DK141628B - Analogous Process for the Preparation of Aminopyrazolisoquinoline Derivatives. - Google Patents

Description

(11) PUBLICATION 141428 DENMARK (B1), nt cl · 3 c 07 D 471/04 § (21) Application No. 5 ^ 57/77 (22) Filed on the 8th Dec. 1977 (23) Race stage 28 Jun. 1975 (44) The application presented and submitted to the public on 12 May J 1 98Ο DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM (* »Woritet requested from the

50. jun. 1972, Cl 1248, HU

(71) CHINOIN GYOGYSZER ES VEGYESZETI TERMEKEK GYARA RT., Budapest IV.,

Two hours 1-5, HU.

(72) Inventor: Kalman Takacs, Budapest VIII., VaB u. 12., HU: Laszlo Szeke * = res, Szeged, Kazinczy u. 2., HU: Kalman Harsanyl, Budapest XI., Egry Jozsef u. 19-21 ., HU: Gyula Father, SzegecCT Becsi Map. 27-59 ·, HU: An = dras Neszmelyi, Budapest II., Tarogato u. 8., HU: Eva Benedek, Gyor, Sagvari Endre u. 16., HU.

(74) Plenipotentiary in the proceedings:

Office of Industrial Excellence v. Svend Schønning.

(64) Analogous Procedure for Methods of Preparation of Aminopyrazolisoquinolines.

The present invention relates to an analogous process for the preparation of novel aminopyrazolisoquinoline derivatives of the general formula or acid addition salts thereof, wherein A and D have the meanings set forth in the preamble of claim.

2 141628

It has been found that the compounds of the general formula I decrease coronary flow resistance, promote coronary flow, reduce cardiac muscle oxygen consumption, improve quotient O2 supply / O2 consumption which express the heart's oxygen supply and favorably affect the efficiency of cardiac work.

The process for preparing the novel amino-pyrazolysoquinoline derivatives of the general formula I is characterized by heating a compound of the general formula

CH-C-N

i II

N / C

R ^

wherein A is as defined above and R is an alkyl group having 1-3 carbon atoms, a phenylalkyl group having 1-3 carbon atoms in the alkyl moiety or a phenyl group, in moderate or highly alkaline medium, in a solvent or in a melt, wherein, if desired, a won compound of formula I wherein D is hydrogen is reacted with an alkanoylating agent, a benzoylating agent, a phenylalkanoylating agent or a benzenesulfonylating agent to introduce a group D which is an optionally substituted alkanoyl group having at most 3 halogen atoms. with 1-4 carbon atoms, a benzoyl group, a phenylalkanoyl group having 1-4 carbon atoms in the alkyl moiety or an optionally substituted benzene sulfonyl group optionally with an alkyl group or optionally converting a won compound of formula I wherein D is hydrogen, with an aldehyde or ketone of the general formula D '= 0, where D' is an alkylidene group of 1-4 carbon atoms or a phenylalkylidene group of 1-4 carbon atoms in al. the chylidene moiety, followed by reduction, or if desired, hydrolyzes a won compound of formula I wherein D is an acyl group as defined above and / or if desired converts the won compound to an acid addition salt thereof or liberates the free base from a won acid addition salt .

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

3 141628 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 (Table 1).

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. Gy. 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 based on the arterial pressure coefficient (mm Hg) and the coronary flow measured in the sinus coronarius (ml / min / 100 g). (Table 2).

3. Effect on cardiac oxygenation

During the mentioned dog test, at the same time as the coronary flow measurement, oxygen saturation in blood samples which were extracted from the coronary sinus through the oximeter measuring cuvette with a stationary velocity pump was continuously recorded and returned to the brachial vein. In addition, the oxygen saturation of the arterial blood was determined and with the manometer also the hemoglobin content of the blood was 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 adequate oxygen supply, the quotient 02 supply / 02 requirement was calculated. For further details, see L. Szekeres, J. Gy. Papp and E. Fischer: European J. Pharmacol., 2, 1, 1967. (Table 3).

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, O2 consumption of the left heart chamber was calculated. Based on the quotient: left heart chamber work (kgm / min) / left heart chamber 02 consumption (ml / min / 100 g), the magnitude of the efficiency of left heart chamber work was also determined. (Table 4).

4 141628 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 LD ^ q 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).

The results are shown in Tables 1-5. The compound under investigation is a) 2-amino-5,6-dihydro-8,9-dimethoxypyrazole [5,1-a] isoquinoline (cf. Example 4).

___Table 1_

Dose _ Arterial pressure_ mg / kg i.v. n Basic value Changed value Difference ___mm Hg__mm Hg __% _ 1 5 127 104 -18 2 5 124 92 -26 4 6 105 67 -36

Table 2

Dose of coronary artery coronary resistance mg / kg i.v. n ml / min / 100 g_ml / min / 100 g_

Basic value Changed Diff. Basic value Changed Diff. ____ value% __ value __% 1 5 24 87 + 4 1.86 1.46 -22 2 5 82 100 + 22 1.90 1.31 -31 4 6 84 108 + 29 1.33 0.71 -47

Table 3

Dose Left consumption of O2 Supply / 02 ~ consumption mg / kq i.v. n cardiac ___

Basic- Changed Diff. Basic- Changed Diff.

_ value value% __ value value% 1 5 9.8 8.0 -18 1.48 1.68 +14 2 5 9.4! 7.5 -20 1.51 i 1.93 +28 4 6 8.7 8.7 1.77 2.12 i +20 i ___! ___ i__

Table 4 141628 5

Dose mg / kg i.v. n Efficiency of left chamber work ___ Basic value Changed value Difference,% _ 1 5 0.35 0.49 +40 2 5 0.36 0.46 +28 _4__6__0.27__0.33 __ + 22_

Table 5

The compound's LD ^ value and 95% s tolerance limits: LD ^ q = 70 (34-148) mg / kg.

It can be seen that the compound tested at a dose of 1- 4 mg / kg i.v. decreases arterial pressure, increases coronary flow, decreases coronary resistance, reduces cardiac muscle oxygen consumption and improves, i.e. increases the quotient C 2 supply / C 2 consumption which expresses the heart's oxygen supply and thus adversely affects the heart's efficiency. These results show that the compound in animal studies meets the requirements that an effective anti-angina drug must be made.

Further tests on a selection of the compounds of the present invention yielded the following results.

b) 2-Benzylamino-5,6-dihydro-8,9-dimethoxypyrazolo [5,1-a] isoquinoline.

At an intravenous dose of 2-4 mg / kg, this compound reduces arterial pressure by 10-15%, increases coronary flow and improves, ie. increases the quotient 02 supply / 02 ”consumption, which expresses the heart's oxygen supply.

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

This compound decreases at an intravenous dose of 2- 4 mg / kg arterial pressure by 15%, increases coronary flow by 15-20% and adversely affects the efficiency of cardiac work.

d) 2-Benzoylamino-5,6-dihydro-8,9-dimethoxypyrazolo [5,1-a] isoquinoline.

This compound decreases at an intravenous dose of 2-4 mg / kg arterial pressure by 15%, increases coronary flow by 15-20% and adversely affects the efficiency of cardiac work. E) 2-Ethylamino-5,6-dihydro-8,9-dimethoxypyrazolo [5,1-a] isoquinoline.

At an intravenous dose of 2-4 mg / kg, this compound reduces arterial pressure by 10-15%, increases coronary flow and improves, ie. increases the quotient C ^ supply / C ^ consumption, which is the expression of the heart's oxygen supply.

In addition, a comparison has been made between the compound of the invention, 2-amino-5,6-dihydro-8,9-dimethoxypyrazolo [5,1-a] isoquinoline (TK-916) and the compound corotin which is recognized in this field. , well-functioning trading product.

The comparison results are shown in Table 6.

Table 6

Antianginavirkning

Connective Coronary Transduction (^ “Consumption _____ LDj-q iv Relative Therapist Relative Therapist-Rat Effect Tactical Impact Tissue Index Dex Corotin 11 mg / kg 1.00 3.9 1.00 4.6 TK 916 80 mg / kg 1.3 29.6 0.23 7.6

It is seen that the compounds of this invention have an excellent antiangina effect compared to corotin.

Compared to the commonly known compound quinidine, the compounds of this invention are substantially more effective in treating anterior and cardiac arrhythmias.

The process according to the invention is explained in more detail below by some examples.

Example 1 7 141628

To 200 mg of 3- (6,7-dimethoxy-3,4-dihydro-1-isoquinolyl) methyl-5-benzyl-1,2,4-oxadiazole is added 5 ml of xylene and the reaction mixture is refluxed for 8 hours. After cooling, add 10 ml of gasoline to the mixture. 170 mg of 2-phenylacetylamino-5,6-dihydro-8,9-dimethoxypyrazole [5,1-a] isoquinoline is obtained, m.p. 225-227 ° C (from butanol).

Calcd. For C 21 H 21 N 3 O 3: 40 H 5.82 N 11.56

Found: C, 69.50; H, 5.80; N, 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-1,2,4- oxadiazole and the reaction mixture are refluxed for 3 hours. Then the alcohol is evaporated under vacuum and water is added to the residue. 1.2 g of 2-benzoylamino-5,6-dihydro-8,9-dimethoxypyrazole [5,1-a] isoquinoline are obtained, m.p. 185 ° C (from alcohol).

Calculated for C 20 H 19 N 3 O 3: C, 68.75; H, 5.48; N, 12.03

Found: C, 68.52; H, 5.65; N, 11.83%.

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 for 8 hours. After cooling, 0.9 g of crystalline 2-benzoylamino-5,6-dihydro-8,9-dimethoxypyrazole [5,1-a] isoquinoline is obtained which is identical to the product described in Example 2.

Example 4 25 ml of alcohol and 7 ml of a 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 are refluxed for 8 hours. Then the alcohol is evaporated under vacuum and water is added to the residue. 0.6 g of 2-amino-5,6-dihydro-8,9-dimethoxypyrazole [5,1-a] isoquinoline is obtained in crystalline form with m.p. 216-217 ° C (from alcohol).

Calculated for C 13 H 15 N 3 O 2: C 63.65 H 6.16 N 17.13 Found: C 63.45 H 6.40 N 16.95%.

In the nuclear magnetic resonance spectrum of the product, the proton appears at position 1 at 5.85 ppm.

161628

ISLAND

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-dimethoxypyrazole [5,1-a] isoquinoline and the reaction mixture is refluxed for 4 hours. After cooling, 1.1 g of 2-benzylideneamino-5,6-dihydro-8,9-dimethoxypyrazole [5,1-d] isoquinoline is obtained in crystalline form, m.p. 163 ° C.

Calculated for C 20 H 19 N 3 O 2: C 72.05 H 5.75 N 12.61

Found: C 71.88 H 6.01 N 12.50%.

Dissolve 0.9 g of the product obtained above in 100 ml of methanol and add 0.2 g of sodium borohydride to the solution. The solution is allowed to stand for 1 hour, after which the solvent is evaporated under vacuum. Water is added to the residue. 0.8 g of 2-benzylamino-5,6-dihydro-8,9-dimethoxypyrazole [5,1-a] isoquinoline is obtained, m.p. 156 ° C (from alcohol).

Calcd for C 71.62 H 6.31 N 12.53

Found: C 71.86 H 6.08 N 12.64 5.7 g of this product are dissolved in 80 ml of acetone, the solution is acidified with absolute alcohol in hydrochloric acid. 5.5 g of 2-benzylamino-5,6-dihydrodimethoxypyrazole [5,1-a] isoquinoline hydrochloride are obtained in crystalline form, m.p. 206-208 ° C.

Calculated for C₂2H₂qN30O₂Cl: C 64.59 H 5.96 N 11.31 Cl 9.53

Found: C 64.70 H 6.12 N 11.52 Cl 9.38%.

In the nuclear magnetic resonance spectrum of the product, the proton appears at position 1 at 5.73 ppm.

Example 6 5.0 ml of acetic anhydride is added to 1 g of 2-amino-5,6-di-hydro-8,9-dimethoxypyrazole [5,1-a] isoquinoline, the reaction mixture is heated for 10 minutes on a water bath and the mixture is allowed to stand for 1 hour. The mixture is poured onto ice and 0.8 g of 2-acetylamino-5,6-dihydro-8,9-dimethoxypyrazole [5,1-a] isoquinoline are obtained in crystallized form, m.p. 223 ° C (from 75% alcohol).

Calcd for C 16 H 17 N 3 O 3: c 62.70 H 5.96 N 14.63

Found: C, 62.56; H, 5.78; N, 14.60%.

141628

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-dimethoxypyrazole [5,1-a] isoquinoline and with stirring 1.15 g of chloroacetyl chloride are added dropwise 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. 2 g of 2-chloroacetylamino-5,6-dihydro-8,9-dimethoxypyrazole [5,1-a] isoquinoline are obtained, m.p. 152-154 ° C (from alcohol). Calc'd for C 15 H 16 N 3 C 3 Cl: C 55.99 H 5.01 N 13.06 Cl 11.02 Found: C 56.10 H 4.93 N 12.80 Cl 10.82%.

Example 8 1 g of 2-amino-5,6-dihydro-8,9-dimethoxypyrazole [5,1-a] Isoquinoline is reacted with 0.7 g of benzoyl chloride in the manner described in Example 6 and 1 g of 2-benzoylamino is obtained. 5,6-dihydro-8,9-dimetoxypyra-imidazole [5,1-a] isoquinoline. Mp: 185 ° C (from alcohol).

Calculated for C 20 H 19 N 3 O 3: C, 68.75; H, 5.48; N, 12.03

Found: C, 68.52; H, 5.65; N, 11.83

Example 9

To 0.5 g of acetylamino-5,6-dihydro-8,9-dimethoxypyrazole [5,1-a] isoquinoline is added 10 ml of 2N hydrochloric acid solution and the reaction mixture is refluxed for 1/2 hour. After cooling, 0.5 g of 2-amino-5,6-dihydro-8,9-dimethoxypyrazole [5,1-a] isoquinoline hydrochloride dihydrate is obtained in crystalline form, m.p. 128-130 ° C. Calcd for c13 H2 () N3 O4 Cl: C 49.13 H 6.34 N 13.22

Found: C 49.30 H 6.11 N 12.98%.

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 for 8 hours. . The solvent is evaporated in vacuo and the residue is recrystallized from aqueous alcohol.

0.7 g of 2-butyrylamino-5,6-dihydro-8,9-dimethoxypyrazole [5,1-a] isoquinoline hemihydrate is obtained, m.p. 125-127 ° C.

Calcd for, 1/2 0: C 62.94 H 6.84 N 12.96

Found: C 62.80 H 6.71 N 12.75

Claims (1)

Example 11 10 ml of pyridine and 19 g of p-toluenesulfonic acid chloride are added to 2.45 g of 2-amino-5,6-dihydro-8,9-dimethoxypyrazole [5,1-a] isoquinoline and the reaction mixture is refluxed for 5 minutes. . After cooling, the reaction mixture is poured into water. 3.3 g of 2- (4-toluenesulfonylamino) -5,6-dihydro-8,9-dimethoxypyrazole [5,1-a] isoquinoline are obtained, m.p. 259-261 ° C (from dioxane). Calcd for C 20 H 21 N 3 ° 4S: C 60.13 H 5.29 N 10.52 Found: C 59.94 H 5.45 N 10.36 Analogous process for the preparation of aminopyrazole-isoquinoline derivatives of the general formula TY thereof, where A is an alkoxy group of 1-4 carbon atoms 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, optionally substituted with a maximum of 3 halogen atoms, alkanoyl group of 1-4 carbon atoms, a benzoyl group, a phenyl alkanoyl group having 1-4 carbon atoms in the alkyl moiety or an optionally substituted benzenesulfonyl group optionally with an alkyl group having 1-4 carbon atoms, characterized by heating a compound of the general formula ΑΥγ ™ CH-C - NX X0 XR