DK141067B - Process for Preparation of Aminoimidazolisoquinoline Derivatives. - Google Patents

Description

(jef) (11) PUBLICATION MANUAL 141 OB 7 DENMARK (Μ) int ci.3 c 07 o 471/02 * (21) Application No. 5454/77 (22) filed on the 8th of December. 1977 m (23) Lebedee <3un · * 973 (44) The application presented and the petition published on 7 · J 3Π »1 980

DIRECTORATE OF

PATENT AND TRADE MARKET (30) Priority requested from it

30. jun. 1972, Cl 1248, HU

(71) CHINOIN GTOGYSZER ES VEGYESZETI TERMEKEK GYARA HT., Budapest IV., Two hours 1-5, HU.

(72) Inventor: Kalman Takacs, Budapest VIII. Vas u. 12, HU: Laszlo Szeke * 8 res, Szeged, Kazinczy u. 2., HU: Kalman Harsanyi, Budapest XI., "" Egry Jozsef u. 19- 21., HU: Gyula Father, SzegedT Becsi Map 37-39 ·, HU: An = dras Neszmelyi, Budapest II., Tarogato u. 8., HU: Eva Benedek, Gyor,

Sagvari Change u. 16., HU.

(74) Plenipotentiary in the proceedings:

Office of Industrial Energetic v. Svend Schønnlng, (54) Process for the preparation of aminolmdazolisoquinoline derivatives.

The present invention relates to a particular process for the preparation of novel aminoimidazolisoquinoline derivatives of the general formula A "X.-NHD

-N

or acid addition salts thereof, in which formulas A, Y and D have the meanings set forth in the preamble of the claim.

It has been found that the compounds of the general formula I decrease coronary flow resistance, promote throughput, decrease heart muscle oxygen consumption, improve quotient (-supply / O 2 consumption which expresses the heart's oxygen supply and favorably affect the efficiency of cardiac work).

The process for preparing the novel amino-imidazole derivatives of general formula I is characterized by acylating an isoquinolylacetamidoxim of the general formula

A

a-C-NH_

Y 1-OH

wherein A and Y have the above meanings, with a sulfonic acid halide or a carboxylic acid derivative in excess or in equimolar amount, upon reacting, if desired, a won compound of formula I wherein D is hydrogen, with an alkanoylating agent, a benzoylating agent , a phenylalkanoylating agent or a benzenesulfonylating agent for introducing a group D which is an optionally substituted alkanoyl group having from 1 to 4 carbon atoms, a benzoyl group, a phenylalkanoyl group having 1-4 carbon atoms in the alkyl moiety or an optionally having an alkyl group having 1- 4 carbon atoms substituted benzenesulfonyl group or, if desired, reacting a compound of formula I wherein D is hydrogen with an aldehyde or ketone of the general formula

D '= O

wherein D 'is an alkylene group of 1-4 carbon atoms or a phenylalkylene group of 1-4 carbon atoms in the alkylene moiety, followed by reduction, or if desired, hydrolyzes a compound of formula I wherein D is an acyl group and / or if desired converts it obtained compound to an acid addition salt thereof or release the free base from a won acid addition salt.

141067 3

The process according to the invention is inherently peculiar. Thus, according to the literature (F. Eloy and R. Lenaers Chem. Rews. 62, 177 (1962)), one would expect that upon acylation of compounds of formula II, O-acyl derivatives of compounds of formula II would be formed and that which, upon cyclization of the latter, 1,2,4-oxadiazo derivatives would be obtained. However, it has surprisingly been found that upon acylation of the isoquinolylacetamide oxyiro, imidazo [5,1-a] isoquinoline derivatives are formed, and thus not as expected from the above literature site 1,2,4-oxadlazole derivatives: · * CH3 ° YoO in CH2 -? - NH2 \ N-OH \, CH30_2

CH "-C-N

L Y

Experiment A

The pharmacological studies are performed by the following methods on anesthetized dogs (Nembutal 25 mg / kg i.v.).

1. Effect on arterial pressure

The arterial pressure was measured in the main artery of anesthetized dogs by means of a measuring instrument with an electrometer and the measured values were recorded continuously on a multimeter.

4 141067 2. Coronary expansion effect

Coronary flow was measured by a thermodilution process, which operates on the basis of a stationary sustained cold fluid infusion initiated in the coronary sinus (L. Szekeres, J. G. Papp and E. Fischer: Acta Physiol. Acad. Sci. Hung, 33, 115, 1969). and was continuously recorded on a micrograph by means of a thermocouple also introduced into the sinus coronarius and expressed in ml / min / 100 g. The coronary resistance is indicated in a self-selected unit on the basis of the arterial pressure coefficient (mm Hg) and the coronary flow measured in the sinus. coronarius (ml / min / 100 g).

3. Effect on cardiac oxygenation

During the mentioned dog test, at the same time as the coronary flow measurement, oxygen saturation in blood samples extracted from the coronary sinus through the oximeter measuring cuvette with a stationary velocity peristaltic pump was also continuously recorded and returned to the brachial vein. In addition, the oxygen saturation of the arterial blood was determined and with the pressure gauge the hemoglobin content of the blood was also determined. From these results, the oxygen consumption of the left heart chamber (ml / 100 g / min) was calculated. In addition, to characterize the oxidative metabolism of the heart muscle and the sufficient oxygen supply, the quotient 02 supply / 02 required was calculated. For further details, see L. Szekeres, J. Gy. Papp and E. Fischer: European J. Pharmacol., 2, 1, 1967.

4. Impact on the efficiency of left ventricular function

Following L. Szekeres, J. Gy. Papp and E. Fischer: Acta Physiol. Acad. Sci. Hung., 33, 115, 1969, the minute volume and arterial pressure were recorded by the "cold fluid infusion method" and the work of the left ventricle was calculated. In addition, as already described, the C ^ consumption of the left heart chamber was calculated. Based on the quotient: left heart chamber work (kgm / min) / left heart chamber C ^ consumption (ml / min / 100 g), the magnitude of the efficiency of left heart chamber work was also determined.

5. Toxicity

The acute toxicity determination was performed on rats weighing 150-200 g. The dose was injected for a maximum of 5 seconds in a volume of 0.2 ml / 100 g in the tail vein. The LDjjq value and tolerance limits were calculated according to Litchfield and Wilcoxon on the basis of the number of dead animals over 24 hours (J. Pharmacol, exp. Ther., 96, 99, 1949).

141067 5

Results: 1) 3-Amino-5,6-dihydro-8,9-diethoxyimidazole5,1-a] isoquinoline.

The compound increases at a dose of 3 mg / kg contractility by 20%, decreases resistance in the pulmonary vessel area at a dose of 3 mg / kg by 20%. In the in situ condition, the electrical fibrillar threshold was increased by 72% in the cat's anterior chamber muscle at a dose of 2 mg / kg.

2) 3-Acetylamino-5,6-dihydro-8,9-dimethoxyimidazo [5,1-a] isoquinoline.

The compound increases at a dose of 2-3 mg / kg contractility by 20%, decreases resistance in the pulmonary vessel area at a dose of 4 mg / kg by 20%. In the insitu condition, the electrical fibrillar threshold was increased by 50% in the cat's anterior chamber 1 at a dose of 2 mg / kg.

3) 3-Ethylamino-5,6-dihydro-8,9-dimethoxyimidazo [5,1-a] isoquinoline.

The compound increases at a dose of 2 mg / kg contractility by 25%. The efficiency of the heart function is improved. At a dose of 2 mg / kg, blood flow / min is increased. in anesthetized dogs by 25%. In the in situ condition, the electrical fibrillar threshold was increased by 90% in the cat's anterior chamber muscle at a dose of 2 mg / kg.

Experiment B

Compounds tested: HE-36: 3-benzylamino-5,6-dihydro-8,9-dimethoxyimidazo [5,1-a] isoquinoline hydrochloride (Example 4).

HE-26: 3-amino-5,6-dihydro-8,9-diethoxyimidazo [5,1-a] isoquinoline (Example 3).

Quinidine: A commercially available product recognized as an excellent antiarrhythmic agent.

Attempt:

The toxic effect of the compounds was investigated by intravenous administration in rats and the antiarrhythmic effect was determined on the basis of the electrical fibrillar threshold in the cat's anterior and cardiac muscle. The results are presented in Table 1 below. It is evident from the results in Table 1 that the compounds of the present invention have a significantly better antiarrhythmic effect over the known comparison compound.

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The process according to the invention is explained in more detail below by means of some examples,

Example 1 50 ml of pyridine are added to 13.2 g of 6,7-dimethoxy-3,4-dihydroisoquinoline (1) -acetamidoxime, and 9.5 g of tosyl chloride are added under stirring and cooling within 15 minutes. The reaction mixture is stirred for 2 hours at 70 ° C and left to stand overnight in a refrigerator. The separated product is filtered off, washed with absolute alcohol and dried. 9.2 g of 3-amino-5,6-dihydro-8,9-dimethoxyimidazo [5,1-a] isoquinoline hydrochloride are obtained. Mp: 272-274 ° C (from alcohol). To release the base, the hydrochloride salt is dissolved in hot water and the solution is alkalized with 10% sodium hydroxide solution. The base crystallizes and can be purified by recrystallization from alcohol.

Calculated for: C, 63.65; H, 6.16; N, 17.13

Found: C 63.42 H 6.32 N 16.92%.

In the product's nuclear magnetic resonance spectrum (AEI-RS 60 MHz), the proton in position 1 appears in a solution in CDC13 ~ DMS0 at 6.70 ppm.

Example 2 In the manner set forth in Example 1, 29 g of 6,7-dimethoxy-3,4-dihydroisoquinolyl- (1) -acetamidoxime and 13 ml of benzoyl chloride are obtained 25.6 g of 3-amino-5,6- dihydro-8,9-dimethoxyimidazo [5,1-a] isoquinoline hydrochloride. The product is identical to the product obtained in Example 1.

The same product is obtained when in the reaction described above instead of benzoyl chloride chloro formic acid ethyl ester is used.

8 U1067

Example 3 60 ml of pyridine are added to 14.56 g of 6,7-diethoxy-3,4-dihydroisoquinolyl- (1) -acetamidoxime, and 7.6 g of benzoyl chloride are added dropwise to the mixture with stirring and cooling. The solution is stirred for 1 hour at 50-60 ° C and then the solvent is evaporated under vacuum. The residue is suspended in ethyl acetate and 12.65 g of 3-amino-5,6-dihydro-8,9-diethoxyimidazo [5,1-a] isoquinoline hydrochloride monohydrate is obtained, m.p. 206-208 ° C (from alcohol).

Calc'd for C 15 H 22 N 3 O 3 Cl: C 54.96 H 6.77 N 12.81 Cl 10.82 Found: C 54.81 H 6.64 N 12.76 Cl 10.69%.

The hydrochloride salt obtained above is dissolved in 70 ml of warm water and the solution is decolorized with charcoal, filtered and alkalized with a 10% sodium hydroxide solution. 9.7 g of 3-amino-5,6-dihydro-8,9-diethoxyimidazo [5,1-a] isoquinoline are obtained, m.p. 212-214 ° C (from alcohol).

Example 4 1.1 g of benzaldehyde and 20 ml of absolute alcohol are added to 2.3 g of 3-amino-5,6-dihydro-8,9-dimethoxyimidazo [5,1-a] isoquinoline and the reaction mixture is refluxed for 5 hours. . After cooling, 3.1 g of crystallized 3-benzylideneamino-5,6-dihydro- 8,9-dimethoxyimidazo [5,1-a] isoquinoline is obtained, m.p. 176 ° C (from alcohol). Calculated for C 20 H 19 N 3 O 2: C 72.05 H 5.75 N 12.61

Found: C, 72.35; H, 5.80; N, 12.69%.

1.6 g of the product obtained above is dissolved in 100 ml of methanol and 0.5 g of sodium borohydride is added to the solution within 1/2 hour. The solution is allowed to stand for 1 hour at room temperature and the solvent is removed. Water is added to the residue and the product crystallizes. The product is filtered and dried. 1.7 g of 3-benzylamino-5,6-dihydro-8,9-dimethoxyimidazo [5,1-a] isoquinoline are obtained. Mp. 135 ° C.

Calculated for C₂2H₂NN30O₂: C 71.62 H 6.31 N 12.53

Found: C, 71.52; H, 5.98; N, 12.42%.

In the nuclear magnetic resonance spectrum, the proton appears at position 1 at 6.85 ppm.

141067 9

Example 5 30 ml of acetic anhydride are added to 8 g of 3 'amino-5,6-dihydro-8,9-dimethoxyimidazo [5,1-a] isoquinoline and the mixture is heated on a water bath for 1/2 hour. The mixture is then poured into 150 ml of ice water. The solution is neutralized with sodium carbonate and the separated crystals are filtered. 6.2 g of 3-acetylamino-5,6-dihydro-8,9-dimethoxyimidazo [5,1-a] isoquinoline are obtained, m.p. 225 ° C (from absolute alcohol).

Calculated for C 15 H 17 N 3 O 3: C 62.70 H 5.96 N 14.63 Found: C 62.40 H 5.90 N 14.69%.

Example 6 30 ml of chloroform and 1.4 g of potassium carbonate are added to 2.45 g of 3-amino-5,6-dihydro-8,9-dimethoxyimidazo [5,1-a] isoquinoline and, with stirring, 1.15 g of chloroacetyl chloride are added dropwise. ^ s to the mixture. The mixture is stirred at room temperature for 5 hours and 20 ml of water is added. The chloroform phase is separated, dried over sodium sulfate and evaporated. 1.4 g of 3-chloroacetylamino-5,6-dihydro-8,9-dimethoxyimidazo [5,1-a] isoquinoline are obtained, m.p. 251 ^ 0 (from alcohol).

Calcd for C 15 H 16 N 3 ° 3 Cl: C 55.99 H 5.01 N 13.06 Cl 11.02

Found: C 56.20 H 4.93 N 12.84 Cl 11.16%.

Example 7 15 ml of water and 0.7 g of benzoyl chloride are added to 1 g of 3-amino-5,6-dihydro-8,9-dimethoxyimidazo [5,1-a] isoquinoline and the pH of the reaction mixture is cooled under cooling and stirring for 10 minutes. -11 by addition of 10% s sodium hydroxide solution. 1.3 g of 3-benzoylamino-5,6-dihydro-8,9-dimethoxyimidazo [5,1-a] isoquinoline is obtained, m.p. 258 ° C (from alcohol).

Calc'd for <- 20 20 t 19 N 3 ° 3: 68.75 H 5.48 N 12.03

Found: C, 68.60; H, 5.74; N, 12.05%.

Example 8

To 1.3 g of 3-acetylamino-5,6-dihydro-8,9-dimethoxyimidazo [5,1-a] isoquinoline are added 15 ml of a 5% sodium hydroxide solution and the mixture is refluxed for 1 hour. After cooling, 0.8 g of 3-amino-5,6-dihydro-8,9-dimethoxy imidazo [5,1-a] isoquinoline is recovered in crystalline form. The product is identical to the product of Example 1. Mp. 234-236 ° C.

Example 9 2.4 g of 3-amino-5,6-dihydro-8,9-dimethoxyimidazo [5,1-alisoquinoline is heated for 3 hours with 1.2 ml of butyraldehyde and 45 ml of anhydrous ethanol. Half of the solvent is distilled off and 1.0 ml of butyraldehyde is added to the residue. The reaction mixture is boiled for 3 hours and then cooled to room temperature. Within 30 minutes, 0.6 g of sodium borohydride is added with stirring. The reaction mixture is boiled for 30 minutes and then evaporated to dryness. To the residue is added 15 ml of water and the separated product is filtered. 2.1 g of 3-butylamino-5,6-dihydro-8,9-dimethoxyimidazo [5,1-a] isoquinoline monohydrate are obtained, m.p. 134-136 ° C (from 96% ethanol) -

Calculated: C 63.93 H 7.89 N 13.16 Found: C 63.62 H 7.98 N 12.88%.

Claims (1)

A process for preparing aminoimidazolisoquinoline derivatives of the general formula L Nv X-NHD Λ-Γ Y or acid addition salts thereof, wherein A is an alkoxy group having 1-4 carbon atoms, Y being a hydrogen atom or an alkyl group having 1-4 carbon atoms, or a phenyl group, and D is a hydrogen atom, an alkyl group of 1-4 carbon atoms, a phenylalkyl group of 1-4 carbon atoms in the alkyl moiety, an optionally substituted alkanoyl group of 1-4 carbon atoms, a benzoyl group, a phenylalkanoyl group of 1-4 carbon atoms in the alkyl moiety or, optionally, with an alkyl group of 1-4 carbon atoms substituted by benzenesulfonyl group, characterized in that an isoquinolyl acetamidoxime of the general formula ίΛΛ / 11, CC-NHO Y₂S-OH where A and Y have the meanings given above, is acylated by a sulfonic acid halide or a carboxylic acid derivative in excess or in equimolar amount to react, if desired, a won compound of formula I wherein D is hydro gene, with an alkanoylating agent, a benzoylating agent, a phenylalkanoylating agent or a benzenesulfonylating agent for introducing a group D,