LU82608A1 - NEW ISOQUINOLEIN DERIVATIVES AND THEIR PREPARATION - Google Patents

Description

i ♦ - i -

The present invention relates to new derivatives of • isoquinoline and a process for their preparation.

The invention relates more particularly to derivatives of / "(3,4-dimethoxyphenyl) -1 amino-propyl7“ 1 dimethoxy-5,7 isoquinoline / corresponding to the general formula: CH30— T / Rl

CH-CH0-CH0-N ^ I

X

Y ^ 0CH3 OCH- 3 in which - R ^ represents a hydrogen atom or a methyl radical and - R3 represents an alkyl radical comprising from 1 to 5 carbon atoms or a cycloalkyl radical comprising from 5 to 7 10 carbon atoms, the alkyl or cycloalkyl radical being optionally substituted by a hydroxy, 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 advantageous for their therapeutic properties, in particular in the cardiac and vascular fields.

The present invention also relates to a process for the preparation of derivatives of (3,4-dimethoxy-phenyl) -1 3-amino-propyl7 ~ l-6,7-dimethoxy isoquinoline, corresponding to the general formula I, defined above ; the process comprising the condensation, in a polar solvent, between 0 ° and 25 ° C, of / "(3,4-dimethoxyphenyl) -1 oxo-3 propyl7-l dimethoxy-6,7 25 isoquinoline, corresponding to formula II below: - 2 - CH3 ° -X> \ ^

CH-CHo-CH0 II

Λ! Y ^ OCHj:. 0CH.} With a compound of general formula HNR1R2 in which Rj ^ and R2 are defined as above, and the reduction of the resulting compound by one of the usual techniques, „” for example hydrogenation or preferably, the action of 5 sodium borohydride.

The solvent generally used is an alcohol, preferably ethanol. Although the process according to the invention is applicable when, at the same time, R 1 and R 2 represent hydrogen atoms and when neither and neither R 2 represents a hydrogen atom, it offers the best yields in the preparation of amines secondary (that is to say when R ^ represents a hydrogen atom) and. tertiary amines in which R ^^ represents a methyl radical. Tertiary derivatives can also be obtained from secondary derivatives by well known nitrogen substitution techniques such as iodoalkylation and reductive formylation.

The / "(3,4-dimethoxyphenyl) - 1 oxo-3 propyl7 ~ l dimethoxy- 6,7 isoquinoline II starting can be prepared according to the methods described in detail with reference to Examples A, B 20 and C above With regard to the analytical data cited in Examples A, B and C, and in Examples 1 to 10 thereafter, the latter illustrating the invention, the data of the thin layer chromatography (TLC) were obtained in using Merck F 254 plates; the NMR spectra were 25: recorded on a Perkin-Elmer R 24 device (60 MHz) and the IR spectra were recorded on a Perkin-Elmer 257 device.

- 3 -

Example A

Formation of the carbahion of methyl (3,4-dimethoxyphenyl) 7. 7,7-dimethoxy isoquinoleine a) liquid ammonia / sodium amide method 5 In a three-liter three-necked flask fitted with stirring and a dry ice condenser, 300 ml of liquid ammonia, 0.1 g of ferric chloride acting as catalyst and 0.8 g (0.03 mole) of sodium are successively poured in (cf. Org Synthese Coll., Vol. 5 The reaction mixture is stirred for 1 hour and a half and then 10 g (0.0295 mole) of papaverine is added thereto in small amounts. To complete the formation of the carbanion, the mixture is stirred 2 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

10 g (0.0295 mole) of papaverine and 100 ml of hexamethylphosphotriamide are poured into a one-liter reactor equipped with heating, cooling and stirring means. Maintaining the temperature at about 5 ° C, gradually adding 18.5 ml (0.03 mole) of commercial butyl lithium in solution in hexane. When the addition is complete, stirring is continued for 1 hour at room temperature.

c) sodium amide / hexamethylphosphotriamide method In the same apparatus as in method (b) above, 10 g (0.0295 mole) of papaverine and 30 ml of hexamethylphosphotriamide are poured. 1.2 g (0.03 mole) of sodium amide are added gently, with stirring; the mixture turns red but there is no release of gas. The mixture is heated 30 to 70-75 ° C, causing evolution of ammonia; stirring is continued for 3 hours, until the end of gas evolution. The reaction mixture is then cooled to be used as it is in the synthesis reactions.

d) amide diisopropyl lithium / tetrahydrofuran method In the same apparatus as in method (a) above, cooled by an ethanol / dry ice bath, 400 ml of dry tetrahydrofuran are poured. The amide of diisopropyl lithium is prepared by adding dropwise, 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 min at 10 ° C; after cooling to -40 ° C, 10 g (0.0295 mole) of papaverine powder are added and the mixture is stirred for 4 hours at -40 ° C, then allowed to return to room temperature before being used as it is .

e) potassium amide / dimethyl formamide method 10 In the same apparatus as in example b) above, 10 g (0.0295 mole) of papaverine and 35 ml of dimethyl formamide are poured. 1.7 g (0.03 mole) of potassium amide are added slowly, with stirring. At the end of the addition, stirring is continued by heating the reaction mixture at 70 ° C. for 3 hours and After cooling, the reaction mixture is used as it is for the other syntheses.

For the characterization and identification of the carbanion, the oxidation reaction leading to the (dimethoxy-3,4-benzoyl) -l dimethoxy-6,7 isoquinoline (papaveraldin) is used.

In the carbanion solution, a stream of dry oxygen is bubbled for 2.5 hours; 200 ml of dry toluene are then poured into it and the ammonia is allowed to evaporate. The; solution is treated at room temperature with 200 ml of water and dried. Melting point: 208 ° C (literature: 209-210 ° C).

25 Example B

Formation of the intermediate acetal: / "(3,4-dimethoxy-1-phenyl-3,3-diethoxy-propyl7-1-dimethoxy-6,7 isoguinotin A A solution containing 0.016 mol of the carbanion obtained according to one of the methods described in Example A, 5.3 g (0.025 mole) of 2,2-diethoxyethyl bromide is added slowly.

After stirring for 1 hour, 200 ml of dry toluene are added and the ammonia is allowed to evaporate. At room temperature, 200 ml of water are added and the whole is filtered on celite. The toluene solution; is then decanted, washed, dried over anhydrous sodium sulfate and concentrated. The oil obtained is directly hydrolyzed, which gives 9.6 g of the product. Yield 97%.

- 5 - NMR (£ C14) • »ι · * δρριη ï 8/20 (d, 1H, CH-N =); 7 (m, 6H / aromatic)? 4.25 (t, 1H, CH-CH2); 3.75 (m, 12H, OCH3); ^ OÇH, 3.3 (m, 4H, CH); ^ 0¾ ^ OCH9CH, 5 2.4 (m, 3H, ‘CH2-CH); 1.1 (2t, βΗ, ^ * J).

^ oc2h5 ^ och2ch3

; Example C

Formation of 11 aldehyde; / * (3,4-dimethoxyphenyl) -1 3-oxo-propyl 7-1 dimethoxy-6,7 isoquinoline 8.7 g (0.014 mole) of the compound prepared in Example B 10 above are hydrolyzed 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. 7.25 g of an oil are obtained. Yield 95%.

15 IR

vcm “1: 2730, 1715 (CH = 0) NMR (CDC13) δρρπι: 9.6 (s, 1H, CH = 0); 8.35 (d, 1H, CH-N =); 7 (m, 6H, aromatics); 5.25 (t, 1H, CH); 3.8 (m, 12H, 0CH3); 2.9 (m, 2H, CH, -C).

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

Example 1 ZTdimethoxy-3,4-phenyl) -! amino-3 propyle7 ~ l dimethoxy-6,7 25 i soquinolé ine

R! - R2 = H

This compound can be prepared from the aldehyde in three different ways.

> - 6 - a) direct orig 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 a hydrogenation autoclave with 1 g of Raney nickel. We operate under a pressure of 90 atmospheres. The solution is filtered and the solvent is distilled off. The product is obtained with a poor yield because the hydrogenation: under pressure also affects the isoquinoline nucleus. The next two paths, however, lead to excellent 10 ‘results.

b) route to the oxime 7.6 g (0.02 mole) of the aldehyde, 50 ml of water and 60 ml of ethanol are brought to reflux 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 / '(3,4-dimethoxyphenyl) - are obtained! hydroxy-3 imino propyle7 “l dimethoxy-6,7 isoquinoline.

NMR (CDCl3) Cppm: 8.3 (d, 1H, CH-N =); 7.05 (m, 7H, aromatics and CH = N); 4.9 (m, 1H, CH-CH2); 3.8 (m, 13H, OCH3 and OH); 3.05 (m, 2H, CH2).

The reduction of this oxime by aluminum-lithium hydride or its catalytic hydrogenation to its chemical reduction leads to the desired compound with good yields (85 to 95%).

NMR (CDCl3) 6 ppm: 8.45 (d, 1H, CH-N =); 7.1 (m, 6H, aromatics); 4.8 (t, 1H, CH-CH2); 3.85 (m, 12H, OCH3) y 2.45 (m, 4H, 30 eH2ÇH2-N)? 1.5 (m, 2H, NH2).

The dimaleate is prepared in ethanol.

Melting point: 130 ° C.

: Anhydrotitrimetric dosage: 98%.

- 7 - c) debenzylation cell, · *

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 are placed in 150 ml of ethanol and 1 g of 10% palladium catalyst on carbon. Hydrogenated at 50 ° C for 3 hours. The catalyst is filtered and the solvent is evaporated off under reduced pressure. After alkalinization, 3.75 g 10 (90% yield) of an oil are extracted with dichloromethane.

Example 2 / ~ (3,4-dimethoxy phenyl) -! (methyl-1 propylamino) -3 propyl7 -1 dimethoxy-6,7 isoguinoline R ^ = H R2 = methyl-1 propyl 15 13 g of the aldehyde, 2.5 g of methyl-1 propylamine and 120 ml of agitation are stirred. 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 treated as described in the previous examples. 11.2 g of a yellow oil are isolated. It is dissolved in 100 ml of isopropanol and 25.4 ml of IN 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 of boiling isopropanol and recrystallized. 6.3 g of the product are obtained.

Fusion point ; 246 ° C.

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

Rf = 0.5 1 spot 30 NMR (base) (CDCl3) <$ ppm: 8.45 (d, 1H, = CH-N =); 7.3-7.5 (m, 2H, aromatics); 6.15-7 (m, 4H, aromatics); 4.85 (m, 1H / ^ TCH-CHj); 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-dimethoxy-phenyl) ~ 1 cÿclQhéxyT-3 amino prop'y 1 ^ 7-1-dimethoxy-6,7 isoquinoline r ^ = h R2 = 5 According to the procedure of Example 2 but in using cyclohexylamine instead of 1-methyl-propylamine, 8.1 g of the product are obtained. Yield 88%. r Melting point; 135 ° C (ethanol).

NMR (CDC13) * 10 6ppm: 8.35 (d, 1H, CH-N =)? 7.10 (m, OH, aromatics); 4.8 (t, 1H, 'CH)? 3.85 (m, 12H, OCH3); 2.4 (m, 5H, CHg “CH2" N-CHzZ.); 1.85 (1H, N-H); 1.4 (m, 1OH,

H

Cyclic CH2).

Hydrochloride melting point> 250 ° C (ethanol) 15 Anhydrotitrimetric determination: 100% (2 basic functions)

Elementary analysis ^ 28 ^ 36 ^ 2 ^ 4 '(500.5)

Hold. C% 72.4 H% 7.76 N% 6.03

Found 72.31 7.65 5.94 î

Example 4 20 Z ~ (3,4-dimethoxyphenylj -1 (methyl-a-phenethylamino) -3 propyl / -! Dimethoxy-6,7 isoquinoline - Ή R2 - methyl-a-phenethyl

7.6 g (0.02 mole) of the aldehyde are stirred with 2.7 g (0.02 mole) of methyl-a-phenethylamine in 80 ml of ethanol

O

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

After 1 hour of stirring, the mixture is cooled to 0 ° C and 2 g of sodium borohydride are added in small amounts.

The mixture is again stirred 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, which gives 8.5 g of an oil. 85% yield. 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 taken up in 50 ml of boiling isopropanol.

Fusion point ; 220eC.

5 Anhydrotitrimetric dosage: 100% (2 basic functions).

NMR (CDCl3) ppppm ï 8.30 (d, 1H, CH-N =); 7.05 (m, 11H, aromatics); 4.70 (t, 1H, ^ H-CH2); 3.85 (m, 12H, OÇH3)? 2.60 (m, 7H, CH2 "—2_NH ~ 'Cg2); 2.30 (1H, NH); 10: 1.0 (d, 3H, ch3-ch).

Elementary analysis C3iH36N2 ° 4 'HC1 (536.5)

Hold. C% 69.3 H% 6.89 N% 5.22

Found 69.1 6.75 5.31

Example 5 15 21 "(3,4-dimethoxyphenyl) -! (Methyl-N methyl-g benzylamino) -3 propy1 ^ 7-1 dimethoxy-6,7 isoquinoline = CH3 R2 = methyl-α 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, treated as in Example 2. 14 g of an oil are obtained.

25 g of this oil is gently brought to reflux for 2.5 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 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; it is left to crystallize. The crystals are combined and dried to give 4.3 g of the product; r melting point; 130 ° C.

- 10 -, IR: r279i0cnf1 N-CH-3.

NMR (CDCl3) 6 ppm: 8.35 (d, 1H, CH-N =); 6.7-7.35 (m, 11H, aromatics); 4.8 (t, 1H,: ^ CH-CH2); 3.95 (d, 6H, 0CH3); 5 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-CH3).

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

• Rf - 0.7

The hydrochloride is formed in alcohol. This alcohol is evaporated and the meringue is dried.

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 which is N-methylated as in Example a) above are obtained. 2.3 g of a new oil are therefore isolated, which crystallizes from isopropanol. Melting point at 115 ° C.

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

Rf - 0.7 20 The hydrochloride is prepared as in example (a) above. Example 6 / ~ (3,4-dimethoxyphenylj -1 (methyl-N methyl-1 phenoxy-2 ethylamino) -3 propyle7-l dimethoxy-6,7 isoquinoline R ^ = CH3 R2 = methyl-1 phenoxy-2 ethyl 25 12 g of the aldehyde, 4.75 g of 1-methyl-2-phenoxy-ethylamine and 125 ml of distilled ethanol are stirred on 1 g of molecular sieve for 30 minutes, the mixture is cooled to 0 ° C. and 3 g of sodium borohydride 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, there is obtained 13.5 g of a new oil from which -lion forms, the hydrochloride with IN hydrochloric acid 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 of mono-5 hydrochloride isolated in the form of a meringue.

TLC: 1 stain (methanol / aceton / concentrated hydrochloric acid 90/10/4).

: Rf = 0.5.

IR (film base: 2800 cm * N-CH ^) 10 NMR (base) (CDCl3) 6 ppm: 8.4 (d, 1H, CH = N); 6.6-7.5 (m, 11H, aromatics); 5 (m, 1H, ~ ^ CH-CH2); 3.75-3.95 (m, 12H, 0CH3); 2.35 (d, 3H, N-CH3); 1.05 (d, 3H, CH-CH-j).

Example 7 15 / '(3,4-dimethoxyphenyl) -! benzylamino-3 propyl / -! dimethoxy- 6,7 isoquinoline R1 = H R2 = benzyl

According to the same method as in Example 2 but using benzylamine instead of 1-methyl-propylamine, '20 the above compound is obtained with a yield of 80%.

Hydrochloride melting point: 223 ° C (isopropanol)

Anhydrotitrimetric dosage: 99% (2 basic functions)

Elemental analysis C29H32N204, HCl (508.5)

Hold. C% 68.5 H% 6.50 N% ..5.50 25 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-CH2) 3 3.9 (m, 14H, OCH3 and CH ^ y); 2.7 (m, 4H, CH2-CH2-N)? 2.3 (s, 1H, N-H).

% - 12 -

Example 8, · * / "(3,4-dimethoxy-phenyl-1 (methyl-N t.-butyl-4 cyclohëxylamino) -3 propyl ^ J" 1-dimethoxy-6,7 isoquinoline

Rx - CH3 R2 = t.butyl-4 cyclohexyl 5 12 g of the aldehyde, 4.9 g of t.butyl-4 cyclohexylamine and 120 ml of distilled ethanol are stirred for 30 minutes. a molecular sieve. The processing is described in the previous examples. 13.8 g of an oil are obtained. This ; the 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. 6.5 g of recrystallized product are obtained, melting point: 126 ° C.

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

1 spot Rf = 0.6 15 NMR (CDCl3) ppm: 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 ^); 4.9 (S, 6H, OÇH3); 4.75 (s, 6H, 0¾); 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 £ X-dimethoxy-3/4 phenyl (4-phenyl cyclohexylamino) -3 propyl7 -1 dimethoxy-6,7 isoquinoline R ^ = H R2 = 4-phenyl cyclohexyl 25 12 g of the aldehyde, 5.5 g of phenyl -4 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 treated as in the previous examples.

15.6 g of an oil are obtained. The monohydrochloride in isopropanol is prepared with 1 equivalent of hydrochloric acid N.

‘The monohydrochloride solution is concentrated to dryness, taken up in the minimum amount of boiling isopropanol and evaporated.

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

- 13 - (hci) v; . .

- TLC (methanol / acetone / concentrated hydrochloric acid 90/10/4) 1 spot Rf = 0.6

Elementary analysis C34H40N2 ° 4 'HC1 5 Wedge. C% 70.70 H% 7.11 N% 4.85

Found 69.75 7.22 4.68: NMR (base) (CDCl3) ppm: 8.4 (d, 1H, = CH-N =); 6.6-7.5 (m, 11H, aromatic)? 4.95 (m, 1H, ^ rCH-CH2); 3.9 (s, 6H, OCE3); 3.75 (s, 6H, 10 OCH3); 1-3 (m, 15H including 1H exchangeable).

Example 10 / “(3,4-dimethoxy phënyi) -1 (methyl-1 hydroxy-4 butÿlamino) -3 propyl / -! dimethoxy-6,7 isoquinoline

Rj = "Ή R2 = 4-hydroxy-butyl 15 11.7 g of the aldehyde, 3.2 g of 1-methyl-4-hydroxy butylamine, 120 ml of ethanol and 1 g of molecular sieve are stirred for 30 minutes at The mixture is cooled to room temperature and 3 g of sodium borohydride are added in small quantities. The process is carried out as in previous examples. 12.3 g of an oil are obtained. The monohydrochloride is prepared with 1 equivalent of hydrochloric acid IN in isopropanol The solution of the monohydrochloride is concentrated to dryness, taken up in the minimum of boiling isopropanol and recrystallized in two days, 7.6 g of the product are obtained, melting point: 166 ° C.

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

Rf: 0.6 1 spot

Elementary analysis C27H36N2 ° 5 'HC1

Hold. C% 64.22 H% 7.33 N% 5.55 30 Found 64.00 7.33 5.48 - 14 - NMR Gbase) (CDCI 3) mppm: 8745 (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).

5 TOXICITY

- The toxicity of the compounds of the present invention was: determined by the usual methods on mice (p.o and i.p.). The corresponding LD 50 values are given ‘in the following table with the data for papaverine and 10 for prenylamine - reference compounds - (figures in mg / kg).

'' ......... · ΙΡ * ....—- il · ...... -....... 11 - 1 | No. of the example DL 50 p.o. DL 50 i.p.

papaverine 290 98 prenylamine 225 2 # 500 # 120 * 3 # 450 4 # 900 5 # 400 # 140 6 # 450 # 150 7 # 450 # 150 8 # 900 # 160 * 9 # 1000 # 150 * 10 # 900 # 150 * solubilized with ascorbic acid.

> PHARMACOLOGY

The compounds of the present invention exhibit very favorable activity in the cardiovascular field.

To evaluate the advantage of the compounds of the invention, comparisons were made with papaverine, effective in the same field of action, and with prenylamine (diphenyl-3,3-propyl) N methyl-α-phenylamine) , whose chemical structure r is close.

* - 15 - 1 / Cardiac studies (3 to 5 dogs for each test) i i. "

Papaverine is known to elevate both the rhythm and the work of the heart. For this experiment, each batch of 3-5 dogs was treated intravenously with »5 3 mg / kg for prenylamine or with the molecular equivalent for papaverine and for the compounds of examples 2 to 10. No increase in rhythm was not noted either for prenylamine or for the compounds of Examples 2 to 10.

As for the cardiac work, it was determined on the 10 ,: It same compounds by calculating the first derivative of the pressure of the left ventricle (dp / dt). The prenylamine and the compounds of Examples 2, 4, 6, 8 and 10 reduce the dp / dt or show no activity in this field; the compounds of examples 3, 5, 7 and 9 cause an increase in the dp / dt of between 11% and 26% of the figure obtained for papaverine, which is very advantageous for the compounds of the invention.

2 / Antiarrhythmic effect (Lawson test on mice)

For this experiment, each batch of 20 female 20 mice (20-22 g) was treated orally at doses corresponding to 20% of the LD 50. The operation consists in inhaling chloroform until apnea 45 min after administration of the dose, followed by a thoracotomy and measurement of the time (in seconds) between apnea and fibrillation.

If the value 100 is assigned to the activity of the prenylamine taken as a reference, the compounds of Examples 2-10 have an activity between 100 and 187. An appreciable activity has also been noted at a dose of 10% LD 50 for the compounds of Examples 2, 4, 6 and 8 while prenylamine 30 had no action at this dose.

3 / Adrenalytic activity on the rat The adrenalytic activity was determined on batches of 5-6 rats receiving 10% of the LD 50 of each compound orally. After administration, rats were injected with norepinephrine or epinephrine. If the value 100 is assigned to the activity of prenylamine taken as a reference, the; r results gave values ranging from 60 to 132 (norepinephrine) -best compounds; examples 2, 4, 6 and 8- or 48. at 111 „5 (epinephrine) -best compound: example 9. The values found for papaverine during this experiment were 44 for norepinephrine and 93 for 1 ' epinephrine.

.4 / -Study of hemodynamic factors (anesthetized dogs)

After IV injection of 3 mg / kg of prenylamine or 10 the molecular equivalent of papaverine or compounds 2 to 10, the following hemodynamic factors were measured or calculated: - blood pressure (PS) - total peripheral resistance calculated from 15 blood pressure and aortic flow (RPT) - femoral flow (DF) - coronary flow (DC)

The corresponding results are reported in the following table by comparison with the activity of papaverine on the coronary flow taken conventionally equal to 100.

COMPOUND PS R P T. DF D C · PRENY. - 48% - 54% + 25% + 50% PAPAV. - 23 - 67 +70 +100 ft! 3 0 - 33 - + 88 .4 - 22 - 29 + 69 + 58 7 - 36 - 65 - 33 +118 5 - 33 - 65 +82 +104, | 6 - 40 0 0 +86 2 - 30 - 29 +113 0 | 8 - 46 - 56 - +98 I 9 - 21 - 38 + 54 + 66 d 10 - 31 - 38 - 29 +96 Λ - 17 -

All of these compounds have an activity on total peripheral resistance and / or on coronary flow; this action is all the more advantageous since the compounds according to the invention do not exhibit the undesirable side effect c 5 of papaverine as is demonstrated in paragraph 1 / above.

In the previous experiment, a molecular amount of ascorbic acid was added to the various compounds to be used in dissolved form when they were insoluble; in water.

3 "

PRESENTATION - DOSAGE

The compounds according to the present invention can be administered orally in any suitable therapeutic form, for example, tablets or capsules comprising from 15 to 100 mg of active product per dosage unit with a suitable excipient such as, for example, lactose. .

The injectable forms comprise ampoules containing 10 to 50 mg of active product, if necessary is dissolved in water by the addition of a therapeutically acceptable acid, such as, for example, ascorbic acid, as specified above.

The dosage in human therapy is 20 to 200 mg / day orally and 10 to 100 mg / day by injection (I.V.).

The compounds of the present invention are anti-arrhythmic and coronary or peripheral vasodilators.

They have a very favorable action in the protection of myocardial cells against anoxia and prevent calcium loss in the myocardium.

Claims (1)

5. Rl represents a hydrogen atom or a methyl radical and - R2 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 cyclo-10 radical alkyl being optionally substituted by a hydroxy, 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 its therapeutically acceptable salts. 2 / A process for the preparation of the compounds according to claim 1, comprising the condensation, in a polar solvent, between 0 ° and 25 ° C, of / Idimethoxy-3,4-phenyl) -1 3-oxo-propyl7-1 dimethoxy -6.7 isoquinoline, corresponding to the formula: Γ - 19 - CB30 _ [^ Y ^ 1 CH3 ° - ch-ch2-cho A 0CH3; och3 ï with a - compound of general formula HNR ^ ï ^ in which and R2 are defined as above and the reduction - of the compound obtained by one of the usual techniques. 3 / Therapeutic composition active in the cardiovascular field, comprising as essential element from 10 to 100 mg of a compound according to claim, with a suitable excipient. è