JPH062741B2 - Secondary isoquinoline sulfonamide derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention has an effect on vascular smooth muscles in mammals, and has vasodilators, cerebral circulation improvers, angina remedies, cerebrovascular thrombosis,
The present invention relates to a novel substance useful as a preventive / therapeutic drug for hypertension.

(Prior Art) The compounds represented by the following formulas (II), (III), (IV), (V), and (VI) are known substances and are useful as therapeutic agents for circulatory organs. Are known.

[In the formula, R ⁴ is an alkyl group, an aryl group, an aralkyl group, a benzoyl group, a cinnamyl group or a furoyl group. R ⁵ and ^{6 which} are the same or different, are a hydrogen atom or a lower alkyl group, or are bonded to each other directly or through an oxygen atom to form a heterocycle with the adjacent N. A group, R ⁷ is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, and R ³ is 1 to 10 carbon atoms
Represents an alkyl group, an aryl group or an aralkyl group, and B is an alkylene group having n carbon atoms in which m hydrogen atoms are substituted with an alkyl group, an aryl group or an aralkyl group, wherein n is 10 A positive integer not exceeding m,
Is an integer of 0 to 2 × n), R ⁹ is a hydrogen atom, and has 1 carbon atom.
To 10 alkyl or aryl groups, R ¹⁰ and R ¹¹
Represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aryl group, an aralkyl group, or a group which is bonded directly or through an O atom to form a heterocycle with an adjacent nitrogen atom, and u and v are 0 to 9 Represents the integer. (Structure of the Invention) The present invention has the general formula (I) (In the formula, A is an alkylene group having 2 to 6 carbon atoms in which hydrogen bonded to carbon may be substituted with an alkyl group having 1 to 8 carbon atoms, R ¹ is a straight chain having 1 to 10 carbon atoms or A branched alkyl group, or a benzyl group, R ² and R ^{3 each} represent a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, an aryl group or an aralkyl group, Or R ² and ³ each represent a group which is bonded directly or through an oxygen atom to form a heterocyclic ring with the adjacent nitrogen atom, and an isoquinoline sulfonamide derivative and a pharmaceutically acceptable acid addition salt thereof. .

The following compounds can be mentioned as specific compounds represented by the general formula (I).

(1) N- (2-aminoethyl) -N-methyl-5-isoquinolinesulfonamide (2) N- (2-aminoethyl) -N-isopropyl-5
-Isoquinoline sulfonamide (3) N- (2-aminoethyl) -N-butyl-5-isoquinoline sulfonamide (4) N- (2-aminoethyl) -N-hexyl-5-isoquinoline sulfonamide (5) N -(2-Aminoethyl) -N-octyl-5-isoquinolinesulfonamide (6) N- (2-aminoethyl) -N-benzyl-5-isoquinolinesulfonamide (7) N- (3-aminopropyl)- N-hexyl-5
Isoquinoline sulfonamide (8) N- (4-aminobutyl) -N-hexyl-5-isoquinoline sulfonamide (9) N- (5-aminopentyl) -N-hexyl-5-
Isoquinoline sulfonamide (10) N- (6-aminohexyl) -N-propyl-5-
Isoquinoline sulfonamide (11) N- (2-aminopropyl) -N-hexyl-5-
Isoquinoline sulfonamide (12) N- (2-aminobutyl) -N-hexyl-5-isoquinoline sulfonamide (13) N- (2-aminooctyl) -N-hexyl-5-
Isoquinoline sulfonamide (14) N- (2-aminodecyl) -N-propyl-5-isoquinoline sulfonamide (15) N- (2-aminodecyl) -N-hexyl-5-isoquinoline sulfonamide (16) N- (2 -Amino-1-methylpropyl) -N-butyl-5-isoquinolinesulfonamide (17) N- (2-amino-1-methylethyl) -N-ethyl-5-isoquinolinesulfonamide (18) N- (1 -Aminomethyl-2-methylpropyl)-
N-propyl-5-isoquinolinesulfonamide (19) N- (1-aminomethylbutyl) -N-hexyl-
5-Isoquinolinesulfonamide (20) N- (3-amino-2-methylpropyl) -N-propyl-5-isoquinolinesulfonamide (21) N- (4-amino-1-methylbutyl) -N-hexyl-5 -Isoquinoline sulfonamide (22) N- (5-aminomethylhexyl) -N-ethyl-
5-Isoquinolinesulfonamide (23) N- (4-amino-3-methylbutyl) -N-hexyl-5-isoquinolinesulfonamide (24) N- (4-amino-1-propylhexyl) -N-
Hexyl-5-isoquinolinesulfonamide (25) N- (2-methylaminoethyl) -N-methyl-5
-Isoquinoline sulfonamide (26) N- (2-ethylaminoethyl) -N-ethyl-5
-Isoquinoline sulfonamide (27) N- (2-butylaminoethyl) -N-hexyl-
5-Isoquinolinesulfonamide (28) N-ethyl-N- (2-hexylaminoethyl)-
5-isoquinolinesulfonamide (29) N- (2-hexylaminoethyl) -N-hexyl-5-isoquinolinesulfonamide (30) N- (2-benzylaminoethyl) -N-benzyl-5-isoquinolinesulfonamide ( 31) N-Butyl-N- (2-phenylethylaminoethyl) -5-isoquinolinesulfonamide (32) N- (2-benzylaminoethyl) -N-hexyl-5-isoquinolinesulfonamide (33) N- (3-hexylaminopropyl) -N-hexyl-5-isoquinolinesulfonamide (34) N- (6-benzylaminohexyl) -N-pentyl-5-isoquinolinesulfonamide (35) N- (6-hexylaminohexyl) ) -N-Hexyl-5-isoquinolinesulfonamide (36) N- (2-ethylaminopropyl) -N-hexyl-5-a Soquinoline sulfonamide (37) N- (2-hexylaminopropyl) -N-hexyl-5-isoquinoline sulfonamide (38) N- (2-propylaminooctyl) -N-butyl-5-isoquinoline sulfonamide (39 ) N-hexyl-N- (2-isopropylamino-1
-Methylethyl) -5-isoquinolinesulfonamide (40) N- (4-benzylamino-1-methylbutyl)-
N-propyl-5-isoquinolinesulfonamide (41) N-methyl-N- (6-propylamino-5-methylhexyl) -5-isoquinolinesulfonamide (42) N- (2-dimethylaminoethyl) -N- Methyl-
5-isoquinolinesulfonamide (43) N- (2-dimethylaminoethyl) -N-hexyl-5-isoquinolinesulfonamide (44) N-benzyl-N- (2-dihexylaminoethyl) 5-isoquinolinesulfonamide (45 ) N-hexyl-N- (2-piperidinoethyl) -5
-Isoquinoline sulfonamide (46) N-hexyl-N- (2-morpholinoethyl) -5
-Isoquinoline sulfonamide (47) N- (2-cyclohexylmethylaminoethyl)-
N-Ethyl-5-isoquinolinesulfonamide (48) N-hexyl-N- (2-piperidinopropyl)-
5-Isoquinolinesulfonamide (49) N- (2-diethylamino-1-methylethyl)-
N-hexyl-5-isoquinolinesulfonamide (50) N-ethyl-N- (5-piperidinopentyl) -5
-Isoquinoline sulfonamide The present invention also provides an acid addition salt of the isoquinoline derivative represented by the general formula (I). This salt is a non-toxic pharmaceutically acceptable salt, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and acetic acid, citric acid,
Organic acids such as tartaric acid, lactic acid, succinic acid, fumaric acid, maleic acid and methanesulfonic acid can be mentioned.

The compound represented by the general formula (I) of the present invention can be synthesized by the following method.

To 5-isoquinolinesulfonic acid, thionyl chloride and a catalytic amount of dimethylformamide were used and heated under reflux for 3 hours to give 5-isoquinolinesulfonic acid chloride (VI
I) is obtained.

In addition to this, the general formula (VIII) (Wherein A and R ¹ have the same meanings as described above), and the compound of the general formula (IX) (Wherein R ₁ and A have the same meanings as described above).

In this reaction, it is desirable to use the compound of the general formula (VIII) in an equimolar to 5-fold molar amount with respect to the general formula (VII).
At this time, an acid acceptor may be present. Acid acceptors include sodium hydrogen carbonate, sodium hydroxide, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, alkali metal compounds such as sodium methylate, organic tertiary compounds such as pyridine, trimethylamine and triethylamine. Examples include amines. The reaction temperature is preferably -20 ° C to 50 ° C, and the reaction time is 0.
5 to 6 hours are preferred. As the reaction solvent, alkanols such as methanol and ethanol, halogenated hydrocarbons such as dichloromethane and chloroform, ethers such as tetrahydrofuran, dioxane and diethyl ether can be used.

a) When the compound of the general formula (IX) is reacted with p-toluenesulfonic acid chloride, an intermediate of the general formula (X) is obtained.

(In the formula, R ¹ and A have the same meanings as described above.) The reaction for obtaining the intermediate of the general formula (X) from the intermediate of the general formula (IX) is described by El F. Fieser and M. Fizer. Regent of Organic Synthesis (LF
Fieser and M. Fieser, "Reagent for Organic Synthesi
s ") Volume 1, page 1180 can be used.

b) A compound of general formula (IX) can be written as general formula (XI).

(In the formula, B is an alkylene group having 1 to 5 carbon atoms in which hydrogen bonded to carbon may be substituted with an alkyl group having 1 to 8 carbon atoms, and R ¹² and R ¹³ are hydrogen atoms or 1 to 5 carbon atoms. In the compound of the general formula (XI), a secondary alcohol, that is, R ¹² is a hydrogen atom, and R ₁₃ is a dimethyl sulfoxide in the case of an alkyl group having 1 to 8 carbon atoms. By coupling with oxalic acid dichloride, an intermediate represented by the general formula (XII) is obtained.

(In the formula, B is an alkylene group having 1 to 5 carbon atoms in which hydrogen bonded to carbon may be substituted with an alkyl group having 1 to 8 carbon atoms, and R ₁₃ is an alkyl group having 1 to 8 carbon atoms. The reaction of obtaining the intermediate of the general formula (XII) from the intermediate of the general formula (IX) is described in Journal of Organic Chemistry, Vol. 43, 1.
No. 2, page 2480, (1978) can be used.

c) The compounds represented by the general formulas (X) and (XII) synthesized by the methods a) and b) are added to the compounds of the general formula (XIII) (In the formula, R ² and R ³ have the same meanings as described above.) The compound represented by the general formula (I) can be obtained by reacting the amine.

(In the formula, R ¹ , R ² , R ³ and A have the same meanings as described above.) The reaction between the intermediate of the general formula (X) and the amine of the general formula (XIII) is carried out by using methanol or ethanol as a solvent. And the like, halogenated hydrocarbons such as methylene chloride and chloroform, and ethers such as diethyl ether, dioxane, and tetrahydrofuran. The reaction temperature is preferably 0 ° C to 70 ° C, and the reaction time is 30 minutes to 3 days.

The reaction of the intermediate of the general formula (XII) and the amine of the general formula (XIII) to obtain the general formula (I) is carried out by the Journal of the American Chemical Society (Journal of the American Chemical Society).
American Chemical Society) 93, 2897,
The method described in (1971) can be used.

The action of the compound of the present invention on smooth muscle was confirmed by the relaxing action of the mesenteric artery of the rabbit, and the vasodilating action was confirmed by the increase in blood flow of the femoral artery and vertebral artery in dogs.

The smooth muscle relaxing action was proved by the fact that the superior dilated artery isolated from the rabbit was hung in a spiral shape and contracted with potassium chloride, and the compound of the present invention was added thereto to relax it.
For example, N- (2-aminoethyl) -N-hexyl-5
When isoquinoline sulfonamide (4) was added, the concentration at which 50% was relaxed (ED ₅₀ ) was 1 μM, with 100% as the complete relaxation.

Dilation of the femoral artery and vertebral artery
~ 15 kg) was anesthetized by intravenous administration of pentobarbital 35 mg / kg, and a femoral artery and a vertebral artery were fitted with a non-invasive flop (manufactured by Nihon Kohden), and electromagnetic blood statistics (Nihon Kohden MF-27) were used. Blood flow was measured. Under this condition, the compound of the present invention, for example, N- (2-aminoethyl) -N-hexyl-5-isoquinolinesulfonamide, is passed through a polyethylene tube inserted into the femoral vein side chain.
When 0.3 mg / kg is administered intravenously, femoral artery blood flow is 38
%, The vertebral artery blood flow increased by 170%.

Moreover, the acute toxicity value LD ₅₀ for when administered intravenously to ddY male mice was found to be 94.6 mg / kg. The results of these tests show that the compounds have a stronger pharmacological effect and weaker toxicity than the compounds of the prior art, for example, the compounds represented by the formulas (IV) and (VI), and are highly useful as drugs for circulatory organs.

(Examples) Hereinafter, the present invention will be described in more detail with reference to Examples.

Example 1 To 150 g of 5-isoquinolinesulfonic acid 1/2 sulfate, 1200 ml of thionyl chloride and 0.4 ml of dimethylformamide were added, and the mixture was heated under reflux for 3 hours. Thionyl chloride and dimethylformamide were distilled off under reduced pressure, and methylene chloride 300 was added to the residue.
After adding ml, stirring and passing, and drying under reduced pressure, 160 g (quantitative) of 5-isoquinolinesulfonic acid chloride 1/2 sulfate was obtained.

5-isoquinoline sulfonic acid chloride 1/2 sulfate 10.00 g
100 ml of water and 100 ml of methylene chloride were added to and dissolved. Sodium bicarbonate was added to this solution to adjust the pH of the aqueous layer.
I set it to 6.0. The methylene chloride layer was added dropwise to a methylene chloride solution (100 ml) of 5.14 g of Nn-hexylethanolamine and 5.12 ml of triethylamine under ice cooling over 5 minutes, and the mixture was stirred at room temperature for 2 hours. The obtained solution was washed twice with water, methylene chloride was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Wako gel C-200 manufactured by Wako Pure Chemical Industries, elution solvent 5% by volume methanol / chloroform), and N- (2-Hydroxyethyl) -N-hexyl-
4.74 g of 5-isoquinolinesulfonamide was obtained (yield 3
9%). To this, 70 ml of pyridine and 3.08 g of p-toluenesulfonyl chloride were added, and after heating at 60 ° C. for 4 hours,
Pyridine was distilled off under reduced pressure, and 50 ml of chloroform and pH 2 were added.
20 ml of hydrochloric acid water was added and the layers were separated, and the organic layer was dried over anhydrous magnesium sulfate. The solution was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography (Wako Gel C-2 manufactured by Wako Pure Chemical Industries, Ltd.).
00, elution solvent 3 v / v% methanol / chloroform)
Purified with N-hexyl-N- (p-toluenesulfonyloxyethyl) -5-isoquinolinesulfonamide 2.
34 g was obtained (34% yield).

40 ml of ethanol containing 4 g of ammonia gas was added to 2.34 g of N-hexyl-N- (p-toluenesulfonyloxyethyl) -5-isoquinolinesulfonamide and heated in a pressure vessel at 90 ° C for 2 days. The solvent was distilled off under reduced pressure, and silica gel column chromatography (Wako gel C-2
00, elution solvent 3 volume percent methanol / chloroform) to obtain 1.34 g of N- (2-aminoethyl) -N-hexyl-5-isoquinolinesulfonamide (4) (yield 84%).

NMR spectrum (CDCl ₃ ): δppm 0.6 to 1.6 (13H) 2.7 to 3.0 (2H) 3.1 to 3.6 (4H) 7.5 to 7.9 (1H) 8. 1-8.8 (4H) 9.4 (1H, s) IR spectrum: ν _max (cm ⁻¹ ) 2920,1610,1320,1150,1130 Mass spectrum (m / e): 335 Similarly, Table 1 The compound shown in was obtained.

Example 2 9.20 g of 5-isoquinolinesulfonic acid chloride 1/2 sulfate
100 ml of water and 100 ml of methylene chloride were added to and dissolved. Sodium bicarbonate was added to this solution to adjust the pH of the aqueous layer.
I set it to 6.0. The methylene chloride layer was cooled with ice under N-hexyl-
A solution of 5.30 g of 2-hydroxypropylamine and 4.03 g of triethylamine was added dropwise to a methylene chloride solution (100 ml) over 5 minutes, and the mixture was stirred at room temperature for 2 hours. The obtained solution was washed twice with water, dried over anhydrous magnesium sulfate, and then methylene chloride was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (Wako gel C-200 manufactured by Wako Pure Chemical Industries, elution solvent 2 volume percent methanol / Chloroform) and N
9.02 g of-(2-hydroxypropyl) -N-hexyl-5-isoquinolinesulfonamide was obtained (77%).

12 ml of methylene chloride solution of 4.08 ml of dimethyl sulfoxide
Was cooled to an internal temperature of -50 ° C or lower 2.
4 ml of methylene chloride solution (60 ml) was added dropwise and N- (2
A solution of 8.34 g of -hydroxypropyl) -N-hexyl-5-isoquinolinesulfonamide in 24 ml of methylene chloride was added dropwise over 20 minutes, followed by stirring for 15 minutes at -50 to -60 ° C. Then, 16.8 ml of triethylamine was added dropwise to 1.5.
Allow to reach room temperature over time. Add 50 ml of water and p with 1N hydrochloric acid.
After H5 and liquid separation, the organic layer is washed with 50 ml of brine and dried over anhydrous magnesium sulfate, and then methylene chloride is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel C-200, elution solvent 1 volume percent methanol / chloroform), and N-acetonyl-
7.17 g of N-hexyl-5-isoquinoline sulfonamide
Was obtained (yield 86%).

IR spectrum: ν _max (cm ^-1 ) 2920,1720,1615,1330,1160,1140,990 N-acetonyl-N-hexyl-5-isoquinolinesulfonamide 5.89 g in anhydrous methanol solution (75 ml) 13.03 g ammonium acetate. And 0.75 g of sodium cyanoborohydride were added, and the mixture was stirred at room temperature for 19 hours. Under reduced pressure, 3
Methanol was distilled off at 0 ° C, and 50 ml of chloroform and 1N were added.
50 ml of sodium hydroxide solution was added for extraction, the organic layer was dried over anhydrous magnesium sulfate, and chloroform was distilled off under reduced pressure. The residue was purified by silica gel chromatography (Wakogel C-200, elution solvent 5% by volume methanol / chloroform) and N- (2-aminopropyl) -N-hexyl-5-isoquinolinesulfonamide.
(11) 2.75 g was obtained (yield 46%).

NMR spectrum (CDCl ₃ ): δ ppm 0.5 to 1.6 (16H) 2.8 to 3.4 (5H) 7.5 to 7.8 (1H) 8.1 to 8.8 (4H) 9. 4 (1H, s) IR spectrum: ν _max (cm ⁻¹ ) 2920,1610,1310,1140,1130 Mass spectrum (m / e): 349 In the same manner, the compounds shown in Table 2 were obtained.

Example 3 5.56 g of 5-isoquinolinesulfonic acid chloride 1/2 sulfate obtained in Example 1 was dissolved by adding 50 ml of water and 50 ml of methylene chloride. Sodium bicarbonate was added to this solution to bring the pH of the aqueous layer to 6.0. The methylene chloride layer was added dropwise at room temperature to a methylene chloride solution (50 ml) of 4.17 g of N-hexyl-N- (1-hydroxymethylpentyl) amine and 2.07 g of triethylamine over 5 minutes, and the mixture was stirred for 2 hours. The obtained solution was washed twice with water and dried over anhydrous magnesium sulfate, methylene chloride was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography (Wako Gel-20 manufactured by Wako Pure Chemical Industries, Ltd.).
0, eluting solvent chloroform), N-hexyl-
3.9 g of N- (1-hydroxymethylpentyl) -5-isoquinolinesulfonamide was obtained (yield 39%).

To 2.67 g of N-hexyl-N- (1-hydroxymethylpentyne) -5-isoquinolinesulfonamide, 30 ml of pyridine and 1.56 g of p-toluenesulfonyl chloride were added, and after heating at 60 ° C for 17 hours, the pyridine was distilled off under reduced pressure. did. 50 ml of chloroform and 50 ml of hydrochloric acid with pH 3 in the residue
Was extracted, and the organic layer was dried over anhydrous magnesium sulfate, and chloroform was distilled off under reduced pressure. The residue was purified by silica gel chromatography (Wakogel C-200, eluting solvent chloroform), and N-hexyl-N- (1-p
-Toluenesulfonyloxymethylpentyl) -5-isoquinolinesulfonamide 2.37 g was obtained (yield 64
%).

N-hexyl-N- (1-p-toluenesulfonyloxymethylpentyl) -5-isoquinolinesulfonamide
40 ml of ethanol containing 4 g of ammonia gas was added to 2.37 g and heated at 100 ° C. for 13 hours in a pressure vessel. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Wakogel C-200, eluting solvent 5% by volume methanol / chloroform) and N- (1-aminomethylpentyl) -N-hexyl-5-isoquinoline. 0.70 g of sulfonamide was obtained (yield 35%).

NMR spectrum (CDCl ₃ ): δ ppm 0.6 to 1.7 (22H) 3.0 to 3.8 (5H) 7.5 to 7.8 (1H) 8.0 to 8.8 (4H) 9. 4 (1H, s) IR spectrum: νmax (cm ⁻¹ ) 2925,1610,1310,1140,1125 Mass spectrum (m / e): 391 In the same manner, the compounds shown in Table 3 were obtained.

Example 4 100 g of water and 100 ml of methylene chloride were added and dissolved in 10.0 g of 5-isoquinolinesulfonic acid chloride 1/2 sulfate. Sodium bicarbonate was added to this solution to adjust the pH of the aqueous layer.
I set it to 6.0. The methylene chloride layer was added to a methylene chloride solution (100 ml) of N-ethyl-ethanolamine (9.2 g) at room temperature.
Over 5 minutes, and stirred for 2 hours. The obtained solution was washed twice with water, dried over anhydrous magnesium sulfate, and then methylene chloride was distilled off under reduced pressure to obtain 8.65 g of N-ethyl-N- (2-hydroxyethyl) -5-isoquinolinesulfonamide ( Yield 73%).

5.77 g of N-ethyl-N (2-hydroxyethyl) -5-isoquinolinesulfonamide was added to 100 ml of pyridine and p-
Toluenesulfonyl chloride (4 g) was added, the mixture was heated at 80 ° C. for 2 days, and then pyridine was distilled off under reduced pressure. 100 ml of methylene chloride was added to the residue, washed three times with 100 ml of hydrochloric acid water of pH 5, dried over anhydrous magnesium sulfate, and then methylene chloride was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (Wako Gel C -200, eluting solvent 5 volume percent methanol / chloroform) and
3.96 g of -ethyl-N- (2-p-toluenesulfonyloxyethyl) -5-isoquinolinesulfonamide was obtained (yield 47%).

Hexylamine (1.25 g), potassium carbonate (1.14 g) and dioxane (20 ml) were added to N-ethyl-N- (2-p-toluenesulfonyloxyethyl) -5-isoquinolinesulfonamide (3.96 g) and heated in a pressure vessel at 110 ° C for 3 days. Then, dioxane was distilled off under reduced pressure, and 60 ml of methylene chloride and 3 parts of water were added.
0 ml was added for extraction, the organic layer was dried over anhydrous magnesium sulfate, and methylene chloride was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel C-200,
Elution solvent 5 volume percent methanol / chloroform)
And purified to obtain 2.5 g of N-ethyl-N- (2-hexylaminoethyl) -5-isoquinolinesulfonamide (28) (yield 74%).

NMR spectrum (CDCl ₃ ): δ ppm 0.6 to 1.6 (14H) 2.2 to 2.8 (4H) 3.1 to 3.6 (4H) 7.4 to 7.7 (1H) 8. 0-8.8 (4H) 9.3 (1H, s) IR spectrum: ν _max (cm ⁻¹ ) 2920,1610,1450,1320,1150,1130 Mass spectrum (m / e): 363 Similarly, The compounds shown in Table 4 were obtained.

Example 5 N-acetonyl-N-hexyl-5 obtained in Example 2
-A solution of isoquinoline sulfonamide (5.0 g) in anhydrous methanol (25 ml) was added at room temperature to ethylamine hydrochloride (3.28 g).
And potassium hydroxide 283mg anhydrous methanol (50ml)
The solution was added dropwise over 20 minutes and stirred for 15 minutes. 344 mg of sodium cyanoborohydride in anhydrous methanol (1
(0 ml) was added dropwise at room temperature and stirred overnight, 1.67 g of potassium hydroxide was added, stirred for 10 minutes, water was added, and the mixture was extracted twice with 50 ml of chloroform, dried over anhydrous magnesium sulfate, and then chloroform was removed under reduced pressure. Distilled off. The residue was purified by silica gel chromatography (Wako Gel C-20 manufactured by Wako Pure Chemical Industries, Ltd.
0, eluting solvent chloroform) to obtain 2.76 g of N- (2-ethylaminopropyl) -N-hexyl-5-isoquinolinesulfonamide (36) (yield 51
%).

NMR spectrum (CDCl ₃ ): δ ppm 0.6 to 1.7 (17H) 2.8 to 3.7 (7H) 7.4 to 7.7 (1H) 8.0 to 8.8 (4H) 9. 3 (1H, s) IR spectrum: νmax (cm ⁻¹ ) 2925,1615,1450,1320,1150,1140 Mass spectrum (m / e): 377 In the same manner, the compounds shown in Table 5 were obtained.

Example 6 5-Isoquinolinesulfonic acid chloride 1/2 sulfate 10.0
To g, 100 ml of water and 100 ml of methylene chloride were added and dissolved. Sodium bicarbonate was added to this solution to adjust the pH of the aqueous layer.
To 6.0. The methylene chloride layer was added to a methylene chloride solution (50 ml) of 10.5 g of N-hexylethanolamine at room temperature.
Over 5 minutes and stirred for 3 hours. The obtained solution was washed twice with water, dried over anhydrous magnesium sulfate, and then methylene chloride was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (Wako gel C-200 manufactured by Wako Pure Chemical Industries, elution solvent 2 volume percent methanol / Chloroform), N-hexyl-N- (2-hydroxyethyl) -5
-7.7 g of isoquinoline sulfonamide was obtained (63% yield).

To 5.0 g of N-hexyl-N- (hydroxyethyl) -5-isoquinolinesulfonamide, 80 ml of pyridine and 3.4 g of p-toluenesulfonyl chloride were added, and after heating at 80 ° C for 2 days, pyridine was distilled off under reduced pressure. Chloroform (100 ml) was added to the residue, washed three times with 100 ml of pH 5 hydrochloric acid water, and dried over anhydrous magnesium sulfate, and chloroform was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel C-200, eluent chloroform) to obtain 5.47 g of N-hexyl-N- (2-p-toluenesulfonyloxyethyl) -5-isoquinolinesulfonamide (yield). 75%).

2.85 g of piperidine and 30 ml of ethanol were added to 5.47 g of N-hexyl-N- (2-p-toluenesulfonyloxyethyl) -5-isoquinolinesulfonamide, and the mixture was heated in a pressure vessel at 80 ° C. for 3 hours. The solvent was distilled off under reduced pressure, 100 ml of chloroform and 100 ml of water were added for extraction, the extract was dried over anhydrous magnesium sulfate, and then chloroform was distilled off under reduced pressure.
The residue was purified by silica gel column chromatography (Wako gel C-200, elution solvent 3 volume percent methanol /
Chloroform) to obtain 3.6 g of N-hexyl-N- (2-piperidinoethyl) -5-isoquinolinesulfonamide (45) (yield 80%) NMR spectrum (CDCl ₃ ): δppm 0.6 to 1 .6 (17H) 1.8 to 2.8 (6H) 3.1 to 3.6 (4H) 7.5 to 7.8 (1H) 8.2 to 8.9 (4H) 9.3 (1H , S) IR spectrum: νmax (cm ^-1 ) 2920, 1620, 1330, 1160, 1130 Mass spectrum (m / e): 403 In the same manner, compounds shown in Table 6 were obtained.

Example 7 N- (2-aminoethyl) -N-hexyl-5-isoquinolinesulfonamide (4) obtained in Example 1 (1.34 g)
100 ml of water was added to the mixture, pH was adjusted to 5 with hydrochloric acid, dried to dryness, recrystallized with a 5:95 mixture of ethanol and acetone, and N- (2-aminoethyl) -N-hexyl-5-isoquinolinesulfonamide. 0.7 g of monohydrochloride was obtained (yield 52%).

NMR spectrum (CD ₃₀ OD): δ ppm 0.7 to 1.8 (11H) 3.0 to 3.8 (6H) 8.1 to 8.4 (1H) 8.8 to 9.3 (4H) 10 1 (1H, s) IR spectrum: νmax (cm ^-1 ) 2900,1600,1350,1160,1140 Elemental analysis value (%) Actual value C 54.70, H 6.95, N 11.10, Cl 9.20 Logical value C 54.90, H 7.05, N 11.30, Cl 9.53 Similarly, hydrochlorides of the compounds shown in Table 7 were obtained.

Test Example 1 Relaxing action on mesenteric artery Rabbit (Japanese native species, body weight 3 kg) was exsanguinated and laparotomized,
The superior mesenteric artery is removed. 2 mm x according to the standard procedure for blood vessels
Cut into 25 mm spirals and fill with Krebs-Hensleit nutrient solution through a mixed gas of 95% O ₂ : 5% CO ₂ 20
Hang on a ml organ bath. When one of the blood vessels is connected to an isometric transducer and a load of 1.5 g is applied, the transducers that contract and relax the blood vessels are transferred (Nihon Kohden, F
D load cap TB-912T). Hydrochloric acid salt of the compound of the present invention was added under the contraction condition of 1/2 volume of KCl maximum contraction with 15 to 20 mmol KCl aqueous solution, and its relaxing action was observed. 10 for its complete relaxation
Table 8 shows the concentration (ED ₅₀ value) at 0% and 50% relaxation.

Example 2 Effect on femoral artery and vertebral artery blood flow in dogs Experiments were conducted according to the method described in this section. The results are shown in Table 9.

Test Example 3 ICR♂ mice were intravenously administered and the acute toxicity value was determined.
The results are shown in Table 10.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location A61K 31/535 ACB 9360-4C

Claims (17)

[Claims] 1. A general formula (I) (In the formula, A is an alkylene group having 2 to 6 carbon atoms in which hydrogen bonded to carbon may be substituted with an alkyl group having 1 to 8 carbon atoms, R ¹ is a straight chain having 1 to 10 carbon atoms or A branched alkyl group, or a benzyl group, R ² and R ^{3 each} represent a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, an aryl group or an aralkyl group, Or R ² and R ³ each represent a group which is bonded directly or through an oxygen atom to form a heterocycle with an adjacent nitrogen atom.), An isoquinoline sulfonamide derivative and an acid addition salt thereof. ^2. The compound according to claim 1, wherein R ² and R ³ are both hydrogen atoms. 3. A is an alkylene group having 2 to 4 carbon atoms,
The compound according to claim 2, which is also an alkylene group having 2 to 4 carbon atoms in which one hydrogen atom is substituted with an alkyl group having 1 to 4 carbon atoms. 4. The compound according to claim 3, wherein R ¹ is a linear or branched alkyl group having 1 to 6 carbon atoms or a benzyl group. 5. The compound according to claim 4, wherein A is an ethylene group or an ethylene group in which one hydrogen atom is substituted with an alkyl group having 1 to 4 carbon atoms. 6. The compound according to claim 5, wherein R ¹ is a linear alkyl group having 1 to 6 carbon atoms. 7. A method according to claim 6, wherein A is an ethylene group.
The compound according to the item. 8. R ² is a hydrogen atom and R ³ has 1 to 6 carbon atoms.
The compound according to claim 1, which is an alkyl group, an aryl group, or an aralkyl group having a single linear or branched group. 9. A is an alkylene group having 2 to 4 carbon atoms,
9. The compound according to claim 8, which is an alkylene group having 2 to 4 carbon atoms in which one hydrogen atom is substituted with an alkyl group having 1 to 4 carbon atoms. 10. A method according to claim 9, wherein R ¹ is a linear or branched alkyl group having 1 to 6 carbon atoms.
The compound according to the item. 11. The compound according to claim 10, wherein A is an ethylene group. 12. An alkyl group, an aryl group, wherein R ² and R ³ both have a linear or branched chain having 1 to 6 carbon atoms,
The compound according to claim 1, which is an aralkyl group. 13. The compound according to claim 12, wherein A is an ethylene group or an ethylene group in which one hydrogen is substituted with an alkyl group having 1 to 4 carbon atoms. 14. A method according to claim 1, wherein R ¹ is a linear or branched alkyl group having 1 to 6 carbon atoms.
The compound according to item 3. 15. The compound according to claim 1, wherein R ² and R ³ are groups bonded to each other directly or through an oxygen atom to form a heterocycle with an adjacent nitrogen atom. 16. The compound according to claim 15, wherein A is an ethylene group or an ethylene group in which one hydrogen is substituted with an alkyl group having 1 to 4 carbon atoms. 17. A method according to claim 1, wherein R ¹ is a linear or branched alkyl group having 1 to 6 carbon atoms.
The compound according to item 6.