JPH04103566A - Polymer compound - Google Patents

Abstract

PURPOSE:To obtain a polymer compound usable as medical material, base for DDS, etc., rapidly decomposable in vivo, not causing in vivo residue, excreted not of body through metabolic pathway, comprising a repeating structure composed of amino acid ester in the main chain. CONSTITUTION:A polymer compound comprising a repeating structure shown by formula I (R<1> and R<2> are H, alkyl or aralkyl; X and Y are alkylene, (n) is >=2 natural number) in the main chain. The polymer compound is obtained by reacting an amino acid dimer shown by formula II with a dicarboxylic acid shown by formula II under an amide forming condition by using a proper condensation agent in the presence of a base. The dimer is prepared by esterifying an amino acid shown by formula IV with a diol compound shown by the formula HO-X-OH. The polymer compound is insoluble in water but decomposable with a specific hydrolase in vivo by properly selecting the kind of amino acid and rapidly solubilized in water.

Description

[Detailed description of the invention] [Background of the invention] (Industrial application field) This invention relates to a novel polymer compound.

Specifically, the present invention relates to a polymer compound having an ester structure in its main chain, which is considered to be easily decomposed by the action of hydrolytic enzymes present in living organisms.

(Prior Art) Polymers that decompose in an environment where a biocatalyst is present, such as in a living body, are called biodegradable or bioabsorbable polymers. Among these polymers, for example, polyesters containing α-hydroxy acids as monomers are rapidly decomposed in vivo, do not produce residues, and are further excreted through metabolic pathways, so they are used as medical materials such as surgical sutures. It is used in the field of Furthermore, in recent years, such polymers have been widely studied as base materials for controlled drug release systems (hereinafter abbreviated as DDS) for controlling drug administration to living organisms.

First of all, it is desired that the base for DS has the function of releasing a certain amount of drug into the body within a certain period of time.

Conventionally known bases include homopolymers such as lactic acid and glycolic acid, and fupolymers thereof. These polyesters are obtained by heating lactic acid or glycolic acid as a low molecular weight oligomer under low pressure. The polymer can be obtained by first synthesizing cyclized dimers (lactide, glycolide) of lactic acid and glycolic acid, and subjecting them to catalytic ring-opening addition polymerization. Naturally occurring L-form polyesters are highly crystalline, and chemically synthesized polylactic acid and polyglycolic acid are also generally crystalline. Crystalline polymers consist of a crystalline part and a non-crystalline part, and because the crystalline part is much less biodegradable than the non-crystalline part, it is said that it exhibits non-uniform degradability in living organisms. There are problems. Therefore, D
As a base material for DS, a non-grade polymer or a polymer with low crystallinity is desirable. Additionally, drugs generally tend to be ubiquitous in non-quality parts of the base. Therefore, when such a crystalline polymer is used as a base for DDS, the non-sterile part decomposes first and releases most of the drug, and then the crystalline part containing little or no drug is formed. They tend to exhibit the undesirable phenomenon of remaining in the body.

Furthermore, the desired properties of the base material for DDS include:
It has the function of releasing drugs in a concentrated manner. It is generally believed that the above-mentioned polymers made of lactic acid, glycolic acid, etc. are difficult to meet this important problem because their decomposition related to drug release mainly relies on a non-enzymatic hydrolysis mechanism.

At present, a base for DDS that satisfactorily meets these issues has not yet been found.

As described above, there is a large gap between the issues required for DDS bases and the current situation, and the development of new polymer compounds for bases is awaited.

[Summary of the invention]

An object of the present invention is to provide a novel polymer compound to meet the above-mentioned problems. Specifically, it is an object of the present invention to provide a polymer compound having an amino acid ester structure in the polymer main chain that is considered to be easily decomposed by hydrolytic enzymes in living organisms.

Therefore, the polymer compound according to the present invention has the following formula (I)
It has a repeating structure represented by the following in its main chain.

(In the formula, R and R2 may be the same or different, and each represents a water atom, an alkyl group, or an aralkyl group, and X and Y may be the same or different, and each represents an alkylene group. (n represents a natural number of 2 or more.) According to the present invention, a polymer compound having an amino acid ester structure in its main chain can be obtained. This polymer compound is insoluble in water, but by appropriately selecting the type of amino acid, it is decomposed by a specific in-vivo hydrolase and quickly becomes water-soluble (see test examples below). Furthermore, the polymer compound according to the present invention is composed of a substance that is considered to have almost no toxicity, and therefore has extremely low toxicity. Therefore, it is expected to have a wide range of applications as a DDS base.

[Detailed description of the invention]

Polymer Compound The polymer compound according to the present invention is represented by the above formula (I).

The molecular weight of the polymer compound according to the present invention, expressed as a natural number representing the degree of polymerization of formula (I), ie, the number of repeating units, is 2 or more, preferably 2 or more and coOO or less.

The number of repeating units can be calculated from the number average molecular weight, which can be measured by a method such as gel permeation chromatography or osmotic pressure method.

In formula (I), R1 and R- may be the same or different and each represents a hydrogen atom, an alkyl group or an aralkyl group. In the case of an alkyl group, an alkyl group having about 1 to 10 carbon atoms, preferably about 1 to 5 carbon atoms, is preferable from the viewpoint of in vivo hydrolyzability, solubility of decomposed products, etc. This alkyl group may be linear or branched.

Specific examples include methyl, ethyl, propyl, butyl,
Examples include isobutyl, t-butyl, pentyl, and hexyl groups. In the case of an aralkyl group, about 7 to 11 carbon atoms,
The number is preferably about 7 to 9, which is preferred for the same reason as in the case of the alkyl group described above.

The aryl part of the aralkyl group has about 6 to 10 carbon atoms, such as phenyl, tolyl, 1-naphthyl, 2-naphthyl groups, etc., while the alkyl part of the aralkyl group has about 1 to 10 carbon atoms. There are about 3 examples. Therefore, specific examples of the aralkyl group include benzyl, 1-naphthylmethyl, and 2-naphthylmethyl groups.

Furthermore, the carbon atom substituted by R or R2 is R1
Alternatively, when R2 is not a hydrogen atom, it may take the configuration of either L or D, depending on the intended use of the polymer compound.

Further, depending on the purpose, L and D may be present in equivalent amounts or in a predetermined ratio.

R1 and R2 in formula (I) may be the same or different. Further, it is essential that the polymer compound according to the present invention has two or more repeating units, but these repeating units may be the same or different with respect to R and R2. Even if the arrangement state of the repeating unit is random when they are different,
It may be a block arrangement. By appropriately selecting the types and abundances of R and R2 in the polymer compound according to the present invention, appropriate in-vivo hydrolyzability and various physical properties as a polymer compound can be obtained.

In formula (I), X and Y may be the same or different, and each represents a linear or branched alkylene group. This alkylene group has about 2 to 10 carbon atoms, preferably about 2 to 5 carbon atoms, and is hydrolyzable in the body.
This is preferable from the viewpoint of solubility of decomposition products. Specific examples of this alkylene group include ethylene, trimethylene, tetramethylene, pentamethylene, and hexamethylene groups.

Similar to R1 and R2 described above, the types of X and Y,
The form of existence and the amount thereof in the polymer compound can be appropriately selected in consideration of the hydrolyzability, various physical properties, etc. required of the polymer compound.

The structure of the terminal groups of the polymeric compound according to the invention generally does not have a significant influence on the properties of the polymeric compound, as long as the molecular weight of the polymeric compound is large. In the case of the production method described below, the terminal group will normally have the terminal structure of compound (n) or compound (IV) described below.

The polymer compound according to the present invention has the property of being decomposed into products by the action of hydrolytic enzymes and the like in living organisms. That is, it is rapidly decomposed in the body, does not produce any residue, and is further excreted from the body through metabolic pathways. The compounds according to the invention can therefore be used in medical materials such as surgical sutures.
It can be used as a base for S.

Preparation of the polymeric compound The polymeric compound according to the present invention can be prepared by any suitable method. A suitable production example is as follows.

Formation of Amino Acid Dimer In producing the polymer compound according to the present invention, first,
An amino acid dimer represented by the following general formula (II) is produced.

(In the formula, R1, R2, and X are as defined in formula (I).) The amino acid that is the starting material for the amino acid dimer represented by formula (I .

HN -CH-CO2H(m) (In the formula, R has the same meaning as R1 and R2.) When R is a hydrogen atom, the amino acid name is glycine. Similarly, when R is an alkyl group - examples include alanine, valine, leucine, isoleucine. When R is an aralkyl group - examples include phenylalanine. When R is an alkyl group or an aralkyl group, the carbon atom substituted by R is asymmetric, and its conformation may be L or D.

Further, the amino acid of formula (m) as a starting material may be a mixture of equivalent or different amounts of the L-form and the D-form from the viewpoint of imparting desired physical strength and hydrolyzability to the polymer compound.

By appropriately selecting R, that is, by appropriately selecting the amino acid of formula (III) as the starting material,
Polymer compounds according to the present invention having arbitrary R1 and R- can be obtained.

The dimer of the amino acid represented by formula (n) is a diol compound represented by the following formula: HO-X-OH (wherein X is as defined in formula (I)) ), and can be obtained by reacting the amino acid (II[) with the diol compound under ester-forming conditions.

Here, [reacting under ester-forming conditions] means the formula (
In addition to reacting the amino acid of III) with the diol compound in its original form, for example by using an esterification catalyst, when at least one of the two compounds is reacted in the form of its functional derivative, It includes a specific type of reaction.

In this case, the functional derivatives of both compounds include formula (m)
Examples of amino acids include salts, acid halides, and active esters. On the other hand, examples of functional derivatives of diol compounds include cybaride, ditosylate, and the like. In this ester formation, it is preferable to protect the amino group of the amino acid as necessary.

As a specific example of such a reaction, an appropriate amino acid is
In the presence of a suitable acid (e.g. para-toluenesulfonic acid, hydrogen chloride, etc.), a compound represented by the following formula: HO-X-OH (wherein X is as defined in formula (I)) and Alternatively, the amino group is protected with an appropriate protecting group (e.g., enamine obtained by dehydration with methyl acetoacetate), and the protected amino acid is esterified with an appropriate carboxylate (e.g., potassium salt, triethylamine salt, etc.), and then a compound represented by the following formula: Hal-X-Hal (wherein, X is as defined in formula (I), and Hal is a halogen atom, such as FSCl, Br, I) and subsequent deprotection.

These reactions are carried out at 10-100°C, preferably at 20-8°C.
The process can be carried out easily and smoothly at a temperature of 0°C.

Note that this dimer is a compound that has both an ester and an amino group in its molecule, so the amino group is isolated as a salt of an appropriate acid (e.g., hydrogen chloride or para-toluenesulfonic acid) as shown in the above formula. It is desirable to preserve and handle it from the viewpoint of stability.

Formation of Polymer The polymer compound according to the present invention is a dicarboxylic acid represented by the following formula (IV): HOCO-Y-COOH (IV) (Formula (wherein Y is as defined in formula (I)) can be produced by condensation polymerization, that is, by reacting under amide-forming conditions.

The reaction is preferably carried out in a solvent that dissolves at least one of the reactants, at 0-100°C, preferably at 20-80°C,
It is carried out by contacting both reactants all at once, stepwise, or multiple times for each at the same or several steps of temperature in the range of . Specific examples of solvents for such reactions include N,N-dimethylformamide, N,N
Examples include -dimethylacetamide, chloroform, N-methylpyrrolidone, and a mixed solvent thereof.

Here, "reacting under amide forming conditions" means the formula (I
In addition to reacting the amino acid dimer of I) with the dicarboxylic acid of formula (IV) as such, for example by using a condensing agent, at least one of the compounds may be reacted in the form of its functional derivative. In the case where the reaction is carried out in a specific manner, it includes a specific reaction type.

Examples of functional derivatives of dicarboxylic acids in this case include acid halides such as acid chloride, active esters such as N-hydroxysuccinimide ester, and the like.

A specific example of such a reaction is to combine the compound of formula (II) and the dicarboxylic acid with a suitable condensing agent (e.g., dicyclohexylcarbodiimide, 1(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride). A method of reacting a dicarboxylic acid with an appropriate acyl activator (for example, 3-
(succinimidoxy)-1,2-benziisothiazole-1,1-dioxide, etc.), the formula (n)
It can be produced by adding a compound and reacting it in the presence of an appropriate base or the like.

Furthermore, the dicarboxylic acid is converted into an acyl activated form (e.g., acid chloride, ester form with N-hydroxysuccinimide, etc.)
It can also be produced by a method of reacting the compound of formula (n) in the presence of an appropriate base or the like.

The ratio of the dicarboxylic acid component to the amino acid dimer is 1;
1 is desirable, but it can be varied depending on the desired molecular weight or desired end group. That is,
Probably, if the ratio is 1=1, each reactant will be present at the end, and if one is in excess, an excess of the reactant will be present at the end.

Furthermore, - at the terminal of the supported polymer compound, R1,
A block copolymer in which different repeating units are arranged in blocks by polymerizing and adding another compound (n) to R2 and X and/or another dicarboxylic acid compound (IV) to Y is obtained. In addition, from the beginning, a plurality of types of compounds of formula (n) and/or
Alternatively, if dicarboxylic acid compound (IV) is used, a random copolymer can be obtained.

When the polymerization reaction solvent has the ability to dissolve the produced polymer compound, the produced polymer compound can be obtained in the form of a solution. In that case, a substance that does not dissolve the produced polymer compound but is soluble in the polymerization reaction solvent, such as water, lower alkanol, lower ketone, lower ether, etc., is added to the solution to remove the dissolved polymer compound. All you have to do is let it precipitate.

Examples Example 1 Glycine (7.51 g) was suspended in methanol (50 ml), 85% KOH (6.6 g) was added, and the mixture was stirred for 30 minutes. Methyl acetoacetate (I1, 6 g) was added, and the mixture was further stirred for 1 hour, and the precipitate was collected in an oven while cooling with water. Recrystallization from methanol gave N-protected glycine potassium salt (melting point (decomposition): 241°C) at 16.2. Obtained.

In a similar manner, 17.3 g of N-protected L-alanine potassium salt (melting point (decomposition) = 208°C) was obtained from L-alanine (8.91 g).

L-phenylalanine (I6.5 g) was N-protected and mono-phenylalanine potassium salt (melting point (decomposition) 2 209°C
) 24.6g.

21.7 g of N-protected leucine potassium salt (melting point (decomposition): 219°C) from L-leucine (I3.1 g).

20.1 g of N-protected monoleucine potassium salt (melting point (decomposition): 219°C) was obtained from D-leucine (I3.1 g).

Example 2 N-protected amino acid synthesized in Example 1 (205 uaol)
, 30 ml of N,N-dimethylformamide (hereinafter referred to as D
In addition to 1,2-dibromoethane (abbreviated as MF), 1,2-dibromoethane (I0a
tsol) was added and stirred at 50°C for 6 hours. After cooling, add 40ml of distilled water and add ethyl acetate (4X50
ml), washed with water (4×50 ml) and dried over magnesium sulfate. After removing the solvent under reduced pressure, acetone (50%
ml) and paratoluenesulfonic acid monohydrate (2 ml).
0s+ool) was added and stirred for 30 minutes. After adding 100 ml of ether, the precipitate was collected and recrystallized from an ethanol-ether mixed solvent. In this method, G2 (melting point: 154
℃), 3.93 g of A2 (melting point = 197℃) of the following structural formula from N-protected L-alanine potassium salt, N
5.28 g of F2 (melting point: 235°C) of the following structural formula was obtained from the protected L-phenylalanine potassium salt, and L2 (melting point: 238°C) of the following structural formula was obtained from the N-protected monoleucine potassium salt.
) and 5.77 g of DL2 (melting point = 238°C) having the following structural formula were obtained from N-protected monoleucine potassium salt.

Example 3 The reaction was carried out in the same manner as in Example 2, except that 1,3-dibromopropane was used instead of 2-dibromoeta, and N-protected monophenylalanine potassium salt of the following structural formula was obtained from N-protected glycine potassium salt. From A3 of the following structural formula (
5.82g of F3 (melting point = 225°C) of the following structural formula was prepared from N-protected monoleucine potassium salt.
．． 6.22 g of DL3 (melting point: 225° C.) having the following structural formula was obtained from 30 g of N-protected monoleucine potassium salt.

Example 4 Compounds obtained in Examples 2 and 3 (G2, A2, F2
, F2, DL2, A3, F3, DL3) (I0, C1+
go+) and adipic acid bis(N-hydroxysuccinimide) ester (I0.0ml) in DMF (
20 ml), and triethylamine (201 mol) was added dropwise while stirring at room temperature.

After continued stirring for 24 hours, the reaction mixture was dissolved in methanol (if G2, A2 was used) or water (F2, F2).
, DL2, A3, F3, DL3). The precipitate was collected and diluted with ethanol-ether (I: 3
) After thorough washing with a mixed solvent, the mixture was dried under reduced pressure to obtain the following polymer compound in the form of a white powder.

Starting material L2 L3 Example 5 A total of 10 μmol of F3 and A3 obtained in Example 3
A polymer was synthesized in the same manner as in Example 4.

That is, F3 and A3 in the ratio shown in the table below, and adipic acid bis(N-hydroxysuccinimide) ester (I0
,0 mg+ol) was added to DMF (20 ml), and triethylamine (20 mol) was added dropwise while stirring at room temperature. After continuing stirring for 24 hours, the reaction solution was poured into water. Collect the precipitate and add ethanol-ether (
I: 3) After thorough washing with a mixed solvent, it was dried under reduced pressure to obtain the following high-molecular compound G2 A2 F2 L2 DL2 F3 L3 DL3 Yield (%) child compound in the form of a white powder.

Starting materials (revised o1) L3 F3 1 Yield (%) Example 6 A total of 10III of L3 and DL3 obtained in Example 3
A polymer was synthesized in the same manner as in Example 4 using IO1. That is, L3 and DL3 in the ratio shown in the table below, and adipic acid bis(N-hydroxyconolylimide) ester (I
0.0+ mol) was added to DMF (20 ml), and triethylamine (20+ mol) was added dropwise while stirring at room temperature. After continuing stirring for 24 hours, the reaction solution was poured into water. The precipitate was filtered to the bottom of the furnace and mixed with ethanol-ether (
I:3) After thorough washing with a mixed solvent, the mixture was dried under reduced pressure to obtain the following polymer compound in the form of a white powder.

Starting material (swol) L3 DL3 1 Yield (%) Example 7 Among the polymers obtained in Example 4, PF2, PL2, P
Using DL2, a degradation experiment using an in vivo hydrolase was conducted. The polymer compound of the present invention was crushed into a diameter of 100 μm or less in a glass mortar at 10.0 μm, commercially available (Sigma) enzyme 1.0 μm, and 50 mM buffer solution 3.0 μm.
ml into a 12 ml diameter glass test tube and at 30°C.
It was shaken at 75 cycles per minute. After 12 hours, a portion of the reaction solution (approximately 350 .mu.l) was centrifugally filtered (using a 0.22 .mu. filter), and the total organic carbon content in the solution was measured using Shimadzu TOC500. In addition, experiments were conducted in which the enzyme was removed from this reaction system, and an experiment in which the polymer compound was removed. The results are shown in the table below.

Polymer compounds Enzymes None Pepsin trypsin Chymotrypsin esterase none pepsin none trypsin none Chymotrypsin none esterase none pepsin none trypsin F2 L2 H 2,0 7,6 7,8 8,0 2,0 2,0 7,6 7,6 7,8 7,8 8,0 8,0 2,0 2,0 7,6 7,6 Total organic carbon amount (ppa) DL2 none Chymotrypsin none esterase none pepsin none trypsin none Chymotrypsin 7.8 7.8 8.0 8.0 2.0 2.0 7.6 7.6 7.8 7.8 ]98

Claims (1)

[Claims] 1. A polymer compound having a repeating structure represented by the following formula (I) in its main chain. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 and R^2 may be the same or different,
Each represents a hydrogen atom, an alkyl group, or an aralkyl group, and X and Y may be the same or different, and each represents an alkylene group. n represents a natural number of 2 or more. ) 2, R^1 and R^2 are hydrogen atoms, carbon numbers 1 to 10
an alkyl group having 7 to 11 carbon atoms,
2. The polymer compound according to claim 1, wherein X and Y are each an alkylene group having 2 to 10 carbon atoms. 3. Claim 1, wherein n represents a natural number from 2 to 100.
The polymer compound described.