JPS6114828B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel antithrombotic medical material and a method for producing the same.

In recent years, polymer materials have come to be used in the field of medical materials.
When used in areas that come into direct contact with blood, such as catheters, artificial kidneys, artificial hearts, artificial lungs, and sutures, there is a problem in that it causes thrombus formation. Thrombus formation means that fibrinogen in the blood is finally converted to fibrin through a series of complex enzyme reactions involving many coagulation factors. on the other hand,
At the same time as fibrin is formed in the blood coagulation system, an equilibrium state is maintained by constantly dissolving the once formed fibrin in the fibrinolytic system. The conventional development of antithrombotic materials focused primarily on the blood coagulation system, and involved applying heparin, which acts as an inhibitor of the blood coagulation system, to the material surface to inhibit the conversion of fibrinogen to fibrin.

The present inventors have focused on the dissolution of insoluble fibrin that has been formed, and have investigated the application of pyrazolidine derivatives having specific alcoholic hydroxyl groups to the surface of polymeric materials. The present invention was achieved by discovering that a material can be obtained.

That is, the present invention provides (1) an antithrombotic medical material in which a pyrazolidine derivative having an alcoholic hydroxyl group represented by the following general formula () is bonded or adsorbed to a polymeric substance; and (2) an antithrombotic medical material having the following general formula ().
A pyrazolidine derivative having an alcoholic hydroxyl group represented by (hereinafter abbreviated as a pyrazolidine derivative having an alcoholic hydroxyl group). This is a method for producing an antithrombotic medical material, which is characterized in that the pyrazolidine derivative having an alcoholic hydroxyl group is bound or adsorbed to the polymeric substance by treating the polymeric substance with a solution in which the alcoholic hydroxyl group-containing pyrazolidine derivative is dissolved.

However, in the formula, R ¹ represents an alkyl group or a substituted alkyl group, R ² represents a hydrogen atom or a hydroxyl group, and n represents an integer of 1 to 6. More specifically, R ¹ in the formula is an alkyl group having 10 or less carbon atoms, an oxoalkyl group such as oxoethyl, oxopropyl, oxobutyl, oxopentyl, oxohexyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl,
hydroxyalkyl groups such as hydroxyhexyl,
Phenylsulfinyl alkyl groups such as phenylsulfinylethyl, phenylsulfinylpropyl, phenylsulfinylbutyl, phenyloxoethyl, phenyloxopropyl, phenyloxobutyl, phenyloxopentyl, phenyloxohexyl phenyloxoalkyl groups, such as
Furanyloxoalkyl groups such as furanyloxopropyl, furanyloxobutyl, furanyloxopentyl, furanyloxohexyl, cyclohexyloxoalkyl groups such as cyclohexyloxopropyl, cyclohexyloxobutyl, cyclohexyloxopentyl, cyclohexyl, oxohexyl, etc. represents a substituted alkyl group,
R ² represents a hydrogen atom or a hydroxyl group, and n is 1 to
Represents an integer of 6.

Examples of the compound represented by the general formula () include the following.

4-n-butyl-4-hydroxymethyl-1.
2-diphenyl-3,5-dioxopyrazolidine, 4-n-butyl-4-hydroxymethyl-1
-Phenyl-2-(P-hydroxyphenyl)-
3,5-dioxopyrazolidine, 4-(3-oxobutyl)-4-hydroxymethyl-1,2-diphenyl-3,5-dioxopyrazolidine, 4-
(4,4-dimethyl-3-oxopentyl)-4-
Hydroxymethyl-1,2-diphenyl-3,5
-dioxopyrazolidine, 4-[2-(phenylsulfinyl)ethyl]-4-hydroxymethyl-
1,2-diphenyl-3,5-dioxopyrazolidine, 4-[1-(2-furanyl)-3-oxobutyl]-4-hydroxymethyl-1,2-diphenyl-3,5-dioxopyrazolidine , 4-[(2
-oxocyclohexyl)ethyl]-4-hydroxymethyl-1,2-diphenyl-3,5-dioxopyrazolidine, 4-(4,4-dimethyl-3
-hydroxypentyl)-4-hydroxymethyl-1,2-diphenyl-3,5-dioxopyrazolidine, 4-n-butyl-4-hydroxyethyl-1,2-diphenyl-3,5-dioxopyrazolidine These pyrazolidine derivatives having an alcoholic hydroxyl group exhibit excellent fibrinolytic activity, and since they have highly reactive alcoholic hydroxyl groups, they can be easily combined with polymeric substances without reducing fibrinolytic activity, or they can be easily combined with polymeric substances without reducing fibrinolytic activity. It can be adsorbed to , and it is also chemically stable.

The polymeric substance in the present invention refers to an organic or inorganic substance with a large molecular weight. Examples of such polymeric materials include polyamide, polyester polyvinyl chloride, polystyrene, polyurethane,
Polyacrylic acid ester, polymethacrylic acid ester, polycarbonate, polyacrylonitrile, polyacrylamide, polyacrylic acid, polymethacrylic acid, polyethylene, polypropylene,
Polyvinyl alcohol, silicone resin, polymaleic anhydride, polyethyleneimine, cellulose,
organic substances such as starch, protein, and natural rubber;
Examples include inorganic substances such as glass, asbestos, mica, activated carbon, and polyphosphazene.

The antithrombotic medical material of the present invention can be produced by various methods. For example, if the polymer substance has a reactive functional group that can form a covalent bond (or a polymer substance that has a reactive functional group that can form a covalent bond), alcohol An antithrombotic medical material in which a pyrazolidine derivative having an alcoholic hydroxyl group is covalently bonded to a polymer substance can be produced by treating the material with a solution containing a pyrazolidine derivative having an alcoholic hydroxyl group. Examples of the reactive functional group capable of forming a covalent bond include groups such as an epoxide group, a chloroformyl group, a bromoacetyl group, an isocyanate group, an acid anhydride group, and a halogenated triazine group. For polymeric substances that have no or only a few reactive functional groups capable of forming covalent bonds, a sufficient amount of reactive functional groups can be introduced by polymeric reaction.
Furthermore, a polymer reaction can also be performed on a polymer substance having a sufficient amount of reactive functional groups in order to convert them into other reactive functional groups. For example, polymeric substances such as polyamide having amino groups and polyvinyl alcohol having hydroxyl groups can be epoxidized by reacting them with bisepoxide. Moreover, if a polyacid anhydride such as a maleic anhydride-ethylene copolymer is used instead of bisepoxide, those polymeric substances can be converted into an acid anhydride. Furthermore, glass or silicon can be aminated by reacting with γ-aminopropyltriethoxylane, and by reacting the amino group with bisepoxide or polyacid anhydride, these polymers can be aminated. The surface of the substance can be epoxidized or acid anhydride-formed. The reactive functional group capable of forming a covalent bond reacts with the hydroxyl group of the pyrazolidine derivative having an alcoholic hydroxyl group to form a covalent bond. Examples of the solvent for dissolving the pyrazolidine derivative having an alcoholic hydroxyl group include water, benzene, acetone, dioxane, tetrahydrofuran, ethylene chloride, chloroform, ethyl acetate, dimethylformamide, pyridine, or other general organic solvents that do not participate in the reaction. It will be done. These can be used alone, but if necessary, they can be used in combination. When treating a polymeric substance with a solution in which a pyrazolidine derivative having an alcoholic hydroxyl group is dissolved, the treatment temperature may be above the melting point of the solvent and below the boiling point of the solvent, but a range of 0 to 100°C is particularly desirable. It is also desirable to carry out the reaction in the presence of a catalyst such as an acid or an alkali, if necessary. Furthermore, during treatment, it is desirable to renew the surface of the polymeric substance by stirring, circulation, etc.

The antithrombotic medical material of the present invention can also be produced by adsorbing a pyrazolidine derivative having an alcoholic hydroxyl group onto a polymeric substance as follows. That is, by dissolving a polymeric substance in a solvent that can wet or swell or dissolve a pyrazolidine derivative having an alcoholic hydroxyl group, and treating the polymeric substance with this solution, alcoholic hydroxyl groups can be added to the polymeric substance. It is possible to produce an antithrombotic medical material to which a pyrazolidine derivative having the following is adsorbed. In this case, examples of solvents include water, methanol, ethanol, propanol, benzene,
Common organic solvents such as acetone, dioxane, tetrahydrofuran, chloroform, dimethylformamide, and pyridine are used. These can be used alone, but if necessary, they can be used in combination.

Furthermore, by adding acids, alkalis, salts, etc., it is possible to adjust the wettability, swelling properties, and solubility of polymeric substances or the solubility of pyrazolidine derivatives having alcoholic hydroxyl groups. The treatment temperature may be above the melting point of the solvent and below the boiling point of the solvent, but a range of 0 to 100°C is particularly desirable. Further, during the treatment, it is desirable to perform the treatment while renewing the surface of the polymeric substance.

Further, in the present invention, a fibrinolytic active enzyme can be bound or adsorbed to a polymer substance together with a pyrazolidine derivative having an alcoholic hydroxyl group. That is, by treating a polymer substance with a solution in which a fibrinolytic active enzyme is dissolved together with a pyrazolidine derivative having an alcoholic hydroxyl group, the fibrinolytic active enzyme is bound or adsorbed to the polymer substance. It is possible to produce antithrombotic medical materials. The fibrinolytic active enzyme used herein refers to an enzyme that contributes to the dissolution of fibrin, and includes, for example, plasmin, purinolase, urokinase, and streptokinase.
The simplest method for binding or adsorbing these fibrinolytic active acetic acids to a polymeric substance is to treat the polymeric substance with a solution containing a pyrazolidine derivative having an alcoholic hydroxyl group. The goal is to allow enzymes to coexist. By this treatment, the fibrinolytic active enzyme and the pyrazolidine derivative having an alcoholic hydroxyl group can be simultaneously bound or adsorbed to the polymeric substance. Furthermore, the fibrinolytic active enzyme and the pyrazolidine derivative having an alcoholic hydroxyl group may be bonded or adsorbed stepwise, for example, the pyrazolidine derivative having an alcoholic hydroxyl group may be first bonded or adsorbed, and then the fibrinolytic active enzyme may be bonded or adsorbed. I can and
Or it may be the other way around. For this purpose, the polymeric substance may be treated stepwise with a solution in which a pyrazolidine derivative having an alcoholic hydroxyl group and a fibrinolytic active enzyme are dissolved respectively. When dissolving fibrinolytic active enzymes, it is necessary to select a solvent that does not inactivate the fibrinolytic active enzymes.
Water is the most preferable solvent for dissolving the pyrazolidine derivative having an alcoholic hydroxyl group and the fibrinolytic active enzyme, but if necessary, water may be mixed with a solvent that can be mixed with water such as dioxane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, or pyridine. A mixed solvent of can be used. The fibrinolytic active enzyme solution is used after adjusting its ionic strength, pH, etc., as necessary. In the case of a polymeric substance having a reactive functional group capable of forming a covalent bond, both can be covalently bonded. Furthermore, when using a solvent that can wet, swell, or dissolve the polymeric substance and also dissolve the pyrazolidine derivative having an alcoholic hydroxyl group and the fibrinolytic active enzyme, it is possible to adsorb both to the polymeric substance. can.

In the present invention, the polymeric substance treated with a solution containing a pyrazolidine derivative having an alcoholic hydroxyl group may be processed into various shapes such as powder, beads, filament, cloth, film, tube, or membrane depending on the purpose. It's okay to be hot. Furthermore, after binding or adsorbing a pyrazolidine derivative having an alcoholic hydroxyl group, it can be processed into various shapes.

The antithrombotic medical material of the present invention has excellent fibrinolytic activity and has the feature that its effect lasts for a long time, so it is particularly suitable for blood contact medical materials such as artificial blood vessels, catheters, artificial valves, artificial hearts, and blood vessels. Useful as sutures, etc. Furthermore, the method of the present invention is extremely easy to operate, and the raw materials are inexpensive, making it extremely advantageous in terms of cost.

EXAMPLES Next, the present invention will be explained in more detail with reference to Examples. Antithrombotic properties were evaluated using Chandler's rotating tube method [ABChandler Laboratory
Investigation, 7 , 110 (1958)] (Human citrated blood was injected into a tube, and the clot formation time after addition of Ca ⁺⁺ was measured.

Example 1 9.3 g of phenylbutazone was dissolved in 50 ml of ethanol, 9 ml of formalin (37%) was added, and the mixture was refluxed for 2 hours. After cooling, filter to obtain 9.9 g of 4-n-butyl-4-hydroxymethyl-1,2-diphenyl-3,5-dioxopyrazolidine as a white solid.
(mp 146°C) (corresponds to the general formula () where R ¹ = n-butyl, R ² = hydrogen, and n = 1) was obtained.

3N-hydrochloric acid at a temperature of 30°C was passed through a nylon 6 tube with an inner diameter of 3 mm and an outer diameter of 5 mm at a flow rate of 100 ml/min.
Circulated for 30 minutes. After pouring out the hydrochloric acid from the tube, washing was performed by circulating ion-exchanged water. The inside of the nylon tube treated with hydrochloric acid
A mixed solution consisting of 100 ml of 10% polyethyleneimine aqueous solution and 500 ml of methanol was circulated at room temperature for 2 hours at a flow rate of 100 ml/min. Next, 200 ml of a 5 wt % methanol solution of dicyclohexyl carbodiimide was added, followed by circulation at a flow rate of 100 ml/min for 6 hours. After pouring out the treatment liquid from the tube, it was washed by circulating methanol and then dried under reduced pressure. 4wt of maleic anhydride-methyl vinyl ether copolymer was passed through this polyethyleneimine-treated nylon tube at a flow rate of 100ml/min.
% acetone solution was circulated for 1 hour at room temperature, washed with dehydrated acetone, and then dried. 1 nylon tube treated with maleic anhydride-methyl vinyl ether copolymer obtained as above.
m, and the temperature inside it is 70 at a flow rate of 50ml/min.
100ml of a 4wt% dioxane solution of 4-n-butyl-4-hydroxymethyl-1,2-diphenyl-3,5-dioxopyrazolidine (a trace amount of concentrated hydrochloric acid was added as a catalyst) at ℃ was circulated for 5 hours. did. The treated tube was washed with dioxane and then dried under reduced pressure. In this way, a material in which 4-n-butyl-4-hydroxymethyl-1,2-diphenyl-3,5-dioxopyrazolidine was covalently bonded to a nylon tube treated with maleic anhydride-methyl vinyl ether copolymer was prepared. Obtained. The clot formation time of the obtained material was measured by Chandler's rotating tube method and was over 45 minutes.

For comparison, the clot formation times of an untreated nylon 6 tube and a medical silicone tube with the same inner diameter were measured and were 10 minutes and 20 minutes, respectively.

Example 2 Bis(4-hydroxybutyl) terephthalate (75 parts by weight), poly(tetramethylene oxide) glycol with a molecular weight of 2000 (75 parts by weight), and tetrabutyl titanate (0.075 parts by weight) were charged into a reactor and heated under a nitrogen atmosphere. , 250℃, 1mm while stirring
A copolymer was obtained by carrying out a polycondensation reaction for 90 minutes under high vacuum below Hg. After the reaction was completed, the copolymer was extruded into water to obtain a tube with an inner diameter of 3 mm and an outer diameter of 5 mm.

Inside this tube, 100 ml of 10% polyethyleneimine aqueous solution and 500 ml of methanol were mixed at a flow rate of 100 ml/min.
A mixed solution consisting of was circulated at room temperature for 2 hours. Next, 200 ml of a 5 wt % methanol solution of dicyclohexyl carbodiimide was added and the mixture was continuously circulated for 6 hours. After the treatment liquid was poured out from inside the tube, it was washed by circulating methanol and then dried under reduced pressure. The inside of this polyester/polyether copolymer tube treated with polyethyleneimine
4 wt% acetone solution of maleic anhydride-methyl vinyl ether copolymer at a flow rate of 100 ml/min.
ml was circulated for 1 hour at room temperature, washed with dehydrated acetone, and then dried. A 1 m tube of the maleic anhydride-methyl vinyl ether copolymer-treated polyester/polyether copolymer tube obtained in this way was placed inside the tube at a flow rate of 50 ml/min at a temperature of 50°C. 100 ml of a 4 wt % solution of 4-hydroxymethyl-1,2-diphenyl-3,5-dioxopyrazolidine in dioxane (a trace amount of concentrated hydrochloric acid was added as a catalyst) was circulated for 5 hours. The treated tube was washed with dioxane and then dried under reduced pressure. 4-n- thus obtained
When the clot formation time of a polyester/polyether copolymer tube to which butyl-4-hydroxymethyl-1,2-diphenyl-3,5-dioxopyrazolidine was covalently bonded was measured, it was over 45 minutes. When the thrombus formation time was repeatedly measured in the same tube, it was 45 minutes or more even in 5 or more measurements.

For comparison, the clot formation time of an untreated polyester/polyether copolymer tube with the same inner diameter was measured and was 20 minutes.

Example 3 γ-aminopropyltriethoxysilane was placed inside a silicone tube with an inner diameter of 3 mm and an outer diameter of 4 mm.
After circulating 100 ml of a 10 wt% chloroform solution at a flow rate of 50 ml/min at room temperature for 5 hours, it was dried under reduced pressure. Inside this silicone tube, a 4wt% acetone solution of maleic anhydride-methyl vinyl ether copolymer was added.
After circulating 200 ml at a flow rate of 100 ml/min at room temperature for 1 hour, it was washed with dehydrated acetone and then dried. A 1 m long silicone tube treated with the maleic anhydride-methyl vinyl ether copolymer thus obtained was taken, and 4-n-butyl-4-hydroxymethyl-4-n-butyl-4-hydroxymethyl- 100 ml of a 4 wt % solution of 1,2-diphenyl-3,5-dioxopyrazolidine in dioxane (a trace amount of concentrated hydrochloric acid was added as a catalyst) was circulated for 5 hours. The treated tube was washed with dioxane and then dried under reduced pressure. 4-n- thus obtained
The time required for blood clot formation in a silicon tube to which butyl-4-hydroxymethyl-1,2-diphenyl-3,5-dioxopyrazolidine was covalently bonded was measured and was found to be over 45 minutes. When the thrombus formation time was repeatedly measured in the same tube, it was 45 minutes or more even in five or more measurements.

Example 4 4-n-butyl was poured into a 1 m silicone tube with an inner diameter of 3 mm and an outer diameter of 5 mm at a flow rate of 50 ml/min.
100 ml of a 15 wt % acetone solution of 4-hydroxymethyl-1,2-diphenyl-3,5-dioxopyrazolidine was circulated for 5 hours. When the time for blood clot formation in the silicone tube adsorbed with 4-n-butyl-4-hydroxymethyl-1,2-diphenyl-3,5-dioxopyrazolidine thus obtained was measured, it was over 45 minutes. It was hot.

Claims (1)

[Scope of Claims] 1. An antithrombotic medical material in which a pyrazolidine derivative having an alcoholic hydroxyl group represented by the following general formula () is bonded or adsorbed to a polymeric substance. (In the formula, R ¹ represents an alkyl group or a substituted alkyl group, R ² represents a hydrogen atom or a hydroxyl group, and n
represents an integer from 1 to 6. ) 2 By treating a polymeric substance with a solution containing a pyrazolidine derivative having an alcoholic hydroxyl group represented by the following general formula (), the pyrazolidine derivative having an alcoholic hydroxyl group is bound or adsorbed to the polymeric substance. A method for producing an antithrombotic medical material, characterized by: (In the formula, R ¹ represents an alkyl group or a substituted alkyl group, R ² represents a hydrogen atom or a hydroxyl group, and n
represents an integer from 1 to 6. )