SU852173A3 - Method of preparing 5,6-dihydroimidazo(5,1-a)isoquinoline derivatives or their salts - Google Patents

Abstract

5,6-Dihydroimidazo[5,1-a]isoquinoline derivatives of the general formula <IMAGE> in which R denotes hydrogen, or alkyl containing 1-4 carbon atoms, A is nitryl or carbamoyl, B denotes a lone electron pair or oxygen, and Y denotes hydrogen, alkyl containing 1-5 carbon atoms, phenyl, hydroxyphenyl, aminophenyl, an optionally substituted furyl, alkoxyphenyl, halophenyl, or an alkenyl group containing 2-4 carbon atoms and being optionally substituted by a substituted phenyl, or, if B is different from oxygen, denotes a hydroxyl group, and their salts formed with acids and bases, possess a selective bronchodilatory effect.

Description

in the form of tautomers, in which the hydroxylchyl group passes into the oxo group. These tautomers are also within the scope of the present invention.

Salts of compounds of formula 1 are obtained by treating the base of the compound with an inorganic acid, and in the case when Y is hydroxyl, by treating with a base.

The reaction between compounds of general formulas I and III is usually carried out in the presence of an acid. The acid can be used in equivalent amounts or in excess. The reaction is usually carried out in the presence of a solvent. Suitable solvents are water or alcohols containing 1-4 carbon atoms or mixtures thereof. Other suitable solvents include halogenated hydrocarbons, ethers, ketones, acid amides, etc. The reaction is carried out, as a rule, at the boiling point of the reaction mixture, usually in the range of 70-1209s. The reaction products are usually separated from the reaction mixture by filtration, and traces of compounds of the general formula II, if desired, if Y represents a hydroxyl group, are removed by washing with sodium carbonate solution.

The proposed method is particularly advantageous to carry out in such a way that the product of general formula I, g-which was obtained as a result of isonitrosation, is not isolated from the reaction mixture, and the acidic reaction mixture is reacted directly with the corresponding aldehyde of general formula III.

The process is generally carried out at normal pressure, however, an elevated or reduced pressure can be used.

The compounds of general formula I and their salts obtained by the proposed method have a selective bronchodilatory effect and do not have a pronounced effect on the myocardium of the heart. These compounds may find use in anthistamic drugs.

So, the compound of example 9 - 5,6-dihydro-8, 9-dimethoxy-1-cyano-2H-imidazo (5,1-a) isoquinolinone-3 already in a concentration of 0.1-0.5 mg / ml has a pronounced the effect on guinea pigs on the trachea, which is not inhibited by C1-isopropylamino-3- (1-naphthyloxy) -propanol inderal. 2. The compound causes an inotropic effect on. isolated cardiac activity, in particular, in the papillary lamina of the cat (only at a concentration of 50 mg / ml, which indicates that the compounds are 100–500 times more potent than breathing than heart activity.

Comparison with terbutaline 2-tert.butmin-1- (3,5-dioxyphenyl) ethanol shows that for him the ratio of the concentration that acts on respiration (0.05 mg / ml) to the concentration that acts on the heart (0.10 , 5 mg / mp) is equal to 10-50 and the resultant compound obtained according to the method of the invention is much more selective than the known compound.

A comparison with another well-known agent, DL-l- (3,4-dioxyphenyl) -2- and zopropylaminoene tanolais isoprepaline, shows that the compound of example 9 acts on the papillary (atsu 5000t is 50,000 times weaker.

The compound is of low toxicity (82 mg / ml when administered intravenously).

The following examples illustrate the proposed method, but not

0 limit it.

Example: A mixture of 2.61 g (10 mol) of 1- (isonitrosocyanomethyl) -b, 7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, 18 ml of a 37% formaldehyde solution and 18 ml of 96% ethanol boil in a water bath. After 15 minutes the mixture becomes homogeneous, after 2-3 hours a solid precipitates out. After 5 hours of boiling, the reaction mixture is cooled and filtered. 2.05 g of 1-cyano-5,6-dihydro-8,9-dimethoxy imidazo (5,1-a) isoquinoline is obtained, m.p. 218-220C. The product can be recrystallized from butanol, acetonitrile, pyridine, dichloroan or dimethylformamide, the product does not dissolve in aqueous acids or alkalis. Molecular weight - 255 (mass spectroscopy)

Found,%: C 65.75; And 5.05;

0 N 16.26.

Calculated,%: C 65.86; H 5.13, N 16.46,

Example 2. A mixture of 2.61 g (10 mmol) of 1-41 zonitrosocyanate (methyl) -6, 7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, 60 mp of 50% aqueous ethanol and 3 ml of benzaldehyde kit. 6 h. Excess benzaldehyde is removed by steam distillation. 2.96 g of crude product are obtained. It melts at 170-180 ° C. After recrystallization from acetonitrile, 1.6 g of 1-cyan6-5,6-dihydro-8, 9-dimethoxy-3-phenylimidazo (5,1-a) -isrhinoline with t, pl. ,

five

Found,%: C 72.42, H 5.12} N 12.64.

Calculated,%: C, 72.49; H 5.17; N 12.68.

Example 3, A mixture of 13.05 g (50 mmol) of 1- (isonitrosocyan-6methyl) O-6, 7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, 10 ml of salicylic aldehyde and 180 ml of 50% aqueous ethanol is boiled t for 6 hours. The reaction mixture remains homogeneous throughout the entire boil. After cooling and filtering the reaction mixture, 15.84 g of 1-cyano-5,6-digi-ro-8-dimethoxy-3- (2 hydroxyphenyl) imidazo .- (5,1-a) isoquinoline is obtained, after recrystallization from nitromethane the product melts at 2 ° C. Found,%: C 69.21; H 4.78; N 11.96. Calculated,%: with 69.16, H 4.93, N 12.10. Example 4. 7.65 g (30 mmol 1 cyano-5,6-dihydro-8,9-dimethoxy imidazo (5, la) isoxynoline are boiled in a mixture of 76 MP of a 10% aqueous solution of sodium hydroxide and 200 ml of 96% ethanol within 5 hours. Spi is distilled off, after which the 5, b-dihydro-8,9-dimethoxy-1-carbamo imidazo (5,1-a) isoquinalin formed forms a crystal and 7.92 g of product are obtained. mp 250-252c After recrystallization from 50% aqueous ethanol, 7.06 g of product is obtained, with the same mp found: C 61.49; H 5.36; N 15; 29. "Calculated,%: C, 61.62; H, 5.53; N, 15.37. 3.0 g of the above-named free base is dissolved in 50 ml of 2N hot salt Acidic acid. The solution is cooled, after which 3.11 g of hydrochloride precipitates. M.P. 2BO ° C (decomposes) Found: C 54.24; H 5.06 X N 13.5 °; cr 11.67: Calculated,% C 54.280; n 5.20; N 13.57; Ct 11.44. Similarly, sulfate dihydrate 5, -hydrogen-8,9-dimethoxy-1-carbamoylimidazo (5.1 -a) isoquinoline (Y b.Pl. during foaming 215 Found: C 49.58; H 5.06, N 12.28. Calculated,%: C 49.40; H 5.33; N 12.34. Example 5.1.14 g (5 mmoles) of 1-cyano-5, b-dihydro-8,9-dihydroxy I nol 1 dazo (5,1-a) isoquinoline is stirred in portions into 3 ml of concentrated sulfuric acid and The mixture is left to stand overnight in the refrigerator. Thereafter, crushed ice is added to the mixture and the precipitated precipitate is filtered off. 1.70 g of hydrosulfate 5, b-dihyd ro-8, 9-dioxy-1-arbgi “1OOLYMIDEE-” are added. - (5,1-a) isoquinoline (, H S). Found: C, 48.74; H, 4.40; N, 14.20. Calculated,%: C 48.97, H 4, li; N 14.28. Example 6. A mixture of 2.61 g (10 mmol) of 1- (isonitrososociaiomethyl) -6, 7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, 36 ml of 50% ethanol and 2 ml of butyraldehyde are boiled for 6 h. At the end of the reaction, the reaction mixture is treated with activated carbon –filled charcoal and filtered. From the filtrate, 1-cyano-5,6.-Dihydro-8,9-dimethoxy-3-propylimidazo (5,1-a) isoquinoline crystallizes. T. pl. 1351400С, yield 2.75 g. Example 7. A mixture of 0.87 g (2.5 mmol) of 1-cyano-5, b-dihydro-8,9-dimethoxy-3- (2-hydroxyphenyl) -imidazo (5 , 1-a) isoquinoline), 10 ml of 10% sodium hydroxide solution and 20 ml of 96% ethanol are boiled for 5 hours under reflux. The alcohol is distilled off, the aqueous solution is neutralized with 1N hydrochloric acid to, 5. Get 5, b-dihydro-8,9-dimethoxy-3- (2-hydroxyphenyl) -l-carbamoylimidazo- (5, 1-a) isohins and 1H. Output 0.91 g, so pl. 245-247 ° C (from 50% ethanol) Found,% C 65.95; H 5.06; N 11.56. Calculated,%: C 65.76; H 5.24; M 11.50. Example 8. A mixture of 1.1 g (3.33) 1-cyano-5, b-dihydro-8,9-dimethoxy-3-phenylimidazo (5,1-a) isoquinoline, 10 ml of 10% sodium hydroxide solution and 20 ml of 9.6% ethanol is refluxed for 8 hours. The alcohol is distilled off. The resulting residue (0.90 g) is melted in the range of 223-235 ° C. The product can be recrystallized from acetonitrile or 50% ethanol. Pure 5,6-dihydro-8,9-dimethoxy-8-phenyl-1carbamoylimidazo (5,1-a) isoquinoline (0.71 g) melts at 229-230 s. Found,%: C 68.92; H 5.27; N 11.87. Calculated,%: C 86.76; H 5.48; N 12.03. Example 9. A mixture of 77.7 g (0.3 mol) of 1- (isonitrosocyanomethyl) -3, 4-dihydro-b, 7-dimethoxy-isoquinoline, 450 ml of water, 240 ml-1N hydrochloric acid and 90 ml of 37% Formaldehyde solution is boiled for 2 hours with stirring. The solution becomes colorless and a white precipitate forms. 81.55 g of 1-cyano-5,6-dihydro-8, 9-dimethoxy-2H-imidazo (5,1-a) isoquinolin-3-one is obtained by filtration. M.p. 310-315 p. The product can be recrystallized from 5 times the amount of dimethylformamide. The product is dissolved in 1N sodium hydroxide solution to form the sodium salt, m.p. 3203250s. Found,%: C 61.77; H 4.78; N 15.31. &amp; numerically,%: C 61.98; H 4.83; 15.49. The preparation of the sodium salt is preferably carried out by dissolving the product in a hot 2n sodium hydroxide solution. After cooling the solution, the sodium salt crystallizes, which can be easily recrystallized from 96% ethanol. The sodium salt is highly soluble in water. At m-r 10. A mixture of 2.59 g (10 mmol) of 1- {isonitro-cyanomethyl) -3, 4-digilro-b, 7-dimethoxy-isoquinoline, 18 ml of 37% formaldehyde solution and 18 MP of 961% bale alcohol t for 3 h. After 2 h the crystalline product precipitates. The reaction mixture is filtered. 2.6 g of 1-cyano-8,9-dimethoxy-2H-imidazo (5,1-a) and eoquinolin-3-one are obtained, m.p. 320-32bs (recrystallized from 15 ml of dimethylformamide),

Example 11. 2.3 g (10 mmol) of 1- (cyanomethylene) -6,7-dimethoxy-1,2,3, 4-tetrahydroisoquinoline are suspended in a mixture of 11 ml of 1N hydrochloric acid and 10 MP of water and the reaction mixture is cooled to 0-5 ° C. 0.70 g of sodium nitrite in bhjn water is slowly added dropwise. The addition is continued for more than 0.5 hours. The solution containing the lilac residue is continued to be entangled at room temperature for another 2 hours, 3 ml of a 37% aqueous solution of formaldehyde are added and the mixture is heated to reflux with stirring. The solution becomes discolored and a fresh beige precipitate forms. After filtering the reaction mixture, 2.8 g of 1-cyano-5,6-digidayu-3, 9-dimethoxy-2H-imidazo (5,1-a) isoquinolin-3-one, m.p. 320-325 ° C. After perekrilo; talizatsii from 15 ml of dimethylformamide get 2.4 g of the target product.

Example 12. A mixture of 12.95 g (50 mmol) of 1- (isonitrosocyanomethyl) -3, 4-dihydro-6,7-dimethoxyisoquinoline, 40 ml of 1N hydrochloric acid, 100 ml of water and 10 ml of salicylic aldehyde is boiled under stirring 4 h. The solution is cooled and filtered, the precipitate is shed (3 x 15 mp) with absolute ethanol. 12.97 g of 1-cyano-5,6-dihydro-8, 9-dimethoxy-3- (4-hydroxyphenyl-imidazo (5,1-a) isoquinoline-2-oxide are obtained. T. - pl. 270-273 ° s

The product is recrystallized from 380 ml of nitromethane, and a pure product is obtained. An additional 3.23 g of analytically pure product can be obtained from the reaction mixture mother liquor.

Found,%: C, 66.40; H 4.9-2; I am 11.35.

Credited,%: C 66,12; H 4.72 N, 11.57.

Example 13.12.95 g (50 mmol) of 1- (isonitrosocyanomethyl) -3,4-dihydro-6, 7-dimethoxy-isoquinoline is reacted with 10 ml of benzaldehyde using an analogue of Example 12. 12.05 g of 1-cyano-5,6-dihydro are obtained. -8,9-dimethoxy-3-fe or imidazo (5,1-a) isoquinol of H-2-oxide, so pl. 26 O - 26 2 C. recrystallization from nitrates is obtained 10.41 g of product, m.p. 268270 “S.

Another 2.0 g of product can be obtained from the mother liquor.

Found,%: C 69.45, H 5.14; N 12.31.

Calculated,%: C 69.19; H 4.93 / N 12.09.

Example 14. 5.18 g (20 mmol) of 1- (isonitrosocyanomethyl) -3,4-dihydro-6,7-dimethoxy-isoquinoline is reacted with 4.0 g of butyraldehyde as in Example 12. A dark solution is obtained, which is treated with activated carbon and filtered. 4.54 g of crude 1-cyano-5, 6-dihydro-8,9-dimethoxy-3-propyl imidazo (5,1-a) isoquinolin2-oxide is precipitated from the filtrate by treating with 30 ml of a saturated aqueous solution of sodium hydroxide. The product is recrystallized from 25 MP abssypny ethanol. Yield 4.02 g, m.p. pure product

0

Example 15. 1.11 g (30 mmol) of 1- (isonitrosocyanomethyl) -3,4-dihydro-6,7-dimethoxy-isoquinoline is reacted with 5.44 g (40 mmol) of anisic aldehyde (as in Example 12), After filtering The reaction mixture is obtained as a crude product, which contains a significant amount of an isonitroso derivative. The crude product is boiled with a 10% sodium carbonate solution. 2.47 g of 1-cyano-5, 6-di hydro-8,9-dimeto xi-3- (4-methoxyphenylimidazo) - (5,1-a) isoquinoline-2-oxide is obtained. M.p. 262-c (with decomposition),) Example 16. 2.59 g (0.01 mol) of 1- (isonitrosocyanomethyl) -3,4-dihydro-6,7-dimethoxyisoquinoline and 2.65 g of o-nitrocoric aldehyde boil t in a mixture of 8 ml of 1N hydrochloric acid and 20 ml of water for 4 hours. 3.71 g of product is obtained by filtration. After recrystallization from 50 ml of dimethylformamide, 1.74 g of pure 1-cyano-5,6-dihydro-8 is obtained , 9-dimethoxy-3- (-o-nitrostyrylimidazo) - (5,1-a) and zoquinoline-2-oxide. M.p. 268-270 ° С (with decomposition).

Found,%: C 62.89 / H 4.19; N 13.20.

Calculated,%: C 63.15, H 4.34; N 13.39.

Example 17. 5.18 g (0.02 mmol 1- (isonitrosocyanomethyl) -3, 4-dihydro-6, 7-dimethoxyisoquinoline is boiled with stirring for 2 hours with 4.5 g (0 , 06 mol) of glycolic acid in 40 MP of water. 5.0 g of 1-cyaio-5,6-dihydro-8,9-dimethoxy-2 H-imidazo (5,1-a) isochmolin-3-one is obtained. The product is identical to the product obtained in examples 9-11.

Example 18. 5.18 g of 1- (isonitrosocyanomethyl) -3,4-dihydro-b, 7-dimethoxy-isoquinoline is mixed with 20 MP of a 20% aqueous solution of acetone, thaldehyde, then 16 ml are added

Claims (1)

Claim The method of obtaining derivatives of 5,6-dihydroimidazo (5,1-a) isoquinoline I formulas where R is alkyl with 1-4 atoms - - hydrogen or mami carbon; - nitrile or carbamoyl group; - oxygen or electron pair; - hydrogen, alkyl with 1-3 carbon atoms, unsubstituted phenyl or phenyl substituted with an oxyalkoxy group with 1-4 carbon atoms, halogen, dimethylamino group, styryl, nitrostyryl or, nitrofuryl, and when B is not oxygen, hydroxyl, or their salts , characterized in that, of the general formula about the connection S-X-0H I 'A And they have the above a Z where R and values, a Z is hydrogen or together form a multiple bond, they are reacted with the aldehyde of the general Formula ’• ¥ - СНО, where Y has the above values, followed by isolation of the target product in the form of a base or salt.