JPH09302039A - Sustained-release antithrombotic copolymer - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an antithrombotic material or antithrombotic agent having a longer duration of antithrombotic effect by copolymerizing a specified ethylenic compound with a water-soluble compound. SOLUTION: An ethylenic compound represented by formula I [wherein A is an arbitrary bond; R<1> is H or a 1-5C alkyl; R<2> is formula II (wherein R<4> is a 1-6C alkyl, a 2-7C alkoxyalkyl or tetrahydrofurfuryl; and R<5> is a 1-3C alkylene), formula III (wherein R<6> is H or a 1-4C alkyl); R<3> is formula IV (wherein R<7> and R<8> are each H, a 1-4C alkoxyl, a 1-4C alkylanino or a 1-4C dialkylamino; formula V (wherein R<9> is H or a 1-4C alkyl; m is 0-18; n is 0 or 1; and p is 3 or 4) is copolymerized with a water-soluble compound represented by formula VI (wherein R<10> to R<12> are each H or a 1-4C alkyl) to obtain a sustained-release antithrombotic copolymer which sustainedly releases formula VII (wherein R<2> and R<3> and p are as defined in formula I) upon hydrolysis. When this compound is stored in the form of an aqueous solution, arginine derivatives resulting from the hydrolysis of ester bonds are sustainedly released from the copolymer.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a sustained-release antithrombotic copolymer comprising an ethylenic compound bound with an arginine derivative having antithrombotic properties.

[0002]

2. Description of the Related Art Conventionally, artificial blood vessels using polymeric materials,
Artificial hearts, blood processing instruments such as catheters, blood transfusion tubes, etc. are widely used. As is well known, blood coagulates when it comes into contact with a foreign substance, and therefore it is necessary to impart antithrombotic properties to the polymer materials used in the above various medical devices. Conventionally, a method of adhering or coating an anticoagulant substance such as heparin on the surface of a polymer material has been proposed, but the duration of the effect is not always sufficient.

[0003]

It is desired to develop an antithrombotic material or an antithrombotic agent having a longer duration of antithrombotic effect.

[0004]

Means for Solving the Problems As a result of extensive studies on a method for extending the duration of antithrombotic effect, the present inventors have found that addition of a hydroxyl group-containing group through a carboxyl group of an arginine derivative having antithrombin activity. A water-soluble copolymer composed of a compound having an ester bond with a polymerizable ethylenic compound and a compound of the formula (VI) copolymerizable therewith was synthesized. The present invention was found to find that when this compound is stored in the form of an aqueous solution, the arginine derivative is gradually released from the copolymer due to hydrolysis of the ester bond. That is, the gist of the present invention is represented by the following general formula (I)

[0005]

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[In the above formula, A represents an arbitrary bond, and R ¹
Represents a hydrogen atom or a C ₁ -C ₅ alkyl group, R ²
Is the following general formula (II) or (III)

[0007]

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[0008]

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(In the formula, R ⁴ is C ₁ which may have a substituent.
To C ₆ alkyl group, C _{2 to} C ₇ alkoxyalkyl group or tetrahydrofurfuryl group, and R ⁵ is C ₁
To C ₃ alkylene group, R ⁶ represents a hydrogen atom or a C _{1 to} C ₄ alkyl group which may have a substituent. )
R ³ is represented by the following general formula (IV) or (V)

[0010]

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[0011]

[Chemical 12]

(Where R⁷And R⁸Are independent
Hydrogen atom, C₁~ C_FourAlkoxy group or C₁~ C
_FourThe alkylamino or dialkylamino groups of
Then R ⁹Is a hydrogen atom or C which may have a substituent₁~
C_FourRepresents an alkyl group. ), N is 0 or 1
Represents an integer, m represents an integer of 0 to 18, and p represents 3 or
Represents an integer of 4. ] And an ethylenic compound represented by
General formula (VI)

[0013]

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(Wherein R ¹⁰ , R ¹¹ and R ¹² each independently represent a hydrogen atom or a C ₁ -C ₄ alkyl group) and are copolymerized with a water-soluble compound, Hydrolyzed to give the following compound (VII)

[0015]

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(In the formula, R ² , R ³ and p are the same as above.) The sustained-release antithrombotic copolymer is characterized by being sustained-released.

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below.
The ethylenic compound of the general formula (I) is produced by reacting an arginine derivative having a carboxyl group with an ethylenic compound having a hydroxyl group. The arginine derivative which is a raw material of the present invention is an arginine derivative having one carboxyl group and having antithrombin activity, which is represented by the following general formula (VIII).

[0017]

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In the above formula, p represents an integer of 3 or 4,
R ² represents the following general formula (II) or (III).

[0019]

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[0020]

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R of the group of the above general formula (II)^FourAs a
Cyl group, ethyl group, propyl group, butyl group, pentyl
Group, C such as hexyl group₁~ C₆Alkyl group of methoxy
Methyl group, methoxyethyl group, ethoxymethyl group, eth
Xyethyl group, butoxymethyl group, butoxyethyl group, etc.
C_Two~ C₇Alkoxyalkyl group or tetrahydr
Rofurfuryl group, R^FiveAs a methylene
C such as group, ethylene group and trimethylene group₁~ C_ThreeAl
Examples thereof include a xylene group. R in the group of the above general formula (III) ⁶When
Is a methyl group which may have a hydrogen atom or a substituent,
C such as ethyl group, propyl group and butyl group₁~ C_FourAl
Examples include a kill group. In addition, R in the general formula (VIII)^ThreeIs below
Represents general formula (IV) or (V).

[0022]

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[0023]

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R ⁷ and R ^{8 in} the group of the general formula (IV) are each independently a hydrogen atom; a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a C ₁ -C ₄ alkoxy group; a methylamino group. , C ₁ -C ₄ alkylamino groups or dialkylamino groups such as ethylamino group, propylamino group, butylamino group, dimethylamino group, diethylamino group, methylethylamino group, and methylpropylamino group. R ⁹ of the group of the above general formula (V)
Represents a hydrogen atom or a C ₁ -C ₄ alkyl group which may have a substituent, such as a methyl group, an ethyl group, a propyl group and a butyl group.

The above-mentioned arginine derivatives are disclosed in JP-A-52
-97934, JP-A-55-33499,
European Published Patent No. 8746, Journal of Medical Chemistry (J. Med. Chem.)
23 , 1293-1299 (1980), or Biochemistry 23 , 8
5 to 90 (1984). Specific examples include the compounds shown in Table 1 below.

[0026]

[Table 1]

[0027]

[Table 2]

The ethylenic compound represented by the general formula (I) of the present invention can be obtained by reacting the above-mentioned arginine derivative (VIII) with the compound represented by the following general formula (IX).

[0029]

Embedded image CH ₂ = CR ^1- (A) _n- (CH ₂ ) _m -OH (IX)

As A of the compound of the above general formula (IX),
Examples of the divalent bond include -COO-, -O-,-
CONH- is preferred. Examples of R ¹ include a hydrogen atom or a C _{1 to} C ₅ alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group and a pentyl group, and a hydrogen atom or a methyl group is particularly preferable. n is an integer of 0 or 1, m is an integer of 0-18, preferably an integer of 0-6, and more preferably an integer of 0-2. As this compound, hydroxyalkyl acrylates and hydroxyalkyl methacrylates are preferable because of their stability during reaction with an arginyl derivative and easy availability of raw materials, and the following general formula (X)

[0031]

Embedded image CH ₂ = CR ¹ COO (CH ₂ ) _m OH (X)

(Wherein R ¹ and m are as defined above) are preferred. Examples of hydroxyalkyl acrylates include hydroxyethyl acrylate, hydroxypropyl acrylate, hydroxybutyl acrylate, and the like. Examples of the hydroxyalkyl methacrylates include hydroxyethyl methacrylate, hydroxypropyl methacrylate, hydroxybutyl methacrylate and the like. Of these, particularly preferred are hydroxyethyl methacrylate, hydroxyethyl acrylate, and hydroxybutyl acrylate.

The ethylenic compound of the present invention represented by the general formula (I) can be efficiently obtained by reacting the arginine derivative with the ethylenic compound having a hydroxyl group. The reaction temperature is in the range of 0 to 80 ° C., preferably 10 to 50 ° C. At lower temperatures, the reaction proceeds slowly, and at higher temperatures, the polymerization reaction proceeds. The reaction time is in the range of 2 hours to 96 hours, preferably 12 to 48 hours. If the time is shorter than this, the reaction will not proceed sufficiently,
Further, if the time is longer than this, the yield is reduced due to side reaction. As the catalyst, dicyclohexylcarbodiimide,
A combination of a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and an amine such as 1-hydroxybenzotriazole is preferable.

The solvent is preferably an ethylenic compound used in the reaction, and the use of an organic solvent such as DMF is not preferable because the side reaction easily proceeds. The condensing agent and amine are preferably used in a molar ratio of 1 to 4 times that of the arginine derivative. The ethylenic compound preferably has a molar ratio of 5 to 1 with respect to the arginine derivative.
It is used in the range of 000 times. If the amount of the ethylenic compound used is lower than this range, the reaction becomes nonuniform, or if it is higher than this range, purification becomes difficult.

As a post-treatment method, a method of carrying out rough purification by repeating washing with water and then purifying by column chromatography is preferable. A general formula (V that gives a water-soluble copolymer that is copolymerizable with the above-mentioned arginine derivative
Examples of the acrylate compound represented by I) usually include acrylamide, methacrylamide, N, N-dimethylacrylamide, N-isopropylacrylamide and the like. Among these, acrylamide and N, N-dimethylacrylamide are particularly preferable.

The method for producing a copolymer obtained by copolymerizing the ethylenic compound of the general formula (I) and the water-soluble compound of the general formula (VI) is shown below. The ethylenic compound of the general formula (I) and the water-soluble compound of the general formula (VI) are dissolved in an aqueous polymerization initiator solution such as 4,4 ″ -azobiscyanovaleric acid. The aqueous solution is put in a glass test tube. After degassing, the tube is sealed and heated for 2 to 12 hours at 40 to 100 ° C. to perform polymerization.After the polymerization, the obtained solution is poured into a reprecipitation solvent such as acetone or methanol to reprecipitate, and then, The obtained solid can be dissolved in a good solvent such as water and poured into a reprecipitation solvent to recover the copolymer of the present invention. It can be highly purified and purified.

The copolymer comprising the ethylenic compound of the general formula (I) and the water-soluble compound of the general formula (VI) is particularly preferably 0.1 to 20 mol% of the ethylenic compound and 99.
The composition is preferably 9 to 80 mol%. The number average molecular weight range of the copolymer thus obtained is 2
5,000 to 5 million. The antithrombotic property of the obtained copolymer is determined by the inhibition constant Ki calculated from the measurement result of the fluorescent substrate method,
It is evaluated by relative whole blood coagulation time (RWBCT). This evaluation is performed immediately after preparation of the polymer aqueous solution and 7 days after preparation.

The Ki measured immediately after preparation of the aqueous copolymer solution in which the arginine derivative was bound through the ester bond in the present invention was very large and the antithrombin activity was small, but it was measured after standing at 37 ° C. for 7 days. The Ki value was much lower than immediately after preparation, and the antithrombin activity was improved. The decomposition rate of the arginine derivative that can be calculated from Ki is preferably 5 to 95% after standing at 37 ° C. for 7 days, and more preferably 15 to 35%. On the other hand, in the aqueous copolymer solution bound via an amide bond,
The antithrombin activity is small immediately after the solution is prepared and 7 days later.

In the evaluation of the relative whole blood coagulation time, the RWBCT measured after the aqueous solution of the copolymer in which the arginine derivative was bound via the ester bond was stored for 7 days was significantly increased as compared with that immediately after preparation. On the other hand, in the copolymer aqueous solution bound through the amide bond, RWBCT is close to 1,
No extension was seen upon storage. In addition, generation of an arginine derivative by hydrolysis was confirmed by TLC. This was performed for the aqueous solution immediately after preparation and the aqueous solution after 7 days from preparation. Although the arginine derivative was not formed in the aqueous solution immediately after preparation, the formation of the arginine derivative was confirmed 7 days after preparation.

The method of using the copolymer of the ethylenic compound bound with the arginine derivative of the present invention and the water-soluble compound as an antithrombotic material is a method of graft-polymerizing a polymeric material such as polyurethane, a polymeric material. And a method of fixing after coating on the surface of the polymer material. Further, use of the arginine derivative as an antithrombotic agent having a longer blood half-life can be mentioned. Conventionally,
It is known that when a water-soluble monomer is graft-polymerized on the surface of a base material, a surface having excellent antithrombogenicity can be obtained. However, when combined with sustained release of the drug, the drug is rapidly released, which is preferable. Absent. In this method, since the drug is covalently immobilized, the sustained release of the drug is delayed and the antithrombotic effect is expected to continue. Specific applications of these antithrombotic polymeric materials include artificial kidneys, artificial blood vessels, artificial lenses, artificial heart lungs, artificial valves, artificial hearts, artificial livers, catheters, stents, blood bags, which require antithrombogenicity. Examples include syringes and blood collection tools.

[0041]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to the following examples unless it exceeds the gist. <Reference Example 1> 2.0 mmol of (2R, 4R) under ice cooling
-4-methyl-1- [N ² - ((RS) -3- methyl -
1,2,3,4-Tetrahydro-8-quinolinylsulfonyl) -L-arginyl] -2-piperidinecarboxylic acid (hereinafter referred to as argatroban), 4.4 mmol of 1-ethyl-3- (3-dimethyl) Aminopropyl) carbodiimide hydrochloride and 6.0 mmol of hydroxybenzotriazole were added with 41.6 mmol (5.4 g) of hydroxyethyl methacrylate and stirred at room temperature for 2
The reaction was carried out for 4 hours. At the end of the reaction, 100 ml of chloroform was added, followed by washing with 2% saline, and then the chloroform was distilled off under reduced pressure. The obtained residue was washed with diethyl ether and vacuum dried to react hydroxyethyl methacrylate with argatroban. The product was obtained with a yield of 79.9%.

The IR spectra of argatroban and the reaction product are shown in FIGS. 1 and 2. In FIG. 2, the absorption corresponding to CO of the ester was detected near 1730 cm ⁻¹ . This suggests the introduction of ester bonds. The NMR spectra of argatroban and the reaction product are shown in FIGS. 3 and 4. In FIG. 4, the methylene proton of the methacryloyl group was detected at 5.6 and 6.1 ppm,
The area ratio with aromatic protons was almost in agreement with the calculated value.
This suggests the introduction of methacryloyl groups.
The MS spectrum of the reaction product is shown in FIG. The detected molecular weight 621 matches that of the calculated value. From these measured values, it was confirmed that the reaction product was the following compound (a).

[0043]

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<Reference Example 2> Under ice cooling, 2.0 mmol of agatroban, 4.4 mmol of 1-ethyl-3- (3-
Dimethylaminopropyl) carbodiimide hydrochloride and 6.0 mmol of hydroxybenzotriazole
0.0 mmol (4.6 g) of hydroxyethyl acrylate was added, and the mixture was reacted under stirring at room temperature for 24 hours. At the end of the reaction, add 150 ml of chloroform, then 2
After washing with sodium chloride solution, chloroform was distilled off under reduced pressure, the obtained residue was washed with diethyl ether, and then vacuum dried to obtain a reaction product of hydroxyethyl acrylate and argatroban in a yield of 80.9%. .

The NMR spectrum of the reaction product is shown in FIG. In FIG. 6, the methylene proton of the acryloyl group is
It was detected at 5.8 to 6.4 ppm, and the area ratio with the aromatic protons almost coincided with the calculated value. This suggests the introduction of methacryloyl groups. The MS spectrum of the reaction product is shown in FIG. The detected molecular weight 607 matches that of the calculated value. From these measured values, it was confirmed that the reaction product was the following compound (b).

[0046]

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Reference Example 3 2.0 mmol of argatroban and 4.4 mmol of 1-ethyl-3- (3 under ice cooling.
4-dimethylaminopropyl) carbodiimide hydrochloride and 6.0 mmol of hydroxybenzotriazole
0.0 mmol of hydroxybutyl acrylate was added, and the mixture was reacted under stirring at room temperature for 24 hours. 1 at the end of the reaction
After adding 25 ml of chloroform and then washing with 2% saline, the chloroform was distilled off under reduced pressure, the obtained residue was washed with diethyl ether and then vacuum dried to obtain a reaction product of hydroxybutyl acrylate and argatroban. Obtained in a yield of 80.0%.

The NMR spectrum is shown in FIG. In FIG. 8, the methylene protons of the acryloyl group are 5.8 to 6.
It was detected at 4 ppm, and the area ratio with the aromatic protons almost coincided with the calculated value. This suggests the introduction of an acryloyl group. The MS spectrum of the reaction product is shown in FIG.
Shown in The detected molecular weight 635 matches that of the calculated value. From these measured values, it was confirmed that the reaction product was the following compound (c).

[0049]

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Reference Example 4 1.0 mmol of argatroban and 1.50 mmol of hydroxybenzotriazole 1.0 mmol of aminomethylstyrene were dissolved in 20 ml of DMF, and 1.1 mmol of 1-ethyl-.
3- (3-dimethylaminopropyl) carbodiimide.
Hydrochloride was added, and the mixture was reacted at room temperature for 24 hours with stirring. At the end of the reaction, add 300 ml of chloroform, then 2
After washing with saline solution, the chloroform was distilled off under reduced pressure, and the residue was washed with diethyl ether and dried under vacuum. The yield of the obtained reaction product of aminomethylstyrene and argatroban was 7
It was obtained at 8.1%. From the NMR spectrum (FIG. 10) and the MS spectrum (FIG. 11) of the obtained compound, it was confirmed to be the following compound (d).

[0051]

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<Example 1> Compound 6 obtained in Reference Example 1
6 nmol and 6.5 mmol of acrylamide were dissolved in 10 ml of water containing 3.6 nmol of azobiscyanovaleric acid, and this was placed in a glass test tube. After degassing, the tube was sealed and heated at 80 ° C. for 6 hours. This reaction solution was poured into 100 ml of acetone for reprecipitation. Next, the obtained solid was dissolved in water, and the treatment of pouring this into acetone was repeated to obtain a copolymer having a number average molecular weight of 426,000.

Example 2 Using the compound obtained in Reference Example 2 instead of the compound obtained in Reference Example 1, Example 1
The same operation as described above was performed. <Example 3> The same operation as in Example 1 was carried out by using the compound obtained in Reference Example 3 instead of the compound obtained in Reference Example 1. Comparative Example 1 Using the compound obtained in Reference Example 4 instead of the compound obtained in Reference Example 1, the same operation as in Example 1 was carried out to obtain a copolymer.

<Comparative Example 2> Acrylamide 7.0 mmo
l is azobis cyanovaleric acid 3.6 nmol
Was dissolved in 10 ml of water containing and was placed in a glass test tube. After degassing, the tube was sealed and heated at 80 ° C. for 6 hours. This reaction solution was poured into 100 ml of acetone for reprecipitation. Then, the obtained solid was dissolved in water, and the treatment of pouring it into acetone was repeated.

<Example 4> Examples 1 to 3 and Comparative Example 1
The following evaluations were performed on the (co) polymers prepared in Steps 1 to 2. i) Copolymer aqueous solution corresponding to 83.3 nM arginine derivative 1.5 ml ii) 125 mM Tris-HCl (pH 8.0), 3
75 mM NaCl, 2.5 mM CaCl ₂ , 0.2
Aqueous solution consisting of 5 mg / ml BSA (bovine serum albumin) 1.0 ml 5 mM Boc-V in a mixed solution of the above i) and ii)
2.5 μl, 3.3 μl, 5 μl or 10 μl of the al-Pro-Arg-MCA DMSO solution was added to each solution, and 3 μl of a 60 U / l thrombin aqueous solution was added. From the change with time of the fluorescence wavelength (excitation wavelength 380 nm) at 440 nm of this solution, the inhibition constant (K
i) was determined. The inhibition constant Ki is Lineweave.
From the slope and intercept of the r-Burk plot, the following (1)
It was calculated using the equation.

[0056]

[Equation 1]

V is the hydrolysis rate of the fluorescent substrate, Vmax
Is the hydrolysis rate in the presence of a large excess of substrate, K _M is Mic
haelis constant, [I] indicates the inhibitor concentration, and [S] indicates the substrate concentration. The smaller the Ki, the greater the interaction with thrombin. The same measurement was performed in the case where an aqueous solution of a copolymer corresponding to 42 μM of arginine derivative was stored at 37 ° C. for 7 days. The decomposition rate of argatroban was calculated from Ki using the equation (1). In this case, it is assumed that only the arginine derivative released by hydrolysis has activity. Table 2 shows the results.

[0058]

[Table 3]

From the above results, it was found that the antithrombin activity was improved by storing the ester copolymer solution at 37 ° C. for 7 days. <Example 5> The (co) polymers prepared in Examples 1 to 3 and Comparative Examples 1 and 2 were evaluated as follows. About 12
ml human blood was collected from the vein, of which 11.37
ml 4.4 w / v% trisodium citrate dihydrate, 1.6 w / v% citric anhydride, 4.4 w / v%
The mixture was added to a polypropylene tube containing 0.63 ml of an aqueous solution of glucose in Example 1 and mixed well. (ACD blood)

950 μl of ACD blood was added to and mixed with a glass test tube having an inner diameter of 1 cm containing 50 μl of an aqueous solution having a concentration of 1 × 10 ⁻³ M corresponding to the above-mentioned (co) polymer arginine derivative. The concentration of arginine derivative in blood is 5 × 10
^-5 M. 0.2M calcium chloride solution 1
00 μl was mixed and left at 37 ° C. The time from the addition of the calcium chloride aqueous solution to the disappearance of blood fluidity was measured. The ratio to the blood coagulation time in the sample containing no copolymer was defined as RWBCT. Similar measurement 3
It was carried out using an aqueous copolymer solution stored at 7 ° C. for 7 days.
The results are shown in Table-3.

[0061]

[Table 4]

From the above results, it was found that the anticoagulant activity was improved by storing the aqueous solution of the ester copolymer at 37 ° C. for 7 days. <Example 6> 2 μl of a (copolymer) aqueous solution corresponding to 2 mM of an arginine derivative immediately after preparation was spotted on a TLC plate. The above solution stored at 37 ° C for 7 days after preparation was also spotted in the same manner. This TLC plate was developed with chloroform: methanol = 8: 2 and then irradiated with UV of 321 nm to observe the development of spots. R
The f values (spot development distance / developing solution development distance) are shown in the table below.

[0063]

[Table 5]

As is clear from the results, the formation of a component corresponding to Rf of argatroban was confirmed in the ester copolymers (Examples 1, 2 and 3) after storage for 7 days. It is considered that the improved antithrombin activity and anticoagulant activity in Examples 4 and 5 were due to argatroban released by hydrolysis.

[0065]

The antithrombotic polymeric material is obtained by grafting or blending the copolymer of the present invention with the acrylate compound composed of the ethylenic compound bound with the arginine derivative onto the polymeric material. Expected to be Further, it can be considered that the arginine derivative can be used as an antithrombotic agent having a longer half-life in blood.

[Brief description of drawings]

FIG. 1 is an IR spectrum diagram of argatroban.

2 is an IR spectrum diagram for structural identification of the argatroban-bonded ethylenic compound produced in Reference Example 1. FIG.

FIG. 3 is an NMR spectrum diagram of argatroban.

FIG. 4 is an NMR spectrum diagram for structurally identifying the ethylenic compound bound with argatroban produced in Reference Example 1.

FIG. 5 is a mass spectrum diagram for structurally identifying the ethylenic compound to which argatroban produced in Reference Example 1 is bound.

FIG. 6 is an NMR spectrum diagram for structurally identifying an ethylenic compound having argatroban bound in Reference Example 2.

FIG. 7 is a mass spectrum diagram for structurally identifying the ethylenic compound having argatroban bound therein produced in Reference Example 2.

8 is an NMR spectrum diagram for structural identification of an ethylenic compound having argatroban bound in Reference Example 3.

FIG. 9 is a mass spectrum diagram for structurally identifying the ethylenic compound to which argatroban produced in Reference Example 3 is bound.

FIG. 10 is an NMR spectrum diagram for structurally identifying the ethylenic compound bound with the arginine derivative of the present invention, which was produced in Reference Example 4.

FIG. 11 is a mass spectrum diagram for structurally identifying the ethylenic compound bound with the arginine derivative of the present invention, which was produced in Reference Example 4.

Claims (2)

[Claims] 1. A compound represented by the following general formula (I) [In the above formula, A represents an arbitrary bond, R ¹ represents a hydrogen atom or a C _{1 to} C ₅ alkyl group, and R ² represents the following general formula (II) or (III). Embedded image (In the formula, R ⁴ represents a C _{1 to} C ₆ alkyl group which may have a substituent, a C _{2 to} C ₇ alkoxyalkyl group or a tetrahydrofurfuryl group, and R ⁵ represents a C _{1 to} C _{3 group} . Represents an alkylene group, R ⁶ represents a hydrogen atom or a C ₁ -C ₄ alkyl group which may have a substituent), and R ³
Is the following general formula (IV) or (V) Embedded image (In the formula, R ⁷ and R ⁸ are each independently a hydrogen atom,
Represents a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ alkylamino group or a C ₁ -C ₄ dialkylamino group, R
⁹ represents a hydrogen atom or a C ₁ -C ₄ alkyl group which may have a substituent. ), M represents an integer of 0 to 18, n represents an integer of 0 or 1, and p represents an integer of 3 or 4. ] The ethylenic compound represented by the following general formula (VI): (In the formula, R ¹⁰ , R ¹¹ and R ¹² each independently represent a hydrogen atom or a C _{1 to} C ₄ alkyl group.) A water-soluble compound represented by ,
The following compound (VII) (In the formula, R ² , R ³ and p are the same as above.) A sustained-release antithrombotic copolymer characterized by being sustained-released. 2. A in the general formula (I) is —COO—,
The sustained release antithrombotic copolymer according to claim ¹ , wherein R ¹ is a hydrogen atom or a methyl group.