FI77027C - SAFETY PREPARATION OF PHARMACOLOGICAL VERKS 1- / 1- (3,4-DIMETOXIFENYL) -3-AMINO-PROPYL / -6,7-DIMETOXY-Isoquinoline INFOERING. - Google Patents

Description

ANNOUNCEMENT ISSUE

• Tan? [B] (11) utläggningsskrift 7 7027 (51) Kv.lk.4 / lnt.CI.4 C 07 D 217/18

SUOMI FINLAND

(FI) (21) Patent application - Patentansökning 802118 (22) Application date - Ansökningsdag 02.07.80

National Board of Patents and Registration (23) Start date - Giltighetsdag 02.07.80

Patent-och reflisterstyrelsen (41) Published public - Biivit offentiig 20 01 8l (44) Date of dispatch and of publication. - «q on

Ansökan utlagd och utl.skriften publicerad ju. .oo (86) Kv. application-Int ansökan (32) (33) (31) Privilege requested - Begärd priority 19-07-79 e 1so-Br itann ia-Storbr i Tann ien (GB) 7925276 (71) Andre Buzas, 25, route de Versailles, Bievres, France-Frankrike (FR) (72) Andre Buzas, Bievres, Gilbert Lavielle, Orleans,

France-France (FR) (7A) Leitz Inger Oy (5 * 0 The method for the preparation of pharmacologically active 1- / 1- (3, * t-dimethoxyphenyl) -3-aminopropyl / -6,7-dimethoxyisoquinol The present invention relates to a process for the preparation of a pharmacologically active 1- [1- (3,3 * t-dimethoxyphenyl) -3-aminopropyl] -6,7 "-dimethoxyisoquinoline compound. 3,4-dimethoxyphenyl) -3-aminopropyl-6-,7-dimethoxyisoquinoline of formula I

CH3 ° 'N ^ N Av

CH-CH 2 -CH 2 -N 2. .

Ä. * 2 ζχ ...

OCH 3 wherein R 1 is a hydrogen atom or a methyl group; and R 2 is an alkyl group having 1 to 5 carbon atoms which may be substituted by a hydroxy, phenyl or 2,77027 phenoxy group or a cyclohexyl group which may be substituted by an alkyl group having 1 to 5 carbon atoms or a phenyl group, and therapeutically acceptable salts thereof.

The compounds of the invention are of interest because of their therapeutic properties, especially in the cardiovascular field.

According to the invention, 1- [1- (3,4-dimethoxy-phenyl) -3-oxo-poryl] -6,7-dimethoxy-isoquinoline derivatives of the formula I can be prepared by condensation in a polar solvent at a temperature between 0 and 25 ° C, of the formula II 1- [1- (3,4-dimethoxy-phenyl) -3-oxo-propyl] -6,7-dimethoxy-isoquinoline with a compound of general formula NHR1R2 wherein R1 and R e has the same meaning as above, and the compound obtained is reduced, for example, with sodium borohydride.

The solvent generally used is an alcohol, preferably ethanol.

Although the process of the invention can be applied when both R1 and R2 represent hydrogen atoms and when neither of R1 and R2 is a hydrogen atom, it gives the best yields for the preparation of secondary amines, i. when R 1 is a hydrogen atom (and tertiary amines when R 1 represents a methyl group. Tertiary derivatives can also be obtained starting from secondary derivatives by well-known nitrogen substitution methods such as iodoalkylation or reductive formulation.

The starting 1- (1- (3,4-dimethoxyphenyl) -3-oxopropyl] -6,7-dimethoxyisoquinoline II can be prepared by the methods described in more detail in Examples A, B and C below. Examples A, B and C and the following Examples 1 to 9, which illustrate the invention, the analytical data were obtained as follows: Thin layer chromatographic (TLC) data were obtained using Merck F 254 plates? NMR spectra were run on a Perkin-Elmer R 24 (60 MHz) instrument? and IR spectra were recorded on a Perkin-Elmer 257 instrument.

Example A

Formation of the carbanion of 1 - [(3,4-dimethoxy-phenyl) -methyl] -6,7-dimethoxy-isoquinoline__ (a) Liquid ammonia / sodium amide method To a 1 liter three-necked flask equipped with a stirrer and a dry ice-cooler add 300 ml in succession liquid ammonia, 0.1 g of catalyst ferric chloride and 0.8 g (0.03 mol) of sodium (cf. Org. Synthese Coll., Vol. 5, p. 523). The reaction mixture is stirred for 1 1/2 hours, after which 10 g (0.0295 mol) of papaverine are added in small portions. The formation of carbanion is completed by stirring the mixture for 2 hours. A red solution is obtained which is used as such in synthetic reactions, for example in the examples described below.

b) Butyllithium / hexamethylphosphotriamide method Pour 10 g (0.0295 moles) of papaverine and 100 ml of hexamethylphosphotriamide into a 1 liter reactor equipped with heating, cooling and stirring equipment. While maintaining the temperature at about 5 ° C, 18.5 ml (0.03 moles) of commercial butyllithium as a solution in hexane are gradually added. After the addition, stir for an additional 1 hour at ambient temperature.

4 77027 c) Sodium amide / hexamethylphosphotriamide method 10 g (0.0295 mol) of papaverine and 30 ml of hexamethylphosphotriaride are poured into the same apparatus as in the previous method b).

1.2 g (0.03 mol) of sodium amide are added gently with stirring; the mixture turns red but no gases evolve. The mixture is heated to 70-75 ° C to give off ammonia; stirring is continued for 3 hours until gas evolution ceases. The reaction mixture is cooled and used as such in synthetic reactions.

d) Lithium diisopropylamide / tetrahydrofuran method 400 ml of dry tetrahydrofuran are poured into the apparatus used in method a) above, which is cooled in an ethanol / dry ice bath. Lithium isopropylamide is prepared in situ by dropwise addition of 18.5 ml of butyllithium (0.03 mol) dissolved in hexane at -30 ° C; 4.2 ml (0.03 mol) of diisopropylamine are added and the mixture is stirred for 15 minutes at 10 ° C. Cool to -40 ° C and add 10 g (0.0295 moles) of papaverine (powder) and stir the mixture for 4 hours at -40 ° C.

e) Potassium amide / dimethylformamide method 10 g (0.0295 mol) of papaverine and 35 ml of dimethylformamide are poured into the apparatus used in Example b) above. 1.7 g (0.03 mol) of potassium amide are added slowly while stirring. After the addition, stirring is continued while heating the reaction mixture at 70 ° C for 3 1/2 hours. The reaction mixture is used as such after cooling for further syntheses.

To characterize and identify the carbanion, an oxidation reaction using 1- (3,4-dimethoxy-bentoyl) -6,7-dimethoxy-isoquinoline (papveraldine) is used. A solution of the carbanion prepared according to A) is bubbled with dry oxygen for 2 1/2 hours; then pour 200 ml of dry toluene and allow the ammonia to evaporate. The solution is treated at ambient temperature with 200 ml of water and dried. Sp. 208 ° C (literature: 209-210 ° C).

5,77027

Example B 'v Ä'

Formation of the acetal intermediate: 1- [1- (3,4-dimethoxyphenyl) -3,3-diethoxypropyl] -6,7-dimethoxyisoquinoline-5.3 g (0.025 moles) of 2,2-diethoxyethyl bromide are added slowly to a solution containing 0.016 moles of the carbanion obtained by one of the methods described in Example A. Stir for 1 hour, then add 200 ml of dry toluene and allow the ammonia to evaporate. At ambient temperature, 200 ml of water are added and the whole mixture is filtered through celite. The toluene solution is then decanted, washed, dried over anhydrous sodium sulfate and concentrated. The resulting oil is hydrolyzed directly to give 9.6 g of product. Yield 97%.

NMR (CCl 4)

Sppm: 8.20 (d, 1H, CH-N =); 7 (m, 6H, aromatic protons); 4.25 (t, 1H, CH-CH 2); 3.75 (m, 12H, OCH 3)} .___ "OCH_ 3.3 (m, 4H, CH 2); ° C 2 H 2 O 2 δ and och 2 Ch., 2.4 (m, 3H, CH 2 -CH b)} 1.1 (2t, 6H) oc2h5 och2ch3

Example C

Aldehyde formation: 1- [1- (3,4-dimethoxy-phenyl) -3-oxo-propyl] -6,7-dimethoxy-isoquinoline-8.7 g (0.014 mol) of the compound prepared in Example B above are hydrolyzed over 2 hours. At 200 ° C in 200 ml of 2% hydrochloric acid solution. Alkalize to pH 12 with sodium carbonate, then extract the mixture three times with 50 ml of dichloromethane. 7.25 g of oil are obtained. Yield 95%.

IR

vcm "1: 2730, 1715 (CH = O) NMR (CDCl 3) δ ppm: 9.6 (s, 1H, CH = O) ·, 8.35 (d, 1H, CH-N =)} δ (m, 6H, aromatic protons)} 5.25 (t, 1H, CH)} 3.8 (m, 12H, OCH 3)} 2.9 (m, 2H, CH 9 -C) -

^ H

6,77027 This compound is referred to as the "aldehyde" in the following Examples 1-9.

Example 1 1- [1- (3,4-Dimethoxy-phenyl) -3- (1-methyl-propylamino) -propyl] -6,7-dimethoxy-isoquinoline_

R1 = H

R 2 = 1-methylpropyl 13 g of aldehyde, 2.5 g of 1-methylpropylamine and 120 ml of ethanol and 1 g of molecular sieve are stirred for 30 minutes at ambient temperature. The mixture is cooled to 0 ° C and 3 g of sodium borohydride are added. The mixture is stirred overnight at ambient temperature and treated as in the previous examples. 11.2 g of a yellow oil are isolated, which is dissolved in 100 ml of isopropanol. The hydrochloride is formed by adding 25.4 ml of 1 N hydrochloric acid (1 equivalent). The solution is concentrated to dryness and the residue is taken up in as little hot isopropanol as possible and allowed to crystallize. 6.3 g of product are obtained, m.p. 246 ° C.

TLC (methanol / acetone / concentrated hydrochloric acid 90/10/4).

Rf = 0.5 1 spot NMR (base) (CDCl 3)

Sppm: 8.45 (d, 1H, = CH-N =); 7.3-7.5 (m, 2H, aromatic protons); 6.15-7 (m, 4H, aromatic protons); 4.85 (m, 1H, CH-CH2); 3.95 (s, 6H, OCH 3); 3.75 (s, 6H, OCH 3); 2.1-3 (m. 5H); 1.1-1.6 (m, 3H, of which 1H is interchangeable with NH); 0.7-1 (m. 6H).

Example 2 1- (1- (3,4-Dimethoxy-phenyl) -3-cyclohexylamino-propyl] -6,7-dimethoxy-isoquinoline__

R1 = H

R2 = cyclohexyl

By proceeding in the same manner as in Example 1, but using 7,77027 cyclohexylamine instead of 1-methylpropylamine, 8.1 g of the title compound were obtained. Yield 88%.

Sp. 135 ° C (ethanol).

NMR (CDCl 3) ppm: 8.35 (d, 1H, CH-N =); 7.10 (m, 6H, aromatic protons);

4.8 (t, 1 H, CH); 3.85 (m, 12H, OCH 3); 2.4 (m, 5H, CH 2 -CH 2 -N-CH); 1.85 (1H, N-H); 1.4 (m, 10H, cyclic CH 2) · H

Hydrochlorides, m.p. > 250 ° C (ethanol)

Anhydrous content by titration: 100% (2 basic functions)

Elemental analysis for C 28 H 36 N 2 O 4 * HCl (500.5)

Calculated: C% 72.4 H% 7.76 N% 6.03

Found: 72.31 7.65 5.94

Example 3 1- [1- (3,4-Dimethoxy-phenyl) -3- (o <-methyl-phenethylamino) -propyl] -6,7-dimethoxy-isoquinoline ____

R1 = H

R 2 = n-n-ethylphenethyl

7.6 g (0.02 moles) of aldehyde, 2.7 g (0.02 moles) of οί-methylphenethylamine in 80 ml of absolute

O

ethanol and 500 mg molecular sieve (3 A). After stirring for 1 hour, the mixture is cooled to 0 [deg.] C. and 2 g of sodium borohydride are added in small portions. The mixture is stirred at ambient temperature for 2 hours. The reaction medium is then concentrated under reduced pressure, water is added and the whole is extracted with dichloromethane. The extracts are washed with water and dried. The dichloromethane is evaporated to give 8.5 g of product as an oil. Yield 85%. The hydrochloride of this oil is formed using 8.5 ml of 2N hydrochloric acid in 100 ml of ethanol. The solution is concentrated and the residue is taken up in 50 ml of boiling isopropanol. Sp. 220 ° C.

8 77027

Anhydrous content by titration: 100% (2 basic functions).

NMR (CDCl 3) ppm: 8.30 (d, 1H, CH-N =); 7.05 (m, 11H, aromatic protons); 4.70 (t, 1H, --CH - CH2); 3.85 (m, 12H, OCH 3); 2.60 (m, 7H, CH 2 "CH 2" nh- (CH 2 · 2)) · 2.30 (1H, NH); 1.0 (d, 3H, CH 3 -CH).

Elemental analysis for C31H35N2O4 · HCl (536.5)

Calculated: C% 69.3 H% 6.89 N% 5.22

Found: 69.1 6.75 5.31

Example 4 1- [1- (3,4-Dimethoxy-phenyl) -3- (N-methyl-o (methyl-benzylamino) -propyl] -6,7-dimethoxy-isoquinoline_

R1 = CH3 R2 = o (-methyl-benzyl a) A mixture of two diastereoisomers

11.5 g of aldehyde and 3.6 g of o <-methyl-benzylamine in 100 ml of ethanol are mixed together in the presence of 1 g of a molecular sieve. After stirring for 30 minutes, the reaction mixture is cooled to 0-5 ° C and 2 g of sodium borohydride are gradually added. Further processing is carried out according to Example 1. 14 g of oil I are obtained.

7 g of this oil are carefully refluxed for 2 1/2 hours in a solution of 18 ml of formic acid and 5 ml of a 30% aqueous formaldehyde solution. The reaction mixture is cooled and poured into saturated sodium carbonate solution. It is extracted with chloroform and the extracts are washed with water and dried. The extracts are then concentrated to give 7.5 g of an oil which is taken up in isopropanol and allowed to crystallize. The crystals are collected and dried to give 4.3 g of product, m.p. 130 ° C.

9 -1 7 V O 2 7 IR: 2790 cm x N-CH.J t ι υ t NMR (CDCl 3) ppm: 8.35 (d, 1H, CH-N =); 6.7-7.35 (m, 11H, aromatic protons); 4.8 (t, 1H, CH-CH 2); 3.95 (d, 6H, OCH 3> j 3.75 (d, 6H, OCH 3) ♦, 3.65 (q, 1H, CH-CH-j) ·, 3-2 (m, 4H, CH 2 -CH 2) ), 2.2 (s, 3H, N-CH 3), 1.25 (d, 3H, CH-CH 3).

TLC: 2 spots (dichloromethane / methanol 80/20).

Rf 0.7.

The dihydrochloride is formed in alcohol. The alcohol is evaporated and the residue is dried.

b) Separation of diastereoisomers

The remaining 7 g of oil I are chromatographed on a silica gel column (90 g, eluting with dichloromethane / methanol 98/2). First, 2.8 g of white product are recovered, which is N-methylated as described in (a) above. 2.3 g of an oil are thus obtained, which crystallizes from isopropanol, m.p. 115 ° C.

TLC: 1 spot (dichloromethane / methanol 80/20)

Rf 0.7.

The dihydrochloride is prepared as in a) above.

Example 5 1- [1- (3,4-Dimethoxy-phenyl) -3- (N-methyl-1-methyl-2-phenoxy-ethylamino) -propyl] -6,7-dimethoxy-isoquinoline_R 1 = CH 3 R 2 = 1-methyl-2-phenoxy-ethyl 12 g of aldehyde, 4.75 g of 1-methyl-2-phenoxyethylamine and 125 ml of distilled ethanol are mixed for 30 minutes together with 1 g of molecular sieve. The mixture is cooled to 0 ° C and 3 g of sodium borohydride are added in small portions. The reaction mixture is stirred overnight and treated as in the previous examples to give 13 g of an oil. 13 g of oil are N-methylated by the method described in Example 4. After drying and evaporation, 13.5 g of oil are obtained, from which the hydrochloride is formed with 1N hydrochloric acid in isopropanol. The solution is evaporated to dryness and the salt is chromatographed on a silica gel column (260 g) eluting with dichloromethane / methanol 95/5) to give 8 g of meringue monohydrochloride.

77027 10 TLC: 1 spot (methanol / acetone / concentrated hydrochloric acid 90/10/4).

R f = 0.5 IR (base film: 2800 cm -1 N-CH 2) NMR (base) (CDCl 3) δ ppm: 8.4 (d, 1H, CH = N); 6.6-7.5 (m, 11H, aromatic protons); Δ (m, 1H, -CH-CH2); 3.75-3.95 (m, 12H, OCH-j); 2.35 (d, 3H, N-CH 3); 1.05 (d, 3H, CH-CH 3).

Example 6 1- [1- (3,4-Dimethoxy-phenyl) -3-benzylamino-propyl] -6,7-dimethoxy-isoquinoline_

R 1 = h r 2 = benzyl 1; L

By operating as described in Example 1, but using benzylamine instead of 1-methylpropylamine, the title compound was obtained in 80% yield.

Hydrochlorides, m.p. 223 ° C (isopropanol) anhydrous content by titration: 99% (2 basic functions)

Elemental analysis for C 29 H 32 N 2 O 4 * HCl (508.5)

Calculated: C% 68.5 H% 6.50 N% 5.50

Found: 68.65 6.32 5.25 NMR (CDCl 3) δ ppm: 8.3 (d, 1H, CH-N =); 7.1 (m, 11H, aromatic protons); 4.8 (t, 1H, CH-CH 2); 3.9 (m, 14H, OCH 3 and CH 2 -N 2); 2.7 (m, 4H, CH 2 -CH 2 -N); 2.3 (s, 1 H, N-H).

Example 7 1 - [(3,4-Dimethoxy-phenyl) -3- (N-methyl-4-t-butyl-cyclohexylamino) -propyl] -6,7-dimethoxy-isoquinoline-R 2 = CH 3 R 2 = 4 -t-butyl-cyclohexyl 12 g of aldehyde, 4.9 g of 4-t-butylcyclohexylamine and 120 ml of distilled ethanol are mixed with a molecular sieve for 30 minutes. Further processing takes place as in the previous examples. 13.8 g of an oil are obtained, which is then N-methylated as described in Example 5. After further work-up, 14 g of compound are obtained, which is taken up in boiling diethyl ether and crystallized therefrom. 6.5 g of recrystallized material are obtained, m.p. 126 ° C.

TLC (methanol / acetone / concentrated hydrochloric acid 90/10/4) 1 spot Rf = 0/6 NMR (CDCl 3) δppm: 8.4 (d, 1H, = CH-N =); 7.2-7.5 (m, 2H, aromatic protons); 6.4-7 (m, 4H, aromatic protons); 4.8 (m, 1H, CH-CEU); 4.9 (s, 6H, OCH 3) ·; 4.75 (s, 6H, OCH 3); 2.2 (s, 3H, N-CH 3); 0.8 (s, 9H, tBu).

The monohydrochloride is formed and isolated in meringue form. Example 8 1 - [(3,4-Dimethoxy-phenyl) -3- (4-phenyl-cyclohexylamino) -propyl] -6,7-dimethoxy-isoquinoline_

R1 = H R2 = 4-phenyl-cyclohexyl 12 g of aldehyde, 5.5 g of 4-phenyl-cyclohexylamine, 120 ml of absolute ethanol and 1 g of molecular sieve are stirred for 30 minutes. The mixture is cooled and 3 g of sodium borohydride are added. The mixture is stirred overnight and worked up as in the previous examples. 15.6 g of oil are obtained. The monohydrochloride is formed in isopropanol with one equivalent of N-hydrochloric acid. The monohydrochloride solution is concentrated to dryness, taken up in as little hot isopropanol as possible and allowed to recrystallize. 8 g of product are obtained, m.p. 160 ° C.

(HCl) TLC (methanol / acetone / concentrated hydrochloric acid 90/10/4).

1 spot Rf = 0.6

Elemental analysis ^ 34H40N2O4 * HCl

Calculated: C% 70.70 H% 7.11 N% 4.85

Found: 69.75 7.22 4.68 NMR (base) CDCl 3) δppm: 8.4 (d, 1H, = CH-N =); 6.6-7.5 (m, 11H, aromatic protons); 4.95 (m, 1H, CH 2 CH 2); 3.9 (s, 6H, OCH-j); 3.75 (s, 6H, OCH 3); 1-3 (m, 15H, of which 1H variable).

12

Example 9 7 7 0 2 7 1- [1- (3/4-Dimethoxy-phenyl) -3- (1-methyl-4-hydroxy-butylamino) -propyl] -6,7-dimethoxy-isoquinoline ____ = H R2-1-methyl-4-hydroxybutyl 11.7 g of aldehyde, 3.2 g of 1-methyl-4-hydroxybutylamine, 120 ml of ethanol and 1 g of molecular sieve are stirred for 30 minutes at ambient temperature. The mixture is cooled and 3 g of sodium borohydride are added in small portions. Further processing is performed as in the previous examples. 12.3 g of oil are obtained. The monohydrochloride is formed using 1 equivalent of 1 N hydrochloric acid in isopropanol. The monohydrochloride solution is concentrated to dryness, taken up in as little hot isopropanol as possible and allowed to recrystallize over two days. 7.6 g of product are obtained, m.p. 166 ° C.

TLC (methanol / acetone / concentrated hydrochloric acid 90/10/4).

Rf = 0.6 1 spot

Elemental analysis ^ 27H36N2 ° 5 * HCl

Calculated: C% 64.22 H% 7.33 N% 5.55

Found: 64.00 7.33 5.48 NMR (base) (CDCl 3) δppm: 8.45 (d, 1H) and 6.5-7.6 (m, 6H); 4.95 (m, 1 H)} 4 (d, 6 H) and 3.8 (s, 6 H); 3.6 (m, 4H) * 2.6 (m, 5H) * 1.6 (m, 4H)} 1 (d, 3H).

toxicity

The toxicity of the compounds of the invention has been determined by conventional methods in mice (P.O. and I.P.). The corresponding LD 50 values are given in the following table together with the values of papaverine and prenylamine used as reference compounds (figures in mg / kg).

13 77027

Example No.__LP 50 P.O .__ LP 60 I.P._

Papaverine 290 98

Prenylamine 225 1 # 500 # 120 * 2 # 450 3 # 900 4 # 400 # 140 5 # 450 # 150 6 # 450 # 150 7 # 900 # 160 * 8 # 1000 # 150 * _9_ # 900_ # 150 * __ * dissolved ascorbic acid.

Pharmacology

The compounds of the invention have very favorable activity in the cardiovascular field. To evaluate the interest of the compounds of the invention, the activity was compared with chemically similar papaverine and prenylamine (N- (3,3-diphenylpropyl)? -Methylphenylethylamine).

1 / Cardiac examinations (3-5 dogs for each assay)

Papaverine is known for its effect on increasing heart rate and heart rate. In this experiment, each batch of 3-5 dogs was treated by intravenous administration of 3 mg / kg prenylamine or a molar equivalent of papaverine and the compounds of Example 1-9. No increase in heart rate was observed with prenylamine or the compounds of Examples 1-9.

Cardiac function was determined with the same 11 compounds by calculating the first derivative of left ventricular pressure (dp / dt). Prenylamine and the compounds of Examples 1, 3, 5, 7, and 9 either reduced dp / dt or were not active at all in this experiment; the compounds of Examples 2, 4, 6 and 8 increase dp / dt by 11-26% of the value obtained for papaverine, which is a great advantage for the compounds of the invention.

i4 77027 2 / Anti-arrhythmic effect (Lawson's test in mice) In this experiment, each batch of 20 female mice (20-22 g) was treated orally at doses corresponding to 20% of the LD 50 value. In the treatment, chloroform was inhaled until apnea, 45 minutes after dosing, followed by a thoracotomy and the time between apnea and fibrillation was measured in seconds.

If the activity of prenylamine is taken to be 100, the activity of the compounds of Examples 1-9 is between 100 and 187. The compounds of Examples 1, 3, 5 and 7 also showed considerable activity at a dose of 10% of LD 50, whereas at this dose prenylamine had no effect.

3 / Adrenalytic activity in rats

Adrenalytic activity was determined in batches of 5-6 rats by oral administration of each compound at 10% LD 50. Following administration, rats were injected with norepinephrine or epinephrine. If the activity of prenylamine is taken as 100 for comparison, the result is 60 to 132 (norepinephrine) - the best compounds of Examples 1, 3, 5 and 7 or 48 to 111 (epinephrine) - the best compound of Examples 8. In this experiment, the value obtained for papaverine was 44 for norepinephrine and 93 with epinephrine.

4 / Hemodynamic factor study (anesterized dogs) 3 mg / kg prenylamine or a molar equivalent of papaverine or compounds 1-9 was injected I.V., after which the following hemodynamic factors were measured or calculated.

- Blood pressure (mBP).

- Total peripheral resistance calculated from blood pressure and aortic blood flow (TPR).

- Coronary blood flow (CBF).

The corresponding results are shown in the following table as reference figures when the effect of papaverine on cardiac blood flow is taken as 100.

is 77027

Compound__m B P__T P R__F B F__C B F

Preny. - 48% - 54% + 25% + 50%

Papav. - 23 - 67 +70 + 100 2 0 - 33 + 88 3 - 22 - 29 + 69 + 58 6 - 36 - 65 - 33 + 118 4 - 33 - 65 +82 + 104 5 - 40 0 0 + 86 1 - 30-29 + 113 0 7 - 46 - 56 - + 98 8 - 21 - 38 + 54 + 66 9 _ - 31 1-38 __- 29 [+ 96

All compounds have activity against total peripheral resistance and / or cardiac blood flow; this effect is all the more interesting because the compounds of the invention do not have the unfavorable side effect of papaverine found in 1 / above.

In previous experiments, an equal molar amount of ascorbic acid was added to the compounds to be used in dissolved form when these compounds were insoluble in water.

Of administration-fosfoloqia

The compounds of the invention may be administered orally in any therapeutic form, for example as tablets or gelatin capsules containing from 20 to 100 mg of active compound per dosage unit, together with a suitable carrier such as lactose.

Injectable forms include vials containing 10 to 50 mg of active ingredient, optionally dissolved in water with the addition of a therapeutically acceptable acid such as ascorbic acid.

The dosage for human treatment is 20 to 200 mg / day in oral form and 10 to 100 mg / day in injectable (I.V.) form.

16 77027

The compounds of the invention may be used as antiarrhythmic agents, cardiac or peripheral vasodilators. They have a very beneficial effect on the protection of myocardial cells against anoxia and prevent the loss of calcium in myocardium.

Pharmacological Test Results Comparative pharmacological tests were performed on the compounds of Example 1 (P 2906) and Example 5 (P 2984) of U.S. Patent No. 3,966,724, papaverine, and the compound of Example 3 of the present application.

The experiments have been performed as described on pages 14 and 15 of the specification.

The experiments gave the following results:

m B P TPR EBP CBF

Compound blood pressure peripheral thigh blood cardiac blood ___total resistance flow__flow

Papaverine - 45% - 51% + 74% + 100% P 2906 - 22% - 13% + 44% + 52% P 2984 - 19% - 17% + 49% + 48%

Eg 3 * _- 26% - 29% __ 4- 72% __ + 63% * Experience renewed for comparison

The results show that the compound according to the invention achieves about twice the total peripheral resistance as P 2906 and P 2984. The compound of formula I causes 50% higher blood flow to the thighs than P 2906 and P 2984. Cardiac blood flow is also higher when the compound of formula I is used.

The compounds of the invention further have the advantage that they do not increase cardiac stress, such as papaverine (see page 14 of the specification) and P 2906 (57%) and P 2984 (68%).

Claims (1)

A process for the preparation of a pharmacologically active 1- [1- (3,4-dimethoxyphenyl) -3-aminopropyl] -6,7-dimethoxyisoquinoline of the formula I is ch3o- k 1 N CH-CH T 1.2 m och 3 wherein R 1 is a hydrogen atom or a methyl group; and R 2 is an alkyl group having 1 to 5 carbon atoms which may be substituted by a hydroxy, phenyl or phenoxy group or a cyclohexyl group which may be substituted by an alkyl group or a phenyl group having 1 to 5 carbon atoms, and therapeutically acceptable salts thereof, characterized by condensation in a polar solvent at between 0 and 25 ° C, 1- [1- (3,4-dimethoxy-phenyl) -3-oxo-poryl] -6,7-dimethoxy-isoquinoline of the formula ch3 ° -CH3 ° -CH "CH2" CHO. (II) yL, OCH3 with a compound of general formula NHR1R2, wherein R1 and R2 are as defined above, and the resulting compound is reduced, e.g. with sodium borohydride.