JP2665522B2 - New alpha-oxyacid polymer - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel α-oxyacid polymer useful as a bioabsorbable polymer. The present invention also relates to a novel monomer used for producing the α-oxy acid polymer.

2. Description of the Related Art In recent years, bioabsorbable polymers have been increasingly used for medical materials, and in particular, α-oxyacid polymers having low toxicity and immunogenicity in vivo and high biocompatibility have been widely used. Have been.

In general, an α-oxyacid polymer is formed by mutually esterifying α-oxyacids, undergoes non-enzymatic hydrolysis in a living body to become an α-oxyacid, and is excreted from the body through a metabolic pathway. Therefore, it has no danger of accumulating in the body, so it is a suitable material as a temporary repair material for living organisms and a carrier for drugs. Polyglycolic acid (PGA), polylactic acid (PLA) and its copolymers have already been converted into fibers. It has been marketed as an absorbable surgical suture and has been clinically applied.

However, since PGA and PLA have high crystallinity and are water-insoluble, it is difficult to control the hydrolysis rate and impart functionality. Therefore, development of a material aiming at imparting hydrophilicity and functionality is required. In particular, a polymer of malic acid, which is a kind of α-hydroxy acid, is receiving attention.

Since malic acid has two carboxyl groups in one molecule, the polymer of malic acid has the formula: And α-polymalic acid having an α-type repeating unit represented by the formula: There is a β-polymalic acid having a β-type repeating unit represented by The synthesis of α-polymalic acid has the formula: In the ring-opening polymerization of the dibenzyl ester of the maleide shown in [3], the proceedings of the Society of Polymer Science, 35, 2330 (1985)]
The synthesis of polymalic acid has the formula: (ACSPolym.Prep.) 20, 608 (1979); Polymer Science and Technology (Polym.Sci.Techno)
l.) 23, 219 (1983)].

However, all of these monomers are difficult to synthesize and cannot be synthesized in large quantities. In particular, the yield of α-polymalic acid is low, and the synthesis method has not yet been established.

Thus, in view of the circumstances, the present inventors have found that malic acid α
In order to efficiently synthesize an α-oxyacid polymer having a -type binding unit, intensive studies have been made. As a result, we succeeded in synthesizing a new six-membered ring diester monomer having a mixed unit of malic acid and glycolic acid, and
They found that oxyacid polymers can be obtained efficiently,
The present invention has been completed.

Means for Solving the Problems The present invention provides a compound of the formula (I): Wherein R is a hydrogen or carboxyl protecting group, n is R
Means a number such that the molecular weight is about 1,000 to 300,000 when is hydrogen.] The present invention provides an α-oxyacid polymer comprising repeating units represented by the following formula:

Further, the present invention provides a compound of formula (II), which is a useful monomer for the synthesis of the polymer of formula (I): [Wherein, R represents hydrogen or a carboxyl protecting group].

Examples of the carboxyl protecting group represented by R in the formulas (I) and (II) include, for example, methyl, ethyl, n-
Lower alkyl such as propyl, isopropyl and t-butyl; and aralkyl such as benzyl. Preferred are methyl, ethyl and benzyl.

The polymer represented by the formula (I) of the present invention generally has R
When is hydrogen, about 1,00 to 300,000, preferably 10,000
It has a molecular weight of 100100,000.

The compounds of the formulas (I) and (II) have optical isomers, and all the optical isomers including the racemate are included in the present invention.

The polymer of formula (I) is obtained by subjecting the monomer of formula (II) to, for example, solution polymerization or bulk polymerization in the presence of an initiator,
If desired, the compound can be synthesized by removing an existing protecting group. The monomer of the formula (II) can be produced using L-aspartic acid as a starting material according to a method known per se, for example, the method shown in the following reaction formula I.

In the reaction formula I, a cyclic six-membered ring diester monomer which is a compound of the formula (II) of the present invention, L-3-benzyloxycarbonylmethyl-1,4-dioxane-2,5-dione (L-
BMD) and a method for synthesizing the glycolic acid-malic acid copolymer of formula (I). That is, the carboxyl group at the β-position of L-aspartic acid (a) as a starting material is esterified, for example, benzyl-esterified to give a protected derivative (b), and then diazotized and hydrolyzed to give L-β- Synthesize benzylmalate (c). Then, in a solvent, for example, ethers, aromatic hydrocarbons or halogenated hydrocarbons, preferably in diethyl ether, for example, in the presence of a base such as triethylamine,
The compound is coupled with bromoacetyl chloride and L
-Bromoacetylbenzylmalate (d) is obtained. Further, a solvent such as dimethylformamide (DMF), N
Intramolecular cyclization with an aprotic polar solvent such as -methylpyrrolidone (NMP), preferably in DMF, for example with sodium bicarbonate, gives the compound of formula (II).

The compound of formula (II) can be used as such or, for example,
After purification by recrystallization or the like, it is used for the synthesis of the compound of the formula (I).

In a nitrogen atmosphere, a compound of the formula (II) is dissolved in a solvent, for example,
In toluene, in the presence of an initiator such as diethyl zinc, tin octylate, aluminum isopropoxide, etc.
Solution polymerization is carried out at 80 to 120 ° C, preferably 100 ° C, and a copolymer of glycolic acid and benzylmalate (Ia)
Are synthesized. Then, if a polymer in which R is hydrogen is desired, the polymer of formula (Ia) is converted to a polar solvent, for example,
Hydrogenolysis is performed in a mixed solvent of ethanol and ethyl acetate in the presence of a catalyst, for example, a platinum dioxide catalyst, to remove the benzyl group, and to obtain a malic acid-glycolic acid copolymer (I
-B) is obtained.

Alternatively, under nitrogen atmosphere, the compound of formula (II)
Melting at ~ 170 ° C and bulk polymerization in the presence of an initiator also yields novel α-oxyacid polymers of formula (I).

The thus obtained novel α-oxyacid polymer of the formula (I) of the present invention can be used as a carrier for various medical materials and drugs such as absorbable surgical sutures, like polyglycolic acid and polylactic acid. it can.

EXAMPLES Next, the present invention will be described in more detail with reference to examples.
The α-oxyacid polymers (Ia) and (I-
As the molecular weight of b), GPC based on polystyrene
Was used.

Example 1 L-3-benzyloxycarbonylmethyl-
Production of 1,4-dioxa-2,5-dione (L-BMD) Dissolve 20 g of L-aspartic acid in 200 ml of 80% sulfuric acid,
While maintaining the temperature at 500 ° C., 500 g of benzyl alcohol was added and reacted to obtain L-benzyl aspartate in which the carboxy group at the β-position was protected. 100 g of this product in 1400 ml of 1N sulfuric acid
And sodium nitrite while stirring at 0-5 ° C.
100 ml of an aqueous solution containing 47 g was added dropwise over about 3 hours, and 30
Stirring was continued for minutes. Further, 30 ml of an aqueous solution containing 10 g of sodium nitrite was added dropwise over about 30 minutes, and the mixture was left overnight at room temperature. The mixture was extracted with ether, the extract was dried over sodium sulfate, concentrated, and the remaining crude crystals were recrystallized from benzene to obtain L-β-benzylmalate. This compound
20 g and 18.4 g of bromoacetyl chloride in 300 m of ether
After cooling to 5 ° C. or lower, 50 ml of an ether solution containing 9.9 g of a 1.1-fold molar amount of triethylamine was added dropwise over 30 minutes. The reaction mixture was further stirred at room temperature for 6 hours, filtered, 50 ml of water was added to the filtrate and stirred for 30 minutes. Water was added several times to carry out liquid separation, sodium sulfate was added to the ether layer, and the mixture was dried and then concentrated to obtain 29.7 g of L-bromoacetylbenzylmalate. 96% yield. ¹ H-NMR (acetone-d ₆ ) δ (ppm): 3.02 (q, CH ₂ CO, 2
H), 4.02 (s, OCH ₂ CO, 2H), 5.12 (s, CH ₂ Ph, 2H), 5.50
(Q, OCH, 1H), 7.35 (s, C 6 H 5, 5H) an L- bromoacetyl benzyl maleate 10g of DMF50ml solution, the DMF950ml solution of sodium hydrogen carbonate 3.7 g (heterogeneous solution) at room temperature It was dropped over about 8 hours. The mixture was further reacted at the same temperature for 12 hours, filtered, DMF was concentrated, and the residue was washed with 50 ml of isopropanol. After filtration, the obtained platinum powder was dissolved in 200 ml of acetone, and insolubles were removed by filtration.
The filtrate was concentrated. The residue was washed with a small amount of isopropanol, filtered and dried thoroughly. Sublimate this white powder,
The crystals were recrystallized with 400 ml of isopropanol, and L-
2.3 g (yield 27%) of 3-benzyloxycarbonylmethyl-1,4-dioxane-2,5-dione (L-BMD) was obtained. Melting point 150 ° C. ▲ [α] ^D ₂₅ ▼ = -127 ゜. ¹ H-NMR (acetone-d ₆ ) δ (ppm) 3.18 (q, CH ₂ CO, 2
H), 5.16 (q, OCH ₂ CO, 2H), 5.20 (s, CH ₂ Ph, 2H), 5.68
(T, OCH, 1H), 7.38 (s, C ₆ H ₅ , 5H) Proton NMR spectra of the obtained L-bromoacetylbenzylmalate and its cyclized product L-BMD are shown in FIGS. 1 and 2. Shown in Before the cyclization, a signal based on the glycolate unit appeared in a singlet at 4.0 ppm, whereas after the cyclization, this signal appeared as an AB quartet at 5.2 ppm, indicating a cyclized structure. In addition, the absorption of lactone and benzyl ester was 1660 cm in IR, respectively.
^-1 and 1620 cm ^-1 , which were consistent with this structure. Furthermore, the values of the elemental analysis were also consistent, and the structure of L-BMD was confirmed.

Example 2 Production of α-oxyacid polymer (Ia) Under a nitrogen atmosphere, 3 ml of toluene was added to 0.2 g of the BMD obtained in Example 1 and dissolved at 100 ° C. 26 μl of a 10 wt% solution of diethyl zinc in hexane was added to this solution, and at 100 ° C.,
The polymerization was carried out for 3 hours. After the polymerization, the solvent was concentrated and removed, and the obtained polymer was dissolved in 3 ml of acetone and reprecipitated in 30 ml of ether. After drying, poly L-BMD (I
-A) 0.19 g was obtained. 95% yield. ¹ H-NMR (acetone-d ₆ ) δ (ppm) 3.08 (m, CH ₂ CO, 2
H), 4.80 (s, OCH ₂ CO, 2H), 5.15 (s, CH ₂ Ph, 2H), 5.66
(M, OCH, 1H), 7.35 (s, C 6 H 5, 5H) Example 3 alpha-as producing initiator oxy acid polymer (I-a), tin octoate in toluene in place of diethyl zinc ( According to the method of Example 2, 0.185 g of the title compound having a molecular weight of 12,900 was prepared using 61 µm of 0.1 / ml). 93% yield.

Example 4 Production of α-oxyacid polymer (Ia) In place of diethylzinc, 31 μl of a toluene solution of aluminum isopropoxide (0.1 g / ml) was used as the initiator, and a molecular weight of 2,900 was obtained according to the method of Example 2. 1.96 g of the title compound were prepared. Yield 98%.

Example 5 Production of α-oxyacid polymer (Ia) 0.2 g of the monomer produced in Example 1 under a nitrogen atmosphere
(Melting point 150 ° C.) was heated to 160 ° C. and completely melted.
To this, 35 μl of a 10 wt% toluene solution of tin octylate was added to degas, and toluene was removed.
The reaction was performed for 0 hours. Dissolve the reaction mixture in 3 ml of acetone,
Reprecipitation was performed from 30 ml of ether. The mixture was filtered and dried to obtain 0.19 g of a white powdery poly L-BMD having a molecular weight of 23,000. 95% yield.

Example 6 Production of α-oxyacid polymer (Ib) 0.09 g of the polymer obtained in Example 2 was dissolved in 20 ml of a methanol / ethyl acetate (1: 3) solvent, and 10 mg of platinum dioxide was added to the solution. Was. The reaction vessel was filled with hydrogen, and the mixture was stirred while maintaining the temperature at 30 ° C. until hydrogen absorption ceased. Filter to remove the platinum dioxide catalyst, concentrate the solvent,
Α-oxyacid polymer (Ib) 5 having a desired molecular weight of 1,200
9 mg were obtained. 96% yield. ¹ H-NMR (methanol-d ₄ ) δ (ppm) 3.18 (d, CH ₂ CO, 2
H), 4.97 (d, OCH ₂ CO, 2H), 5.82 (m, OCH, 1H) α-oxyacid polymer before and after hydrogenolysis ((Ia) obtained in Example 2) and (Example (I
FIG. 3 shows the proton NMR spectrum of -b)).
In (Ia), the signal based on benzyl gas was about 7.4 ppm.
And appear as singlets at 5.2pm respectively.
However, this signal was not observed in the copolymer (Ib), indicating that benzyl gas had almost disappeared.

In addition, the specific rotation of the polymer (in acetone) remains in the range of −30 ° to −32 ° even when the aggregation conditions are changed, and the carbonyl signal becomes three types of singlets in ¹³ C-NMR. Therefore, it was found that the polymer had an alternating polymer structure of glycolic acid and α-malic acid.

Effects of the Invention According to the present invention, a high biocompatible novel α-oxyacid polymer having glycolic acid and α-malic acid binding unit can be obtained in good yield.

[Brief description of the drawings]

1 and 2 are NMR spectra of the compound (d) and the monomer of the formula (II), respectively. FIG. 3 is the NMR spectra of the polymers of formulas (Ia) and (Ib).

 ────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-63-92641 (JP, A) JP-A-60-101118 (JP, A) Macromolecules, 21 [11] (1988) p. 3338-3340

Claims (2)

(57) [Claims] 1. The formula: Wherein R is hydrogen, lower alkyl or aralkyl, n
Means a number such that the molecular weight when R is hydrogen is about 1,000 to 300,000.] An α-oxyacid polymer comprising repeating units represented by the following formula: 2. The formula: [Wherein, R represents hydrogen, lower alkyl or aralkyl].