JPH0481986B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention affects vascular smooth muscle in mammals and can be used as a vasodilator, a cerebral circulation improving agent, a therapeutic agent for angina pectoris, a preventive treatment for cerebrovascular thrombosis, and hypertension. It concerns new and useful substances. (Prior Art) Compounds represented by the following formulas (), (), (), (), and () are known substances and are known to be useful as therapeutic agents for circulatory organs. [In the formula, R ⁵ is an alkyl group, an aryl group, an aralkyl group, a benzoyl group, a cinnamyl group, a furoyl group, or a formula

A group represented by [Formula] (wherein R′ represents a lower alkyl group),
R ⁶ and R ⁷ are the same or different and are a hydrogen atom, a lower alkyl group, or a group that is bonded to each other directly or through an oxygen atom to form a heterocycle with the adjacent N; R ³ is a hydrogen atom or a carbon ^R9 represents an alkyl group having 1 to 10 carbon atoms, an aryl group, or an aralkyl group, and B represents an alkyl group, aryl group, or aralkyl group having m hydrogen atoms having 1 to 10 carbon atoms; Alkylene group with n carbon atoms substituted with a group (n is a positive integer not exceeding 10, m is an integer from 0 to 2×n), R ¹⁰
is a hydrogen atom, an alkyl group or an aryl group having 1 to 10 carbon atoms, R ¹¹ and R ¹² are hydrogen atoms, and a carbon number 1
represents an alkyl group, an aryl group, an aralkyl group, or a group bonded directly or through an O atom to form a heterocycle with an adjacent nitrogen atom, and u and v each represent an integer of 0 to 9. ] (Structure of the invention) The present invention is based on the general formula () (In the formula, A has 2 carbon atoms in which the hydrogen bonded to carbon may be substituted with an alkyl group having 1 to 6 carbon atoms)
to 6 alkylene groups, R ¹ is a hydroxyl group or a chlorine atom, R ² and R ³ are hydrogen atoms, or are straight chain or branched alkyl groups having 1 to 6 carbon atoms, or are directly bonded to each other and have a carbon atom. The bonded hydrogen atom represents an ethylene group or a propylene group which may be substituted with an alkyl group having 1 to 6 carbon atoms, and R ⁴ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an amidino group. ) and its pharmaceutically acceptable acid addition salts. Specific examples of the compounds represented by the general formula () of the present invention include the following compounds. (1) N-(2-aminoethyl)-1-chloro-5-
Isoquinoline sulfonamide (2) N-(4-aminobutyl)-1-chloro-5-
Isoquinolinesulfonamide (3) N-(2-amino-1-methylethyl)-1-
Chlor-5-isoquinolinesulfonamide (4) N-(2-amino-1-methylpentyl)-1
-chloro-5-isoquinoline(5) N-(3-amino-2-methylbutyl)-1-
Chlor-5-isoquinolinesulfonamide (6) N-(3-di-n-butylaminopropyl)-
1-Chlor-5-isoquinolinesulfonamide (7) N-(N-cyclohexyl-N-methylaminoethyl)-1-chloro-5-isoquinolinesulfonamide (8) N-(2-guanidinoethyl)-1-chlor −
5-(isoquinolinesulfonamide(9) N-(4-guanidinobutyl)-1-chloro-
5-isoquinolinesulfonamide (10) N-(2-guanidino-1-methylethyl)-
1-Chloro-5-isoquinolinesulfonamide (11) N-(1-guanidinomethylbentyl)-1-
Chloro-5-isoquinolinesulfonamide (12) N-(2-guanidino-3-methylbutyl)-
1-chloro-5-isoquinolinesulfonamide (13) N-(3-guanidino-2-methylpropyl)
-1-chloro-5-isoquinolinesulfonamide (14) N-(4-guanidino-3-methylbutyl)-
1-chloro-5-isoquinolinesulfonamide (15) 2-methyl-4-(1-chloro-5-isoquinolinesulfonyl)piperazine (16) 2-ethyl-4-(1-chloro-5-isoquinolinesulfonyl)piperazine ( 17) 2-isobutyl-4-(1-chloro-5-isoquinolinesulfonyl)piperazine (18) 2,5-dimethyl-4-(1-chloro-5-
Isoquinolinesulfonyl)piperazine (19) 1-ethyl-4-(1-chloro-5-isoquinolinesulfonyl)piperazine (20) 1-amidino-4-(1-chloro-5-isoquinolinesulfonyl)piperazine (21) 1-amidino -4-(1-chloro-5-isoquinolinesulfonyl)homopiperazine (22) 1-amidino-3-methyl-4-(1-chloro-5-isoquinolinesulfonyl)piperazine (23) 1-amidino-2,5- dimethyl-4-
(1-chloro-5-isoquinolinesulfonyl)
Piperazine (24) N-(2-aminoethyl)-1-hydroxy-5-isoquinolinesulfonamide (25) N-(4-aminobutyl)-1-hydroxy-5-isoquinolinesulfonamide (26) N-(2 -amino-1-methylethyl)-1
-Hydroxy-5-isoquinolinesulfonamide (27) N-(2-amino-1-methylheptyl)-
1-Hydroxy-5-isoquinolinesulfonamide (28) N-(3-amino-2-methylbutyl)-1
-Hydroxy-5-isoquinolinesulfonamide (29) N-{3-(N,N-dibutylamino)propyl}-1-hydroxy-5-isoquinolinesulfonamide (30) N-{2-(N-cyclohexyl-N -methylamino)ethyl}-1-hydroxy-5-isoquinolinesulfonamide (31) N-(2-guanidinoethyl)-1-hydroxy-5-isoquinolinesulfonamide (32) N-(4-guanidinobutyl)-1 -Hydroxy-5-isoquinolinesulfonamide (33) N-(2-guanidino-1-methylethyl)
-1-Hydroxy-5-isoquinolinesulfonamide (34) N-(1-guanidinomethylpentyl)-1
-Hydroxy-5-isoquinolinesulfonamide (35) N-(2-guanidino-3-methylbutyl)
-1-Hydroxy-5-isoquinolinesulfonamide (36) N-(3-guanidino-2-methylpropyl)-1-hydroxy-5-isoquinolinesulfonamide (37) N-(4-guanidino-3-methylbutyl)
-1-hydroxy-5-isolinequinosulfonamide (38) 2-methyl-4-(1-hydroxy-5-
isoquinolinesulfonyl)piperazine (39) 2-ethyl-4-(1-hydroxy-5-
isoquinolinesulfonyl)piperazine (40) 2-isobutyl-4-(1-hydroxy-
5-isoquinolinesulfonyl)piperazine (41) 2,5-dimethyl-4-(1-hydroxy-5-isoquinolinesulfonyl)piperazine (42) 1-methyl-4-(1-hydroxy-5-
isoquinolinesulfonyl)piperazine (43) 1-amidino-4-(1-hydroxy-5
-isoquinolinesulfonyl)piperazine (44) 1-amidino-4-(1-hydroxy-5
-isoquinolinesulfonyl) homopiperazine (45) 1-amidino-3-methyl-4-(1-hydroxy-5-isoquinolinesulfonyl)piperazine (46) 1-amidino-2,5-dimethyl-4-
(1-Hydroxy-5-isoquinolinesulfonyl)piperazine (47) N-(2-methylaminoethyl)-1-chloro-5-isoquinolinesulfonamide (48) N-(2-ethylaminoethyl)-1-chlor -5-isoquinolinesulfonamide (49) N-(2-propylaminoethyl)-1-chloro-5-isoquinolinesulfonamide (50) N-(2-butylaminoethyl)-1-chloro-5-isoquinoline Sulfonic acid amide (51) N-(2-hexylaminoethyl)-1-chloro-5-isoquinolinesulfonic acid amide (52) 1-(1-chloro-5-isoquinolinesulfonyl)piperazine (53) 1-(1- Chlor-5-isoquinolinesulfonyl) homopiperazine (54) N-(2-methylaminoethyl)-1-hydroxy-5-isoquinolinesulfonamide (55) N-(2-ethylaminoethyl)-1-hydroxy-5 -isoquinolinesulfonic acid amide (56) N-(2-propylaminoethyl)-1-hydroxy-5-isoquinolinesulfonic acid amide (57) N-(2-butylaminoethyl)-1-hydroxy-5-isoquinolinesulfonic acid Amide (58) N-(2-hexylaminoethyl)-1-hydroxy-5-isoquinolinesulfonic acid amide (59) 1-(1-hydroxy-5-isoquinolinesulfonyl)piperazine (60) 1-(1-hydroxy- 5-isoquinolinesulfonyl) homopiperazine The present invention also provides an acid addition salt of the isoquinoline derivative represented by the general formula (). This salt is a pharmaceutically acceptable non-toxic salt,
Examples include 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, and methanesulfonic acid. Among the compounds represented by the general formula () of the present invention, those in which R ¹ is a chlorine element can be synthesized by the following method. (a) 1-chloro-5-isoquinolinesulfonic acid chloride, which is easily obtained from 1-chloro-5-isoquinolinesulfonic acid, has the general formula () (In the formula, R ² , R ³ , R ⁴ and A have the same meanings as above.) A compound represented by the following is reacted and synthesized. The compound represented by the general formula () is 1-chloro-5-
It is desirable to use 2.5 times to 5 times the molar amount of isoquinoline sulfonic acid chloride. Further, the reaction temperature is preferably -20°C to 50°C, and the reaction time is preferably 0.5 to 6 hours. As the reaction solvent, alkanols such as methanol and ethanol, halogenated hydrocarbons such as dichloromethane and chloroform, and ethers such as tetrahydrofuran, dioxane and diethyl ether can be used. Furthermore, mixtures of alkanols such as methanol and ethanol and water, and mixtures of ethers such as diethyl ether, tetrahydrofuran and dioxane and water can also be used. (b) 1-chloro-5-isoquinolinesulfonic acid chloride has the general formula () (In the formula, R ² , R ³ and A have the same meanings as above, and X represents a protecting group.) A compound represented by the general formula () is reacted. (In the formula, R ² , R ³ , A and X have the same meanings as above.) An intermediate represented by
is removed by a conventional method to obtain general formula (X) (In the formula, R ² , R ³ and A have the same meanings as above.) A compound represented by the following is synthesized. As the protecting group X, formyl group, acetyl group, benzoyl group, benzyloxycarbonyl group, t-butoxycarbonyl group, etc. can be used. When synthesizing the compound represented by the general formula (), it is preferable to use an acid acceptor, and examples of the acid acceptor include alkali metal compounds such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, and sodium hydroxide, pyridine, trimethylamine, Organic tertiary amines such as triethylamine can be used. The acid acceptor is preferably used in an amount of 1.0 to 3 times the molar amount of 1-chloro-5-isoquinolinesulfonic acid chloride. The amount of the compound represented by the general formula () to be used is preferably 1 to 2 times the amount of 1-chloro-5-isoquinolinesulfonic acid chloride.
Further, it is preferable to select the same conditions as in (a) for the reaction solvent, reaction temperature, and reaction time. Protecting group X from the compound represented by the general formula ()
Although the method for removing differs depending on the protecting group X, all of them are general known methods. That is, in the case of formyl group, acetyl group, benzoyl group, hydrolysis with acid or alkali, in the case of t-butoxycarbonyl group, hydrolysis with acid, and in the case of benzyloxycarbonyl group, hydrolysis with acid or hydrogenation. The protective group can be removed by reductive decomposition. (c) General formula (XI) is added to the compound represented by general formula (X). (In the formula, Y represents an oxygen atom or a sulfur atom, and Hz represents an acid residue.) By reacting the compound represented by the general formula (XII), (In the formula, R ² , R ³ and A have the same meanings as above.) A compound represented by the following is synthesized. As the compound represented by the general formula (XI), s
-Methyisothiourea sulfate, o-methylisourea hydrochloride, o-methylisourea sulfate, etc. can be used. As the reaction solvent, it is preferable to use alkanols such as methanol and ethanol, a mixture of a solvent such as acetonitrile and acetone, and water, or water alone. General formula (XI) for compounds of general formula ()
The amount of the compound to be used is preferably 1.5 to 4 times the molar amount. During the reaction, it is desirable to maintain the pH at 9 or higher.
The reaction temperature is preferably 50°C to 100°C, and the reaction time is preferably 1 to 4 hours. (d) 1-chloro-5-isoquinolinesulfonic acid chloride has the general formula () (In the formula, A and R ² represent the same meanings as above.) By reacting the compound represented by the general formula (XI)
Obtain the intermediate shown by (In the formula, R ² and A represent the same meanings as above.) After reacting this with para-toluenesulfonic acid chloride to obtain an intermediate represented by the general formula (), (In the formula, R ² and A represent the same meanings as above.) General formula () (In the formula, R ³ represents the same meaning as above, R ¹³
represents an alkyl group having 1 to 4 carbon atoms. ) by reacting the amine represented by the general formula ()
A compound represented by can be obtained. (In the formula, R ² , R ³ and A have the same meanings as above, and R ¹³ represents an alkyl group having 1 to 4 carbon atoms or a hydrogen atom.) 1-Chloro-5-isoquinolinesulfonic acid chloride and general The reaction with the compound of formula () is
The reaction can be carried out in the same manner as the reaction of 1-chloro-5-isoquinolinesulfonic acid chloride and the compound of general formula () shown in (b). General formula () from the intermediate of general formula (XI)
The reaction to obtain the intermediate is performed by LFFieser and MFFieser Regent Four Organic Synthesis
and M. Fieser, “Reagents for Organic
The method described in "Synthesis") Vol. 1180pp can be used. The reaction between the intermediate of general formula () and the amine of general formula () can be carried out using methanol, alkanols such as ethanol, methylene chloride,
Halogenated hydrocarbons such as chloroform, ethers such as diethyl ether, dioxane, and tetrahydrofuran can be used. The reaction temperature is preferably 0°C to 70°C, and the reaction time is 30 minutes to 1 day. (e) By treating the compound represented by general formula () synthesized by the methods of (a), (b), (c), and (d) with an aqueous solution of an inorganic acid, ) is obtained. (In the formula, R ² , R ³ , R ⁴ , and A have the same meanings as above.) As the inorganic acid, hydrochloric acid, sulfuric acid, and nitric acid can be used. The concentration of inorganic acid is 0.25 (mol/
) to 10 (mol/l) is preferred. The reaction time is preferably 50°C to 100°C, and preferably 2 hours to 6 hours. The effect of the compound of the present invention on smooth muscle was confirmed by the relaxing effect on the superior mesenteric artery of domestic rabbits. Also,
The antihypertensive effect was confirmed by oral administration to male spontaneously hypertensive rats and pessimistic measurement of tail artery pressure. (Example) Hereinafter, the present invention will be explained in more detail with reference to Examples. Example 1 145 g of 1-chloroisoquinoline was added dropwise to 500 g of 60% oleum under ice cooling, and the solution was heated to 80°C for 18
heated for an hour. The obtained solution was poured into 1 kg of ice water and stirred at 5°C for 2 hours. Filter the precipitated crystals, wash with 100 ml of methanol and 100 ml of ether,
After drying under reduced pressure, 126 g of 1-chloro-5-isoquinolinesulfonic acid 1/2 sulfate was obtained. 1-chloro-5-isoquinolinesulfonic acid 1/2
40 ml of thionyl chloride and 0.4 ml of dimethylformamide were added to 2.93 g of sulfate, and the mixture was heated under reflux for 2 hours.
Thionyl chloride and dimethylformamide were distilled off under reduced pressure, and 50 ml of water and 50 ml of methylene chloride were added to the residue to dissolve it. 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 to a methylene chloride solution (50 ml) containing 2.40 g of ethylenediamine over 5 minutes under ice cooling, and the mixture was stirred at room temperature for 2 hours. From the resulting solution, methylene chloride was distilled off under reduced pressure, and the residue was purified by silica gel chromatography [Wako Pure Chemical Industries, Ltd., Wako Gel C-200,
Elution solvent methanol/chloroform = 5/95 (volume ratio)], N-(2-aminoethyl)-1-chloro-
2.48 g of 5-isoquinolinesulfonamide (1) was obtained (yield 87%). NMR spectrum DCl, D ₂ O δ value 2.49-3.10ppm (4H) 7.30-7.89ppm (1H) 8.02-8.75ppm (4H) IR spectrum 3350, 1320, 1210, 1160 cm ^-1 Similarly, the compounds shown in Table 1 were Obtained.

[Table] Example 2 1-chloro-5-isoquinolinesulfonic acid 1/
40 ml of thionyl chloride and 0.4 ml of dimethylformamide were added to 2.93 g of disulfate, and the mixture was heated under reflux for 2 hours.
Thionyl chloride and dimethylformamide were distilled off under reduced pressure, and 50 ml of water was added to the residue to dissolve it. Sodium bicarbonate was added to the solution to bring the pH to 6.0, and the solution was extracted twice with 50 ml of methylene chloride. After drying the organic layer over anhydrous sodium sulfate, methylene chloride was distilled off under reduced pressure. 30 ml of tetrahydrofuran was added to the residue to dissolve it, and the resulting solution was kept at an internal temperature of 5°C.
The mixture was added dropwise to 30 ml of an aqueous solution of -amidino-3-methylpiperazine 1/2 sulfate (5.73 g) over 5 minutes. After stirring the resulting solution at room temperature for 1 hour, the solvent was distilled off under reduced pressure. 20 ml of 0.1N hydrochloric acid was added to the residue and stirred, and insoluble matter was filtered off. 1N sodium hydroxide was added to the solution to adjust the pH to 12.5, and the precipitate that had separated out was filtered. The obtained crystals were washed with 20 ml of water, 20 ml of methanol, and 20 ml of ether to obtain 3.00 g of 1-amidino-3-methyl-4-(1-chloro-5-isoquinolinesulfonyl)piperazine (yield: 85%). ). IR spectrum (KBr) 1690, 1650, 1240 cm ^-1 Compounds shown in Table 2 were obtained in the same manner.

[Table] Example 3 1-chloro-5-isoquinolinesulfonic acid 1/
50 ml of thionyl chloride and 0.5 ml of dimethylformamide were added to 5.86 g of disulfate, and the mixture was heated under reflux for 2 hours.
Thionyl chloride and dimethylformamide were distilled off under reduced pressure, and 50 ml of water was added to the residue to dissolve it. Sodium bicarbonate was added to the solution to bring the pH to 6.0, and the solution was extracted twice with 50 ml of methylene chloride. 1-benzyloxycarbonylamino- by cooling the methylene chloride layer with ice.
It was added dropwise over 5 minutes to a methylene chloride solution containing 7.31 g of 2-aminopropane and 3.03 g of triethylamine. After the dropwise addition, the mixture was stirred at room temperature for 1 hour, and extracted with 50 ml of water. The organic layer was washed twice with hydrochloric acid water at pH 3.0, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, 150 ml of methanol and 0.5 g of 5% palladium on carbon were added to the residue, and the mixture was stirred at room temperature under hydrogen gas pressure (40 psi) for 5 hours. After separating the palladium catalyst, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Wako Pure Chemical Industries, Ltd. Wakogel C-200, elution solvent 10v/v% methanol/chloroform) to obtain N-(2 4.86 g of -amino-1-propyl)-1-chloro-5-isoquinolinesulfonamide was obtained (yield: 81%). Compounds shown in Table 3 were obtained in the same manner.

[Table] Example 4 N-(2-amino-1-propyl)-1-chloro-5-isoquinolinesulfonamide 3.0 g, s-
4.17g of methylisothiourea 1/2 sulfate, 50g of water
ml and 1.2 g of sodium hydroxide were added, and the mixture was heated to 60° C. for 2 hours while stirring. The resulting solution was heated to 5°C.
When the precipitate formed is filtered and washed with water, N
3.25 g of -(2-guanidino-1-methylethyl)-1-chloro-5-isoquinolinesulfonamide was obtained (yield 95%). IR spectrum (KBr) 1690, 1640 cm ^-1 Compounds shown in Table 4 were obtained in the same manner.

[Table] Example 5 1-chloro-5-isoquinolinesulfonic acid 1/
50 ml of thionyl chloride and 0.5 ml of dimethylformamide were added to the disulfate (5.85 g), and the mixture was heated under reflux for 2 hours. Thionyl and dimethylformamide were distilled off under reduced pressure, and 50 ml of water was added to the residue, followed by addition of sodium bicarbonate to adjust the pH to 6.0. This solution was extracted twice with 50 ml of methylene chloride. The methylene chloride layer was added to a methylene chloride solution (50 ml) containing 1.84 g of ethanolamine and 3.03 g of triethylamine under ice cooling.
The mixture was added dropwise over a period of minutes, and the mixture was stirred and reacted at room temperature for 2 hours. The resulting solution was washed three times with 30 ml of water, the methylene chloride layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and N-(2-hydroxyethyl)-1-chloro-5-isoquinolinesulfonamide was obtained. 5.04g was obtained (yield 96%). N-(2-hydroxyethyl)-1-chloro-5
- 2.63 g of isoquinolinesulfonamide and 3.81 g of p-toluenesulfonic acid chloride were dissolved in 40 ml of pyridine, and the solution was left at 5° C. for 24 hours. Add the obtained liquid to 100g of ice water and add 100ml of methylene chloride.
Extracted twice. After drying the methylene chloride layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 4.32 g of N-(p-toluenesulfonyloxyethyl)-1-chloro-5-isoquinolinesulfonamide (yield: 98
%). N-(p-toluenesulfonyloxyethyl)-
1-chloro-5-isoquinoline sulfonamide 4
50 ml of methylene chloride and 1 ml of 40% methylamine methanol solution were added to the mixture, and the mixture was heated at 70° C. for 4 hours in a pressure vessel. The solvent was distilled off under reduced pressure, and silica gel chromatography (Wako Pure Chemical Industries, Ltd., C-200 gel,
N-(methylaminoethyl)-1-
Chlor-5-isoquinoline sulfonamide 2.15g
was obtained (yield 79%). Compounds shown in Table 5 were obtained in the same manner.

[Table] Example 6 6 (mol/) in 10 g of N-(2-aminoethyl)-1-chloro-5-isoquinolinesulfonamide
100 ml of aqueous hydrochloric acid solution was added and heated at 65°C for 6 hours.
Filter the precipitated crystals, wash twice with 30 ml of water,
After washing twice with ethanol (30 ml), N-(2
8.94 g of -aminoethyl)-1-hydroxy-5-isoquinolinesulfonamide monohydrochloride was obtained (yield: 84%). NMR spectrum (CD ₃ ) ₂ SO + CD ₃ OD 2.8-3.2 ppm 4H 7.2-8.8 ppm 5H IR spectrum KBr disk 1160, 1630, 1690, 3300 cm ^-1 Compounds shown in Table 6 were obtained in the same manner.

【table】

[Table] Example 7 Dissolve 1 g of N-(2-aminoethyl)-1-chloro-5-isoquinolinesulfonamide in 20 ml of methanol, add 1N HCl aqueous solution, and adjust the pH of the solution.
Adjusted to 6.0. The solvent was distilled off under reduced pressure, recrystallized from methanol, and N-(2-aminoethyl)-1-
0.843 g of chloro-5-isoquinolinesulfonamide monohydrochloride was obtained (yield 75%). Elemental analysis value C 41.21% H 4.10% N 13.09% S 9.4% Cl20.5% Monohydrochloride of the compound shown in Table 7 was obtained in the same manner.

【table】

[Table] Example 8 1-chloro-5-isoquinolinesulfonic acid 1/
To 5.85 g of 2H ₂ SO ₄ were added 50 ml of thionyl chloride and 0.5 ml of dimethylformamide, and the mixture was heated under reflux for 2 hours.
Thionyl chloride was distilled off under reduced pressure and dissolved in 50 ml of ice water and 100 ml of methylene chloride. Sodium bicarbonate was added until the aqueous layer reached pH 6, and the methylene chloride layer was separated. This methylene chloride layer was added dropwise over 20 minutes to a 100 ml methylene chloride solution containing 6.1 g of N-(2-aminoethyl)-Nt-butoxycarbonylhexylamine and 3.0 g of triethylamine under ice cooling. Stir at 15-20℃ for 1 hour, and add 50% water to the reaction solution.
Washed with ml. After drying over sodium sulfate, methylene chloride was distilled off under reduced pressure. 10 ml of trifluoroacetic acid was added to the residue under ice cooling, and the mixture was stirred at room temperature for 2 hours.
Add 30ml of ice water and adjust the pH with 5% caustic soda solution.
10 and extracted twice with 50 ml of methylene chloride. The methylene chloride solution was washed with water, dried over sodium sulfate, and then methylene chloride was distilled off under reduced pressure. Column chromatography of the residue (3% MeOH/chloroform) using silica gel (Wako Gel C-200, 100 g)
to give N-(2-hexylaminoethyl)-1
6.1 g of -chloro-5-isoquinolinesulfonic acid amide (51) was obtained (yield 81%). NMR spectrum DCl-D ₂ O δ value 0.6-2.0 11H 2.4-3.5 6H 7.5-8.0 1H 8.1-8.8 4H IR spectrum 3400, 1330, 1160 cm ^-1 The following compounds were obtained in the same manner. Compound No. Yield (%) 48 79 49 80 50 75 Example 9 6 to 4 g of N-(2-hexylaminoethyl)-1-chloro-5-isoquinolinesulfonic acid amide
(Mole/) It was added to 50 ml of hydrochloric acid water and heated at 65°C for 6 hours. After cooling for 2 hours, the precipitated crystals were collected and recrystallized from ethanol to give N-(2-
hexylaminoethyl)-1-hydroxy-5-
Isoquinoline sulfonamide (58) hydrochloride 3.1
g (yield 74%). NMR spectrum (CD ₃ ) ₂ SO + CD ₃ OD 0.5-2.0 11H 2.5-4.0 6H 7.5-8.0 1H 8.0-9.0 4H IR spectrum 1160, 1630, 1685, 3300 cm ^-1 Example 10 1-Chlor-5-isoquinolinesulfonic acid 1 /
50 ml of thionyl chloride and 0.5 ml of dimethylformamide were added to 5.85 g of disulfate, and the mixture was heated under reflux for 2 hours.
Thionyl chloride was distilled off under reduced pressure, and the residue was dissolved in 20 ml of ice water and 100 ml of methylene chloride. Sodium bicarbonate was added to adjust the pH of the aqueous layer to 6, and the methylene chloride layer was separated. Add this methylene chloride layer to piperazine 5.16
The mixture was added dropwise to a 100 ml solution of methylene chloride containing g over 20 minutes under ice cooling, and stirred at 15 to 20°C for 1 hour. The reaction solution was washed three times with 50 ml of water, dried over sodium sulfate, and methylene chloride was distilled off under reduced pressure. The residue was subjected to column chromatography (solvent 5% methanol/chloroform) on silica gel (Wako Gel C-200, 150 g) to obtain 1-(1-chloro-5-
Isoquinolinesulfonyl)piperazine (52) 5.5
g (yield 88%). NMR spectrum (DCl, D ₂ O) δ value 2.8-3.8 8H 7.5-8.0 1H 8.0-8.8 4H IR spectrum 3360, 1350, 1330, 1160, 1140 cm ^-1 Example 11 Homopiperazine instead of 5.16 g of piperazine
5.5 g of 1-(1-chloro-5-isoquinolinesulfonyl)homopiperazine (53) was obtained in exactly the same manner as in Example 10, except that 6.0 g was used (yield: 84
%). NMR spectrum (DCl, _D2O ) 1.7-2.3 2H 3.1-3.7 8H 7.2-7.7 1H 7.7-8.8 4H IR spectrum 3400, 1330, 1140 cm ^-1 Example 12 N-(2-aminoethyl)- 1
-Chlor-5-isoquinoline sulfonic acid amide 10
1-(1-Hydroxy-5-isoquinolinesulfonyl)homopiperazine (60) hydrochloric acid was prepared in the same manner as in Example 6, except that 9.7g of 1-(1-chloro-5-isoquinolinesulfonyl)homopiperazine was used instead of g. 6.9 g of salt was obtained (67% yield). NMR spectrum (DCl, D ₂ O) 1.5-2.2 2H 3.1-3.8 8H 7.2-7.7 1H 7.7-8.9 4H IR spectrum 3300, 1690, 1630, 1340, 1160 cm ^-1 Test example 1 Domestic rabbit (Japanese native species, body weight 3Kg) was exsanguinated to death.
The abdomen is opened and the superior mesenteric artery is removed. Cut the blood vessels into 2 mm x 25 mm spirals according to the standard method, and place them in 95% O ₂ :
Suspend in a 20ml organ bath filled with Krebs-Hensleit nutrient solution passed through a gas mixture of 5% _CO2 .
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, FD).
It is recorded as the load applied to the pickup (TB-912T). The hydrochloride of the compound of the present invention was added to a 15-20 mmol KCl aqueous solution under conditions of contraction of approximately 1/2 of the maximum contraction of KCl, and its relaxing effect was observed. The complete relaxation is taken as 100%, and the concentration that causes 50% relaxation (ED ₅₀ value) is shown in Table 8.

【table】

[Table] Test Example 2 The test solution was forcibly administered orally to male spontaneously hypertensive rats (SHR, Wistar Kyoto) weighing 300 to 350 g, and the tail artery pressure was measured non-invasively.
The test solution was prepared by dissolving it in distilled water so that the amount of solution to be administered was 1 ml per 100 g of body weight. Insoluble specimens were suspended in a 0.5% carboxymethylcellulose aqueous solution. Systolic pressure was measured using a non-invasive blood pressure measuring device after placing the rat in a heating box at 30-32°C for about 10 minutes. Immediately before and after drug administration, 1, 2, 4, 6
Blood pressure was measured after hours. The antihypertensive effect was evaluated by the difference (ΔP) from the pre-administration blood pressure. Table 9 shows the maximum value of blood pressure reduction (ΔP). Similarly, Table 10 shows comparative substances (△
P) was calculated. The results are shown in Table 10.

【table】

[Table] Comparative example

[Table] Test Example 3 ICR♂ was administered intravenously to mice, and acute toxicity values were determined. LD ₅₀ 8~160mg/Kg 31~135mg/Kg Comparative example

Claims (1)

[Claims] 1 General formula () (In the formula, A has 2 carbon atoms in which the hydrogen bonded to carbon may be substituted with an alkyl group having 1 to 6 carbon atoms)
to 6 alkylene groups, R ¹ is a hydroxyl group or a chlorine atom, R ² and R ³ are hydrogen atoms, a linear or branched alkyl group having 1 to 6 carbon atoms, or they are directly bonded to each other. Represents an ethylene group or propylene group in which the hydrogen atom bonded to carbon may be substituted with an alkyl group having 1 to 6 carbon atoms, and R ⁴ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an amidino group. . ) Substituted isoquinoline derivatives shown in 2. The compound according to claim 1, wherein R ¹ is a chlorine atom. 3. The compound according to claim 2, wherein R ² is a hydrogen atom. 4. The compound according to claim 3, wherein R ³ and R ⁴ are both hydrogen atoms. 5 A is an ethylene group or 1 hydrogen has 1 carbon number
5. The compound according to claim 4, which is an ethylene group substituted with 4 to 4 alkyl groups. 6 Claim 3 in which R ⁴ is an amidino group
Compounds described in Section. 7. Claim 6, wherein A is an alkylene group having 2 to 4 carbon atoms or 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. Compounds described. 8. The compound according to claim 3, wherein R ⁴ is an alkyl group having 1 to 6 carbon atoms. 9. The compound according to claim 8, wherein A is an ethylene group. 10 R ² and R ³ are ethylene groups directly bonded to each other or ethylene groups directly bonded to each other in which one hydrogen atom is substituted with an alkyl group having 1 to 4 carbon atoms, and A is an ethylene group or 1 hydrogen atom. 3. The compound according to claim 2, wherein the atom is an ethylene group substituted with a methyl group or a propylene group. 11. The compound according to claim 10, wherein R ⁴ is a hydrogen atom or an amidino group. 12. The compound according to claim 11, wherein R ² and R ³ are ethylene groups directly bonded to each other, and A is an ethylene group or a propylene group. 13. The compound according to claim 1, wherein R ¹ is a hydroxyl group. 14 Claim 1 in which R ² is a hydrogen atom
Compound according to item 3. 15. The compound according to claim 14, wherein R ³ and R ⁴ are both hydrogen atoms. 16. The compound according to claim 15, wherein 16A 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. 17. The compound according to claim 14, wherein R ⁴ is an amidino group. 18. Claim 17, wherein A is an alkylene group having 2 to 4 carbon atoms or 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. Compounds described. 19. The compound according to claim 14, wherein R ⁴ is an alkyl group having 1 to 6 carbon atoms. 20 Claim 1 in which A is an ethylene group
Compound according to item 9. 21 R ² and R ³ are an ethylene group or an ethylene group in which one hydrogen atom is substituted with an alkyl group having 1 to 4 carbon atoms, and A is an ethylene group or an ethylene group in which one hydrogen atom is substituted with a methyl group. 14. The compound according to claim 13, which is an ethylene group or a propylene group. 22. The compound according to claim 21, wherein R ⁴ is a hydrogen atom or an amidino group. 23 Claim 2 in which A is an ethylene group
Compound according to item 2.