JPH0535144B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD OF THE INVENTION The present invention relates to novel isoquinoline derivatives, therapeutically acceptable addition salts thereof and therapeutic compositions thereof. These isoquinoline derivatives are useful as cardiotonic agents. Prior Art Digitalis preparations such as digoxin or digitoxin are used as cardiotonic agents in the treatment of heart failure (for example, Pharmaceutical Handbook p. 324-7 (1977
(Yakugyo Jihosha). On the other hand, as compounds having cardiotonic effects, nicotinonitrile derivatives (e.g., JP-A-57-70868), imidazolone derivatives (e.g.,
JP-A-59-155368) and dihydropyridazinone derivatives (for example, JP-A-58-74679) have been reported. Problems to be Solved by the Invention The digitalis preparations currently used for treatment require skill to use because of their narrow safety margin, and they also pose a problem of side effects such as arrhythmia. In addition, recently reported nicotinonitrile derivatives, imidazolone derivatives, dihydropyridazinone derivatives, etc. have problems such as low cardiac activity, narrow safety margin, increased cardiac rhythm rate, and high animal toxicity. It has points. Means for Solving the Problems As a result of intensive studies aimed at finding a compound with a wide safety margin and no side effects, the present inventors found that isoquinoline derivatives have high cardiotonic activity and low toxicity. Heading, we arrived at the present invention. In detail, the isoquinoline derivative of the present invention has the general formula: [In the formula, R means a 4-pyridyl group, a lower alkoxyl group having 1 to 6 carbon atoms, a 2-methoxyethoxyl group, or a substituted aminocarbonyl group] and a therapeutically acceptable salt thereof. be. Furthermore, the compound of the formula () of the present invention may take the formula () as a tautomer, but It goes without saying that compounds of formula () are also included in the present invention. The isoquinoline derivative of the present invention can be produced, for example, by the following method. R in the above reaction formula represents the same meaning as above, R' is a lower alkyl group having 1 to 6 carbon atoms, 2
-methoxyethyl group or substituted aminocarbonyl group, and X represents a halogen atom. The novel isoquinoline derivatives of the present invention can be produced by combining the conventional reactions shown above. That is, when R is a pyridyl group, () can be produced from the Grignard compound or lithium compound and () by dehydration reaction in the presence of a dehydrating agent such as thionyl chloride. This (V) in the presence of a catalyst such as palladium on carbon,
() can be produced by carrying out a hydrogenation reaction and then, or simultaneously, treating with an acid such as hydrochloric acid water. In addition, when R is an alkoxyl group or a 2-methoxyethoxyl group, this () can be produced by reacting () with an alkyl halide in the presence of an alkali such as sodium hydroxide or potassium hydroxide. It can be produced by oxidizing with an oxidizing agent such as chromic acid. In addition, when R is a substituted aminocarbonyl group, () and ()
It can be produced by treating a Diels-Alder adduct with an acid such as hydrochloric acid. This acetylation reaction of () is carried out using an acetylating agent such as acetylimidazole, acetic anhydride, acetyl chloride, or acetate ester.
It can be carried out in the presence of acetic acid, lithium diisopropylamide, or zinc chloride, or by using an acetylating agent such as acetic anhydride or acetyl chloride with an enamine prepared from () and a secondary amine such as pyrrolidine, piperidine, or morpholine. Then, () can be produced. The compound () of the present invention is prepared by combining () and cyanothioacetamide in the presence of an amine such as diethylamine or piperidine, or in an alcohol such as methanol or ethanol in the presence of sodium alkoxide. It can be produced by condensation. () can also be prepared by condensing () with cyanoacetamide, for example, in the presence of an amine such as diethylamine or piperidine, or in an alcohol such as methanol or ethanol in the presence of sodium alkoxide. It can also be produced by reacting () with phosphorus pentasulfide. When the compound of the present invention is used as a cardiotonic agent, oral administration is preferable, but parenteral administration such as intravenous administration may also be used, and the compound can be formulated into various dosage forms suitable for each method. For example, the compounds of the present invention and their salts may be prepared by themselves or mixed with non-toxic adjuvants such as pharmaceutically acceptable excipients, carriers, binders, stabilizers, diluents, and flavoring agents. I can do it. These drugs can be made into tablets, capsules, granules, powders, syrups, elixirs, etc. when administered orally, or injectable preparations when administered parenterally. The dosage for humans is determined by a doctor in consideration of the patient's condition, age, administration method, etc.
For example, in the case of oral administration, the dosage is selected to be about 0.1 mg to 10 mg per 1 kg of body weight per day.
Of course, it is not limited to this. Effects of the Invention According to the present invention, a novel isoquinoline derivative could be produced. It has been found that the novel isoquinoline derivative of the present invention is useful as a cardiotonic agent, and is also a compound with low toxicity and a wide safety margin. Their usefulness as cardiotonic agents is demonstrated by their efficacy in standard pharmacological test methods, e.g. by demonstrating significant recovery of anesthetized cardiac function reduced by intravenous administration of propranolol. be done. Next, the present invention will be explained in more detail using Examples and Test Examples. Example 1 4-cyano-2,3,5,6,7,8-hexahydro-1-methyl-7-(4-pyridyl)-3
-Thioxoisoquinoline (1) 4-Hydroxy-4-(4-pyridyl)cyclohexanone ethylene acetal To 35 ml of ether was added 20 ml of a 1.6 M hexane solution of n-butyllithium at -78°. next,
A solution of 5 g of 4-bromopyridine in 30 ml of ether was added. Next, 5 g of 1,4-cyclohexanedione monoethylene acetal dissolved in 30 ml of tetrahydrofuran was added. Next, the reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with chloroform. After drying the extract, it was concentrated to remove ether insoluble matter, and 4-hydroxy-4-(4-pyridyl) was obtained.
5 g of cyclohexanone ethylene acetal was obtained. mp165.5~7.5℃, NMRδ ^CDCl3 _TMS : 1.6~2.2
(8H, m.), 3.9 (1H, s.), 4.00 (4H, s.), 7.45
(2H, dd), 8.44 (2H, dd). (2) 4-(4-pyridyl)cyclohex-3-enone ethylene acetal 5 g of 4-hydroxy-4-(4-pyridyl) cyclohexanone ethylene acetal was dissolved in 40 ml of pyridine, and 8 ml of thionyl chloride was added at -10°. Next, after stirring at 0°, the reaction solution was poured into ice, an excess aqueous sodium hydroxide solution was added, and the mixture was extracted with methylene chloride. After drying the extract and concentrating it to remove ether insoluble matter, 4-
4 g of (4-pyridyl)cyclohex-3-enone ethylene acetal was obtained. mp67~70℃,
NMRδ ^CDCl3 _TMS : 1.86 (8H, t.), 2.4~2.7 (4H,
m.), 4.04 (4H, s.), 6.24 (1H, t.), 7.28 (2H,
d.), 8.52 (2H, d.). (3) 4-(4-pyridyl)cyclohexanone 4-
Dissolve 4 g of (4-pyridyl)cyclohex-3-enone ethylene acetal in 70 ml of 0.5N hydrochloric acid, add 400 mg of 10% palladium on carbon, and stir at room temperature.
Hydrogenation was carried out at normal pressure. Next, after removing the palladium on carbon, the mixture was made alkaline with an aqueous sodium hydroxide solution and extracted with methylene chloride. After drying the extract, it was concentrated to give 4-(4-pyridyl)
2.7 g of cyclohexanone was obtained. NMRδ ^CDCl3 _TMS :
1.7~2.3 (4H, m.), 2,4~2.6 (4H, m.),
2.8~3.2 (1H, m.), 7.15 (2H, d.), 8.51 (2H,
d.) (4) 2-Acetyl-4-(4-pyridyl)cyclohexanone 3.2 ml of diisopropylamine was dissolved in 40 ml of tetrahydrofuran, and 14.2 ml of a 1.6 M hexane solution of n-butyllithium was added at -20°. Next, 4-(4-pyridyl)cyclohexanone 2
g dissolved in 40 ml of tetrahydrofuran was added at -40°C. The reaction solution was cooled to −78°,
2.5 g of acetylimidazole dissolved in 40 ml of tetrahydrofuran was added. Next, after stirring at room temperature, the reaction solution was poured into ice water, washed with ether, and the aqueous layer was saturated with ammonium chloride and extracted with methylene chloride. The extract was dried and concentrated to obtain 1.65 g of 2-acetyl-4-(4-pyridyl)cyclohexanone. NMRδ ^CDCl3 _TMS : 1.7~
2.2 (3H, m.), 2.16 (3H, s.), 2.3~2.6 (3H,
m.). 2,6~2.9 (1H, m.), 7.10 (2H, dd),
8.55 (2H, dd), 15.7 (1H, s.) (5) 4-cyano-2,3,5,6,7,8-hexahydro-1-methyl-7-(4-pyridyl)-
3-thioxoisoquinoline 2-acetyl-4-(4-pyridyl)cyclohexanone 2.2g, cyanothioacetamide 1g,
and a small amount of piperidine were added to 30 ml of ethanol and heated under reflux for 30 minutes. After cooling, the precipitated crystals were collected and washed with hot ethanol.
-cyano-2,3,5,6,7,8-hexahydro-1-methyl-7-(4-pyridyl)-3-
1.8 g of thioxoisoquinoline was obtained. mp295～
8℃ (decomposition point), NMRδ ^D MSO ^-d _6TMS : 1.7-2.1
(2H, m.), 2.37 (3H, s.), 2.4~3.0 (5H, m.),
7.36 (2H, d.), 8.48 (2H, d.), 13.8 (1H, s.). Example 2 4-cyano-2,3,5,6,7,8-hexahydro-7-methoxy-1-methyl-3-thioxoisoquinoline (1) 2-acetyl-4-methoxycyclohexanone 60% sodium hydride 1.12g of ethyl acetate
A solution of 1.78 g of 4-methoxycyclohexanone dissolved in 0.5 ml of benzene was added. After heating at 40° for 3 hours, it was left at room temperature for 3 hours. A small amount of methanol was added, poured into water, neutralized by adding hydrochloric acid, and extracted with ether.
The extract was washed with water, dried, and concentrated to obtain 1.16 g of 2-acetyl-4-methoxycyclohexonone. NMRδ ^CCl4 _TMS : 2.06 (3H, s.), 1.7~2.5
(6H, m.), 3.28 (3H, s.), 3.4 (1H, m.), 15.9
(1H, s.). (2) 4-cyano-2,3,5,6,7,8-hexahydro-7-methoxy-1-methyl-3-oxoisoquinoline 1.06 g of 2-acetyl-4-methoxycyclohexanone, 0.46 g of cyanoacetamide, and
Add a small amount of piperidine to 5 ml of ethanol,
The mixture was heated to reflux for an hour. After cooling, the precipitated crystals were collected and recrystallized with methanol to give 4-cyano-2,3,5,6,7,8-hexahydro-
0.4 g of 7-methoxy-1-methyl-3-oxoisoquinoline was obtained. mp257~9℃,
NMRδ ^CF3COOH _TMS 3:2.2 (2H.m.), 2.57 (3H.S.),
3.0 (2H, m.), 3.20 (2H, m.), 3.66 (3H, s.),
4.2 (1H, m.). (3) 4-cyano-2,3,5,6,7,8-hexahydro-7-methoxy-1-methyl-3-thioxoisoquinoline 4-cyano-2,3,5,6,7,8- 2.18 g of hexahydro-7-methoxy-1-methyl-3-oxoisoquinoline was dissolved in 20 ml of pyridine, 1.1 g of phosphorus pentasulfide was added, and the mixture was heated under reflux for 10 hours.
Furthermore, 1.2 g of phosphorus pentasulfide was added, and the mixture was heated under reflux for 10 hours. Next, the solvent was distilled off, and the methanol-soluble portion was subjected to silica gel column chromatography (developing solvent was chloroform:methanol = 20:1).
4-cyano-2,3,5,6,
0.65 g of 7,8-hexahydro-7-methoxy-1-methyl-3-thioxoisoquinoline was obtained. mp255~6℃ (decomposition point), NMRδ ^CDCl3 _TMS : 1.7
~2.0 (2H, m.), 2.37 (3H, s.), 2.4~2.9 (4H,
m.) 3.30 (3H, s.), 3.6-3.7 (1H, m.), 13.8
(1H, s.). Example 3 4-cyano-2,3,5,6,7,8-hexahydro-7-(2-methoxyethoxy)-1-methyl-3-thioxoisoquinoline (1) 4-(2-methoxyethoxy) Cyclohexanol Cyclohexanediol 11.6g and 60%
2g of sodium hydride in dimethylformamide
120ml and heated at 80-85°C for 5.5 hours. Next, 4.7g of chloroethyl methyl ether at 50℃
was added and left for 30 minutes. Then at 80-100℃
Heated for 14 hours. After cooling, the reaction solution was poured into water and extracted with ethyl acetate. After washing with water, drying, and concentrating, the residue was subjected to silica gel column chromatography (developing solvent: hexane: ethyl acetate = 1:
1) to produce 4-(2-methoxyethoxy)
1.4 g of cyclohexanol was obtained. NMRδ ^CCl4 _TMS : 1.1~2.0 (8H, m.), 3.26 (3H, s.),
3.40 (4H, s.), 3.1~3.6 (2H, m.), 3,65
(1H, s.). (2) 4-(2-methoxyethoxy)cyclohexanone 2 g of 4-methoxyethoxycyclohexanol was added to a suspension of 6.5 g of pyridinium chlorochromate in 30 ml of methylene chloride, and the mixture was stirred overnight at room temperature. Next, add ether to the reaction solution,
Purification by florisil column chromatography yielded 1.8 g of 4-(2-methoxyethoxy)cyclohexanone. NMRδ ^CCl4 _TMS : 1.6-2.7 (8H,
m.), 3.28 (3H, s.), 3.3-3.8 (5H, m.). (3) 2-acetyl-4-(2-methoxyethoxy)
Cyclohexanone 2.1 g of diisopropylamine was dissolved in 40 ml of tetrahydrofuran, and 12.7 ml of a 1.6 molar hexane solution of n-butyllithium was added at -25°C. Next, 1.8 g of 4-(2-methoxyethoxy)cyclohexanone dissolved in 15 ml of tetrahydrofuran was added. The reaction solution was cooled to −78°,
2.3 g of acetylimidazole dissolved in 15 ml of tetrahydrofuran was added. Next, after stirring at room temperature, the reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with methylene chloride. The extract was washed with saturated brine and dried, and the methylene chloride was concentrated to give a crude product of 2-acetyl-4-(2-methoxyethoxy)cyclohexanone.
2.3g was obtained. (4) 4-cyano-2,3,5,6,7,8-hexahydro-7-(2-methoxyethoxy)-1-
Methyl-3-thioxoisoquinoline 2-acetyl-4-(2-methoxyethoxy)
2.3 g of crude cyclohexanone, 1 g of cyanothioacetamide and a small amount of piperidine were added to 15 ml of ethanol and heated under reflux for 5 hours. After the reaction, the ethanol was concentrated and the residue was recrystallized twice from ethanol to give 4-cyano-2,
3,5,6,7,8-hexahydro-7-(2
0.2 g of -methoxyethoxy)-1-methyl-3-thioxoisoquinoline was obtained. mp200℃ (decomposition point), NMRδ ^CDCl3 _TMS : 1.8~2.2 (2H, m.), 2.50 (3H,
s.), 2.6~3.1 (4H, m.) 3.40 (3H, s.), 3.8~
4.1 (1H, m.), 13.5 (1H, m.). Example 4 4-cyano-2,3,5,6,7,8-hexahydro-1-methyl-7-pyrrolidinocarbonyl-3-thioxoisoquinoline (1) 4-pyrrolidinocarbonylcyclohexanone 2-trimethylsiloxy- 368g of 1,3-butadiene and 250g of acryloylpyrrolidine
was dissolved in 250 ml of toluene and heated under reflux for 33 hours. Next, concentrate the toluene and add 1N-hydrochloric acid to 1
was added and stirred at room temperature. Then extracted with ether and methylene chloride. Dry the liquid exudate,
After concentration, ether was added to the residue for crystallization to obtain 107 g of 4-pyrrolidinocarbonylcyclohexanone. Furthermore, the liquid was concentrated to obtain 189 g of a crude product. NMRδ ^DMSO-d _6TMS : 1.4-2.6
(13H, m.), 3.2~3.4 (2H, m.), 3.4~3.7 (2H,
m.). (2) 2-acetyl-4-pyrrolidinocarbonylcyclohexanone 4-pyrrolidinocarbonylcyclohexanone
Dissolve 107g in 500ml of benzene and add 69% of pyrrolidine.
ml and heated under reflux for 4.5 hours while dehydrating.
After cooling, concentrate and dissolve the residue in 500ml of dioxane.
104 ml of acetic anhydride was added under ice-cooling, and the mixture was allowed to stand at room temperature. Next, water was added and the mixture was heated under reflux for 2.5 hours. After cooling, the mixture was neutralized with an aqueous sodium hydroxide solution, saturated with ammonia chloride, washed with ether, and extracted with methylene chloride. After drying the extract, it was concentrated to give 2-acetyl-4-
130 g of a crude product of pyrrolidinocarbonylcyclohexanone was obtained. (3) Crude product of 4-cyano-2,3,5,6,7,8-hexahydro-1-methyl-7-pyrrolidinocarbonyl-3-thioxoisoquinoline 2-acetyl-4-pyrrolidinocarbonylcyclohexanone 10 g of cyanothioacetamide, 4.2 g of cyanothioacetamide, and a small amount of piperidine were added to 100 ml of ethanol, and the mixture was heated under reflux for 3 hours.
After cooling, the precipitated crystals were collected and 4-cyano-2,3,5,6,7,8-hexahydro-1-methyl-7-pyrrolidinocarbonyl-3
-1.1 g of thioxoisoquinoline was obtained. mp300
℃ or higher, NMRδ ^DMSO _TMS −d ₆ : 1.4 to 2.0 (H, m.),
2.30 (3H, s.), 2.6~2.9 (3H, m.), 3.22 (2H,
t.), 3.44 (2H, t.), 13.6 (1H, s.). Example 5 4-cyano-2,3,5,6,7,8-hexahydro-1-methyl-7-(4-pyridyl)-3
-Tablet containing thioxoisoquinoline as active ingredient 4-cyano-2,3,5,6,7,8-hexahydro-1-methyl-7-(4-pyridyl)-3-
50 g of thioxoisoquinoline, 38 g of lactose, 35 g of corn starch and 20 g of crystalline cellulose are thoroughly mixed, kneaded and granulated with a solution of 5 g of hydroxypropylcellulose in water, and dried at 50° C. for 4 hours. This includes magnesium stearate 2
Add g and mix well and use a tablet machine to make 1 tablet.
Compress to obtain tablets with a weight of 150 mg. Example 6 4-cyano-2,3,5,6,7,8-hexahydro-1-methyl-7-(4-pyridyl)-3
-Capsules containing thioxoisoquinoline as an active ingredient 4-cyano-2,3,5,6,7,8-hexahydro-1-methyl-7-(4-pyridyl)-3-
Mix well 100 g of thioxoisoquinoline, 70 g of lactose, 70 g of corn starch, 40 g of crystalline cellulose and 6 g of magnesium stearate.
Fill 300mg of this into hard capsules using a capsule filling machine to obtain capsules. Example 7 4-cyano-2,3,5,6,7,8-hexahydro-1-methyl-7-(4-pyridyl)-3
- Granules containing thioxoisoquinoline as an active ingredient 4-cyano-2,3,5,6,7,8-hexahydro-1-methyl-7-(4-pyridyl)-3-
100g thioxoisoquinoline, 150g lactose, 140g corn starch and 80g crystalline cellulose
Mix well, knead and granulate with a solution of 20 g of hydroxypropyl cellulose dissolved in 400 ml of water,
Dry at 50°C for 4 hours. After sizing this with a 12-mesh screen, 8 g of magnesium stearate is added and mixed well to form granules. Example 8 4-cyano-2,3,5,6,7,8-hexahydro-1-methyl-7-(4-pyridyl)-3
- Suppositories containing thioxoisoquinoline as an active ingredient 4-cyano-2,3,5,6,7,8-hexahydro-1-methyl-7-(4-pyridyl)-3-
Thioxoisoquinoline 10g and Uitepzol W-25 (Danamil Nobel Chemicals,
Take 90g (West Germany), heat and dissolve at 60℃, and mix well. This is poured into a mold so that each piece weighs 1.5g or 3g, and is cooled and solidified to form a suppository. Test Example 1 Pharmacological Test Male and female mixed-breed adult dogs weighing 8 to 12 kg were anesthetized with 30 mg/kg of sodium pentobarbital intravenously. A catheter tip pressure sensor was inserted into the left ventricle from the right carotid artery to measure left ventricular pressure, and a differential meter was used to calculate the first differential of left ventricular pressure to determine the maximum rate of change in left ventricular pressure (LVdP/dt max). A polyethylene cannula connected to a pressure transducer was inserted into the right femoral artery, and systemic blood pressure and heart rate were measured from the pulse wave using a heart rate monitor. Drug administration was performed through the right femoral vein, and continuous administration was performed through the left femoral vein. Each parameter was recorded simultaneously on a thermal recorder. Intravenous administration of propranolol 4 mg/Kg and
A stable state of heart failure was created by continuous intravenous administration of 0.1 mg/Kg/min. That is, blood pressure, heart rate, and left ventricular pressure are slightly decreased, and LVdP/dtmax is significantly decreased. This LVdP/dtmax
The dose of the test drug that returned the decrease in 100% to the value before propranolol administration was determined and defined as the effective dose (ED ₁₀₀ ). Changes in blood pressure and heart rate at ED ₁₀₀ were expressed as percentage changes relative to the values at the time of propranolol administration. Present the results.

[Table] Test Example 2 Acute Toxicity Test Five-week-old DDY male mice were fasted for 18 hours, and drugs dissolved or suspended in physiological saline were orally administered to each group of five mice. After administration, the progress was observed for 7 days,
The _LD50 value was determined. As a result, the LD ₅₀ value of the active ingredient of the medicament of the present invention was 600 mg/Kg or more.

Claims (1)

[Claims] 1. General formula An isoquinoline derivative represented by [wherein R means a 4-pyridyl group, a lower alkoxyl group having 1 to 6 carbon atoms, a 2-methoxyethoxyl group, or a substituted aminocarbonyl group] and a therapeutically acceptable salt thereof. 2 4-cyano-2,3,5,6,7,8-hexahydro-1-methyl-7-(4-pyridyl)-3
-thioxoisoquinoline.The compound according to claim 1, which is -thioxoisoquinoline. 3. The compound according to claim 1, which is 4-cyano-2,3,5,6,7,8-hexahydro-7-methoxy-1-methyl-3-thiokylyisoquinoline. 4. The compound according to claim 1, which is 4-cyano-2,3,5,6,7,8-hexahydro-7-(2-methoxyethoxy)-1-methyl-3-thiokyliisoquinoline. 5. The compound according to claim 1, which is 4-cyano-2,3,5,6,7,8-hexahydro-1-methyl-7-pyrrolidinocarbonyl-3-thioxoisoquinoline. 6 General formula Isoquinoline derivatives represented by [wherein R means a 4-pyridyl group, a lower alkoxyl group having 1 to 6 carbon atoms, a 2-methoxyethoxyl group, or a substituted aminocarbonyl group], and therapeutically acceptable salts thereof A cardiotonic composition containing as an active ingredient.