JPH09309947A - Aliphatic polyester having cholesterol group as side chain - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an aliphatic polyester having cholesterol groups as side chains, which is used a biomaterial being excellent in mechanical compatibility and interfacial compatibility and degradable in the living body. SOLUTION: An aliphatic polyester (a) represented by formula I [wherein X is formula II, -O(CH2 CH2 )- (wherein (m) is 1-10), -O(CH2 )p - (wherein (p) is 2-30 or a bonding group; and (n) is 10 or above] is produced in a reaction route shown in formula III. A crosslinked polymer of compound (a) and a copolymer thereof with polyethylene glycol (the content of the polyethylene glycol is 0-40wt.% based on the copolymer) are also used for use the same as that of compound (a). An example of the process for producing compound (a) is described. below p-Hydroxybenzoic acid is acetylated with acetic anhydride, the product of acetylation is converted into a acid chloride by reaction with thionyl chloride, the acid chloride is reacted with cholesterol, the formed product is treated with sodium methylate, the treated product is glycidylated with chloromethyloxysilane, and the product of glycidylation is reacted with succinic anhydride.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an aliphatic polyester having a cholesterol group in a side chain which is useful as a biomaterial.

[0002]

2. Description of the Related Art Many living tissues have an ordered structure similar to liquid crystals. Therefore, when a material exhibiting liquid crystallinity is used as a biomaterial, high biocompatibility may be obtained in some cases. However, artificial materials as biomaterials must be compatible with living bodies, not just structural materials. Generally, factors to be considered when considering the biocompatibility of medical materials include mechanical compatibility and interface compatibility. The material implanted in the living tissue necessarily receives mechanical stimulation from the tissue and must be adapted to the stimulation. Also, the embedded material must have an interface where the blood comes in contact with the material so that the blood does not coagulate at the contact site. That is, a blood compatible material that is less likely to form a thrombus on the material surface is needed. Furthermore, it is ideal that biomaterials are degraded and metabolized and eventually disappear even if they are implanted in the living body.

One such biomaterial is segmented polyurethane. Although this is a material excellent in mechanical properties and decomposed in vivo, it has a disadvantage that blood coagulates at the site where the material comes in contact.

[0004]

SUMMARY OF THE INVENTION It is an object of the present invention to have excellent mechanical compatibility, interfacial compatibility (ie, the property that blood does not coagulate at a site where biomaterials come in contact), and It is to provide a polymer that is degraded in the body.

[0005]

SUMMARY OF THE INVENTION As a result of intensive studies to achieve the above-mentioned problems, the present inventors have found that some aliphatic polyesters having a cholesterol group in the side chain, their crosslinked polymers, and their polyethylenes. The inventors found that the copolymer with glycol has mechanical compatibility, interfacial compatibility, and decomposition in vivo, and completed the present invention.

That is, the present invention

[0007]

[Chemical formula 3]

[Wherein X is the formula

[0009]

[Chemical formula 4]

A group represented by the formula: -O (CH ₂ CH ₂ ) m
-(In the formula, m represents an integer of 1 to 10) or a group represented by the formula -O (CH ₂ ) p-(wherein p is 2 to 3)
Indicates an integer of 0. Or a bond, and n represents an integer of 10 or more. And the present invention is a crosslinked polymer of the polymer of the formula (I), and the present invention further comprises the polymer of the formula (I) and polyethylene glycol And copolymers thereof.

Among the polymers of the formula (I) according to the invention,
The polymer in which is a connector has the most desirable properties.
The polymer of the formula (I) of the present invention can be produced, for example, by the following reaction scheme.

[0012]

[Chemical formula 5]

(In the reaction scheme, X and n are as defined above.) Further, a crosslinked polymer of the polymer of the formula (I) can be produced, for example, by the following reaction scheme.

[0014]

[Chemical formula 6]

Furthermore, a copolymer of the polymer of the formula (I) and polyethylene glycol can be produced, for example, according to the following reaction scheme.

[0016]

[Chemical formula 7]

The copolymer of the polymer of the formula (I) and polyethylene glycol is preferably such that the content of polyethylene glycol in the copolymer is 0 to 40% by weight.

Polymers in which X is a group of formula (II) in formula (III) can be synthesized by the following reaction scheme.

[0019]

[Image 8]

Also, in the formula (III), X is a group of the formula -O
The polymer of the group represented by (CH ₂ ) p-can be synthesized by the following reaction scheme.

[0021]

Embedded image

[0022]

According to the present invention, excellent mechanical compatibility
It has become possible to provide polymers which have interfacial compatibility and which are degraded in vivo. Therefore, it can be safely used as a biomaterial without causing thrombus and the like.

[0023]

EXAMPLES The present invention will be described in more detail with reference to the following Examples and Test Examples. Example 1 In a polymer of formula (I), X is a group of formula (II)
Synthesis

[0024]

[Image 10]

1) 50.0 g of p-hydroxybenzoic acid
(0.36 mol) in 4 N aqueous solution of potassium hydroxide 2
It was dissolved in 00 ml and stirred on an ice bath. here,
Add 67.5 g (0.66 mol) of acetic anhydride,
Stir for 1 hour while diluting with 00 ml. The aqueous solution was acidified to pH 3 with hydrochloric acid and subsequently stirred for 1 hour. The precipitated solid was filtered, washed with water until the filtrate was neutral, and then recrystallized with methanol to obtain 61.3 g of p-acetoxybenzoic acid.

2) 7.2 g of the compound obtained in 1) (40.
0 mmol) was dissolved in 20 ml of thionyl chloride, a catalytic amount of N, N-dimethylformamide was added, and the mixture was stirred at room temperature for 2 hours and then at 50 ° C. for 2 hours. Thereafter, excess thionyl chloride was distilled off under reduced pressure to obtain an acid chloride. Next, 40 ml of a dry tetrahydrofuran solution of the acid chloride synthesized above was slowly added dropwise to 60 ml of a dry tetrahydrofuran solution of 15.0 g (38.8 mmol) of cholesterol and 10.1 g (100 mmol) of triethylamine on an ice bath. Stir overnight. Remove the solvent under reduced pressure,
The resulting residue was washed twice with water and twice with methanol. The obtained crude product is recrystallized with acetone, separated and purified, and cholesteryl-p-acetoxybenzoic acid 15.3.
I got g. NMR (CDCl ₃ ) δ (ppm); 8.2 to 7.3
(4H, m), 5.5 (1 H, s), 2.9 to 0.6
(47 H, m).

3) 9.5 g of the compound obtained in 2) (17.
3 mmol) is dissolved in 50 ml of tetrahydrofuran,
Stir at room temperature. To this solution was dropped 3.4 g (1 equivalent) of a methanol solution of sodium methylate (28% by weight). After 10 minutes, the reaction solution was poured into 500 ml of water and the aqueous solution was acidified to pH 5 with hydrochloric acid. The precipitated solid was filtered, washed with methanol and recrystallized from ethyl acetate to obtain 7.9 g of cholesteryl-p-hydroxybenzoate. IR (KBr); 3600-3200 cm ^-1 (-OH phenol), 2940-2850 cm ^-1 (CH alkane), 1670 cm ^-1 (C = O ester), 1610 c
m ^-1 , 1510 cm ^-1 (CH 2 aromatic).

4) 5.1 g of the compound obtained in 3) (10.
1 mmol) was dissolved in a mixture of 50 ml of chloromethyl oxirane and 10 ml of tetrahydrofuran, 0.8 g (20 mmol) of powdered sodium hydroxide was added thereto, and the mixture was stirred at 100 ° C. for 30 minutes. The reaction solution was diluted with 100 ml of tetrahydrofuran and the insolubles were separated by filtration. After the filtrate was evaporated to dryness, the residue was washed with hexane and recrystallized with acetone to obtain 4.0 g of cholesteryl-p-glycidyloxybenzoate. NMR (CDCl ₃ ) δ (ppm); 8.2 to 7.2
(4H, m), 5.6 (1 H, s), 4.3 (2 H,
m), 3.5 (1 H, m), 3.0 (2 H, m), 2. m.
6 to 0.6 (44 H, m).

5) 1.00 g of the compound obtained in 4) (1.
78 mmol) and 0.18 g (1.78 m) of succinic anhydride
mol) and 3.6 mg (1 mol%) of aluminum triisopropoxide as catalyst, 0.7 as solvent
ml of toluene was introduced into a glass ampoule. The tube was sealed under a nitrogen atmosphere and allowed to react at 110 ° C. for 24 hours. The product was dissolved in a small amount of chloroform and reprecipitated in methanol to obtain 1.0 g of the title polymer.

IR (KBr); 3000-2800 cm
^-1 (CH alkane), 1750 cm ^-1 (C = O aliphatic ester), 1670 cm ^-1 (C = O aromatic ester),
1610 cm ^-1 , 1510 cm ^-1 (CH 2 aromatic).

EXAMPLE 2 Synthesis of a Polymer of the Formula (I) Where X is a Connector

[0032]

[Image 11]

1) Cholesterol 25.0 g (64.
6 mmol) is dissolved in a mixture of 40 ml of epibromohydrin and 20 ml of tetrahydrofuran, and 8.0 g (200 ml) of powdered sodium hydroxide and 1.0 g of tetra-n-butylammonium hydrogen sulfate are added and the mixture is heated to 100 ° C. Stir for hours. The reaction solution was diluted with 200 ml of tetrahydrofuran, the insolubles were filtered off, and the filtrate was evaporated to dryness. The crude product was separated and purified by silica gel column chromatography (developing solvent; ethyl acetate: hexane = 1: 9) to obtain 8.3 g of cholesteryl glycidyl ether. NMR (CDCl ₃ ) δ (ppm); 5.5 (1 H,
s), 3.7 (2 H, m), 3.2 (1 H, m), 2.
7 (2H, m), 2.6 to 0.6 (52 H, m). 2) 0.92 g (2.0 mmol) of the compound obtained in 1)
And 0.20 g (2.0 mmol) of succinic anhydride, and 4.1 mg (1 mol%) of aluminum triisopropoxide as a catalyst, and 0.5 ml of toluene as a solvent were introduced into a glass ampoule. The tube was sealed under a nitrogen atmosphere and allowed to react at 110 ° C. for 24 hours. The product was diluted with a small amount of chloroform and reprecipitated into methanol. In addition, it was dissolved and reprecipitated in methanol to obtain 0.75 g of the title polymer. IR (KBr); 2950 to 2850 cm ^-1 , 1460
cm- ¹ (CH2 alkane), 1740 cm- ¹ (C = O aliphatic ester), 1100 cm- ¹ (CO2 ether).

EXAMPLE 3 In the formula (I), X is represented by the formula -O (CH ₂ ) p-
Of polymers that are

[0035]

[Chemical formula 12]

1) 23.2 g of cholesterol (60.
0 mmol) was dissolved in 120 ml of pyridine and stirred on an ice bath. After 30 ml of a tetrahydrofuran solution of 22.8 g (120 mmol) of p-toluenesulfonyl chloride was slowly added dropwise to this solution, the mixture was stirred overnight at room temperature. The reaction solution was then poured into 1 l of water and the precipitate was filtered off. The filtrate was again washed with water, then twice with methanol and recrystallized with acetone to obtain 26.8 g of cholesteryl tosylate. NMR (CDCl ₃ ) δ (ppm); 7.8 to 7.4
(4H, m), 5.4 (1 H, s), 2.5 (3 H,
s), 2.6 to 0.6 (44 H, m).

2) 5.4 g of the compound obtained in 1) (10.
0 mmol) and 16.7 g of hexamethylene glycol
(150 mmol) was dissolved in 100 ml of 1,4-dioxane and allowed to react at 100 ° C. for 30 hours. The solvent was evaporated under reduced pressure and the residue was washed 3 times with 300 ml of hexane.
The crude product obtained by concentrating the filtrate is subjected to silica gel column chromatography (developing solvent; ethyl acetate: hexane = 1: 1
5) to obtain 3.5 g of 6-hydroxyhexyl cholesteryl ether. NMR (CDCl ₃ ) δ (ppm); 5.5 (1 H,
s), 4.0 (5 H, m), 2.8 to 0.6 (52 H,
m).

3) 5.0 g of the compound obtained in 2) (10.
3 mmol) is dissolved in 30 ml of epibromohydrin,
1.6 g (40.0 mmo) of powdered sodium hydroxide
l) and tetra-n-butylammonium hydrogen sulfate 0.3
g was added and stirred at 100 ° C. for 3 hours. 10 reaction solutions
Dilute with 0 ml of tetrahydrofuran, filter off the insolubles and dry the filtrate. The crude product was separated and purified by silica gel column chromatography (developing solvent; ethyl acetate: hexane = 1: 9) to obtain 1.2 g of cholesteryloxyhexyl glycidyl ether. NMR (CDCl ₃ ) δ (ppm); 5.4 (1 H,
s), 4.0 to 3.4 (6 H, m), 3.2 (1 H,
m), 2.8 (2 H, m), 2.5 to 0.6 (52 H,
m).

4) 1.09 g of the compound obtained in 3) (2.
0 mmol) and 0.20 g of succinic anhydride (2.0 mmo)
l) and 0.5 ml of toluene as catalyst were introduced into a glass ampoule. Seal this in a nitrogen atmosphere, 1
The reaction was allowed to proceed at 10 ° C. for 24 hours. The product was diluted with a small amount of chloroform and reprecipitated into methanol. In addition, it was dissolved and reprecipitated in methanol to obtain 0.7 g of the title polymer.

IR (KBr); 2950 to 2850 cm
^-1 , 1460 cm ^-1 (CH alkane), 1740 cm
^-1 (C = O aliphatic ester), 1110 cm ^-1 (CO 2 ether).

Example 4

[0042]

Embedded image

0.81 g (1.76 mmol) of the polymer obtained in Example 2 (hereinafter referred to as PES), 0.20 g (2.0 mmol) of succinic anhydride, 25 mg of 1,4-butanediol diglycidyl ether .12 mmo
l) and 4.1 mg (1 mol%) of aluminum triisopropoxide as catalyst, toluene 0. 1 as solvent.
7 ml was introduced into a glass ampoule. The tube was sealed under a nitrogen atmosphere and allowed to react at 110 ° C. for 24 hours. To the product is added 30 ml of chloroform to remove insolubles, the filtrate is concentrated and reprecipitated into methanol, PES
0.5 g of crosslinked polymer was obtained. IR (KBr); 2950 to 2850 cm ^-1 , 1470
cm- ¹ (CH2 alkane), 1740 cm- ¹ (C = O aliphatic ester), 1110 cm- ¹ (CO2 ether).

Embodiment 5

[0045]

[Image 14]

0.96 g of polymer obtained in Example 3 (1.
76 mmol), 0.20 g of succinic anhydride (2.0 mm)
ol), 25 mg (0.12 mmol) of 1,4-butanediol diglycidyl ether and 4.1 m as a catalyst
g (1 mol%) of aluminum triisopropoxide, 0.7 ml of toluene as solvent was introduced into a glass ampoule. The tube is sealed in a nitrogen atmosphere and heated to 110 ° C.
Reaction for 24 hours. To the product, 30 ml of chloroform was added to remove insolubles, and the filtrate was concentrated and reprecipitated into methanol to obtain 0.4 g of a crosslinked polymer of the polymer obtained in Example 3. IR (KBr); 2950 to 2850 cm ^-1 , 1470
cm- ¹ (CH2 alkane), 1740 cm- ¹ (C = O aliphatic ester), 1110 cm- ¹ (CO2 ether).

EXAMPLE 6 Co-weight of PES and polyethylene glycol (3000)
Coalescing synthesis

[0048]

[Image 15]

0.92 g of the compound obtained in Example 2 (1)
(2.0 mmol), succinic anhydride 0.20 g (2.0
mmol), 0.20 g of polyethylene glycol having a number average molecular weight of 3000, and 9.1 mg (0.03) as a catalyst
45 mmol) of aluminum triisopropoxide,
As a solvent, 0.5 ml of toluene was introduced into a glass ampoule. The tube is sealed in a nitrogen atmosphere and
It was allowed to react for 4 hours. The product was diluted with chloroform and reprecipitated into methanol to give 4.9 g of the title polymer.
IR (KBr); 2950 to 2850 cm ^-1 , 146
0 cm ^-1 (CH alkane), 1740 cm ^-1 (C = O aliphatic ester), 1240 cm ^-1 (CO polyethylene glycol), 1110 cm ^-1 (CO ether).

EXAMPLE 7 Joint of PES and Polyethylene Glycol (13000)
Polymer synthesis

[0051]

Embedded image

0.69 g of the compound obtained in Example 2 (1)
(1.5 mmol), succinic anhydride 0.15 g (1.5
mmol), 0.59 g of polyethylene glycol having a number average molecular weight of 13,000, and 6.1 mg (0.
030 mmol) of aluminum triisopropoxide, 0.7 ml of toluene as solvent were introduced into a glass ampoule. The tube is sealed in a nitrogen atmosphere and heated to 110 ° C.
Reaction for 24 hours. The product was diluted with chloroform and reprecipitated into methanol to give 1.2 g of the title polymer. IR (KBr); 2950 to 2850 cm ^-1 , 1
460 cm ^-1 (CH alkane), 1740 cm ^-1 (C = O
Aliphatic ester), 1240 cm ^-1 (CO 2 polyethylene glycol), 1110 cm ^-1 (CO 2 ether).

EXAMPLE 8 Joint of PES and polyethylene glycol (27000)
Polymer synthesis

[0054]

[Image 17]

0.46 g of the compound obtained in Example 2 (1)
(1.0 mmol), succinic anhydride 0.10 g (1.0
mmol), 0.56 g of polyethylene glycol having a number average molecular weight of 27,000, and 2.5 mg (0.
013 mmol) aluminum triisopropoxide, 0.5 ml of toluene as solvent was introduced into a glass ampoule. The tube is sealed in a nitrogen atmosphere and heated to 110 ° C.
Reaction for 24 hours. The product was diluted with chloroform and reprecipitated into hexane to give 0.9 g of the title polymer. IR (KBr); 2950 to 2850 cm ^-1 , 14
60 cm ^-1 (CH alkane), 1740 cm ^-1 (C = O
Aliphatic ester), 1240 cm ^-1 (CO 2 polyethylene glycol), 1110 cm ^-1 (CO 2 ether).

(Test Example) [Blood Contact Test] A PET disk of 14 mm in diameter was used with 0.5 w of each polymer.
t. Coated with chloroform solution and allowed to dry naturally. The disc was dried under vacuum for 12 hours to make a sample for testing. Fix the test disc with a silicon ring on a 24-well cell culture petri dish, 0.7
It was soaked overnight in ml of phosphate buffer solution (PBS, pH 7.4 ionic strength 0.15 M). After removing PBS, 0.7
The rabbit PRP was injected in ml, and the contact test with blood was performed. After a predetermined time (60 minutes, 180 minutes), PRP was removed with an aspirator and carefully washed off non-adherent platelets with PBS. Next, 2.5 vol.
0.7 ml of a% PBS solution was injected and left at room temperature for 2 hours to immobilize the deposit. After washing the disc with a sufficient amount of distilled water, it was freeze-dried and used for SEM observation. In addition, segmented polyurethane (SP as a comparison of the test
U, manufactured by Up John Co., Ltd.) was used.

As a result, on the SPU surface, a large amount of platelets aggregated and adhered, whereas the polymer of the present invention showed less platelet adhesion. Also, among them, PES / polyethylene glycol (100/0) having high hydrophobicity, and PES / PEG (50/50) having high hydrophilicity,
Copolymer PES / PEG (8
0/20), PES / PEG (59/41) showed a large platelet adhesion inhibitory effect (but S
Several groups outperformed PU. ). Furthermore, the platelets adhered in the enlarged photograph are pseudopoded, greatly deformed and aggregated, whereas the platelets on the surface of the copolymer of the present invention have a relatively discoid shape relatively. It can be seen that it is maintained, and moreover, it adheres singly without aggregation.

Claims (5)

[Claim of claim] Formula (1) [Wherein X is the formula A group represented by the formula -O (CH ₂ CH ₂ ) m-(wherein
m is an integer of 1 to 10; Or a group represented by the formula -O (CH ₂ ) p-(wherein p represents an integer of 2 to 30) or a bond;
Represents an integer of 10 or more. Aliphatic polyester which has a cholesterol group in the side chain represented by these. 2. An aliphatic polyester having a cholesterol group in a side chain according to claim 1, wherein X is a connector. 3. A crosslinked polymer of aliphatic polyester having cholesterol group in a side chain according to claim 1 or 2. 4. A copolymer of an aliphatic polyester having a cholesterol group in a side chain and polyethylene glycol according to claim 1 or 2. 5. A copolymer according to claim 4, wherein the amount of polyethylene glycol is from 0 to 40% by weight.