JPH0780854B2 - Isoquinoline sulfonic acid amide compound - Google Patents

Description

Detailed Description of the Invention

[0001]

The present invention relates to the following general formula (1) useful as a therapeutic drug for cardiovascular diseases.

[Chemical 2] [In the formula, A is an ethylene group in which m hydrogen atoms (m is an integer of 0 to 4) are substituted with an alkyl group having 1 to 6 carbon atoms, and B is n (n is an integer of 0 to 4). An ethylene group or a trimethylene group in which a hydrogen atom is substituted with an alkyl group having 1 to 6 carbon atoms, R ¹ and R ² are hydrogen atoms or an alkyl group having 1 to 6 carbon atoms, or are directly bonded to each other and have a carbon number of It represents 2 to 4 polymethylene groups. ] The following general formula which provides the amidine derivative and its acid addition salt

[Chemical 3] (In the formula, A and B have the same meanings as described above.) The present invention relates to an isoquinolinesulfonic acid amide compound and an acid addition salt thereof.

In the general formula (1), examples of the alkyl group substituting the hydrogen atoms of A and B include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and an n group.
Examples include -butyl group and sec-butyl group. R ¹ ,
Examples of R ² include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an n-hexyl group and the like. Examples of the case where R ¹ and R ² are directly bonded to each other include an ethylene group and a trimethylene group. Examples of the specific compound represented by the general formula (1) which is useful as a therapeutic agent for cardiovascular disease include the following compounds.

(1) 4-amidino-1- (5-isoquinolinesulfonyl) piperazine (2) 4-amidino-1- (5-isoquinolinesulfonyl) -2-methylpiperazine (3) 4-amidino-2,2- Dimethyl-1- (5-isoquinolinesulfonyl) piperazine (4) 4-Amidino-2,5-dimethyl-1- (5-isoquinolinesulfonyl) piperazine (5) 4-Amidino-2-ethyl-1- (5-isoquinoline Sulfonyl) piperazine (6) 4-amidino-1- (5-isoquinolinesulfonyl) homopiperazine (7) 4-amidino-2,3-dimethyl-1- (5-isoquinolinesulfonyl) piperazine (8) 4- (N ¹ , N ² -Dimethylamidino) -1-
(5-Isoquinolinesulfonyl) piperazine (9) 1- (5-isoquinolinesulfonyl) -4- (N
¹ - Mechiruamijino) piperazine (10) 4- (N ¹ - Echiruamijino) -1- (5-isoquinolinesulfonyl) piperazine (11) 4- (2-imidazolin-2-yl) -1-
(5-Isoquinolinesulfonyl) piperazine (12) 1- (5-isoquinolinesulfonyl) -4-
[2- (3,4,5,6-tetrahydropyrimidyl)]
Piperazine ^{(13) 4- (N 1,} N 2 - dimethyl-amidinophenyl) -1-
(5-Isoquinolinesulfonyl) homopiperazine (14) 4-amidino-1- (5-isoquinolinesulfonyl) -3-methylpiperazine (15) 4-amidino-3,3-dimethyl-1- (5-
Isoquinolinesulfonyl) piperazine (16) 4-amidino-3-butyl-1- (5-isoquinolinesulfonyl) piperazine

The acid addition salt of the amidine derivative represented by the general formula (1) in the present invention is a pharmaceutically acceptable non-toxic salt, and the acid is, for example, hydrochloric acid, Examples thereof include inorganic acids such as 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.

[0005]

2. Description of the Related Art Up to now, a synthetic method for producing a compound similar to the isoquinolinesulfonic acid amide compound of the present invention has been known (for example, JP-A-57-154643). However, a method for specifically producing the isoquinolinesulfonic acid amide compound of the present invention is not known.

[0006]

The present invention provides an intermediate which is necessary and important for synthesizing an amidine derivative represented by the general formula (1) which is useful as a therapeutic agent for cardiovascular disease. The purpose is to do.

[0007]

The isoquinoline sulfonic acid amide compound of the present invention is an intermediate for synthesizing an amidine derivative represented by the general formula (1). The amidine derivative represented by the general formula (1) is For example, it can be synthesized according to the following formula.

[Chemical 4] (In the formula, A, B, R ¹ and R ² have the same meanings as described above.)

The compound represented by the formula (3) can be easily synthesized according to the following chemical formula 5.

[Chemical 5] (In the formula, A, B, R ¹ and R ² have the same meanings as described above, X represents an oxygen atom or a sulfur atom, and R ³ represents an alkyl group.)

Examples of the compound represented by the formula (5) include:
S-methylisothiourea, O-methylisourea, S-ethylisothiourea, O-ethylisourea, N, N ', S
-Trimethylisothiourea, N, N ', O-trimethylisourea, N, S-dimethylisothiourea, N, O-dimethylisourea, N-ethyl-S-methylisothiourea, N-ethyl-O-methylisourea , 2-methylthio-2-imidazoline, 2-methoxy-2-imidazoline, 2-methylthio-3,4,5,6-tetrahydropyrimidine and the like hydroiodates, hydrobromides, hydrochlorides,
Sulfuric acid, p-toluene sulfonate, etc. can be mentioned.

Examples of the compound represented by the formula (4) include:
Piperazine, 2,5-dimethylpiperazine, 2,3-dimethylpiperazine, 2-methylpiperazine, 2-ethylpiperazine, homopiperazine, 2-butylpiperazine,
2,2-Dimethylpiperazine, 2-methylhomopiperazine, 5-methylhomopiperazine, 6-ethylhomopiperazine and the like can be mentioned. As the solvent in the reaction of the compound of the formula (4) and the compound of the formula (5), alcohols such as methanol and ethanol alone or a mixture thereof with water, or a mixture of ethers such as tetrahydrofuran or dioxane and water is preferable. The water content rate (volume ratio) of alcohols, ethers and water is 30 to 30%.
100% is particularly preferred. The amount of the compound of the formula (4) used with respect to the compound of the formula (5) is preferably 1 to 10 times, and particularly preferably 3 to 6 times. The reaction temperature in the reaction between the compound of formula (4) and the compound of formula (5) is 20 to 1
00 ° C is preferred. The reaction time is preferably 0.5 to 24 hours, particularly preferably 1 to 4 hours.

Examples of the compound represented by the formula (3) obtained by reacting the compound of the formula (4) with the compound of the formula (5) are, for example, 1-amidinopiperazine, 1-amidinohomopiperazine and 1-amidino-3-. Methylpiperazine, 1-amidino-2,5-dimethylpiperazine, 1-amidino-
2,2-dimethylpiperazine, 1-amidino-2,3-
Dimethylpiperazine, 1-amidino-3,5-dimethylpiperazine, 1-amidino-3-methylhomopiperazine, 1-amidino-3-ethylpiperazine, 1-
(N ^1, N ² - dimethyl-amidinophenyl) piperazine, 1-
(N ¹ -methylamidino) piperazine, 1- (N ¹ -ethylamidino) piperazine, 1- (N ¹ , N ² -dimethylamidino) homopiperazine, 1- (2-imidazolin-2-yl) piperazine, 1- [2- (3,4,5,6
-Tetrahydropyrimidine)] piperazine and the like.

An acid acceptor may be used in the reaction for obtaining the compound of formula (1) from the compound of formula (2) and the compound of formula (3). As the acid acceptor, sodium hydrogen carbonate,
Examples thereof include sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, pyridine, trimethylamine, triethylamine and triethylenediamine. When an acid acceptor is used, the amount used is preferably 1 to 10 times, and particularly preferably 1 to 2 times the molar amount of the compound of the formula (2). In the reaction of the compound of formula (2) with the compound of formula (3), the amount of the compound of formula (3) used with respect to the compound of formula (2) is preferably 1 to 5 times the molar amount when an acid acceptor is used. In particular, a 1- to 3-fold molar amount is preferable. When an acid acceptor is not used in the reaction, a molar amount of 2 to 10 times is preferable,
A 2-5 fold molar amount is particularly preferred.

The reaction solvent in the reaction between the compound of formula (2) and the compound of formula (3) is, for example, ethers such as diethyl ether, tetrahydrofuran, dioxane,
Alcohols such as methanol and ethanol, acetonitrile, dimethylformamide, dimethylsulfoxide, and the like, and mixtures of these with water are used. The reaction temperature of the reaction between the compound of formula (2) and the compound of formula (3) is usually preferably -30 ° C to 120 ° C, but 0 ° C to 80 ° C.
C is especially preferred. The reaction time is preferably 0.5 to 48 hours, particularly preferably 1 to 4 hours. An intermediate providing an amidine derivative represented by the general formula (1), which is a useful compound in the present invention, can be easily obtained by the following method, and the intermediate stabilizes the amidine derivative represented by the general formula (1). It has been found to be something that can be provided in a simple way.

The isoquinoline sulfonic acid amide compound provided by the present invention can be synthesized by the following chemical formula 6.

[Chemical 6]

Further, this intermediate can provide a target compound represented by the general formula (1) which is useful according to the following chemical formula 7.

[Chemical 7] (In the formula, A, B, X, R ¹ , R ² and R ³ have the same meanings as described above.)

The present invention has been completed based on the above findings, and has the following general formula (wherein A and B have the same meanings as described above).

[Chemical 8] Is an isoquinoline sulfonic acid amide compound and an acid addition salt thereof.

Formulas (4) and (5) in the above reaction formula
As the compound shown in, the same compound as that used in the above-mentioned synthetic method is used. However, equation (4)
When an asymmetric compound is used as the compound of 1, the obtained compound has a structure different from that of the compound produced by the above-mentioned method. For example, as expressed by the following chemical formula 9,

[Chemical 9]

When 2,2-dimethylpiperazine is used as the compound of formula (4) and S-methylisothiourea sulfate is used as the compound of formula (5), 4-amidino-2,2-dimethyl-1 is used in the above-mentioned method. This gives 4- (5-isoquinolinesulfonyl) piperazine, whereas 4-
Amidino-3,3-dimethyl-1- (5-isoquinolinesulfonyl) piperazine is obtained.

The following general formula

[Chemical 10] Examples of the isoquinolinesulfonic acid amide compound represented by the general formula (4), which is one of the starting materials, include piperazine, 2,5-dimethylpiperazine, 2,3-dimethylpiperazine, 2-methylpiperazine, and 2-ethyl. Piperazine, homopiperazine, 2-butylpiperazine, 2,
2-dimethylpiperazine, 2-methylhomopiperazine,
5-Methylhomopiperazine, 6-ethylhomopiperazine, etc. are mentioned as the compound condensed with General formula (2).
Specifically, 1- (5-isoquinolinesulfonyl) -3
-Butylpiperazine, 1- (5-isoquinolinesulfonyl) homopiperazine, 1- (5-isoquinolinesulfonyl) -3-methylhomopiperazine, 1- (5-isoquinolinesulfonyl) -5-methylhomopiperazine, 1-
(5-isoquinolinesulfonyl) -6-ethylhomopiperazine may be mentioned.

An acid acceptor may then be present in the reaction of the compound of formula (2) with the compound of formula (4) in obtaining the intermediate of the invention. Acid acceptors include sodium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, alkali metal compounds such as sodium methylate, organic tertiary amines such as pyridine, trimethylamine, triethylamine and triethylenediamine. The kind is mentioned. As a reaction solvent, alkanols such as methanol and ethanol, halogenated hydrocarbons such as dichloromethane, chloroform, ethers such as tetrahydrofuran, dioxane and diethyl ether, acetonitrile, dimethylformamide, dimethylsulfoxide and the like are used.

In the reaction of the compound of formula (2) with the compound of formula (4), the amount of the compound of formula (4) used with respect to the compound of formula (2) is 1 to 10 when an acid acceptor is used in the reaction.
The molar range is preferably 2 times, more preferably 1 to 3 times, and 2 to 20 when an acid acceptor is not used in the reaction.
A double mole is preferable, and a range of 2 to 10 moles is particularly preferable. When an acid acceptor is used, the amount of the acid acceptor used is preferably 1 to 10 times, and particularly preferably 1 to 6 times the molar amount of the sulfonic acid chloride represented by the formula (2). In the reaction between the compound of formula (2) and the compound of formula (4), the reaction temperature is usually -30 ° C to 150 ° C, and 0 ° C to 120 ° C.
C. is preferable, and the range of 0 to 80.degree. C. is particularly preferable. The reaction time is preferably 0.5 to 72 hours, particularly preferably 1 to 5 hours.

Further, the compound of the formula (5) and the formula (6) for providing a useful end product by using the intermediate of the present invention.
The reaction of the compound of 1) preferably uses an acid acceptor. Examples of the acid acceptor include alkali metal compounds such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate and sodium hydroxide, and organic tertiary amines such as pyridine, trimethylamine, triethylamine and triethylenediamine. In the reaction of the compound of the formula (5) and the compound of the formula (6), as the solvent, for example, water, alkanols such as methanol and ethanol alone, or a mixture thereof with water, ethers such as tetrahydrofuran and dioxane, and the like. A mixture of water is preferred. The mixing ratio of alkanols and ethers to water is preferably such that the water content (volume ratio) is 20 to 100%.

The amount of the acid acceptor used in the reaction between the compound of formula (5) and the compound of formula (6) is preferably 1 to 10 times by mole, and preferably 1 to 4 times by mole with respect to the compound of formula (5). Amounts are particularly preferred. Formula (6) for the compound of formula (5)
The compound is preferably used in an amount of 1 to 10 times,
A 4-fold molar amount is particularly preferred. In the reaction for obtaining the compound of formula (1) from the compound of formula (5) and the compound of formula (6), the reaction temperature is preferably 20 ° C to 150 ° C, and 50
C.-120.degree. C. is particularly preferred. The reaction time is 2 to 6
Time is preferred.

The intermediates provided by the present invention can provide an amidine derivative represented by the general formula (1) and a pharmaceutically acceptable acid addition salt thereof. According to the studies of the present inventors, The amidine derivative represented by the general formula (1) has a long-lasting strong smooth muscle relaxing action and a strong blood flow increasing action, and for example, a vasodilator, a cerebral circulation improving agent, a therapeutic agent for angina pectoris. , A substance useful as a prophylactic and therapeutic drug for cerebral cardiovascular thrombosis and hypertension. The action of the amidine derivative of the present invention on smooth muscle was confirmed by the relaxing action of the superior mesenteric artery of the rabbit, and the vasodilating action was confirmed by the increase of blood flow in the femoral artery and vertebral artery in dogs. The smooth muscle relaxing action was proved by suspending the superior mesenteric artery extracted from a rabbit in a spiral shape, contracting it with potassium chloride, and relaxing it by adding the compound of the present invention thereto.

For example, when 4-amidino-1- (5-isoquinolinesulfonyl) piperazine is added to the contracted artery, its complete relaxation is defined as 100%, and 50%.
The concentration (ED ₅₀ ) that relaxed was 0.5 μM. Dilation of the femoral and vertebral arteries can be achieved by
15 kg) and sodium pentobarbital 35 mg /
Anesthetized by intravenous administration of kg, a femoral artery and a vertebral artery were fitted with a non-invasive probe (manufactured by Nihon Kohden), and blood flow was measured by an electromagnetic blood flow meter (Nihon Kohden MF-27). . Under this condition, the compound of the present invention, for example, 4-amidino-1- (5-isoquinolinesulfonyl) piperazine, was transferred via a polyethylene tube inserted into the side chain of the femoral vein.
When administered intravenously at mg / kg, the femoral artery blood flow is 40
%, The vertebral artery blood flow increased by 105%, and the duration was 30 minutes or longer. In addition, as for the other compounds of the present invention, a similar increase in blood flow was observed as a result of the same experiment. At this time, no significant toxicity was observed.

[0026]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto. (Example 1) A chloroform solution (40 ml) of 2-butylpiperazine (12.5 g) was added to a chloroform solution (40 g) of 5-isoquinolinesulfonyl chloride (5.0 g).
(ml) was added dropwise under ice cooling in 10 minutes. 1 more under ice cooling
After reacting with stirring for an hour, the reaction solution was extracted with a 2N aqueous hydrochloric acid solution. The aqueous layer was adjusted to pH 1 with 10% aqueous sodium hydroxide solution.
It was set to 0 and extracted with chloroform (80 ml). The chloroform layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue is silica gel (Wako Gel C
-200) 150 g, separated by column chromatography using developing solvent 5% methanol / chloroform (volume ratio), 1- (5-isoquinolinesulfonyl)-
3-Butylpiperazine (6.59 g, 90%) was obtained. Elemental analysis value () Theoretical value C 61.22% (61.24%), H 6.98%
(6.95%), N 12.80% (12.60%),
S 9.72% (9.62%)

(Example 2) Homopiperazine (8.8 g)
A chloroform solution (40 ml) of 5-isoquinolinesulfonyl chloride (5.0 g) was added dropwise to the chloroform solution (40 ml) of 10 minutes under ice cooling. After stirring and reaction for 1 hour under ice cooling, the reaction solution was extracted with a 2N aqueous hydrochloric acid solution. The aqueous layer was adjusted to pH 10 with 10% aqueous sodium hydroxide solution and extracted with chloroform (80 ml).
The chloroform layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue is 150 g of silica gel (Wakogel C-200), developing solvent 5% methanol /
Separation by column chromatography using chloroform (volume ratio) gave 1- (5-isoquinolinesulfonyl) homopiperazine (6.01 g, 89%). Elemental analysis value () Theoretical value C 57.59% (57.71%), H 5.92%
(5.88%), N 14.29% (14.42%),
S 10.83% (11.00%)

Example 3 To a chloroform solution (40 ml) of 2-methylhomopiperazine (10.0 g) was added 5 parts.
A chloroform solution (40 ml) of isoquinoline sulfonyl chloride (5.0 g) was added dropwise over 10 minutes under ice cooling. After stirring and reaction for 1 hour under ice cooling, the reaction solution was extracted with a 2N aqueous hydrochloric acid solution. The aqueous layer was adjusted to pH 10 with a 10% aqueous sodium hydroxide solution, and chloroform (80 m
Extracted in l). The chloroform layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was separated by column chromatography using 150 g of silica gel (Wakogel C-200) and developing solvent 5% methanol / chloroform (volume ratio), and 1- (5-isoquinolinesulfonyl) -3-methylhomopiperazine (6.37 g, 95%). Elemental analysis value () Theoretical value C 58.91% (58.99%), H 6.37%
(6.27%), N 13.49% (13.76%),
S 10.71% (10.50%)

Example 4 To a chloroform solution (40 ml) of 5-methylhomopiperazine (10.0 g) was added 5 parts.
A chloroform solution (40 ml) of isoquinoline sulfonyl chloride (5.0 g) was added dropwise over 10 minutes under ice cooling. After stirring and reaction for 1 hour under ice cooling, the reaction solution was extracted with a 2N aqueous hydrochloric acid solution. The aqueous layer was adjusted to pH 10 with a 10% aqueous sodium hydroxide solution, and chloroform (80 m
Extracted in l). The chloroform layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was separated by column chromatography using 150 g of silica gel (Wakogel C-200) and developing solvent 5% methanol / chloroform (volume ratio), and 1- (5-isoquinolinesulfonyl) -5-methylhomopiperazine (6.10 g, 91%). Elemental analysis value () Theoretical value C 58.89% (58.99%), H 6.38%
(6.27%), N 13.59% (13.76%),
S 10.75% (10.50%)

Example 5 A chloroform solution (40 ml) of 6-ethylhomopiperazine (11.26 g) was added,
A chloroform solution (40 ml) of 5-isoquinolinesulfonyl chloride (5.0 g) was added dropwise over 10 minutes under ice cooling. After stirring and reaction for 1 hour under ice cooling, the reaction solution was extracted with a 2N aqueous hydrochloric acid solution. The aqueous layer was adjusted to pH 10 with a 10% aqueous sodium hydroxide solution, and chloroform (80 m
Extracted in l). The chloroform layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was separated by column chromatography using 150 g of silica gel (Wakogel C-200) and developing solvent 5% methanol / chloroform (volume ratio), and 1- (5-isoquinolinesulfonyl) -6-ethylhomopiperazine (6.38 g, 91%). Elemental analysis value () Theoretical value C 59.99% (60.16%), H 6.78%
(6.63%), N 13.09% (13.15%),
S 10.21% (10.04%)

Reference Example 1 1- (5-isoquinolinesulfonyl) -3-methylpiperazine (5 g), S-methylisothiourea sulfate (7.17 g), sodium hydroxide (3.5 g), and ethanol (30 ml). ), Water (5m
1) was added and the mixture was heated under reflux for 2 hours. The resulting solution was cooled to room temperature, the crystals were filtered and washed with water and ethanol. The obtained crystals are dissolved in 50 ml of 2N hydrochloric acid water,
Add 4N aqueous sodium hydroxide to adjust pH to 12,
The precipitated crystals were collected by filtration, washed with methanol (30 ml), and 4-amidino-1- (5-isoquinolinesulfonyl) -2-methylpiperazine (14) (3.20 g, 5
6%) was obtained. Mass spectrum m / e 333, 316, 291, 2
21 IR spectrum ν (cm ⁻¹ ) 3320, 1680,
1590, 1180 NMR spectrum D ₂ O, DCl (δ = ppm)
1.3 (3H), 2.5-3.6 (7H), 7.8-
8.3 (1H), 8.4 to 8.9 (4H), 9.8 (1
H)

Similarly, 4-amidino-3,3-dimethyl-1- (5-isoquinolinesulfonyl) piperazine (15) and 4-amidino-3-butyl-1- (5-isoquinolinesulfonyl) piperazine (16) were obtained. Obtained. The reaction formula is shown in Chemical formula 11, and the respective reaction conditions and analysis results are shown in Table 1.

[Chemical 11]

[0033]

[Table 1]

Reference Example 2 Synthesis Example of Compound of 1-Amidinopiperazine Hydrochloride 5 g of O-methylisourea hydrochloride was added to 100 cc of an aqueous solution of 15.6 g of piperazine, and the mixture was reacted with stirring at 80 ° C. for 2 hours. After the reaction, the obtained solution was dried under reduced pressure at room temperature. 40 ml of ethanol was added to the obtained crystals,
Excess piperazine was dissolved, the crystals were filtered and washed 3 times with 40 ml ethanol. The obtained crystals were recrystallized from water-ethanol (1: 2) to give 6.70 g of white crystals of 1-amidinopiperazine hydrochloride (A-1) (yield 9
0%) was obtained.

Similarly, 1-amidino-3-methylpiperazine hydrochloride (A-2), 1-amidino-3,3-dimethylpiperazine sulfate (A-3), 1-amidino-2,
5-Dimethylpiperazine sulfate (A-4), 1-amidino-3-ethylpiperazine sulfate (A-5), 1-amidinohomopiperazine sulfate (A-6), 1-amidino-
2,3-Dimethylpiperazine sulfate (A-7), 1-
(N, N'-Dimethylamidino) piperazine sulfate (A
-8), 1- (N-methylamidino) piperazine sulfate (A-9), 1- (N-ethylamidino) piperazine sulfate (A-10), 1- (2-imidazolin-2-yl) piperazine Hydrobromide (A-11), 1- [2-
(3,4,5,6-Tetrahydropyrimidyl)] piperazine hydroiodide (A-12) and 1- (N, N′-dimethylamidino) homopiperazine sulfate (A-13) were obtained. . The reaction formula is shown in Chemical formula 12, and the reaction condition results are shown in Table 2.
Table 4 shows the results of elemental analysis of the compounds of Table 3 and Chemical formula 13.

[0036]

[Chemical 12]

[0037]

[Table 2]

[0038]

[Table 3]

[0039]

[Chemical 13]

[0040]

[Table 4]

Reference Example 3 To a solution of 1-amidinopiperazine hydrochloride (5 g) in water (20 ml), a solution of 5-isoquinolinesulfonyl chloride (5.34 g) in tetrahydrofuran (20 ml) and 1N aqueous sodium hydroxide solution was added with ice. The mixture was added dropwise over 15 minutes while stirring under cooling. The dropping rate of the aqueous sodium hydroxide solution was adjusted so that the pH of the solution was maintained at 8.0 to 8.5. 1 more after dropping
The mixture was reacted with stirring under ice cooling for a time. To the resulting solution was added 2N hydrochloric acid to adjust the pH to 1, and the precipitated crystals were filtered. To the filtrate was added 5N aqueous sodium hydroxide solution to adjust the pH to 13
The precipitated crystals were collected by filtration. The obtained crystals are 2
It was dissolved in 50 ml of a normal hydrochloric acid aqueous solution, 2N sodium hydroxide aqueous solution was added to adjust the pH to 13, and the precipitated crystals were collected by filtration. The obtained crystals were washed with water (30 cc), methanol (30 ml), ethanol (30 ml), ether (30 ml), and 4-amidino-1- (5-isoquinolinesulfonyl) piperazine (1) (6.36 g,
85%).

Mass spectrum m / e 319, 30
2, 287, 221 IR spectrum ν (cm ⁻¹ ) 3320, 1675,
1590, 1170 NMR spectrum D ₂ O, DCl (δ = ppm)
2.6-3.7 (8H), 7.7-8.3 (1H),
8.4-8.9 (4H), 9.8 (1H) Similarly, 4-amidino-1- (5-isoquinolinesulfonyl) -2-methylpiperazine (2) was obtained. Yield 8
3%. Mass spectrum m / e 333, 316, 291, 2
21 IR spectrum ν (cm ⁻¹ ) 3330, 1670,
1590, 1170 NMR spectrum D ₂ O, DCl (δ = ppm)
1.3 (3H), 2.4 to 3.6 (7H), 7.8 to
8.2 (1H), 8.3 to 8.9 (4H), 9.8 (1
H)

Reference Example 4 5-isoquinolinesulfonyl chloride (1.78) was added to an aqueous solution (20 ml) of 1-amidino-2,5-dimethylpiperazine sulfate (4 g) under ice cooling.
An ether solution (5 ml) of g) was added dropwise. The solution was reacted with stirring for 2 hours under ice cooling. The obtained solution was treated in the same manner as in Reference Example 3 to obtain 4-amidino-2,5-dimethyl-1- (5-isoquinolinesulfonyl) piperazine (4). (2.04 g, 75%) Mass spectrum m / e 347, 330, 305, 2
21 IR spectrum ν (cm ⁻¹ ) 3330, 1680,
1590, 1170 NMR spectrum D ₂ O, DCl (δ = ppm)
0.8-1.4 (6H), 2.5-4.2 (6H),
7.8-8.3 (1H), 8.4-8.9 (4H),
9.8 (1H)

Reference Example 5 5-isoquinolinesulfonyl chloride (2.96 g) in tetrahydrofuran (2
0 ml) to 1-amidinohomopiperazine sulfate (A-
6) An aqueous solution (10 ml) of (4 g) and an aqueous solution (10 ml) of potassium carbonate (0.63 g) were added dropwise over 5 minutes under ice cooling. The solution was reacted with stirring at room temperature for 1 hour. The obtained solution was treated in the same manner as in Reference Example 4 to obtain 4-amidino-1- (5-isoquinolinesulfonyl) homopiperazine (6) (3.41 g, 79%). Mass spectrum m / e 333, 316, 291, 2
21 IR spectrum ν (cm ⁻¹ ) 3330, 1675,
1590, 1170 NMR spectrum D ₂ O, DCl (δ = ppm)
1.5-1.9 (2H), 2.6-3.7 (8H),
7.5-8.3 (1H), 8.4-8.9 (4H),
9.8 (1H) Reaction formula is changed to Chemical formula 14, and also (3) (7) (5) (8)
Table 5 shows the reaction conditions and analysis results of (9), (10), (13), (12) and (11).

[0045]

[Chemical 14]

[0046]

[Table 5]

Reference Example 6 2 g of 4-amidino-1- (5-isoquinolinesulfonyl) piperazine was suspended in methanol (10 ml), water (10 ml) and 1N hydrochloric acid aqueous solution 6.57 ml were added, and the mixture was heated to 40 ° C. Warm and dissolve. The solution was evaporated to dryness under reduced pressure and water: methanol (volume ratio 2:
Recrystallized with 1) and 4-amidino-1- (5-isoquinolinesulfonyl) piperazine monohydrochloride (1.98 g, 8
9%) was obtained. Elemental analysis value () Theoretical value C 47.30% (47.26%), H 5.00%
(5.099%), N 19.53% (19.68%)
%), S 9.18% (9.010%), Cl 10.
01% (9.963%) Similarly, monohydrochloride of each compound shown in Table 6 was obtained. The reaction formula is shown in Chemical formula 15.

[0048]

[Chemical 15]

[0049]

[Table 6]

(Experimental Example 1) Rabbit (Japanese native species, weight 3k)
After the lethal exsanguination of (g), the abdomen is opened and the superior mesenteric vein is excised.
According to a conventional method, the blood vessel is cut into a spiral shape of 2 mm × 25 mm, and the blood vessel is suspended in a 20 ml organ bath filled with a Krebs-Hensleit nutrient solution which has been passed through a mixed gas of 95% 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 reaction of the blood vessel is recorded as the load applied to the transducer (Nihon Kohden, FD pickup TB-912T).
The hydrochloric acid salt of the compound of the present invention was added under a contraction condition of about 1/2 amount of the maximum contraction of KCl in a 15 to 20 mmol KCl aqueous solution, and its relaxing action was observed. 100 for complete relaxation
%, And the concentration for 50% relaxation (ED ₅₀ value) is shown in Table 7.

[0051]

[Table 7]

Test Example 2 Effect on femoral artery and vertebral artery blood flow in dogs. A dog (male dog, body weight 8 to 15 kg) was anesthetized by intravenous administration of pentobarbetal sodium 35 mg / kg,
A non-invasive probe (manufactured by Nihon Kohden) was attached to the femoral artery and vertebral artery, and blood flow was measured with an electromagnetic blood flow meter (Nihon Kohden MF-27). Table 8 shows the results of intravenous administration of the following compound hydrochlorides under this condition through a polyethylene tube inserted into the femoral vein side chain.

[0053]

[Table 8]

[0054]

INDUSTRIAL APPLICABILITY According to the present invention, an isoquinoline sulfonic acid amide compound, which is an important intermediate and is necessary for synthesizing an amidine derivative useful as a therapeutic agent for cardiovascular diseases, can be simply and easily obtained. Can be stably provided.

Claims (1)

[Claims] 1. The following general formula: [In the formula, A is an ethylene group in which m hydrogen atoms (m is an integer of 0 to 4) are substituted with an alkyl group having 1 to 6 carbon atoms, and B is n (n is an integer of 0 to 4). It represents an ethylene group or trimethylene group in which a hydrogen atom is substituted with an alkyl group having 1 to 6 carbon atoms. ] The isoquinoline sulfonic acid amide compound shown by these, and its acid addition salt.