FR2461702A1 - NOVEL ISOQUINOLINE DERIVATIVES AND PROCESS FOR THEIR PREPARATION - Google Patents

Abstract

THE PRESENT INVENTION CONCERNS NEW (DIMETHOXY-3,4 PHENYL) -1 AMINO-3 PROPYL-1 DIMETHOXY-6,7 ISOQUINOLEINES RESPONDING TO GENERAL FORMULA I: (CF DRAWING IN BOPI) IN WHICH: -R REPRESENTS A D-ATOM 'HYDROGEN OR A RADICAL METHYL, ET -R REPRESENTS A RADICAL ALCOYL COMPRISING 1 TO 5ATOMS OF CARBON OR A RADICAL CYCLOALCOYL COMPRISING 5 TO 7 ATOMS OF CARBON, THE RADICAL ALCOYL OR CYCLOALCOYL BEING OPTIONALLY PHYENYL OR PHYXENYL, AND THE RADICAL ALCOYL OR CYCLOALCOYL BEING OPTIONALLY PHYXO-HYDRO-HYDROALCOYL OR A HYDRO-CYCLOALCOYL RADICAL CYCLOALCOYL BEING OPTIONALLY SUBSTITUTED BY A RADICAL ALCOYL COMPRISING 1 TO 5ATOMS OF CARBON, THEIR THERAPEUTICALLY ACCEPTABLE SALTS AND THEIR METHOD OF PREPARATION.

Description

The present invention relates to novel derivatives of

  isoquiboline and a process for their preparation.

  The invention relates more particularly to derivatives

  3,4-dimethoxy-phenyl-1-amino-3-propyl-7-dimethoxy-

  6.7 isoquinoline, corresponding to the general formula CH30 CH30 f

CH-CH2-CH2-NN '

R2

[OCH3

  CH 3 in which - R 1 represents a hydrogen atom or a methyl radical and - R 2 represents an alkyl radical comprising from 1 to 5 carbon atoms or a cycloalkyl radical comprising from 5 to 7 carbon atoms, the alkyl or cycloalkyl radical being optionally substituted by a hydroxyl, phenyl or phenoxy radical and the cycloalkyl radical being optionally substituted by an alkyl radical comprising from 1 to 5 carbon atoms,

  as well as their therapeutically acceptable salts.

  The compounds according to the present invention are of interest for their therapeutic properties, in particular in the

heart and vascular areas.

  The present invention also relates to a process for the preparation of the derivatives of the 3- (3,4-dimethoxyphenyl) -3-amino-propyl-7-dimethoxy-6,7-isoquinoline, corresponding to the general formula I, defined above; comprising condensation, in a polar solvent, between 0 and 25 C, of [(3,4-dimethoxy-phenyl) -1-oxo-3-propyl] -1,7-dimethoxy-6,7-isoquinoline, corresponding to formula II below: - 2 - CH30N CH3O.

CH-CH2-CHO II

"'OCH3

  OCH 3 with a compound of the general formula HNR 1 R 2 in which R 1 and R 2 are defined as above, and the reduction of the resulting compound by one of the usual techniques, for example the hydrogenation or preferably the action of sodium borohydride . The solvent generally used is an alcohol, preferably ethanol. Although the process according to the invention is applicable when both R1 and R2 represent hydrogen atoms and when neither R1 nor R2 represents a hydrogen atom, it offers the best yields in the preparation of secondary amines (i.e., when R.sub.1 represents a hydrogen atom) and tertiary amines in which R.sub.1 represents a methyl radical. Tertiary derivatives can also be obtained from secondary derivatives by the well-known techniques of nitrogen substitution such as iodoalkylation and

reductive formylation.

  3,4-Dimethoxy-phenyl-1-oxo-3-propyl-7-dimethoxy-

  6.7 starting isoquinoline II can be prepared according to the methods described in detail with reference to Examples A, B and C below. With regard to the analytical data cited in Examples A, B and C, and in Examples 1 to 2, the latter illustrating the invention, the TLC data was obtained using plates. Merck F 254; the NMR spectra were recorded on a Perkin-Elmer R 24 (60 MHz) apparatus and the

  IR spectra were recorded on a Perkin-Elmer 257 device.

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Example A

  Formation of (3,4-dimethoxyphenyl) methyl-7,7-dimethoxy-isoguinoline carbanor

  a) liquid ammonia / sodium amide-

  In a 1-liter one-necked flask equipped with stirring means and a dry ice regulator, 300 ml of liquid ammonia, 0.1 g of ferric chloride acting as a catalyst and 0.8 g (0.03), are successively poured in. mole) (see Org Synthese Coll., Vol.5, p.523). The reaction mixture is stirred for 1.5 hours and then 10 g (0.0295 moles) of papaverine are added in small amounts. To complete the carbanion formation, the mixture is stirred for 2 hours. A red solution is obtained, to be used as such in the synthesis reactions, for example those described in the

examples below.

  b) Butyl lithium / hexamethylphosphotriamide method - In a one-liter reactor equipped with heating, cooling and stirring means, 10 g (0.0295 mol) of papaverine and 100 ml of hexamethylphosphotriamide are poured. Keeping the temperature at about 5 ° C, 18.5 ml is gradually added

  (0.03 mole) commercial butyl lithium dissolved in hexane.

  When the addition is complete, stirring is maintained for

1 hour at room temperature.

  c) sodium amide / hexamethylphosphotriamide method In the same apparatus as in method (b) above,

  10 g (0.0295 moles) of papaverine and 30 ml of hexamethyl-

  phosphotriamide. 1.2 g (0.03 mole) of sodium amide are added slowly, with stirring; the mixture turns red but there is no gassing. The mixture is heated to 70-750C, causing evolution of ammonia; we keep

  stirring for 3 hours until the end of the evolution of gas.

  The reaction mixture is then cooled to be used

  as such in the synthesis reactions.

  d) diisopropyl lithium amide / tetrahydrofuran method In the same apparatus as in method (a) above, cooled with an ethanol / dry ice bath, 400 ml of dry 4-tetrahydrofuran are poured. The diisopropyl lithium amide is prepared by adding, drop by drop, at -30 ° C., 18.5 ml of butyl lithium (0.03 mol) dissolved in hexane; 4.2 ml (0.03 mole) of diisopropylamine are added and the mixture is stirred for 15 minutes at 10 ° C .; after cooling to -40 ° C., g (0.0295 mol) of powdered papaverine is added and the mixture is stirred for 4 hours at -40 ° C. and then allowed to come back to room temperature.

  room temperature before use as is.

  e) potass-iu / dimethyl amide-formamide method 10. In the same apparatus as in Example b) above, 10 g (0.0295 mol) of papaverine and 35 ml of dimethylformamide are poured. 1.7 g (0.03 mol) of potassium amide are added slowly with stirring. At the end of the addition, the stirring is maintained by heating the reaction mixture at 70 ° C. for 3 hours and a half. After cooling, the reaction mixture

  is used as is for other syntheses.

  For characterization and identification of carbanion,

  the oxidation reaction resulting in the (dimethoxy)

  3,4 benzoyl) -1 dimethoxy-6,7 isoquinoline (papaveraldine).

  In the carbanion solution, a stream of dry oxygen is bubbled through for 2.5 hours; ml of dry toluene is then poured in and the ammonia is evaporated. The solution is treated at room temperature with 200 ml of water

  and dried. Melting point: 208 C (Literature: 209-210 ° C).

Example B

  Formation of the intermediate-acetal: (3,4-dimethoxyphenyl) -1-diethoxy-3-propyl-1-dimethoxy-6,7-isoquinoline To a solution containing 0.016 mole of the carbanion obtained according to one of the methods described in Example A, we add

  slowly 5.3 g (0.025 mol) of 2,2-diethoxyethyl bromide.

  After stirring for 1 hour, 200 ml of dry toluene are added and the ammonia is evaporated. At room temperature, ml of water is added and the whole is filtered through celite. The toluene solution is then decanted, washed, dried over anhydrous sodium sulphate and concentrated. The oil obtained is hydrolyzed directly which

  gives 9.6 g of the product. Yield 97%.

- 5 -

NMR (CC14)

  Lc4) δppm: 8-20 (d, 1H, CH-N =); 7 (m, 6H, aromatics); 4.25 (t, 1H, CHCH2); 3.75 (m, 12H, OCH 3); OCH 2 3.3 (m, 4H, CH); OCH 2 <2.4 m, 3H, AC HS OCH CH 2.4 (m, 3H, CH 2 -CH 25); 1.1 (2t, 6H <0 CH3

2 5 OC2H5CH3

Example C

  Formation of aldehyde: 1- (3,4-Dimethoxyphenyl) -1-oxo-propyl-1-dimethoxy-6,7-isoquinoline 8.7 g (0.014 mol) of the compound prepared in Example B above are hydrolysed for 2 hours at 50 ° C. in 200 ml of a 2% hydrochloric acid solution. After alkalinization to pH 12 with sodium carbonate, the mixture is extracted 3 times with 50 ml of dichloromethane. We obtain 7.25 g of a

oil. Yield 95%.

IR vcm-1: 2730, 1715 (CH = O)

NMR (CDCl3)

  6 ppm: 9.6 (s, 1H, CH = O); 8.35 (d, 1H, CH-N =); 7 (m, 6H, aromatics); 5, 25 (t, 1H, CH); 3.8 (m, 12H, OCH3); 2 "0

2.9 <m, 2H, CH 2 -C).

  in Examples 1 to 10 which follow, this compound is called "aldehyde".

Example 1

  Z (3,4-dimethoxyphenyl) -I-amino-3-propyl-7-dimethoxy-6,7-isoquinoline

R1 = R2 = H

  This compound can be prepared from the aldehyde according to three

different ways.

24 61702

  A) Direct route by reductive amination 12 g of the aldehyde are added to a cooled solution of 100 ml of ethanol saturated with ammonia and the mixture is placed in an autoclave to be hydrogenated with 1 g of nickel. Raney. It operates under a pressure of 91 bar. The solution is filtered and the solvent is distilled off. The product is obtained in poor yield because the hydrogenation under pressure also affects the isoquinoline ring. The two following routes, on the other hand, lead to excellent

results.

  b) oxime route 7.6 g (0.02 mole) of the aldehyde, 60 ml of water and 60 ml of ethanol are refluxed for 1 hour and a half in a 250 ml flask with 2 g of sodium hydroxide and 4.2 g of hydroxylamine hydrochloride. The solvents are then removed by distillation and the residue is taken up in dichloromethane

  and washed with water. 6.4 g (80% yield) of [(dimethoxy)

  3,4-phenyl) -1-hydroxy-3-imino-propyl-1-dimethoxy-6,7-isoquinoline.

NMR (CDCl3)

  Δppm: 8.3 (d, 1H, CH-N =); 7.05 (m, 7H, aromatics and CH = N); 4.9 (m, 1H, CH-CH 2); 3.8 (m, 13H, OCH3 and OH);

3.05 (m, 2H, CH 2).

  The reduction of this oxime by lithium aluminum hydride or its catalytic hydrogenation or its chemical reduction leads to

  to the desired compound in good yields (85 to 95%).

NMR (CDCl3)

  Δppm: 8.45 (d, 1H, CH-N =); 7.1 (m, 6H, aromatics); 4.8 (t, 1H, CH-CH 2); 3.85 (m, 12H, OCH 3); 2.45 (m, 4H,

CH2CH2-N); 1.5 (m, 2H, NH 2).

  The dimaleate is prepared in ethanol.

Melting point: 130 C.

Anhydrotetrimetric determination: 98%.

  C) Debenzylation pathway The compound obtained in Example 4 below is treated as follows: In a hydrogenation flask, 5.1 g (0.01 mole) of the compound described in Example 4 is placed in 150 ml of ethanol and 1 g of palladium catalyst, 10%, on charcoal. It is hydrogenated at 50 ° C. for 3 hours. The catalyst is filtered and the solvent is evaporated under reduced pressure. After alkalinization, 3.75 g are extracted with dichloromethane.

10. (90% yield) of an oil.

Example 2

  1- (3,4-dimethoxyphenyl) -1- (1-methylpropylamino) propyl] -1,6-dimethoxy-isoqguiolin R1 = H R2 = 1-methylpropyl 13 g of the aldehyde, 2.5 g of methyl propylamine and 120 ml of ethanol for 30 minutes on 1 g of molecular sieve at room temperature. The mixture is cooled to 0 ° C. and 3 g of sodium borohydride are added. The mixture is stirred overnight at room temperature and processed next

  the description given in the previous examples. We isolate

  11.2 g of a yellow oil. It is dissolved in 100 ml of isopropanol and 25.4 ml of 1N hydrochloric acid (1 equivalent) are added to form the hydrochloride. The solution is concentrated to dryness and the residue is taken up in the minimum boiling isopropanol and recrystallized. 6.3 g is obtained

of the product.

Melting point: 246 C.

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

  Rf = 0.5 1 NMR spot (base) (CDCl3) eppm: 8.45 (d, 1H, = CH-N =); 7.3-7.5 (m, 2H, aromatics); 6.15-7 (m, 4H, aromatics); 4.85 (m, 1H, ZCH-CH 2); 3.95 (s, 6H, OCH3); 3.75 (s, 6H, OCH3); 2.1-3 (m, 5H);

  1.1-1.6 (m, 3H including 1H exchangeable NH); 0.7-1 (m, 6H).

- 8 -

Example 3

  - (3,4-Dimethoxyphenyl) cyclohexyl-33'-amino-propyl-7-dimethoxy-6-7-isoquinoline R1 = H R2 = cyclohexyl Following the procedure of Example 2 but using cyclohexylamine instead of methyl-i

  propylamine, 8.1 g of the product is obtained. Yield 88%.

Melting point: 135 C (ethanol).

NMR (CDCl3)

  6 ppm: 8.35 (d, 1H, CH-N =); 7.10 (m, 6H, aromatics); 4.8 (t, 1H, CH) -; 3.85 (m, 12H, OCH3); 2.4 (m, 5H, CH 2 -CH 2 -N-CH-); 1.85 (1H, N-H); 1.4 (m, 10H, H

Cyclic CH2).

  Hydrochloride Melting Point> 250 C (Ethanol) Anhydrotetrimetric Determination: 100% (2 basic functions) Elemental Analysis C28H36N2O4, HCl (500.5) Calc. C% 72.4 H% 7.76 N% 6.03 Found - 72.31 7.65 5.94

Example 4

  3- (3-Dimethoxy-4-phenyl) -I (methyl-α-phenethylamino) -3-propyl] -dimethoxy-1,6,7-i-quinoline R = H 2 R = methyl-α-phenethyl

1 2

  7.6 g (0.02 mol) of the aldehyde are stirred with 2.7 g (0.02 mol) of methyl-α-phenethylamine in 80 ml of ethanol.

  absolute in the presence of 500 mg of molecular sieve (3-A).

  After stirring for 1 hour, the mixture is cooled to 0.degree.

  2 g of sodium borohydride are added in small quantities.

  The mixture is stirred again for 2 hours at room temperature. 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 an oil. Yield 85%. The hydrochloride of this oil is formed using 8.5 ml of 2N hydrochloric acid in millet of ethanol. The solution is concentrated and the residue is

  taken up in 50 ml of boiling isopropanol.

Melting point: 220 ° C.

  Anhydrotetrimetric determination: 100% (2 basic functions).

NMR (CDCl3)

  δppm: 8.30 (d, 1H, CH-N =); 7.05 (m, 11H, aromatics); 4.70 (t, 1H, -CH-CH 2); 3.85 (m, 12H, OCH 3); 2.60 (m, 7H, CH 2 -CH 2 -NH-, CH 2 1); 2.30 (1H, NH);

1.0 (d, 3H, CH3-CH).

  Elemental analysis C31H36N2O4, HCl (536.5) Calc. C% 69.3 H% 6.89 N% 5.22 Found 69.1 6.75 5.31

Example 5

  [(3,4-Dimethoxyphenyl) -1 (methyl-N-methyl-3-benzylamino) propyl] -1,6-dimethoxy-isoquinoline R1 = CH3 R2 = methyl-benzyl a) mixture of the two diastereoisomers 11.5 g of the aldehyde are stirred with 3.6 g of methyl-benzylamine in 100 ml of ethanol in the presence of 1 g of molecular sieve. After stirring for 30 minutes, the reaction mixture is cooled to 0-5 ° C., and 2 g of sodium are gradually added. We treat as in Example 2. We obtain

14 g of an oil.

  7 g of this oil are slowly refluxed for 2.5 hours in a solution of 18 ml of formic acid and 5 ml of a 30% aqueous solution of formaldehyde. The reaction mixture is cooled and poured into a saturated solution of sodium carbonate. 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; we let crystallize. The crystals are combined and dried to give 4.3 g of the product;

melting point: 130 C.

- 10 -

IR: 2790cm-1 N-CH 3)

NMR (CDCl3)

  6 ppm: 8.35 (d, 1H, CH-N =); 6.7-7.35 (m, 11H, aromatics); 4.8 (t, 1H, CHCH2); 3.95 (d, 6H, OCH3); 3.75 (d, 6H, OCH3); 3.65 (q, 1H, CH-CH3); 3-2 (m, 4H,

  CH2-CH2); 2.2 (s, 3H, N-CH3); 1.25 (d, 3H, CH-CH 3).

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

  Rf O 0.7 The hydrochloride is formed in alcohol. This alcohol is evaporated

and dry the meringue.

  b) Separation of the Diastereoisomers The remaining 7 g of the oil obtained in the first step of a) above are chromatographed on a silica column (90 g, eluent dichloromethane / methanol 98/2). First, 2.8 g of a white product is obtained which is N-methylated as in Example a) above. 2.3 g of a new

  oil that crystallizes in isopropanol. Melting point: 115 C.

  TLC: 1 stain (80/20 dichloromethane / methanol) Rf 0.7

  The hydrochloride is prepared as in Example (a) above.

Example 6

  [(3,4-Dimethoxyphenyl) -1- (1-methyl-1-methyl-2-phenoxyethylamino) -propyl] -1-dimethoxy-6,7-isoquinoline R1 = CH3 R2 = methyl-2-phenoxyethyl-ethyl 12 g of the aldehyde, 4.75 g of methyl-2-phenoxyethylamine and 125 ml of ethanol distilled on 1 g of molecular sieve for 30 minutes. The mixture is cooled to 0 ° C. and 3 g of sodium borohydride are added in small quantities. The reaction mixture is stirred overnight and treated as in the previous examples to give 13 g of an oil. These 13 g of oil are N-methylated according to the method described in Example 5. After drying and evaporation, 13.5 g of a new oil is obtained from which

- l! -

  The hydrochloride is added with hydrochloric acid.

,. %;AT

  in isopropanol. The solution is evaporated to dryness and the salt is chromatographed on a silica column (260 g,

  eluent dichloromethane / methanol 95/5) and gives 8 g mono-

  hydrochloride isolated in the form of a meringue. TLC: 1 stain (methanol / acetone / concentrated hydrochloric acid

/ 10/4).

Rf = 0.5.

  IR (base film: 2800 cm -1 N-CH 3) NMR (base) (CDCl 3) δppm: 8.4 (d, 1H, CH = N); 6.6-7.5 (m, 11H, aromatics); (m, 1HZJCH-CH 2); 3.75-3.95 (m, 12H, OCH 3);

  2.35 (d, 3H, N-CH3); 1.05 (d, 3H, CH-CH3).

Example 7

  3- (3,4-Dimethoxyphenyl) -3-benzylaminopropyl-dimethoxy-

  6.7 isoquinoline R1 H R2 = benzyl Using the same method as in example 2 but using benzylamine instead of methyl-1 propylamine,

  the above compound is obtained with a yield of 80%.

  Hydrochloride melting point: 223 C (isopropanol) Anhydrotetrimetric determination: 99% (2 basic functions) Analysis. elemental C29H32N204, HC1 (508.5) Calc. C% 68.5 H% 6.50 N% 5.50 Found 68.65 6.32 5, 25

NMR (CDCl3)

  Sppm: 8.3 (d, 1H, CH-N =); 7.1 (m, 11H, aromatics); 4.8 (t, 1H, CH-CH 2); 3.9 (m, 14H, OCH 3 and CH 2);

  2.7 (m, 4H, CH 2 -CH 2 -N); 2.3 (s, 1H, N-H).

-12-

Example 8

-, {.

  (3,4-Dimethoxyphenyl) -1- (methyl-N-butyl-4-cyclohexylamino) -

  3-propyl-7-dimethoxy-6,7-isoquinoline R1 = CH3 R2 = 4-tert-butylcyclohexyl 12 g of the aldehyde, 4.9 g of 4-tert-butylcyclohexylamine and 120 ml of distilled ethanol are stirred for 30 minutes. minutes on a molecular sieve. The treatment is described in the previous examples. 13.8 g of an oil are obtained. This oil is then N-methylated as in Example 5. After treatment, 14 g of a compound are obtained which is taken up and crystallized from boiling ethyl ether. We obtain 6.5 g

  of recrystallized product, m.p .: 126 C.

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

1 spot Rf = 0.6

NMR (CDCl3)

  Δppm: 8.4 (d, 1H, = CH-N =); 7.2-7.5 (m, 2H, aromatics); 6.4-7 (m, 4H, aromatics); 4.8 (m, 1H, CH-CH 2); 4.9 (s, 6H, OCH 3); 4.75 (s, 6H, OCH3); 2.2 (s, 3H,

N-CH3); 0.8 (s, 9H, tBu).

  The monohydrochloride is formed and isolated in the form of a meringue.

Example 9

  [-3,4-dimethoxyphenyl] - (4-phenylcyclohexylamino) -3-propyl] -1,7-dimethoxy-6,7-isoquinoline R1 = HR = 4-phenylcyclohexyl R2 12 g of the aldehyde, 5.5 g of 4-phenylcyclohexylamine, 1 ml of absolute ethanol and 1% of molecular sieves are stirred for 30 minutes. The mixture is cooled and 3 g of sodium borohydride are added. The mixture is agitated

  all night and treated as in the previous examples.

  15.6 g of an oil are obtained. The monohydrochloride is prepared in isopropanol with 1 equivalent of hydrochloric acid N. The solution of the monohydrochloride is concentrated to dryness,

  recovery in the minimum of boiling isopropanol and evaporated.

  8 g of the product are obtained - melting point: 160 ° C.

- 13 -

(HC1) ':

  TLC (methanol / acetone / 90/10/4 concentrated hydrochloric acid) 1 stain Rf = 0.6 Elemental analysis C34H40N2O4, HCl Calc. C% 70.70 H% 7.11 N% 4.85 Found 69.75 7.22 4.68 NMR (base) (CDCl3) 6 ppm: 8.4 (d, 1H, = CH-N =); 6.67.5 (m, 11H, aromatics); 4.95 (m, 1H, CH-CH 2); 3; 9 (s, 6H, OCH 3); 3.75 (s, 6H,

  -OCH3); 1-3 (m, 15H including 1H exchangeable).

Example 10

  (3-dimethoxy-4-phenyl) -1 (1-methyl-4-hydroxy-butylamino) -3-propyl-1-dimethoxy-6,7-isoquinoline R = H R 2 = 1-methyl-4-hydroxy-butyl 11.7 g of the aldehyde, 3.2 g of methyl-1-hydroxy-4-butylamine, 120 ml of ethanol and 1 g of molecular sieve are stirred for 30 minutes at room temperature. The mixture is cooled and 3 g of sodium borohydride are added in small quantities. It is treated as in the previous examples. 12.3 g of an oil are obtained. The monohydrochloride is prepared with 1 equivalent of 1N hydrochloric acid in isopropanol. The solution of the monohydrochloride is concentrated to dryness, taken up in the minimum boiling isopropanol and recrystallized in two days. We obtain 7.6 g

of the product, m.p .: 166 C.

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

  Rf: 0.6 1 spot Elemental analysis C27H36N205, HC1 Calc. C% 64.22 H% 7, 33 N% 5.55 Found 64.00 7.33 5.48

- 14 -

NMR (base) (CDC1i3) -

  Ompm: 8.45 (d, 1H); 6.5-7.6 (m, 6H); 4.95 (m, 1H); 4 (d, 6H); 3.8 (s, 6H); 3.6 (m, 4H); 2.6 (m, 5H);

1.6 (m, 4H); 1 (d, 3H).

24 6 1,702

- 15 -

Claims (2)

* c.REVENDICATIONS   -. 1 / Nov. 3,4-Dimethoxy-phenyl) -1-amino-3-propyl-6-dimethoxy-6,7-isoquinolines, having the general formula I: CH 3 CH I CH30 R1 CH-CH-CH 2 -N I | R2   OCH 3 OCH 3 in which - R 1 represents a hydrogen atom or a methyl radical and - R 2 represents an alkyl radical comprising from 1 to 5 carbon atoms or a cycloalkyl radical comprising   from 5 to 7 carbon atoms, the alkyl or cycloalkyl radical   wherein alkyl is optionally substituted with a hydroxy, phenyl or phenoxy radical and the cycloalkyl radical is optionally substituted with an alkyl radical having from 1 to 5 carbon atoms,   as well as their therapeutically acceptable salts.   2 / Process for preparing the compounds according to the   cation 1, comprising the condensation, in a polar solvent, between 0 and 25 C, of 3,4-dimethoxy-phenyl)   1-oxo-3-propyl-dimethoxy-6,7-isoquinoline, replies to the formula: - 16 - CH3O CH-CH 2-CHO   with a compound of the general formula HNR1R2 in which R1 and R2 are defined as above and the reduction   of the compound obtained by one of the usual techniques.