FI56383C - PROCEDURE FOR FRAMSTRACTORING OF NUTRITIONAL 2-AMINO-5,6-DIHYDRO-8,9-DIALCOXY-PYRAZOLO (5,1-A) Isoquinoline DERIVATIVES - Google Patents

Description

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Patent · och reglsteratyrelsen AmöIuui utiagd och uti ^ kriftsn publicsrad 28.09.79 (32) (33) (31) Pyydetty ttuoiksui -Begird prloritst 30.06.72

Hungary-Hungary (HU) CI-1248 (71) Chinoin Pharmaceuticals and Chemicals Gyära RT., Τβ u. 1-5 »" Budapest IV, Hungary-Hungary (HU) (72) Kiiman Takäcs, Budapest, Laszlo Szekeres, Szeged, Kiiman Harsinyi,

Budapest, Gyula Papp, Szeged, Andris Neszmelyi, Budapest,

Eva Benedek, Gyor, Hungary-Hungary (HU) (7 ^) Oy Kolster Ab (5 * 0 Method for the development of new 2-amino-5,6-dihydro-8,9-dialkoxy-pyrazolo / 5,11- 2-Amino-5,6-dihydro-8,9-dialkoxy-pyrazolo [5,1-a] isoquinoline derivatives (62) Separated from application 205 (73) (for the preparation of α-isoquinoline derivatives). The present invention relates to a process for the preparation of novel cardiac active 2-amino-5,6-dihydro-8,9-dialkoxy-pyrazolo [4,1-a] isoquinoline derivatives. for the preparation of which, is the general formula XCl IUL.

wherein A is an alkoxy group having 1 carbon atom, and D is a hydrogen atom, an alkyl group containing 1 carbon atom, an alkanoyl group optionally substituted by 1 to 1 carbon atoms of halogen atoms, or a benzyl, benzoyl, phenacetyl 2,5363 li- or toluenesulfonyl group, and acid additions thereof for the preparation of salts.

It has been found that the compounds of general formula (i) reduce coronary flow resistance, promote flow, reduce myocardial oxygen consumption, improve the quotient of Og supply / O2 requirement, which indicates the oxidative capacity of the heart and have a beneficial effect on the severity of cardiac function.

According to the invention, compounds of formula (i) are prepared by a) cyclizing a 3,5-disubstituted compound of formula I in which D is a hydrogen atom, an alkanoyl group having 1 to 4 carbon atoms, optionally substituted by halogen atoms, or a benzoyl or phenacetyl group. - - 1.2.4-Oxazole derivative * having the formula: xx? - 'CHT1

NN

0 R

wherein A is as defined above and R is an alkyl group, phenyl group or benzyl group optionally substituted by halogen atoms having 1 to 3 carbon atoms, by heating either as a melt or in a suitable organic solvent such as xylene or tetralin by redistillation, or in a slightly alkaline alcohol alkali metal hydroxide solution, a compound of formula (i) wherein D is an alkanoyl group having 1 to 4 carbon atoms, a benzoyl group or a phenacetyl group optionally substituted by halogen atoms to give a compound of formula (I) wherein D is a hydrogen atom, or b) a compound of formula (i) to prepare compounds in which D is as defined in the species definition, a 3,5-disubstituted-1,2,4-oxazole derivative of formula (II) in which A and R are as defined above is cyclized by refluxing in a strongly basic alcohol-alkali metal hydroxide solution and, if desired, reacting a compound of formula (i) wherein D is a hydrogen atom with the corresponding aldehyde and, if desired, reducing the compound of formula (i) thus formed, optionally not first isolated, to a compound of formula (I) wherein D is 1-4 an alkyl group containing a carbon atom, or a benzyl group, or acylated to a compound of formula (i) wherein D is an alkanoyl group having 1 to 4 carbon atoms, a benzoyl group, a phenacetyl group or a toluenesulfonyl group optionally substituted by halogen atoms, and the resulting compound of formula (i) , or the acid addition salt is converted to the free base,

Pharmacological studies were performed in anesthetized dogs (Nembuta-li 25 mg / kg i.v.) by the following methods $ 1. Effect on arterial pressure

The mean arterial pressure in the main artery of the dogs was measured intravenously with a measuring device that included an electrical manometer, and the measured values were recorded continuously with a Multiscriptor. The results are shown in Table I.

2. Coronary dilating effect

Coronary flow was measured by a thermodilution method based on continuous infusion of cold fluid into Sinus Coronarius * (Szekeres L.,

Papp J. Gy., Fisher, E .: Acta Physiol. Acad. Sci. Hung. 33, 115, 1969), and recorded on a micrograph continuously in the same manner using a thermocouple inserted into Sinus Coronarius, the results being reported in ml / min / 100 g. Coronary resistance was expressed as self-selected units as the quotient of mean arterial pressure (mm Hg) and coronary flow (measured in Sinus Coronarius * in ml / min / 100 g). The results are shown in Table TI, 3. Effect on cardiac oxygen uptake

During these canine experiments, simultaneously with coronary flow, the oxygen content of the blood sample, which was aspirated from Sinus Coronarius * with a peristaltic pump at a constant rate through an oxygen meter measuring cuvette and returned to the upper arm vein, was also recorded. In this case, the oxygen content of the arteries was also measured, and the hemoglobin content of the blood was also determined with a manometer. Based on these data, left ventricular oxygen consumption (ml / 100 g / min) was calculated. To characterize myocardial oxygen metabolism and adequate oxygen uptake, a quotient of 0 ,, supply / O ^ need was also calculated. (For more details, see Szekeres, L., Papp, J. Gy., Fischer, E .; European J. Pharmacol 2, 1 (1967)). The results are shown in Table III.

h. Effect on the efficiency of work performed by the left ventricle

By the method of Szeres, L., Papp, J. Gy,, Fischer, E. (Acta Physiol. Acad. Sci. Hung. 33, 115, 1969), the so-called by the "cold fluid infusion method", the minute volume and mean arterial pressure were recorded, from which the left ventricular rate was calculated, as well as the O 2 consumption of the left ventricle was calculated, as already described, and thus determined from the following quotient; left ventricular work (mg / min): left ventricular Og consumption ml / min / 100 g also the effect of the compound on left ventricular work. The results are shown in Table IV.

5. Toxicity

Acute toxicity was studied in rats weighing 150-200 g. A dose (0.2 ml / 100 g) was injected into the tail vein over a maximum of 5 seconds.

* · 56383 The LD50 value and the tolerance limit were determined by the method of Litchfield1 and Wilcoxon on the basis of the number of animals that died in 2 hours (J. Pharmacol, exp. Ther.

96, 19 * »9).

Results of pharmacological tests

The following are the results of pharmacological tests of some of the compounds of the invention: a) 2-amino-5,6-dihydro-8,9-dimethoxypyrazolo [5,1-a] isoquinoline Arterial pressure __

Dose Baseline value of experimental animals Changed value Difference mg / kg number mm Hg mm Hg% i.v.

1 1 · | I I - I ......... «I. . I M ·,. - <I J I O lii ........ 1 «- 1 5 127 IOU -18 2 5 12U 92" 26 1+ 6 105 97 -36

Test 2.

Dose Test Coronary Artery Flow_ Coronary Impairment mg / kg Animal Baseline Altered Difference Baseline Altered Difference i.v. number * * value value% pressure value% 1 5 2m 87 +1+ 1.86 1.1 * 6 -22 2 5 82 100 +22 1.90 1.31 -31 U 6 81+ 108 +29 1.33 0.71 -1 * 7

Test 3.

Dose Test- Left ventricular 0g- Og supply / Og requirement mg / kg animal consumption ml / min / 100 g_____________ i.v. number basic ~ Changed Difference Basic Changed Difference value value% value value% 1 5 9.8 8.0 -18 1.1 * 8 1.68 + ll + 2 5 9.1 * 7.5 -20 1.51 1 , 93 +28 1 * 6 8.7 8.7 - 1.77 2.12 +20

Test 1 *.

Dose Test- Effect on left atrial function mg / kg of animals ^ Baseline Changed value Difference% i.v. number 1 5 0.35 0.1 * 9 + 1 + 0 2 5 0.36 0.1 * 6 +28 1 * 6 0.27 0.33 +22 S6383

Test 5.

The toxicity (LD ^ q) of the compound was 70/3 ^ -11 + 8 mg / kg (95% tolerance limits. At 1-1 + mg / kg the compound improves contractility by 29%, at 3 mg / kg pulmonary vascular resistance decreases %, at a dose of 3 mg / kg lowers the resistance in the pulmonary vasculature by 20% In a caged cat, the electrical atrial fibrillation threshold increases in situ at a dose of 2 mg / kg by 72%.

h) 2-Benzylamino-5,6-dihydro-8,9-imimethoxy-4-pyrrolo Solo [5,1-a] isoquinoline. The product reduces arterial pressure at a dose of 2-1 + mg / kg i.v., about 10-15% t improves flow through the lungs, increases heart efficiency.

c) n-Acetyl® amino-5,6-dihydro-8,9 "dimethoxy-pyrazolo [5,1-a] isoquinoline. The compound reduces arterial pressure by about 15% at a dose of 2-1 + mg / kg iv, at a dose of 1+ mg / kg of resistance in the pulmonary vascular region by 15-20%, and increases cardiac efficiency, d) 2-β-thiaziazino-η 5,6-dihydro-8,9-methoxy-pyrazolo / 5,1-β-isoquinoline. -1+ mg / kg i, v. Arterial pressure 10-15

Blood circulation in the lungs improves by 15-20%. The rate of heart function is improved.

e) 2-Benzoyl-5,6-dihydro-8,9-dimethoxy-pyrazolo [5,1-a] isoquinoline. The compound reduces at a dose of 2-1 + mg / kg i.v. arterial pressure of about 15%, improves blood circulation in the lungs by 15 ^ 20% and enhances heart function.

The compounds prepared by the process of the invention are more preferred than the corresponding known compounds. The following table compares a compound of the invention with corontin, a well known, effective commercial product; LD Pulmonary circulation Cardiac oxygen consumption, 5 healing effect «(mouse) relative therapeutic relative therapeutic effect index index 2-amino-5,6-dihydro-8,9-dimethoxy-pyrazolo [5,1-b] isoquinoline 80 mg / kg 1.3 29.6 0.23 7 »6 corontin 11 mg / kg 1.0 3.9 1.00 l +, 6 6 66383

The compounds of the general formula I and their salts can be used in pharmacy as pharmaceutical preparations containing the active ingredient and non-toxic, inert, organic or inorganic carriers commonly used in pharmaceutical preparations. The preparations are formulated into solid dosage forms (e.g., tablets, film-coated tablets, granules, enteric granules, pills, capsules) or liquid dosage forms, e.g., suspensions, solutions, or emulsions. Suitable carriers are talc, starch, gelatin, water, polyethylene glycols, etc. The preparations may additionally contain other excipients such as wetting agents, emulsifying or suspending agents, buffers or salts for varying the osmotic pressure, and disintegrants and / or other pharmaceutically active substances.

Example 1 To 200 mg of 3- (6,7-dimethoxy-3,4-dihydro-1-isoquinolyl) methyl-5-benzyl-1,2,4-oxidiazole is added 5 ml of xylene, and the reaction mixture is refluxed. 8 hours. The mixture is allowed to cool and then 10 ml of petrol are added. 170 mg of 2-phenylacetylamino-5,6-dihydro-8,9-dimethoxypyrazolo [5,1-d] isoquinoline are obtained, m.p. 225-227 ° C (butanol).

Analysis: Calculated% found% C 69.40 69.50 H 5.82 5.80 N 11.56 11.45.

Example 2 50 ml of alcohol and 10 ml of 10% sodium hydroxide solution are added to 1.75 g of 3- (6,7-dimethoxy-3,4-dihydro-1-isoquinolyl) methyl-5-phenyl-1,2,2 4-oxadiazole, and the reaction mixture is refluxed for 3 hours. The alcohol is evaporated off in vacuo and water is added to the residue. 1.2 g of 2-benzoylamino-5,6-dihydro-8,9-dimethoxypyrazolo [5,1-b] isoquinoline are obtained, m.p. 185 ° C (alcoholic).

Analysis: Calculated% found% C 68.75 68.52 H 5.48 5.65 N 12.03 11.83.

7 56303

Example 3 To 1 g of 3- (6,7-dimethoxy-3,4-dihydro-1-isoquinolyl) -methyl-5-phenyl-1,2,4-oxadiazole is added 10 ml of xylene, and the reaction mixture is refluxed. 8 hours. After cooling the mixture, 0.9 g of crystalline 2-benzoylamino-5,6-dihydro-8,9-dimethoxypyrazolo (S, 1-8) isoquinoline is obtained, which is identical to the compound prepared in Example 2.

Example 4 25 ml of alcohol and 7 ml of 40% sodium hydroxide solution are added to 1 g of 3- (6,7-dimethoxy-3,4-dihydro-1-isoquinolyl) methyl-5-phenyl-1,2, 4-oxadiazole, and the reaction mixture is refluxed for 8 hours. The alcohol is then evaporated in vacuo and water is added to the residue. 0.6 g of crystalline 2-amino-5,6-dihydro-8,9-dimethoxypyrazolo [5,1-b] isoquinoline is obtained, m.p. 216-217 ° C (from alcohol).

Analysis: Calculated% C 18 H 18 N 2 O 2 O% obtained% C 63.65 63, 1 + 5 H 6.16 6.40 N 17.13 The 16.95 NMR spectrum shows a 1-position proton at 5.85 ppm.

Example 5 0.6 g of benzaldehyde and 10 ml of absolute alcohol are added to 1.2 g of 2-amino-5,6-dihydro-8,9-dimethoxypyrazolo [5,1-4] isoquinoline, and the reaction mixture is refluxed for 4 hours. . After cooling, 1.1 g of crystalline 2-benzylideneamino-5,6-dihydro-8,9-dimethoxypyrazolo [1,1-a] isoquinoline are obtained, m.p. 163 ° C.

Analysis: C 20 H 18 N 3 O 2 calculated% obtained% C 72.05 71.88 H 5.75 6.01 N 12.61 12.50 0.9 g of the product obtained above is dissolved in 100 ml of methanol, and 0.2 g of sodium borohydride. The solution is allowed to stand for one hour, then the solvent is evaporated off under vacuum and water is added to the residue. 0.8 g of 2-benzylamino-5,6-dihydro-8,9-dimethoxypyrazolo [5,1-a] isoquinoline is obtained, m.p. 156 ° C (alcoholic).

Analysis: C 20 H 21 N 3 O 2 Calculated% obtained% C 71.62 71.86 H 6.31 6.08 N 12.53 12.64.

* 8 56383 5.7 g of this product are dissolved in 80 ml of acetone and the solution is acidified with HCl / abs. ethanol solution. 5.5 g of crystalline 2-benzylamino-5,6-dihydro-8,9-dimethoxypyrazolo [5,1-b] isoquinoline hydrochloride are obtained, m.p. 206-208 ° C.

Analysis: Calculated% obtained% C 6i *, 59 64.70 H 5.96 6.12 N 11.31 11.52

Cl 9.53 9.38 The NMR spectrum shows a 1-position proton at 5.73 ppm.

Example 6 5.0 ml of acetic anhydride are added to 1 g of 2-amino-5,6-dihydro-8,9-dimethoxypyrazolo [5,1-b] isoquinoline, and the reaction mixture is heated on a water bath for 10 minutes, after which the mixture is allowed to stand for one hour. . The mixture is poured onto ice to give 0.8 g of crystalline 2-acetylamino-5,6-dihydro-8,9-dimethoxypyrazolo [5,1-b] isoquinoline, m.p. 223 ° C (75% alcohol).

Analysis: Calculated for C 18 H 18 N 2 O 3%% obtained% C 62.70 62.56 H 5.96 5.78 N 14.63 14.60.

Example 7 20 ml of chloroform and 1.4 g of potassium carbonate are added to 2.45 g of 2-amino-5,6-dihydro-8,9-dimethoxypyrazolo [5,1-b] isoquinoline, and the mixture is added dropwise with stirring. 15 g of chloroacetyl chloride. The mixture is stirred at room temperature for 5 hours, then 20 ml of water are added. The chloroform phase is separated, dried over sodium sulfate and evaporated to dryness. 2 g of 2-chloroacetylamino-5,6-dihydro-8,9-dimethoxypyrazolo-η 5 -1,7-isoquinoline are obtained, m.p. 152-154 ° C (alcoholic).

Analysis: Calculated% for C 18 H 19 N 2 O 2 Cl 2%% C 55.99 56.10 H 5.01 4.93 N 13.06 12.80

Cl 11.02 10.82.

9 56383

Example 8 1 g of 2-amino-5,6-dihydro-8,9-dimethoxypyrazolo [5,1-3] isoquinoline is reacted with 0.7 g of benzoyl chloride as described in Example 6 to give 1 g of 2- benzoylamino-5,6-dihydra-8,9-dimethoxypyrazolo [5,1-b] isoquinoline, m.p. 185 ° C (alcoholic).

Analysis: C 20 H 19 N 3 O 3 Calculated% obtained% C 68.75 68.52 H 5.48 5.65 N 12.03 11.83

Example 9 To 0.5 g of acetylamino-5,6-dihydro-8,9-dimethoxypyrazolo-η 5 -1,4-isoquinoline is added 10 ml of 2-hydrochloric acid, after which the solution is refluxed for 1/2 hour. After cooling, 0.5 g of 2-amino-5,6-dihydro-8,9-dimethoxypyrazolo [5,1-a] isoquinoline hydrochloride dihydrate is obtained in the form of crystals, m.p. 128-130 ° C.

Analysis: Calculated% C 18 H 19 N 2 O 2 Cl% obtained% C 49.13 49.30 H 6.34 6.11 N 13.22 12.98

Cl 11.16 11.27.

Example 10 10 ml of xylene are added to 1 g of 3- (6,7-dimethoxy-3,4-dihydro-1-isoquinolyl) methyl-5-propyl-1,2,4-oxadiazole, and the reaction mixture is refluxed. 8 hours. The solvent is evaporated off under vacuum and the residue is recrystallized from aqueous alcohol. 0.7 g of 2-butyrylamino-5,6-dihydro-8,9-dimethoxypyrazolo [5,1-b] isoquinoline hemihydrate is obtained, m.p. 125-127 ° C.

Analysis: 3% calculated% obtained% C 62.94 62.80 H 6.84 6.71 N12.9 6 12.75.

10 56383

Example 11 1 ml of pyridine and 1.9 g of p-toluenesulfonic acid chloride are added to 2.45 g of 2-amino-5,6-dihydro-8,9-dimethoxypyrazolo-E, 1,1'-isoquinoline, and the reaction mixture is boiled for 5 minutes. reflux. After cooling, the reaction mixture is poured into water. 3.3 g of 2- (4-toluenesulphonylamino) -5,6-dihydro-8,9-dimethoxypyrazolo [1,1-b] isoquinoline are obtained, m.p. 259-261 ° C (from dioxane).

Analysis: Calculated% C 20 H 21 N 3 O 4 S% found C 60.18 59.94 H 5.29 5.45 N 10.52 10.36.

Claims (3)

11 56383 Claim; Process for the preparation of novel cardiac active 2-amino-5,6-dihydro-8,9-dialkoxy-pyrazolo [5,1-a] isoquinoline derivatives of general formula XXI [| --- NHD wherein A is 1-b a carbon-containing alkoxy group, and D is a hydrogen atom, an alkyl group having 1 to U carbon atoms, an alkanoyl group containing 1 to 1 carbon atoms optionally substituted by halogen atoms, or a benzyl, benzoyl, phenacetyl or toluenesulfonyl group, and to prepare acid addition salts thereof, a) for the preparation of compounds of formula I in which D is a hydrogen atom, an alkanoyl group containing 1-U carbon atoms optionally substituted by halogen atoms, or a benzoyl or phenacetyl group, cyclization of 3,5-disubstituted-1,2-U-oxazole derivatives the formula is' TjO <«> ΪηίΠ Nn Λ 0 R wherein A is as defined above, and R is an alkyl group, a phenyl group or a benzyl group optionally substituted by halogen atoms having 1 to 3 carbon atoms, by heating either as a melt or in a suitable organic solvent such as xylene or tetralin by redistillation, or in a slightly alkaline alcohol alkali metal hydroxide and, if desired, hydrolyzing the obtained compound of formula (i) wherein D is an alkanoyl group containing 1 to U carbon atoms optionally substituted by halogen atoms, a benzoyl group or a phenacetyl group to give a compound of formula (i) wherein D is a hydrogen atom, or b) i) for the preparation of compounds of formula wherein D is as defined in the species definition, a 3,5-disubstituted-3,8-N-oxazole derivative of formula (II) in which A and R are as defined above is cyclized, strongly in an alkaline alcohol alkali metal hydroxide solution by redistillation, and if desired reacting the compound of formula (I) wherein D is a hydrogen atom with the corresponding aldehyde and, if desired, reducing the compound of formula (I) thus formed, optionally not first isolated, to a compound of formula (i) wherein D is 1 An alkyl group containing a * * -1 * carbon atom, or a benzyl group, or is acylated to a compound of formula (I) in which D is optionally substituted by halogen atoms. An alkannyl group containing 1 to U carbon atoms, a benzoyl group, a phenacetyl group or a toluenesulfonyl group, and, if desired, the obtained compound of the formula (I) is converted into an acid addition salt, or the acid addition salt is converted into a free base- 56383 Patentkrav; For example, 2-amino-5,6'-dihydro'-8,9-dialkoxy-pyrrolo [1,5'-a] isoquinoline derivatives are obtained with the following formula: xxi II --NHD color A alkoxy group having a 1-U cholatom, an alkyl group having an alkyl group having a 1-U cholatom, a halogen atom having a substituent having an alkanoyl group having a 1-U cholatom, or benzyl, benzoyl, phenacetyl or a toluene sulfonyl group, a residue which is a substituent, a solid which, according to the formula (I), color D is not a hydrogen atom, and a halogen atom substituted by an alkanoyl group having 1 to U chapters, or phenacetyl group, cyclized to 3,5-disubstituted-1,2-U-oxazole derivatives of formula AIII (id Tj-N PI! 0. A compound having one or more substituents on the halogen atom substituted with an alkyl group of 1 to 3 cholera, a phenyl group or a benzyl group, the genomic uptake of which is the same as that of a warmed organic compound, , or a certain alkali metal alkali metal hydroxide solution under intermittent distillation, and, on its own, hydrolysers and particularly preferred derivatives of formula (I), which may be substituted with halogenated substituents on the alkanoyl group with 1-U cholesterol, or benzene förening med formeln (l), där D är en väteatom, or