JP2002256067A - Ew polyamino acid ester - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a polyamino acid ester wherein its application is expected as a new functional polymer having properties such as biocompatibility, biodegradability and electrolyzability, in the field of medical materials, hygienic materials, agricultural and fishery materials, coating materials, surface treatment agents and the like. SOLUTION: This polyamino acid ester and its salt contain, as polymerizing components, β-hydroxyasparagic acid and/or its derivatives expressed by formula (1) [p denotes an integer of 2 or 3, and R denotes a hydrogen atom, 1-5 alkyl group, alkylcarbonyl group, benzoyl group, alkyloxycarbonyl group, benzyloxycarbonyl group or alkylcarboxyl group].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a polyamino acid ester comprising β-hydroxyaspartic acid or a derivative thereof as a polymerization component, and a salt thereof.

[0002]

BACKGROUND ART Fermentatively produced γ as a polyamino acid
Α-polyglutamic acid, ε-polylysine, etc., and α such as glutamic acid, aspartic acid, glycine, lysine, etc.
-Homopolymers, copolymers of amino acids synthesized directly from amino acids, block copolymers with other polymers are known. These polyamino acids are biocompatible,
Developed as biodegradable polymers in the fields of sutures, bone fixation and joining materials, wound dressings, medical materials such as pharmaceutical sustained release preparation materials, synthetic leather surface treatment agents, fiber treatment agents, cosmetic base materials, etc. ing. As amino acid polyesters, USP 5,990,
266, and is being developed as a biodegradable polymer.

[0003]

DISCLOSURE OF THE INVENTION The present invention is directed to a novel poly (vinyl alcohol) having a variety of properties from thermoplasticity to thermosetting and having biodegradability, using β-hydroxyaspartic acid and one of its derivatives as amino acids. It is intended to provide an amino acid ester.

[0004]

The present invention provides (1) the following formula (1)

[0005]

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[Wherein p represents an integer of 1 to 3. R represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkylcarbonyl group, a benzoyl group, an alkyloxycarbonyl group, a benzyloxycarbonyl group or an alkylcarboxyl group. A polyamino acid ester comprising β-hydroxyaspartic acid and / or a derivative thereof represented by the formula (I) as a polymerization component, and a salt thereof. A polyamino acid ester having β-hydroxyaspartic acid and / or a derivative thereof represented by the following formula as a polymerization component, and a salt thereof: (2) the following formula (2):

[0007]

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Wherein m is the number of repetitions, and
Shows the degree of polymerization required for the number average molecular weight of the polyester diol to be 500 or more. p and R are as defined in the above formula (1)
Has the same meaning as in Y represents a residue of the glycol compound. A polyamino acid ester obtained by reacting a β-hydroxyaspartic acid polyester diol represented by the formula (I) with a dicarboxylic acid and / or an anhydride thereof, and a salt thereof, (3) Formula (3)

[0009]

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[Wherein, n represents 0 or an integer of 1 or more.
m, p, R and Y have the same meaning as in the above formula (2). R ¹ is a dicarboxylic acid residue. A polyamino acid ester and a salt thereof represented by the following formula (4):

[0011]

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Wherein p and R have the same meanings as in the above formula (1). X represents a hydrogen atom or an alkali metal. s is an integer of 2 to 10,000, and q and r are s ≧
q + r is satisfied, q is an integer of 0 to s, and r is an integer of 0 to s. However, q and r do not become 0 at the same time. A polyamino acid ester represented by the following formula (5):

[0013]

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[In the formula, t represents an integer of 1 or more. p and R represent the same meaning as in the above formula (1). Z represents a residue of a glycol or epoxy compound. And (6) a biodegradable polyamino acid ester and salt thereof according to any one of (1) to (5) above, and (7) a substrate for cell culture. The polyamino acid ester and the salt thereof according to any one of the above (1) to (5) for a material, and (8) the polyamino acid ester according to any one of the above (1) to (5) for a tissue culture support Polyamino acid esters and salts thereof, (9) Polyamino acid esters and salts thereof according to any one of the above (1) to (5) for carriers of immobilized enzymes, (10) for carriers of immobilized cells The polyamino acid ester and salt thereof according to any one of the above (1) to (5), (11) the polyamino acid ester according to any one of the above (1) to (5) for a carrier of a drug delivery system. Polyamino acid esters and salts thereof, (12) gene carriers in gene therapy (1) to the Pertaining polyamino acid ester and a salt thereof according to any one of (5).

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION The polyamino acid ester of the present invention has the following formula (1)

[0016]

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Wherein p is an integer of 1 to 3. R is a hydrogen atom,
And represents an alkyl group having 1 to 5 carbon atoms, an alkylcarbonyl group, a benzoyl group, an alkyloxycarbonyl group, a benzyloxycarbonyl group or an alkylcarboxyl group. Β-hydroxyaspartic acid and / or
Alternatively, a derivative thereof is used as a polymerization component. The polyamino acid ester of the present invention is not particularly limited as long as β-hydroxyaspartic acid and / or its derivative represented by the above formula (1) is used as a polymerization component, but preferred embodiments will be specifically described below. . In addition, when the compound in which p is 3 in the formula (1) is a polymerization component, the amino group in the polyamino acid ester of the present invention exists as an ammonium ion.

For example, as described in the above (2), a polyester diol represented by the formula (2) obtained by polycondensing a compound represented by the formula (1) and / or a derivative thereof with a glycol compound is reacted with a dicarboxylic acid and The polyamino acid ester of the present invention can be obtained by chain extension with an anhydride thereof.

The β-hydroxyaspartic acid of the formula (1) and its derivatives can be obtained by the fermentation method disclosed in JP-A-07-107990 and the synthesis method disclosed in JP-A-11-222471. Specifically, for example, it is obtained by reacting epoxysuccinic acid with ammonia or a primary and / or secondary amine compound. Specific examples of the amine compound include:
Examples thereof include (di) methylamine, (di) ethylamine, (di) propylamine, benzylamine, and aniline. In addition, the active hydrogen of the amino group of β-hydroxyaspartic acid and an alkylcarbonyl group, a benzoyl group,
The compound of the formula (1) can be obtained by substituting an alkyloxycarbonyl group or a benzyloxycarbonyl group by a known method, or a compound of the formula (1) wherein p = 3 by ammonium-forming an amino group by a known method. You can also get β
-The structure of hydroxyaspartic acid and its derivatives is L
It may be -threo or D-threo, L-erythro-form, D-erythro-form, or a mixture thereof.

The polyester diol of the formula (2) used in the present invention can be obtained by dissolving or dispersing the compound of the formula (1) in a solvent and decondensing with a glycol compound while dehydrating in the presence of a catalyst. .

Specific examples of glycol compounds that can be used include ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, propylene glycol, dipropylene glycol, 1,3-
Propanediol, 1,4-butanediol, 1,3-
Butanediol, 2,3-butanediol, 1,5-pentanediol, 1,4-pentanediol, 2,4-
Pentanediol, 1,6-hexanediol, 1,2
-Hexanediol, 1,5-hexanediol, 2,
5-hexanediol, 1,7-heptanediol,
1,8-octanediol, 1,9-nonanediol,
1,10-decanediol, neopentyl glycol,
Examples thereof include, but are not limited to, polytetramethylene glycol, tricyclodecane dimethylol, and mixtures thereof.

The molar ratio of the compound of the formula (1) to the glycol compound is usually from 1: 1.1 to 1: 2, preferably from 1: 1.
8 As the solvent, benzene, toluene, xylene, hexane, heptane, octane, cyclohexane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, sulfolane, polyphosphoric acid, and the like are used. It is preferable to select a good combination. Particularly, toluene, heptane and sulfolane are preferred. Examples of the catalyst include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, organic acids such as p-toluenesulfonic acid, methanesulfonic acid and trifluoromethanesulfonic acid, aluminum chloride, titanium tetrachloride, tin chloride, tetraethoxytitanium and tetraethoxytitanium. Lewis acids such as propoxytitanium, tetrabutoxytitanium, dibutoxydiacetoxytitanium and the like are effective.
The amount of the catalyst to be used is generally 0.01 to 10% by weight, preferably 0.05 to 5% by weight, based on the total weight of the compound of the formula (1) and the glycol compound. The reaction temperature is usually 50 to
The temperature is 150 ° C, preferably 90 to 130 ° C. The reaction time is generally 4 to 50 hours, preferably 6 to 24 hours. The polyesterdiol of the formula (2) thus obtained has a number average molecular weight of usually 500 to 8000, preferably 1 to 8,000.
000-5000.

Next, the obtained polyester diol is further reacted with a dicarboxylic acid compound and / or an anhydride thereof to extend the chain, whereby the polyamino acid ester of the present invention can be obtained. Here, the dicarboxylic acid or anhydride thereof may be an aliphatic compound, an alicyclic compound, an aromatic compound or a mixture thereof, but may be an aliphatic dicarboxylic acid having 2 to 20 carbon atoms, an alicyclic compound. Formula-based dicarboxylic acids and / or their anhydrides are preferred. Specific examples of dicarboxylic acids or anhydrides that can be used include malonic acid. Succinic acid, glutaric acid, adipic acid, pimaric acid, suberic acid, azelaic acid, sebacic acid, dodecanoic acid, succinic anhydride, glutaric anhydride, (anhydrous) cyclohexanedicarboxylic acid, (anhydrous) cyclohexenedicarboxylic acid, and mixtures thereof But are not limited to these. The dicarboxylic acid compound and / or its anhydride are added to the reaction system following the step of synthesizing the polyester diol as described above, and there is no particular need to isolate the polyester diol. After adding the dicarboxylic acid and / or its anhydride to the system, the reaction is continued under the same reaction conditions as the conditions for synthesizing the polyester diol. The amount of the dicarboxylic acid and / or anhydride is usually 1 to 50 parts by weight, preferably 1 to 30 parts by weight, per 100 parts by weight of the polyester diol. The polyamino acid ester of the present invention thus obtained is usually represented by the above formula (3),
The number of repetitions (n) cannot be unconditionally determined because the desired molecular weight varies depending on the application, but is usually 0 or 1 or more, preferably 1 to 200, and particularly preferably 2 to 100.
Is an integer. The number average molecular weight of the polyester of the present invention is usually 5,000 to 500,000, preferably 10 to 500,000.
000 to 200,000.

Further, other preferred embodiments of the polyamino acid ester of the present invention include the following. That is, as described in the above (4), the compound of the formula (1) and / or a derivative thereof is polycondensed as a monomer to obtain the polyamino acid ester of the present invention represented by the above formula (4). Can be.

In the formula (4), when p = 2 or 3, one of R is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, the other is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, A combination of an alkylcarbonyl group, a benzoyl group, an alkyloxycarbonyl group, a benzyloxycarbonyl group, and an alkylcarboxyl group is preferable, and a combination in which one is a hydrogen atom or a methyl group and the other is a hydrogen atom or a methyl group is particularly preferable. Here, the alkyl group having 1 to 5 carbon atoms means an ethyl group, n-
Propyl group, i-propyl group, n-butyl group, i-butyl group,
Examples include a t-butyl group and a pentyl group.

In the formula (4), X represents a hydrogen atom or an alkali metal. Examples of the alkali metal include lithium, sodium, potassium, rubidium and cesium, and a hydrogen atom, sodium or potassium is preferable.

In the formula (4), q or r is 0.
When not, two kinds of bonds of an ester bond between a β-hydroxyl group and a β-carboxyl group of a raw material and an ester bond between a β-hydroxyl group and an α-carboxyl group are included. In the present invention, these bonds are alternately formed. They may be arranged, irregularly arranged, or form blocks.

In order to obtain the polyamino acid ester of the present invention by subjecting the compound of the formula (1) to polycondensation as a monomer as it is, for example, the compound of the formula (1) and / or its A method in which the derivative is dissolved in a solvent and reacted while removing water as a by-product can be employed. Examples of the catalyst that can be used at this time include the same catalysts as in the case of obtaining the polyester diol for obtaining the polyamino acid ester described in (2) above, and hydrochloric acid or phosphoric acid is preferable. The amount of the catalyst to be used is generally 0 to 20% by weight, preferably 0.01 to 1% by weight, relative to the compound of the formula (1).
5% by weight.

As the solvent, the same solvents as in the case of obtaining the above-mentioned polyester diol can be used alone or in combination, but it is preferable to select a solvent suitable for a method for removing by-product water. That is, if an azeotropic phenomenon with water is used, a solvent that is immiscible with water, such as toluene and cyclohexane, can be used alone or in combination.
Of these solvents, toluene, heptane or cyclohexane is preferred. . When anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous calcium chloride, molecular sieves, or the like is used as a dehydrating material, any solvent that does not react with the dehydrating material may be used. The reaction temperature is usually 50 to 150 ° C, preferably 90 to 130 ° C. The reaction time is 6 to 50 hours, preferably 8 to 24 hours. The polyamino acid ester thus obtained has the formula (4)
The number of repetitions (s) cannot be determined unconditionally because the desired molecular weight varies depending on the application, but it is usually 2
It is an integer of from 10,000 to 10,000, preferably from 5 to 1,000, and particularly preferably from 10 to 500. This molecular weight is, for example, GP
It can be measured by C (gel permeation chromatograph).

The salt of a polyamino acid ester obtained by directly polycondensing the compound of the formula (1) as a monomer means a structure in which the amino group of the polyamino acid ester forms a salt with an acid. . Examples of the acid include inorganic acids such as hydrochloric acid, phosphoric acid, and sulfuric acid, and organic acids such as acetic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid. Further, a carboxyl group in a polyamino acid ester is an amino group of another polyamino acid ester. And a salt (intermolecular salt), or the amino group and carboxyl group in the polyamino acid ester may form a salt (inner salt). Among these acids, salts with hydrochloric acid, phosphoric acid, and acetic acid and salts between polyamino acid esters (intermolecular salt or inner salt) are preferable.

Further, other preferred embodiments of the polyamino acid ester of the present invention include the following. That is, as described in the above (5), the polyamino acid ester of the present invention can also be obtained by polycondensing the compound of the formula (1) and / or a derivative thereof with a glycol compound or a diepoxy compound.

Examples of the glycol compound include the same compounds as described above. Further, as the diepoxy compound, neopentyl diglycidyl ether, 1,4-
Butane diglycidyl ether, 1,5-pentane diglycidyl ether, 1,6-hexane diglycidyl ether, 1,7-heptane diglycidyl ether, 1,8-
Aliphatic epoxy compounds such as octane diglycidyl ether, 1,9-nonanediglycidyl ether, 1,10-decanediglycidyl ether, 1,2,7,8-diepoxyoctane, 3,4-epoxycyclohexylmethyl- Alicyclic epoxy compounds such as 3 ', 4'-epoxycyclohexanecarboxylate, bis- (3,4-epoxycyclohexyl) adipate, bisphenol A diglycidyl ether, bisphenol F diglycidyl ether, 4,4'-biphenol diglycidyl Ether, hydroquinone diglycidyl ether, resorcin diglycidyl ether, catechol diglycidyl ether, 1,5-naphthalenediglycidyl ether, 1,
Examples include aromatic epoxy compounds such as 6-naphthalenediglycidyl ether and 2,7-naphthalenediglycidyl ether, and mixtures thereof, but are not limited thereto.

The reaction is carried out by dissolving or dispersing the compound of the formula (1) and / or a derivative thereof and a predetermined glycol compound and / or epoxy compound in a solvent, and performing polycondensation while dehydrating in the presence of a catalyst. The molar ratio of the compound of the formula (1) or a derivative thereof to the glycol compound or epoxy compound is usually 0.5: 1 to 1: 1.5, preferably 1: 1.
As the solvent, the same solvents as those used for obtaining the above polyester diol can be used alone or in combination, but it is preferable to select a combination having a good dehydration efficiency.
Of these solvents, toluene, heptane and sulfolane are preferred. As the catalyst, the same catalyst as that used for obtaining the polyester diol can be used. The amount of the catalyst to be used is generally 0.01 to 10% by weight, preferably 0.05 to 5% by weight, based on the total weight of the compound of the formula (1), the glycol compound and the epoxy compound. The reaction temperature is usually 50 to 150 ° C, preferably 90 to 130 ° C. The reaction time is usually 6 to 50 hours, preferably 8 hours to
24 hours.

When producing a polyester using glutamic acid as a raw material disclosed in US Pat. No. 5,990,266, glutamic acid tends to have a cyclic lactam structure during the reaction. Although protection is required, in the case of the present invention, a high molecular weight polymer can be obtained without protecting the amino group of the compound of the formula (1). The polyamino acid ester of the present invention obtained here is represented by the formula (5), and the number of repetitions (t) cannot be unconditionally determined because the desired molecular weight varies depending on the use, but is usually 1 or more, preferably 1 to 1. 40
0, particularly preferably 2 to 200. The number average molecular weight of the polyamino acid ester of the present invention obtained here is usually 5,000 to 200,000, preferably 1,000.
１００100,000. This molecular weight can be measured, for example, by GPC (gel permeation chromatography).

The polyamino acid ester of the present invention is characterized by having both a hydroxyl group and an amino group in the side chain, and can be expected to be applied as various functional polymers, particularly as biodegradable polymers and biocompatible polymers. . It is possible to bind or adsorb biological components such as proteins, DNAs, sugars, cells, etc., and drugs by utilizing the functional groups of the side chains. When culturing many animal cells in vitro, it is necessary to adhere to a substrate material, and collagen that has been modified with a growth factor is usually used. Since such a growth factor can also bind and / or adhere to the polyamino acid ester of the present invention, the polyamino acid ester of the present invention can be used as a substrate material for cell culture, and can be applied to a tissue culture support. It is possible.

In addition, enzymes and cells can be immobilized on the polyamino acid ester of the present invention, and this can be applied to a bioreactor to produce pharmaceuticals or chemicals which are difficult to produce by synthesis. Can be used for treatment.

By binding or microencapsulating a drug to the polyamino acid ester of the present invention, it is possible to deliver the drug at a required time and in a required amount to a required place, that is, a drug delivery system. It can be used as a carrier.

The polyamino acid ester of the present invention has biodegradability and is extremely useful in the global environment. Sanitary articles such as disposable diapers, shaves, toothbrushes, sanitary articles, shopping / garbage bags, disposable gloves. , Daily necessities such as cosmetic containers, stationery, toys, cushioning materials, horticultural products such as nursery pots, nurseries, etc., multi-films, water retention materials, fishing nets,
It can be expected to be used for agricultural and fishing materials such as ropes.

[0039]

EXAMPLES The present invention will be described more specifically below with reference to examples, but the present invention is not limited to these examples. The number average molecular weight or weight average molecular weight is GP
C (gel permeation chromatography). The measurement conditions are as follows. Column: Shodex KD803 x 2 Eluent: DMF (dimethylformamide) containing 10 mM LiBr Column temperature: 40 ° C Flow rate: 1.0 mL / min Standard substance: polystyrene standard

Example A1 300 ml equipped with a stirrer, a fractionating condenser and a thermometer
In a separable flask, 40 ml of toluene and 4 sulfolane
0 ml, cyclohexane 20 ml, β-hydroxyaspartic acid 14.9 g, 1,6-hexanediol 2
4.3 g and 15 ml of hydrochloric acid were charged, and the mixture was heated and reacted under reflux of the solvent (110 ° C.) for 5 hours while separating water. The number average molecular weight of the polyester diol obtained here is 3
000. Next, 10 g of succinic anhydride was added and reacted at 125 ° C. under reduced pressure (70 mmHg) for 6 hours. The reaction solution was poured into isopropanol to precipitate a polymer, which was filtered and dried, and then the polyamino acid ester 45 of the present invention was dried.
g was obtained. When the molecular weight of the obtained polyamino acid ester was measured, the number average molecular weight was 11,000.

Example A2 300 ml with stirrer, fractionating condenser and thermometer
In a separable flask, 40 ml of toluene and 4 sulfolane
0 ml, cyclohexane 20 ml, β-hydroxyaspartic acid 14.9 g, 1,4-butanediol 18.
0 g and hydrochloric acid (15 ml) were charged and heated to reflux the solvent (1.
(10 ° C.) for 5 hours while separating water. The number average molecular weight of the polyester diol obtained here is 300
It was 0. Next, 10 g of succinic anhydride was added and reacted at 125 ° C. under reduced pressure (70 mmHg) for 6 hours. The reaction solution was poured into isopropanol to precipitate a polymer, which was filtered and dried to obtain 40 g of the polyamino acid ester of the present invention. When the molecular weight of the obtained polyamino acid ester was measured, the number average molecular weight was 10,000.

Example A3 300 ml equipped with a stirrer, a fractionating condenser and a thermometer
In a separable flask, 40 ml of toluene and 4 sulfolane
0 ml, cyclohexane 20 ml, β-hydroxyaspartic acid 14.9 g, 1,4-butanediol
2 g and 15 ml of hydrochloric acid were charged and heated to reflux the solvent (1.
(10 ° C.) for 4 hours while separating water. The number average molecular weight of the obtained polyester diol is 250
It was 0. Then, 11.4 g of glutaric anhydride was added and reacted at 105 ° C. for 5 hours under reduced pressure (70 mmHg). The obtained reaction solution was poured into isopropanol to precipitate a polymer, which was filtered and dried to obtain 40 g of the polyamino acid polyester of the present invention. When the molecular weight of the obtained polyamino acid ester was measured, the number average molecular weight was 9,000.

Example A4 300 ml equipped with a stirrer, a fractionating condenser and a thermometer
In a separable flask, 35 ml of toluene, 35 ml of cyclohexane, 30 ml of sulfolane, 14.9 g of β-hydroxyaspartic acid, 1,3-propanediol 1
3.7 g and 10 ml of phosphoric acid were charged, and the mixture was heated and reacted under reflux of the solvent (110 ° C.) for 6 hours while separating water.
The number average molecular weight of the polyester diol obtained here was 3,800. Next, 9 g of succinic anhydride was added and reacted at 110 ° C. for 5 hours under reduced pressure (80 mmHg).
The obtained reaction solution was poured into propanol to precipitate a polymer, which was filtered and dried to obtain 30 g of the polyamino acid polyester of the present invention. When the molecular weight of the obtained polyamino acid ester was measured, the number average molecular weight was 2100
It was 0.

Example A5 300 ml equipped with a stirrer, a fractionating condenser and a thermometer
In a separable flask, 35 ml of toluene, 35 ml of cyclohexane, 30 ml of sulfolane, 14.9 g of β-hydroxyaspartic acid, and 19.5 of diethylene glycol were used.
g and 15 ml of hydrochloric acid, and the mixture was heated and reacted under reflux of the solvent for 6 hours while separating water. The number average molecular weight of the obtained polyester diol was 4000. Next, 11.8 g of succinic acid was added, and the mixture was added under reduced pressure (70 mmHg).
The reaction was performed at 10 ° C. for 7 hours. The obtained reaction solution was poured into 50% by weight of ethanol water to precipitate a polymer, which was then filtered,
After drying, 37 g of the polyamino acid polyester of the present invention was obtained. When the molecular weight of the obtained polyamino acid ester was measured, the number average molecular weight was 9,500.

Example A6 300 ml equipped with a stirrer, a fractionating condenser and a thermometer
70 ml of toluene and 3 of sulfolane in a separable flask
0 ml, 20 ml of cyclohexane, 14.9 g of β-hydroxyaspartic acid, 40.5 g of tricyclodecane dimethylol and 15 ml of hydrochloric acid were charged, and the mixture was heated and reacted under reflux of the solvent for 5 hours while separating water. The number average molecular weight of the polyester diol obtained here was 5,000. Then, 10 g of succinic anhydride was added and the mixture was added under reduced pressure (70 mmH
g) and reacted at 125 ° C. for 5 hours. The obtained reaction solution was poured into acetone to precipitate a polymer, which was filtered and dried to obtain 57 g of the polyamino acid polyester of the present invention. When the molecular weight of the obtained polyamino acid ester was measured, the number average molecular weight was 32,000.

Example A7 300 ml equipped with a stirrer, a fractionating condenser and a thermometer
70 ml of toluene and 3 of sulfolane in a separable flask
0 ml, 17.7 g of N-dimethyl-β-hydroxyaspartic acid, 24.3 g of 1,6-hexanediol, and 0.1 g of tetrapropoxytitanium were charged, and heated to separate water for 4 hours under reflux of the solvent (119 ° C.). While reacting. The number average molecular weight of the obtained polyester diol was 3,500. Next, 10 g of succinic anhydride was added and reacted at 120 ° C. under reduced pressure (70 mmHg). The obtained polymer was poured into isopropanol to precipitate the polymer, which was filtered and dried to obtain 48 g of the polyamino acid polyester of the present invention. When the molecular weight of the obtained polyamino acid ester was measured, the number average molecular weight was 11
000.

Example A8 300 ml with stirrer, fractionating condenser and thermometer
70 ml of toluene and 3 of sulfolane in a separable flask
0 ml, N-dimethyl-β-hydroxyaspartic acid 17.7 g, diethylene glycol 19. g and 21 g of p-toluenesulfonic acid, and the mixture was heated and reacted under reflux of the solvent for 7 hours while separating water. The number average molecular weight of the polyester diol obtained here was 3,000. Then, 11.4 g of glutaric anhydride was added and reacted at 110 ° C. for 5 hours under reduced pressure (70 mmHg). The obtained reaction solution was poured into 50% ethanol water to precipitate a polymer, which was filtered and dried to obtain 45 g of the polyamino acid polyester of the present invention. When the molecular weight of the obtained polyamino acid ester was measured, the number average molecular weight was 15
000.

Example B1 300 ml with stirrer, fractionating condenser and thermometer
Β-hydroxyaspartic acid in a separable flask
10.08 g, 150 ml of toluene and 20 ml of concentrated hydrochloric acid were weighed. This is heated and heated under reflux with toluene.
The reaction was performed for 7 hours. After stopping the reaction, the solvent and the product were separated by decantation, and the solvent was removed. The obtained product was dried in a vacuum drier for 5.2 hours to obtain 8.5 g of a polyamino acid ester of the present invention. When the molecular weight of the obtained polyamino acid ester was measured, the number average molecular weight was 4038 and the weight average molecular weight was 4207.

Example B2 300 ml with stirrer, fractionating condenser and thermometer
Β-hydroxyaspartic acid 1 in a separable flask
0.08 g, 150 ml of toluene, 10 ml of concentrated hydrochloric acid and 3 ml of phosphoric acid were weighed. This was heated and reacted for 12 hours under reflux of toluene. After stopping the reaction, the solvent and the product were separated by decantation, and the solvent was removed. The obtained product was dried with a vacuum dryer for 8 hours to obtain 8.0 g of the polyamino acid ester of the present invention. When the molecular weight of the obtained polyamino acid ester was measured by GPC,
The number average molecular weight was 4318 and the weight average molecular weight was 4508.

Example C1 300 ml with stirrer, fractionating condenser and thermometer
70 ml of toluene and 3 of sulfolane in a separable flask
0 ml, 14.9 g of β-hydroxyaspartic acid,
9.2 g of 1,4 butanediol and 15 ml of hydrochloric acid were charged and reacted while heating and refluxing toluene for 10 hours to separate water. The obtained reaction solution was poured into isopropanol to precipitate a polymer, which was filtered and dried to obtain 21 g of a polyamino acid ester of the present invention. When the molecular weight of the obtained polyamino acid ester was measured, the number average molecular weight was 3,500.

Example C2 300 ml with stirrer, fractionating condenser and thermometer
70 ml of toluene and 3 of sulfolane in a separable flask
0 ml, 14.9 g of β-hydroxyaspartic acid,
12.1 g of 1,6-hexanediol and 15 ml of hydrochloric acid were charged and reacted while heating and refluxing toluene for 10 hours to separate water. The reaction was further performed at 110 ° C. for 5 hours under reduced pressure. The obtained reaction solution was poured into isopropanol to precipitate a polymer, which was filtered and dried to obtain 25 g of the polyamino acid ester of the present invention. When the molecular weight of the obtained polyamino acid ester was measured, the number average molecular weight was 10,000.

Example C3 300 ml with stirrer, fractionating condenser and thermometer
In a separable flask, 35 ml of toluene, 35 ml of cyclohexane, 30 ml of sulfolane, 14.9 g of β-hydroxyaspartic acid, and 1,3-propanediol 7.
7 g and 10 ml of phosphoric acid were charged, and the mixture was heated and reacted under reflux of the solvent for 10 hours while separating water. Further under reduced pressure,
The reaction was performed at 110 ° C. for 5 hours. The obtained reaction solution was poured into propanol to precipitate a polymer, which was filtered and dried to obtain 21 g of the polyamino acid ester of the present invention. When the molecular weight of the obtained polyamino acid ester was measured, the number average molecular weight was 11,000.

Example C4 300 ml with stirrer, fractionating condenser and thermometer
In a separable flask, toluene 35 ml, cyclohexane 35 ml, sulfolane 30 ml, β-hydroxyaspartic acid 14.9 g, diethylene glycol 10.8
g and hydrochloric acid (15 ml), and heated to 10
The reaction was conducted while separating water for hours. The obtained reaction solution is 5
The polymer was precipitated by pouring into 0% ethanol water, filtered and dried to obtain 25 g of the polyamino acid ester of the present invention. When the molecular weight of the obtained polyamino acid ester was measured, the number average molecular weight was 3,000.

Example C5 300 ml with stirrer, fractionating condenser and thermometer
70 ml of toluene and 3 of sulfolane in a separable flask
0 ml, β-hydroxyaspartic acid 14.9 g, tricyclodecane dimethylol 20.3 g, hydrochloric acid 15 ml
Was heated and reacted while separating water under reflux of the solvent for 10 hours. Furthermore, under reduced pressure (70 mHg),
Allowed to react for hours. The obtained reaction solution was poured into acetone to precipitate a polymer, which was filtered and dried to obtain 33 g of a polyamino acid ester of the present invention. When the molecular weight of the obtained polyamino acid ester was measured, the number average molecular weight was 14,000.

Example C6 300 ml with stirrer, fractionating condenser and thermometer
70 ml of toluene and 3 of sulfolane in a separable flask
0 ml, 14.9 g of β-hydroxyaspartic acid, 20.8 g of tetraethylene glycol, and 0.1 g of tetrapropoxytitanium were charged and reacted while heating and separating water under reflux of the solvent for 10 hours. The obtained reaction solution was poured into butanol to precipitate a polymer, which was filtered and dried to obtain 30 g of the polyamino acid ester of the present invention. When the molecular weight of the obtained polyamino acid ester was measured, the number average molecular weight was 4,500.

Example C7 300 ml with stirrer, fractionating condenser and thermometer
6. In a separable flask, 70 ml of toluene, 30 ml of N-methylpyrrolidone, β-hydroxyaspartic acid
5 g, polytetramethylene glycol (PTMG650
32.5 g, manufactured by Mitsubishi Chemical Corporation;
05 g was charged and heated to react under reflux of the solvent for 10 hours while separating water. The obtained reaction solution was poured into acetone to precipitate a polymer, which was filtered and dried to obtain 25 g of the polyamino acid ester of the present invention. When the molecular weight of the obtained polyamino acid ester was measured, the number average molecular weight was 3,500.

Example C8 300 ml with stirrer, fractionating condenser and thermometer
70 ml of toluene and 3 of sulfolane in a separable flask
0 ml, 17.7 g of N-dimethyl-β-hydroxyaspartic acid, 10.8 g of diethylene glycol, and 21 g of p-toluenesulfonic acid were charged, and reacted while heating and refluxing the solvent for 10 hours to separate water. The reaction was further performed at 110 ° C. for 10 hours under reduced pressure (70 mmHg).
The obtained reaction solution was poured into 50% ethanol water to precipitate a polymer, which was filtered and dried to obtain 27 g of the polyamino acid ester of the present invention. When the molecular weight of the obtained polyamino acid ester was measured, the number average molecular weight was 150.
00.

Example C9 300 ml with stirrer, fractionating condenser and thermometer
A separable flask was charged with 100 ml of sulfolane, 14.9 g of β-hydroxyaspartic acid, 20.2 g of 1,4-butanediglycidyl ether, and 21 g of p-toluenesulfonic acid, and heated at 120 ° C. to react for 10 hours. The obtained reaction solution was poured into isopropyl alcohol to precipitate a polymer, which was filtered and dried to obtain 25 g of a polyamino acid ester of the present invention. When the molecular weight of the obtained polyamino acid ester was measured, the number average molecular weight was 5,500.

Example C10 300 ml with stirrer, fractionating condenser and thermometer
100 ml of sulfolane, 26.8 g of N-benzyloxycarbonyl-β-hydroxyaspartic acid, bisphenol A diglycidyl ether 3 in a separable flask
4 g, 21 g of p-toluenesulfonic acid,
C. and reacted for 10 hours. The solvent was removed from the obtained reaction solution to obtain 58 g of the polyamino acid ester of the present invention.
I got When the molecular weight of the obtained polyamino acid ester was measured, the number average molecular weight was 11,000.

Test Example 1 A biodegradability test was conducted on the polyamino acid ester produced in Example A2. For the test method, refer to “Test Methods for New Chemical Substances, etc.” (Kaiho No. 5
No. 15, 49 base station No. 392, July 13, 1974) <Degradation test of chemical substances by microorganisms> and "Ready Biodegradability: 301C, MOdified MITI" specified in "OECD Guidelines for Testing of Chemicals". T
est (I) (July 17, 1992) ", except that the degree of decomposition was calculated only by the oxygen consumption. As a result, the degree of decomposition was 33.
%Met. FIG. 1 shows a BOD curve.

[0061]

The polyamino acid polyesters and salts thereof of the present invention are polyesters having a hydroxyl group and an amino group and are used as medical materials as novel functional polymers having biocompatibility, biodegradability, electrolytic properties and the like. It is expected to be applied in fields such as sanitary materials, agricultural and fishery materials, coating materials, surface treatment agents, and the like.

[Brief description of the drawings]

FIG. 1 shows a BOD (Biological Oxygen Deoxygenase) in a biodegradability test of a polyamino acid ester produced in Example A2.
mand) curve

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4B033 NA22 NB34 NF06 NG05 4B065 AA87 BC41 4C076 EE24A EE59A FF68 4C084 AA13 MA01 MA05 NA13 ZC801 4J029 AA02 AA03 AB01 AC01 AD01 AE01 AE03 CA03 CA02 CA03 CA02 EF01 HA01 HB01 HB06 KE09

Claims (12)

[Claims] (1) The following formula (1): [In the formula, p represents an integer of 1 to 3. R represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkylcarbonyl group, a benzoyl group, an alkyloxycarbonyl group, a benzyloxycarbonyl group or an alkylcarboxyl group. A polyamino acid ester comprising β-hydroxyaspartic acid and / or a derivative thereof represented by the formula (I) as a polymerization component, and a salt thereof. (2) The following formula (2): [In the formula, m is the number of repetitions, and indicates the degree of polymerization necessary for the number average molecular weight of the polyester diol of formula (2) to be 500 or more. p and R represent the same meaning as in the above formula (1). Y represents a residue of the glycol compound. A polyamino acid ester and a salt thereof obtained by reacting the β-hydroxyaspartic acid polyester diol represented by the formula (1) with a dicarboxylic acid and / or an anhydride thereof. (3) Formula (3) [In the formula, n represents 0 or an integer of 1 or more. m, p, R and Y have the same meaning as in the above formula (2). R ¹
Is a dicarboxylic acid residue. And a salt thereof. 4. A compound represented by the following formula (4): [In the formula, p and R represent the same meaning as in the above formula (1). X represents a hydrogen atom or an alkali metal. s is an integer of 2 to 10,000, q and r satisfy s ≧ q + r, q is an integer of 0 to s, and r is an integer of 0 to s. However, q and r do not become 0 at the same time. And a salt thereof. 5. The following formula (5): [Wherein, t represents an integer of 1 or more. p and R represent the same meaning as in the above formula (1). Z represents a residue of a glycol or epoxy compound. And a salt thereof. 6. The polyamino acid ester and a salt thereof according to claim 1, which is biodegradable. 7. A polyamino acid ester and a salt thereof according to claim 1, which is used as a substrate material for cell culture. 8. The method according to claim 1, which is for a tissue culture support.
Item 2. The polyamino acid ester and the salt thereof according to Item 1. 9. The polyamino acid ester and a salt thereof according to claim 1, which is used as a carrier for an immobilized enzyme. 10. The polyamino acid ester and a salt thereof according to claim 1, which is used as a carrier for immobilized cells. 11. The polyamino acid ester and a salt thereof according to claim 1, which is used as a carrier for a drug delivery system. 12. A polyamino acid ester and a salt thereof according to claim 1, which is used as a gene carrier in gene therapy.