JPH0144188B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula () (In the formula, m and n are integers of 0 to 9, R ₁ represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or an aryl group, R ₂ and R ₃ represent a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, group, cycloalkyl group,
is an aryl group, an aralkyl group, or R ₂ ,
R ₃ represents a group that is bonded directly or via an oxygen atom to form a heterocycle together with the adjacent N. ) and an acid addition salt thereof. Examples of the above R ₁ include hydrogen, methyl group,
Ethyl group, n-propyl group, isopropyl group, n
-butyl group, isobutyl group, sec-butyl group, n
-bentyl group, cyclobentyl group, n-hexyl group, cyclohexyl group, phenyl group,

[Formula] includes, for example, amino group, methylamino group, ethylamino group, n-propylamino group, isopropylamino group, n-butylamino group, isobutylamino group, n-hexylamino group, cyclohexylamino group, dimethyl Amino group, diethylamino group, di-n-butylamino group, N-methyl-N-cyclopentylamino group,
N-methyl-N-cyclohexylamino group, N-
Methyl-N-phenylamino group, N-methyl-N
-benzylamino group, N-ethyl-N-benzylamino group, N-isopropyl-N-benzylamino group, pyrrolidino group, piperidino group, and morpholino group. Specifically, for example, the following compounds can be mentioned. (1) N-(2-aminoethyl)-5-isoquinolinesulfonamide (2) N-(3-aminopropyl)-5-isoquinolinesulfonamide (3) N-(4-aminobutyl)-5- Isoquinolinesulfonamide (4) N-(6-aminohexyl)-5-isoquinolinesulfonamide (5) N-(8-aminooctyl)-5-isoquinolinesulfonamide (6) N-(10-aminodecyl) -5-isoquinolinesulfonic acid amide (7) N-(2-amino-1-methylethyl)-5-
Isoquinolinesulfonamide (8) N-(1-aminomethylpropyl)-5-isoquinolinesulfonamide (9) N-(1-aminomethylbutyl)-5-isoquinolinesulfonamide (10) N-(1- Aminomethylpentyl)-5-isoquinolinesulfonamide (11) N-(2-aminopropyl)-5-isoquinolinesulfonamide (12) N-(2-aminobutyl)-5-isoquinolinesulfonamide (13) N-(2-amino-3-methylbutyl)-5
-isoquinolinesulfonamide (14) N-(2-aminohexyl)-5-isoquinolinesulfonamide (15) N-(1-aminomethylbenzyl)-5-isoquinolinesulfonamide (16) N-(2- amino-2-phenylethyl)-
5-isoquinolinesulfonamide (17) N-(2-methylaminoethyl)-5-isoquinolinesulfonamide (18) N-(2-ethylaminoethyl)-5-isoquinolinesulfonamide (19) N-( 2-isopropylaminoethyl)-5-
Isoquinoline sulfonamide (20) N-(2-n-butylaminoethyl)-5-
Isoquinolinesulfonamide (21) N[2-(N-methyl-N-benzylamino)ethyl]-5-isoquinolinesulfonamide (22) N-[2-(N-ethyl-N-benzylamino)ethyl] -5-isoquinolinesulfonamide (23) N-[2-(N-isopropyl-N-benzylamino)ethyl]-5-isoquinolinesulfonamide (24) N-[2-(N-n-butyl-N -benzylamino)ethyl]-5-isoquinolinesulfonamide (25) N-(3-dimethylaminopropyl)-5-
Isoquinoline sulfonamide (26) N-(3-diethylaminopropyl)-5-
Isoquinoline sulfonamide (27) N-(3-di-n-butylaminopropyl)
-5-isoquinolinesulfonamide (28) N-(3-piperidinopropyl)-5-isoquinolinesulfonamide (29) N-(3-morpholinopropyl)-5-isoquinolinesulfonamide (30) N- [3-(N-Methyl-N-cyclohexylamino)propyl]-5-isoquinolinesulfonamide (31) N-[3-(N-methyl-N-phenylamino)propyl]-5-isoquinolinesulfonamide (32 ) N-[3-(N-methyl-N-benzylamino)propyl]5-isoquinoline sulfonic acid amide The present invention also provides an acid addition salt of the isoquinoline derivative represented by the above general formula ().
This salt is a pharmaceutically acceptable non-toxic salt,
For example, inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid, and organic acids such as acetic acid, citric acid, tartaric acid, lactic acid, succinic acid, fumaric acid, maleic acid, methanesulfonic acid, and p-toluenesulfonic acid. can be mentioned. The isoquinoline sulfonic acid amide derivative represented by the general formula () provided by the present invention can be synthesized, for example, according to the following formula. (In the formula, R ₁ , R ₂ and R ₃ have the same meanings as above.) That is, 5-isoquinolinesulfonic acid is heated under reflux for 3 hours using thionyl chloride and a catalytic amount of dimethylformamide. 5-
It can be obtained by reacting isoquinoline sulfonic acid chloride () with a compound represented by the general formula (). Examples of the compound represented by formula () include:
1,2-diaminoethane, 1,3-diaminopropane, 1,4-diaminobutane, 1,5-diaminopentane, 1,6-diaminohexane, 1,8
-diaminooctane, 1,10-diaminodecane,
2-(N-methyl-N-benzylamino)ethylamine, 2-(N-ethyl-N-benzylamino)
Ethylamine, 2-((N-isopropyl-N-benzylamino)ethylamine, 2-(N-n-butyl-N-benzylamino)ethylamino, 3-
Dimethylaminopropylamine, 3-diethylaminopropylamine, 3-(di-n-propylamino)propylamine, 3-(diisopropylamino)propylamine, 3-(di-n-butylamino)propylamine, 3-(diisobutyl) amino)propylamine, 3-(N-methyl-N-cyclohexylamino)propylamine, 3-(N
-Methyl-N-phenylamino)propylamine, 3-(N-methyl-N-benzylamino)propylamine, 3-piperidinopropylamine,
Examples include 3-pyrrolidinopropylamine and 3-morpholinopropylamine. An acid acceptor may be present in this reaction. Acid receptors include sodium bicarbonate,
Alkali metal compounds such as sodium hydroxide, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydride, sodium methylate, pyridine, trimethylamine, triethylamine,
Examples include organic tertiary amines such as triethylenediamine. As the reaction solvent, alkanols such as methanol and ethanol, halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as tetrahydrofuran and dioxane, acetonitrile, dimethylformamide, dimethylsulfoxide, etc. are used. The amount of the compound represented by the general formula () relative to the acid chloride () is preferably in the range of 1 to 10 times the mole, more preferably 1 to 3 times the mole, when the acid acceptor is present. When it is not present, it is preferably 2 to 20 times the mole, particularly preferably 2 to 10 times the mole. When using an acid acceptor, the amount used is preferably 1 to 10 equivalents, particularly preferably 1 to 6 equivalents, relative to the compound represented by formula (). The reaction temperature is generally -30°C to 150°C, preferably 0°C to 120°C, particularly preferably 0°C to 80°C. Furthermore, when R ₂ is a hydrogen atom, it can be synthesized according to the following formula. (In the formula, R ₁ , R ₃ , m, and n have the same meanings as above, and X represents a protecting group.) Examples of the protecting group X include an acyl group such as a formine group, an acetyl group, and a benzoyl group. , benzoyloxycarbonyl group, amylmethyl-alkyl-oxycarbonyl group such as t-butoxycarbonyl group, benzyl group, and the like. Examples of the compound of formula () include N'-acetyl-1,2-diaminoethane, N'-acetyl-1,3-diaminopropane, N'-acetyl-1,4-diaminobutane, and N'-acetyl-1,4-diaminobutane. -1,
5-diaminobentane, N'-acetyl-1,6
-diaminohexane, N'-acetyl-1,8-
Diaminooctane, N'-acetyl-1,10-diaminodecane, 2-benzyloxycarbonylamino-1-methylethylamine, 1-(benzyloxylcarbonylaminomethyl)propylamine, 1-(benzyloxylcarbonylaminomethyl)benthylamine , 2-(benzyloxylcarbonylamino)propylamine, 2-benzyloxycarbonylamino-3-methylbutylamine, 2-acetamidopropylamine, 2-acetamido-3-methylbutylamine, 2-acetamido-2-phenylethylamine , 2-(N-benzyl-N-methylamino)ethylamine, 2-
(N-benzyl-N-ethylamino)ethylamine, 2-(N-benzyl-N-isopropylamino)ethylamine, 2-benzyloxycarbonylamino-1-phenylethylamine, 2-benzyloxycarbonylamino-2-phenyl Examples include ethylamine and N'-formyl-1,4-diaminobutane. The reaction conditions to obtain () from () and () are:
It can be carried out under the same reaction conditions as those for () and () above. The method for obtaining the desired product () from () is selected depending on the protecting group X, but all of them are commonly known methods. For example, in the case of an acyl group such as a formyl group or acetyl group, hydrolysis with acid or alkali, in the case of a benzyl group, hydrogenation, in the case of a benzyloxycarbonyl group, hydrogenation or acid decomposition, and t-butyloxycarbonyl group. In the case of groups, the purpose can be achieved by acid decomposition. The compound represented by the general formula () and its pharmaceutically acceptable acid addition salt provided by the present invention are:
According to the research of the present inventors, it has a strong smooth muscle relaxing effect and increases blood flow, and is useful as a vasodilator, a cerebral circulation improving agent, a therapeutic agent for angina pectoris, and the prevention and treatment of thrombosis in the cerebrocardiovascular system. It is a substance useful as a medicine. The effect of the compound of the present invention on smooth muscle was confirmed by a relaxing effect on the superior mesenteric artery in dogs, and the vasodilating effect was confirmed by an increase in blood flow in the femoral artery and vertebral artery in dogs. The smooth muscle relaxing effect was demonstrated by suspending a superior mesenteric artery isolated from a family member in the form of a spiral, constricting it with potassium chloride, and relaxing it by adding the compound of the present invention. For example, N-(4-aminobutyl)-5-isoquinolinesulfonic acid amide (3)
, the complete relaxation is taken as 100%, and 50
% relaxing concentration (ED ₅₀ ) was 11 μM. To dilate the femoral artery and vertebral artery, a dog (mongrel, weight 8-15 kg) is anesthetized with 35 mg/kg of pentoparbital sodium intravenously, and the femoral artery and vertebral artery are injected with a non-invasive flow probe (Japanese). Attach an electromagnetic blood flow meter (Nihon Kohden MF-).
Blood flow was measured at 27). Under these conditions, a compound of the present invention, such as N-(4-aminobutyl)-5-isoquinolinesulfonic acid amide (3)1, is administered via a polyethylene tube inserted into the femoral vein side chain.
When mg/Kg is administered intravenously, the femoral artery blood flow is
33%, and vertebral artery blood flow increased by 36%. Furthermore, when the compounds of the present invention are administered intravenously or intraarterially for the above-mentioned purposes, no significant toxicity is observed; for example, N-(4-aminobutyl)-5-isoquinolinesulfonamide (3 The acute toxicity value LD ₅₀ of ) was 87 mg/Kg when administered intravenously to male mice. EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto. Method for producing raw material (5-isoquinolinesulfonic acid chloride) 800ml of thionyl chloride and 0.3ml of dimethylformamide were added to 100g of 5-isoquinolinesulfonic acid, and the mixture was heated under reflux at 80 to 85°C for 3 hours. Thionyl chloride and dimethylformamide were distilled off under reduced pressure, 300 ml of methylene chloride was added to the residue, stirred, filtered, and dried under reduced pressure to obtain 120 g (quantitative) of 5-isoquinolinesulfonic acid chloride hydrochloride. 5-isoquinolinesulfonic acid chloride hydrochloride 20g, water 400ml, methylene chloride 500ml
was added and dissolved. Sodium bicarbonate is added to this solution to adjust the pH of the aqueous layer to 6.0, and the methylene chloride layer is concentrated to dryness under reduced pressure to obtain 5-isoquinolinesulfonic acid chloride. Example 1 8.8 g of 1,4-diaminobutane was dissolved in 200 ml of chloroform, and a solution of 4.55 g of 5-isoquinolinesulfonic acid chloride dissolved in 100 ml of chloroform was added dropwise to this solution under ice cooling. After dripping,
The mixture was stirred at 20 to 25°C for 2 hours, and the reaction solution was extracted with 10% hydrochloric acid water. Adjust the aqueous layer to PH10 with 10% caustic soda,
Extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate. Chloroform was concentrated, and the residue was subjected to column chromatography using 200 g of silica gel and a developing solvent of 2% methanol/chloroform (volume ratio).
3.44 g of (aminobutyl)-5-isoquinolinesulfonic acid amide (3) was obtained as an oily substance. Yield 62
% Mass spectrum (m/e): 279 (M ⁺ ),
221NMR spectrum ( _CDCl3 ): 1.5-2.0 (4H, 2
×CH ₂ ), 2.5-3.2 (4H, 2×NCH ₂ ), 2.4 (2H,
_N- ( ^ω _- aminoalkyl) ^-
5-isoquinolinesulfonic acid amide was obtained (Table 1
-1, Table 1-2).

【table】

[Table] Example 2 Chloroform 50 containing 1.4 g of 3-dimethylaminopropylamino and 1.4 g of triethylamine
30 ml of a chloroform solution containing 2.6 g of 5-isoquinolinesulfonic acid chloride was added dropwise to the ml solution under ice cooling. After removal, the mixture was stirred at 2 to 10°C for 4 hours. The reaction mixture was washed with water and dried over anhydrous magnesium sulfate. Chloroform was distilled off under reduced pressure, and the residue was subjected to column chromatography (chloroform) on silica gel (70 g) to obtain 2.38 g of N-(3-dimethylaminopropyl)-5-isoquinolinesulfonic acid amide (25). . Yield 71% Mass spectrum (m/e): 293, 249, 235,
221, 207, 192 IR absorption spectrum (ν ^cap _nax , cm ^-1 ): 2950, 2860,
2840, 1460, 1320, 1150, 1130, 830, 760 NMR spectrum ( _CDCl3 ): 1.6 (2H, _CH2 ),
2.0~2.6 (8H, 2×NCH ₃ +NCH ₂ ), 3.1 (2H,
_NCH2 ) 6.2 (NH), 7.4~7.7 (1H), 8.0~8.6
(4H), 9.3 (1H) Similarly, N-(3-diethylaminopropyl)
-5-isoquinolinesulfonic acid amide (26), N
-(3-di-n-butylaminopropyl)-5-isoquinolinesulfonamide (27), N-(3-piperidinopropyl)-5-isoquinolinesulfonamide (28), N-(3-mol Holipropyl) -
5-isoquinolinesulfonic acid amide (29), N-
[3-(N-methyl-N-cyclohexylamino)
propyl]-5-isoquinolinesulfonamide (30), N-[3-(N-methyl-N-phenylamino)propyl]-5-isoquinolinesulfonamide (31), N-[3-(N-methyl- N-benzylamino)propyl]-5-isoquinolinesulfonic acid amide (32) was obtained. The results are shown in Table 2-1 and Table 2.
-2.

【table】

【table】

[Table] Example 3 2-benzyloxylcarbonylamino-1-
2.23g of methylethylamine, triethylamino
Dissolve 1.2 g in 40 ml of chloroform, and add to this dissolution,
A solution of 2.28 g of 5-isoquinolinesulfonic acid chloride dissolved in 20 ml of chloroform was added dropwise under ice cooling. After dropping, the mixture was stirred at 20 to 25°C for 2 hours. The reaction solution was washed successively with saturated sodium bicarbonate solution and water, dried over magnesium sulfate, and chloroform was distilled off under reduced pressure to give N-(2-benzyloxycarbonylamino-1-methylethyl)-5-isoquinolinesulfonic acid amide. 3.55g was obtained. 89%. IR spectrum (ν ^cap _nax , cm ^-1 ): 3350, 1700,
1330, 1160 MNR spectrum ( _CDCl3 ): 0.95 (3H, _CH3 ),
2.5~4.5 (3H), 5.0 (2H, OCH _2φ ), 6.6 (1H), 7.2
(5H), 7.6 (1H), 8.0-8.6 (4H), 9.3 (1H) 25% hydrogen bromide in 2.0 g of N-(2-benzyloxylcarbonylamino-1-methylethyl)-5-isoquinolinesulfonamide -5 ml of acetic acid solution
was added and stirred at 20-25°C for 20 hours. ether
30 ml was added and the precipitated crystals were collected. The crystals were dissolved in water, washed with chloroform, and then 1N−
The mixture was made alkaline with NaOH and extracted with chloroform. After washing the chloroform layer with water, it was dried over magnesium sulfate, dried under reduced pressure with chloroform, and N-
1.2 g of (2-amino-1-methylethyl)-5-isoquinolinesulfonic acid amide (7) was obtained. Yield 90% Mass spectrum (m/e): 265, 240, 221,
192, 128 IR spectrum (ν ^cap _nax cm ^-1 ): 3400, 2900, 1610,
1460, 1330, 1160, 1140 NMR spectrum ( _CDCl3 ): 1.1 (3H), 1.7
(2H), 2.6 (2H), 3.7 (1H), 6.5 (1H), 7.6 (1H)
,
8.0-8.7 (4H), 9.3 (1H) N-(1-aminomethyllopyl)-5-isoquinolinesulfonamide (8), N-(1-aminomethylpentyl) by the same method as Example 3 -5
-isoquinoline sulfonamide (10), N-(2-
Amino-1-phenylethyl)-5-isoquinolinesulfonic acid amide (15) was obtained. The results are shown in Tables 3-1, 3-2, and 3-3.

【table】

【table】

【table】

[Table] Example 4 2.0 g of 2-acetamidopropylamino and 2.6 g of triethylamino were dissolved in 50 ml of chloroform,
A solution of 3.28 g of 5-isoquinolinesulfonic acid amide dissolved in 50 ml of chloroform was added dropwise to this under ice cooling. After stirring at 15 to 25°C for 2 hours, the reaction mixture was washed with water and dried over magnesium sulfate. Chloroform was distilled off under reduced pressure and N-(2-acetamidopropyl)-
3.67 g of 5-isoquinolinesulfonic acid amide was obtained. Yield 83% IR spectrum (ν ^cap _nax , cm ^-1 ): 3300, 1670,
1365, 1150, 1130 NMR spectrum ( _CDCl3 ): 1.0 (3H, d,
_CH3 ), 2.2 (3H, _COCH3 ), 2.6~3.8 (3H), 5.5~
7.0 (2H), 7.6 (1H), 8.0-8.7 (4H), 9.3 (1H) A reaction mixture of 3.0 g of N-(2-acetamidopropyl)-5-isoquinolinesulfonic acid amide and 50 ml of 10% hydrochloric acid was heated at 90% Stirred at ~100°C for 36 hours. After the reaction was washed with chloroform, the mixture was made alkaline with 1N-NaOH and extracted with chloroform. The chloroform layer was washed with water, dried with magnesium sulfate,
Chloroform was distilled off under reduced pressure. The residue was subjected to column chromatography (chloroform) on alumina (70 g) to obtain N-(2-aminopropyl)-5.
-1.14 g of isoquinoline sulfonic acid amide (11) was obtained. Yield 44% Mass spectrum (m/e): 265, 222, 193,
129, 128 IR absorption spectrum (ν ^ccp _nax , cm ^-1 ): 3400, 1610,
1460, 1370, 1150, 1130 NMR spectrum ( _CDCl3 ): 1.0 (3H), 1.7
(2H), 2.9-4.0 (3H), 6.8 (1H), 7.5 (1H), 8.1
~
8.6 (4H), 9.3 (1H) In the same manner as in Example 4, N-(2-amino-3
-Methylbutyl)-5-isoquinolinesulfonamide (13), N-(2-amino-2-phenylethyl)-5-isoquinolinesulfonamide (16)
I got it. The results are shown in Tables 4-1, 4-2, and 4-3.

【table】

【table】

【table】

[Table] Example 5 2-(N-methyl-N-benzylchloroform)
3.24g of ethylamine and triethylchlorohorn
2.0g was dissolved in 70ml of methylene chloride, and in this solution was added 5-5, which was dissolved in 50ml of methylene chloride under ice-cooling.
A solution of 3.0 g of isoquinoline sulfonic acid chloride was extracted. After dropping, the mixture was stirred at 15 to 25°C for 1 hour. After washing the reaction solution with water, it was extracted with 10% aqueous hydrochloric acid. The aqueous layer was washed with chloroform, made alkaline with 1N-NaOH, and extracted with chloroform. The chloroform layer was washed with water, dried over magnesium sulfate, and then evaporated under reduced pressure. The residue was subjected to column chromatography using 100 g of silica gel to obtain 3.84 g of N-[2-(N-methyl-N-benzylamino)ethyl]5-isoquinolinesulfonic acid amide (21). yield
84% Mass spectrum (m/e): 355, 340, 264,
221, 128 IR absorption spectrum (ν ^cap _nax , cm ^-1 ): 3050, 2950,
1620, 1450, 1330, 1155, 1135 NMR spectrum ( _CDCl3 ): 1.9 (3H, _NCH3 ),
2.3~2.7 (2H), 3.0~3.3 (2H), 3.5 (2H, _CH2φ ),
6.8 (1H), 7.2 (5H), 7.6 (1H), 8.0~8.5 (4H),
9.3 (1H) In the same manner as in Example 5, N-[2-(N-isopropyl-N-benzylamino)ethyl]-5-isoquinolinesulfonic acid amide (23) was obtained. The results are shown in Tables 5-1 and 5-2.

【table】

[Table] Example 6 N-[2-(N-methyl-N-benzylamino)
Dissolve 2.0 g of ethyl]-5-isoquinolinesulfonic acid amide (21) in 100 ml of ethanol, add 0.2 g of 10% palladium-carbon, and stir vigorously for 5 hours at 20-25°C in a hydrogen stream of 2.0-2.5 atm. did. After passing through palladium-carbon, it was concentrated to dryness and N-(2-
0.95 g of methylaminoethyl-5-isoquinolinesulfonic acid amide (17) was obtained. Yield 64% Mass spectrum (m/e): 265, 250, 221,
128 IR absorption spectrum (ν ^cap _nax , cm ^-1 ): 3400, 1610,
1350, 1330, 1160, 1140 NMR spectrum ( _CDCl3 ): 1.7 (1H, NH),
2.9 (3H, _CH3 ), 2.5~3.1 (2H), 3.1~3.5 (2H),
7.0 (1H), 7.6 (1H), 8.1-8.5 (4H), 9.3 (1H) N-(2-isopropylaminoethyl)-5-isoxynolinesulfonamide (19) was obtained in the same manner as in Example 6. Ta. The results are shown in Table 6-1 and Table 6-2.

【table】

[Table] Test Example 1 Relaxation effect on mesenteric artery A domestic rabbit (Japanese native species, weight approximately 3 kg) is exsanguinated to death, then opened and the superior mesenteric artery is removed. Cut the blood vessel spirally into 2 mm x 25 mm according to the standard method, and cut the blood vessel into 95%
Suspend in a 20 ml organ bath filled with Krebs-Hensleit nutrient solution passed through a gas mixture of O ₂ :5% CO ₂ . When one side of the blood vessel is connected to an isometric transducer and a load of 1.5 g is applied, the contraction and relaxation reactions of the blood vessel are detected using the transducer (Nihon Kohden,
It is recorded as the load applied to the FD pickup (TB-912T). The compound of the present invention was added under conditions of contraction of approximately 1/2 of the maximum contraction of KCl at 15 to 20 mM KCl, and its relaxing effect was observed. that complete relaxation
Table 7 shows the concentration (ED ₅₀ value) that causes 50% relaxation, which is set as 100%.

【table】

[Table] Test Example 2 Effect on femoral artery and vertebral artery blood flow in dogs An experiment was conducted according to the method described in the text. The results are shown in Table 8.

[Table] Test Example 3 _LD50 values when ddY was administered intravenously to male mice are shown in Table 9.

【table】

Claims (1)

[Claims] 1 General formula () (In the formula, m and n are integers of 0 to 9, R ₁ represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or an aryl group, R ₂ and R ₃ represent a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, group, cycloalkyl group, aryl group, aralkyl group, or R ₂ ,
R ₃ represents a group that is bonded directly or via an oxygen atom to form a heterocycle together with adjacent N. ) Isoquinoline sulfonic acid amide derivatives and acid addition salts thereof. 2 In the general formula (), m and n are m+n
is an integer from 0 to 9 not exceeding 9, R ₁ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a phenyl group, R ₂ and R ₃ are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, phenyl 2. The compound according to claim 1, wherein R ₂ and R ₃ are bonded to each other directly or via an oxygen atom to form a heterocycle. 3. The compound according to claim 2, wherein R ₂ and R ₃ are both hydrogen atoms. 4. The compound according to claim 3, wherein R ₁ is a hydrogen atom. 5 m+n is 1 and R ₁ has 1 to 6 carbon atoms
The compound according to claim 3, which is an alkyl group of 6. The compound according to claim 5, wherein the alkyl group is a methyl group, ethyl group, propyl group or butyl group. 7. The compound according to claim 3, wherein m+n is 1 and R ₁ is a phenyl group. 8 m+n is 1 or 2, R ₁ is a hydrogen atom,
R ₂ is hydrogen or an alkyl group having 1 to 4 carbon atoms,
R ₃ is an alkyl group having 1 to 6 carbon atoms, a phenyl group, a benzyl group, or a group in which R ₂ and R ₃ are bonded directly or through an oxygen atom to form a heterocycle with the adjacent N. A compound according to claim 2. 9 m+n is 1, R ₂ is a hydrogen atom, R ₃ is a methyl group,
9. The compound according to claim 8, which is an ethyl group or a propyl group. 10. The compound according to claim 8, wherein m+n is 1, _R2 is a methyl group, ethyl group, or propyl group, and _R3 is a benzyl group. 11 m+n is 2, R ₂ is an alkyl group having 1 to 4 carbon atoms, and R ₃ is an alkyl group having 1 to 6 carbon atoms, a phenyl group or a benzine group, according to claim 8 Compound. 12. The compound according to claim 11, wherein [Formula] is a dimethylamino group, a diethylamino group, a dibutylamino group, or an N-methyl-N-cyclohexylamino group. 13. The compound according to claim 8, wherein m+n is 2 and [Formula] is a heterocycle. 14. The compound according to claim 13, wherein the heterocycle is piperidine or morpholine.