JPH053851B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Field of Application) The present invention relates to a vasodilator and an agent for preventing and treating hypertension. (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 ₁ 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 ₂ ,
R ₃ 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 via an oxygen atom to form a heterocycle with the adjacent nitrogen atom, R ₄ is a hydrogen atom or has 1 carbon atom to 10 alkyl group, R ₅ represents an alkyl group, aryl group, or aralkyl group having 1 to 10 carbon atoms, and C represents m hydrogen atoms substituted with an alkyl group, aryl group, or aralkyl group having 1 to 10 carbon atoms; an alkylene group with n carbon atoms (n is a positive integer not exceeding 10, m is an integer of 0 to 2×n), R ₆ is a hydrogen atom, an alkyl group or aryl group with 1 to 10 carbon atoms, R ₇ , _R8 is a hydrogen atom, with 1 or more carbon atoms
Represents 10 alkyl groups, aryl groups, aralkyl groups, or groups bonded directly or through oxygen atoms to form a heterocycle with adjacent nitrogen atoms,
u and v represent integers from 0 to 9. ] (Structure of the invention) The present invention is based on the general formula () (In the formula, A is an ethylene group, and the hydrogen bonded to the carbon may be substituted with an alkyl group having 1 to 6 carbon atoms, a phenyl group, or a benzyl group. B is a trimethylene group, The hydrogen bonded to the carbon may be substituted with an alkyl group having 1 to 6 carbon atoms, a phenyl group, or a benzyl group.R represents a hydrogen atom) or an acid addition salt thereof. The present invention relates to a vasodilator and an antihypertensive agent as ingredients. Specific examples of the compounds represented by the general formula () of the present invention include the following compounds. (1) 1-(5-isoquinolinesulfonyl)homopiperazine(2) 1-(5-isoquinolinesulfonyl)-2-methylhomopiperazine(3) 1-(5-isoquinolinesulfonyl)-3-methylhomopiperazine(4) 1-(5-isoquinolinesulfonyl)-6-methylhomopiperazine (5) 1-(5-isoquinolinesulfonyl)-2,3
-dimethylhomopiperazine(6) 1-(5-isoquinolinesulfonyl)-3,3
-Dimethylhomopiperazine(7) 1-(5-isoquinolinesulfonyl)-3-ethylhomopiperazine(8) 1-(5-isoquinolinesulfonyl)-3-propylhomopiperazine(9) 1-(5-isoquinolinesulfonyl)- 3-isobutylhomopiperazine (10) 1-(5-isoquinolinesulfonyl)-3-phenylhomopiperazine (11) 1-(5-isoquinolinesulfonyl)-3-benzylhomopiperazine (12) 1-(5-isoquinolinesulfonyl) )-6-Ethylhomopiperazine (13) 1-(5-isoquinolinesulfonyl)-6-propylhomopiperazine (14) 1-(5-isoquinolinesulfonyl)-6-butylhomopiperazine (15) 1-(5-isoquinoline sulfonyl)-6-pentylhomopiperazine (16) 1-(5-isoquinolinesulfonyl)-6-hexylhomopiperazine (17) 1-(5-isoquinolinesulfonyl)-6-phenylhomopiperazine (18) 1- (5-isoquinolinesulfonyl)-6-benzylhomopiperazine The acid addition salt of the isoquinoline derivative represented by the general formula () is a pharmaceutically acceptable non-toxic salt, such as hydrochloric acid, hydrogen bromide, etc. Examples include salts with inorganic acids such as acid, phosphoric acid and sulfuric acid, and salts with organic acids such as acetic acid, citric acid, tartaric acid, lactic acid, succinic acid, fumaric acid, maleic acid and methanesulfonic acid. The compound represented by the general formula () used as an active ingredient in the present invention can be synthesized, for example, according to the following formula. (In the formula, A, B, and R represent the same meanings as above.) That is, 5-isoquinolinesulfonic acid chloride () easily obtained from 5-isoquinolinesulfonic acid and the homopiperazine derivative represented by the formula () are reacted. It can be obtained by Examples of homopiperazine derivatives () used in this reaction include homopiperazine, 2-
Methyl homopiperazine, 2-ethyl homopiperazine, 2-propyl homopiperazine, 2-butyl homopiperazine, 2-isobutyl homopiperazine,
2-phenylhomopiperazine, 2-benzylhomopiperazine, 5-methylhomopiperazine, 5-ethylhomopiperazine, 6-methylhomopiperazine, 6-ethylhomopiperazine, 6-propylhomopiperazine, 6-butylhomopiperazine, 6 −
Hexylhomopiperazine, 6-phenylhomopiperazine, 6-benzylhomopiperazine, 2,3-
Mention may be made of dimethylhomopiperazine, 2,2-dimethylhomopiperazine, and 5,7-dimethylhomopiperazine. An acid acceptor may be present in this reaction. Acid acceptors include alkali metal compounds such as sodium bicarbonate, sodium hydroxide, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydride, sodium methylate, and organic compounds such as pyridine, trimethylamine, triethylamine, and triethylenediamine. Examples include tertiary amines. As the reaction solvent, halogenated hydrocarbons such as dichloromethane and chloroform, ethers such as tetrahydrofuran and dioxane, acetonitrile, dimethylformamide, dimethylsulfoxide, etc. are used. The amount of the homopiperazine derivative () to be used relative to the acid chloride () is preferably 1 to 10 times the molar range when an acid acceptor is present, and more preferably 1 to 3 times the molar range when an acid acceptor is present. In this case, it is preferably 2 to 20 times the mole, particularly preferably 2 to 10 times the mole. If an acid acceptor is used, the amount used is determined by the formula ()
It is preferably in the range of 1 to 10 equivalents, particularly preferably 1 to 6 equivalents, relative to the homopiperazine derivative represented by. The reaction temperature is usually -30 to 150°C, preferably 0 to 120°C, particularly preferably 0 to 80°C. Furthermore, among the compounds represented by the general formula (),
A compound in which R is a hydrogen atom can be further synthesized, for example, according to the following formula. (In the formula, A and B represent the same meanings as above, and X represents a protecting group.) Examples of the protecting group X include a formyl group, an acetyl group, an acyl group such as a benzoyl group, a benzyloxycarbonyl group, Examples include allylmethyl groups such as t-butyloxycarbonyl groups, alkyloxycarbonyl groups, and benzyl groups. Examples of the compound represented by formula () include:
1-formyl-3-methylhomopiperazine, 1-
Acetyl-3-methylhomopiperazine, 1-benzyloxycarbonyl-3-methylhomopiperazine, 1-t-butoxycarbonyl-3-methylhomopiperazine, 1-benzyl-3-methylhomopiperazine, 1-benzyloxycarbonyl-3 −
Examples include ethylpiperazine and 1-benzyloxycarbonyl-3-propylpiperazine. The method for obtaining () from () and () can be carried out under the same reaction conditions as for () and () above. The method for obtaining the desired product () from () is selected depending on the protecting group X, but any method can be achieved by commonly known methods. For example, acyl groups such as formyl and acetyl groups are treated with acid or alkaline hydrolysis, benzyl groups are treated with hydrogenation, benzyloxycarbonyl groups are treated with hydrogenation or acid decomposed, and t-butyloxycarbonyl groups are treated with hydrogenation or acid decomposition. In some cases, the objective can be achieved by acid decomposition. To isolate and purify the target product from the reaction solution, for example, the aqueous layer extracted with dilute hydrochloric acid is made basic, extracted with a solvent such as chloroform, and the concentrated residue is recrystallized, or with a silica gel or alumina column. It can be purified by chromatography. The compound represented by the general formula () and its pharmaceutically acceptable acid addition salt provided by the present invention are:
It exhibits strong vascular smooth muscle relaxing effects, blood flow increasing effects, and blood pressure lowering effects, and is a useful substance as a vasodilator and a preventive/therapeutic agent for hypertension. The effect of the compound of the present invention on smooth muscle is due to the relaxing effect on the superior mesenteric artery in domestic rabbits, the vasodilatory effect is due to an increase in blood flow in the femoral artery and vertebral artery in dogs, and the antihypertensive effect is due to the effect on spontaneous hypertension in males. After oral administration to rats, confirmation was made by non-invasively measuring tail artery pressure. The vascular smooth muscle relaxing effect was confirmed by suspending the superior mesenteric artery isolated from a rabbit in a spiral shape, contracting it with potassium chloride, and relaxing it when the compound of the present invention was added thereto. For example, when 1-(5-isoquinolinesulfonyl)homopiperazine was added, the concentration (ED ₅₀ ) that caused 50% relaxation was 0.8 μM, assuming that complete relaxation was 100%. The dilation effect of the femoral artery and vertebral artery was confirmed by administering 35 mg/pentobarbital to dogs (mongrels, weight 8-15 kg).
Anesthetize by intra-arterial administration of Kg, non-invasive flow ropes (manufactured by Nihon Kohden) are attached to the femoral and vertebral arteries, and blood flow is measured with an electromagnetic blood flow meter (Nihon Kohden MF-27). Confirmed by. Under these conditions, the compound of the present invention, for example, 0.3 mg of 1-(5-isoquinolinesulfonyl)homopiperazine/
When Kg is administered intravenously, the femoral artery blood flow is 48
%, vertebral artery blood flow increased by 160%. Furthermore, the acute toxicity value LD ₅₀ when administered intravenously to ddY male mice was 73.5 mg/Kg. These test results are based on conventional techniques, e.g.
Compared to the compounds shown in parentheses, the pharmacological effects are stronger;
On the other hand, the toxicity was weak, indicating that the compound of the present invention is a highly useful compound as a circulatory organ drug. (Example) Compounds used as active ingredients in the present invention will be explained in detail with reference to Examples. Example 1 1200 ml of thionyl chloride and 0.4 ml of dimethylformamide were added to 150 g of 5-isoquinolinesulfonic acid,
The mixture was heated under reflux for 3 hours. Thionyl chloride and dimethylformamide were distilled off under reduced pressure, 300 ml of methylene chloride was added to the residue, stirred and filtered, and the obtained crystals were dried under reduced pressure to obtain 160 g of 5-isoquinolinesulfonic acid chloride hydrochloride. 5-isoquinolinesulfonic acid chloride hydrochloride
5.5 g was dissolved in 50 ml of ice water, brought to pH 6 with saturated sodium bicarbonate solution and extracted with 100 ml of methylene chloride. This methylene chloride solution was added dropwise to a solution of 50 ml of methylene chloride containing 5.0 g of homopiperazine over 20 minutes under ice cooling. After dropping, 15-20℃
The mixture was stirred for 2 hours. The reaction solution was washed with water and dried over magnesium sulfate. After distilling off methylene chloride under reduced pressure, the residue was converted into silica gel (Wakogel C-
200, 200g) to obtain 5.1g of 1-(5-isoquinolinesulfonyl)homopiperazine (1). Yield 84%. IR spectrum (cm ^-1 ): 3320, 1620, 1330, 1150 NMR spectrum ( _CD3OD -DCl): 2.1-2.7
(2H), 3.6~4.2 (8H), 7.6~7.9 (1H), 8.1~8.8
(4H), 9.3(1H) 1-(5-isoquinolinesulfonyl)-3-methylhomopiperazine (3), 1-(5-isoquinolinesulfonyl)-
6-methylhomopiperazine (4), 1-(5-isoquinolinesulfonyl)-2,3-dimethylhomopiperazine (5), 1-(5-isoquinolinesulfonyl)-3,3-dimethylhomopiperazine (6), 1
-(5-isoquinolinesulfonyl)-3-ethylhomopiperazine (7), 1-(5-isoquinolinesulfonyl)-3-isobutylhomopiperazine (9),
1-(5-isoquinolinesulfonyl)-3-phenylhomopiperazine (10), 1-(5-isoquinolinesulfonyl)-6-ethylhomopiperazine (12),
1-(5-isoquinolinesulfonyl)-6-propylhomopiperazine (13), 1-(5-isoquinolinesulfonyl)-6-hexylhomopiperazine (16), 1-(5-isoquinolinesulfonyl)-6-
Benzyl homopiperazine (18) was obtained. The results are shown in Tables 1 and 2.

【table】

[Table] Example 2 5-isoquinolinesulfonic acid chloride hydrochloride
5.5 g was dissolved in 50 ml of ice water, brought to pH 6 with saturated sodium bicarbonate solution and extracted with 100 ml of methylene chloride. This methylene chloride solution was added to 1-benzyloxycarbonyl-3-methylhomopiperazine.
It was added dropwise to a solution of 50 ml of methylene chloride containing 6.0 g of triethylamine and 3.5 g of triethylamine over 1 hour under ice cooling. After the dropwise addition, the mixture was stirred at 5 to 15°C for 12 hours. The reaction solution is washed with water and dried over magnesium sulfate.
Methylene chloride was distilled off under reduced pressure, and 30 ml of 25% hydrobromic acid-acetic acid was added to the residue, followed by stirring at 15 to 20°C for 5 hours. This reaction solution was poured into 100 ml of ice water, adjusted to pH 10 with 5N caustic soda solution, and extracted with chloroform. The chloroform was washed with water, dried over magnesium sulfate, and the chloroform was distilled off under reduced pressure. The residue was subjected to column chromatography (developing solvent: 3% methanol/chloroform) on silica gel (Wako Gel C-200, 200 g) to obtain 3.38 g of 1-(5-isoquinolinesulfonyl)-2-methylhomopiperazine (2). Ta. Yield 53%. Mass spectrum (m/e): 305 IR spectrum (cm ^-1 ): 3320, 1620, 1330, 1150 NMR spectrum (CD ₃ OD-DCl): 1.0 to 1.2
(3H), 2.0~2.8 (2H), 3.6~4.2 (7H), 7.6~7.9
(1H), 8.1-8.8 (4H), 9.3 (1H) Example 3 5 g of 1-(5-isoquinolinesulfonyl) homopiperazine was dissolved in 40 ml of methanol, and 1N-hydrochloric acid was added to adjust the pH of the solution to 6.0. . The solvent was distilled off under reduced pressure, and the residue was recrystallized from methanol and ether to obtain 1-(5-isoquinolinesulfonyl)homopiperazine monohydrochloride. Melting point 219-221°C (decomposition). Elemental analysis values: C; 51.50%, H; 5.88%, N;
12.90% Monohydrochloride salts of the compounds shown in Table 3 were obtained in the same manner.

[Table] Test Example 1 After exsanguinating a domestic rabbit (Japanese native species, weighing approximately 3 kg), the abdomen is opened and the superior mesenteric artery is removed. Cut the blood vessel spirally into 2 mm x 25 mm according to the standard method, and cut the blood vessel into 95%
Suspend in a 20 ml organ bath filled with Krebs-Hensleit nutrient solution passed through a gas mixture of O ₂ :5% CO ₂ . When one side of the blood vessel is connected to an isometric transducer and a load of 1.5 g is applied, the contraction and relaxation reactions of the blood vessel are detected by the transducer (Nihon Kohden).
It is recorded as the load applied to the FD pickup (TB-912T). The hydrochloride of the compound of the present invention was added to a 15 to 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 4.

[Table] Test Example 2 The test solution was forcibly administered orally to male spontaneously hypertensive rats (SHR, Wister 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. To measure the systolic pressure, place the rat in a heating box at 30-32°C for approximately 10 minutes.
Measurements were made using a non-invasive blood pressure measuring device. Blood pressure was measured immediately before drug administration and 1, 2, 4, and 6 hours after administration. The antihypertensive effect is determined by the difference (△
P, mmHg). Table 5 shows blood pressure drop (△P)
showed the maximum value. Also, regarding comparative substances, △
The maximum value of P was determined and shown in Table 6.

[Table] Comparative example

【table】

[Table] Test Example 3 Effect on femoral artery and vertebral artery blood flow in dogs An experiment was conducted according to the method described in the text. The results are shown in Table 7.

[Table] Test Example 4 ICR♂ was administered intravenously to mice, and acute toxicity values were determined. The results are shown in Table 8.

【table】

【table】

Claims (1)

[Claims] 1 General formula () (In the formula, A is an ethylene group, and the hydrogen bonded to the carbon may be substituted with an alkyl group having 1 to 6 carbon atoms, a phenyl group, or a benzyl group. B is a trimethylene group, The hydrogen bonded to the carbon may be substituted with an alkyl group having 1 to 6 carbon atoms, a phenyl group, or a benzyl group.R represents a hydrogen atom) or an acid addition salt thereof. Vasodilator as an ingredient.