FR2568251A1 - NEW ISOQUINOLEINE DERIVATIVES AND THEIR THERAPEUTIC APPLICATIONS - Google Patents

Abstract

NEW DERIVATIVE OF ISOQUINOLEINE. IT IS REPRESENTED BY THE GENERAL FORMULA: (CF DRAWING IN BOPI) IN WHICH R IS A METHYL OR METHOXYMETHYL GROUP, AND R AND R ARE EACH A HYDROGEN ATOM, OR A LOWER ALKYL, A LOWER ALKOXY, A CYCLOHEXYL , A SUBSTITUTE PHENYL, A PYRIDYL OR AN OXO GROUP (0); AS WELL AS ITS PHARMACEUTICALLY ACCEPTABLE SALTS. THESE COMPOUNDS ARE INTERESTING AS HEART REMEDIES WITH HIGH ACTIVITY AND LOW TOXICITY, WITH A WIDE SAFETY INTERVAL AND NO SIDE EFFECTS.

Description

The present invention relates to new isoquinoline derivatives and to their therapeutically acceptable salts, in particular usable as -corridia remedies.

Digitalis preparations, such as digoxin and digitoxin, are commonly used as cardiac tonics (see, for example, Iyakuhin Yoran, pp. 324327, 1977, Yakugyo Jiho Sha). Other cardiac remedies have also been mentioned, such as nicotinonitrile derivatives (Japanese patent publication N070868 / 1982), imidazolone derivatives (JP patent publication N01555368 / 1984) and dihydropyridazinone derivatives (JP patent publication N074679 / 1983 ).

The digitalis preparations, currently in use, have a very limited safety interval, so they must be handled by competent persons. In addition, it has been found that these preparations can help each other with side effects, including arrhythmia. On the other hand, the nicotinonitrile, imidazolone and dihydropyridazinone derivatives exhibit certain drawbacks such as weak cardiac effect, very limited safety interval, increased myocardial rate or high toxicity in animals.

The present invention makes it possible to avoid these drawbacks of the prior art and to obtain a compound with high cardiotonic activity, and low toxicity, having a wide safety interval and no side effects.

dans laquelle R1 est un groupement méthyle ou méthoxyméthyle et R2 et R3 sont chacun un atome d'hydrogène, un alkyle inférieur, un alkoxyle inférieur, un cyclohexyle, un phényle, un phényle substitué, un pyridyle ou un groupement oxo ( = 0). L'invention comprend également les sels thérapeutiquement acceptables de ces composés.La forme tautomère de formule

du composé (I), fait, naturellement, partie de la présente invention
Le nouveau dérivé isoquinoléique selon l'invention peut être préparé, par exemple, de l'une des manières suivantes

The new compound according to the invention is an isoquinoline derivative, represented by the following general formula

wherein R1 is a methyl or methoxymethyl group and R2 and R3 are each a hydrogen atom, lower alkyl, lower alkoxyl, cyclohexyl, phenyl, substituted phenyl, pyridyl or oxo group (= 0). The invention also includes therapeutically acceptable salts of these compounds. The tautomeric form of formula

of compound (I), which is, of course, part of the present invention
The new isoquinoleic derivative according to the invention can be prepared, for example, in one of the following ways

<tb> (1)
<tb><SEP> A <SEP> N <SEP> X
<tb><SEP> o <SEP> o <SEP> Brt, l <SEP> 0 <SEP> 0
<tb><SEP> ~~ <SEP> t9 <SEP> dehydration
<tb><SEP> r ~ - <SEP> N <SEP> (IY)
<tb><SEP> N
<tb><SEP> N
<tb><SEP> o <SEP> 0 <SEP> hydrogenation <SEP> acylation
<tb><SEP> - <SEP> o <SEP> atO <SEP> o
<tb><SEP> acid <SEP> o <SEP> COR1
<tb><SEP> CX
<tb><SEP>, COR '
<tb><SEP> (V) <SEP> (VI)
<tb><SEP> CNCH, CONH, <SEP> H
<tb><SEP> R1
<tb><SEP> N
<tb>

<tb> (2) <SEP> COR1 <SEP> FN
<tb> W <SEP> 1 <SEP> 6a
<tb> R4È <SEP> R4
<tb> R4 <SEP> f <SEP>) <SEP> acylation <SEP> CNCH2CONH2
<tb><SEP><<SEP> 5 <SEP> R4 <SEP><<SEP> R5 <SEP> R
<tb><SEP> (Ix) <SEP> (x) <SEP> (XI) R5 <SEP> R
<tb>
R1 being defined as above, and R4 and R5 being identical to R2 and R3 as defined above, the pyridyl group excepted.

The compound (I) according to the invention, in which R2 is a hydrogen atom and R3 is a pyridyl group, can be prepared according to reaction (1); that is to say that one condenses the ethylenic monoacetal of cyclohexanedione1,4 (III) with bromo-2, bromine3 or bromo-4 pyridine, in the presence of n-butyllithium, to obtain the compound ( IV); then this compound (IV) is reacted with thionyl chloride in pyridine to obtain a compound (V), which is then hydrogenated in a mineral acid to obtain a compound (VI); this compound (VI) is acylated to compound (VII); this acetylation can be carried out using an appropriate acetylating agent, such as acetylimidazole, acetic anhydride, acetyl halide, or acetate, in the presence of sodium alkoxide, sodium hydride, sodium trifluoride. boron / acetic acid, lithium diisopropylamide, or zinc chloride; or, the compound (VI) can be converted to enamine with pyrrolidine or the like, which is then acylated with acetic anhydride. The compound (VII) thus obtained is condensed with cyanoacetamide in the presence of a secondary amine such as piperidine or diethylamine, or of a sodium alkoxide in an alcohol such as methanol or ethanol, in order to give a compound (VIII).

This compound (VITS) corresponds to one of the definitions of the compound (I) according to the invention.

During reaction (2), a cyclohexanone derivative (IX) is acylated as described for reaction (1), yielding a compound (X) which is then condensed with cyanoacetamide to give a compound (XI) , which corresponds to one of the definitions of compost (I) according to the invention.

it is preferable to administer the cardiological remedy according to the invention orally. However, it can also be administered parenterally, for example intravenously. Depending on the mode of administration, it can be incorporated into different formulas. For example, the compound according to the invention, or its salts, can be administered as it is or as a mixture with various non-toxic aQ juvants as excipients, vehicles, binders, stabilizers, diluents or perfumes, pharmaceutically acceptable. These preparations can be put in the form of tablets, capsules, granules, powder, syrup and elixir, for oral administration, and in that of injection for parenteral administration.

The dose of compound according to the invention to be administered to the patient must be determined by the doctors, and depends on various factors such as the condition and age of the patient, as well as on the mode of administration. For example, 0.1 to 10 mg / kg of body weight of this compound can be administered per day orally, although these limits can be exceeded.

The new isoquinoline derivative according to the invention is of interest as a cardiological remedy and exhibits low toxicity as well as a wide range of harmlessness.

Its efficacy is shown by a standard pharmacological test. For example, it can be considered of interest when it exhibits a clear repairing effect on cardiac function, diminished by intravenous administration, under anesthesia, of proplanol.

The present invention is illustrated by the following Preparation Examples and Test Examples.

EXAMPLE 1 Cyanoz4 hexahydro-2,3,5,6,7,8 methyl-1 oxo-3 (pyridyl-4 ') 7 isoquinoline 1) Ethylenic acetal of 4-hydroxy (4 (pyridyl-4') - 4 cyclo
hexanone
20 ml of a 1.6 M solution of n-butyl lithium in hexane are added to 35 ml of ether cooled to -78 C. 5 g of 4-bromo-pyridine in 30 ml of ether are introduced into the mixture thus obtained, then 5 g of ethylenic monoacetal of 1,4-cyclohexanedione dissolved in 30 ml of tetrahydrofuran. When the reaction is complete, the reaction mixture is poured into a saturated aqueous solution of ammonium chloride, and purified by extraction with chloroform to obtain 5 g of 4-hydroxy (4'-pyridyl) ethylenic acetal. ) -4 cyclohexanone. Melting point: 165.5 to 167.5 C.

ScOc13 NMR: 1.6-2.2 (8H, m), 3.9 (1H, s), 4 (4H, s), 7t45
TMS
(2H, dd & 8.44 (2H, dd).

2) (Pyridyl-4 ') - 4-cyclohexen -3 one ethylenic acetal
Was dissolved in 40 ml of pyridine, 5 g of ethylenic acetal of 4-hydroxy (4 'pyridyl) - 4 cyclohexanone, and 8 ml of thionyl chloride was added thereto at -100C. The mixture obtained is stirred at 00C and poured onto ice, then an aqueous solution of sodium hydroxide is added thereto. After purification of this reaction mixture by extraction with methylene chloride, 4 g of 4-hydroxy (4-pyridyl) -4-cyclohexen-3 ethylenic acetal are obtained. Melting point 670-700C.

CDCl3 NMRo; 1.86 (2H, t), 2.4-2.7 (4H, m), 4.04 (4H, s),
TMS 6.24 (1H, t). 7.28 (2H, d) and 8.52 <2H, d) 3) (pyridyl-4 ') - 4 cyclohexanone 4 g of ethylenic acetal of (pyridyl-4'S4cyclohexen -3 one are dissolved in 70 ml of 0.5N hydrochloric acid, and 400 mg of 10% palladium carbon are added thereto in order to hydrogenate the starting compound at room temperature and atmospheric pressure. alkaline reaction mixture, using an aqueous solution of sodium hydroxide, then extracted with methylene chloride to obtain 2.7 g of (pyridyl-4 ') - 4 cyclohexanone.

NMR # CDCl3: 1.7-2.3 (4H, m), 2.4-2.6 (4H, m), 2.8-3.2
TMS @@@@ M), 7.15 (2H, d) and 8.51 (2H, m).

4) Acetyl-2 (pyridyl-4 ') - 4 cyclohexanone
3.2 ml of diisopropylamine are dissolved in 40 ml of tetrahydrofuran, and 14.2 ml of a 1.6 M solution of n-butyllithium in hexane are added thereto at -20 ° C. A solution prepared by dissolving 2 g of (pyridyl-4 ′) -4 cyclohexanone in 40 ml of tetrahydrofuran is then introduced therein, at -40 ° C. The reaction mixture obtained is cooled to -780C, and 2.5 g of acetylimidazole dissolved in 40 ml of tetrahydrofuran are added thereto. After stirring at room temperature, this mixture is poured into water and rinsed with ether. The aqueous phase is saturated with ammonium chloride and is extracted with methylene chloride to give 1.65 g of acetyl-2 (4 'pyridyl) - 4 cyclohexanone.

CDCl
S NMR: 1.7-2.2 (3H, m), 2.16 (3H, s), 2.3-2.6 (3H,
TMS m), 2.6 ~ 2.9 (1H, m), 7.10 (2H, dd), 8.55 (2H,
dd) and 15.7 (1H, s).

5) Cyano-4 hexahydro-2,3,5,6,7,8 methyl-1 oxo ~ 3 (pyridyl
4 ') - 7 isoquinoleine 1.65 g of acetyl-2 (pyridyl-4') - 4 cyclohexanone and 0.64 g of cyanoacetamide are dissolved in ethanol, and a small amount of piperidine is added. The reaction mixture obtained is heated at reflux for 7 hours. When the reaction is complete, the crystals which separate by precipitation are filtered off, which gives 0.7 g of cyano4 hexahydro-2,3,5,6,7,8 methyl-1 oxo-3 (pyridyl-4 ') -4 isoquinoline. Fusion point ; 3100C (decomposition).

NMR # DMSO-d6: 1.7-2.1 (2H, m), 2.22 (3H, s) 2.3-2.7
TMS
(2H m), 2.8-3 (3H, m), 7.35 (2H, dd) and
8.5 (2H, dd).

EXAMPLE 2
4-cyano-hexahydro-2,3,5,6,7,8 1-methyl oxo-3 (2 'pyridyl) 7isoquinoline 1) 4-hydroxy (2' pyridyl) ethylenic acetal - 4 cyclohexa
none
The procedure of 1) of Example 1 is repeated, but using 5 g of 2-bromo-pyridine instead of 4-bromo-pyridine; 4.7 g of ethylenic acetal 4 (2 'pyridyl) - 4 cyclohexanone are obtained.

SCDC13 NMR: 1.5-1.9 (4H, m), 1.9-2.4 (4H, m), 3.96 (4H,
TMS s), 7.2 (1H, dd), 7.4 (1H, d), 7.68 (1H, ddd)
and 8.48 (1H, dd),
2) (Pyridyl-2 ') - 4-cyclohexen-3 one ethylenic acetal
The procedure of 2) of Example 1 is repeated, but with 4.6 g of ethylenic acetal of 4-hydroxy (2 'pyridyl) - 4 cyclohexanone, to obtain 3.3 g of ethylenic acetal of (pyridyl-2 ') - 4 cyclohexen-3 one.

NMR # CDCl3: 1.92 (2H, t), 2.4-2.56 (2H, m), 2.64-2.82
TMS (2H, m), 3.96 (4H, s), 6.44-6.60 (1H, m),
7.12 (1H, dd) 7.36 (1H, d), 7.58 (1H, ddd)
and 8.52 (1H, dd).

3) (pyridyl-2 ') - 4 cyclohexanone
The procedure 3) of Example 1 is repeated, but with 3.3 g of ethylenic acetal of (pyridyl-2 ') - 4 cyclohexen-3 one, to obtain 2.2 g of (pyridyl-2') -4 cyclohexanone.

CDCl3
# NMR: 1.8-2.6 (8H, m), 3-3.32 (1H, m), 7-7.3 (2H, m),
TMS 7.62 (1H, ddd) and 8.48 (1H, dd).

4) Acetyl-2 (pyridyl-2 ') - 4 cyclohexanone
The procedure of 4) of Example 1 is followed, but with 1.9 g of (pyridyl-2 ') - 4 cyclohexanone to obtain acetyl-2 (pyridyl-2') - 4 cyclohexanone. All of this raw compound is submitted as it is to the next operational stage.

5) Cyano-4 Hexahydro-2,3,5,6,7,8 methyl-1 oxo-3 (pyridyl
2 ') - 7 isoquinoline
The total amount of the crude product prepared in 4) is treated as described in 5) of Example 1, to give 0.76 g of 4-cyanohexahydro-2,3,5,6,7,8 methyl- 1 oxo3 (pyridyl-2 ') - 7 isoquinoline. Melting point above 3000C.

DMSO-d6
TMS: 1.8-2.2 (2H, m), 2.24 (3H, s), 2.4-2.6 (2H,
m), 2.8-3.1 (3H, m), 7.2-7.5 (2H, m), 7.76
(1H, m), 8.54 (1H, m) and 12.3 (1H, s).

EXAMPLE 3
4-cyano-hexahydro-2,3,5,6,7,8 methyl-1 oxo-3 (pyridyl-3 ') - 7 isoquinoline 1) 4-hydroxy (3' pyridyl) 4 cyclo ethylenic acetal
hexanone
The procedure is repeated in 1) of Example 1, but with 5 g of 3-bromo-pyridine, to obtain 3.5 g of ethylenic acetal of 4-hydroxy (3 'pyridyl) - 4 cyclohexanone.

ICDCl3 NMR: 1.56-2.52 (8H, m), 3.3 (1H, s), 3.94 (4H, s),
TMS 7.24 (1H, dd), 7.84 (1H, ddd), 8.36 (1H, dd)
and 8.68 (1H, d).

2) (Pyridyl-3 ') - 4-cyclohexen-3 one ethylenic acetal
The procedure is as in 2) of Example 1, but using the ethylenic acetal of 4-hydroxy (3 'pyridyl) - 4 cyclohexanone, and 2.6 g of ethylenic acetal of (pyridyl -3 ') 4 cyclohexen-3 one, NMR # CDCl3: 1.82 (2H, t), 2.4-2.52 (2Hn m), 2.52-2.76
TMS
(2H, m), 3.98 (4H, s), 5.96-6.08 (1H, m),
7.24 (1H, dd) 7.64 (1H, ddd), 8.44 (1H, dd)
and 8.64 (1H, d).

3) (pyridyl-3 ') - 4 cyclohexanone
In accordance with 3) of Example 1, but using 2.6 g of (pyridyl-3 ') - 4 cyclohexen-3 one ethylenic acetal, (pyridyl-3') - 4 cyclohexanone is obtained.

CDCl3 NMR # CDCl3: 1.7-2.7 (8H, m), 2.92-3.3 (1H, m), 7.44 (1H,
TMS dd), 7.54 (1H, ddd), 8.44 (1H, dd) and 8.5 (1H, d).

4) Acetyl-2 (pyridyl-3 ') - 4 cyclohexanone
The procedure of 4) of Example 1 is repeated, but with (pyridyl-3 ') - 4 cyclohexanone, to obtain acetyl-2 (pyridyl-3') - 4 cyclohexanone. All of this raw product is submitted as is at the later stage.

5) Cyano-4 hexahydro-2,3,5,6,7,8 methyl-1 oxo-3 (pyridyl3 ') - 7 isoquinoline
All of the product prepared in 4) is treated as described in 5) of Example 1, which gives 0.57 g of 4-cyanohexahydro-2,3,5,6,7,8 methyl- 1 oxo-3 (pyridyl3 ') - 7 isoquinoline. Melting point: greater than 300 C.

NMR # DMSO-d6: 1.7 (2H, m), 2.22 (3H, s), 2.3-2.76 (2H, m), 2.76-3.1
TMS (3H, m), 7.36 (1H, dd), 7.72 (4H, ddd), 8.42 (1H, dd) and 8.52 (1H, d).

EXAMPLE 4
4-cyanohexahydro-2,3,5,6,7,8 7-methoxy 1-methyl-3-oxo isoquinoline 1) 2-acetyl 4-methoxy cyclohexanone
1.12 g of 60% sodium hydride are added to 2.5 g of ethyl acetate, 1.78 g of a benzene solution of 4-methoxy cyclohexanone is introduced therein. After reaction at 400C for 3 hours, methanol is added to decompose the excess sodium hydride, then the reaction mixture is poured into water, neutralized with hydrochloric acid and extracted. with ether to give 1.02 g of 2-acetyl-4-methoxy cyclohexanone.

NMR # CC14: 2.06 (3H, s), 1.7-2.5 (8H, s), 3.28 (3H, s),
TMS
3.4 (1H, m) and 15.9 (1H, s).

2) Cyano-4 hexahydro-2,3,5,6,7,8 methoxy-7 methyl-1 oxo-3
isoquinoline
1.02 g of 2-acetyl-4-methoxy cyclohexanone and 0.462 g of cyanoacetamide are mixed with 5 ml of ethanol, and a small amount of piperidine is added thereto. The mixture thus obtained is heated at reflux for 2 hours. The crystals which precipitate are filtered off and recrystallized from methanol, to give 0.42 g of cyano-4 hexahydro-2,3,5,6,7,8 methoxy-7 methyl-1 oxo-3 isoquinoline. Melting point 257 -259 C.

NMR # CF3COOH: 2.25 (2H, m), 2.57 (3H, s), 2.97 (2H, m),
TMS
3.2 (2H, m), 3.66 (3H, s), and 4.16 (1H, m).

EXAMPLE 5
4-cyano-1,7-dimethyl hexahydro-2,3,5,6,7,8 3-oxo-isoquinoline 1) 2-acetyl 4-methyl cyclohexanone
24 g of 40% acetic acid / boron trifluoride complex are cooled with ice, and a mixture of 5.6 g of 4-methyl cyclohexanone and acetic anhydride is added dropwise thereto. After stirring at room temperature for 4 hours, about 50 ml of a saturated aqueous solution of sodium acetate are introduced therein, and the reaction mixture obtained is heated under reflux for 1 hour. After cooling, this mixture is extracted with ether, rinsed with an aqueous solution of sodium bicarbonate and water, then dried and the ether removed by distillation. The total amount of crude 2-acetyl 4-methyl cyclohexanone thus obtained is subjected as it is to the next step.

2) 4-cyano-1,7-dimethylhexahydro-2,3,5,6,7,8 oxo-3 isoquinoline
To the total amount of crude product prepared in 1), 35 ml of ethanol, 3.36 g of cyanoacetamide and a small amount of piperidine are added, and the reaction mixture thus obtained is heated under reflux for 4 hours. The crystals which precipitate are filtered off and recrystallized from a mixture of methanol and water, to give 4.22 g of 4-cyano-1,7-dimethyl hexahydro-2, 3,5,6,7,8 oxo -3 isoquinoline. Melting point above 2900C.

CF COOH
NMR 3: 1.23 (3H, d), 2.60 (3H, s), and 1.8-3.3
TMS <7H, m).

EXAMPLE 6
Cyano-4 hexahydro-2,3,5,6,7,8 methyl-1 oxo-3 phenyl-7 isoquinoline 1) Acetyl-2 phenyl-4 cyclohexanone
To 5.5 g of acetic acid / boron trifluoride complex, cooled with ice, a benzene solution of 2 g of 4-phenyl cyclohexanone and 2.35 g of acetic anhydride is added dropwise. After stirring under cooling with ice for 30 minutes, then at room temperature for 4 hours, 10 ml of a saturated aqueous solution of ammonium acetate are introduced, and the reaction mixture thus obtained is stirred at 800C for 1 hour. 1/2, then is purified by extraction with ether, which gives 1.77 g of acetyl-2-4-phenyl cyclohexanone. Melting point 53 ~ 54 C.

DMSO-d6
S NMR TMS: 1.90 (3H, m), 2 10 (3H, s), 2.50 (6H, m)
7.26 (5H, s) and 10.58 (1H, s).

2) Cyano-4 hexahydro-2,3,5,6,7,8 methyl-1 oxo-3 phenyl-7
isoquinoline 1.68 g of 2-acetyl-4-phenyl cyclohexanone, 0.73 g of cyanoacetamide, and a small amount of piperidine, are mixed with 10 ml of ethanol, and the resulting reaction mixture is heated under reflux for 2 hours . After cooling, the precipitated crystals are filtered off and purified to give 1.5 g of 4-cyanohexahydro-2,3,5,6,7,8 1-methyl-3-oxo-7-phenylisoquinoline 'Higher melting point at 2900C.

S NMR: 1.90 (3H, m), 2.20 (3H, s), 2.80 (4H, m), 7.28 (5H, s)
TMS and 12.14 (1H, s).

EXAMPLE 7
4-cyanohexahydro-2,3,5,6,7,8 methoxymethyl-7-methyl-3-oxo-3-isoquinoline 1) Methoxy-2-methyl-4-methyl cyclohexanone 2.5 g of 60% sodium hydride are put in suspension in 50 ml of benzene, and there is added dropwise, under cooling, a mixture of 5.6 g of 4-methyl cyclohexanone and 5; 4 g of methoxy ethyl acetate After stirring at room temperature for 2 hours, 20 ml of water are added, and the pH value of the reaction mixture is adjusted to 3, with concentrated hydrochloric acid. After separation of the benzene phase, the aqueous phase is extracted with ether. The benzene solution and the ether solution are combined, rinsed with water, dried and concentrated, to give 7.4 g of 2-methoxyacetyl crude 4-methyl cyclohexanone. This raw product is submitted as is at the next stage of the transaction.

2) Cyano-4 hexahydro-2,3,5,6,7,8 methoxymethyl-1 methyl-7
3-oxo-isoquinoline 3.7 g of the above crude product, 1.68 g of cyanoacetamide and 1 ml of piperidine are mixed with 50 ml of ethanol, and the resulting reaction mixture is heated under reflux for 4 hours. The crystals thus formed are filtered and purified; to give 1.5 g of 4-cyanohexahydro-2,3,5,6,7,8-1-methoxymethyl-7-methyl-3-oxc-isoquinoline. Melting point: 205 -208 C.

NMR # DMSO-d6: 1.01 (3H, d), 1.2-2 (4H, m), 2.5-2.6 (1H, m),
TMS 2.7-2.9 (2H, m), 3.28 (3H, s), 4.32 (2H, s) and 11.86 (1H, s).

Table 1 shows other compounds prepared in ways similar to those described in Examples 1-7.

TABLE 1

No. <SEP> R <SEP> R * <SEP> R * <SEP> F <SEP> (C) <SEP> RMN <SEP>(#) *
<tb><SEP> 8 <SEP> CH3 <SEP> 5-CH3 <SEP> H <SEP> 267 <SEP> (dec.) <SEP> 1.23 <SEP> (3H, <SEP> d), <SEP > 1.5 <SEP> - <SEP> 2.4 <SEP> (7H, <SEP> m), <SEP> 2.18 <SEP> (3H, <SEP> s)
<tb><SEP> 9 <SEP> CH3 <SEP> 6-CH3 <SEP> H <SEP>> 290 <SEP> 1.22 <SEP> (3H, <SEP> d), <SEP> 1.3 <SEP> - <SEP> 1.7 <SEP> (1H, <SEP> m), <SEP> 1.7 <SEP> - <SEP> 2.3 <SEP> (2H, <SEP> m),
<tb><SEP> 2.57 <SEP> (3H, <SEP> s), <SEP> 2.4 <SEP> - <SEP> 2.9 <SEP> (3H, <SEP> m)
<tb> 10 <SEP> CH3 <SEP> 8-CH3 <SEP> H <SEP>> 300 <SEP> 1.07 <SEP> (3H, <SEP> d), <SEP> 1.6 <SEP> - <SEP> 1.9 <SEP> (4H, <SEP> m), <SEP> 2.28 <SEP> (3H, <SEP> s),
<tb><SEP> 2.6 <SEP> - <SEP> 3.0 <SEP> (3H, <SEP> m), <SEP> 12.16 <SEP> (1H, <SEP> s)
<tb> 11 <SEP> CH3 <SEP> 7-C2H5 <SEP> H <SEP> 288 <SEP> (dec.) <SEP> 0.96 <SEP> (3H, <SEP> t), <SEP> 1.2 <SEP> - <SEP> 1.6 <SEP> (4H, <SEP> m), <SEP> 1.7 <SEP> - <SEP> 2.1 <SEP> (2H, <SEP> m),
<tb><SEP> 2.24 <SEP> (3H, <SEP> s), <SEP> 2.6 <SEP> - <SEP> 2.9 <SEP> (3H, <SEP> m), <SEP> 12.2 <SEP> (3H, <SEP> s)
<tb> 12 <SEP> CH3 <SEP> 7- # <SEP> H <SEP> 250 <SEP> - <SEP> 252 <SEP> 1.0 <SEP> - <SEP> 2.80 <SEP> ( 18H, <SEP> s), <SEP> 2.10 <SEP> (3H, <SEP> s), <SEP> 12.0 <SEP> (1H, <SEP> s)
<tb> 13 <SEP> CH3 <SEP> 7 # <SEP> H <SEP> 293 <SEP> (dec.) <SEP> 2.39 <SEP> (3H, <SEP> s), <SEP> 2 , 0 <SEP> - <SEP> 3.2 <SEP> (7H, <SEP> m), <SEP> 3.84 <SEP> (3H, <SEP> s),
<tb><SEP> 3.86 <SEP> (3H, <SEP> s), <SEP> 6.7 <SEP> - <SEP> 6.9 <SEP> (3H, <SEP> m), <SEP> 14.0 <SEP> (1H, <SEP> s)
<tb> 14 <SEP> CH3 <SEP> 7 = O <SEP> H <SEP> 260 <SEP> (dec.) <SEP> 2.23 <SEP> (3H, <SEP> s), <SEP> 2.48 <SEP> (2H, <SEP> dd), <SEP> 3.08 <SEP> (2H, <SEP> dd), <SEP> 3.30 <SEP> (2H, <SEP> s) ,
<tb><SEP> 12.70 <SEP> (1H, <SEP> s)
<tb> 15 <SEP> CH3 <SEP> 8 = O <SEP> H <SEP> 218 <SEP> (dec.) <SEP> 2,0 <SEP> - <SEP> 2,2 <SEP> (2H , <SEP> m), <SEP> 2.62 <SEP> (2H, <SEP> dd), <SEP> 2.82 <SEP> (3H, <SEP> s),
<tb><SEP> 3.08 <SEP> (2H, <SEP> dd), <SEP> 13.55 <SEP> (1H, <SEP> s)
<tb> 16 <SEP> CH3 <SEP> 7-OCH3 <SEP> 7-OCH3 <SEP> 280 <SEP> (dec.) <SEP> 1.92 <SEP> (2H, <SEP> dd), <SEP> 2.24 <SEP> (3H, <SEP> s), <SEP> 2.58 <SEP> (2H, <SEP> s), <SEP> 2.72 <SEP> (2H, <SEP> dd),
<tb><SEP> 3.16 <SEP> (6H, <SEP> s), <SEP> 12.65 <SEP> (1H, <SEP> s)
<tb> 17 <SEP> CH3 <SEP> 7-OCH3 <SEP> 8 = O <SEP> 245 <SEP> (dec.) <SEP> 1.9 <SEP> - <SEP> 2.3 <SEP> (2H, <SEP> m), <SEP> 2.62 <SEP> (3H, <SEP> s), <SEP> 3.50 <SEP> (2H, <SEP> dd)
<tb><SEP> 3.28 <SEP> (3H, <SEP> s), <SEP> 3.86 <SEP> (1H, <SEP> dd), <SEP> 12.40 <SEP> (1H , <SEP> s)
<tb>
Note (relative to Table 1 on page 13)
* 1: Each digit preceding the placeholder indicates
his position
* 2: The solvent is: DMSO-d6 for N 8, 10, 11, 12,
14,16 and 17
CDCl3 for numbers 13 and 15
CF3-COOH for number 9.

F (C): Melting point.

TEST EXAMPLE 1
Adult mongrel dogs, male and female, weighing 8 to 12 kg, are anesthetized by intravenous administration of 30 mg / kg sodium pentobarbital. A tonosensor catheter is inserted from the dog's right carotid artery into the left ventricle to determine intraventricular pressure. The primary differential of the left intraventricular pressure is calculated using a differential measuring device, thus determining the maximum variation of the left intraventricular pressure (LV dp / dt max), a polyethylene cannula, connected to a pressure transducer, is introduced into the dog's right crural artery, to determine general blood pressure, while the pulse is determined from the pulse wave with a cardiometer.

The first administration is from the right crural artery, while the continuous administration is from the left crural vein. Each parameter is recorded at the same time on a thermal recorder.

The dog is brought to a stable state of heart failure, by intravenous administration of 4 mg / kg of propranolol and continuous intravenous administration of 0.1 mg / Rgtminute of the same product. , the heartbeat rate and left intraventricular pressure of the dog are somewhat reduced, and their LV dp / dt is greatly reduced.

The dose of a test compound capable of restoring the decreased LV dp / dt max to the level prior to the administration of propranolol is determined, and is called the effective dose (ED100). Changes in blood pressure and heart rate at ED100 are compared with those caused by administration of propranolol. Table 2 gives the results.

TABLE 2
N * DE100 Pressure Frequency
(mg / kg, iv) cardiac blood
(%) (%)
1 0.1 -877 27.6
2 0.1 -5.1 18.7
3 0.1 11.3 26.1
4 1.0 -16.7 22.1
5 0.3 -24.6 25.5
6 0.1 4.0 11.0
7 3.0 "11.8 18.8
8 1.0 -6.7 20.2
9 1.0 -11.9 24.8
10 3.0 -28.3 31.1
11 0.3 -10; 8 24.5
12 0.1 -16.8 13.6
13 1.0 -21.6 34.4
14 3.0 -18.5 26.7
15 3.0 -17.1 21.6
16 0.3 -10.1 31.4
17 3.0 -20.7 24.2 * 1: Numbers 1 to 7 are the examples above and numbers 8 to 17 are products in Table 1.

TEST EXAMPLE 2
Sour toxicity test
Male ddy mice, 5 weeks old, having fasted for 18 hours, are divided into groups each comprising 5 animals. Each group is administered orally a test compound dissolved or suspended in physiological saline. After administration, the animals are observed for 7 days in order to determine the LD50. It is found that the LD50 of the active constituent, of the pharmaceutical product according to the invention, is greater than 400 mg / kg.

Claims (5)

Claims 1. Isoquinoline derivative characterized by the general formula

wherein R1 is methyl or methoxymethyl, and R2 and R3 are each hydrogen or lower alkyl, lower alRoxy, cyclohexyl, phenyl, substituted phenyl, pyridyl or oxo (= 0) , as well as its pharmaceutically acceptable salts. 2 A compound according to claim 1, characterized in that it is cyano-4 hexahydro-2,3,5,6,7,8 methyl-1 oxo-3 (pyridyl-4 ') - 7 isoquinoline. 3. Compound according to claim 1, characterized in that it is cyano-4 hexahydro-2,3,5,6,7,8 methyl-1 oxo-3 (pyridyl-2 ') -7 isoquinoline. 4. Compound according to claim 1, characterized in that it is cyano-4 hexahydro-2,3,5,6,7,8 methoxy-7 methyl-1 oxo-3 isoquinoline. 5. Cardiological medicament, characterized in that it contains as active constituent a compound according to one of claims 1 to 4.