WO2014133102A1

WO2014133102A1 - Biocompatible polymer as antithrombogenic material, cyclic carbonate useful as precursor thereof, and method for producing same

Info

Publication number: WO2014133102A1
Application number: PCT/JP2014/054948
Authority: WO
Inventors: 賢田中; 和樹福島; 千香子佐藤; 彩乃佐々木; 裕人井上
Original assignee: 国立大学法人山形大学
Priority date: 2013-02-27
Filing date: 2014-02-27
Publication date: 2014-09-04

Abstract

Provided is a biocompatible polymer composition comprising a structure having at least one side chain ether group and a main chain formed from a biodegradable polymer skeleton, as well as an intermediate compound for producing the polymer composition, and a method for producing the same. The intermediate compound is produced by exposing a diol compound having carboxyl groups to a carbon source for cyclization of the diol moiety of the diol compound in the presence of an organic solvent while protecting the carboxyl groups using an organic base, and then a biocompatible polymer is produced by ring-opening polymerization of the intermediate compound. A medical device having superior antithrombogenicity can be provided by using this polymer composition.

Description

Biocompatible polymer as antithrombotic material, cyclic carbonate useful as an intermediate thereof, and production method thereof

The present invention mainly relates to a biocompatible polymer as an antithrombotic material, a cyclic carbonate useful as an intermediate thereof, and a method for producing the same. More specifically, when it is placed in a living body or comes into contact with a substance derived from a living body, blood compatibility such as an anti-coagulant action and a target biological substance can be selectively adsorbed. A polymer for use as a medical material having a function and capable of being chemically decomposed in vivo or in vitro, a novel compound for synthesizing the polymer, and a polymer using the compound And a composition containing the polymer and a medical device using the composition. Furthermore, the present invention relates to a cyclic carbonate having a functional group such as a carboxyl group in the molecule, a derivative thereof, a method for producing the same, etc.

In general, when a biological component such as blood comes into contact with the surface of a medical material, the surface of the material is recognized as a foreign substance, and nonspecific adsorption, denaturation, multilayer adsorption, etc. of proteins in the biological tissue occur on the material surface. As a result, activation of the coagulation system, complement system, platelet system, etc. occurs. For this reason, in order to prevent the medical device surface which is a contact interface with the living body from being recognized as a foreign substance, it is desired to impart biocompatibility to the medical device surface. Specifically, in medical devices such as artificial lung devices, dialysis devices, blood storage bags, platelet storage bags, blood circuits, artificial hearts, indwelling needles, catheters, guide wires, stents, artificial blood vessels, endoscopes, blood It is desired that a portion that contacts a biological material such as has excellent biocompatibility.

As a means of imparting biocompatibility to the surface of medical devices, conventional materials have been artificially synthesized and applied to the surface of various medical devices to reduce the burden on the living body. Attempts have been made. Examples of such biocompatible materials include 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer, polyethylene glycol (PEG), poly (2-methoxyethyl acrylate) (PMEA), polyalkoxyalkyl (meth) acrylamide, etc. Is known and has been put to practical use in various applications. By using these biocompatible materials at sites where blood or other biological components such as the surface of medical materials come into contact, the surface of medical devices is prevented from being recognized as a foreign substance, and the coagulation system, complement system, platelets Activation of the system and the like is suppressed.

The MPC polymer is a kind of betaine that maintains electrical neutrality in a living environment, and binds a phospholipid polar group covering a living cell membrane to a polymerizable group such as a vinyl group via an ester bond. And a polymer produced by polymerizing the polymerizable group, and has a structure in which a phospholipid polar group is provided as a side chain with respect to the alkyl chain (main chain).
Polyethylene glycol (PEG) has a structure having an ether structure (C ₂ H ₄ —O) as a repeating unit, and is known to exhibit very excellent biocompatibility. However, since PEG itself is water-soluble, it needs to be used as a block copolymer or graft copolymer with another polymer for the purpose of imparting water resistance when used as a medical material. is there. On the other hand, poly (2-methoxyethyl acrylate) (PMEA) and the like are obtained by polymerizing a monomer in which a group mainly composed of an ether structure, which is a structural unit of PEG, is bonded to a vinyl group or the like to form an alkyl chain (main chain). On the other hand, it has a structure provided as a side chain having an ether structure as a main component. It has been clarified that by adopting such a structure, water resistance can be imparted by an alkyl chain while maintaining the biocompatibility exhibited by PEG.
Polyalkoxyalkyl (meth) acrylamide has an ether structure at the end of the side chain and has a structure with (meth) acrylamide as a repeating unit, and due to its moderate hydrophilicity, the activity of coagulation system, complement system and platelet system It has been found that it is possible to suppress oxidization and to express excellent blood affinity.

Including MPC polymer having side chain containing phospholipid polar group on main chain, PEG composed of ether structure, PMEA which is polymer having side chain composed mainly of ether structure, and ether structure and amide bond Even though polymer materials having hydrophilic groups such as ether structures and amide bonds, such as polyalkoxyalkyl (meth) acrylamide having a high molecular weight, have a high biocompatibility despite having a completely different structure from substances constituting the living body. The reason for showing is not necessarily clear. On the other hand, recent research has revealed that these polymers can contain water molecules in a state called “intermediate water” observed in biological materials (see, for example, Non-Patent Document 1). I want to be) That is, as described in the above document, a substance exhibiting biocompatibility can contain “intermediate water” regardless of whether it is a biologically derived substance or an artificial synthetic product. It has been experimentally shown that non-specific adsorption of proteins in living tissue is prevented by the presence of water molecules in a state called as being on the surface of the substance, and as a result, bioaffinity is expressed. In order for a given substance to contain “intermediate water”, it is not always necessary for the substance to have a structure suitable for containing “intermediate water” like PEG. It has been revealed that “intermediate water” can also be contained by providing a structure suitable for containing “water” as a side chain.

Intermediate water contained in a biocompatible substance is typically characterized by the release and absorption of unique latent heat that is seen in the temperature rise process after supercooling. In other words, for substances containing intermediate water, in the process of gradually heating to near room temperature after cooling to about −100 ° C., latent heat release is observed near −40 ° C., and latent heat is below freezing above −10 ° C. Absorption and absorption of specific latent heat is observed, such as the absorption of. Various verifications have revealed that the release and absorption of these latent heats is caused by the fact that a certain proportion of water molecules contained in the substance cause ordering and disordering. A molecule is defined as intermediate water. Intermediate water is presumed to be weakly constrained by specific effects from the molecules that make up the substance, but it has been shown that it is also contained in biological materials such as phospholipids in biological tissues. It is thought to be related to prevention of non-specific adsorption of proteins. In addition to the PMC polymer provided with a phospholipid polar group contained in the living body as a side chain, the substance such as PEG, PMEA, polyalkoxyalkyl (meth) alkylamide, etc. can contain intermediate water. It is thought to be related to the expression of affinity.

On the other hand, the existence of biodegradable polymers having biodegradability that has been decomposed and disappeared by the action of hydrolysis or enzymatic degradation has been known so far. Biodegradable polymers are generally used for the purpose of reducing the burden on the natural environment by being destroyed by action from the natural world after being discarded. On the other hand, in recent years, the use of biodegradable polymers in medical devices such as surgical sutures, stents, and catheters that are indwelled in the body eliminates the need for procedures such as thread removal after the treatment is completed. It has become common to add a function to release the release.
In biodegradable polymers used for medical devices placed in the body, in addition to the property of degrading in a predetermined period, substances generated by decomposition are not toxic to the living body and are discharged from the body by metabolism. It is common to be designed. As an example of a medical device in which such a biodegradable polymer is used, for example, in Patent Document 1, a biodegradable polymer and drug mixed layer having a predetermined structure is provided on the surface of an in-vivo indwelling object. Thus, a technique is described in which a drug is gradually released as the biodegradable polymer is decomposed. Patent Document 2 discloses a biodegradable polymer used for catheters and the like, and does not generate carboxylic acid when decomposed in vivo, thereby reducing the risk of inflammation due to local pH reduction. And polymers that are considered biocompatible are described.
However, in the biodegradable polymer used in the medical device as described above, there are limited prior examples in consideration of the affinity (biological affinity) to the living body when it exists as a polymer. That is, while being used in a medical device, it is a polymer showing biocompatibility that does not cause a foreign body reaction to blood or tissue in the living body, and is biodegraded and metabolized within a predetermined period. Few polymers have been provided so far. For example, Patent Document 3 describes a polymer in which a phospholipid component exhibiting blood affinity, non-thrombogenicity, and the like is introduced to a biodegradable polymer by a covalent bond, so that both biodegradability and blood affinity are compatible. Attempts have been made, but the manifestation of this property has not been confirmed.

Biodegradable polymers and the like can be prepared by ring-opening polymerization (ROP) using a cyclic carbonate or the like useful as an intermediate. In order to expand the application of the synthesized polymer, it is essential to easily and inexpensively produce cyclic monomers having various functional groups. Although some cyclic esters having functional groups have been reported, the introduction site of functional groups is limited due to steric bulk and ring distortion, and it is difficult to produce specific cyclic esters at low cost. Its usefulness is limited because of its low stability and poor reaction yield. On the other hand, there have been many reports on methods for synthesizing functionalized cyclic carbonates starting from 1,3-diol.

For example, as shown in Scheme 1 below, the group R of the cyclic carbonate MTC-XR (X represents O, NH, S or the like) obtained from the diol compound bis-MPA having a carboxyl group is bonded via a carboxyl group. Various functional groups R that can be reacted can be applied. Such 6-membered cyclic carbonate easily gives an aliphatic polycarbonate by ring-opening polymerization, and since it exhibits biodegradability, its application to medical materials such as drug carriers and cell culture substrates has been widely studied. In particular, functions such as drug loading ability, cell recognition ability, selective cell adhesion ability, and antithrombogenicity are added by the functional group R bonded to the carbonate using the structure — (C═O) X— as a linker. Recently, biodegradable polymers have attracted attention as highly functional medical materials and smart biomaterials.

As a method for producing the cyclic carbonate MTC-XR, it has been conventionally known that it can be produced by a plurality of production methods as in the above scheme. In any of the above schemes, bis-MPA or the like is used as a starting material, and a cyclic carbonate is typically produced by cyclizing the diol moiety by a cyclization reaction in an aprotic organic solvent. In addition, bis-MPA containing a carboxyl group is used as a starting material for synthesizing a cyclic carbonate mainly from the point of introducing an appropriate side chain into a polymer obtained by ring-opening polymerization of a cyclic carbonate. Before and after, a substitution reaction of a carboxyl group with a reactive reagent is performed.
In the synthesis of the cyclic carbonate as described above, the cyclization reaction needs to be performed in an aprotic organic solvent or the like, whereas bis-MPA has a high polarity and thus has low solubility in an organic solvent. There is a problem, and typically, an operation for increasing the solubility in an organic solvent is performed by previously performing some substitution reaction on the carboxyl group. On the other hand, since the substitution reaction with the carboxyl group generally undergoes esterification or amidation with a reactive reagent, such as a substituted alcohol or amine, it is necessary to consider the influence on the diol moiety at that time. . In particular, when esterifying a carboxyl group, it is necessary to consider the competition of the esterification reaction with the diol moiety. Therefore, in the synthesis of cyclic carbonates starting from bis-MPA, etc., it is necessary to appropriately pass through the protection and deprotection steps for the diol moiety and carboxyl group, and various synthetic routes as described above have been proposed in the past. Has been.

Production method A in Scheme 1 is reported in Non-Patent Document 2 and the like, and after protecting the carboxyl group as a benzyl ester, cyclization reaction is performed in an organic solvent, and then the carboxyl group is deprotected and deprotected. A reactive functional group is introduced by a nucleophilic acyl substitution reaction of an alcohol or amine with respect to the carboxyl group regenerated by the above. In production method A, a wide range of nucleophiles can be used, but the number of steps is large. That is, the benzyl ester of the carboxyl group is chemically stable, and in order to perform deprotection by a hydrogenolysis method or the like, an intermediate must be isolated. It has the problem of decreasing.
Production method B is reported in Non-Patent Document 3, etc., in which the reaction of introducing a reactive functional group into a carboxyl group is preceded, followed by a cyclization reaction. By using a large excess of the nucleophile, the self-condensation reaction of bis-MPA is suppressed in the initial stage reaction. However, it is limited to the case of using alcohol or amine having a low boiling point and chemically stable from the viewpoint of purification and isolation, which requires heating at a high temperature. In addition, the reaction conditions and reaction substrates are greatly limited, and there are significant drawbacks in designing molecules having various functions.
Production method C has been reported in

Non-Patent Documents

4 and 5, etc., and is a method of protecting the diol site in advance and then modifying the carboxyl group with a reactive functional group, followed by deprotection of the diol site and cyclization reaction. . According to production method C, there is no concern of self-condensation in the reaction of introducing a reactive functional group into a carboxyl group by protecting the diol site, and the range of nucleophiles that can be used is expanded compared with production method B. On the other hand, as in production method B, the group R introduced into the carboxyl group is required to have resistance to the deprotection reaction or cyclization reaction of the diol moiety performed under subsequent acidic conditions.

Recently, Patent Document 4 and Non-Patent Document 6 have proposed that cyclization reaction and carboxyl group protection be performed in one step using bispentafluorophenyl carbonate (PFC) as shown in Scheme 2 below. Yes. In other words, bis-MPA and PFC are reacted in a predetermined environment to cyclize the diol moiety of bis-MPA and to make the pentafluorophenyl ester substituent function as an active ester to protect and activate the carboxyl group. Has been proposed. It has been reported that the pentafluorophenyl ester substituent functions as a leaving group and can undergo a substitution reaction with an alcohol or amine under mild conditions.

According to this method, the various steps related to the protection / deprotection of the diol moiety and the carboxyl group in the step of synthesizing various cyclic carbonates using bis-MPA as a starting material as shown in Scheme 1 can be omitted. It is possible to carry out the cyclization reaction of the diol site while protecting the carboxyl group in a single step.
Although the number of steps can be greatly reduced while maintaining the diversity of nucleophiles that can be introduced in the same manner as in production method A, PFC is expensive and has a problem in availability. Moreover, when removal of the by-produced pentafluorophenol is insufficient, it is disadvantageous to influence the subsequent polymerization reaction.

JP 2009-61021 A JP 2012-232909 A JP 2012-46761 A US Patent Publication No. 2010305281

As described above, the possibility of a material having biocompatibility that does not cause a foreign body reaction to blood or tissue in the living body when the polymer is present in the living body is not necessarily a biodegradable polymer. It has not been revealed so far. For this reason, for example, in a stent placed in a blood vessel, it is also common to prevent restenosis by mixing an antithrombotic drug such as heparin with a biodegradable polymer provided on the stent surface. It has become.
On the other hand, in the conventional method for synthesizing a cyclic carbonate having a carboxyl group using a diol compound having a carboxyl group as a starting material, the solubility of the starting material in an organic solvent is low and the functional groups contained in the starting material Therefore, it is difficult to reduce the cost because various steps related to protection / deprotection are required to control various reactions competing with each other. Further, according to the method described in the above scheme 2, while being excellent in that the process can be simplified, bispentafluorophenyl carbonate (PFC) used for the reaction is expensive and has a problem in availability, Problems remain in terms of cost reduction. In addition, when removal of by-product pentafluorophenol is insufficient, there is a problem that affects the polymerization reaction of the synthesized cyclic carbonate.
In order to solve the above problems, an object of the present invention is to provide a polymer that exhibits biocompatibility and exhibits good biodegradability. It is another object of the present invention to provide a novel compound used as a monomer in the production of the polymer, a method for producing the compound, and a method for producing a polymer using the compound. It is another object of the present invention to provide a medical device using the polymer. In particular, the present invention uses a novel method for synthesizing a cyclic carbonate having a carboxyl group or a derivative thereof simply and efficiently using a diol compound having a carboxyl group as a starting material for the compound used as the monomer, and the method. It is an object of the present invention to provide an intermediate compound of the polymer produced.

In order to solve the above problems, the present invention has the following features.
(1) A biocompatible polymer composition comprising a structure containing at least one ether group in the side chain and a main chain comprising a biodegradable polymer skeleton.
(2) The biodegradable polymer skeleton has the formula: (I)
-C _B -A- (I)
(Where
C _B is selected from unit structures having a carbonate bond, an ester bond, an amide bond, a urethane bond or a urea bond;
A is a C _1-8 alkylene group in which a hydrogen atom is replaced by at least one group —Y;
Y is represented by the formula: -LZ (wherein Z is a structure having at least one chain ether, cyclic ether or acetal structure, L is a linker between the main chain and Z, an alkylene group, Selected from unit structures having an ether bond, a thioether bond, an ester bond, an amide bond, a urethane bond or a urea bond, or a combination thereof))
The biocompatible polymer composition according to the above (1), comprising a repeating unit represented by:
(3) A is substituted with at least one carbon atom other than the carbon atom adjacent to C _B in the C _1-8 alkylene group with a heteroatom selected from N, O or S, and / or The biocompatible polymer composition according to (2) above, wherein the hydrogen atom in the C _1-8 alkylene group is a group substituted with a lower alkyl group.
(4) The linker L is a group shown below:

Or a bioaffinity as described in (2) or (3) above, which is selected from the group having a 1,2,3-triazole group at the binding part of Z and Z Polymer composition.
(5) Z is the following formula (II):

[Wherein, l is an integer of 1 to 30, U is a hydrogen atom or a linear or branched alkyl group having 5 or less carbon atoms, or the following formula (III):

(Wherein l ′ is an integer of 1 to 5)]
Or Z is a group represented by the following formula (IV):

(Wherein l ″ is an integer of 1 to 5), or Z is the following formula (V):

(In the formula, M ′ is a hydrogen atom or a linear or branched alkyl group having 3 or less carbon atoms, and E and E ′ are each independently —O— or —CH ₂ —. Provided that at least one is —O— and Q ′ and Q ″ each independently represent a hydrogen atom, a linear or branched alkyl having 6 or less carbon atoms, alkenyl or alkynyl, C _3-8 Represents alicyclic alkyl or benzyl, or Q ′ and Q ″ together form an alkylene group having 2 to 5 carbon atoms, and k and k ′ are each independently an integer of 0 to 2 Is)
The biocompatible polymer composition according to any one of the above (2) to (4), which is a group represented by:
(6) The biocompatible polymer composition according to any one of (1) to (5), wherein the main chain is a copolymer of a biodegradable polymer and a non-biodegradable polymer.
(7) The following general formula (VII):

(Where
X and X ′ are independently of each other —O—, —NH— or —CH ₂ —, but at least one is not —CH ₂ —;
Y is a structural moiety represented by the group -LZ (wherein L and Z are as defined in claim 2);
M is a hydrogen atom, a linear or branched alkyl group having 3 or less carbon atoms, or a group -LZ;
m and m ′ are each independently an integer of 0 to 5, provided that when X and X ′ are both —O—, at least one of m and m ′ is not 0, and m and m ′ The sum of 'is 7 or less;
Each of these may be different in each repeating unit,
The monomer compound represented by these.
(8) A method for producing a biocompatible polymer composition, comprising a step of ring-opening polymerization of the monomer compound represented by the general formula (VII) described in (7) above.
(9) A biocompatible polymer composition produced by ring-opening polymerization of the monomer compound described in (7) above.
(10) Any one of the above (1) to (6) for suppressing a foreign body reaction to blood or tissue until it is decomposed when used in contact with tissue or blood in a living body The biocompatible polymer composition described in 1.
(11) A medical device comprising the biocompatible polymer composition according to any one of (1) to (6), (9) and (10) above.

In addition, contrary to expectation, surprisingly, the diol compound having a carboxyl group is subjected to a cyclization reaction in the presence of an organic solvent while protecting the carboxyl group with an organic base. The present inventors have found that cyclic carbonates can be efficiently synthesized without using expensive reagents while omitting the protection and deprotection reactions. That is, in one aspect of the present invention, a diol compound having a carboxyl group is converted to a compound represented by the formula (VIII): R ¹ — (C═O) —R ² [wherein R in the presence of an organic base and an organic solvent. ¹ and R ² are each independently a halogen atom, an imidazolium group, or —OR ³ (wherein R ³ is a lower alkyl group optionally substituted with a halogen atom, or a halogen atom, an alkoxycarbonyl group, a nitro group, or And an aryl group optionally substituted with at least one substituent selected from the group consisting of a cyano group, an alkoxy group, an alkyl group, and a haloalkyl group. A method for producing a cyclic carbonate is provided.

Prior to the cyclization reaction, the diol compound having a carboxyl group is preferably dissolved in an organic solvent in the presence of an organic base. This is because the organic base in the reaction mixture is converted into a carboxyl group in the diol compound. It is considered that this is because, by forming a non-covalent interaction with the compound, for example, forming a complex, the dissolution of the diol compound in an organic solvent is promoted, and it also serves as a protecting group for the carboxyl group. Therefore, the organic base used in the method of the present invention is not particularly limited as long as it can interact with the carboxyl group in the diol compound in the organic solvent, and various organic bases are appropriately selected according to the polarity of the organic solvent to be used. be able to.

According to the present invention, it is possible to provide a polymer material that exhibits biocompatibility such as antithrombogenicity to a living body and exhibits good biodegradability. Furthermore, according to the present invention, it is possible to simply achieve the synthesis of a cyclic carbonate having a carboxyl group or the like using a diol compound as a starting material while omitting the protection / deprotection reaction of the carboxyl group in the conventional method. Most surprisingly, a series of reactions can be performed continuously or semi-continuously, and the synthesis of various cyclic carbonate derivatives can be performed without complication.

2 is a ¹ H-NMR spectrum of MPA-ME shown in Example 1. 2 is a ¹ H-NMR spectrum of MTC-ME shown in Example 2. 2 is a ¹ H-NMR spectrum of P (MTC-ME) shown in Example 3. 2 is a ¹ H-NMR spectrum of PTMC shown in Comparative Example 1. ^{1 is} a ¹ H-NMR spectrum (400 MHz, acetone-d ₆ ) of an intermediate (MTC-TEA) obtained in Example 4. ^{1 is} a ¹ H-NMR spectrum (400 MHz, acetone-d ₆ ) of MTC-OH obtained in Example 4. ^{1 is} a ¹ H-NMR spectrum (400 MHz, acetone-d ₆ ) of MTC-Cl obtained in Example 5. ^{1 is} a ¹ H-NMR spectrum (400 MHz, acetone-d ₆ ) of MTC-THF obtained in Example 6. ^{1 is} a ¹ H-NMR spectrum (500 MHz, acetone-d ₆ ) of MTC-OH (Comparative Example 2). 10 is a graph showing the results of DSC measurement in Example 8. 2 is a graph showing the number of HUVECs adhered on each polymer substrate cultured in Example 11 and its change with time. It is a graph which shows the adhesion number of HT-1080 after 1 hour culture | cultivation on each polymer substrate cultured in Example 12. FIG. 10 is a graph showing the platelet adhesion number in Example 13.

Definition of Terms In the present invention, the following terms are used to indicate the contents described for each, whether they appear alone or in combination.

In this specification, the term “alkyl group” refers to a monovalent saturated hydrocarbon group including a linear or branched carbon chain having a skeleton of carbon atoms. The term “alkylene group” refers to a divalent hydrocarbon group composed of a linear carbon chain. The term “alkylene oxide chain” refers to a structure in which a carbon atom other than the end of the alkylene group is replaced with an ether bond. The “lower alkyl group” or “lower alkylene group” refers to the above alkyl or alkylene group having 1 to 6 carbon atoms.

The term “alkenyl” refers to a monovalent saturated hydrocarbon group containing a straight or branched carbon chain having one or more carbon-carbon double bonds in the skeleton of carbon atoms. The number of carbon atoms in the alkenyl is not particularly limited, but is preferably 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms, and most preferably 2 to 6 carbon atoms. Examples of alkenyl include, but are not limited to, ethenyl (vinyl), propenyl, butenyl, 2-methylpropenyl, pentenyl, hexenyl and the like. The term “alkynyl” refers to a monovalent saturated hydrocarbon group containing a straight or branched carbon chain having one or more carbon-carbon triple bonds in the skeleton of carbon atoms. The number of carbon atoms in the alkynyl is not particularly limited, but preferably 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms, and most preferably 2 to 6 carbon atoms. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, 2-methylpropynyl, pentynyl, hexynyl and the like.

In this specification, the term “alkoxy” refers to a monovalent saturated hydrocarbon group in which the above alkyl group is bonded to an oxygen atom and is bonded to another molecular structure through the oxygen atom. The number of carbon atoms in alkoxy is not particularly limited, but is preferably 1 to 20 carbon atoms, more preferably 1 to 10 carbon atoms, and most preferably 1 to 6 carbon atoms. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, tert-butoxy, pentoxy, hexoxy and the like.

The term “alicyclic alkyl” refers to a monovalent aliphatic cyclic hydrocarbon group in which a carbon skeleton forms a ring. The alicyclic alkyl is expressed by the number of carbon atoms forming the ring. For example, “C _3-8 alicyclic alkyl” means that the number of carbon atoms forming the ring is 3 to 8. Show. Examples of alicyclic alkyl are cyclopropyl (C ₃ H ₅ ), cyclobutyl (C ₄ H ₇ ), cyclopentyl (C ₅ H ₉ ), cyclohexyl (C ₆ H ₁₁ ), cycloheptyl (C ₇ H ₁₃ ), Including but not limited to cyclooctyl (C ₈ H ₁₅ ) and the like.

The terms “chain ether” or “alkylene oxide” can be used interchangeably, and a structure in which one —CH ₂ — moiety other than the terminal in the alkyl group is replaced with an ether bond (—O—). Indicates. The term “cyclic ether” refers to a structure in which one —CH ₂ — moiety of the alicyclic alkyl is replaced with an ether bond.

The term “aryl group” refers to an aromatic substituent containing one ring or two or three condensed rings. Aryl groups preferably contain 6 to 18 carbon atoms and include phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl and indanyl.

The term “monomer” or “monomer” refers to a low molecular weight molecule that can be used interchangeably and can be a component of the basic structure of a polymer. The monomer usually has a functional group serving as a reaction point of the polymerization reaction, such as a carbon-carbon double bond or an ester bond.

The terms “polymer” or “polymer” can be used interchangeably and refer to molecules having a structure composed of repeating monomer units, which can be obtained from a monomer having a low molecular weight. The term “polymer” refers to a macromolecule formed by covalently bonding a large number of atoms, such as a protein, a nucleic acid and the like, in addition to a polymer.

In the polymer, the term “average degree of polymerization” refers to the average number of monomer units contained in one polymer molecule. That is, in the polymer composition, polymer molecules having different lengths are dispersed within a certain range.

Regarding the degree of polymerization of the polymer, the “number average molecular weight” means the average molecular weight per molecule in the polymer composition, and the “weight average molecular weight” means the molecular weight calculated by weighting the weight. Further, the ratio between the number average molecular weight and the weight average molecular weight is referred to as the degree of dispersion, which is a measure of the molecular weight distribution of the polymer composition. The closer the degree of dispersion is to 1, the closer the average degree of polymerization in the polymer composition and the more polymer chains of the same length.

In the present invention, the term “biocompatible material” refers to a material that is difficult to be recognized as a foreign substance when it comes into contact with a biological substance because it can contain intermediate water. Biocompatible materials exhibit activity that induces or does not induce specific protein adsorption or cell adhesion, for example, if the material does not have biological activity such as complement activity, thrombus activity, tissue invasiveness, etc. Contains materials. In the present invention, the term “blood compatible material” refers to a material that does not cause blood coagulation mainly due to adhesion or activation of platelets.

In the present invention, the “biodegradable polymer” refers to a polymer that can be chemically decomposed by an action such as hydrolysis, enzymatic decomposition, or microbial decomposition. Examples of biodegradable polymers include chemically synthesized polymers such as polylactic acid, polyesters such as polycaprolactone, polycarbonates, and the like, polymers derived from living organisms such as polypeptides, polysaccharides, celluloses, and combinations thereof. Can be mentioned.

In the present invention, “side chain” refers to a branched structure bonded to a polymer main chain.

Therefore, one embodiment of the present invention is a biocompatible polymer composition comprising a structure containing at least one ether group in the side chain and a main chain composed of a biodegradable polymer skeleton. In the present specification, the “biocompatible polymer composition” refers to a polymer composition having a structure particularly suitable for suppressing blood coagulation and preventing the formation of thrombus, such as medical materials in such applications. Can be used for

One embodiment of the present invention is a biocompatible polymer composition having a repeating unit represented by the following formula (I).
-C _B -A- (I)
In the above formula (I), C _B is an ether bond, a thioether bond, an ester bond, an amide bond, selected from a unit structure having a urethane bond or a urea bond, or a combination thereof, as a non-limiting example, the following Examples of unit structures listed in Scheme 3 include:

In the above formula (I), A is a C _1-8 alkylene group in which a hydrogen atom is substituted by at least one group —Y. A is optionally substituted at least one carbon atom other than the carbon atom adjacent to C _B in the C _1-8 alkylene group with a heteroatom selected from N, O or S, and / or C The hydrogen atom in the _1-8 alkylene group may be substituted with a lower alkyl group. The group Y is a group represented by the formula: -LZ, and L is a linker between the main chain and Z, and is an alkylene group, an ether bond, a thioether bond, an ester bond, an amide bond, or a urethane bond. Alternatively, it is selected from unit structures having a urea bond or a combination thereof. Z is not particularly limited as long as it is a molecular chain having at least one chain ether such as polyethylene glycol, cyclic ether, or acetal structure, that is, at least one ether group. Each of these may be different in each repeating unit.

That is, the polymer according to the present invention, among the biodegradable polymers known conventionally, as shown similar to that of the aliphatic polyester-based or polyamide-based, the alkylene group represented by A or the like as a main chain in the C _B It includes a repeating unit bonded by a carbonate bond, an ester bond, a urethane bond, a urea bond, an amide bond, or the like. In addition, a side chain containing an ether structure is introduced to a carbon atom contained in the alkylene group or the like by a predetermined bonding mode.
It has been conventionally known that when a side chain containing an ether structure is introduced into a polymer having an alkyl chain as a main chain, the polymer exhibits biocompatibility. On the other hand, in the present invention, by introducing a side chain containing the ether structure into a main chain that is expected to be biodegradable having an alkylene group or the like bonded thereto by a carbonate bond or the like, biodegradability is achieved. This is based on the finding that biocompatibility can be imparted without loss.

The degree of polymerization of the polymer according to the present invention is not particularly limited, but the average molecular weight of the polymer also changes depending on the degree of polymerization, and the operability when used as a material changes depending on the molecular weight. From such a point, the average molecular weight of the polymer according to the present invention is preferably in the range of 2000 to 1000000, more preferably in the range of 5000 to 800000, and most preferably in the range of 8000 to 500000. The molecular weight distribution of the polymer according to the present invention is not particularly limited, but is preferably in the range of 1.0 to 10, more preferably in the range of 1.0 to 8, and preferably in the range of 1.05 to 5.0. The range is most preferable. In the polymer according to the present invention, the structure of each of C _B and A of formula (I) may be different in each repeating unit. Such a polymer can be synthesized by performing a polymerization reaction using two or more kinds of monomer molecules as a raw material of the polymer.

In the above formula (I), the structural portion Z is not particularly limited as long as it is a molecular chain having at least one chain ether such as polyethylene glycol, a cyclic ether or an acetal structure, that is, at least one ether group.
In one embodiment of the present invention, the structural moiety Z can be represented by the following formula (II).

In the formula (II), the repeating number (l) is an integer of 1 to 30, and U is a hydrogen atom or a linear or branched alkyl group having 5 or less carbon atoms. The repetition represented by the formula (II) corresponds to a chain ether, and when the number of repetitions (l) is large, there is a tendency that the solubility of the side chain in water tends to be high. Will have. For this reason, although the structure represented by the formula (II) depends on the density or the like introduced into the polymer, typically, l is 20 or less, and preferably 10 or less. In particular, when the structure represented by the formula (II) is introduced into the polymer at a high density, even if l is 5 or less in order to ensure the water resistance of the polymer, the polymer contains intermediate water in a sufficient ratio. can do. Further, by setting l to 1, 2, 3 or so, a polymer capable of adsorbing predetermined cells while suppressing platelet adhesion while ensuring sufficient water resistance and reducing the content of intermediate water. can do. Further, the repetition represented by the formula (II) corresponds to ethylene glycol (—C ₂ H ₄ —O—), but is not limited to this in the present invention, and propylene is used to improve the water resistance of the polymer. It is also possible to use a structure corresponding to glycol (—C ₃ H ₆ —O—).
In the structure U provided at the end of the chain ether, the water resistance of the polymer is improved by using the alkyl group having a large carbon number, while the intermediate water contained by the decrease in the carbon number is increased. Typically, methyl (carbon number 1) is preferred as U.
U may be a group that can be represented by the following formula (III).

In the formula (III), l ′ can be an integer of 1 to 5, but when l ′ is 1 (that is, a 3-membered ring), the ring is opened in water and becomes unstable. , L ′ is preferably 2, 3, 4 or 5.
In another specific embodiment of the present invention, the structural portion Z can be represented by the following formula (IV).

The structure represented by the formula (IV) corresponds to a cyclic ether, and by introducing such a structure into the side chain, it becomes possible to contain intermediate water. In formula (IV), l ″ can be an integer of 1 to 5, but when l ″ is 1 (that is, a 3-membered ring), the ring opens in water and becomes unstable. , L ″ are preferably 2, 3, 4 or 5.
In another aspect of the present invention, the structural portion Z can be represented by the following formula (V).

In the formula (V), M ′ is a hydrogen atom or a linear or branched alkyl group having 3 or less carbon atoms, preferably methyl. E and E ′ are independently of each other —O— or —CH ₂ —, and at least one of them may be —O—, but preferably has an acetal structure in which both are —O—. Q ′ and Q ″ each independently represent a hydrogen atom, linear or branched alkyl having 6 or less carbon atoms, alkenyl or alkynyl, C _3-8 alicyclic alkyl or benzyl, 'And Q "together form an alkylene group having 2 to 5 carbon atoms, and are preferably a hydrogen atom or an alkyl having 6 or less carbon atoms in order to keep the proportion of the intermediate water that can be contained to a desirable level. Most preferably, Q and Q ′ are both a hydrogen atom or methyl. k and k ′ are each independently an integer of 0 to 2, but from the viewpoint of availability of raw materials, it is preferable that k = 1 and k ′ = 0.
The structural part Z as described above has at least one ether group (—O—), and thus can exhibit high molecular mobility as seen in, for example, polyethylene glycol. It is considered that intermediate water can be contained as a polymer by having such a structure in the side chain. And by adjusting the number of ether groups contained in the structural part Z, the bulkiness of the structural part Z itself, etc., the amount of intermediate water that can be contained in the resulting polymer is adjusted to adjust the degree of antithrombogenicity. be able to.

In the above formula (I), the linker L is a part that plays a role of linking the main chain and the structural part Z, and is typically an ether group, an ester group, an amide group, an amino group, a urethane group, a urea group, an alkylene group. Divalent functional groups such as groups can be used. It is known that the structural part Z can generally have high molecular mobility by having an ether structure as described above. By having such a structure in the side chain part, It is considered that intermediate water can be contained as a polymer. For this reason, as the linker L that connects the main chain and the structural portion Z, it is desirable to select and use various types of structures that do not inhibit molecular mobility according to the individual structure of the structural portion Z. In addition, in order to satisfactorily contain intermediate water as a polymer and exhibit biocompatibility, it is desirable that each part of the polymer does not become hydrophobic, and in particular, it is desirable that adsorption of biological substances such as proteins hardly occurs. . For this reason, as the structure of the linker L, it is desirable that the hydrophobic structure is not excessively large and does not include a functional group having a strong polarity. Moreover, it is desirable to use a linker having a structure that can easily carry out the reaction of introducing the structural moiety Z when the monomer molecule is synthesized.
The specific structure of the linker L that is desirably used depends on the structure of the structural part Z to be used, but in general, the ether group, ester group, amide group, amino group, urethane group, urea group, alkylene group are generally used. In addition to the above, a unit structure as exemplified in Scheme 3 above can be given. In forming a bond between the linker L and the structural part Z, for example, a reaction called a click reaction (see, for example, Angew. Chem. Int. Ed., 2001, 40, 2004-2021) can be used. A linker having a 1,2,3-triazole structure derived from azide and alkylene can also be introduced. As an exemplary synthesis method, the linker L and the structural moiety exemplified above are reacted by reacting an azide with a group such as the ethenyl group (—C≡C—) introduced at the end of the linker L exemplified above. It is possible to obtain a structure in which Z is bonded via a 1,2,3-triazole ring. These structures can be used as the linker L as well.

Among the divalent functional groups used as the linker shown above, when a functional group containing an N—H bond such as an amide group, amino group, urethane group, or urea group is used as the linker L, this Although the linker portion is preferable in that it exhibits hydrophilicity, there is a tendency that proteins existing in the living body are easily adsorbed to the polymer, and therefore, a biological substance in the body may be attached depending on the use. In addition, when an alkylene group such as methylene or ethylene is used, hydrophobicity is exhibited, and the proportion of intermediate water that can be contained in the polymer tends to decrease. On the other hand, when an ether group is used as a linker, the starting material for synthesis generally has an alcohol on both the main chain side and the side chain side, so that an additional by-product is generated in the reaction of introducing a protective group, making separation difficult. And the yield is expected to decrease. For this reason, it is particularly preferable to use an ester group as the linker L from the viewpoint of ease of production and biocompatibility.

In the polymer according to the present invention, the side chain having the above-described structure is not necessarily present for all the repeating units of the main chain. On the other hand, from the viewpoint of ease of synthesis and easy prediction of the degree of antithrombogenicity from the structure of the polymer, generally, a compound in which a structural portion Z is introduced in advance as a monomer compound used in the polymerization is mainly used. It is preferable that side chains including the structural portion Z exist for all the repeating units of the chain polymer.
It is also possible to introduce two structural parts Z via a linker into one carbon atom constituting the main chain contained in the part A in the above formula (I). Further, in the monomer used in the polymerization, in the polymer obtained by polymerization by introducing one or a plurality of carbonyl bonds or the like (C _B ) and one or more structural portions Z, It is also possible to arbitrarily adjust the number of structural parts Z existing between carbonyl bonds or the like (C _B ).
The moiety represented by “C _B ” in the above formula (I) is a carbonate bond, an ester bond, a urethane bond, a urea bond, an amide bond, etc., all of which are oxygen atoms at at least one of the carbonyl carbon and the adjacent positions. It is comprised by the group in which an atom or a nitrogen atom exists. By introducing such a structure into the main chain of the polymer at a relatively high density, as in the case of conventionally known aliphatic polyester and polyamide biodegradable polymers, this part undergoes hydrolysis in vivo. It is thought that biodegradability is expressed.
In the polymer according to the present invention, binding mode, which is used as a binding moiety C _B can be appropriately determined based applications polymers are used, such as in particular the period required for biodegradation. If the binding moiety C _B using a urethane bond or an amide bond can be obtained with low polymer of biodegradation rate of a relatively body. On the other hand, when these bonding modes are used, it is expected that amine (NH ₂ ) or carboxylic acid is generated as a product during biodegradation, thereby limiting the application. In addition, the ester bond is expected to exhibit a relatively high biodegradation rate, but it is expected that a carboxylic acid is generated as a product during biodegradation in the same manner as the amide bond. On the other hand, when a carbonate bond is used as the binding portion C _B , it is expected to show a higher biodegradation rate than a urethane bond or an amide bond, and carbon dioxide and alcohol are obtained by biodegradation. It can be preferably used because it is expected.

In the above formula (I), the alkylene group “A” is a C _1-8 alkylene group in which a hydrogen atom is substituted with at least one group —Y and optionally a lower alkyl group, and optionally adjacent to C _B. At least one carbon other than the carbon to be substituted may be replaced with a heteroatom selected from N, O or S. In connection with the selection of the linking moiety C _B , the alkylene group A can have at least one carbon atom and can be biodegradable with up to about 8 carbon chains. From the viewpoint of sex. Further, in an alkylene group having 3 or more carbon atoms, an alkylene oxide chain corresponding to a structure in which at least one of carbon atoms other than those located at both ends is substituted with an ether group can be used. Thus, by including an alkylene oxide chain having an ether group introduced in the main chain, it is possible to improve mechanical strength such as impact resistance as a polymer as compared with the case of using an alkyl chain, and It also becomes possible to impart hydrophilicity to the chain.
In addition, as described above, an ether related to the inclusion of intermediate water in any carbon atom contained in the alkylene group or the like with respect to the main chain composed of an alkylene group or the like bonded to each other by the bonding portion C _B by the side chain by introducing a structure or the like, while maintaining biodegradability due to the binding moiety C _B, it may be a polymer that can contain intermediate water.

One preferred specific embodiment of the present invention, in the formula (I), is _{C B,} is an ester bond (-C (= O) O-), or carbonate bond (-OC (= O) O-) A biocompatible polymer composition comprising repeating units. More specifically, the biodegradable polymer skeleton has the following formula (VI):

(Where
X and X ′ are independently of each other —O—, —NH— or —CH ₂ —, but at least one is not —CH ₂ —;
M is a hydrogen atom, a linear or branched alkyl group having 3 or less carbon atoms, or a group -LZ;
m and m ′ are each independently an integer of 0 to 5, provided that when X and X ′ are both —O—, at least one of m and m ′ is not 0, and m and m ′ The sum of 'is 7 or less;
Y is a structural moiety represented by the group -LZ (wherein L and Z are as defined above);
Each of these may be different in each repeating unit,
n represents the degree of polymerization and is preferably a biocompatible polymer composition in the range of 2 to 2000.

M is preferably an alkyl group, and most preferably a methyl group.
The values of m and m ′ are determined by the selection of the monomer raw material compound. From the viewpoint of monomer preparation, the sum of m and m ′ is preferably in the range of 1 to 4, and m and m ′. Are most preferably 1.

As one aspect of the present invention, the main chain can be a copolymer of a biodegradable polymer and a non-biodegradable polymer. As the non-biodegradable polymer, a polymer known to those skilled in the art can be appropriately used according to the required physical properties. Examples thereof include polymethyl methacrylate (PMMA), polyethyl methacrylate (PEMA), and polyvinyl. Examples include, but are not limited to, pyrrolidone (PVP), polyurethane, polyester, polyolefin, polystyrene, polyvinyl chloride, polyvinyl ether, polyvinylidene fluoride, polyfluoroalkene, nylon, and silicone. The non-biodegradable polymer skeleton may form a block copolymer with the biodegradable polymer skeleton, or may randomly copolymerize with a monomer unit that forms the biodegradable polymer. Moreover, in order to obtain desired physical properties, a copolymer with a plurality of non-biodegradable polymers may be formed.

The biocompatible polymer according to the present invention can be produced, for example, by ring-opening polymerization of a monomer having a cyclic structure into which a portion to be a side chain of a polymer obtained by polymerization is introduced in advance as follows.

For example, the general formula (VII), X adjacent the carbonyl carbon, as X ', by selecting from CH 2, _O, N, as the binding moiety C _B contained in the main chain of the polymer after polymerization, carbonate Any of a bond (O / O), an ester bond (CH ₂ / O), a urethane bond (O / N), an amide bond (CH ₂ / N), and a urea bond (N / N) is selected.
Further, the alkylene m, as m ', an integer including zero independently of one another (carbonate bond, in the case of the urea bond, either is not 0) by selecting, bound by a binding moiety C _B The length of the base A is determined. And as "Y" of the said general formula (VII), the structural part Z is combined with the carbon atom through the appropriate linker L, and the side chain part which has an ether structure is provided in the polymer side chain part after superposition | polymerization be able to. As “M” in the above general formula (VII), a structural part Z can be bonded through a linker L in the same manner as hydrogen, an alkyl group, or “Y”.
The biocompatible polymer according to the present invention can be produced by ring-opening the cyclic monomer obtained as described above at any of the bonds adjacent to the carbonyl carbon and polymerizing each other. .
In the above description, the cyclic monomer including one portion Y including the structural portion Z has been described. However, the present invention is not limited to this, and one or two structural portions Z are also provided for appropriate carbon atoms contained in m and m ′. It is also possible to provide a portion Y including Further, by substituting appropriate carbon atoms contained in m and m ′ (when O and N are selected as X and X ′, excluding carbon atoms adjacent to O and N) with oxygen, An ether structure can be introduced into the main chain portion of the polymer after polymerization. It is also possible to substitute the carbon atom of the alkylene group A with a heteroatom such as N or S.

For example, in general formula (VII):
X and X 'are both oxygen atoms to form a cyclic carbonate, m and m' are both 1, M is a methyl group,
When Y having a predetermined ether structure bonded by an ester bond is used, ring-opening polymerization of the cyclic carbonate has a main chain in which a C = 3 alkylene group is bonded by a carbonate bond. A polymer in which the ether structure and a methyl group are provided as side chains with respect to the central carbon atom of the group can be obtained.

In the present invention, as the monomer compound used as described above, for example,
5-methyl-5- (2-methoxyethyl) oxycarbonyl-1,3-dioxan-2-one,
5-methyl-5- (2-ethoxyethyl) oxycarbonyl-1,3-dioxane-2-one,
5-methyl-5- (2-tetrahydrofuranylmethyl) oxycarbonyl-1,3-dioxane-2-one,
5-methyl-5- (3-tetrahydrofuranylmethyl) oxycarbonyl-1,3-dioxane-2-one,
5-methyl-5- (3-tetrahydropyranylmethyl) oxycarbonyl-1,3-dioxan-2-one 5-methyl-5- [2- (2-methoxyethoxy) ethyl] oxycarbonyl-1,3- Dioxane-2-one,
5-methyl-5- (2-epoxyoxyethyl) oxycarbonyl-1,3-dioxane-2-one,
4-methyl-4- (2-methoxyethyl) oxycarbonyl-1,3-dioxane-2-one,
4-methyl-4- (2-ethoxyethyl) oxycarbonyl-1,3-dioxane-2-one,
4-methyl-4- (2-tetrahydrofuranylmethyl) oxycarbonyl-1,3-dioxane-2-one,
4-methyl-4- (3-tetrahydrofuranylmethyl) oxycarbonyl-1,3-dioxane-2-one,
4-methyl-4- (3-tetrahydropyranylmethyl) oxycarbonyl-1,3-dioxan-2-one 4-methyl-4- [2- (2-methoxyethoxy) ethyl] oxycarbonyl-1,3- Dioxane-2-one,
4-methyl-4- (2-epoxyoxyethyl) oxycarbonyl-1,3-dioxane-2-one,
γ-methyl-γ- (2-methoxyethyl) oxycarbonyl-δ-valerolactone,
γ-methyl-γ- (2-ethoxyethyl) oxycarbonyl-δ-valerolactone,
γ-methyl-γ- (2-tetrahydrofuranylmethyl) oxycarbonyl-δ-valerolactone,
γ-methyl-γ- (3-tetrahydrofuranylmethyl) oxycarbonyl-δ-valerolactone,
γ-methyl-γ- (3-tetrahydropyranylmethyl) oxycarbonyl-δ-valerolactone,
However, the present invention is not limited thereto, and a monomer to be used can be appropriately selected depending on the structure of the target polymer.

In the above, a method for producing a biocompatible polymer according to the present invention by polymerizing a bond in which biodegradability such as a carbonate bond and a structure including a predetermined ether group are introduced has been described. The present invention is not limited to this, and a polymer having a bond expected to be biodegradable is introduced into the present invention by introducing a structure containing a predetermined ether group with respect to a predetermined carbon atom forming the main chain. Such a biocompatible polymer may be produced. In the biocompatible polymer composition of the present invention, it is not always necessary that a structure containing an ether group is bonded as a side chain over all the repeating units of the main chain polymer, but the ease of synthesis and the characteristics of the polymer can be easily predicted. From this viewpoint, it is also preferable to polymerize a single type of monomer having a structure containing an ether group introduced therein to form a polymer.
In addition, for example, by using a monomer in which a plurality of carbonyl carbons forming a carbonate bond or the like in a polymer are introduced into a cyclic part of a cyclic monomer to be used, and a structure containing an ether group is introduced into an appropriate carbon forming a cyclic part. It is also possible to produce a polymer in which the distribution of side chains having a structure containing an ether group introduced between bonds that are expected to be biodegradable, such as carbonate bonds, is not the same in adjacent repeating units.

Also, in one embodiment of the present invention, the main chain portion can contain either a biodegradable polymer or a non-biodegradable polymer. A polymer having such a structure can be obtained, for example, by copolymerization of a biodegradable polymer and a non-biodegradable polymer.

In the compound represented by the general formula (VII), for example, when X and X ′ are both —O—, that is, a cyclic carbonate, such a compound is synthesized using methods known to those skilled in the art. can do. For example, as shown in Scheme 4 below, starting from a diol derivative, (a) a reaction for introducing a structure containing an ether group, and (b) phosgene, diphenyl carbonate or carbon monoxide in the presence of a catalyst, etc. It can synthesize | combine by the process including the reaction which makes the carbonic acid source of this act, and forms a cyclic carbonate.

Wherein M, m, m ′, Y and Z are as defined above, P and P ′ represent a leaving group, and R is —O-phenyl or a chlorine atom Yes or no)

As yet another example, a compound of the general formula (VII) in which the linker moiety L is an ester bond is prepared as a carboxylic acid having a diol structure, such as 2,2-bis (methylol) propionic acid, as the step (a). It can be obtained by reacting an alcohol having a structure containing an ether group, such as 2-methoxyethanol, to form a bis (hydroxy) ester, and then reacting triphosgene as step (b).

The step of synthesizing the bis (hydroxy) ester is performed by heating in a solvent, for example, in the presence of an ion exchange resin. In the case of using a solvent, the type of the solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the raw material, but the alcohol having the structural part Z as the raw material is liquid and sufficiently dissolves the diol Can also be used as a solvent. The reaction temperature can range from room temperature to the boiling point of the solvent, but is preferably from room temperature to 100 ° C., and most preferably from 50 to 90 ° C. in order to improve the yield. While the reaction time varies depending on the raw material compound and the heating temperature, it is in the range of 1 to 100 hours, preferably 10 to 50 hours.

When the linker part L has a structure other than an ester, selection of a raw material compound, for example, when L is an amide, an alcohol having a structural part Z is an amine, and L is an ether group (—O—) The diol derivative is synthesized by appropriately changing the carboxylic acid having a diol structure to a halide. The reaction conditions used in this case are known to those skilled in the art.

The step of forming the cyclic carbonate is carried out, for example, by allowing triphosgene to act on the obtained diol derivative in a suitable solvent in the presence of a base. The solvent used is not particularly limited, and examples thereof include halogen solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether, tetrahydrofuran and 1,4-dioxane, aromatic solvents such as benzene and toluene, and ethyl acetate. However, it is not limited to these. The base is used to decompose triphosgene to generate phosgene in the reaction system. Examples of the base used include, but are not limited to, triethylamine, diisopropylethylamine, pyridine and the like.

In the compound represented by the general formula (VII), when one of X and X ′ is —O—, that is, a lactone, such a compound should be synthesized using methods known to those skilled in the art. Can do.

The lactone represented by the general formula (VII) is synthesized by a method including (a) a reaction for introducing a structure containing an ether group and (b) a lactonization reaction. The reaction for introducing a structure containing an ether group is as described above in the synthesis of carbonate. The lactonization reaction may be, for example, an intramolecular condensation of hydroxycarboxylic acid, a condensation reaction such as iodolactone formation or Staudinger ketene cycloaddition reaction, an oxidation reaction using a peracid such as Baeyer-Villiger oxidation of a cyclic ketone, or The reaction can be performed using a reaction known to those skilled in the art, such as oxidation of cyclized lactol. An oxidation reaction using a peracid is preferred because of its versatility for the synthesis of various monomer compounds. For example, the lactone represented by the general formula (VII) can be synthesized according to Scheme 5 as shown below. The raw material compounds are commercially available or can be obtained by synthetic methods known to those skilled in the art.

(Wherein M, m, m ′ and Z are as defined above)

Furthermore, one of the aspects of the present invention is that, in addition to the knowledge for the preparation of the cyclic compound as described above, particularly the cyclic carbonate, the carboxyl group is protected with an organic base against a diol compound having a carboxyl group. However, it is based on the fact that a carbonic acid source for cyclization reaction is allowed to act on the diol portion of the diol compound in the presence of an organic solvent, thereby producing a cyclic carbonate having a carboxyl group protected by an organic base. In addition, by performing acid treatment or the like on the cyclic carbonate synthesized by the method, an organic base that protects the carboxyl group is easily eliminated to generate a carboxylic acid. It can be used for the synthesis of a cyclic carbonate having an introduced carboxyl group.
From the results of various studies, it is considered that the mechanism by which a diol compound having a carboxyl group causes the above reaction is as follows. That is, by interposing an organic base for capturing protons generated from the carboxyl group of the diol compound, a complex of the diol compound and the organic base is formed, and the carboxyl group of the diol compound is protected by the organic base. At this time, when a substance that generates a cation is used as the organic base, the complex exhibits solubility in an organic solvent, and when an anion exchange resin or the like is used as the organic base, anion exchange is performed. When the complex is formed on the surface of the resin, the diol compound that is a part of the complex can be stably present in the organic solvent.
By applying the carbonic acid source “— (C═O) —” for cyclizing the diol moiety to the diol compound stably existing in the organic solvent as described above, the carboxyl group portion is not affected. The diol moiety is thought to be cyclized. According to the present invention, since the diol moiety is cyclized while protecting the carboxyl group of the diol compound with an appropriate organic base, the selection of the structure of the carbonic acid source used for the cyclization reaction is explained below. Thus, an appropriate carbon source can be used according to the diol compound to be used. On the other hand, by using an organic base particularly as a protecting group for protecting the carboxyl group, the solubility of the diol compound in an organic solvent can be increased, and deprotection after the cyclization reaction can be easily performed. The cyclization reaction and the deprotection of the carboxyl group can be performed efficiently. In addition, since a protecting group for protecting the carboxyl group can be appropriately selected independently of the compound used as the carbonic acid source in the cyclization reaction, depending on the structure of the functional group introduced into the carbonyl group in the cyclic carbonate to be synthesized, etc. It is possible to use protective groups.

The compound used as the carbonic acid source for producing the cyclic carbonate is not particularly limited as long as it reacts with the diol moiety of the diol compound and cyclizes. For example, in addition to using carbon monoxide (CO) or carbon dioxide (CO ₂ ), it is also possible to use a compound represented by the following formula (VIII).
R ¹ — (C═O) —R ² (VIII)
In the compound of formula (VIII), R ¹ and R ² may be any one that can be liberated from the carbonyl carbon under appropriate conditions, and is a halogen atom containing fluorine, chlorine, bromine, or an imidazolium group , —OR ³ , wherein R ³ is an alkyl group having 6 or less carbon atoms or a halogen substituent thereof, an aryl group such as benzene or naphthalene, or an aryl group substituted with one or more substituents (Here, examples of the substituent include a halogen atom containing fluorine, chlorine and bromine, an alkoxycarbonyl group, a nitro group, a cyano group, an alkoxy group, an alkyl group, and a haloalkyl group). The structures of R ¹ and R ² may be the same or different. In addition, since R ¹ and R ² are liberated during the production of carbonate, it is preferable that R ¹ and R ² after liberation do not exhibit undesired effects in a series of reaction systems.
That is, examples of the compound represented by the formula (VIII) include, but are not limited to, aliphatic carbonate diesters such as dimethyl carbonate, diethyl carbonate and dibutyl carbonate, aromatic carbonate diesters such as diphenyl carbonate and dinaphthyl carbonate, methyl carbonate Examples thereof include mixed carbonic acid diesters such as phenyl, phosgene, triphosgene (bis (trichloromethyl carbonate)), carbonyldiimidazole (CDI) and the like. Dimethyl carbonate, diphenyl carbonate or triphosgene is preferable in terms of ease of acquisition or handling, safety, and the like.
In the compound represented by the formula (VIII), by selecting appropriate R ¹ and R ² , the bond strength with the carbonyl carbon and the like change, and in particular the temperature at which R ¹ and R ² are liberated from the carbonyl carbon. It is possible to change. When using a compound in which carbonyl carbon is easily liberated by selection of R ¹ and R ² , it is preferable to carry out the cyclization reaction of the diol compound at a relatively low temperature. In addition, when selecting R ¹ and R ² that form a strong bond with carbonyl carbon, in addition to performing a cyclization reaction in a heating environment, the release of carbonyl carbon should be promoted using an appropriate catalyst or the like. Is also preferable.
Further, by selecting a hydrocarbon group having a relatively large molecular weight as R ¹ and R ² , the solubility in an organic solvent used as a reaction field for the cyclization reaction of the diol compound is improved, and a cyclic carbonate at a high density is obtained. This is preferable in that it can be synthesized.
In the present invention, the amount of the compound used as the carbon source in the cyclization reaction of the diol compound is preferably equimolar or more, more preferably equimolar or more and 2 mol or less per diol molecule. This is the amount that the carbonyl unit acts on.
In the present invention, an organic solvent is typically selected as the reaction field for the cyclization reaction in which the diol moiety of the diol compound is cyclized with carbonyl carbon. In order to allow the cyclization reaction to proceed well, In particular, an aprotic organic solvent is preferably used.

In the present invention, as long as a cyclization reaction occurs between the carbonic acid source compound and the diol compound, the mixing procedure with an organic base, an organic solvent, or the like is not particularly limited. In the embodiment, it is preferable to carry out the cyclization reaction of the diol moiety by allowing a compound that is a carbonic acid source to act on a diol compound dissolved in an organic solvent by the intervention of an organic base or the like.

Therefore, in one preferred embodiment, the method for producing a cyclic carbonate of the present invention comprises a first step of dissolving a diol compound having a carboxyl group in an organic solvent in the presence of an organic base, and the organic solvent. The form containing the said 2nd process with which the said diol compound and the compound which is a carbonic acid source are made to react is mentioned.

In one embodiment of the present invention, the diol compound having a carboxyl group can be represented by the formula (IX).

In the formula, R ⁴ is a part that determines the presence or configuration of the side chain of the polycarbonate obtained by polymerization of the cyclic carbonate to be synthesized and its configuration, and R ⁴ is appropriately determined according to the properties expected in the polycarbonate . That is, when a side chain is not provided at a corresponding position in the polycarbonate, R ⁴ is a hydrogen atom, and when a side chain is provided, a functional group or the like corresponding to the side chain is introduced as R ⁴ . In particular, in the case of a cyclic carbonate for obtaining a biocompatible polycarbonate described below, R ⁴ is a hydrogen atom or a lower alkyl group, and a C _1-3 alkyl group is particularly preferred as the lower alkyl group. Most preferably, it is methyl.
M and m ′ in the formula (IX) determine the number of cyclic parts of the cyclic carbonate to be synthesized. From the viewpoint of ease of the cyclization reaction and stability of the cyclic carbonate to be synthesized, m and m ′ The sum of 'is preferably about 1 to 7 or less. Further, the sum is preferably in the range of 1 to 3 so that the cyclic carbonate can be selectively produced. In this range, m and m ′ may be an integer of 0 to 5 independently of each other, but if the difference between m and m ′ is large, the cyclization reaction tends to be difficult, and the ring The difference between m and m ′ is 2 or less from the viewpoint of the easiness of the conversion reaction. From the viewpoint of the formation of cyclic carbonate, it is most preferable that m and m ′ are both 1.

In the present invention, the term organic base means an organic compound that acts as a proton acceptor, and includes, for example, a compound having an atom such as nitrogen or phosphorus, an ion exchange resin, and the like as a proton accepting site. Such an organic base forms a complex with an ionic bond by extracting a proton from the carboxyl group with respect to the diol compound having a carboxyl group, thereby increasing the solubility of the diol compound in an organic solvent, and at the diol site. The function of protecting the carboxyl group during the cyclization reaction is expected. For this reason, the organic base used in the present invention is not particularly limited as long as it can capture a proton generated from a carboxyl group, but from the viewpoint of increasing the solubility in an organic solvent, the organic base having an alkyl substituent Are preferably used. In addition, when a strong organic base that remains basic after formation of a complex (salt) with a carboxylic acid is used, the polymerization of the cyclized monomer tends to be promoted. It is desirable to select and use an organic base according to the above.
In addition, when a reaction reagent is allowed to act on a diol compound having a carboxyl group, it is necessary to consider the competition of the reaction between the carboxyl group moiety and the diol moiety, but generally organic bases are unlikely to react with the diol moiety. Suitable for protecting carboxyl groups. In this respect, tertiary amines such as triethylamine are preferably used because there is no hydrogen on nitrogen and the possibility of participating in the cyclization reaction of the diol site is particularly low. Also, triethylamine is preferably used from the viewpoint that the excess organic base after complex formation with the diol compound can be removed by drying under reduced pressure.
Examples of organic bases used in the present invention include, but are not limited to, tertiary alkylamines such as trimethylamine, triethylamine, N, N-diisopropylethylamine, 1,4-diazabicyclo [2,2,2] octane (DABCO ), Cyclic amines such as methylmorpholine, aromatic amines such as pyridine and imidazole, nitrogen-containing compounds such as amidine and guanidine, compounds containing phosphorus atoms such as phosphazene, oniums such as oxonium, imidazolium, ammonium, sulfonium and phosphonium Examples thereof include ionic hydroxides and anion exchange resins. A tertiary amine such as triethylamine is preferable. The organic base used in the present invention is expected to trap the groups R ¹ and R ² eliminated from the compound of formula (VIII), which is a carbonic acid source.

Onium hydroxide (onium hydroxide) is a substance composed of an onium cation and a hydroxide anion. As onium hydroxide, 1,3-dimethylimidazolium hydroxide, 1-ethyl-3-methylimidazolium hydroxide, 1-butyl-3-methylimidazolium hydroxide, 1-hexyl-3-methylimidazolium hydroxy 1-octyl-3-methylimidazolium hydroxide, 1-allyl-3-ethylimidazolium hydroxide, 1-allyl-3-butylimidazolium hydroxide, 1,3-diallylimidazolium hydroxide, 1-allyl-3-ethylimidazolium hydroxide, 1-allyl-3-butylimidazolium hydroxide, 1,3-diallylimidazolium hydroxide, Imidazolium hydroxides such as ethyl-2,3-dimethylimidazolium hydroxide, 1-butyl-2,3-dimethylimidazolium hydroxide, 1-hexyl-2,3-dimethylimidazolium hydroxide;
2-ethyl-1,3,5-trimethylpyrazolium hydroxide, 2-propyl-1,3,5-trimethylpyrazolium hydroxide, 2-butyl-1,3,5-trimethylpyrazolium hydroxide , Pyrazolium hydroxides such as 2-hexyl-1,3,5-trimethylpyrazolium hydroxide;
1-ethylpyridinium hydroxide, 1-butylpyridinium hydroxide, 1-hexylpyridinium hydroxide, 1-octylpyridinium hydroxide, 1-ethyl-3-methylpyridinium hydroxide, 1-ethyl-3-hydroxymethylpyridinium hydroxide 1-butyl-3-methylpyridinium hydroxide, 1-butyl-4-methylpyridinium hydroxide, 1-octyl-4-methylpyridinium hydroxide, 1-butyl-3,4-dimethylpyridinium hydroxide, 1-butyl -Pyridinium hydroxides such as 3,5-dimethylpyridinium hydroxide;
1-propyl-1-methylpyrrolidinium hydroxide, 1-butyl-1-methylpyrrolidinium hydroxide, 1-hexyl-1-methylpyrrolidinium hydroxide, 1-octyl-1-methylpyrrolidinium hydroxy And pyrrolidinium hydroxides such as 1-butyl-1-propylpyrrolidinium hydroxide;
Piperidinium hydroxides such as 1-propyl-1-methylpiperidinium hydroxide, 1-butyl-1-methylpiperidinium hydroxide, 1- (2-methoxyethyl) -1-methylpiperidinium hydroxide ;
Morpholinium hydroxides such as 4-propyl-4-methylmorpholinium hydroxide, 4- (2-methoxyethyl) -4-methylmorpholinium hydroxide;
Tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrapropylammonium hydroxide, tetrabutylammonium hydroxide, tetraheptylammonium hydroxide, tetrahexylammonium hydroxide, tetraoctylammonium hydroxide, triethylmethylammonium hydroxide, propyltrimethylammonium Hydroxide, diethyl-2-methoxyethylmethylammonium hydroxide, methyltrioctylammonium hydroxide, cyclohexyltrimethylammonium hydroxide, 2-hydroxyethyltrimethylammonium hydroxide, trimethylphenylammonium hydroxide, benzyltrimethylammonium hydroxide, benzyl Ributylammonium hydroxide, benzyltriethylammonium hydroxide, dimethyldistearylammonium hydroxide, diallyldimethylammonium hydroxide, 2-methoxyethoxymethyltrimethylammonium hydroxide, tetrakis (pentafluoroethyl) ammonium hydroxide, N-methoxytrimethylammonium Quaternary ammonium hydroxides such as hydroxide, N-ethoxytrimethylammonium hydroxide, N-propoxytrimethylammonium hydroxide;
Phosphonium hydroxides such as trihexyltetradecylphosphonium hydroxide;
Sulfonium hydroxides such as trimethylsulfonium hydroxide;
Guanidinium hydroxides such as guanidinium hydroxide and 2-ethyl-1,1,3,3-tetramethylguanidinium hydroxide;
Isouronium hydroxides such as 2-ethyl-1,1,3,3-tetramethylisouronium hydroxide; and isothionium such as 2-ethyl-1,1,3,3-tetramethylisothiouronium hydroxide; Examples include auronium hydroxide.

The mixing operation of the organic base and the diol compound is not particularly limited as long as the complex formation reaction proceeds smoothly, and is appropriately determined according to the type of organic base and diol compound used. The amount of the organic base typically used in the present invention is preferably equal to or more than the equivalent of the carboxyl group of the diol compound to be added, and in particular 2 to 5 times equivalent of organic in order to stably protect the carboxyl group. It is preferable to use a base. The complex formation between the organic base and the diol compound may be performed by mixing both in an appropriate organic solvent. When a diol compound having low solubility in the organic solvent is used, the diol dispersed in the organic solvent by an appropriate method is used. It is preferable to allow an organic base to act on the compound. Complex formation between the organic base and the diol compound is confirmed by appropriate means such that the diol compound existing as a dispersed phase in the organic solvent dissolves in the organic solvent due to the presence of the organic base to form a uniform solution. The

The mixing of the organic base and the diol compound can be performed in an appropriate temperature environment such as room temperature, but it is also preferable to perform it in a cooling environment from the viewpoint of preventing various side reactions. If the excess organic base present after the complex formation does not undesirably affect the subsequent cyclization reaction of the diol compound, the organic base and the diol compound are mixed to form a complex in the organic solvent. In addition, a carbonic acid source for causing a cyclization reaction of the diol compound may be added to produce a cyclic carbonate. In that case, it is preferable to form a complex of the organic base and the diol compound in an organic solvent suitable for the cyclization reaction of the diol compound.
When the complex formation reaction and the cyclization reaction are performed in the same reaction field, it is not always necessary to cause the cyclization reaction after all the complex formation is completed. For example, a diol compound supplied from another phase may be complexed. And the cyclization reaction for the formed complex can proceed simultaneously.

In the present invention, an organic solvent is generally desirable as a reaction field for the cyclization reaction in which the diol portion of the diol compound is cyclized with carbonyl carbon, but in order to suppress the participation in the cyclization reaction and increase the yield, In particular, an aprotic organic solvent is preferably used. That is, the organic solvent used in the present invention can be used without particular limitation as long as it does not inhibit the reaction of the present invention. For example, halogen solvents such as dichloromethane and chloroform, diethyl ether, tetrahydrofuran, 1, Examples thereof include, but are not limited to, ether solvents such as 4-dioxane, aromatic solvents such as benzene and toluene, acetonitrile, ethyl acetate, and the like. Preferred are dichloromethane and tetrahydrofuran.

In the method of the present invention, the cyclization reaction between the diol compound and the compound of the formula (VIII) is appropriately selected according to the type of the compound of the formula (VIII) or the solvent used, but not more than the boiling point of the solvent used. The temperature is, for example, 100 ° C. or lower, and can also be performed at room temperature or lower.

One embodiment of the present invention is a method for producing the above cyclic carbonate, further comprising the step of treating the cyclic carbonate obtained by the above method with an acid to recover the carboxylic acid of the cyclic carbonate. Examples of the acid used in the step include inorganic acids such as hydrochloric acid and sulfuric acid, organic carboxylic acids such as trifluoroacetic acid, methanesulfonic acid, and paratoluenesulfonic acid, organic sulfonic acids, and organic phosphonic acids, cation exchange resins, Although it is not limited to these as long as it reacts more strongly than the carboxylic acid with the basic compound in the complex such as a solid acid and regenerates the carboxyl group, it preferably forms a complex with the basic compound to form a precipitated substance. Those that form and facilitate separation are desirable. In addition to the method of adding these acidic substances to the complex cyclic carbonate solution to remove the precipitated by-product, the implementation method includes the addition of the complex cyclic carbonate to a tube containing a cation exchange resin or a solid acid. A method of passing a solution can also be used.

Therefore, the manufacturing method of the cyclic carbonate in one embodiment of this invention is represented by the following scheme 6.

(Wherein R ⁴ is a hydrogen atom or a lower alkyl group, and m and m ′ are each independently an integer of 0 to 5, provided that at least one of them is not 0, and m and The sum of m ′ is 7 or less)

In another embodiment of the present invention, the carboxylic acid derivative of the cyclic carbonate obtained by the above method is reacted with a halogenating agent (for example, PX ₃ , PX ₅ , SOX ₂ or NCX) to form a carboxylic acid of the cyclic carbonate. It is the manufacturing method of the said cyclic carbonate further including the process of producing | generating a halide. Preferably, the halogenating agent is selected from thionyl chloride, phosphorus pentachloride, oxalyl chloride, phosphorus tribromide and cyanuric fluoride, most preferably thionyl chloride. The amount of thionyl chloride preferably used as the halogenating agent is, for example, 1 equivalent or more and 5 equivalents or less.

In another embodiment of the present invention, the carboxylic acid halide of the cyclic carbonate obtained by the above method is reacted with an alcohol or amine containing a structural moiety having at least one ether group, represented by the group R. The method for producing a cyclic carbonate further comprises a step of synthesizing a carboxylic acid derivative of the cyclic carbonate.

The structural part having at least one ether group is preferably a structure having at least one chain ether, cyclic ether or acetal structure, and the structural part is used to convert the cyclic carbonate obtained by the method of the present invention into a polycarbonate material. The physical properties imparted to the polycarbonate can be arbitrarily designed. As a specific embodiment, the structural portion can be represented by the following formula (II).

(In the above formula (II), the number of repetitions (l) and U are as defined above)

In another specific embodiment, the structural portion R having at least one ether group may have a structure represented by the following formula (V).

(In the above formula (V), M ′, E and E ′, Q ′ and Q ″ and k and k ′ are as defined above)

In one embodiment of the present invention, the above method comprises a reaction vessel for performing a cyclization reaction, an ion exchange column packed with an ion exchange resin, and a reaction vessel for performing esterification or amidation from halogenation to form an intermediate. Can also be carried out in a continuous process without isolation and purification. Moreover, it can carry out by the one pot synthesis method with a single reaction vessel.

A method for producing a cyclic carbonate in one embodiment of the present invention having a 6-membered ring structure can be represented by Scheme 7 shown below. By the method of the present embodiment, a cyclic carbonate derivative (MTC-XR) can be obtained efficiently. MTC-XR has a structure in which a group R is bonded to a cyclic carbonate moiety with (-(C = O) X-) as a linker moiety (L), and can be converted to a polycarbonate by ring-opening polymerization. It is useful as a raw material for smart biomaterials according to

In this embodiment, in order to produce a compound MTC-XR in which the linker moiety L is an ester bond, that is, X is O, as a first step, a carboxylic acid having a diol structure, such as 2,2-bis ( For methylol) propionic acid, a 1: 1 complex with a basic organic compound is formed and solubilized in an organic solvent, and as a second step, it is reacted with a carbonic acid source such as triphosgene to form a cyclic carbonate. As a third step, after removing the basic compound at the complex site with an acidic substance and regenerating the carboxyl group, as in the fourth step, it is esterified with an alcohol having a structural portion indicated by the group R, etc. How to get. In the esterification, the carboxylic acid obtained in the third step is reacted with a halogenating agent (for example, PX ′ ₃ , PX ′ ₅ , SOX ′ ₂ or NCX ′, where X ′ is a halogen atom) to produce an acyl halide. Including getting.
The complex obtained in the first step may not be isolated, and an excess of the basic organic compound can be used to capture the elimination component of the carbonic acid source used in the cyclic carbonation in the second step. In this case, the first and second steps can be one continuous step. Further, a fourth step may be performed on the complex cyclic carbonate to esterify with an alcohol having a structural portion represented by the group R.

Also, starting from the above MTC-TEA, an amide (—C (═O) NH—) or a thioester (—C (=) is obtained by reacting an amine or thiol containing a structural moiety having at least one ether group. O) MTC-XR using S-) as a linker is synthesized. The reaction conditions used in this case are known to those skilled in the art.

Intermediate compounds obtained by the process of the present invention are also an object of the present invention. That is, one embodiment in the present invention is represented by the following formula (X):

(Wherein R ⁴ is a hydrogen atom or a lower alkyl group, and m and m ′ are each independently an integer of 0 to 5, provided that at least one of m and m ′ is not 0; And the sum of m and m ′ is 7 or less).

The structural portion represented by the group R introduced into the carbonate by the method of the present invention is preferably a structural portion having at least one ether group as described above, and MTC-XR synthesized by the method of such an embodiment. For example, a compound in which a cyclic carbonate moiety and a structural moiety having at least one ether group are linked by an ester bond (—C (═O) O—) can be obtained. That is, a preferred group of compounds obtained by the method of the present invention is represented by the following formula (XII):

(Where
m, m ′ and R ⁴ are as defined above,
l is an integer from 0 to 30, where
When l is not 0, U is lower alkyl or a cyclic ether group having 3 to 7 ring members,
When l is 0, U is:

(In the formula, M ′ is a hydrogen atom or a linear or branched alkyl group having 3 or less carbon atoms, and E and E ′ are each independently a direct bond, —O— or —CH _2. -Provided that at least one is -O- and Q 'and Q "are independently of each other a hydrogen atom, a linear or branched alkyl having 6 or less carbon atoms, alkenyl or alkynyl, C _3-8 represents an alicyclic alkyl or benzyl, or Q ′ and Q ″ together form an alkylene group having 2 to 5 carbon atoms, and k and k ′ are each independently 0 to It is an integer of 2).

In one more specific embodiment of the present invention, the compound obtained by the method of the present invention has the following formula (XI):

(Wherein m, m ′, R ⁴ , M ′, E and E ′, Q ′ and Q ″, and k and k ′ are as defined above).

Specific examples of compounds of formula (XI) include, but are not limited to, the following compounds:
5-methyl-5- (2-tetrahydrofuranylmethyl) oxycarbonyl-1,3-dioxane-2-one,
5-methyl-5- (3-tetrahydrofuranylmethyl) oxycarbonyl-1,3-dioxane-2-one,
5-methyl-5- (3-tetrahydropyranylmethyl) oxycarbonyl-1,3-dioxane-2-one 4-methyl-4- (2-tetrahydrofuranylmethyl) oxycarbonyl-1,3-dioxane-2- on,
4-methyl-4- (3-tetrahydrofuranylmethyl) oxycarbonyl-1,3-dioxane-2-one, and 4-methyl-4- (3-tetrahydropyranylmethyl) oxycarbonyl-1,3-dioxane- 2-on,
Etc.

One embodiment of the present invention is a method for producing an antithrombotic polymer comprising a step of ring-opening polymerization of a compound represented by the general formula (VII). Specifically, various polycarbonates can be produced by ring-opening polymerization of a cyclic carbonate obtained by the method of the present invention, for example, a cyclic carbonate represented by the formula (XI).

The ring-opening polymerization of the compound represented by the general formula (VII) is carried out by a method known to those skilled in the art. As the ring-opening polymerization method, a cationic polymerization reaction, an anionic polymerization reaction, or the like can be used. The cationic polymerization reaction is carried out using a Lewis acid such as boron trifluoride ether complex, titanium tetrachloride or aluminum chloride, a protonic acid such as hydrochloric acid or methanesulfonic acid, or an alkyl cation generator such as methyl iodide as an initiator. be able to. Anionic ring-opening polymerization can be performed using an alkali metal, a metal hydride, a metal alkoxide, an organometallic compound, or the like as an initiator.

In the case where the compound represented by the general formula (VII) is a cyclic carbonate, both cationic polymerization and anionic polymerization can be used in both cases where the compound is a lactone. When the cyclic carbonate is cationically polymerized, it is preferable to use an initiator that generates a counter anion having a large nucleophilicity, such as an alkyl halide, in order to suppress by-production of the polyether accompanying decarboxylation. . In addition, tin octylate, which is believed to proceed through a coordinated insertion mechanism and is approved for use by the US Food and Drug Administration (FDA), is currently the most commonly used ring-opening polymerization of cyclic monomers. It is also possible to carry out the ring-opening polymerization reaction by using alcohol as an initiator. Furthermore, in recent years, organic molecular catalysts that have been attracting attention both moderately activate monomers and alcohol initiators by hydrogen bonds to advance the polymerization reaction, and thus suppress chain transfer reactions such as transesterification as well as decarboxylation. It is easy to obtain a polymer with a relatively uniform molecular weight distribution, using a thiourea structure or a Lewis acid containing an aromatic fluoroalcohol as a monomer activation catalyst, and a tertiary amine as an initiator activation catalyst. A polymerization reaction can also be performed.

The ring-opening polymerization of the compound represented by the general formula (VII) is, for example, a polymerization initiator such as 1-pyrenebutanol, lauryl alcohol, decanol or stearyl alcohol in a solvent such as dichloromethane, chloroform, diethyl ether, tetrahydrofuran or toluene. In the presence of a cyclic amine polymerization initiator such as 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU), dimethylaminopyridine (DMAP) or triethylenediamine (DABCO), optionally a bifunctional group This is carried out by reacting at room temperature under a nitrogen atmosphere using an organic molecular catalyst such as a thiourea compound such as 1- (3,5-bis (trifluoromethyl) phenyl) -3-cyclohexyl-2-thiourea.

In the polymerization method of the present invention, the reaction system is preferably performed in a nitrogen atmosphere from which oxygen and water are removed from the viewpoint of suppressing side reactions. The reaction temperature can be selected in the range of room temperature to the boiling point of the solvent. From the viewpoint of controlling the reaction, the temperature is preferably in the range of room temperature to 50 ° C., and most preferably at room temperature. The reaction time varies depending on the raw material compound of general formula (VII), the reaction temperature, and the presence or absence of a catalyst. For example, when using a catalyst at room temperature, the reaction time is 1 minute to 12 hours, preferably 30 Min to 6 hours, more preferably 1 to 3 hours. The completion of the reaction can be judged by whether or not the compound of the general formula (VII), which is a monomer, is present in the reaction system, and can be confirmed by a method such as ¹ H-NMR or TLC. When the polymerization reaction has proceeded sufficiently, the polymerization reaction can be terminated by adding a reaction terminator. Examples of the reaction terminator include acetic acid, hydrochloric acid, sulfuric acid, benzoic acid and the like, but the type is not particularly limited.

The ring-opening polymerization reaction can be carried out in a solution phase by dissolving it in a solvent that dissolves the cyclic carbonate as a monomer. However, the polymerization reaction may be carried out in a suspension state, and further, bulk polymerization or Polymerization can also be performed in a state where a solid monomer is melted. In order to obtain a uniform polymer having a small molecular weight distribution, it is preferable to polymerize in a solution phase. The solvent for performing the solution polymerization is not particularly limited as long as the monomer can be dissolved and the solvent itself does not cause a reaction such as polymerization.

A polycarbonate having a structural part having at least one ether group in the main chain having a carbonate bond as a repeating unit is derived from the biodegradability derived from the main chain polycarbonate and the structure having at least one ether group in the side chain. It is a polymer having characteristics such as blood compatibility and biocompatibility, and exhibits excellent biocompatibility when used as a medical material. Accordingly, such polycarbonates obtained by the above methods, including those of the present invention, are referred to herein as “biocompatible polycarbonates”. The biocompatible polycarbonate obtained by the above method including the method of the present invention can typically be represented by the following formula.

(Where
X is O, NH, or S;
R ⁵ is a structural moiety having at least one ether group as described above;
m and m ′ are each independently an integer of 0 to 5, and the sum of m and m ′ is 7 or less;
Each of these may be different in each repeating unit,
n represents the degree of polymerization, preferably in the range of 2 to 2000).

The values of m and m ′ are determined by the selection of the monomer raw material compound. From the viewpoint of monomer preparation, the sum of m and m ′ is preferably in the range of 1 to 4, and m and m ′. Are most preferably 1.

In the above formula (XIII), the structural portion R ⁵ having at least one ether group is a molecular chain having at least one chain ether such as polyethylene glycol, cyclic ether or acetal structure, that is, at least one ether group. If there is no particular limitation. Since the structural portion R ⁵ has at least one ether group (—O—), it is possible to exhibit high molecular mobility as seen in, for example, polyethylene glycol. It is considered that intermediate water can be contained as a polymer by having it in the side chain. Then, the ether groups contained in the structural moiety R ⁵ numbers, by adjusting the bulkiness or the like structural parts R ⁵ itself, the degree amount is regulated antithrombotic of the resulting polymer capable intermediate water content Can be adjusted.

The method for producing the biocompatible polycarbonate is not limited to the ring-opening polymerization of the cyclic carbonate obtained by the method of the present invention. The polycarbonate polymer is synthesized first, and a predetermined carbon atom of the main chain is determined with respect to a predetermined carbon atom. A biocompatible polycarbonate may be produced by introducing a structure containing an ether group. In this biocompatible polycarbonate composition, it is not always necessary that a structure containing an ether group is bonded as a side chain over all the repeating units of the main chain polymer, but it is easy to synthesize and to make it easy to predict the characteristics of the polymer. From the above, it is also preferable to polymerize a single kind of monomer into which a structure containing an ether group is introduced to form a polymer.

A biocompatible polymer composition produced by ring-opening polymerization of a monomer compound represented by the general formula (VII) is also an object of the present invention.

The biocompatible polymer composition produced according to the present invention may contain, for example, a radical scavenger, a peroxide decomposer, an antioxidant, and an ultraviolet absorber as long as it does not depart from the spirit of the present invention. In addition, additives such as a heat stabilizer, a plasticizer, a flame retardant, and an antistatic agent can be added and used. Moreover, it can be used by mixing with polymers other than the polymer of this invention. Such a composition comprising the biocompatible polymer composition of the present invention is also an object of the present invention.

The various biocompatible polymer compositions produced according to the present invention can be used alone by being dissolved in an appropriate organic solvent, or used by mixing with other polymer compounds depending on the purpose of use. Etc., and can be used as various compositions. Moreover, the medical device of this invention should just have the bioaffinity polymer composition of this invention in at least one part of the surface used in contact with the structure | tissue or blood in a living body. That is, a composition containing the biocompatible polymer composition of the present invention can be used as a surface treatment agent on the surface of a base material constituting a medical device. Moreover, you may comprise at least one part member of a medical device with the bioaffinity polymer composition of this invention, or its composition.

One aspect of the present invention is a biocompatible polymer of the present invention for suppressing a foreign body reaction to blood or tissue until it is decomposed when used in contact with tissue or blood in vivo. It is a composition.

The biocompatible polymer composition of the present invention can be preferably used for medical applications. When the biocompatible polymer composition of the present invention is mixed with another polymer compound and used as a composition, it can be used in an appropriate mixing ratio depending on the intended use. In particular, by setting the ratio of the biocompatible polymer composition of the present invention to 90% by weight or more, a composition having the characteristics of the present invention can be obtained. In addition, depending on the intended use, by setting the ratio of the biocompatible polymer composition of the present invention to 50 to 70% by weight, it is possible to obtain a composition having various characteristics while utilizing the features of the present invention. .

One aspect of the present invention is a medical device comprising the biocompatible polymer composition of the present invention. In addition, the biocompatible polycarbonate composition can be applied to at least a part of the surface of a medical device used in contact with tissue or blood in a living body to obtain a medical device containing the biocompatible polycarbonate. That is, it can be used as a surface treatment agent for the surface of a base material constituting a medical device, and can also be used as a material constituting at least a part of members of the medical device. Here, the “medical device” includes an implantable device such as a prosthesis and a device such as a catheter that may temporarily come into contact with living tissue, and is not limited to a device that is handled in a living body. The medical device of the present invention is a device used for medical applications having the polymer composition of the present invention on at least a part of its surface. The surface of the medical device referred to in the present invention refers to, for example, the surface of the material constituting the medical device that contacts blood when the medical device is used, the surface portion of the hole in the material, and the like.
In this specification, “used in contact with tissue or blood in a living body” is used, for example, in contact with the tissue or blood in a state where it is placed in the living body or in a state where the tissue in the living body is exposed. Naturally, the form and the form used in contact with blood which is an in vivo component taken out of the body in the extracorporeal circulation medical material are included. In addition, “used for medical use” includes the above-mentioned “used in contact with in vivo tissues and blood” or intended use.

In the present invention, the material and shape of the base material constituting the medical device are not particularly limited, and may be any of, for example, a porous body, fiber, nonwoven fabric, particle, film, sheet, tube, hollow fiber, and powder. . The materials include natural polymers such as Kinishiki and hemp, nylon, polyester, polyacrylonitrile, polyolefin, halogenated polyolefin, polyurethane, polyamide, polycarbonate, polysulfone, polyethersulfone, poly (meth) acrylate, and ethylene-vinyl alcohol. Examples thereof include synthetic polymers such as polymers, butadiene-acrylonitrile copolymers, and mixtures thereof. Further, metals, ceramics, composite materials thereof, and the like can be exemplified, and they may be composed of a plurality of base materials. The present invention is applied to at least a part of the surface in contact with blood, preferably almost the entire surface in contact with blood. Desirably, a biocompatible polymer composition is provided.

The biocompatible polymer composition of the present invention can be used as a material constituting a whole medical device used in contact with a tissue or blood in a living body or a material constituting a surface portion thereof, and can be used as an implantable prosthesis. And therapeutic instruments, extracorporeal circulation type artificial organs, surgical sutures, and catheters (circulatory catheters such as angiographic catheters, guide wires, PTCA catheters, gastrointestinal catheters, gastrointestinal catheters, esophageal tubes, etc.) A biocompatible polymer according to the present invention, wherein at least a part of the surface in contact with blood of a medical device such as a catheter, tube, urinary catheter, urinary catheter, etc. It is desirable to be composed of a composition. In addition, the biodegradability of the biocompatible polymer composition according to the present invention can be used particularly preferably for a medical device placed in the body during treatment.

The biocompatible polymer composition of the present invention comprises a hemostatic agent, a biological tissue adhesive, a tissue regeneration repair material, a drug sustained release carrier, a hybrid artificial organ such as an artificial pancreas and an artificial liver, an artificial blood vessel, and an embolization material. It may also be used as a matrix material for a scaffold for cell engineering.

These medical devices may be further provided with surface lubricity because they can be easily inserted into blood vessels and tissues and do not damage the tissues. As a method for imparting surface lubricity, a method in which a water-soluble polymer is insolubilized to form a water-absorbing gel layer on the material surface is excellent. According to this method, a material surface having both biocompatibility and surface lubricity can be provided.

The biocompatible polymer composition of the present invention itself is a material excellent in biocompatibility, but since it can further carry various physiologically active substances, not only blood filters but also blood storage containers and blood circuits It can be used for various medical devices such as indwelling needles, catheters, guide wires, stents, oxygenators, dialysis machines, and endoscopes.
Specifically, the biocompatible polymer composition of the present invention may be coated on at least a part of the substrate surface constituting the blood filter. Further, the polymer compound of the present invention may be coated on at least a part of the blood bag and the surface of the tube communicating with the blood bag in contact with the blood. In addition, blood in an extracorporeal circulation blood circuit composed of an instrument side blood circuit unit composed of a tube, an arterial filter, a centrifugal pump, a hemoconcentrator, a cardio pregear, etc., and an operative field side blood circuit unit composed of a tube, catheter, soccer, etc. At least a part of the surface in contact with the surface may be coated with the biocompatible polymer composition of the present invention.
Further, an inner needle having a sharp needle tip at a distal end, an inner needle hub installed on the proximal end side of the inner needle, a hollow outer needle into which the inner needle can be inserted, and a proximal end side of the outer needle An indwelling needle assembly comprising: an outer needle hub installed on the inner needle; a protector mounted on the inner needle and movable in the axial direction of the inner needle; and a connecting means for connecting the outer needle hub and the protector. At least a portion of the three-dimensional, blood-contacting surface may be coated with the biocompatible polymer composition of the present invention. Moreover, at least a part of the surface of the long tube that contacts the blood of the catheter composed of the adapter connected to the proximal end (hand side) may be coated with the biocompatible polymer composition of the present invention.
Further, at least a part of the surface of the guide wire that comes into contact with blood may be coated with the biocompatible polymer composition of the present invention. In addition, stents of various shapes, such as hollow tubular bodies made of metal materials or polymer materials with pores on the side, metal material wires or polymer material fibers knitted into a cylindrical shape, etc. At least a portion of the surface that contacts blood may be coated with the biocompatible polymer composition of the present invention.
Also, a large number of porous hollow fiber membranes for gas exchange are housed in a housing, blood flows on the outer surface side of the hollow fiber membrane, and oxygen-containing gas flows inside the hollow fiber membrane. The lung may be an artificial lung in which the outer surface or outer layer of the hollow fiber membrane is coated with the biocompatible polymer composition of the present invention.
Further, a dialysate circuit including at least one dialysate container filled with dialysate and at least one drainage container for collecting dialysate, and starting from the dialysate container, or The end point may be a dialyzer having a liquid feeding means for feeding dialysate, and at least a part of the surface in contact with the blood may be coated with the biocompatible polymer composition of the present invention.

As a method for holding the composition containing the biocompatible polymer composition of the present invention on the surface of a medical device or the like, a coating method, a graft polymerization by radiation, electron beam or ultraviolet ray, a chemical reaction with a functional group of a base material is used. Well-known methods, such as a method of introducing by using, may be mentioned. Among these, the coating method is particularly preferable in practical use because the manufacturing operation is easy. Furthermore, there are coating methods, spraying methods, dipping methods and the like as coating methods, and any of them can be applied without any particular limitation. The film thickness is preferably 0.1 μm to 1 mm. For example, in the coating treatment by the application method of the composition containing the biocompatible polymer composition of the present invention, the coating solution is prepared by dissolving the composition containing the biocompatible polymer composition of the present invention in an appropriate solvent. After dipping the member, it can be carried out by a simple operation such as removing excess solution and then air-drying. In addition, in order to more firmly immobilize the biocompatible polymer composition of the present invention on the member to be coated, heat may be applied after coating to further improve the adhesion with the biocompatible polymer composition of the present invention. it can. Moreover, you may fix | immobilize by bridge | crosslinking the surface. As a method for crosslinking, a crosslinkable monomer may be introduced as a comonomer component. Moreover, you may bridge | crosslink by an electron beam, a gamma ray, and light irradiation.

In addition to compounds having a plurality of vinyl groups or allyl groups in one molecule such as methylene bisacrylamide, trimethylolpropane diacrylate, triallyl isocyanate, trimethylolpropane triacrylate, tetramethylolmethane tetraacrylate, etc. And polyethylene glycol diacrylate. Among these, when various functional groups are introduced using polyethylene glycol diacrylate, the introduction rate of the compound having a functional group is high, and further, by introducing a polyethylene glycol chain to make it hydrophilic, as described above This is preferable because nonspecific adsorption of cells and proteins other than the intended purpose is suppressed. In this case, the molecular weight of the polyethylene glycol chain is preferably 100 to 10,000, more preferably 500 to 6,000.

Furthermore, the biocompatible polycarbonate composition includes a hemostatic agent, an adhesive for living tissue, a repair material for tissue regeneration, a carrier for a drug sustained release system, a hybrid artificial organ such as an artificial pancreas and an artificial liver, an artificial blood vessel, an embolizing material, It is particularly preferable to use it as a matrix material for a scaffold for cell engineering. That is, for a certain period of time in a desired place in the living body, it exhibits appropriate blood cell adhesion while exhibiting blood compatibility such as antithrombotic properties and preventing undesirable biological reactions such as blood coagulation. It can be used for various purposes by adhesion of various cells existing in the living body. And, since it has biodegradability, it is considered that it can be replaced with living cells that have been decomposed and adhered by an enzyme or the like after a necessary period of time in vivo.
For example, when used for an artificial blood vessel in a living body, it functions as a scaffold until the vascular endothelial cells adhere and the self tissue regenerates. There is no. It can also be used as an adsorbing and supplementing agent for highly metastatic cancer cells circulating in the blood by utilizing antithrombogenicity and cancer cell adhesion. Compared with the conventional specific adsorption method using an antibody that binds to a surface antigen of cancer cells, a wider range of cancer cells may be adsorbed when using a biocompatible polycarbonate. Furthermore, since cancer cells can be cultured in a state closer to the environment in the living body, it can be used as a culture substrate used for screening for anticancer agents, and the development of anticancer agents is expected to be promoted. The point that the biocompatible polycarbonate has biodegradability shows an advantageous effect even in applications for adsorbing cancer cells in vivo. For example, when cancer cells adsorbed in vivo reach a certain size, they are recognized by the innate immune system, but it is advantageous for the in vivo immune system that the polymer itself is easily decomposed when preyed on by immune cells. It is. Therefore, it is considered that the biocompatible polycarbonate having both blood compatibility and cell adhesion can be used for new applications as a cancer diagnosis and treatment device.
On the other hand, there are various cells in the body. If undifferentiated stem cells can be adsorbed, they will be present in the body when used for repairing or repairing tissues damaged by accidents or diseases. These stem cells can be concentrated at the site of injury and would be extremely advantageous for tissue regeneration.

As described above, various carbonate compounds can be synthesized simply and efficiently by the method of the present invention. Further, when a composition containing a biocompatible polycarbonate composition obtained by a method including the method of the present invention is introduced into at least a part of a surface of a medical device that comes into contact with blood, a coagulation system, a complement system, and a platelet system It is possible to suppress undesirable biological reactions such as activation, and to impart excellent biocompatibility. On the other hand, the biocompatible polycarbonate composition has biodegradability and exhibits appropriate cell adhesion in the living body and has an affinity with the living body, thereby reducing the burden on the living body and the environment. It is considered possible.

Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples. In addition, as long as there was no notice in particular, the chemical | medical agent used in the following examples used the commercial item as it was. In the following examples, confirmation of the structure of the products (intermediate compounds, final compounds) obtained in Examples 1 to 3 and Comparative Example 1, the degree of polymerization, and the number average molecular weight of the polymers obtained in each Example Measurement of molecular weight distribution and confirmation of the presence of intermediate water were performed as follows.

(1) Number average molecular weight ([Mn], unit: g / mol)
Gel permeation chromatography (GPC) calibrated with the standard polystyrene having a known peak molecular weight (“HLC-8220” manufactured by Tosoh Corporation, column configuration: Tosoh TSK-gels super AW5000, super AW4000, super AW3000) Used to measure the number average molecular weight (Mn) and weight average molecular weight (Mw) of the polymer. (Solvent: tetrahydrofuran, temperature: 40 ° C., flow rate: 1.0 mL / min).

(2) Molecular weight distribution ([Mw / Mn])
It calculated | required as the ratio (Mw / Mn) using the value of the weight average molecular weight (Mw) calculated | required by the method of said (1), and a number average molecular weight (Mn).

(3) NMR measurement For structural analysis of the monomer and polymer, ¹ H-NMR measurement and ¹³ C-NMR measurement were performed using an NMR measurement apparatus (JEOL 500 MHz JNM-ECX, manufactured by JEOL Ltd.). The chemical shift was based on CDCl ₃ ( ¹ H: 7.26 ppm, ¹³ C: 77.1 ppm).

[Example 1] Synthesis of 2-methoxyethyl 2,2-bis (methylol) propionate (MPA-ME)

2,2-bis (methylol) propionic acid (bis-MPA; 30.0 g, 0.224 mol), ion exchange resin Ameryst-15 (6.00 g) was added to 2-methoxyethanol (150 mL, 1.91 mol). ) And heated and stirred at 90 ° C. for 45 hours. Thereafter, the ion exchange resin was filtered off from the reaction solution, and the obtained filtrate was concentrated and dried under reduced pressure to give 2-methoxyethyl 2,2-bis (methylol) propionate (MPA-) as a pale yellow oily substance. ME) was obtained (25.1 g, yield 58.5%). ¹ H-NMR (500 MHz, CDCl ₃ ): δ 4.35 (quin, 2H, CH ₂ CH ₂ OCH ₃ ), 3.85 (d, 2H, CH _a H _b OH), 3.73 (d, 2H, CH ₂ H _b OH), 4.35 (quin, 2H, CH ₂ OCH ₃ ), 3.39 (s, 3H, OCH ₃ ), 1.11 (s, 3H, CH ₃ ).

Example 2 Synthesis of 5-methyl-5- (2-methoxyethyl) oxycarbonyl-1,3-dioxan-2-one (MTC-ME)

MPA-ME (25.1 g, 0.131 mol) and pyridine (63.5 mL, 0.787 mol) were added to dichloromethane (DCM; 150 mL) and cooled to −75 ° C. in a dry ice-acetone bath. Next, a DCM solution (200 mL) of triphosgene (19.5 g, 0.0655 mol) was added dropwise, and the mixture was stirred at −75 ° C. for 2 hours and then at room temperature for 2 hours. After completion of the reaction, saturated aqueous ammonium chloride solution (200 mL) was added and stirred for 45 minutes, and then the organic phase was washed twice with 1N aqueous hydrochloric acid solution (200 mL), saturated aqueous sodium bicarbonate solution (200 mL), saturated brine (200 mL), and Washed with ion-exchanged water (200 mL). The obtained organic phase was dried over magnesium sulfate and then concentrated and dried under reduced pressure. Thereafter, the residue was purified by column chromatography (ethyl acetate) to give 5-methyl-5- (2-methoxyethyl) oxycarbonyl-1,3-dioxane-2-one (MTC-ME) as a colorless viscous liquid. Obtained (11.0 g, yield 43.8%). ¹ H-NMR (500MHz, CDCl ₃ ): δ 4.68 (d, 2H, CH _a H _b OCOO), 4.32 (quin, 2H, CH ₂ CH ₂ OCH ₃ ), 4.20 (d, 2H, CH _a H _b OCOO .), 3.57 (quin, 2H , CH 2 OCH 3), 3.33 (s, 3H, OCH 3), 1.31 (s, 3H, CH 3) 13 C-NMR (125MHz, CDCl 3): δ 171.2, 147.6, 73.0, 70.1, 65.0, 59.0, 40.3, 17.6.

[Example 3] Ring-opening polymerization of MTC-ME: Preparation of P (MTC-ME)

In a glove box under a nitrogen atmosphere, MTC-ME (0.441 g, 2.02 mmol) was replaced with 1-pyrenebutanol (PB; 5.2 mg, 0.019 mmol), 1,8-diazabicyclo [5.4.0]. Undec-7-ene (DBU; 6.1 mg, 0.040 mmol) and 1- (3,5-bis (trifluoromethyl) phenyl) -3-cyclohexyl-2-thiourea (TU; 15.0 mg, 0.041 mmol) ) In the presence of) in DCM (1 mL) at room temperature. After stirring for 90 minutes, the consumption of the monomer was confirmed by ¹ H-NMR, and then several drops of acetic anhydride was added as a terminator and stirred overnight. Thereafter, the reaction solution was reprecipitated in diethyl ether: hexane (1: 3, 40 mL) and dried under vacuum to obtain a colorless and viscous polymer, P (MTC-ME) (0.350 g, yield). (Rate 79.3%). GPC: Mn 9556 g / mol, Mw / Mn 1.27. ¹ H-NMR (500MHz, CDCl ₃ ) δ 4.30 (m, 6H, COOCH ₂ ), 3.58 (t, 2H, CH ₂ OCH ₃ ), 3.36 (s, 3H, OCH ₃ ), 1.27 (s, 3H, CH ₃ ).

[Comparative Example 1] Synthesis of PTMC

In a glove box under nitrogen atmosphere, trimethylene carbonate (TMC: 408 mg, 4.0 mmol), PB (11.3 mg, 0.041 mmol), DBU (33.5 mg, 0.22 mmol), TU (75.3 mg). , 0.20 mmol) in the presence of DCM (1 mL) at room temperature. After stirring for 90 minutes, the consumption of the monomer was confirmed by ¹ H-NMR, and then several drops of acetic anhydride was added as a terminator and stirred overnight. The reaction solution was then reprecipitated in methanol (40 mL) and dried under vacuum to give a colorless and viscous polymer PTMC (292.9 mg, 71.8%). GPC: Mn 12000 g / mol, Mw / Mn 1.1. ¹ H-NMR (500MHz, CDCl ₃ ) δ 4.25 (t, 4H, CH ₂ CH ₂ CH ₂ ), 2.05 (quin, 2H, CH ₂ CH ₂ CH ₂ ).

[Example 4] Synthesis of 5-carboxyl-5-methyl-1,3-dioxane-2-one (MTC-OH) via MTC-TEA

2,2-bis (methylol) propionic acid (bis-MPA; 268 mg, 2.0 mmol) as a diol compound that is a starting material for cyclic carbonate was dispersed in methylene chloride (4 mL), and triethylamine (0.97 mL) as an organic base was used. 7.0 mmol), and bis-MPA was dissolved in methylene chloride to obtain a transparent solution. After the solution became clear, the solution was cooled to -75 ° C. in a dry ice-acetone bath. Next, a solution of triphosgene (239 mg, 0.8 mmol) in methylene chloride (3 mL) was added dropwise as a carbonic acid source in the cyclization reaction of the diol compound, and the mixture was stirred at −75 ° C. for 30 minutes and then at room temperature for 2 hours. The reaction was terminated. After completion of the reaction, the precipitate produced by the reaction was removed by filtration. The precipitate was mainly composed of triethylamine hydrochloride. The resulting filtrate was concentrated under reduced pressure and then redissolved in tetrahydrofuran.
FIG. 5 shows a ¹ H-NMR spectrum obtained for the solute synthesized in the same manner as described above and contained in the solution after removing the precipitate (triethylamine hydrochloride). ^{From the 1} H-NMR spectrum, it was identified that MTC-TEA was produced by the above operation.
Next, in order to separate and remove the organic base from MTC-TEA dissolved in tetrahydrofuran, an ion exchange resin Ameryst-15 (registered trademark) (550 mg) was added to the solution, and the mixture was stirred at room temperature for 5 hours. The ion exchange resin was filtered off. The obtained filtrate was concentrated and dried under reduced pressure to obtain a pale yellow solid (245 mg).
FIG. 6 shows the ¹ H-NMR spectrum obtained for the pale yellow solid. FIG. 9 shows a ¹ H-NMR spectrum of 5-carboxyl-5-methyl-1,3-dioxane-2-one (MTC-OH) synthesized by a known method (Comparative Example 1). . Both spectra agreed well, and the pale yellow solid obtained by the above operation was considered to be MTC-OH. The yield of MTC-OH obtained by the above operation was 76.4%.

[Example 5] Synthesis of MTC-Cl

MTC-TEA (2.60 g, 10 mmol) synthesized by the method described in Example 4 was dissolved in 50 mL of methylene chloride, and oxalic chloride (1.05 mL, 1.05 mL, 12 mmol) in methylene chloride (20 mL) was added dropwise over 15 minutes. Thereafter, the solution was stirred at room temperature for 1 hour and concentrated on a rotary evaporator. To the concentrate was added 50 mL of tetrahydrofuran, the insoluble material was filtered off, and the filtrate was concentrated to give a pale yellow solid (1.711 g).
FIG. 7 shows the ¹ H-NMR spectrum of the pale yellow solid obtained above. From the spectrum, the pale yellow solid obtained above was presumed to be MTC-Cl, and the yield was calculated to be 96.1%.

[Example 6] Synthesis of MTC-THF

MTC-Cl (1.403 g, 7.86 mmol) synthesized by the procedure described in Example 5 was dissolved in 20 mL of tetrahydrofuran and cooled to 0 ° C. or lower in an ice bath, and tetrahydrofurfuryl alcohol (0. A solution of 725 g, 7.1 mmol) and triethylamine (1.51 mL, 10.8 mmol) in tetrahydrofuran (10 mL) was added dropwise over 10 minutes. Thereafter, the solution was stirred at room temperature for 3 hours, the insoluble material was filtered off, and then concentrated on a rotary evaporator. 100 mL of ethyl acetate was added to the oily residue, washed once each with 1N aqueous hydrochloric acid and distilled water, and the organic layer was dried over magnesium sulfate and then concentrated and dried under reduced pressure to obtain a transparent oily substance ( 0.6653 g).
FIG. 8 shows a ¹ H-NMR spectrum of the oily substance. From the spectrum, the oily substance obtained above was inferred to be MTC-THF, and the yield was calculated to be 34.7%.

[Example 7] Direct synthesis of MTC-THF from MTC-TEA

MTC-TEA (2.08 g, 7.95 mmol) synthesized by the method described in Example 4 was dissolved in 40 mL of methylene chloride, and oxalic chloride (0. 83 mL, 9.54 mmol) in methylene chloride (15 mL) was added dropwise over 15 minutes. Thereafter, the solution was stirred at room temperature for 3 hours, and then hydrogen chloride gas by-produced under a nitrogen stream was removed. The solution was cooled again to 0 ° C. or lower, and a solution of tetrahydrofurfuryl alcohol (0.732 g, 7.17 mmol) and triethylamine (1.66 mL, 11.3 mmol) dissolved in tetrahydrofuran (10 mL) was added dropwise over 10 minutes. did. Thereafter, the reaction solution was stirred at room temperature for 3 hours, insoluble matters were filtered off, and then concentrated on a rotary evaporator. 100 mL of ethyl acetate was added to the oily residue, washed once each with 1N aqueous hydrochloric acid and distilled water, and the organic layer was dried over magnesium sulfate and then concentrated and dried under reduced pressure to obtain a transparent oily substance ( 0.4867 g). When a ¹ H-NMR spectrum was obtained for the oily substance, it was estimated that MTC-THF was produced, and the yield was calculated to be 25.1%.

[Comparative Example 2] Synthesis of MTC-OH by conventional method

MTC-OH was synthesized according to a known method, for example, non-patent literature [Pratt et al., Chem. Commun., 2008, 114-116]. That is, 5-benzyloxycarbonyl-5-methyl-1,3-dioxan-2-one (MTC-Bn; 253.4 mg, 1.0 mmol) obtained in a yield of 58.9% from bis-MPA Was dissolved in tetrahydrofuran, degassed and purged with nitrogen, 10 wt% palladium-supported Pd / C (63 mg) was added, further degassed and purged with nitrogen, cyclohexene (1.0 mL, 10 mmol) was added, and the mixture was stirred for 18 hours. Thereafter, Pd / C was filtered off, and the filtrate was concentrated under reduced pressure to obtain MTC-OH (149.5 mg, yield 92.2%).
FIG. 9 shows a ¹ H-NMR spectrum of the MTC-OH obtained above.

[Example 8] DSC measurement of P (TMC-ME) DSC measurement was performed on P (TMC-ME) in a dry state and in a state containing 5% water. Measurement was performed using a DSC apparatus (SII Nano Technologies, Inc., “EXSTAR X-DSC7000”) under conditions of a nitrogen flow rate of 50 mL / min and 5.0 ° C./min. The temperature program was (i) cooling from 30 ° C. to −100 ° C., (ii) holding at −100 ° C. for 5 minutes, and (iii) heating from −100 ° C. to 30 ° C. In (iii) above, the presence or absence of intermediate water was confirmed by the presence or absence of an exothermic peak due to low-temperature crystallization of water and an endothermic peak due to low-temperature melting of water. FIG. 10 shows the results of DSC measurement of P (TMC-ME) in a dry state and a state containing 5% water. From the figure of (b) showing the results of DSC measurement of P (TMC-ME) containing 5% water, the behavior associated with low-temperature melting of water around -5 ° C, and low-temperature crystallization of water around -15 ° C It was revealed that the antithrombotic polymer of the present invention retains intermediate water, that is, has biocompatibility and can function as a biocompatible polymer.

[Example 9] Water static contact angle measurement (droplet method)
PET (MTC-ME) and PTMC adjusted to concentrations of 1.0, 0.5, 0.2, and 0.1 w / v% on a PET substrate (diameter 14 mm, thickness 125 μm) pre-cleaned with methanol An acetone solution (40 μL) was applied by spin coating (spin conditions: 500 rpm 5 s, 2000 rpm 10 s, SLOPE 5 s, 4000 rpm 5 s, SLOPE 4 s, 25 ° C.). The second application was performed 10 minutes after the first spin coating. After vacuum drying for 24 hours, the contact angle with water was measured for each of the three points of the center, left end, and right end of each polymer-coated substrate. 2 μL of water droplet was used for each measurement.

[Example 10] Measurement of static contact angle of water (underwater bubble method)
The same polymer-coated substrate as in Example 9 was immersed in a water tank containing Milli-Q water with the coated surface facing downward. Using a micropipettor, the polymer-coated substrate on which bubbles (2 μL) were immersed was adhered to the center, the left end, and the right end, and the contact angle between the coating surface and the bubbles was measured using the θ / 2 method. The results of contact angle measurement of Examples 9 and 10 are shown in Table 1. The contact angle of the polymer obtained in Example 3 showed a small value compared to the case where PET was used as a control, indicating that the surface of the polymer obtained in Example 3 was more hydrophilic. . Moreover, the contact angle of the polymer obtained in Comparative Example 1 showed a larger value than when PET was used, indicating that the polymer surface was more hydrophobic.

Example 11 Human Vascular Endothelial Cell (HUVEC) Culture The prepared polymer-coated substrate was placed in a 6-well plate and UV sterilized for 30 minutes in a clean bench. After the substrate was washed with 500 μL of a phosphate buffered saline (PBS) solution, 500 μL of 20% FBS DMEM / F-12 (HUVEC medium) was added and incubated at 37 ° C. overnight. A 10 cm dish in which HUVEC (P5) was cultured was washed with 2 mL of PBS solution, 2 mL of trypsin / ethylenediaminetetraacetate ion (EDTA) enzyme solution was added, and the cells were collected after incubation at 37 ° C. for 2 minutes. The solution was centrifuged at 1300 rpm for 5 minutes, the supernatant was removed, the number of cells was counted with a microscope, and 20% FBS DMEM / F-12 was added to adjust the seeding density to 5.0 × 10 ⁴ cells / cm ² . did. After removing the medium used for preconditioning, 500 μL of the prepared cell solution and 500 μL of 20% FBS DMEM / F-12 were inoculated and incubated at 37 ° C. Incubation was performed at three time points for 1 hour, 1 day, and 3 days. Each sample was stained by antibody staining, and the cell number and cell morphology were observed with a confocal laser microscope.

The result is shown in FIG. The substrate coated with PMPC, which has a phospholipid polar group in the side chain and was used as a control sample showing blood compatibility, is coated with P (MTC-ME), whereas vascular endothelial cells are hardly adhered. It can be seen that vascular endothelial cells adhere to the same substrate as PET and PMEA for about one day after culturing. The decrease in the number of cells on P (MTC-ME) or PTMC-coated substrate after 3 days of culture is considered to be due to the biodegradability of these polymers.

[Example 12] Culture of human fibrosarcoma cells (HT-1080) A polymer-coated substrate was prepared in the same manner as described above and preconditioned (60 minutes, up to 37 ° C). A 10 cm dish in which HT-1080 was cultured was washed with 2 mL of PBS solution, 3 mL of trypsin / EDTA enzyme solution was added, and the cells were collected after incubation at 37 ° C. for 2 minutes. The solution was centrifuged at 1300 rpm for 5 minutes, the supernatant was removed, the number of cells was counted with a microscope, the medium was added, and the seeding density was adjusted to 1.0 × 10 ⁴ cells / cm ² . After removing the medium used for preconditioning, 1 mL of the prepared cell suspension was inoculated and incubated at 37 ° C. for 1 hour. After culturing, the cells were washed twice with 1 mL of PBS, fixed with 4% paraformaldehyde, washed with 1 mL of PBS, stained with crystal violet, and the number of cells was counted with a phase contrast microscope.

The result is shown in FIG. The substrate coated with P (MTC-ME) was found to exhibit cell adhesion similar to PET and PMEA.

[Example 13] Platelet adhesion test A spin-coated substrate coated with a 0.2 w / v% acetone solution of P (MTC-ME) was cut into 8 mm squares and fixed to a sample table for a scanning electron microscope (SEM). Human blood was centrifuged at 1500 rpm for 5 minutes, and the supernatant was collected as platelet rich plasma (PRP). The remaining blood was further centrifuged at 4000 rpm for 10 minutes, and the supernatant was collected as platelet poor plasma (PPP). Platelet solution with a platelet concentration of 4 × 10 ⁷ cells / mL while diluting PPP 800-fold with phosphate buffered saline (PBS) solution, further diluting PRP, and checking the platelet count with a microscope Was prepared. 200 μL of this platelet solution was dropped on each substrate and allowed to stand at 37 ° C. for 1 hour. Thereafter, each substrate was washed twice with a PBS solution, immersed in a 1% glutaraldehyde solution, and fixed at 37 ° C. for 2 hours. The immobilized sample was washed by immersing in PBS solution for 10 minutes, PBS: water = 1: 1 for 8 minutes, water for 8 minutes, and water for another 8 minutes. Each sample was air-dried at room temperature, and the platelet adhesion number was measured by SEM. The measurement results are three types of adhesion forms of platelets adhering to the surface of each substrate, that is, type I: small degree of activation, circular adhesion form similar to that in blood, type II: medium degree of activation The adhesive form in which pseudo-leg formation was observed, type III: classified into the extended adhesive form with a high degree of activation, and PET was evaluated as a control.

Fig. 13 shows the measurement results of the platelet adhesion number. From this result, it became clear that the antithrombotic polymer of the present invention can suppress the number of adhesion of platelets to be small and exhibits good biocompatibility and antithrombogenicity as compared with PTMC of the comparative example.

[Example 14] Enzymatic degradation test Two types of polymers, P (MTC-ME) and PTMC, were used. 30 mg of polymer and 1 mL of lipase solution were added to a 1.5 mL tube and allowed to stand at 37 ° C. The lipase solution was changed every 2 days. After 9 days, the lipase solution was withdrawn from the tube and the remaining polymer sample was rinsed 3 times with milliQ water. Thereafter, the weight loss was determined from the polymer weight after 24 hours of vacuum drying at room temperature.
The weight loss rates after 9 days of enzyme treatment were P (MTC-ME): 6.4% and PTMC: 1.7%, respectively. From this result, it was revealed that the antithrombotic polymer of the present invention has excellent biodegradability by an enzyme as compared with the PTMC of the comparative example.

Comparison of Example 4 and Comparative Example 2 revealed that the target product can be obtained by the method of the present invention more easily and in a higher yield than the conventional method. In addition, starting from the method of the present invention, a polycarbonate material having physical properties such as biocompatibility can be prepared. The material can selectively adsorb tissues in the living body and has biodegradability. It was shown to be a useful material as a material.

According to the present invention, the polymer composition of the present invention can be used as an antithrombotic material to which substances that cause blood coagulation and the like hardly adhere. The polymer composition of the present invention can be used, for example, as a surface treatment agent for medical devices such as artificial blood vessels or medical devices that may come into contact with or be placed in the living body, such as stents. . Furthermore, since the medical device using the polymer composition of the present invention also has biodegradability, it can be decomposed as a highly functional medical material or smart biomaterial that does not give a load to the living body and the environment, for example, after tissue regeneration. -It can be used as an artificial substitute to be absorbed or as an implantable cell culture scaffold material. Furthermore, cyclic carbonate compounds having various functional groups can be easily obtained by the method of the present invention. The method of the present invention can be used to obtain various polycarbonate materials, and is particularly useful in producing a polycarbonate that can be used as a biocompatible material and a medical device using the polycarbonate.

Claims

A biocompatible polymer composition comprising a structure containing at least one ether group in the side chain and a main chain composed of a biodegradable polymer skeleton.
The biodegradable polymer backbone has the formula (I)
-C B -A- (I)
(Where
C B is selected from unit structures having a carbonate bond, an ester bond, an amide bond, a urethane bond or a urea bond;
A is a C 1-8 alkylene group in which a hydrogen atom is replaced by at least one group —Y;
Y is represented by the formula: -LZ (wherein Z is a structure having at least one chain ether, cyclic ether or acetal structure, L is a linker between the main chain and Z, an alkylene group, Selected from unit structures having an ether bond, a thioether bond, an ester bond, an amide bond, a urethane bond or a urea bond, or a combination thereof))
The biocompatible polymer composition of Claim 1 containing the repeating unit shown by these.
In the above C 1-8 alkylene group, at least one carbon atom other than the carbon atom adjacent to C B is replaced with a heteroatom selected from N, O or S, and / or C 1- The biocompatible polymer composition according to claim 2, wherein the hydrogen atom in the 8 alkylene group is a group substituted with a lower alkyl group.
The linker L is a group shown below:

The biocompatible polymer composition according to claim 2 or 3, wherein the biocompatible polymer composition is selected from the group having a 1,2,3-triazole group at the binding part of the group and Z. .
Z represents the following formula (II):

[Wherein, l is an integer of 1 to 30, U is a hydrogen atom or a linear or branched alkyl group having 5 or less carbon atoms, or the following formula (III):

(Wherein l ′ is an integer of 1 to 5)]
Or Z is a group represented by the following formula (IV):

(Wherein l ″ is an integer of 1 to 5), or Z is the following formula (V):

(In the formula, M ′ is a hydrogen atom or a linear or branched alkyl group having 3 or less carbon atoms, and E and E ′ are each independently —O— or —CH 2 —. Provided that at least one is —O— and Q ′ and Q ″ each independently represent a hydrogen atom, a linear or branched alkyl having 6 or less carbon atoms, alkenyl or alkynyl, C 3-8 Represents alicyclic alkyl or benzyl, or Q ′ and Q ″ together form an alkylene group having 2 to 5 carbon atoms, and k and k ′ are each independently an integer of 0 to 2 Is)
The biocompatible polymer composition according to any one of claims 2 to 4, which is a group represented by:
The biocompatible polymer composition according to any one of claims 1 to 5, wherein the main chain is a copolymer of a biodegradable polymer and a non-biodegradable polymer.
The following general formula (VII):

(Where
X and X ′ are independently of each other —O—, —NH— or —CH 2 —, but at least one is not —CH 2 —;
Y is a structural moiety represented by the group -LZ (wherein L and Z are as defined in claim 2);
M is a hydrogen atom, a linear or branched alkyl group having 3 or less carbon atoms, or a group -LZ;
m and m ′ are each independently an integer of 0 to 5, provided that when X and X ′ are both —O—, at least one of m and m ′ is not 0, and m and m ′ The sum of 'is 7 or less;
Each of these may be different in each repeating unit)
The monomer compound represented by these.
A method for producing a biocompatible polymer composition, comprising a step of ring-opening polymerization of a monomer compound represented by the general formula (VII) according to claim 7.
A biocompatible polymer composition produced by ring-opening polymerization of the monomer compound according to claim 7.
The biocompatibility according to any one of claims 1 to 6, which suppresses a foreign body reaction to blood or tissue until it is decomposed when used in contact with tissue or blood in the living body. Polymer composition.
A medical device comprising the biocompatible polymer composition according to any one of claims 1 to 6, 9, and 10.
A process for producing a cyclic carbonate by cyclizing a diol compound having a carboxyl group, wherein the carboxyl group is protected with an organic base.
In the presence of an organic base and an organic solvent, the diol compound having a carboxyl group is converted to the formula (VIII):
R 1 — (C═O) —R 2 (VIII)
[Wherein R 1 and R 2 are independently of each other a halogen atom, an imidazolium group, or —OR 3 (wherein R 3 is a lower alkyl group optionally substituted with a halogen atom, or a halogen atom, alkoxy A carbonyl group, a nitro group, a cyano group, an alkoxy group, an alkyl group, and an haloalkyl group, which is an aryl group optionally substituted with at least one substituent selected from the group consisting of: The manufacturing method of the cyclic carbonate of Claim 12 including making it react.
The method according to claim 13, comprising dissolving a diol compound having a carboxyl group in an organic solvent in the presence of an organic base before the reaction with the compound of the formula (VIII).
The diol compound having a carboxyl group is represented by the formula (IX):

(Wherein R 4 is a hydrogen atom or a lower alkyl group, and m and m ′ are each independently an integer of 0 to 5, provided that at least one of m and m ′ is not 0; The method according to any one of claims 12 to 14, wherein the sum of m and m 'is 7 or less.
The organic base is a nitrogen base compound such as triethylamine, diisopropylethylamine, butylamine, pyridine, imidazole, amidine or guanidine, a phosphorus atom-containing compound such as phosphazene, or an onium ion such as oxonium, imidazolium, ammonium, sulfonium or phosphonium. The method according to any one of claims 12 to 15, which is a product or an anion exchange resin.
The process according to any one of claims 12 to 16, wherein the organic solvent is selected from the group consisting of dichloromethane, chloroform, diethyl ether, tetrahydrofuran, 1,4-dioxane, benzene, toluene, acetonitrile and ethyl acetate. .
The method according to any one of claims 12 to 17, further comprising a step of treating the cyclic carbonate obtained by the method according to any one of claims 12 to 17 with an acid to recover the carboxylic acid of the cyclic carbonate. The method described in 1.
The method according to any one of claims 12 to 18, further comprising the step of reacting the cyclic carbonate obtained by the method according to any one of claims 12 to 18 with a halogenating agent to produce a carboxylic acid halide of the cyclic carbonate. A method for producing the cyclic carbonate according to claim 1.
The step of synthesizing a carboxylic acid derivative of a cyclic carbonate by reacting the carboxylic acid halide of the cyclic carbonate obtained by the method according to claim 19 with an alcohol or an amine containing a structural moiety having at least one ether group. 20. The method of claim 19, comprising.
21. The method according to claim 20, wherein the structural portion having at least one ether group has at least one chain ether, cyclic ether or acetal structure.
The process according to claims 12 to 21, characterized in that it is carried out continuously or semi-continuously and / or in a single reaction vessel.
Formula (X) below:

(Wherein R 4 is a hydrogen atom or a lower alkyl group, and m and m ′ are each independently an integer of 0 to 5, provided that at least one of m and m ′ is not 0; And the sum of m and m ′ is 7 or less.
Following formula (XI):

(Where
m, m ′, R 4 are as defined in claim 15;
M ′ is a hydrogen atom, a linear or branched alkyl group having 3 or less carbon atoms,
E and E ′ are each independently a direct bond, —O— or —CH 2 —, wherein at least one is —O—,
Q ′ and Q ″ each independently represent a hydrogen atom, linear or branched alkyl having 6 or less carbon atoms, alkenyl or alkynyl, C 3-8 alicyclic alkyl or benzyl, 'And Q "together form an alkylene group having 2 to 5 carbon atoms,
k and k ′ are each independently an integer of 0 to 2)
A compound represented by
5-methyl-5- (2-tetrahydrofuranylmethyl) oxycarbonyl-1,3-dioxane-2-one,
5-methyl-5- (3-tetrahydrofuranylmethyl) oxycarbonyl-1,3-dioxane-2-one,
5-methyl-5- (3-tetrahydropyranylmethyl) oxycarbonyl-1,3-dioxane-2-one 4-methyl-4- (2-tetrahydrofuranylmethyl) oxycarbonyl-1,3-dioxane-2- on,
4-methyl-4- (3-tetrahydrofuranylmethyl) oxycarbonyl-1,3-dioxane-2-one, and 4-methyl-4- (3-tetrahydropyranylmethyl) oxycarbonyl-1,3-dioxane- 25. The compound of claim 24, selected from the group consisting of 2-ones.