 1605, 1583, 1520 cm-1< / BR>
+ amide

Step B. 2-butyl 4-oxoindole

of 13.7 g of the product obtained in stage A is dissolved in 150 cm3dioxane. Then add 400 cm3aqueous solution of caustic soda, and then 18 cm330% hydrogen peroxide. Then bring to boiling point for 2 hours, add acetic acid to pH=3, and then 28% temperature 50oC. the result 10,56 g of the desired product (tpl.= 156oC).

Infrared spectrum (CHCl3):

- 3385 cm-1< / BR>
- 1674 cm-1< / BR>
Aromatic compound - 1613, 1565 cm-1< / BR>
Step B. 2-butyl 4-chlorination.

Under magnetic stirring, at a temperature of 0oC administered 100 mg of the product obtained at stage B, 1 cm3of phosphorus oxychloride, then add 85 microliters N, N-diisopropylethylamine. Then allow to cool to room temperature, heated to the boiling temperature for 2 h, and again allowed to cool to room temperature. Then is evaporated to dryness, dissolved in a minimum amount of methylene chloride, washed with water and then with water saturated with sodium chloride. Then extracted using ethyl acetate, dried with magnesium sulfate, filtered and evaporated to dryness. The obtained residue is purified on silica (eluant : methylene chloride-ethyl acetate (95:5)). The result is 28 mg of the desired product which is used without additional processing.

Example 25. 4'[(2-butyl 4-hintline)methyl] (1,1'-biphenyl) 2-carboxylic acid.

Operations are as in example 23, on the basis of a product obtained there, however, without limiting it, the products of formula (I) defined below are products that can be obtained in the framework of the invention, as Examples 26 to 29:

Example 26. 4'-[[[3-butyl 2-(hydroxymethyl) 4-chinoline] oxy] methyl] (1,1'-biphenyl) 2-carboxylate bromide.

Example 27. 4'-[[[3-butyl 2-(hydroxymethyl) 4-chinoline] oxy] methyl] (1,1'-biphenyl) 2-carboxylic acid.

Example 28. 4-[2-[(2-butyl 4-chinoline]oxy]ethyl]methylbenzoate.

Example 29. 4-[2-[(2-butyl 4-chinoline)oxy]ethyl] benzoic acid.

Examples 27 to 29 is received, as indicated in the previous examples.

Carboxylic acids 26 and 29, respectively, obtained on the basis of their methyl salts 26 and 28 and are characterized by melting point: 174oC for example 27 and 205oC for example 29.

Preparation of 3-butyl-1,4,5,6,7,8-hexahydro-4-oxo-1-quinoline, for example, 30.

1 g of the product obtained in step D of preparation example 1, is introduced into 60 ml of methyl alcohol. Then add about 10 mg of platinum oxide and put on the hydrogenation at a pressure of about 200 mbar.

After about 3 hours shaken at room temperature the solution is filtered and evaporated.

The infrared spectrum in trichlormethane:

=C-N-H - 3430 cm-1< / BR>
- 1632 cm-1< / BR>
Paired system - 1538, 1510 cm-1< / BR>
Example 30. "B" : 4'-[((3-butyl 1,4,5,6,7,8-hexahydro-4-chinoline oxy] methyl] (1,1'-biphenyl)-2-methyl carboxylate, and "A" : 4'-[(3-butyl 1,4,5,6,7,8-hexahydro-4-oxo-1 - chinoline)methyl] -(1,1'-biphenyl)-2-methyl carboxylate.

0.4 g of the product obtained for the preparation of example 30, is introduced into 10 ml of anhydrous acetone.

Then added 0.52 g of potassium carbonate and 0.6 g of methyl bromide (1,1'-biphenyl)-2-methyl carboxylate.

Then heated for one night to boiling point and pour in the reaction medium in 100 ml of water and extracted the aqueous phase with 3 50 ml of ethyl acetate.

After that dried and evaporated to dryness. After chromatography (eluant : methylene chloride-methylene alcohol (98:2)) to obtain 0.15 g of the target product "B", and 0.45 g of product "A".

The infrared spectrum of the product "And" trichlormethane

- 1726 cm-1< / BR>
C=C - 1637 cm-1< / BR>
Aromatic compound - 1595 cm-1< / BR>
C=O - 1495 cm-1< / BR>
The infrared spectrum of the product "B" in trichlormethane

- 1720 cm-1< / BR>
Aromatic compound - 1617, 1600, 1589, - Isleta, and 4'-[(3-butyl 1,4,5,6,7,8-hexahydro-4-oxo-1-chinoline)methyl)-(1,1'-biphenyl)-2-carboxylic acid.

a) 4'-[(3-butyl 1,4,5,6,7,8-hexahydro-4-oxo-1 - chinoline) methyl]-(1,1'-biphenyl)-2-carboxylic acid.

of 0.43 g of product "A" obtained in example 30, is introduced into 10 ml of normal sodium hydroxide solution.

Then heated for 1 h at a temperature of 60oC, shaken for about 1 hour and add 1 ml of ethanol.

Then shaken for one night at a temperature of approximately 40oC. then cooled at room temperature and slowly add glacial acetic acid to crystallization of the acid.

Then shake for about 1 h, centrifuged, washed with water and then ether.

After recrystallization from 80 ml of ethyl alcohol produced 0,310 g of the target product (pl. t = 260oC).

Infrared spectrum (liquid paraffin):

- 1672 cm-1< / BR>
Conjugated system

C=O - 1630 cm-1< / BR>
C=O - 1600 cm-1< / BR>
Aromatic compound - 1535, 1520 cm-1< / BR>
b) 4'-[((3-butyl-1,4,5,6,7,8-hexahydro-4-chinoline) oxy) methyl]-(1,1'-biphenyl)-2-carboxylic acid.

On the basis of product B obtained in example 30, the implementation of the product.

Preparation example 32.

Step A. 3-butyl 4-hydroxy 2-6 chinainternational 2-ethyl 6-methyl.

a) 2-butyl 3-[(4-methoxycarbonyl)phenyl)amino]2-butenedioate of diethyl.

Enter 27.8 g of 4-methyl ester of aminobenzoic acid and 47 g of 2-butyl 3-oxobutanoate of diethyl and add 2 g of activated siliporite.

Then shake for about 30 hours at a temperature of 60oC. After chromatography (eluate : hexane-ethyl acetate (95:5)) to obtain 70 g of the target product.

b) 3-butyl 4-hydroxy 2,6-quinoline, in primary forms 2-ethyl 6-methyl.

70 g of the product obtained in the above paragraph a) is mixed with 70 ml Dowtherm.

Then heated to approximately 250oC for about 30 min, cooled, concentrated in ether and centrifuged.

The result is 45 g of the target product (tpl.= 160oC).

The infrared spectrum in trichlormethane:

=C-NH- - 3422, 3380 cm-1< / BR>
- 1742, 1715, 1631 cm-1< / BR>
Aromatic compound - 1603 cm-1< / BR>
C=C - 1577, 1525 cm-1< / BR>
Step B. 3-butyl 4-hydroxy 6-henrikromby acid.

a) 3-butyl 1,4-dihydro 4-hydroxy 2-6 hinolincarbonova acid

40 g of the product obtained in the above step E, enter 150 80oC for about 4 h was added 100 ml of a mixture of ice and water, acidified with concentrated hydrochloric acid, centrifuged, washed with water and dried. The result is 24 g of the target product (tpl.> 260oC).

b) 3-butyl 4-hydroxy 6-quinoline-carboxylic acid.

24 g of the product obtained in the above paragraph a) is introduced into 350 ml Dowtherm, heated for 5 h to approximately 250oC, cooled to room temperature, concentrated in the ether, centrifuged, washed with water and dried.

The result of 17.8 g of the target product (tpl.= 260oC).

Infrared spectrum (liquid paraffin):

- 1702, 1682, 1640 cm-1< / BR>
C=C - 1616 cm-1< / BR>
Aromatic compound - 1597, 1568, 1492 cm-1< / BR>
Stage B: 3-butyl 6-hydroxymethyl 4-(1H)-chinoline.

3 g of the product obtained in the above step B, is introduced into 800 ml of tetrahydrofuran.

Then add 1.8 g of tetrahydride of lithium and aluminum and shaken for approximately 5 h at room temperature.

Then add about 5 ml of tetrahydrofuran-water (80: 20), slowly add a saturated solution of the double salt tartrate, filtered, washed precipitate tetrahydrofuran

Infrared spectrum (liquid paraffin):

C=O - 1638 cm-1< / BR>
Conjugated system - 1620 cm-1< / BR>
Aromatic compound - 1568 cm-1- 1550 cm-1- 1508 cm-1- 1490 cm-1< / BR>
Phase, 3-butyl 1,4,5,6,7,8-hexahydro 6-methyl-4-(1H)-chinoline (1) (3-butyl 1,4,5,6,7,8-hexahydro 6-hydroxymethyl 4-(1H)-chinoline (2)).

0.5 g of the product obtained in the above stage, is introduced into 100 ml of methanol, add 10 mg of platinum oxide and put about 24 h to hydrogenation at a pressure of about 300 mbar.

Then filtered, washed with methyl alcohol and dried. After chromatography (eluant : methylene chloride-methyl alcohol (95:5)) gain of 0.47 g of the target product (1) (tpl.260oC).

Infrared spectrum (liquid paraffin):

< / BR>
Conjugated system - 1632 cm-1< / BR>
C=C - 16603 cm-1< / BR>
C-N - 1500 cm-1< / BR>
Example 32 B. 4'[((3-butyl 1,4,5,6,7,8-hexahydro-6-methyl-4-chinoline)oxy)methyl] (1,1'-biphenyl)-2-methyl carboxylate, and "A": 4'-((3-butyl-1,4,5,6,7,8-hexahydro-6-methyl-4-oxo-1 - chinoline)methyl] (1,1'-biphenyl)-2-methyl carboxylate.

The operation is performed as in example 30, on the basis of 0.45 g of the product of "1" obtained in the above step G preparation of carboxylate bromide.

Then heated for about 3 hours at the boiling point, pour in the reaction medium in 100 ml of water, extracted three times the aqueous phase with 3 50 ml of ethyl acetate, the organic phase is dried and evaporated.

After chromatography (eluant:methylene chloride-methyl alcohol (95:5)) to obtain 0.1 g of product "B", and of 0.58 g of product "A".

The infrared spectrum in chloroform product "A".

- 1725 cm-1- 1434 cm-1< / BR>
C=O - 1638 cm-1< / BR>
C=O - 1600 cm-1< / BR>
Aromatic compounds - 1545, 1594 cm-1< / BR>
Example 33 B". 4'-[((3-butyl 1,4,5,6,7,8-hexahydro-6-methyl-4-chinoline)oxy)methyl] (1,1'-biphenyl)-2-carboxylic acid, and an "A": 4'-((3-butyl-1,4,5,6,7,8-hexahydro-6-methyl-4-oxo-1-chinoline) methyl] (1,1'-biphenyl)-2-carboxylic acid.

B) 4'-[(3-butyl-1,4,5,6,7,8-hexahydro-6-methyl-4-oxo-1 - chinoline)methyl)-(1,1'-biphenyl)-2-carboxylic acid.

Operations are as in example 31, on the basis of 0.4 g of the product of Example 32 in 10 ml of 2 N. sodium hydroxide.

Then shaken for 1 night at 60oC, cooled at room temperature, acidified with glacial acetic acid to prepare the chin, thicken 2 N. the solution of hydrochloric acid, centrifuged, dried, the imp is B> = 255oC).

Infrared spectrum (liquid paraffin):

- 1675, 1628 cm-1< / BR>
C=C - 1600 cm-1< / BR>
Aromatic compound - 1533 cm-1- 1517 cm-1< / BR>
A) 4'-[((3-butyl-1,4,5,6,7,8-hexahydro-6-methyl-4-chinoline) oxy)methyl] (1,1'-biphenyl)-2-carboxylic acid.

On the basis of product B obtained in example 32, and performing operations in the same conditions as described above in paragraph (a), on the basis of the product of example 32 is possible to obtain the target product.

Based on the product "2" obtained in step G preparation of example 32, and performing operations and the same conditions as in example 32, based on the product of "1" obtained in the above Step G can be obtained the following products:

"B1": 4'[((3-butyl 1,4,5,6,7,8-hexahydro-6-hydroxymethyl-4-chinoline)oxy)methyl] (1,1'-biphenyl) -2-methyl carboxylate, and "A1":4'-[(3-butyl 1,4,5,6,7,8-hexahydro-6-hydroxymethyl-4-oxo-1-chinoline)methyl] -(1,1'- biphenyl)-2-carboxylate bromide

On the basis of the above products "A1" and "B1", and using the same procedure, and that upon receipt of the product of example 33 can respectively be obtained on the basis of "A1", 4'-((3-butyl-1,4,5,6,7,8-hexahydro-6-hydroxymethyl-4-oxo-1 - chinoline)methyl)-1,1'-biphenyl)-2-carboxylic acid, and on the basis of "B1",

Example 34. Carboxylate methyl carboxylic acid of example 35.

Example 35. 4'-(((2-(2-methylpropyl)-8-(trifluoromethyl)-4 - chinoline)oxy)methyl)(1,1'-biphenyl)-2-carboxylic acid.

Characterized by melting point 164oC, the product in example 34 was obtained as described above, for the previous examples, on the basis of his carboxylatomethyl salt (position 2' biphenylenes radical), a component of the example 34, in turn, obtained as described above for the previous examples.

The following examples can also be obtained as described above for examples 36 and 37:

Example 36. 4'[(2-butyl-4-chinoline)methyl]-[(1,1'-biphenyl)-2-tetrazolyl)] -5 - carboxylic acid.

Example 37. 4'-[(2-butyl-3-ethanolic)methyl] - [(1,1'-biphenyl)-2-tetrazolyl)]-4-carboxylic acid.

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As examples of farmakonisi can be prepared with the following formulation.

Tablets that meet the following formula:

Active substance 10 mg

The basis for the finished tablets (excipient: lactose, talc, starch, magnesium stearate) - 100 mg

The formula N 1 for tablets:

Active substance 15 mg

Magnesium stearate 1.5 mg

Microcrystalline cellulose 100 mg

Forml pulp - 4.5 mg

Modified maize starch - 10.5 mg

Talc 1.5 mg

Colloidal silica 0.5 mg

Sodium dodecyl sulfate - 0.75 mg

Magnesium stearate - 0.75 mg

Tablets are prepared by mixing the active substance with eccipienti and the resulting mixture is subjected to direct compression. The obtained tablets can be coated, for example, from sucrose to obtain pills.

The formula for gelatin capsules:

Active ingredient 25 mg

Lactose - which is 171,5 mg

Starch cellulose 50 mg

Talc 25 mg

Colloidal silicon dioxide 0.5 mg

Magnesium stearate 1.0 mg

on a gelatin capsule volume 273 mg

The drug is in the form of gelatin capsules is obtained by mixing the active substance with the media and the resulting mixture is poured into soft or hard gelatin capsules.

The formula for spark:

Active ingredient 100 mg

Wax AM - 1900 mg

Candles are obtained by mixing the wax in the molten state and the active substance with subsequent cooling of the mixture.

Based on available values, you can prepare the drug for injection by dissolving the active substance in the same solution in physiological serum desired horse this test uses fresh membrane preparation obtained on the basis of rat liver. The fabric is crushed by Poltrona in buffer solution Tris 50 mmol pH of 7.4, and then perform 3 centrifugation at 30,000 g for 15 min, with intermediate sampling of precipitation in the buffer solution Tris pH 7,4.

Last precipitation newly introduced in the form of sediment in the incubation buffer solution pH = 7,4 (Tris 20 mm, NaCl 135 mm, KCl 10 mm, glucose 5 mmol, MgCl210 mmol, phenylmethylsulfonyl 0.3 mmol, bacitracin 0.1 mmol (serum albumin bovine 0,2%).

Then aliquot of fraction 2 ml distributed in hemolyze tubes and add125I angiotensin 11 (25000 DPM per tube) and the product subject to control. (To start the product is triple tested at 10-5M). When a controlled product displaces more than 50% of the radioactivity specifically bound to the receptor, it is again tested under a series of 7 concentrations to determine the concentration that inhibits 50% of the radioactivity specifically bound to the receptor. Thus determine the inhibitory concentration 50%.

Nonspecific relationship is determined by adding the product of example 94 patent EEC 0253310 at 10-5M (three times). Then produce incubation at 25oC in the buffer solution Tris pH 7.4 and measure the radioactivity in the presence of scintillator Triton.

The result is expressed as inhibitory concentration 50% (Cl50i.e. in the concentration of the investigated product, expressed in nmol needed to offset 50% of the specific radioactivity fixed on the investigated receptor.

The obtained results:

The product of example - Cl50in nanomolar

4 - 540

7 - 2900

9 - 500

11 - 2600

14 - 3800

35 - 3500

Detection of antagonistic activity of angiotensin II on isolated portal vein.

Portal vein is taken in male rats Wistar (weighing about 350 g) (IFFA Credo, France) after fracture of the cervical vertebra and quickly immersed in a physiological solution (see below) at room temperature. The ring is about 1 mm is installed in the tub with an insulated body with 20 ml of the following physiological solution (composition in mm: NaCl 118,3 - KCl 4,7 - MgSO41,2 - KH2PO41,2 - NaHCO325 - glucose of 11.1 - CaCl22,5), when the medium is maintained at a temperature of 37oC and oxygenated with a mixture of O2(95%) and CO2(5%). First make the tension of 1 g, ring leave from 60 to 90 minutes To prevent spontaneous reduction in the incubation bath add verapamil (1 of 10-6M) and left in contact with the drug for 1 minutes This operation is repeated every 30 min, and between the two stimulation by angiotensin fabric washed 3-4 times. The investigated compound is introduced into the bath for 15 min to new stimulation by angiotensin. Apply higher concentrations of molecules that allows you to calculate Cl50(the concentration that inhibits 50% of the response to angiotensin) nanomolar.

The results:

The product of example - Cl50in nanomolar

4 - 131

3. Research activity on the endothelin receptor.

Membrane preparation obtained from the posterior cortex and cerebellum of the rat. The fabric is crushed by Poltrona in buffer solution Tris 50 mmol pH of 7.4. After soaking for 30 min at a temperature of 25oC (in water bath) the homogenate was centrifuged at 30,000 g for 15 min (2 centrifugation with intermediate selection of precipitation in the buffer solution Tris pH 7,4).

Precipitation newly introduced in the form of sediment in the incubation buffer solution (Tris 25 mmol, pepstatin A 5 μg/ml Aprotinin, 3 µg/ml, PMSF 0.1 mmol, add 3 mmol, AGTC 1 mmol, pH 7,4).

Then aliquot of fraction 2 ml distributed in hemolyze tubes and add125I endothelin (50,000 DPM per tube) and the product pagliusi is 50% of the radioactivity specifically bound to the receptor, it is again tested under a series of 7 concentrations to determine the concentration that inhibits 50% of the radioactivity specifically bound to the receptor. Thus determine the inhibitory concentration 50%.

Nonspecific relationship is determined by the addition of endothelin in 10-6M (three times). Then produce incubation at 25oC for 60 min, set for 5 min in a water bath at 0oC, perform vacuum filtration, washed with Tris buffer solution pH 7.4 and measure the radioactivity in the presence of scintillator Triton.

The result is expressed as inhibitory concentration 50% (Cl50i.e., in concentrations of the investigated product, expressed in nmol needed to offset 50 % of the specific radioactivity fixed on the investigated receptor.

The result.

Found CI50 of the product of example 35 is 14 000 nmol.

4. Study the antagonistic activity of the vasoconstrictor actions of endothelin in rats with remote spinal cord.

Vasoconstriction caused by injection (IV) cumulative doses of endothelin (1-3-10-30 µg/kg), measured by the median of the brain. Controlled products introduced over 10 min to a series of concentrations of endothelin. The weakening of a response of endothelin indicates an antagonistic effect. The product of example 35 shows the antagonistic action, starting with 1 mg/kg (IV).

1. Bicyclic nitrogen-containing derivatives of General formula I

< / BR>
R2Band R3Bsame or different: hydrogen, lower alkyl, lower foralkyl, lower thioalkyl;

A1B, A2B, A3Band A4Bis carbon or nitrogen, and at least one and maximum two of them represent a nitrogen atom and at least one of them is Metin;

R3is hydrogen, hydroxyl, alkyl, hydroxyalkyl, phenyl, alkoxycarbonyl, lower thioalkyl;

R4is hydrogen, hydroxyl, arylalkyl, Allakaket, aryloxy, arylamino that can be attached to either the nitrogen atom or carbon atom, and the aryl radical may be substituted TetraSociology, carboxyaniline, carboxyl, alkoxycarbonyl, nitrile or cianfanelli group, or their salts with mineral and organic acids or bases.

2. Connection on p. 1 of the formula I, in which R2B, R3Band R3Bhave the meanings specified iloxi, moreover, the aryl radical may be substituted TetraSociology, carboxyaniline, carboxyl, alkoxycarbonyl or nitrile group.

3. Connection on p. 1 of formula I, which represents a 4'-[(2-butyl-4-chinoline)methyl]-(1,1'-biphenyl)-2-carboxylic acid.

4. A method of obtaining a bicyclic nitrogen-containing derivatives of the General formula Ib

< / BR>
where R2Band R3B, R3, R4Bhave the values listed in paragraph 1, wherein the aniline of General formula III

< / BR>
where R'2Band R'3Bare specified in paragraph 1 values of R2Band R3B,

subjected to interaction with the compound of General formula IV

R'4B-CH-(CO2alk)-CO-R4B< / BR>
where R'4Band R4Bare specified in paragraph 1 values of R4Bin which reactive groups may be protected, alk represents an alkyl radical containing not more than 6 carbon atoms, the resulting product of General formula V

< / BR>
where R'2B, R'3B, R'4Band R4Bhave the above meanings, is subjected to cyclization to obtain compounds of General formula IIb

< / BR>
which either corresponds to the compound of formula Ib, where methine radical in position 4 is substituted by hydroxyl and in the restoration of hydroxyl or carbonyl group to the Metin,

b) or substitution reactions of hydroxyl radical by halogen atom, followed by processing the compounds formed by the connection of the formula Rp4-M-Gal, where Rp4matter specified in paragraph 1 for R4in which reactive groups may be protected, M is a metal atom selected from the group consisting of magnesium, copper and zinc, Gal - halogen atom, or by treatment with a compound of the formula Rp4Gal with obtaining the compounds of formula Ib,

(C) removal of protective groups,

g) salt formation reaction with a mineral or organic acid or base

d) the esterification reaction of the acid function,

e) reaction of saponification of ester group to an acid,

g) reactions of transformation of alkoxygroup in hydroxyl,

C) reactions of transformation of ceanography in acid,

and reactions repair carboxypropyl to alcohol.

5. A method of obtaining a bicyclic nitrogen-containing derivatives of the General formula Ic

< / BR>
where R2B, R3B, R3and R4Bhave the values listed in paragraph 1, characterized in that halogenation General formula

< / BR>
where R'2Band R'3Bare specified in paragraph 1 values of R2Band R3B, is subjected to the interaction with the derived GPI can be protected, the resulting product of General formula VI

< / BR>
where R'2B, R'3Band R"'4Bhave the above meanings, is subjected to cyclization in the presence of a nitrogen donor such as sodium nitrite, to obtain compounds of General formula IIc

< / BR>
which either corresponds to the compound of formula Ic, where methine radical in position 4 is substituted by hydroxyl, and select either subjected, if necessary, one or more reactions in any order:

a) the full restoration of the hydroxyl or carbonyl group to the Metin,

b) or substitution reactions of hydroxyl radical by halogen atom, followed by processing the compounds formed by the connection of the formula Rp4-M-Gal, where Rp4matter specified in paragraph 1 for R4in which reactive groups may be protected, M is a metal atom selected from the group consisting of magnesium, copper and zinc, Gal - halogen atom, or the processing of compound of formula Rp4Gal with obtaining the compounds of formula Ic,

(C) removal of protective groups,

g) salt formation reaction with a mineral or organic acid or base

d) the esterification reaction of the acid function,

e) reaction of saponification of ester group to an acid,

g) re and reactions repair carboxypropyl to alcohol.

6. A method of obtaining a bicyclic nitrogen-containing derivatives of General formula I

< / BR>
where R2B, R3Band R4have the values listed in paragraph 1, characterized in that cyanoaniline General formula VII

< / BR>
where R'2Band R'3Bhave the meanings specified in paragraph 1 for R2Band R3B, is subjected to the interaction with the compound of the formula VIII

R'4B-CO-Cl,

where R'4Bmatter specified in paragraph 1 for R4in which the reaction of a protected group, the resulting product of formula IX

< / BR>
where R'2B, R'3Band R'4Bhave the above meanings, is subjected to cyclization to obtain the compounds of General formula II

< / BR>
which either corresponds to the compound of formula If where methine radical in position 4 is substituted by hydroxyl, and select either subjected, if necessary, one or more reactions in any order:

a) the full restoration of the hydroxyl or carbonyl group to the Metin,

b) or substitution reactions of hydroxyl radical by halogen atom, followed by processing the compounds formed by the connection of the formula Rp4-M-Gal, where Rp4matter specified in paragraph 1 for R4in which reactive groups may be protected by the Union of the formula Rp4Gal with obtaining the compounds of formula If,

(C) removal of protective groups,

g) salt formation reaction with a mineral or organic acid or base

d) the esterification reaction of the acid function,

e) reaction of saponification of ester group to an acid,

g) reactions of transformation of alkoxygroup in hydroxyl,

C) reactions of transformation of ceanography in acid,

and reactions repair carboxypropyl to alcohol.

7. Pharmaceutical composition having antagonistic activity to the angiotensin II receptor containing the active principle and pharmaceutical additives, characterized in that the active agent contains a compound of formula I under item 1 in an effective amount.

 

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Immunomodulator // 2108100
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