JPH0153245B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the general formula The present invention relates to a therapeutic agent for circulatory system diseases containing a compound represented by the formula (wherein R is a linear or branched alkyl group and n is an integer of 0 to 5) or an acid addition salt thereof as an active ingredient. The compound of the formula is a new compound that has not been described in any literature,
For example, it can be produced by the method described in Japanese Patent Publication No. 60-54317. The compound of the formula has antihypertensive effects, heart rate decreasing effects, blood flow increasing effects, myocardial oxygen consumption decreasing effects, vascular smooth muscle relaxing effects, adrenergic β- and α-blocking effects, diuretic effects, etc. It is useful for the treatment and prevention of heart disease, arrhythmia, brain, heart and peripheral circulation disorders, myocardial infarction, etc. Furthermore, this drug can be used to treat hyperthyroidism, intraocular hypertension, cardiac neuropathy, etc., and is also used as a diuretic. Compounds of formula are rapidly absorbed upon oral administration and their action is sustained. The compounds of formula can be used in free form or in the form of physiologically acceptable acid addition salts. Preferred examples of acids that form addition salts include hydrochloric acid, sulfuric acid, acetic acid, lactic acid, oxalic acid, maleic acid, and p-toluenesulfonic acid. The therapeutic agent for circulatory system diseases of the present invention may use the compound of the formula as it is, but it can be prepared into tablets by conventional methods using excipients, binders, solvents, emulsifiers, etc.
It is preferable to use it in the form of preparations such as sublingual tablets, capsules, powders, granules, suppositories, solutions, injections, and suspensions. Excipients include potato starch, wheat starch,
Starches such as corn starch and rice starch, sugars such as lactose, sucrose, glucose, mannitrate, and sorbitate, celluloses such as crystalline cellulose, calcium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose, calcium phosphate, calcium sulfate, Inorganic substances such as calcium carbonate and talc are used. As the binder, starch, gelatin, gum arabic, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc. are used. As the emulsifier, fatty acid monoglyceride, sorbitan fatty acid ester, polyhydric alcohol ester type nonionic surfactant such as sucrose and polyglycerin fatty acid ester, polyoxyethylene type nonionic surfactant, etc. are used. The dosage of the drug of the present invention varies depending on the patient's condition, but is usually 1 to 100 mg, preferably 5 to 50 mg per day. The acute toxicity LD50 of the compound of formula is 500-1000 mg/Kg for oral administration and intravenous administration for mice.
65-100mg/Kg, extremely low toxicity. Experimental examples regarding the effects of the compound of the formula on blood pressure, heart rate, etc. are shown below. The following drugs were used as test drugs. Compound a: 3,4-dihydro-8-[(2-hydroxy-3-isopropylamino)propoxy]-3-nitrato-2H-benzopyran Compound b: 3,4-dihydro-8-[(2-hydroxy-3 -isopropylamino)propoxy]-3-nitratomethyl-2H-benzopyran Comparative drug: Propranolol hydrochloride 〃: Trichloromethiazide Experimental Example 1 1) The test drug was tested using spontaneously hypertensive rats, renally hypertensive rats, and Dorca hypertensive rats. We investigated the effects of this on blood pressure and heart rate. Blood pressure was measured by an open method using a pressure transducer. Heart rate was measured by driving a tachometer based on pulse pressure. The test drug was suspended in a 0.5% carboxymethylcellulose solution and administered orally. The results are shown in Figures 1-3. 1st
The figure is a graph showing the effects of the test drug on blood pressure and heart rate in spontaneously hypertensive rats, Figure 2 in renally hypertensive rats, and Figure 3 in Dorca hypertensive rats. Curve a in Figures 1 to 3 is a compound
a3mg/Kg, b is the same compound 10mg/Kg, c is the compound b3mg/Kg, d is the same compound 10mg/Kg, e
is for each administration group of the comparative drug at 10 mg/Kg, and f is for the administration group of the same drug at 30 mg/Kg. From these results, it is known that the compound of the present invention exhibits its action rapidly upon oral administration and has a long duration of action. Also, unlike conventional antihypertensive drugs, there is no reflex increase in heart rate associated with a drop in blood pressure, so it is extremely safe. Furthermore, it differs from conventional β-blockers in that it lowers both systolic and diastolic blood pressures to the same extent. 2) Compound a was continuously orally administered to spontaneously hypertensive rats at doses of 3 and 10 mg/Kg for 4 weeks, and blood pressure and body weight were measured. Figure 4 shows the body weight and blood pressure on the start date of administration and every week. Curve a in the figure relates to a group administered with 3 mg/Kg of compound a, b relates to a group administered with 10 mg/Kg of the same compound, and dotted line c relates to a control group. Compounds every week after the start of continuous administration
Figure 5 shows blood pressure at 3 and 8 hours after administration of 10 mg/Kg. Curve a in the figure relates to the drug administration group, and dotted line b relates to the control group. From this result, it is known that even if the compound of the present invention is administered for a long period of time, the blood pressure lowering effect is maintained and the progression of hypertension is suppressed. Furthermore, since it does not show any effect on body weight gain, it is considered safe for long-term administration. Experimental Example 2 Using 5 rats per group, 5 rats were administered after oral administration of the drug.
Urine volume and electrolyte (sodium, potassium) excretion were measured over time by the water jug method. The test drug was suspended in a 0.5% carboxymethylcellulose solution and administered orally. The results are shown in Table 1. Values are mean ± standard deviation. [Table] From these results, it is known that the compound of the present invention has significant diuretic and electrolyte excretion effects. Experimental Example 3 Using an adult dog anesthetized by intravenous administration of 30 mg/Kg of pentobarbital, the effects of compounds a and b were investigated on the following measurement items under artificial respiration. The test drug is dissolved in 0.1N hydrochloric acid, 1 to 300μ
It was administered at the rate of g/Kg. 1) Systemic blood pressure (MBP): Measured by inserting a catheter into the femoral artery and connecting it to a pressure transducer. 2) Heart rate (HR): Measured by driving a tachometer using blood pressure pulse waves. 3) Cardiac output (CO): Measured by attaching an electromagnetic blood flow meter probe to the aortic root. 4) Left ventricular end-diastolic pressure (LVEDP): Measured by introducing a catheter tip transducer into the left ventricle. 5) Coronary blood flow: Measured by attaching an electromagnetic blood flow meter probe to the left circumflex artery. 6) Common carotid artery blood flow: Measured by attaching an electromagnetic blood flow meter probe to the common carotid artery. 7) Renal blood flow: Measured by attaching an electromagnetic blood flow meter probe to the left renal artery. 8) Hind limb arterial blood flow: Measured by attaching an electromagnetic blood flow meter probe to the femoral artery. The measurement results of Nos. 1 to 4 are shown in FIGS. 6 to 9. Figure 6 shows the results of intravenous administration of compound a and Figure 7 shows the cardiac output (CO), systemic blood pressure (MBP), and systemic vascular resistance (TVR=MBP/
2 is a graph showing CO) and heart rate (HR).
Individual lines indicate changes over time for each animal; three dogs were used in Figure 6 and two dogs were used in Figure 7. The test drug was administered in a predetermined amount at approximately 15 minute intervals. Figure 8 shows the left ventricular end-diastolic pressure (LVEDP), systemic blood pressure (MBP), and left ventricular peak systolic velocity (LV dP/dt) in anesthetized dogs when compound a and compound b were administered intravenously, respectively. ) and heart rate (HR). The compound of the present invention can be used in a low amount (3 to 30 μg/
Kg), it showed a sustained hypotensive effect, and at high doses, it showed a transient and significant hypotensive effect, followed by a sustained hypotensive effect. For heart rate, 1-3μ
g/Kg, and showed a decreasing effect on cardiac output at low doses, and a decreasing effect after a transient increase at high doses. Systemic vascular resistance showed a transient decrease at 10 to 30 μg/Kg. It showed a lowering effect on left ventricular end-diastolic pressure at high doses, and a decreasing effect on left ventricular peak systolic velocity starting from low doses. The measurement results for samples 5 to 8 are shown in Table 2. [Table] After the coronary blood flow showed a transient increase after administration,
There was a sustained decline. This transient increasing effect is thought to be due to the vasodilatory effect of the compound of the present invention, and the subsequent decrease is thought to be due to a decrease in cardiac work accompanying a decrease in heart rate. This is also evident from the continuous decrease in coronary vascular resistance.
Therefore, the compound of the present invention has a pharmacological action different from that of conventional β-blockers in that it has an action of reducing coronary vascular resistance. The common carotid artery, hindlimb artery, and renal artery blood flow also show changes similar to the coronary blood flow. These transient increasing effects are also due to vasodilatory effects, and the subsequent decrease is thought to be due to a decrease in cardiac output, since vascular resistance remains unchanged or decreases. The fact that the vascular resistance remains unchanged or decreases is clearly different from the tendency for the vascular resistance to increase after administration of conventional β-blockers. Experimental Example 4 Compounds a and b against various isolated smooth muscles
The effect of this was investigated using the Magnus method. The test drugs were diluted to 10 ^-9 to 4 x 10 ^-4 molar concentrations before use. 1) Extracted atrial specimen: Using left and right atrial muscles of Guinea piglet, the contractile force and rhythm rate were recorded, and the antagonistic effect on isoproterenol was investigated. 2) Extracted bronchus specimen: Antagonistic effect on isoproterenol was investigated using Guinea pig bronchus. 3) Extracted coronary vessel specimen: The effect on potassium contracture was investigated using a canine left circumflex artery strip. 4) Extracted portal vein specimen: The effect on potassium contracture was investigated using a dog portal vein strip. 5) Extracted saphenous vein specimen: Using canine saphenous vein strips, the effect on potassium contracture was investigated. 6) Extracted mesenteric artery specimen: Canine mesenteric artery strips were used to examine (a) potassium contracture and (b) antagonism to norepinephrine. The results are shown in Table 3. The numbers in the table are the inverse logarithm of the molar concentration, pA ₂ is the molar concentration of the test drug required to shift the dose-response curve of isoproterenol, etc. to the higher dose side by 2 times, and pD′ ₂ is the It shows the molar concentration of the test drug required to suppress the maximum reaction by 50% (see Pharmaceutical Development Course Vol. 5, Pharmaceutical Efficacy Evaluation, pp. 741-773, published by Chijin Shoin). [Table] From these results, it is known that the compound a of the present invention has strong β- and α-blocking effects. Examples of manufacturing the effective substances used in the present invention are shown below. Production example 1 3,4-dihydro-8-[(2-hydroxy-3-isopropylamino)propoxy]-3
-Nitratomethyl-2H-1-benzopyran 3,4-dihydro-8-hydroxy-3-hydroxymethyl-2H-1-benzopyran 23.95
g was dissolved in 270 ml of tetrahydrofuran, 14.8 g of triethylamine was added thereto, a solution of 15.9 g of ethyl chlorocarbonate in 135 ml of tetrahydrofuran was added dropwise over 1.5 hours while stirring under ice cooling, and the mixture was stirred at 2°C for 1.5 hours. After the reaction is complete, insoluble materials are removed, and the mother liquor is distilled off under reduced pressure. 500 ml of ethyl acetate is added to the resulting residue and dissolved. Wash sequentially with 2N-hydrochloric acid and saturated saline,
After drying and distilling off the solvent, 33.6 g of 3,4-dihydro-8-ethoxycarbonyloxy-3-hydroxymethyl-2H-1-benzopyran was obtained.
(100% yield) is obtained. Next, dissolve this in 520ml of acetonitrile,
22.47 g of fuming nitric acid and 35.76 g of acetic anhydride under stirring while cooling.
A solution of g in 75 ml of acetonitrile was divided into three parts.
Add dropwise at 10 minute intervals and stir for an additional 10 minutes. After the reaction is complete, add sodium bicarbonate solution to adjust the pH to 7.0, and add ethyl acetate to 500 ml of ethyl acetate.
Extract in ml. After washing this extract with saturated saline and distilling off the solvent, 3,4-dihydro-
8-ethoxycarbonyloxy-3-nitratomethyl-2H-1-benzopyran 39.7g (yield 100
%) is obtained. NMR value: δ( _CDCl3 ) 3.90 _~ 4.63(6H, m, _-CH2ONO2 , -COOC
H ₂ CH ₃ , [Formula]) 6.87-7.10 (3H, m, aromatic ring H) IR value: ν liquid film cm ^-1 1770 (C=O) 1630 (-NO ₂ ) Obtained 3,4-dihydro -8-Ethoxycarbonyloxy-3-nitratomethyl-2H-1-
Dissolve 39.7g of benzopyran in 280ml of methanol,
Add 160 ml of 1N sodium hydroxide solution and stir at room temperature for 20 minutes. After the reaction is complete, add 2N-hydrochloric acid.
The pH was adjusted to 5.0, the solvent was distilled off under reduced pressure, and 500 ml of ethyl acetate was added to the resulting residue for extraction. After washing with saturated brine and drying, the solvent was distilled off under reduced pressure to obtain 27.6 g of a dark brown viscous oil. This oily substance is purified using silica gel column chromatography to obtain 18.1 g (yield 60.3%) of 3,4-dihydro-8-hydroxy-3-nitratomethyl-2H-1-benzopyran. Dissolve this compound in 240 ml of dioxane and
Add 80.15 ml of sodium hydroxide solution and 32.2 ml of epichlorohydrin, and react at 50°C for 2 hours.
After the reaction is completed, 500 ml of chloroform is added, washed with saturated brine, dried, and the solvent is distilled off under reduced pressure to obtain 22.5 g of a brown viscous oil. When this oil was purified using silica gel column chromatography, 3,4-dihydro-8-[(2,
3-epoxy)propoxy]-3-nitratomethyl-2H-1-benzopyran 16.35g (yield 72.5%)
is obtained. NMR value: δ (CDCl ₃ ) 2.28 ~ 3.10 (5H, m, [formula] [formula]) 3.25 ~ 3.57 (1H, m, [formula]) 3.92 ~ 4.38 (4H, m, [formula] [formula]) 4.52 (2H, d, J=6Hz, -C H ₂ ONO ₂ ) 6.63-6.95 (3H, m, aromatic ring H) Obtained 3,4-dihydro-8-[(2,3-
epoxy)propoxy]-3-nitratomethyl-
2H-1-benzopyran 11.35g ethanol 570g
ml, add 144 ml of isopropylamine, and react for 30 minutes under reflux and stirring. After the reaction is completed, the solvent is distilled off under reduced pressure to obtain 15.0 g of a pale brown viscous oil. When this oil is purified using alumina column chromatography, 3,4-dihydro-8-[(2
8.55 g (yield: 62.3%) of -hydroxy-3-isopropylamino)propoxy]-3-nitratomethyl-2H-1-benzopyran is obtained. Elemental analysis value: C ₁₆ H ₂₄ N ₂ O ₆ Calculated value (%) 56.46 7.11 8.23 Experimental value (%) 56.76 7.36 8.17 NMR value: δ (CDCl ₃ ) 1.08 (6H, d, J = 6Hz, [Formula] 4.50 (2H, d, J=6Hz, -C H ₂ ONO ₂ ) 6.62-6.93 (3H, m, aromatic ring H) IR value: ν KBrcm ^-1 1620, 1270 (NO ₂ ) Colorless maleate Needle crystal melting point: 114-116℃ Production example 2 3,4-dihydro-8-[(2-hydroxy-3-isopropylamino)propoxy]-3
-Nitrato-2H-1-benzopyran 3,4-dihydro-3,8-dihydroxy-
23.05 g of 2H-1-benzopyran is dissolved in 320 ml of tetrahydrofuran, 16.7 g of triethylamine is added, and a solution of 17.9 g of ethyl chlorocarbonate in 100 ml of tetrahydrofuran is added dropwise while stirring while cooling. Following the same treatment as in Production Example 1, 33.1 g of 3,4-dihydro-8-ethoxycarbonyloxy-3-hydroxy-2H-1-benzopyran (yield 100
%) is obtained. 34.0 g of the obtained compound in 600 ml of acetonitrile
The solution was cooled, and a solution of 24.1 g of fuming nitric acid and 38.3 g of acetic anhydride in 66 ml of acetonitrile was added under stirring and reacted and purified in the same manner as in Production Example 1, yielding 3,
4-dihydro-8-ethoxycarbonyloxy-
3-Nitrato-2H-1-benzopyran 10.95g
(Yield 27.1%) is obtained. When this compound was hydrolyzed by a conventional method, 7.65 g of 3,4-dihydro-8-hydroxy-3-nitrato-2H-1-benzopyran was obtained as pale yellow prism crystals (yield: 96.3
%) is obtained. Dissolve 7.30 g of the obtained nitrato compound in 41.5 ml of 1N sodium hydroxide solution, and add epichlorohydrin.
Add 6.72g and stir at room temperature for 11 hours. After processing in the same manner as in Production Example 1, colorless crystals of 3,4-dihydro-8-[(2,3-epoxy)propoxy]
-3-Nitrato-2H-1-benzopyran 4.80g
(Yield 52.0%) is obtained. NMR value: δ (CDCl ₃ ) 2.60 ~ 3.63 (5H, m, [formula] [formula]) 3.97 ~ 4.27 (2H, m, [formula]) 5.27 ~ 5.63 (1H, m, [formula]) 6.57 ~ 7.00 (3H, m, aromatic ring H) Dissolve 3.5 g of the obtained epoxy compound in 280 ml of ethanol, add 35 ml of isopropylamine, and stir under reflux for 30 minutes. After the reaction, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography to give 3,4-dihydro-8-[(2-hydroxy -3-isopropylamino)propoxy]-
3-Nitrato-2H-1-benzopyran 3.42g
(Yield 80.0%) is obtained. Elemental analysis value: C ₁₅ H ₂₂ N ₂ O ₆ Calculated value (%) 55.21 6.79 8.58 Experimental value (%) 55.10 6.80 8.47 NMR value: δ (CDCl ₃ ) 1.08 (6H, d, J = 6Hz, [Formula]) 5.30-5.63 (1H, m, [Formula]) 6.63-7.00 (3H, m, aromatic ring H) IR value: ν KBr cm ^-1 1618, 1280 (NO ₂ ) Same as Production Example 1 or 2 The following compound is produced. Production example 3 3,4-dihydro-8-[(2-hydroxy-3-isopropylamino)propoxy]-2
-Nitratomethyl-2H-1-benzopyran Molecular formula: C ₁₆ H ₂₄ N ₂ O ₆ colorless crystals, melting point: 84-86°C NMR value: δ (CDCl ₃ ) 1.06 (6H, d, J = 7Hz, [formula]) 4.72 (2H, m, -C H ₂ ONO ₂ ) 6.65-6.85 (3H, m, aromatic ring H) IR value: ν KBr cm ^-1 1630, 1280 (NO ₂ ) Production example 4 3,4-dihydro-8- [(2-hydroxy-3-t-butylamino)propoxy]-3-
Nitratomethyl-2H-1-benzopyran Molecular formula: C ₁₇ H ₂₆ N ₂ O ₆ Pale yellow viscous oil NMR value: δ (CDCl ₃ ) 1.02 (9H, s, -C (C H ₃ ) ₃ ) 4.52 (2H , d, J=6Hz, -C H ₂ ONO ₂ ) 6.63-6.93 (3H, m, aromatic ring H) IR value: ν liquid film cm ^-1 1630, 1270 (NO ₂ ) Production example 5 3,4-dihydro -8- [[2-Hydroxy-3-(1-ethylpropyl)amino]propoxy]-3-nitratomethyl-2H-1-benzopyran Molecular formula: C ₁₈ H ₂₈ N ₂ O ₆ Pale yellow viscous oil NMR value : δ (CDCl ₃ ) 0.70 to 1.73 (10H, m, [formula]) 4.52 (2H, d, J=6Hz, -C H ₂ ONO ₂ ) 6.63 to 6.97 (3H, m, aromatic ring H) IR value: ν Liquid film cm ^-1 1630, 1270 (NO ₂ ) Production example 6 3,4-dihydro-8-[(2-hydroxy-3-isopropylamino)propoxy]-4
-Nitratomethyl-2H-1-benzopyran Molecular formula: C ₁₆ H ₂₄ N ₂ O ₆ Pale yellow viscous oil NMR value: δ (CDCl ₃ ) 1.10 (6H, d, J = 6 Hz, [Formula]) 4.50 to 4.95 (2H, m, -C H ₂ ONO ₂ ) 6.88 (3H, s, aromatic ring H) IR value: ν liquid film cm ^-1 1630, 1280 (NO ₂ ) Production example 7 3,4-dihydro-8- [ (2-hydroxy-3-isopropylamino)propoxy]-3
-(2-nitrato)ethyl-2H-1-benzopyran Molecular formula: C ₁₇ H ₂₆ N ₂ O ₆ Pale yellow viscous oil NMR value: δ (CDCl ₃ ) 1.09 (6H, d, J = 7 Hz, [Formula ]) 4.62 (2H, t, J=6.5Hz, - CH ₂ C H ₂ ONO ₂ ) 6.65-6.93 (3H, m, aromatic ring H) IR value: ν liquid film cm ^-1 1630, 1280 (NO ₂ ) Production example 8 3,4-dihydro-8-[(3-t-butylamino-2-hydroxy)propoxy]-3-
Nitrato-2H-1-benzopyran molecular formula: C ₁₆ H ₂₄ N ₂ O ₆ pale yellow viscous oil NMR value: δ (CDCl ₃ ) 1.10 (9H, s, [formula]) 5.41 (1H, m, [formula] ]) 6.50 to 6.90 (3H, m, aromatic ring H) IR value: ν liquid film cm ^-1 1630, 1280 (NO ₂ ) Formulation example 1 Tablet Compound in tablet form 6 parts crystalline cellulose 50 parts lactose 34 parts carboxymethyl cellulose Calcium: 9 parts Magnesium stearate: 1 part Mix each component uniformly, and apply directly to a diameter of 5 mm.
mm, tablet weight 50 mg. This tablet has a hardness of 6Kg.
Disintegration time is 1 minute. Formulation example 2 Compound in granule form 1 part Crystalline cellulose 25 parts Lactose 40 parts Corn starch 32 parts A Hydroxypropyl cellulose 2 parts Ethanol 25 parts B After uniformly mixing the ingredients of A, add the solution of B. Kneaded by hand, granulated by extrusion granulation method, and then heated to 50℃
After vacuum drying, it is sieved to make granules. Formulation example 3 Fine granule type compound 2 parts Crystalline cellulose 20 parts Lactose 50 parts White sugar 26 parts Hydroxypropyl cellulose 2 parts Mix each component uniformly, add 25 parts of ethanol, knead, crush and granulate. granulation method, then
After drying with air at 50℃, it is sieved to obtain fine granules. Formulation example 4 Compound in capsule form 10 parts Lactose 40 parts Crystalline cellulose 30 parts Talc 10 parts Mix each component uniformly, and fill 90 mg of the mixture into a No. 5 lock capsule to prepare a capsule.

[Brief explanation of drawings]

Figures 1 to 5 are graphs showing the effects of the compound of the present invention on blood pressure, heart rate, and body weight in hypertensive rats. Figures 6 and 7 are graphs showing the effects of this compound on cardiac output, systemic blood pressure, heart rate, and systemic blood vessels in anesthetized dogs. Graphs showing the effect on resistance. Figures 8 and 9 are graphs showing the effect of this compound on left ventricular end-diastolic pressure, systemic blood pressure, heart rate and left ventricular peak systolic velocity in anesthetized dogs.

Claims (1)

[Claims] 1. General formula (wherein R is a linear or branched alkyl group, n is an integer of 0 to 5) or an acid addition salt thereof as an active ingredient. 2 The active ingredient is 3,4-dihydro-8-[(2-
The therapeutic agent for circulatory system diseases according to claim 1, which is hydroxy-3-isopropylamino)propoxy]-3-nitratomethyl-2H-1-benzopyran. 3 The active ingredient is 3,4-dihydro-8-[(2-
The therapeutic agent for circulatory system diseases according to claim 1, which is hydroxy-3-isopropylamino)propoxy]-3-nitrato-2H-1-benzopyran. 4. The therapeutic agent for circulatory system disease according to claim 1, wherein the circulatory system disease is hypertension. 5. The therapeutic agent for circulatory system disease according to claim 1, wherein the circulatory system disease is angina pectoris. 6. The therapeutic agent for circulatory system disease according to claim 1, wherein the circulatory system disease is arrhythmia. 7. The therapeutic agent for circulatory system disease according to claim 1, wherein the circulatory system disease is peripheral circulatory failure. 8. The therapeutic agent for circulatory system disease according to claim 1, wherein the circulatory system disease is cerebral circulation insufficiency. 9. The therapeutic agent for circulatory system disease according to claim 1, wherein the circulatory system disease is myocardial infarction.