SU614093A1 - Multiple-substituted a,a-diaryl-b-(tert.amino)-propanols showing diuretic and saluretic effect - Google Patents

Description

petroleum ether is separated, dried by potash and evaporated. 23.7 g of 1- {4-methoxy-2-methyl-5-isopropylphenyl) -1-phenyl-2-piperidinopropanol- (1) are obtained, m.p. 134-135C. Example 2. T 1856. 22 g of sb-pyrrolidinopropiophenone is added to the Grignard reagent obtained from 7.3 g of magnesium, 38.5 g of 4-bro-5-methyl-2-tert-butylanisole and 28.2 g of 1, 2-dibromoethane, in 300 ml of ether. After refluxing for 4 hours, the reaction mixture was poured onto ice and acidified with hydrochloric acid. The crystals are filtered off with suction, washed with ether and added to a mixture of concentrated aqueous ammonia and ether. After a brief shaking, the crystals dissolve. The ether layer is separated, dried by potash and evaporated. The remaining viscous brown oil is dissolved in a small amount of isopropanol. After a short time, 28.2 g of 1-4-methoxy-2-methyl-5-tert-butylphenyl) -1-phenyl-2-pyrrolidinopropanol- (1) crystallized out, so pl. 112-113 C. The base is recrystallized from isopropanol, so pl. 113-114 with: Example 3. T 1857. 15 g oo-piperidinopropiophenone is added to Grignard reagent, obtained from 7.3 g of magnesium, 38.5 g of b-bromo-2-methyl-4-tert-butylanisole and 28.2 g of 1,2-dibromoethane, in 300 ml of ether. After refluxing for 4 hours, the reaction mixture was poured onto ice and acidified with hydrochloric acid. The acidic aqueous layer and the oily intermediate layer are separated, the solution is concentrated with an aqueous solution of ammonia and the precipitated base is dissolved in ether. After removal of the ester, 26.5 g of a brown viscous cascade remains, from which 21.5 g crystallize with isopropanol and 21.5 g crystallize. 1- 2-etoksi-z-methyl-5-tert-vinyl-phenyl) -l-phen-l-2-piperidinopropanol- (l), etc. 86-87 s. After recrystallizing from isopropanol, m.p. 87-. EXAMPLE 4: T 1882. 12 g of 1- {3,4-dimethoxyphenyl) -2-piperidinepropanone- (1) is added to the Grignard reagent obtained from 7.3 g of magnesium,; 40.6 g of 4-bromo-2,6-diisopropyl anisole and 28.2 g of 1,2-dibromo ethane, in 300 ml of ether. After refluxing for 4 hours, the reaction mixture was poured onto ice and acidified with hydrochloric acid. The acidic aqueous layer was separated together with an oily intermediate layer, alkalified with a concentrated aqueous ammonia solution, and the liberated base was dissolved in ether . After the termination of an ethereal solution over potash and evaporation, 24.7 g of a brown-brown oil remain, from which 14.8 g of 1- (4-methoxy-3, 5-diisopropylphenyl) -1- (3, 4-) are cut out from rubbing with isopropanol. dimethoxyphenyl) -2-piperidinopropanol- (I), pl. I8-119 C. After recrystallization from isopropanol, so pl. 120-12lc. Example 5.T 2111. 7.5 g oo-pyrrolidinopropiophenone ribavl to a Grignard reagent solution prepared from 3.6 g magnesium, 2i, 5 g 2-methyl-4-tert-hexyl-6-bromoanisole, 14.1 g 1,2-dibromide and. 200 ml of ether. After refluxing for 4 hours, the reaction mixture was poured onto ice and acidified with hydrochloric acid. The acidic aqueous layer together with the oily intermediate layer is made alkaline with a concentrated aqueous solution of ammonia and the liberated base is dissolved in ether, the solution is dried in potash, evaporated to obtain 14.8 g of a brown oil, from which 8.3 crystallize when rubbed with isopropanol. 1- (2-methoxy-3-methyl-5-tert-hexylphenyl) -1-phenyl-2-pyrrolidinopropanol- (1), mp. 96-. After recrystallization from isopropanol so pl. 97-98C. Example 6. T. 2129. 15 g of ob-piperidinopropiophenone in 20 ml of ether are added to a Grignard reagent solution prepared from 5.4 g of magnesium, 26.5 g of 6-bromo-7,8-dimethylchromium and 20.7 g 1,2-dibromoethane, in 80 ml of ether. After boiling for 4 hours under reflux, the reaction mixture is poured onto ice, acidified with hydrochloric acid, suction crystals are still wet mixed with concentrated aqueous ammonia and the mixture is shaken with ether several times. After drying the combined ether extracts over potash, the ether is evaporated and an oil is obtained, which after a short time becomes K1 1. After recrystallization from methanol, 5.2 g of pure 1- (7,8-dimethylchromanyl- (6) 1-1-phenyl-2-piperidinebpropanol- (1) are obtained, mp 125-128 ° C. Example 7. T 2152. 18.0 g (L-piperidinopropiophenone) is added to a Grignard reagent solution prepared from 7.3 g magnesium, 36.4 g 4-bromo-2,3,5,6-tetramethylanisole, 28.2 g 1.2 -dibroethane and 300 ml of ether. After boiling for 4 hours under reflux, the reaction mixture is poured onto ice and acidified with hydrochloric acid. The acidic aqueous layer and the oily intermediate layer are alkalinized with a concentrated aqueous solution of hydrochloride. a and the precipitated base is dissolved in ether. After evaporation, a brown-colored oil remains, from which 10.5 1- (4-methoxy-2, 3, 5, 6-tetramethylphenyl -1-phenyl-2-piperidinopropanol crystallizes out when rubbed with methanol (1), mp 148-150 p. After recrystallization from isopropanol, mp 151-152 ° Example 8.T 2237. 10 g of p-methoxy-oo-piperidinoprop phenone is added to the Grignard reagent solution prepared from 4.8 g of mi, 27.1 g of 4-bromo-2, b-diisopropyl anisole, 18.8 g of 1,2-dibromoethane and 200 ml of ether. After refluxing for 4 hours, the reaction mixture was poured onto ice and acidified with hydrochloric acid. The aqueous acidic solution is separated with an oily intermediate layer, alkalinized with a concentrated aqueous solution of ammonia, and the precipitated base is dissolved in ether. After evaporation, 18.2 g of a brown oil remain, from which, by trituration with methanol, 12.9 g of 1- (4 methoxy-3, 5-diisopropylphenyl) -1- (4-methoxyphenyl) -2-piperidinopropanol- ( 1), so pl. 62-64 ° C. After recrystallization so pl. 64-65 ° C. Example & T 2258. 8 g of p-ethoxy-piperidinopropiophenone are added to a Grignard reagent solution prepared from 4.8 g of magnesium, 27.1 g of 4-bromo-2,6-diisopropyl-isane, 118.8 g of 1,2- dibromoethane and 200 ml of ether. After boiling for 4 hours under reflux, the mixture was poured onto ice and acidified with hydrochloric acid. The acidic aqueous layer and the oily intermediate layer are alkalinized under a concentrated aqueous solution of ammonia and shaken many times with ether. The combined ether extracts are dried over potash, the ether is evaporated and the residue is triturated with isopropanol. 8.5 g of crystalline 1- (4-methoxy-3, 5-diisopropylphenyl) -1- (4-ethoxyphenyl) -2-piperidinopropanol- (1) are obtained, m.p. 81-83® C After recrystallization from isopropyl, m.p. 84-85s. Example 10: T 2259. 21 g of oo-piperidinopropiophenone is added to a Grignard reagent solution prepared from 7.3 g of magnesium, 36.4 g of 2-bromo-4-tert-butylanisole, 28.2 g of 1,2-dibromoethane and 300 ml of ether. After boiling for 4 hours under reflux, the reaction mixture is poured onto ice and acidified (hydrochloric acid. The crystals are sucked off with suction, mixed with ether and mixed with concentrated aqueous ammonia solution until the crystals are shaken or stirred after evaporation of the ether, 33.3 g of the partially crystalline compound remain, which is dissolved in hot methanol. 5.8 g of 1- (2 "tox-5-tert-Sutylphenyl) -1 -phenyl-2-piperidinopropanol- (1), mp 13914 0 ° C. Example 11. T 226 6. 10 g of 1- (4-methoxy-3, 5-dimethylphenyl) -2-piperidinopropanone- (1) is added to a Grignard reagent solution prepared from 4.8 g of magnesium, 27.1 g of 4-bromo-2 , 6-diisopropanilane, 18.8 g of 1,2-dibromoethane and 200 ml of ether. After boiling for 4 hours under reflux, the reaction mixture is poured on ice and acidified with hydrochloric acid. The crystals are sucked off, shaken with ether, mixed with concentrated aqueous ammonia until all the crystals have dissolved. The ether extract is separated, dried over potash, and evaporated to give 16.0 g of a partially crystalline compound. After crystallization from isopropanol, 10.0 g of 1- {4-methoxy-3, 5-diisopropylphenyl) -1- (4-methoxy-3, 5-dimethylphenyl) -2-piperidinopropanol- (1) are obtained, m.p. 118-I9 ° C. Example 12.T 2310. 12 g of p-methoxy-sb-piperidinopropiophenone is added to a Grignard reagent solution prepared from 6.1 g of magnesium, 25.7 g of 4-bromo-2,6-diisopropylphenetol, 23.5 g 1 , 2-dibromoethane and 200 ml of ether. After refluxing for 4 hours, the reaction mixture was poured onto ice and acidified with hydrochloric acid. The acidic aqueous layer and the oily intermediate layer are made alkaline with concentrated aqueous ammonia solution and the separated base is dissolved in ether. After evaporation of the ether, 21.7 g of a brown oil remain, which is dissolved in a small amount of isopropanol and acidified with 70% perchloric acid. At. grinding, 18.9 g of 1- (4-ethoxy-3, 5-diisopropylphenyl) -1 - (4-methoxyphenyl) -2-piperidinopropanol- (1) -perchlorate precipitate to 18.9 g, which after recrystallization from isopropanol melts . Example 13. T 2350.. 10 g of β-pyrrolidinopropiophenone is added to a Grignard reagent solution prepared from 7.3 g of magnesium, 41.5 g of 4-chloro-6-bromthymol methyl ether, 28.2 g of 1,2-dibromoethane and 300 ml of ether. After boiling for 6 hours under reflux, the reaction mixture is poured onto ice and acidified with hydrochloric acid. The crystals are filtered off with suction, shaken with ether, and mixed with a concentrated aqueous solution of ammonia ak until all the crystals have dissolved upon shaking. The ether layer was separated, dried over potash, evaporated, and 11.1 g of 1- (U-chloro-b-methoxy-2-methyl-5-isopropylphenyl) -l-phenyl-2-pyrolidine propanol-1 (1), t .pl. 108109 C. After recrystallization from methanol, m.p. 112-113 C.

Example 14. T 2378. 12 g of p-methoxy-oO-piperidinopropiophenone is added to a Grignard reagent solution prepared from 12.2 g of magnesium, 80.0 g of 2- (2, E-dibromopropyl) -4,5-methylenedioxybromobenzene 18.8 g of 1,2-dibromoethane and 300 ml of ether. After boiling for 6 hours under reflux, the reaction mixture is poured onto ice and acidified with hydrochloric acid. The dark colored crystalline oil partially crystallizes after some time. The crystals are sucked off with suction, washed with ether, and mixed with a concentrated aqueous solution. ammonia, the liberated free bases are dissolved in ether, the solution is dried over potash, evaporated and 4.8 g of 1- (3, 4-methylenedioxy-6-allylphenyl) (4-methoxyphenyl) -2-piperidinopropanol- (1) is isolated, m.p. 117-130 With after treatment with activated carbon and recrystallization from isopropanol so pl. 132-133.5 ° C. .

Example 15. T 2453.

10 g of p-ethoxy-about -piperidinopropiophenone, dissolved in 100 ml of ether, are added to a Grignard reagent solution prepared from 7.3 g of mani, 42.8 g of 4-bromo-2, b-diisopropylphenetol and 28.2 g 1,2-dibROMETHANE in 100 ml of ether. After refluxing for 4 hours, the reaction mixture was poured onto ice and acidified with hydrochloric acid. The oily intermediate layer is separated with an acidic aqueous layer, alkalinized with a concentrated aqueous solution of ammonia, and the liberated base is dissolved in ether. After steaming the ether-dried ester, a brown oil (23 g) remains, which is dissolved in 20 ml of isopropanol. Upon acidification with 70% perchloric acid, 17.4 g of 1- (4-ethoxy-3, 5-diisopropylphenyl) -1- (4-ethoxyphenyl -2-piperidinopropanol- (1) -perchlorate, crystallizes, mp. 160- 161 C (dec.). After recrystallization from isopropanol, pure perchlorate melts at 1-1-162 e. The free base is separated from perchlorate from a dilute sodium hydroxide solution, dissolved in ether and dried over potash. After evaporation, 14 g of 1- ( 4-ethoxy-3,5-diisopropylphenyl) -1 - ((ethoxyphenyl) -2-piperidinopropanol- (1) in the form of a colorless oil in the feoro oil when added is calculated About the amount of hydrochloric acid, the free base can be converted to hydrochloride.

Example 16.T 2455.

7 g of 2,4-dimethoxy-piperidinopropiophenone in 100 ml of ether are added to a Grignard reagent solution prepared from 7.3 g of magnesium, 38.6 g of 2-methoxy-3-methyl-5-tert-butylbromobenzene, 28 , 2 g of 1,2-dibromoethane and 200 ml of ether. After refluxing for 6 hours, the reaction mixture was poured onto ice and acidified with hydrochloric acid. The acidic aqueous layer is alkalinized with a concentrated aqueous solution of ammonia and extracted several times with ether. The combined ether extracts are dried over potash. And evaporated. The remaining brownish oil (13.4 g) crystallizes upon rubbing with a small amount of isopropanol. Pure 1- (2-methoxy-3-methyl-5-tert-butylphenyl) -1- (2 4-dimethoxyphenyl) -2-piperidinopropanol- (1), so pl. 133.5-135 0, obtained after two recrystallizations from 200 ml of isopropanol.

Example 17. T 2458.

5 g of 2-methoxy-4-hydroxy- (or 2-hydroxy-4-methoxy) -ooO-piperidinopropiophenone, dissolved in 100 ml of ether, are added to a Grignard solution prepared from 7.8 g of magnesium, 38.6 g 2-methoxy-3-methyl-5-tert-butylbromobenzene, 28.2 g of 1,2-dibromoethane and 150 ml of ether. The reaction mixture is boiled under reflux for 4 hours, poured onto ice and acidified with hydrochloric acid. The mixture is vigorously shaken, the ether layer is separated and shaken repeatedly with dilute hydrochloric acid. The combined aqueous hydrochloric acid layers are mixed with 200 ml of ether and a concentrated aqueous solution of ammonia is added dropwise until the pH of the mixture is 8. Then the ether is separated, the aqueous alkaline layer is extracted several times with ether and the combined ether extracts are dried over sodium sulfate. After evaporation, 14.5 g of a brown oil remain, which, upon trituration with a small amount of isopropanol, partially crystallizes. The crystals (5.2 g, mp. 146-148 ° C) are sucked off and recrystallized several times from isopropanol. Pure 1- (2-methoxy-3-methyl-5-tert-butylphenyl) -1 (2-methoxy-4-hydroxyphenyl) - (or 2-hydroxy-4-methoxyphenyl) 3 -2-piperidinopropanol- (1) is melted at 153, Example 18. T 2464. 7.0 g of 3,4-dimethoxy-o-piperidinopropiophenone, dissolved in 100 ml of ether, are added to a Grignard reagent solution prepared from 7.3 g of magnesium, 38.6 g 2 -methyl-6-bromo-4-tert-butyl anisole, 28.2 g of 1,2-dibromoethane and 100 ml of ether. The reaction mixture is boiled under reflux for 4 hours. The mixture is poured on ice, acidified with hydrochloric acid, stirred, the ether LAYER is separated and discarded, the lower aqueous layer and the oily intermediate layer is mixed with fresh ether and alkalized with concentrated aqueous ammonia. The ether layer is separated, dried over potash and evaporated. 13.4 g of a light brown oil remain, which are dissolved in 100 ml of methanol. Upon cooling, NII 8.3 g of 1- (2-methoxy-3-methyl-5-tert-butylphenyl) - (3,4-dimethoxyphenyl) -2-piperidinopr panol- {1) crystallized out, m.p. 125-12b C. After processing with activated carbon and two recrystallizations from methanol, m.p. 127-128p. Example 19.T 2481. 6.0 g of 4-benzyloxy-3, 5-diisopropyl-оС -piperidinopropiophenone in 100 ml of ether is added to a Grignard reagent solution prepared and 7.3 g of magnesium, 30.2 g of 2-bromo -4-methylanisole, 28.2 g of 1,2-dibromoethane and 100 ml of ether. After refluxing for 4 hours, the mixture was poured onto ice and acidified with hydrochloric acid. The oily intermediate layer and aqueous layer are mixed with ether and concentrated aqueous ammonia solution, shaken, the ether layer is separated, dried over potash and evaporated. The remaining brown oil (12.1 g) is dissolved in 40 ml of isopropanol and acidified with a saturated isopropanol solution of picric acid. Obtain 12.2 g of picrate, so pl. EZ-SOO C. After recrystallization from isopropanol, the pure picrate melts at 99-101 C. 1- {2-Methoxy-5-methylphenyl) -1- (4-benzyloxy-3 5 -dieopropylphenyl) -2-pygleridinopropanol- (1) is obtained as a colorless oil by decomposing pure Picrdt with ethanolamia. Example 20 T 2493. 5 g of 4-methoxy-3, 5-dimethyl-eu- (methyl-tert-butylamino) -propiophenone and 100 ml of ether are added to a Grignard reagent solution prepared from 7.3 g of magnesium, 35 , 3 g of 6-bromo-4-chloro-2-methylanisole, 28.2 g of 1,2-dibromoethand and 100 ml of ether, and refluxed for 4 hours. The mixture is then poured onto ice, acidified with hydrochloric acid, shaken in a separatory funnel, the aqueous and oily intermediate layer is made alkaline with a concentrated aqueous solution of ammonia and extracted with ether. The extract is dried over potash, evaporated, the remaining brown oil (10.1 g) is dissolved in 20 ml of methanol and mixed with a saturated methanol solution of picric acid until the solution is acidic before the crystals precipitate. 1- (b-Methoxy -5-methyl-3-chlorophenyl) -1- (4-methoxy-3, 5-dimethylphenyl) -2 (methyl tert-butylamino) propanol- (1) -picrate (9.4 g) melts at 179- 180 C. Pure picrate, after two recrystallizations from methanol, melts at 185-lee C. It is decomposed with ethanolamine. The resulting compounds exhibit diuretic and saluretic effects, which is clear from the data in the table. The table shows the effect of compounds on the excretion of water, table salt and potassium.

80 40 80 40 80 40 80

T 1857 3825 (2675-5470)

T 1882 3400 (2656-4352)

T 2111 4450 (3560-5563)

59.7 52.0 56.5 17.77, 5 36.8 33.8

T 2129 320O

T 2152

T 2237 .6400

T 2258 4500

T 2259 560 (444-706)

T 2260 3200

T 2310 520 (361-749)

T 2350 S-4500

2,4,7-Triamy-30Q no-6-f-I nilpteridin

T 2378 1600

T 2453 700 (569-841)

T 2455 4550

T 2458 3200

Table continuation

N-Amidino-3, 5-diamino-6-chloropyrazinecarbox in d

Deviations in relation to the mean value and twice the standard deviation (x + 2 tbsp.) Of the limits of the control experiments. The minus sign indicates that there is no additional matter compared to the control experiments with table salt.

In relation to the average potassium excretion in the control experiment.

Claims (1)

The value is beyond the normal area. These extremely high ratios are due to the fact that the excretion of sodium is maintained, while the absorption of potassium is markedly reduced. In terms of its toxicity, the proposed compounds differ favorably from the known polyurethane diuretic drugs. 6-Chloro-3, 4-dihydro-7-sulfamoyl-2H-1, 2,4-benzothiadiazine-1,1-dioxydate saluretic, in a dose of 10 mol / kg of body weight causes a maximum additional release of an average of 19.9 % water, 29.6% sodium and 17.3% chloride. With the maximum active dose of this saluretic agent (10 µmol / kg body weight), an additional excretion of potassium is 58.3%. The sodium / potassium ratio is 4.86. Claims of the Invention Multiple-substituted ob / L-diaryl-ft- (tert-amino) -propanols of the general form of the table C-CH-CHj I and 4 RV where and T mean lower alkyl with 1-6 straight or branched carbon atoms, with T and K together with the nitrogen atom can form five- or six-membered R-TJ ring independently of each other, hydrogen, alkyl of 1-6 carbon atoms, alkenyl with 2 or 3 carbon atoms, hydroxy group, lower alkoxy with 1-4 atoms carbon, and two adjacent substituents can form together five 1516 OR six-membered heterocycle with one sources of information taken during or two heteroatoms, as well as ben-attention during examination zyloxy or halogen atom, pro-j. mashkovsky md Medicinal diuretic and saluretic agents. M., Medicine, t. 1, some action. 5c. 387. 614093