JPH0751505B2 - Cardiovascular agent - Google Patents

Description

Detailed Description of the Invention [Industrial applications]

The present invention provides a compound represented by the following general formula [II], a physiologically acceptable acid addition salt thereof, and a quaternary salt thereof, nojirimycin and a physiologically acceptable acid addition salt 1,4- The present invention relates to a thrombolytic agent containing a compound selected from the group consisting of bis (3-moranolino-1-propenyl) benzene and a physiologically acceptable acid addition salt thereof, castanospermine, as a main component. Where R ² is hydrogen, alkyl, carboxyalkyl,
Alkyloxycarbonylalkyl, hydroxyalkyl, cycloalkylalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryloxyalkyl, alkenyl, hydroxyalkenyl, substituted or unsubstituted arylalkenyl, aryloxyalkenyl or alkylcarbamoylalkyl. Represent

[Prior art]

Precipitation of fibrin following aggregation of platelets is essential for the formation of a hemostatic plug that occurs when physical damage to blood vessels occurs. On the other hand, a hemostatic plug inhibits blood flow in a blood vessel and causes tissue ischemia and necrosis, which causes myocardial infarction and cerebral infarction. However, it is the fibrin-degrading action of the plasminogen / plasmin system that plays a major role in this mechanism. Plasminogen is activated by plasminogen activator to become plasmin, and plasmin decomposes fibrin (fibrinolysis). Abnormalities in this mechanism cause diseases such as myocardial infarction and cerebral infarction. The causes of these modern diseases are various, but in treating them, thrombolytic therapy that dissolves the generated thrombus and improves the ischemic state of tissue is effective, and therefore plasminogen activator such as urokinase and streptokinase is effective. Is being administered. Therefore, the substance that promotes the secretion of urokinase may be a good drug for the above thrombolytic therapy. By the way, there is a mechanism in vivo that inhibits even excessive fibrinolysis, and, for example, α ₂ -plasmin inhibitor (hereinafter referred to as “α ₂ -PI”), which is a plasmin inhibitor, exerts a plasmin action. It has been shown to inhibit instantly and prevent fibrin degradation. Therefore, α ₂ -PI acts as a treatment inhibitor during thrombolytic therapy, and is also generated as a kind of acute phase protein after surgery and is one of the causes of postoperative thrombosis.

[Problems to be Solved by the Invention]

From the above, it has been suggested that if there is a drug that reduces the activity of α ₂ -PI, the effect of thrombolytic therapy will be further enhanced and that it will be useful for the prevention of postoperative thrombosis and thrombosis. Therefore, an object of the present invention was to provide an excellent α ₂ -PI inhibitor in order to create a drug effective for treating myocardial infarction and cerebral infarction. Further, since urokinase is a plasminogen activator, it was also an important object of the present invention to provide a substance that promotes the secretion of urokinase.

[Means for Solving the Problems]

In order to achieve the above-mentioned object, the present inventors screened many compound groups, but as a result of being endowed with an extremely specific number of compounds, the compound according to the present invention has an excellent α ₂ -PI activity lowering action and urokinase. discovered that it has a secretion-stimulating action, also found to have also the dissolution accelerating effect during thrombolytic effect simultaneously urokinase and these compounds alpha ₂ -PI activity lowering effect, to reach the present invention I was able to. The compound of the present invention has excellent α ₂ -PI, as described in detail below.
It has a lowering action and a urokinase secretagogue action, and is extremely important because it serves as a thrombolytic therapeutic drug for treating myocardial infarction and cerebral infarction. The compounds of the present invention have the structural characteristics recited in the claims. Examples of R ¹ and R ² in the general formulas [I] and [II] include the substituents described above. Examples of the alkyl include those having about 1 to 10 carbon atoms, and lower alkyl such as methyl and ethyl is preferable. Examples of carboxyalkyl include carboxymethyl, carboxyethyl, carboxypropyl and the like, and those having a higher alkyl carbon number are also included in the compound of the present invention. Examples of alkyloxycarbonylalkyl include:
Examples thereof include methoxycarbonylmethyl, methoxycarbonylethyl, methoxycarbonylpropyl, methoxycarbonylbutyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, ethoxycarbonylpropyl, ethoxycarbonylbutyl, etc., but those having a higher alkyl carbon number are also included in the present invention. It is included in the compound. Examples of hydroxyalkyl include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, and the like, and those having a higher alkyl carbon number are also included in the compound of the present invention. Examples of cycloalkylalkyl include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and the like, but those having a higher alkyl carbon number are also included in the compound of the present invention. Examples of the arylalkyl include benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylpentyl, naphthylmethyl, naphthylethyl, naphthylpropyl, naphthylbutyl, and the like, but those having a larger alkyl carbon number are also included in the present invention. It is included in the compound. Examples of the aryloxyalkyl include phenoxymethyl, phenoxyethyl, phenoxypropyl, phenoxybutyl, naphthyloxymethyl, naphthyloxyethyl, naphthyloxypropyl, and naphthyloxybutyl, but the number of carbon atoms of the alkyl is larger. Those are also included in the compound of the present invention. Examples of alkenyl include vinyl, propenyl, butenyl, etc., but those having a larger number of carbon atoms are also included in the compound of the present invention. Examples of hydroxyalkenyl include hydroxyvinyl, hydroxypropenyl, hydroxybutenyl and the like, but those having a larger carbon number are also included in the compound of the present invention. Examples of the arylalkenyl include phenylvinyl, phenylpropenyl, phenylbutenyl, naphthylvinyl, naphthylpropenyl, naphthylbutenyl, etc., but those having a larger carbon number are also included in the compound of the present invention. Examples of the aryloxyalkenyl include phenoxyvinyl, phenoxypropenyl, phenoxybutenyl, naphthyloxyvinyl, naphthyloxypropenyl, naphthyloxybutenyl, etc., but those having a larger carbon number are also included in the compound of the present invention. It is what is done. Examples of the alkylcarbamoylalkyl include methylcarbamoylmethyl, methylcarbamoylethyl, methylcarbamoylpropyl and the like.
Those having a larger carbon number are also included in the compound of the present invention. Examples of the compound of the present invention include, in addition to those described above, nojirimycin in which the 1-position in the basic skeleton of moranolin is substituted with OH and a derivative thereof (eg, N-substituted product). These compound groups also have the same action as the derivative of moranolin (N-substituted form) and are included in the compound of the present invention. The compounds of the present invention also include compounds having a moranoline basic skeleton as a bis form. These also have the same pharmacological effects as the other compounds of the present invention. The compound of the present invention also includes castanospermine and has the same pharmacological effect as that of the other compounds of the present invention. As typical examples of these compounds, the compounds of the present invention include nojirimycin and physiologically acceptable salts thereof, and 1,4
-Bis (3-moranolino-1-propenyl) benzene and its physiologically acceptable salts, as well as castanospermine. Similar to the other compounds of the present invention, these also have excellent α ₂ -PI lowering action and urokinase secretagogue action. The compound of the present invention can be produced by a known method. For example, a production example of N-butylmoranolin is shown below. [Production Example 1] 50 g of moranolin, 126 g of n-butyl bromide and 170 g of potassium carbonate were added to 1300 ml of dimethylformamide, and the mixture was stirred at room temperature for 7 days to complete the reaction. After filtering to remove impurities, the solvent was distilled off under reduced pressure, 1000 ml of strongly acidic ion exchange resin Dowex 50W × 2 (H ⁺ ) was passed through, thoroughly washed with water, and then eluted with 1N aqueous ammonia. The eluate was concentrated under reduced pressure, 50 ml of methanol was added, and the mixture was left standing at room temperature to collect crystals (47 g). This was dissolved in 500 ml of methanol under heat, cooled to room temperature, treated with activated carbon, concentrated to about 100 ml, and allowed to stand at room temperature to collect 40 g of precipitated crystals. Add this to methanol 200
After hot-dissolving in ml, the solution was concentrated lightly and allowed to stand at room temperature, and the precipitated crystals were collected and sufficiently dried at 70 ° C. under reduced pressure to obtain 34 g of N- (n-butyl) moranolin as a target product. Yield 50.6
%. Melting point 128-129 ° C. Elemental analysis value Calculated value (%) C: 54.78 H: 9.65 N: 6.39 Measured value (%) C: 54.57 H: 9.65 N: 6.60 ▲ [α] ²⁴ _D ▼ ＝ -14.59 ° (1%, water) ¹ H −MNR: 0.88 (3H, t, J = 7.2Hz, CH ₃ CH ₂ CH ₂ CH ₂ −), 1.16 to 1.56 (4H, m, CH ₃ CH ₂ CH ₂ CH ₂ −), 2.17 to 2.36 (2H, m, CH ₃ CH ₂ CH ₂ CH ₂ −), 2.48 to 2.82 (2H, m, H−1a, H-5), 3.02 (1H, dd, J = 5.1,11.4Hz, H−1e), 3.22 ( 1H, t, J = 9.0Hz, H-4), 3.66 (1H, t, J = 9.4Hz, H-3), 3.44 to 3.60 (1H, m, H-2), 3.74 to 3.96 (2H, m) , H-6, H-6 ') [Production Example 2] 5 g of moranolin, 13 g of n-butyl bromide and 17 g of potassium carbonate were added to 130 ml of dimethylformamide, and the mixture was reacted at 100 ° C for 5 hours. N- (n
-Butyl) moranolin 5.1 g was obtained. Yield 75.8%. [Production Example 3] 5 g of moranolin was added to 100 ml of methanol, and while stirring at room temperature, 0.7 g of hydrogen chloride was dissolved in 50 ml of methanol.
A solution of 20 ml of n-butyraldehyde and 3 g of Na
CNBH ₃ was added and reacted overnight. After the reaction, the solvent was removed under reduced pressure, the residue was dissolved in water and partitioned with chloroform. Water layer
It was passed through a 200 ml Diaion SA-11A (OH ⁻ ) type column and washed thoroughly with water. The passing solution and the washing solution were combined and passed through a 200 ml Dowex 50W × 28 (H ⁺ ) column, thoroughly washed with water and eluted with 1N ammonia water. The solvent was distilled off from the eluate under reduced pressure, followed by crystallization from ethanol and recrystallization from ethanol to obtain 5.1 g of N- (n-butyl) moranolin. Yield 75.8%. The following compounds can be mentioned as typical examples of the compound of the present invention. Compound No. 1 Moranolin Compound No. 2 N-Methyl Moranolin Compound No. 2a N- (n-butyl) Moranolin Compound No. 3 N- (5-Methoxycarbonylpentyl) Moranolin Tosylate Compound No. 4 N-Hydroxyethyl Moranolin Compound No. 5 N- (4-methoxycarbonylbutyl) moranolin Compound No. 6 nojirimycin bisulfite Compound No. 7 1,4-bis (3-moranolino-1-propenyl) benzene dihydrochloride Compound No. 8 N- (n-hexyl) moranolin tosylate Compound No. 9 N-isoprenylmoranolin Compound No. 10 N- (2-hydroxydecyl) moranolin tosylate Compound No. 11 N- (10-carboxydecyl) moranolin sodium salt Compound No. 12 N- (3-phenylpropyl) moranolin Tosylate Compound No. 13 N-benzylmoranolin Tosylate Compound No. 14 N-Cinnamyl Moranolin Hydrochloride Compound No. 15 N- (4-phenylbutyl) moranolin Tosylate Compound No. 16 N- (2-phenoxyethyl) moranolin Compound No. 17 N- (3-phenoxypropyl) moranolin tosylate Compound No. 18 N- (5-phenylpentyl) moranolin tosylate Compound No. 19 N- (2-cyclopentylethyl) moranolin tosylate Compound No. 20 N- [3- (3- (2-methoxyethoxy) ) Phenyl)
2-2 butenyl] Moranolin Compound No. 21 N, N-Dimethylmoranolin Ammonium iodide Compound No. 22 N-Ethyl Moranolin Compound No. 23 N-Cinnamyl Moranoline Compound No. 24 N-geranyl Moranolin Tosylate Compound No. 25 N- (2 -Hydroxy-3-phenoxypropyl) moranolin tosylate Compound No. 26 N-farnesylmoranolin tosylate Compound No. 27 N-10- (N-methylcarbamoyl) decylmoranolin Compound No. 28 N- (4-phenyl-3-butenyl) moranolin Tosylate Compound No. 29 N- (3-phenyl-2-methyl-2-propenyl) moranolin Compound No. 30 N- [3- (o-chlorophenoxy) propyl] moranolin Compound No. 31 N- (γ-methyl-4-bromocinnamyl ) Moranoline compound number No. 32 N- [4- (3-fluoro-4-methylphenyl) butyl] moranolin Compound No. 33 N- (p-ethoxycinnamyl) moranolin Compound No. 34 N- (p-isopropoxycinnamyl) moranolin Compound No. 35 N- (γ-methyl-m-methylcinnamyl) moranolin Compound No. 36 N- [4- (m-methoxyphenyl) -3-pentenyl] moranolin Compound No. 37 N- (p-ethoxycarbonylphenoxyethyl) moranolin [Emiglitate (Emiglitate)] Compound No. 38 Castanospermine Examples of the compound according to the present invention include the following, in addition to the compounds listed above. N-isobutyl moranoline tosylate N-hydroxyethyl moranoline tosylate N-amino moranoline hydrobromide N-methoxyethyl moranoline tosylate N-methoxyethoxyethyl moranoline tosylate N-decyl moranoline tosylate N- (2-hydroxyhexadecyl ) Moranoline tosylate N- [2-hydroxy-3- (p-tolyloxy) propyl] moranoline tosylate N- [2-hydroxy-3- (p-methoxyphenyloxy) propyl moranoline tosylate N- [2-hydroxy-3-] (P-Chlorophenyloxy) propyl] moranolin tosylate N- (3-carbamoylpropyl) moranolin N-nonylmoranolin tosylate N-undecylmoranolin tosylate N- (2-hydroxy Tetradecyl) moranolin tosylate N- (4,4-diphenyl-3-butenyl) moranolin N- (5-carboxypentyl) moranolin N-farnesylmoranolin N- (γ-methyl-4-chlorocinnamyl) moranolin N- (γ -Methyl-4-methylcinnamyl) moranolin N- [4- (p-chlorophenyl) -3-pentenyl]
Moranolin N- [4- (m-chlorophenyl) -3-pentenyl]
Moranolin N- [4- (o-chlorophenyl) -3-pentenyl]
Moranoline N- [4- (p-phenoxyphenyl) -3-pentenyl] moranoline N- [4- (p-ethoxyphenyl) -3-pentenyl] moranolin N- (m-methoxycinnamyl) moranolin N- [3- (3-Chlorophenyl) -2-butenyl] moranolin N- [4- (4-chlorophenyl) -3-butenyl] moranolin N- (4-carboxycinnamyl) moranolin hydrochloride N- (3-carboxy-2-propenyl) Moranoline N- (m-triethylammonioethoxycinnamyl)
Moranoline dipicrate N-isopropyl Moranoline N- (p-trimethylammonioethoxycinnamyl)
Moranolin chloride hydrochloride When the compound of the present invention is administered as a pharmaceutical, the compound of the present invention is used as it is or in a pharmaceutically acceptable non-toxic and inert carrier, for example, 0.1% to 99.5%, preferably 0.5% to 90%.
%, And is administered to animals including humans. As the carrier, one or more solid, semi-solid, or liquid diluents, fillers, and other auxiliaries for formulation are used.
The pharmaceutical composition is preferably administered in dosage unit form. The pharmaceutical composition of the present invention can be administered orally, intratically such as intravenously, locally (such as transdermally), or rectally. It is needless to say that the dosage form is suitable for these administration methods. For example, oral administration is particularly preferred. The dose as a thrombolytic agent is preferably adjusted in consideration of the patient's condition such as age and body weight, administration route, nature and degree of disease, etc. The amount of the active ingredient per day is generally in the range of 50 to 3000 mg / human, preferably 500 mg to 1000 mg / human. In some cases, lower doses may be sufficient, and conversely, higher doses may be required. Again 1
It is desirable to administer in 2 to 3 divided doses daily.

【Example】

The α ₂ -PI lowering action, urokinase secretagogue action and toxicity of the compound of the present invention will be described in detail below, and the present invention will be described in more detail. Active human hepatoma-derived HepG2 cells in Test Example 1 In vitro (in vitro) is, alpha ₂ - plasmin inhibitor was synthesized over (α ₂ -PI), it is known to secrete. 2 × 10 ^{6 of} these HepG2 cells were seeded on a Falcon plastic culture plate (diameter 100 mm) and cultured using Eagle's minimal medium containing 10% fetal bovine serum. After 3 days, the cells attached to the bottom surface of the plate were washed twice with Dulbecco's phosphate buffer, and the test sample of the compound of the present invention was added.
The cells were further cultured for 3 to 4 days using 8 ml of serum-free Eagle medium (phenol red-free) containing 200 μg / ml. After culturing, collect 7 ml of the medium and use Centriflow (C
It was concentrated to about 1 ml using F25) and further lyophilized. Monomethylamine hydrochloride 8.1mg / ml in freeze-dried sample
Then, 0.7 ml of 50 mM Tris buffer containing the above was added and dissolved to be concentrated to about 10 cultures. 50 μm of 15 mCU plasmin solution was added to 100 μm of the concentrated sample, and further 50 μm of 0.25 μmol S-2251 synthetic chromogenic substrate solution was added and reacted at 37 ° C. for 10 minutes. The reaction was stopped by adding 1 ml of 2% citric acid solution, and S at OD405 nm
The p-nitroanilide released from the −2251 substrate was measured. Using Tris buffer as described above instead of concentrated sample,
Plasmin activity 10 was measured by measuring the degradation of S-2251 substrate.
As a control of 0%, a concentrated sample cultured without adding a test sample was used as a control of 100% α ₂ -PI activity. The obtained results were calculated according to the following formula. A ₁ is the absorbance of the 100% control, A ₂ is the absorbance of the concentrated sample, and A ₃ is the α ₂ -PI activity of 100%.
The absorbance of each control is shown. The number of samples was 3, respectively. The results are shown in Table 1. That the compounds of the present invention reduces the alpha ₂ -PI activity is evident. Test Example 2 In Vivo Activity As the animals to be administered, three male Beagle dogs were used, one each for the control group and the administration group. The test sample (Compound No. 2) was 0.1 mol phosphate buffer (p
H7.2) was used to dissolve to 0.1 mg per 0.1 ml. After dissolution, the solution was sterilized by filtration using a sterilizing filter (pore size 0.2 μm), and then 0.3 ml per 1 kg body weight was administered (30 mg / kg). The administration was carried out through the right forelimb vein for 7 days. The collected blood was mixed with 1 volume of 3.8% sodium citrate so as to have 9 volumes of blood, and centrifuged at 3000 rpm for 15 minutes to separate plasma. The α ₂ -PI activity was measured as an inhibitory effect on the plasmin degradation of the synthetic chromogenic substrate S-2251. The measurement results were shown as changes in the inhibitory activity after administration, assuming that the plasmin inhibitory activity before administration of the test sample was 100% (Table 2).
The number of each sample was 3. alpha ₂ -PI activity by 30 mg / kg continuous administration of the test specimen,
Clearly reduced. C represents a control, and the sample represents a test sample. Test Example 3 In vitro thrombolysis test A test sample (Compound No. 2) was continuously administered to Beagle dogs once a day at a dose of 30 mg / kg, and plasma was administered before the administration and on the fourth administration day. Separated as above. Α ₂ -PI in plasma
The activity was measured, and fibrin clots were prepared in vitro using the plasma, and the solubilities when urokinase, which is a thrombolytic agent, was allowed to act were compared between the plasma before administration and the plasma 4 days after administration. ¹²⁵ I-fibrinogen (0.1 mC
i / ml) was added to 40 μm and mixed, and 50 μm of this was dispensed into test tubes. A 5 U mixed solution of 25 U / ml thrombin and 0.5 M calcium chloride was added to each test tube in an amount of 5 μm and incubated at 37 ° C. for 30 minutes to prepare a fibrin clot. A 2% albumin solution and urokinase of this solution dissolved at 15 and 30 U / ml were added to each test tube in an amount of 1 ml. Incubate for 12 hours at 37 ℃, collect 25μ of supernatant in a tube for RAI, and release in the supernatant by γ-counter.
^{The 125} I-fibrin degradation product was measured. The number of samples was 3, respectively. As shown in Table 3, it is clear that when plasma in which α ₂ -PI activity was decreased by administration of the test sample was used, dissolution of fibrin clot was enhanced as compared with plasma before administration. Test Example 4 In vitro thrombolytic test The ability to induce thrombolytic activity in an established vascular endothelial cell culture system was examined using CPAE (bovine pulmonary artery endothelial cell Endothelia). CPAE cells were purchased from Dainippon Pharmaceutical Laboratory Products Department. CPAE cells were added to 10% FCS in a 25 cm ² culture flask.
− Passage using Eagle MEM medium, transfer 0.1 ml from the cell suspension collected at the time of passage to a test tube with a sterilized pipette, dilute 10-fold with 0.9 ml trypan blue solution, and count the blood cells. Count the number of cells in a plate, dilute with 10% FCS-Eagle MEM medium so that the number of cells will be 2 × 10 ⁵ cells / ml, and add 100 μl to each well in a 96-well microtiter plate (Corning). That is, the cells were injected with a micropipette so that the concentration was 2 × 10 ⁴ cells / well. 37 plates
Cultivation was started at 5 ° C. and 5% CO ₂ . The compound of the present invention is dissolved in a medium to a concentration of 0.2 mg / ml 24 hours after the start of culture, and 1% or less of DMSO is not dissolved.
Aseptic filtration of the solution dissolved in was added to the well with 5μ of it with a sterilized micropipette.
After culturing for 72 hours at 5 ° C. and 5% CO ₂ , the collected culture supernatant was used for measurement. The measurement is performed as follows. Place 5μ of plasminogen in the well of the fibrin plate (Kitasato Institute)
Inject and leave until diffused. After diffusion, add 5μ of culture supernatant
After pouring, the mixture is placed in a single-product gas incubator at 37 ° C, and 4 hours later, it is judged by the formation of a transparent dissolution circle by fibrinolysis. At this time, at the same time, it was confirmed that a transparent circle was formed by fibrinolysis in the well containing t-PA as a positive control. The diameter of the transparent circle was 9-10 mm. Also in the case of the culture supernatant containing the compound of the present invention, 4.5 to 8.5
Although a transparent lysis circle of mm was observed, no change was observed in the case of the culture supernatant of cells to which the compound of the present invention was not added (control). When a lysis circle of 4 mm or more was formed, it was judged that the thrombolytic ability of CPAE cells was induced. After the check of fibrinolytic activity is completed, the wells are placed at the final concentration 2.
After fixing with 5% glutaraldehyde, the liquid is discarded and washed with PBS. After washing, the water is removed and 100 μl of 0.1 crystal violet is added for staining, and the mixture is left for 2 to 3 minutes, and then washed with running water. After draining off the excess dyeing solution, remove water and
Elute the cell-bound dye with μ methanol,
Using the multi-scan (Titer Tech), the ABS method and the matrix method were measured at a wavelength of 580 nm, and we were patient that the cells were not damaged. Table 4 shows the diameter (mm) of the melting circle. The thrombolytic action of the compounds of the invention is evident. Test Example 5 In Vitro Thrombolytic Test It was found that the compound of the present invention has the ability to induce fibrinolytic activity in CPAE cells. This fibrinolytic activity is caused by any substance in addition to the α ₂ -PI lowering effect. In order to confirm whether or not the compound of the present invention was added, the culture solution containing Compound No. 2 was analyzed using the method of fibrin autography. This culture solution, t-PA (tissue type plasminogen activator), and urokinase are electrophoresed on an SDS-polyacrylamide gel using a 10% gel. After electrophoresis, the gel was treated with 2.5% Triton X-100, placed on an agar plate containing fibrinogen, thrombin, and plasminogen, and placed in a 37 ° C, 5% CO ₂ incubator to dissolve fibrin. I confirmed the position. As a result, in the culture supernatant containing the compound of the present invention, large dissolution of fibrin was observed at the molecular weight position of urokinase-type plasminogen activator.
It was revealed that it strongly induces the production of urokinase-type plasminogen activator in AE. Acute toxicity test ddY male mice, 6-week-old, 4 mice per test sample group were used. Experimental method In intravenous administration, after dissolving each sample in 0.9% saline,
It was administered via the tail vein. For intraperitoneal administration, 0.5% C
MC-suspended in physiological saline, 0.1
It was administered intraperitoneally in ml. For oral administration, 0.5% CMC-
The suspension was suspended in physiological saline and orally administered in an amount of 0.2 ml per 10 g of mouse body weight. Observation was performed immediately after the administration, and after observing for 1 week after the administration, the animals were sacrificed with chloroform and autopsied. The LD _{50 of} each test sample is summarized in the following table. The safety of the compounds of the present invention is clear. Example 1 The following substances per tablet were added to the compound of the present invention (Compound No. 2) to give tablets according to a conventional method. In one tablet (in 300 mg) Compound of the present invention (Compound No. 2) 200 mg Lactose 50 mg Corn starch 20 mg Low-substituted hydroxypropyl cellulose 15 mg Hydroxypropyl cellulose 5 mg Magnesium stearate 10 mg 300 mg Example 2 Compound of the present invention (Compound No. 2), The following substances were added per tube to obtain an injection according to a conventional method. In one tube (in 10 ml) Compound of the present invention (Compound No. 2) 200 mg Sodium chloride 90 mg Distilled water for injection 10 ml

Claims (3)

[Claims] 1. A compound represented by the following general formula [I], a physiologically acceptable acid addition salt thereof and a quaternary salt thereof: Nojirimycin and a physiologically acceptable acid addition salt thereof 1,4- bis (3-Moranorino-1-propenyl) benzene and a physiologically acceptable acid addition salts of castanospermine as a main component a compound selected from the group consisting of the ~ alpha ₂ - plasmin inhibitor lowering agent . Where R ¹ is hydrogen, alkyl, carboxyalkyl,
Alkyloxycarbonylalkyl, hydroxyalkyl, cycloalkylalkyl, arylalkyl, aryloxyalkyl, alkenyl, arylalkenyl, halogenoarylalkenyl, lower alkoxyarylalkenyl, lower alkylarylalkenyl, aryloxyarylalkenyl, carboxyarylalkenyl or tri-lower alkyl Represents ammonioethoxyarylalkenyl. 2. A compound represented by the following general formula [II], a physiologically acceptable acid addition salt thereof and a quaternary salt thereof: Nojirimycin and a physiologically acceptable acid addition salt thereof 1,4- A urokinase secretagogue comprising, as a main component, a compound selected from the group consisting of bis (3-moranolino-1-propenyl) benzene and a physiologically acceptable acid addition salt thereof, castanospermine. Where R ² is hydrogen, alkyl, carboxyalkyl,
Alkyloxycarbonylalkyl, hydroxyalkyl, cycloalkylalkyl, lower alkyl or arylalkyl optionally substituted with halogen, aryloxyalkyl, hydroxyaryloxyalkyl,
Halogenoaryloxyalkyl, ethoxycarbonylaryloxyalkyl, lower alkoxyaryloxyalkyl, alkenyl, hydroxyalkenyl, arylalkenyl, halogenoarylalkenyl, lower alkoxyarylalkenyl, lower alkylarylalkenyl, aryloxyarylalkenyl, carboxyarylalkenyl, tri-lower Represents alkylammonioethoxyarylalkenyl, aryloxyalkenyl or alkylcarbamoylalkyl. 3. A compound represented by the following general formula [II], a physiologically acceptable acid addition salt thereof and a quaternary salt thereof: Nojirimycin and a physiologically acceptable acid addition salt thereof 1,4- A thrombolytic agent comprising a compound selected from the group consisting of bis (3-moranolino-1-propenyl) benzene and a physiologically acceptable acid addition salt thereof, castanospermine, as a main component. Where R ² is hydrogen, alkyl, carboxyalkyl,
Alkyloxycarbonylalkyl, hydroxyalkyl, cycloalkylalkyl, lower alkyl or arylalkyl optionally substituted with halogen, aryloxyalkyl, hydroxyaryloxyalkyl,
Halogenoaryloxyalkyl, ethoxycarbonylaryloxyalkyl, lower alkoxyaryloxyalkyl, alkenyl, hydroxyalkenyl, arylalkenyl, halogenoarylalkenyl, lower alkoxyarylalkenyl, lower alkylarylalkenyl, aryloxyarylalkenyl, carboxyarylalkenyl, tri-lower Represents alkylammonioethoxyarylalkenyl, aryloxyalkenyl or alkylcarbamoylalkyl.